ESC Guidelines On Cardio-Oncology - 2022

European Heart Journal (2022) 00, 1–133 ESC GUIDELINES
https://doi.org/10.1093/eurheartj/ehac244
2022 ESC Guidelines on cardio-oncology

developed in collaboration with the European
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Hematology Association (EHA), the European
Society for Therapeutic Radiology and
Oncology (ESTRO) and the International
Cardio-Oncology Society (IC-OS)
Developed by the task force on cardio-oncology of the European
Society of Cardiology (ESC)
Authors/Task Force Members: Alexander R. Lyon*† (Chairperson) (United
Kingdom), Teresa López-Fernández*† (Chairperson) (Spain), Liam S. Couch (Task
Force Coordinator) (United Kingdom), Riccardo Asteggiano (Italy),
Marianne C. Aznar1 (United Kingdom), Jutta Bergler-Klein (Austria),
Giuseppe Boriani (Italy), Daniela Cardinale (Italy), Raul Cordoba2 (Spain),
Bernard Cosyns (Belgium), David J. Cutter (United Kingdom),
Evandro de Azambuja (Belgium), Rudolf A. de Boer (Netherlands), Susan F. Dent3
(United States of America), Dimitrios Farmakis (Cyprus), Sofie A. Gevaert
(Belgium), Diana A. Gorog (United Kingdom), Joerg Herrmann3 (United States of
America), Daniel Lenihan3 (United States of America), Javid Moslehi (United
States of America), Brenda Moura (Portugal), Sonja S. Salinger (Serbia),
Richard Stephens (United Kingdom), Thomas M. Suter (Switzerland),
Sebastian Szmit (Poland), Juan Tamargo (Spain), Paaladinesh Thavendiranathan
(Canada), Carlo G. Tocchetti (Italy), Peter van der Meer (Netherlands),
Helena J.H. van der Pal (Netherlands), and ESC Scientific Document Group
*Corresponding authors: Alexander R. Lyon, National Heart and Lung Institute, Imperial College London and Cardio-Oncology Service, Royal Brompton Hospital, London, United
Kingdom. Tel: +44 207 352 8121, E-mail: [email protected].
Teresa López-Fernández, Cardiology Department, La Paz University Hospital, IdiPAZ Research Institute, Madrid, Spain. Tel: +34 619 227 076, E-mail: [email protected].
†
The two chairpersons contributed equally to the document and are joint corresponding authors.
Author/Task Force Member affiliations are listed in Author information.
1
Representing the European Society for Therapeutic Radiology and Oncology (ESTRO); 2representing the European Hematology Association (EHA); 3representing the International
Cardio-Oncology Society (IC-OS).
ESC Clinical Practice Guidelines (CPG) Committee: listed in the Appendix.
ESC subspecialty communities having participated in the development of this document:
Associations: Association for Acute CardioVascular Care (ACVC), European Association of Cardiovascular Imaging (EACVI), European Association of Preventive Cardiology (EAPC),
European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Heart Rhythm Association (EHRA), Heart Failure Association (HFA).
Councils: Council of Cardio-Oncology, Council on Hypertension, Council on Valvular Heart Disease.
Working Groups: Aorta and Peripheral Vascular Diseases, Cardiovascular Pharmacotherapy, e-Cardiology, Myocardial Function, Pulmonary Circulation and Right Ventricular Function,
Thrombosis.
Patient Forum
2 ESC Guidelines
Document Reviewers: Patrizio Lancellotti (CPG Review Coordinator) (Belgium), Franck Thuny (CPG Review
Coordinator) (France), Magdy Abdelhamid (Egypt), Victor Aboyans (France), Berthe Aleman1 (Netherlands),
Joachim Alexandre (France), Ana Barac3 (United States of America), Michael A. Borger (Germany),
Ruben Casado-Arroyo (Belgium), Jennifer Cautela (France), Jolanta Čelutkienė (Lithuania), Maja Cikes
(Croatia), Alain Cohen-Solal (France), Kreena Dhiman (United Kingdom), Stéphane Ederhy (France),
Thor Edvardsen (Norway), Laurent Fauchier (France), Michael Fradley3 (United States of America), Julia Grapsa
(United Kingdom), Sigrun Halvorsen (Norway), Michael Heuser2 (Germany), Marc Humbert (France),
Tiny Jaarsma (Sweden), Thomas Kahan (Sweden), Aleksandra Konradi (Russian Federation),

Konstantinos C. Koskinas (Switzerland), Dipak Kotecha (United Kingdom), Bonnie Ky3 (United States
of America), Ulf Landmesser (Germany), Basil S. Lewis (Israel), Ales Linhart (Czech Republic), Gregory Y.H. Lip
(United Kingdom), Maja-Lisa Løchen (Norway), Katarzyna Malaczynska-Rajpold (United Kingdom),
Marco Metra (Italy), Richard Mindham (United Kingdom), Marie Moonen (Belgium), Tomas G. Neilan
(United States of America), Jens Cosedis Nielsen (Denmark), Anna-Sonia Petronio (Italy), Eva Prescott
(Denmark), Amina Rakisheva (Kazakhstan), Joe-Elie Salem (France), Gianluigi Savarese (Sweden), Marta Sitges
(Spain), Jurrien ten Berg (Netherlands), Rhian M. Touyz (Canada/United Kingdom), Agnieszka Tycinska
(Poland), Matthias Wilhelm (Switzerland), and Jose Luis Zamorano (Spain)
All experts involved in the development of these Guidelines have submitted declarations of interest. These have
been compiled in a report and published in a supplementary document simultaneously to the Guidelines. The
report is also available on the ESC website www.escardio.org/Guidelines
See the European Heart Journal online for supplementary data that includes background information and
detailed discussion of the data that have provided the basis of the guidelines.
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Keywords Guidelines • Androgen deprivation therapy • Anthracycline • Atrial fibrillation • Arrhythmias • Biomarkers •
Cancer • Cancer survivors • Carcinoid syndrome • Amyloid light-chain cardiac amyloidosis • Cardiac magnetic
resonance • Cardiac tumour • Cardio-oncology • Cardiotoxicity • Coronary artery disease • Chemotherapy •
Echocardiography • Fluoropyrimidine • Heart failure • Haematopoietic stem cell transplantation • Hormone therapy
• Hypertension • Immunotherapy • Ischaemic heart disease • Myocarditis • Pericardial disease • Pulmonary
hypertension • Thrombosis • Risk stratification • Trastuzumab • Valvular heart disease • Vascular endothelial
growth factor inhibitors (VEGFi) • Venous thromboembolism • Pericardial disease • Proteasome inhibitors • QTc
prolongation • Radiotherapy • Strain
The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC
Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford University
Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC ([email protected]).
Disclaimer: The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the
time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recommendations
or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encouraged to take the
ESC Guidelines fully into account when exercising their clinical judgement, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strat-
egies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consid-
eration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor do the ESC Guidelines exempt health
professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities, in order to
manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the health professional’s responsibility to
verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.
This article has been co-published with permission in the European Heart Journal and the European Heart Journal – Cardiovascular Imaging. © The European Society of Cardiology 2022. All
rights reserved. The articles are identical except for minor stylistic and spelling differences in keeping with each journal’s style. Either citation can be used when citing this article. For
permissions please e-mail: [email protected].
ESC Guidelines 3
Table of contents 6.1. Cancer therapy-related cardiac dysfunction ............................... 54

6.1.1. Anthracycline chemotherapy-related cardiac
1. Preamble ................................................................................................................ 8 dysfunction ............................................................................................... 54
2. Introduction ...................................................................................................... 10 6.1.2. Human epidermal receptor 2-targeted therapy-
2.1. Cancer and cardiovascular needs of patients with cancer ... 10 related cardiac dysfunction ............................................................... 56
2.2. Role of cardio-oncology services .................................................... 10 6.1.3. Immune checkpoint inhibitor-associated
2.3. General principles of cardio-oncology .......................................... 11 myocarditis and non-inflammatory heart failure ..................... 58
3. Cancer therapy-related cardiovascular toxicity definitions .......... 14 6.1.4. Chimeric antigen receptor T cell and tumour-

4. Cardiovascular toxicity risk stratification before anticancer infiltrating lymphocytes therapies and heart dysfunction .... 62
therapy ...................................................................................................................... 16 6.1.5. Heart failure during haematopoietic stem cell
4.1. General approach to cardiovascular toxicity risk in patients transplantation ....................................................................................... 63
with cancer ........................................................................................................ 16 6.1.6. Takotsubo syndrome and cancer ...................................... 63
4.2. History and clinical examination ...................................................... 21 6.2. Coronary artery disease ...................................................................... 63
4.3. Electrocardiogram .................................................................................. 21 6.2.1. Acute coronary syndromes .................................................. 63
4.4. Cardiac serum biomarkers ................................................................. 23 6.2.2. Chronic coronary syndromes ............................................. 65
4.5. Cardiovascular imaging ........................................................................ 24 6.3. Valvular heart disease ........................................................................... 65
4.6. Cardiopulmonary fitness assessment ............................................ 25 6.4. Cardiac arrhythmias .............................................................................. 66
4.7. Cardiovascular risk evaluation before cancer surgery ........... 26 6.4.1. Atrial fibrillation ......................................................................... 66
4.8. Genetic testing ........................................................................................ 26 6.4.2. Long corrected QT interval and ventricular
5. Prevention and monitoring of cardiovascular complications arrhythmias .............................................................................................. 70
during cancer therapy ........................................................................................ 26 6.4.3. Bradyarrhythmias ...................................................................... 72
5.1. General principles .................................................................................. 26 6.5. Arterial hypertension ............................................................................ 72
5.2. Primary prevention strategies ........................................................... 28 6.6. Thrombosis and thromboembolic events ................................... 75
5.2.1. Primary prevention of cancer therapy-related 6.6.1. Venous thromboembolism ................................................... 75
cardiovascular toxicity during anthracycline 6.6.2. Arterial thromboembolism .................................................. 76
chemotherapy ........................................................................................ 28 6.6.3. Intracardiac thrombosis ......................................................... 76
5.2.2. Primary prevention of radiation-induced 6.6.4. Anticoagulation therapy ......................................................... 77
cardiovascular toxicity ........................................................................ 28 6.7. Bleeding complications ......................................................................... 78
5.3. Secondary prevention strategies ..................................................... 29 6.7.1. High-risk patients ...................................................................... 78
5.4. Cardiovascular surveillance during cancer therapies .............. 29 6.7.2. Antiplatelet therapy ................................................................. 78
5.4.1. Cardiac serum biomarkers ................................................... 29 6.7.3. Management of bleeding ........................................................ 78
5.4.2. Cardiac imaging .......................................................................... 29 6.8. Peripheral artery disease ..................................................................... 79
5.5. Cancer therapy-related cardiovascular toxicity monitoring 6.9. Pulmonary hypertension ..................................................................... 79
protocols ............................................................................................................ 31 6.10. Pericardial diseases .............................................................................. 80
5.5.1. Anthracycline chemotherapy ............................................... 31 6.10.1. Pericarditis ................................................................................. 80
5.5.2. HER2-targeted therapies ....................................................... 31 6.10.2. Pericardial effusion ................................................................. 80
5.5.3. Fluoropyrimidines ..................................................................... 33 7. End-of-cancer therapy cardiovascular risk assessment .................. 81
5.5.4. Vascular endothelial growth factor inhibitors .............. 33 7.1. Cardiovascular evaluation during the first year after
5.5.5. Multitargeted kinase inhibitors targeting BCR-ABL ... 36 cardiotoxic anticancer therapy ................................................................. 81
5.5.6. Bruton tyrosine kinase inhibitors ....................................... 39 7.2. Which cancer survivors require cardiovascular surveillance
5.5.7. Multiple myeloma therapies ................................................. 40 in the first year after cancer treatment? ............................................... 81
5.5.8. Rapidly accelerated fibrosarcoma and mitogen- 7.3. Management of cancer therapy-related cardiac dysfunction
activated extracellular signal-regulated kinase inhibitor at the end-of-therapy assessment ........................................................... 82
treatment .................................................................................................. 43 7.4. Cardiopulmonary exercise testing and fitness during the
5.5.9. Immune checkpoint inhibitors ............................................ 45 end-of-therapy assessment ......................................................................... 82
5.5.10. Androgen deprivation therapies for prostate 7.5. The role of cardiac rehabilitation .................................................... 82
cancer ......................................................................................................... 46 8. Long-term follow-up and chronic cardiovascular complications
5.5.11. Endocrine therapies for breast cancer ......................... 48 in cancer survivors ............................................................................................... 84
5.5.12. Cyclin-dependent kinase 4/6 inhibitors ........................ 48 8.1. Cancer survivors ..................................................................................... 84
5.5.13. Anaplastic lymphoma kinase inhibitors ......................... 49 8.1.1. Adult survivors of childhood and adolescent
5.5.14. Epidermal growth factor receptor inhibitors ............ 49 cancer ......................................................................................................... 84
5.5.15. Chimeric antigen receptor 8.1.2. Adult cancer survivors ............................................................ 85
T cell and tumour-infiltrating lymphocytes therapies ........... 50 8.2. Myocardial dysfunction and heart failure ..................................... 87
5.5.16. Radiotherapy ............................................................................ 51 8.3. Coronary artery disease ...................................................................... 88
5.5.17. Haematopoietic stem cell transplantation .................. 51 8.4. Valvular heart disease ........................................................................... 89
5.5.18. Other cancer treatments ................................................... 54 8.5. Peripheral artery disease and stroke ............................................. 89
6. Diagnosis and management of acute and subacute 8.6. Pericardial complications ..................................................................... 89
cardiovascular toxicity in patients receiving anticancer treatment ... 54 8.7. Arrhythmias and autonomic disease .............................................. 90
4 ESC Guidelines
8.8. Metabolic syndrome, lipid abnormalities, diabetes mellitus, Recommendation Table 12 — Recommendations for baseline
and hypertension ............................................................................................. 90 risk assessment and monitoring during Bruton tyrosine kinase
8.9. Pregnancy in cancer survivors .......................................................... 90 inhibitor therapy ................................................................................................... 39
8.10. Pulmonary hypertension ................................................................... 91 Recommendation Table 13 — Recommendations for baseline
9. Special populations ......................................................................................... 91 risk assessment and monitoring during multiple myeloma
9.1. Cardiac tumours ..................................................................................... 91 therapies .......................................................................................................... 43
9.2. Pregnant patients with cancer .......................................................... 91 Recommendation Table 14 — Recommendations for baseline
9.2.1. Left ventricular dysfunction and heart failure .............. 92 risk assessment and monitoring during combined rapidly

9.2.2. Venous thromboembolism and pulmonary accelerated fibrosarcoma and mitogen-activated extracellular
embolism .......................................................................................... 92 signal-regulated kinase inhibitor therapy .................................................... 44
9.3. Carcinoid valvular heart disease ...................................................... 95 Recommendation Table 15 — Recommendations for baseline
9.4. Amyloid light-chain cardiac amyloidosis ....................................... 96 risk assessment and monitoring during immunotherapy .................... 46
9.5. Cardiac implantable electronic devices ......................................... 98 Recommendation Table 16 — Recommendations for baseline
10. Patient information, communication, and self-management ... 102 risk assessment and monitoring during androgen deprivation
11. The role of scientific societies in the promotion and therapy for prostate cancer ............................................................................ 48
development of cardio-oncology in modern medicine ..................... 103 Recommendation Table 17 — Recommendations for baseline
12. Key messages ............................................................................................... 103 risk assessment and monitoring during endocrine therapy for
13. Future needs ................................................................................................. 104 breast cancer ......................................................................................................... 48
14. Gaps in evidence ......................................................................................... 105 Recommendation Table 18 — Recommendations for baseline
15. ‘What to do’ and ‘what not to do’ messages from the risk assessment and monitoring during cyclin-dependent kinase
Guidelines .............................................................................................................. 105 4/6 inhibitor therapy ........................................................................................... 49
16. Quality indicators for cardio-oncology ............................................. 114 Recommendation Table 19 — Recommendations for baseline
17. Supplementary data ................................................................................... 114 risk assessment and monitoring during anaplastic lymphoma
18. Data availability statement ...................................................................... 114 kinase and epidermal growth factor receptor inhibitors .................... 49
19. Author information ................................................................................... 114 Recommendation Table 20 — Recommendations for baseline
20. Appendix ........................................................................................................ 114 risk assessment and monitoring in patients receiving chimeric
21. References ..................................................................................................... 115 antigen receptor T cell and tumour-infiltrating lymphocytes
therapies .................................................................................................................. 51
Recommendation Table 21 — Recommendations for baseline
Tables of Recommendations risk assessment of patients before radiotherapy to a volume
including the heart ............................................................................................... 51
Recommendation Table 1 — Recommendations for a general Recommendation Table 22 — Recommendations for baseline
approach to cardiovascular toxicity risk categorization ...................... 21 risk assessment in haematopoietic stem cell transplantation
Recommendation Table 2 — Recommendations for patients ..................................................................................................................... 53
electrocardiogram baseline assessment ..................................................... 23 Recommendation Table 23 — Recommendation for the
Recommendation Table 3 — Recommendation for cardiac management of cardiovascular disease and cancer
biomarker assessment prior to potentially cardiotoxic therapies ....... 24 therapy-related cardiovascular toxicity in patients receiving
Recommendation Table 4 — Recommendations for cardiac anticancer treatment .......................................................................................... 54
imaging modalities in patients with cancer ............................................... 25 Recommendation Table 24 — Recommendations for the
Recommendation Table 5 — Recommendations for management of cancer treatment-related cardiac dysfunction
primary prevention of cancer therapy-related cardiovascular during anthracycline chemotherapy ............................................................. 56
toxicity .............................................................................................................. 28 Recommendation Table 25 — Recommendations for the
Recommendation Table 6 — Recommendation for secondary management of cancer treatment-related cardiac dysfunction
prevention of cancer therapy-related cardiovascular toxicity .......... 29 during human epidermal receptor 2-targeted therapies .................... 58
Recommendation Table 7 — Recommendations for baseline risk Recommendation Table 26 — Recommendations for the
assessment and monitoring during anthracycline chemotherapy diagnosis and management of immune checkpoint
and in the first 12 months after therapy ................................................... 31 inhibitor-associated myocarditis .................................................................... 61
assessment and monitoring during human epidermal receptor diagnosis and management of Takotsubo syndrome in patients
2-targeted therapies and in the first 12 months after therapy ........ 32 with cancer ............................................................................................................. 63
assessment and monitoring during fluoropyrimidine therapy .......... 33 management of acute coronary syndromes in patients receiving
Recommendation Table 10 — Recommendations for baseline anticancer treatment .......................................................................................... 64
risk assessment and monitoring during vascular endothelial Recommendation Table 29 — Recommendation for the
growth factor inhibitors .................................................................................... 36 management of chronic coronary syndromes in patients receiving
Recommendation Table 11 — Recommendations for baseline anticancer treatment .......................................................................................... 65
risk assessment and monitoring during second- and Recommendation Table 30 — Recommendations for the
third-generation breakpoint cluster region–Abelson oncogene management of valvular heart disease in patients receiving
locus tyrosine kinase inhibitors ...................................................................... 39 anticancer treatment .......................................................................................... 65
ESC Guidelines 5
Recommendation Table 31 — Recommendations for the Table 6 Factors that could influence peri-operative risk during
management of atrial fibrillation in patients receiving anticancer cancer surgery and preventive strategies .................................................. 26
treatment ................................................................................................................. 69 Table 7 Cancer treatments that predispose to acute coronary
Recommendation Table 32 — Recommendations for the syndromes ............................................................................................................... 63
management of long corrected QT interval and ventricular Table 8 Risk factors for drug-induced QT prolongation and
arrhythmias in patients receiving anticancer treatment ...................... 72 torsade de pointes ............................................................................................... 70
Recommendation Table 33 — Recommendations for the Table 9 Classification of corrected QT interval prolongation
management of arterial hypertension in patients receiving induced by cancer drug therapy .................................................................... 70

anticancer treatment .......................................................................................... 74 Table 10 Risk factors for future cardiovascular disease at the
Recommendation Table 34 — Recommendations for the end-of-cancer therapy cardiovascular risk assessment ........................ 82
management of venous thromboembolism in patients receiving Table 11 Risk categories for asymptomatic adults who are
anticancer treatment .......................................................................................... 77 childhood and adolescent cancer survivors .............................................. 85
Recommendation Table 35 — Recommendations for venous Table 12 Risk categories for asymptomatic adult cancer survivors ... 86
thromboembolism prophylaxis during anticancer treatment ........... 78 Table 13 Management strategies and surgery indications for
Recommendation Table 36 — Recommendation for management symptomatic and asymptomatic patients with benign and
of peripheral artery disease during anticancer treatment ........................ 79 malignant cardiac tumours ............................................................................... 93
Recommendation Table 37 — Recommendations for the
management of pulmonary hypertension during anticancer
treatment ................................................................................................................. 80
List of figures
Recommendation Table 38 — Recommendations for the Figure 1 Video 1 Central Illustration: Dynamics of
management of pericardial diseases in patients receiving cardiovascular toxicity risk of patients with cancer over their
anticancer treatment .......................................................................................... 81 therapy continuum ....................................................................................... 11
Recommendation Table 39 — Recommendations for Figure 2 Cardio-oncology care pathways .................................................. 12
end-of-cancer therapy cardiovascular risk assessment ........................ 84 Figure 3 Baseline cardiovascular toxicity risk assessment checklist .... 13
Recommendation Table 40 — Recommendations for Figure 4 Dimensions of cancer therapy-related cardiovascular
cardiovascular surveillance in asymptomatic adults who are toxicity risk and disease severity ................................................................... 14
childhood and adolescent cancer survivors .............................................. 85 Figure 5 Baseline cardiovascular toxicity risk assessment before
Recommendation Table 41 — Recommendations for anticancer therapy ............................................................................................... 17
cardiovascular surveillance in asymptomatic adult cancer survivors .... 86 Figure 6 General cardio-oncology approach after Heart Failure
Recommendation Table 42 — Recommendations for adult Association–International Cardio-Oncology Society
cancer survivors who develop cancer therapy-related cardiac cardiovascular toxicity risk assessment ..................................................... 20
dysfunction late after cardiotoxic cancer therapy ................................. 88 Figure 7 Baseline screening recommendations for patients with
Recommendation Table 43 — Recommendations for adult cancer treated with potentially cardiotoxic drugs ................................. 22
cancer survivors with coronary artery disease ....................................... 88 Figure 8 Recommended transthoracic echocardiography and
Recommendation Table 44 — Recommendations for adult cardiac magnetic resonance imaging parameters in the evaluation of
cancer survivors with valvular heart disease ............................................ 89 patients with cancer ..................................................................................................... 24
Recommendation Table 45 — Recommendation for adult cancer Figure 9 Primary and secondary cancer therapy-related
survivors with pericardial complications .................................................... 90 cardiovascular toxicity prevention ........................................................................ 27
Recommendation Table 46 — Recommendations for Figure 10 Cardiovascular toxicity monitoring in patients receiving
cardiovascular monitoring in cancer survivors during pregnancy ... 91 anthracycline chemotherapy ........................................................................... 30
Recommendation Table 47 — Recommendations for cardiovascular Figure 11 Cardiovascular toxicity monitoring in patients receiving
assessment and monitoring of pregnant women with cancer ................... 95 human epidermal receptor 2-targeted therapies ................................... 32
Recommendation Table 48 — Recommendations for carcinoid Figure 12 Vascular endothelial growth factor inhibitors-related
valvular heart diseases ........................................................................................ 95 cardiovascular toxicities .................................................................................... 34
Recommendation Table 49 — Recommendations for amyloid Figure 13 Cardiovascular toxicity monitoring in patients receiving
light-chain cardiac amyloidosis diagnosis and monitoring ................... 98 vascular endothelial growth factor inhibitors .......................................... 35
Recommendation Table 50 — Recommendations for risk Figure 14 Breakpoint cluster region–Abelson oncogene locus
stratification and monitoring for patients with cardiac implantable tyrosine kinase inhibitor-related cardiovascular toxicities ................. 37
electronic devices undergoing radiotherapy ....................................................... 102 Figure 15 Second- and third-generation breakpoint cluster
region–Abelson oncogene locus tyrosine kinase inhibitors
surveillance protocol .......................................................................................... 38
List of tables Figure 16 Multiple myeloma drug-related cardiovascular toxicities ... 40
Figure 17 Cardiovascular monitoring in patients with multiple
Table 1 Classes of recommendations ............................................................ 9 myeloma receiving proteasome inhibitors ................................................ 41
Table 2 Levels of evidence .................................................................................. 9 Figure 18 Risk factors for venous thromboembolic events in
Table 3 Cancer therapy-related cardiovascular toxicity definitions ... 15 patients with multiple myeloma .................................................................... 42
Table 4 Heart Failure Association–International Cardio-Oncology Figure 19 Rapidly accelerated fibrosarcoma and mitogen-activated
Society baseline cardiovascular toxicity risk stratification .................... 18 extracellular signal-regulated kinase inhibitor-related cardiovascular
Table 5 Anthracycline equivalence dose .................................................... 19 toxicities .............................................................................................................................. 44
6 ESC Guidelines
Figure 20 Cardiovascular surveillance in patients treated with

immune checkpoint inhibitors ........................................................................ 45
Abbreviations and acronyms
Figure 21 Androgen deprivation therapy-related cardiovascular 2D Two-dimensional
toxicities ................................................................................................................... 47 3D Three-dimensional
Figure 22 Anaplastic lymphoma kinase and epidermal growth 5-FU 5-fluorouracil
factor receptor inhibitor-related cardiovascular toxicities ................ 50 5HIAA 5-hydroxyindoleacetic acid
Figure 23 Radiotherapy mean heart dose and associated a′ Late diastolic velocity of mitral annulus
cardiovascular toxicity risk ............................................................................... 52 obtained by tissue Doppler imaging

Figure 24 Risk factors and cardiovascular surveillance in patients ABC Atrial fibrillation Better Care
referred for haematopoietic stem cell transplantation ....................... 53 ABI Ankle–brachial index
Figure 25 Management of anthracycline chemotherapy-related AC Anthracycline chemotherapy
cardiac dysfunction .............................................................................................. 55 ACE-I Angiotensin-converting enzyme inhibitors
Figure 26 Management of human epidermal receptor 2-targeted ACS Acute coronary syndromes
therapy-related cardiac dysfunction ............................................................. 57 ADT Androgen deprivation therapy
Figure 27 Direct and indirect immune checkpoint ADVANCE Action in Diabetes and Vascular Disease:
inhibitor-related cardiovascular toxicity ..................................................... 59 Preterax and Diamicron-MR Controlled
Figure 28 Diagnosis and management of immune checkpoint Evaluation
inhibitor-related myocarditis ........................................................................... 60 AF Atrial fibrillation
Figure 29 Diagnosis and management workup in cancer-related AI Aromatase inhibitors
Takotsubo syndrome ......................................................................................... 62 AL-CA Amyloid light-chain cardiac amyloidosis
Figure 30 Pathophysiology of atrial fibrillation associated with ALK Anaplastic lymphoma kinase
cancer ........................................................................................................................ 67 ANS Autonomic nervous system
Figure 31 Structured approach to anticoagulation for atrial ARB Angiotensin receptor blockers
fibrillation in patients with cancer ................................................................. 68 ARISTOTLE Apixaban for Reduction in Stroke and Other
Figure 32 Corrected QT interval monitoring before and during Thromboembolic Events in Atrial Fibrillation
treatment with corrected QT interval-prolonging anticancer drugs ... 71 ASCVD AtheroSclerotic Cardiovascular Disease
Figure 33 Recommended threshold for asymptomatic ASPIRE Carfilzomib, Lenalidomide, and
hypertension treatment in different clinical scenarios ......................... 73 Dexamethasone vs. Lenalidomide and
Figure 34 Treatment of arterial hypertension in patients with Dexamethasone for the Treatment of
cancer ........................................................................................................................ 74 Patients with Relapsed Multiple Myeloma
Figure 35 Risk factors for venous thromboembolism in patients ASTCT American Society for Transplantation and
with cancer ............................................................................................................. 75 Cellular Therapy
Figure 36 Structured approach to anticoagulation for venous ATAC ‘Arimidex’ and Tamoxifen Alone or in
thromboembolism in patients with active cancer ................................. 76 Combination
Figure 37 Management of cancer therapy-related cardiac ATE Arterial thromboembolism
dysfunction after cancer therapy .................................................................. 83 AV Atrioventricular
Figure 38 Long-term follow-up in cancer survivors .............................. 87 BB Beta-blockers
Figure 39 Location of primary and secondary cardiac tumours ...... 92 BC Breast cancer
Figure 40 Diagnostic algorithm for cardiac masses ............................... 93 BCR-ABL Breakpoint cluster region–Abelson oncogene
Figure 41 Cardiac monitoring protocol for pregnant women locus
receiving anthracycline-based chemotherapy .......................................... 94 BIG Breast International Group
Figure 42 Carcinoid heart disease: clinical features and diagnostic BLEED Increased bleeding risk
tests ............................................................................................................................ 96 BMI Body mass index
Figure 43 Non-invasive diagnosis of amyloid light-chain cardiac BNP B-type natriuretic peptide
amyloidosis .............................................................................................................. 97 BP Blood pressure
Figure 44 Risk stratification in patients with a cardiac implantable BTK Bruton tyrosine kinase
electronic device undergoing radiotherapy .............................................. 99 C Chemotherapy cycle
Figure 45 Management of patients with a cardiac implantable CABG Coronary artery bypass graft
electronic device located in the radiotherapy treatment beam .... 100 CAD Coronary artery disease
Figure 46 Management of patients with a cardiac implantable CARDIOTOX CARDIOvascular TOXicity induced by
electronic device located outside the radiotherapy treatment cancer-related therapies
volume .................................................................................................................... 101 CAR-T Chimeric antigen receptor T cell
Figure 47 Patient information, communication, and CCB Calcium channel blockers
self-management ................................................................................................. 102 CCS Chronic coronary syndromes
Figure 48 The role of scientific societies in the promotion and CCTA Coronary computed tomography
development of cardio-oncology ................................................................ 103 angiography
ESC Guidelines 7
CCU Coronary care unit ESC-CCO European Society of Cardiology Council of

CDK Cyclin-dependent kinase Cardio-Oncology
CHA2DS2-VASc Congestive heart failure, Hypertension, Age ESH European Society of Hypertension
≥ 75 years (2 points), Diabetes mellitus, EuroSCORE European System for Cardiac Operative
Stroke (2 points)—Vascular disease, Age Risk Evaluation
65–74 years, Sex category (female) FAC Fractional area change
CIED Cardiac implantable electronic device FDA Food and Drug Administration
CML Chronic myeloid leukaemia FLT3 FMS-like tyrosine kinase 3

CMR Cardiac magnetic resonance FWLS Free wall longitudinal strain
COMPASS-CAT Prospective COmparison of Methods for GI Gastrointestinal
thromboembolic risk assessment with clinical GLS Global longitudinal strain
Perceptions and AwareneSS in real-life GnRH Gonadotropin-releasing hormone
patients—Cancer Associated Thrombosis GU Genitourinary
CPET Cardiopulmonary exercise testing GVHD Graft vs. host disease
CrCl Creatinine clearance Gy Gray
CRF Cardiorespiratory fitness HAS-BLED Hypertension, Abnormal renal and liver
CRS Cytokine release syndrome function, Stroke, Bleeding Labile
CS Cancer survivors international normalized ratio, Elderly,
CT Computed tomography Drugs or alcohol
CTLA-4 Cytotoxic T lymphocyte-associated HbA1c Glycated haemoglobin
antigen-4 HDU High-dependency unit
cTn Cardiac troponin HER2 Human epidermal receptor 2
CTRCD Cancer therapy-related cardiac HF Heart failure
dysfunction HFA Heart Failure Association
CTR-CVT Cancer therapy-related cardiovascular HFmrEF Heart failure with mildly reduced ejection
toxicity fraction
CV Cardiovascular HFpEF Heart failure with preserved ejection fraction
CVD Cardiovascular disease HFrEF Heart failure with reduced ejection fraction
CVRF Cardiovascular risk factors HG Hyperglycaemia
DAPT Dual antiplatelet therapy HIIT High-intensity interval training
DASISION DASatinib vs. Imatinib Study In HSCT Haematopoietic stem cell transplantation
treatment-Naïve chronic myeloid hs-cTn High-sensitivity cardiac troponin
leukaemia patients HTN Hypertension
DL Dyslipidaemia ICD Implantable cardioverter defibrillator
DM Diabetes mellitus ICI Immune checkpoint inhibitors
DNR Do not resuscitate ICOS International Cardio-Oncology Society
DVT Deep vein thrombosis ICU Intensive care unit
E Mitral inflow early diastolic velocity IHD Ischaemic heart disease
obtained by pulsed wave IMiD Immunomodulatory drugs
e′ Early diastolic velocity of the mitral annulus i.v. Intravenous
obtained by tissue Doppler imaging IVC Inferior vena cava
EACTS European Association for Cardio-Thoracic IVS Intraventricular septum
Surgery LA Left atrial
EBC Early breast cancer LAA Left atrial appendage
ECG Electrocardiogram LGE Late gadolinium enhancement
Echo Echocardiography LIMA Left internal mammary artery
ECV Extracellular volume fraction LMWH Low-molecular-weight heparins
eGFR Estimated glomerular filtration rate LQTS Long QT syndrome
EGFR Epidermal growth factor receptor LS Longitudinal strain
EMA European Medicines Agency LV Left ventricular
EMB Endomyocardial biopsy LVD Left ventricular dysfunction
ENGAGE AF-TIMI 48 Effective Anticoagulation with Factor LVEDD Left ventricular end diastolic diameter
Xa Next Generation in Atrial Fibrillation- LVEF Left ventricular ejection fraction
Thrombolysis in Myocardial Infarction 48 LVV Left ventricular volume
ENOXACAN Enoxaparin and Cancer M Months
EoL End of life MACE Major adverse cardiovascular events
ERS European Respiratory Society MCS Mechanical circulatory support
ESC European Society of Cardiology MDT Multidisciplinary team
8 ESC Guidelines
MedDRA Medical dictionary for regulatory activities SMART Second manifestations of arterial disease
MEK Mitogen-activated extracellular sPAP Systolic pulmonary artery pressure
signal-regulated kinase SPEP Serum protein electrophoresis
MHD Mean heart dose STEMI ST-segment elevation myocardial infarction
MI Myocardial infarction STIR Short tau inversion recovery
MM Multiple myeloma STS PROM Society of Thoracic Surgeons – Predicted
MUGA Multigated acquisition nuclear imaging Risk of Mortality
N No SVT Supraventricular tachycardia

NOAC Non-vitamin K antagonist oral SYNTAX SYNergy between percutaneous coronary
anticoagulants intervention with TAXus and cardiac surgery
NP Natriuretic peptides TAPSE Tricuspid annular plane systolic excursion
NSTE-ACS Non-ST-segment elevation acute coronary TAVI Transcatheter aortic valve implantation
syndromes TBIP Thromboembolic risk, Bleeding risk, drug–
NT-proBNP N-terminal pro-B-type natriuretic peptide drug Interactions, Patient preferences
PAD Peripheral artery disease TdP Torsade de pointes
PAH Pulmonary arterial hypertension TIL Tumour-infiltrating lymphocytes
PAP Pulmonary arterial pressure TKI Tyrosine kinase inhibitors
PCI Percutaneous coronary intervention TRV Tricuspid regurgitation velocity
PD-1 Programmed death-1 TTE Transthoracic echocardiography
PD-L1 Programmed death-ligand 1 TTS Takotsubo syndrome
PE Pulmonary embolism tx Treatment
Peric-E Pericardial effusion ULN Upper limit of normal
PET Positron emission tomography UPEP Urine protein electrophoresis
PH Pulmonary hypertension VA Ventricular arrhythmias
PI Proteasome inhibitors VascTox Vascular toxicity
Pleu-E Pleural effusion VEGF Vascular endothelial growth factor
PRECISE-DAPT PREdicting bleeding Complications In VEGFi Vascular endothelial growth factor inhibitors
patients undergoing Stent implantation and VH Very high risk
subsEquent Dual Anti Platelet Therapy VHD Valvular heart disease
PRONOUNCE A Trial Comparing Cardiovascular Safety VKA Vitamin K antagonists
of Degarelix Versus Leuprolide in Patients VTE Venous thromboembolism
With Advanced Prostate Cancer and Y Yes
Cardiovascular Disease
PW Left ventricular posterior wall
QI Quality indicator 1. Preamble
↑QTc Corrected QT interval prolongation
QTc Corrected QT interval Guidelines summarize and evaluate available evidence with the aim of
QTcF Corrected QT interval using Fridericia assisting health professionals in proposing the best management strat-
correction egies for an individual patient with a given condition. Guidelines and
RA Right atrial their recommendations should facilitate decision making of health pro-
RAF Rapidly accelerated fibrosarcoma fessionals in their daily practice. However, guidelines are not a substi-
RCT Randomized controlled trial tute for the patient’s relationship with their practitioner. The final
RIMA Right internal mammary artery decisions concerning an individual patient must be made by the re-
ROCKET AF Rivaroxaban Once Daily Oral Direct Factor sponsible health professional(s), based on what they consider to be
Xa Inhibition Compared with Vitamin K the most appropriate in the circumstances. These decisions are
Antagonism for Prevention of Stroke and made in consultation with the patient and caregiver as appropriate.
Embolism Trial in Atrial Fibrillation Guidelines are intended for use by health professionals. To ensure
RT Radiotherapy that all users have access to the most recent recommendations, the
RV Right ventricular ESC makes its Guidelines freely available. The ESC warns readers
RVEF Right ventricular ejection fraction that the technical language may be misinterpreted and declines any
RVV Right ventricular volume responsibility in this respect.
s′ Systolic velocity of tricuspid annulus A great number of guidelines have been issued in recent years by the
obtained by doppler tissue imaging ESC. Because of their impact on clinical practice, quality criteria for the
SBr Sinus bradycardia development of guidelines have been established to make all decisions
SCORE2 Systematic Coronary Risk Estimation 2 transparent to the user. The recommendations for formulating and is-
SCORE2-OP Systematic Coronary Risk Estimation 2— suing ESC Guidelines can be found on the ESC website (https://www.
Older Persons escardio.org/Guidelines). The ESC Guidelines represent the official pos-
SEER Surveillance, Epidemiology, and End Results ition of the ESC on a given topic and are regularly updated.
ESC Guidelines 9
Table 1 Classes of recommendations
Definition Wording to use

Classes of recommendations
Class I Evidence and/or general agreement Is recommended or is indicated
that a given treatment or procedure is
beneficial, useful, effective.

Class II Conflicting evidence and/or a divergence of opinion about the usefulness/
efficacy of the given treatment or procedure.
Class IIa Weight of evidence/opinion is in Should be considered

favour of usefulness/efficacy.
Class IIb Usefulness/efficacy is less well May be considered

established by evidence/opinion.
Class III Evidence or general agreement that the Is not recommended

given treatment or procedure is not
©ESC 2022
useful/effective, and in some cases
may be harmful.
Table 2 Levels of evidence
Level of Data derived from multiple randomized clinical trials

evidence A or meta-analyses.
Level of Data derived from a single randomized clinical trial

evidence B or large non-randomized studies.
Level of Consensus of opinion of the experts and/or small studies,

evidence C retrospective studies, registries.
©ESC 2022
In addition to the publication of Clinical Practice Guidelines, the ESC Consideration was given to diversity and inclusion, notably with respect
carries out the EURObservational Research Programme of internation- to gender and country of origin. A critical evaluation of diagnostic and
al registries of cardiovascular diseases and interventions, which are es- therapeutic procedures was performed, including assessment of the
sential to assess diagnostic/therapeutic processes, use of resources risk–benefit ratio. The level of evidence and the strength of the recom-
and adherence to guidelines. These registries aim at providing a better mendation of particular management options were weighed and scored
understanding of medical practice in Europe and around the world, according to predefined scales, as outlined below. The Task Force fol-
based on high-quality data collected during routine clinical practice. lowed the ESC voting procedures. All recommendations subject to a
Furthermore, the ESC develops sets of quality indicators (QIs), vote achieved at least 75% among voting members.
which are tools to evaluate the level of implementation of the guide- The experts of the writing and reviewing panels provided declar-
lines and may be used by the ESC, hospitals, healthcare providers and ation of interest forms for all relationships that might be perceived as
professionals to measure clinical practice, and in educational pro- real or potential sources of conflicts of interest. Their declarations of
grammes, alongside the key messages from the guidelines, to im- interest were reviewed according to the ESC declaration of interest
prove quality of care and clinical outcomes. rules and can be found on the ESC website (http://www.escardio.org/
The Members of this Task Force were selected by the ESC to re- Guidelines) and have been compiled in a report and published in a
present professionals involved with the medical care of patients with supplementary document simultaneously to the guidelines.
this pathology. The selection procedure aimed to ensure that there is This process ensures transparency and prevents potential biases in
a representative mix of members predominantly from across the whole the development and review processes. Any changes in declarations
of the ESC region and from relevant ESC Subspecialty Communities. of interest that arise during the writing period were notified to the
10 ESC Guidelines
ESC and updated. The Task Force received its entire financial support after their cancer treatments with respect to their cardiovascular (CV)
from the ESC without any involvement from the healthcare industry. health and wellness. This guideline provides guidance on the definitions,
The ESC CPG supervises and coordinates the preparation of new diagnosis, treatment, and prevention of cancer therapy-related CV
guidelines. The Committee is also responsible for the approval pro- toxicity (CTR-CVT), and the management of CV disease (CVD)
cess of these guidelines. The ESC Guidelines undergo extensive re- caused directly or indirectly by cancer. This area of medicine has lim-
view by the CPG and external experts, including a mix of ited trials and evidence on which to base decision-making and,
members from across the whole of the ESC region and from relevant where evidence is limited, this guideline provides the consensus of
ESC Subspecialty Communities and National Cardiac Societies. After expert opinion to guide healthcare professionals.

appropriate revisions, the guidelines are signed off by all the experts This guideline includes the definitions of CTR-CVT (Section 3),1 and
involved in the Task Force. The finalized document is signed off by provides a personalized approach to care based upon the baseline
the CPG for publication in the European Heart Journal. The guidelines CV toxicity risk assessment (Section 4) and new protocols for CV sur-
were developed after careful consideration of the scientific and med- veillance during cancer treatment (Section 5). The management of acute
ical knowledge and the evidence available at the time of their writing. CTR-CVT is addressed in Section 6, where patients with active cancer are
The task of developing ESC Guidelines also includes the creation of those receiving anticancer treatment. Throughout these sections,
educational tools and implementation programmes for the recommen- decision-making depends upon the risk/benefit balance of oncology
dations, including condensed pocket guideline versions, summary slides, treatment efficacy and the severity and impact of CTR-CVT. Guidance
summary cards for non-specialists and an electronic version for digital is provided for the first 12 months after completion of cardiotoxic treat-
applications (smartphones, etc.). These versions are abridged and thus, ments (Section 7), when subacute CVD can emerge, and when patients
for more detailed information, the user should always access the full- who developed CTR-CVT during cancer treatment are reviewed.
text version of the guidelines, which is freely available via the ESC web- Diagnosis and management of the long-term CV complications of previ-
site and the European Heart Journal. The National Cardiac Societies of ous oncology treatments, beyond 12 months after completing the cardi-
the ESC are encouraged to endorse, adopt, translate and implement all otoxic treatments, and integration into the overall survivorship strategy
ESC Guidelines. Implementation programmes are needed because it for cancer survivors (CS) is presented in Section 8 with new long-term
has been shown that the outcome of disease may be favourably influ- surveillance recommendations for high-risk patients.
enced by the thorough application of clinical recommendations. In Section 9, we address special populations where CVDs are dir-
Health professionals are encouraged to take the ESC Guidelines ectly caused by the cancer, or where special considerations are re-
fully into account when exercising their clinical judgement, as well quired. Section 10 provides information for patients’ involvement in
as in the determination and the implementation of preventive, diag- their own care. The final section highlights the role of the ESC and
nostic or therapeutic medical strategies. However, the ESC the ESC Council of Cardio-Oncology (ESC-CCO).
Guidelines do not override in any way whatsoever the individual re- CTR-CVT risk is a dynamic variable, and the risk changes through-
sponsibility of health professionals to make appropriate and accurate out the pathway of care (Figure 1, Video 1). Absolute risk of
decisions in consideration of each patient’s health condition and in CTR-CVT is important to understand and balance against the abso-
consultation with that patient or the patient’s caregiver where ap- lute benefit of the cancer treatment before and during treatment.
propriate and/or necessary. It is also the health professional’s re- However, CTR-CVT risk can be influenced by several variables, in-
sponsibility to verify the rules and regulations applicable in each cluding implementation of primary prevention treatments, optimiza-
country to drugs and devices at the time of prescription and to re- tion of pre-existing CVD, dose, frequency, and duration of oncology
spect the ethical rules of their profession. treatment, emergence of CV complications during treatment and
Off-label use of medication may be presented in this guideline if their severity, and in CS, the overall cumulative treatment received,
sufficient level of evidence shows that it can be considered medically the time since treatment, and the interaction with other CVDs.
appropriate to a given condition and if patients could benefit from
the recommended therapy. However, the final decisions concerning
2.1. Cancer and cardiovascular needs of
an individual patient must be made by the responsible health profes-
sional giving special consideration to: patients with cancer
Since the 1990s, there has been a steady decline in cancer-related
(1) the specific situation of the patient. In this respect, it is specified mortality mirrored by a steady increase in CS.2,3 In this context,
that, unless otherwise provided for by national regulations, off- treatment-related side effects have gained more significance.
label use of medication should be limited to situations where it Management of CTR-CVT has a tremendous impact on the type of
is in the patient’s interest to do so, with regard to the quality, anticancer therapies that patients can receive as well as the long-term
safety and efficacy of care, and only after the patient has been in- morbidity and mortality outcomes of patients with cancer. Effective
formed and has provided consent; management of patients with both cancer and CVD requires the un-
(2) country-specific health regulations, indications by governmental ique interest and expertise of healthcare providers, which has led to
drug regulatory agencies and the ethical rules to which health the formation of a new discipline: cardio-oncology.4,5 A recently pub-
professionals are subject, where applicable. lished ESC-CCO document describes appropriate criteria for the or-
ganization and implementation of cardio-oncology services.5
2. Introduction
This is the first European Society of Cardiology (ESC) guideline on 2.2. Role of cardio-oncology services
cardio-oncology. The aim of this guideline is to help all the healthcare The overarching goal of the cardio-oncology discipline is to allow pa-
professionals providing care to oncology patients before, during, and tients with cancer to receive the best possible cancer treatments safely,
ESC Guidelines 11
Baseline During cardiotoxic

D Long-term foll
f ow-up after
risk cancer therappy cancer treatment

Primary and Cancer treatment
CTR-CVT secondary surveillance Cancer survivorship programmes
risk prevention Early CTR-CVT
strategies management
High risk
Low risk
Time
Figure 1 Video 1 Central Illustration: Dynamics of cardiovascular toxicity risk of patients with cancer over their therapy continuum. CS, cancer
survivors; CTR-CVT, cancer therapy-related cardiovascular toxicity; CV, cardiovascular; CVD, cardiovascular disease; CVRF, cardiovascular risk fac-
tors; CTR-CVT risk is a dynamic variable that changes through the pathway of care, and is influenced by several conditions including age, cancer
history, pre-existing CVRF or CVD, and previous cardiotoxic cancer therapy. The CTR-CVT risk changes during and after treatment according
to type, dose, frequency, and duration of oncology treatment (blue solid line). Pre-existing CVRF, CVD, or previous cancer treatments may increase
the magnitude of acute and long-term CV toxicity risk (purple solid line). CTR-CVT risk remains variable in extent during anticancer treatment and
may or may not gradually increase over time (dotted lines). Cardio-oncology strategy may reduce the magnitude of CTR-CVT by: (1) optimizing CVD
and CVRF management (green arrows); (2) considering cardioprotective strategies in high-risk patients (green arrows); (3) organizing cancer treat-
ment surveillance; and (4) introducing early cardioprotection after the detection of subclinical CTR-CVT (purple arrows). CV risk assessment within
the first year after completion of cardiotoxic cancer therapy identifies CS who require long-term follow-up. Cancer survivorship programmes that
include annual CV risk assessment and CVRF/CVD management are recommended to minimize long-term CV adverse events (brown arrows).
minimizing CTR-CVT across the entire continuum of cancer care.5 therapies with CV toxicity risk, surveillance should continue until the
Before initiation of cancer therapies with a known CV toxicity profile, treatment is finished.6–8 There is also the need for re-assessment of
the cardio-oncology team should identify and treat CV risk factors CV risks in patients requiring treatment for secondary malignancies.
(CVRF) and pre-existing CVDs and define an appropriate prevention
and surveillance plan for early identification and appropriate manage-
ment of potential CV complications (Figure 2). Another important as- 2.3. General principles of
pect is the participation in interdisciplinary discussions regarding the cardio-oncology
benefits and risks of certain cancer treatments and their continuation A guiding principle of cardio-oncology is the integration of clinical dis-
or interruption should side effects become apparent. After cancer ciplines. Cardio-oncology providers must have knowledge of the
treatment has been completed, the focus shifts to co-ordination of broad scope of cardiology, oncology, and haematology management.5
long-term follow-up and treatment. For patients on long-term cancer Recommendations are formed regarding the most permissible (from a
12 ESC Guidelines
Cardio-Oncology Care Pathways
New cancer During cancer First year after Long term

diagnosis treatmenta cancer treatmentb follow-up

Informing, advising, and supporting patients to promote a healthy lifestyle
Baseline CV
toxicity risk
assessmentc Management of CVRF and CVD according to ESC Guidelines
Annual CVRF
Assessment at 1 year assessmente
Low risk Standard
after completion of
patients surveillance
cancer therapy Reassessment if new CV
signs/symptoms
Annual CVRF assessmente

Assessment at 1 year CV toxicity re-stratification
Moderate risk at 5 years
Cardiology referral d after completion of
patients
cancer therapy TTE every 5 years
Assessment at 3 Annual CVRF

High and months and 1 year assessmente
Cardiology referral d
very high risk after completion of
CVD prevention TTE at years 1, 3, 5 and
patients cancer therapy every 5 years
Cardiology referrald if new CV signs/symptoms or CTR-CVT develop
Class 1 Class 1Ia Class 1Ib
Figure 2 Cardio-oncology care pathways. BP, blood pressure; CS, cancer survivors; CTR-CVT, cancer therapy-related cardiovascular toxicity;
CV, cardiovascular; CVD, cardiovascular disease; CVRF, cardiovascular risk factors; ECG, electrocardiogram; ESC, European Society of
Cardiology; HbA1c, glycated haemoglobin; HFA, Heart Failure Association; ICOS, International Cardio-Oncology Society; NP, natriuretic pep-
tides; RT, radiotherapy; TTE, transthoracic echocardiography. aCV surveillance according to baseline CV toxicity risk, type of cancer, cancer
stage, and cancer therapy. bCTR-CVT risk assessment is recommended during the first year after cardiotoxic cancer treatment to establish a
long-term follow-up care plan. cThe use of HFA-ICOS risk assessment tools should be considered to assess CTR-CVT risk in patients with can-
cer scheduled to receive cardiotoxic anticancer therapy. Clinical assessment and ECG are recommended at baseline in all patients with cancer
and echocardiography, cardiac biomarkers, or other cardiac imaging tests in selected patients according to baseline CV toxicity risk and cancer
treatment type (see Figure 7). dCardio-oncology referral is recommended when available, alternatively patients should be referred to a specia-
lized cardiologist with expertise in managing CVD in patients with cancer. eAnnual CV risk assessment (including clinical review, BP, lipid profile,
HbA1c, ECG, and NP) and CVRF management is recommended in CS who were treated with a potentially cardiotoxic cancer drug or RT to a
volume exposing the heart.
CVD perspective) and the most effective (from an oncological per- scope of CV therapies, including healthy lifestyle promotion and
spective) cancer treatment. Adjudication of CV events occurring in pa- pharmacological, device, and surgical treatments.4,9,10
tients on active therapy is another important aspect of The principle underlying the dynamic course of CTR-CVT develop-
cardio-oncology practice.1,3 This is in addition to recommendations ment in patients with cancer is that the absolute risk depends on their
on best treatment and management practices. This includes the full baseline risk and changes with exposure to cardiotoxic therapies over
ESC Guidelines 13
Baseline CV toxicity risk assessment checklist
Age, sex,

genetics
Previous Medical
CVD CVRF
CTR-CVT
risk factors
Previous
Lifestyle
cardiotoxic
risk factors
therapies
ECG, TTE, and

cardiac biomarkers
abnormalities
Clinical assessment Complementary tests

Cancer treatment history BNP or NT-proBNPb
CV history cTnb
CVRF ECG
Physical examination Fasting plasma glucose / HbA1c
Vital signs measurementa Kidney function / eGFR
Lipid profile
TTEc
Figure 3 Baseline cardiovascular toxicity risk assessment checklist. BNP, B-type natriuretic peptide; cTn, cardiac troponin; CTR-CVT, cancer therapy-related
cardiovascular toxicity; CV, cardiovascular; CVD, CV disease; CVRF, cardiovascular risk factors; ECG, electrocardiogram; eGFR, estimated glomerular filtration
rate; HbA1c, glycated haemoglobin; NT-proBNP, N-terminal pro-BNP; TTE, transthoracic echocardiography. aIncluding blood pressure, heart rate, height,
weight, and body mass index. bCardiac biomarkers (troponin and NP) should be measured in patients at risk of CTRCD where available and results should
be interpreted according to the patient clinical status, type of cancer treatment, and kidney function. cConsider other CV complementary tests in selected
patients: cardiac magnetic resonance, coronary computed tomography angiography, CPET (in selected patients for pre-operative [lung, colon, and rectal can-
cers] risk stratification). See Section 4.6.
time (Figure 3).11 This has been recognized in conceptual models, with still be at high risk according to the severity of the event, which would
risk stratification tools designed to grade patients with cancer into lead to interruption of cancer treatment, e.g. a significant decline in
low, moderate, high, and very high risk of CV complications prior to left ventricular (LV) ejection fraction (LVEF) to , 40% with anthracy-
starting treatment. These have been published by the Heart Failure cline chemotherapy. The timeline of these developments may also be
Association (HFA) of the ESC in collaboration with the International rather different. After the cardiotoxic cancer treatment has been
Cardio-Oncology Society (ICOS) (see Section 4).12,13 Severity, dur- completed, a new risk assessment is recommended to establish differ-
ation, and type of manifestation of CTR-CVT vary by type of malig- ent long-term trajectories of CV health. These trajectories are im-
nancy and cancer treatment. The risk itself can be understood in pacted by the permanent CV toxic effects and cardiac or vascular
two ways: (1) the likelihood of its occurrence and (2) the severity of injury of some cancer therapies, patient-related CVRF, environmental
the complication (Figure 4). For example, a patient could be very likely factors, and stressors (e.g. acute viral infections). The aim should be to
to experience a CTR-CVT, but if this event is mild, oncology treat- personalize approaches to minimize CTR-CVT and improve both
ment should continue. Conversely, a patient at low likelihood could cancer and CV outcomes.
14 ESC Guidelines
Clinical severity of CTR-CVT
Severe and
Mild Moderate
very severe

Likelihood of
CTR-CVT
Low
Intermediate
High
Figure 4 Dimensions of cancer therapy-related cardiovascular toxicity risk and disease severity. CTR-CVT, cancer therapy-related cardiovascular tox-
icity; CV, cardiovascular. The ultimate risk is the combination of the likelihood (based on reported incidence) and degree (severity or grade) of the adverse
event. The most vulnerable patient groups are those at high likelihood of experiencing a severe adverse event. The level of attention that needs to be
devoted to these patients varies accordingly. The risk and type of CTR-CVT, as well as the potential for reversibility, depends on different factors, listed in
Figure 3, that should be considered to define global CV and oncological prognosis and to individualize CTR-CVT surveillance. Additional factors that add to
the complexity of CTR-CVT risk assessment are the cancer type and prognosis, and type, duration, and intensity of cancer treatment.
3. Cancer therapy-related (HF), myocarditis, vascular toxicities, hypertension, cardiac arrhyth-

mias, and corrected QT interval (QTc) prolongation. The definitions
cardiovascular toxicity definitions of other CTR-CVT, including pericardial and valvular heart diseases
Several terminologies and definitions have previously been proposed (VHDs), are the same as those used for the general cardiology popu-
to describe the spectrum of CTR-CVT, leading to inconsistencies in lation. For cardiac injury, cardiomyopathy, and HF, the descriptive
diagnosis and management. The need to harmonize these definitions term cancer therapy-related cardiac dysfunction (CTRCD) is recom-
has frequently been stated and recognized, and resulted in the recent mended as it captures the broad spectrum of possible presentations
international definitions of CTR-CVT1 supported by this guideline and the aetiological link with the broad scope of various cancer ther-
(Table 3; Supplementary data, Table S1). This document will focus apies, including chemotherapy, targeted agents, immune therapies,
on consensus definitions for cardiomyopathy and heart failure and radiation therapy.
ESC Guidelines 15
Table 3 Cancer therapy-related cardiovascular toxicity definitions
CTRCD
Symptomatic CTRCD (HF)a,b Very severe HF requiring inotropic support, mechanical circulatory support, or
consideration of transplantation
Severe HF hospitalization
Moderate Need for outpatient intensification of diuretic and HF therapy
Mild Mild HF symptoms, no intensification of therapy required

Asymptomatic CTRCD Severe New LVEF reduction to ,40%
Moderate New LVEF reduction by ≥10 percentage points to an LVEF
of 40–49%
OR
New LVEF reduction by ,10 percentage points to an LVEF of 40–
49% AND either new relative decline in GLS by .15% from baseline
OR new rise in cardiac biomarkersc
Mild LVEF ≥ 50%
AND new relative decline in GLS by .15% from baseline
AND/OR new rise in cardiac biomarkersc
ICI myocarditis (either pathohistological diagnosis or clinical diagnosis)
Pathohistological diagnosis (EMB) Multifocal inflammatory cell infiltrates with overt cardiomyocyte loss by light microscopy
Clinical diagnosisd cTn elevation (new or significant change from baseline)e with 1 major criterion or 2 minor criteria,
after exclusion of ACS and acute infectious myocarditis based on clinical suspicionf
Major criterion:
• CMR diagnostic for acute myocarditis (modified Lake Louise criteria)g
Minor criteria:
• Clinical syndrome (including any one of the following: fatigue, myalgias, chest pain, diplopia, ptosis,
shortness of breath, orthopnoea, lower-extremity oedema, palpitations, light-headedness/dizziness,
syncope, muscle weakness, cardiogenic shock)
• Ventricular arrhythmia (including cardiac arrest) and/or new conduction system disease
• Decline in LV systolic function, with or without regional wall motion abnormalities in a non-Takotsubo
pattern
• Other immune-related adverse events, particularly myositis, myopathy, myasthenia gravis
• Suggestive CMRh
Severity of myocarditis • Fulminant: Haemodynamic instability, HF requiring non-invasive or invasive ventilation, complete or
high-grade heart block, and/or significant ventricular arrhythmia
• Non-fulminant: including symptomatic but haemodynamically and electrically stable patients and
incidental cases diagnosed at the same time as other immuno-related adverse events. Patients may have
reduced LVEF but no features of severe disease
• Steroid refractory: non-resolving or worsening myocarditis (clinical worsening or persistent troponin
elevation after exclusion of other aetiologies) despite high-dose methylprednisolone
Recovery from myocarditis • Complete recovery: Patients with complete resolution of acute symptoms, normalization of
biomarkers, and recovery of LVEF after discontinuation of immunosuppression. CMR may still show LGE
or elevated T1 due to fibrosis, but any suggestion of acute oedema should be absent
• Recovering: Ongoing improvement in patient clinical symptoms, signs, biomarkers, and imaging
parameters, but not yet normalized, while on tapering doses of immunosuppression
Vascular toxicity (for general cardiology definitions, see Supplementary data, Table S1)
Asymptomatic vascular toxicity CAD Symptomatic vascular Stroke
PAD toxicity Transient ischaemic attack
Carotid artery disease MI
Venous thrombosis ACS
Arterial thrombosis CCS
Peripheral vasoreactivity PAD
Continued
16 ESC Guidelines
Coronary epicardial Vasospastic angina

vasoreactivity
Coronary microvascular Microvascular angina
vasoreactivity Raynaud’s phenomenon
Arterial hypertension
Treatment threshold for In patients with high CV riski: ≥130 mmHg systolic and/or ≥80 mmHg diastolic
hypertension before, during, and Otherwise: ≥140 mmHg systolic and/or ≥90 mmHg diastolic

after therapy
Cancer therapy holding threshold ≥180 mmHg systolic and/or ≥110 mmHg diastolic
Hypertensive emergency (Very high) BP elevation associated with acute hypertension-mediated organ damage (heart, retina, brain,
kidneys, and large arteries), requiring immediate BP reduction to limit extension or promote regression of
target organ damage
Cardiac arrhythmias
QT prolongation Prolonged: QTcF . 500 msj
Bradycardia For general cardiology definitions, see Supplementary data, Table S1
Supraventricular tachycardia
© ESC 2022
Ventricular arrhythmias
AF
ACS, acute coronary syndromes; AF, atrial fibrillation; BNP, B-type natriuretic peptide; BP, blood pressure; CAD, coronary artery disease; CCS, chronic coronary syndromes; CMR,
cardiac magnetic resonance; cTn, cardiac troponin; CTRCD, cancer therapy-related cardiac dysfunction; CV, cardiovascular; ECV, extracellular volume fraction; EMB,
endomyocardial biopsy; ESC, European Society of Cardiology; GLS, global longitudinal strain; HF, heart failure; HFmrEF, HF with mildly reduced ejection fraction; HFpEF, heart
failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; ICI, immune checkpoint inhibitors; LGE, late gadolinium enhancement; LV, left
ventricular; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PAD, peripheral artery disease; QTcF,
corrected QT interval using Fridericia correction; SCORE2, Systematic Coronary Risk Estimation 2; SCORE2-OP, Systematic Coronary Risk Estimation 2—Older Persons.
See Supplementary data, Table S1 for expanded definitions.
a
With LVEF and supportive diagnostic biomarkers based on the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic HF.14
b
Symptomatic CTRCD represents HF, which is a clinical syndrome consisting of cardinal symptoms (e.g. breathlessness, ankle swelling, and fatigue) that may be accompanied by signs (e.g.
elevated jugular venous pressure, pulmonary crackles, and peripheral oedema) and has traditionally been divided into distinct phenotypes based on the measurement of LVEF: ≤40% =
HFrEF; 41–49% = HFmrEF; ≥50% = HFpEF.
c
cTnI/cTnT . 99th percentile, BNP ≥ 35 pg/mL, NT-proBNP ≥ 125 pg/mL or new significant rise from baseline beyond the biological and analytical variation of the assay used.
d
Clinical diagnoses should be confirmed with magnetic resonance imaging or EMB if possible and without causing treatment delays. Treatment with immunosuppression should be
promptly initiated while awaiting further confirmatory testing in symptomatic patients.
e
Both troponin I and troponin T can be used; however, clinical observations suggest that troponin T may be falsely elevated in patients with concomitant myositis and without myocarditis.15–17
f
According to local protocols.
g
Diagnostic CMR: Based on updated Lake Louise criteria18: T2-based criterion + T1-based criterion + supportive criteria (T2-based criteria: regional or global increase of native T2, or T2 signal
intensity; T1-based criteria: regional or global increase of native T1, or regional or global increase in the ECV, or presence of LGE; supportive criteria: pericarditis and/or regional or global LV
systolic dysfunction).
h
Suggestive CMR: meeting some but not all of the modified Lake Louise criteria. The presence of T2- or T1-based criteria may support a diagnosis of acute myocardial inflammation in the
appropriate clinical scenario.
i
SCORE2 (,70 years), SCORE2-OP (≥70 years) or equivalent.19 CV risk stratification: ,50 years: low risk ,2.5%, moderate risk 2.5% to ,7.5%, high risk ≥7.5%; 50–69 years: low risk ,5%;
moderate risk 5% to ,10%; high risk ≥10%; ≥70 years: low risk ,7.5%, moderate risk 7.5% to ,15%, high risk ≥15%.
j
QTcF 480–500 ms: correct reversible causes, minimize other QT prolonging medications, close QTcF monitoring. Fridericia correction is recommended (QTcF = QT/3√RR).20
4. Cardiovascular toxicity risk CVD prevention strategies require a personalized approach. Risk
assessment is a challenging task and it is vital that clinicians adopt a
stratification before anticancer systematic approach without delaying oncological treatment.12,21,22
therapy Figure 5 provides a comprehensive approach to risk assessment.
The choice of the cardiac tests (electrocardiogram [ECG], biomar-
The optimal time to consider CVD prevention strategies in patients kers, and imaging) should be individualized based on CV risk and
with cancer is at the time of cancer diagnosis and prior to the initi- the planned cancer treatments.
ation of cancer treatment.4,5 This enables the oncology team to con-
sider CV risk while making cancer treatment choices, educating
patients regarding their CV risk, personalizing CV surveillance and 4.1. General approach to cardiovascular
follow-up strategies, and making appropriate referrals of high-risk pa- toxicity risk in patients with cancer
tients to cardio-oncology services. These strategies are needed to Pre-treatment CTR-CVT risk assessment should ideally be per-
mitigate CVD risk, and improve the adherence to effective cancer formed using a recognized risk stratification method where multiple
treatments and the overall survival. risk factors are incorporated to determine patient-specific risk.23
ESC Guidelines 17
Baseline cardiovascular toxicity risk assessment
HFA-ICOS risk
assessment:

CVRFa
CVD history
Cancer history
Cancer treatment history
ECG Physical and metabolic Pre-existing CVD or

(Class I) assessmentb at risk of CTRCDc
New, untreated or TTE

Arrhythmias Suspected cTn and NP
uncontrolled medical, and (LVEF and GLS)
Prolonged QTcF CVD increasedd
lifestyle CVRF reducede
Check and correct Refer to Refer to cardiologistg

precipitant factorsf cardiologistg Aggressive management of
(Class I)
(Class I) (Class I) CVRF and pre-existing CVD
according to ESC Guidelines
Healthy lifestyle promotion
(Class I)
Consider primary vs secondary preventive strategies according to CV toxicity risk,

pre-existing CVD, and cancer treatment type
Figure 5 Baseline cardiovascular toxicity risk assessment before anticancer therapy. BNP, B-type natriuretic peptide; cTn, cardiac troponin; CTRCD,
cancer therapy-related cardiac dysfunction; CV, cardiovascular; CVD, CV disease; CVRF, CV risk factors; ECG, electrocardiogram; ESC, European
Society of Cardiology; GLS, global longitudinal strain; HFA, Heart Failure Association; ICOS, International Cardio-Oncology Society; LVEF, left ven-
tricular ejection fraction; NP, natriuretic peptides (including BNP and NT-proBNP); NT-proBNP, N-terminal pro-BNP peptide; QTc, corrected QT
interval; QTcF, corrected QT interval using Fridericia correction; TTE, transthoracic echocardiography. aWhen assessing CVRF, include information
about unhealthy lifestyle including sedentary behaviour, smoking, and alcohol intake. bSee Figure 3. cAccording to cancer treatment and HFA-ICOS
risk assessment. dcTnI/T . 99th percentile, BNP ≥ 35 pg/mL, NT-proBNP ≥ 125 pg/mL. ePatients with baseline LVEF , 50% or in the low normal
range (LVEF 50–54%) should be referred to a specialized cardiologist or cardio-oncologist. When TTE is used, ideally three-dimensional-LVEF and GLS
should be measured. If GLS assessment is not available, other markers of longitudinal function (e.g. annular Doppler velocity) should be considered.
Cardiac magnetic resonance should be considered if echocardiography is of non-diagnostic quality. fAnaemia, infections, electrolyte abnormalities, meta-
bolic problems, other QTc-prolonging drugs. gCardio-oncology referral is recommended when available; alternatively, patients should be referred to a
specialized cardiologist with expertise in managing CVD in patients with cancer.
Only a limited number of retrospective risk scores have been pub- validation is needed, HFA-ICOS risk assessment tools should be con-
lished in patients with cancer. Most of these scores have been devel- sidered to determine pre-treatment risk of CTR-CVT as they are
oped for specific cancer-patient groups and cannot be readily applied easy to use and implement in oncology and haematology services
or extrapolated to other type of malignancies.24–29 While further (Table 4; Supplementary data, Tables S2–S7).12,13 Other CV risk
18 ESC Guidelines
Table 4 Heart Failure Association–International Cardio-Oncology Society baseline cardiovascular toxicity risk
stratification
Baseline CV toxicity Anthracycline HER2-targeted VEGF BCR-ABL Multiple RAF and

risk factors chemotherapy therapies inhibitors inhibitors myeloma MEK
therapies inhibitors
Previous CVD
HF/cardiomyopathy/ VH VH VH H VH VH

CTRCD
Severe VHD H H – – – H
MI or PCI or CABG H H VH – – H
Stable angina H H VH – – H
Arterial vascular disease – – VH VH VH –
Abnormal ankle-brachial – – – H – –
pressure index
PH – – – H – –
Arterial thrombosis with TKI – – – VH – –
Venous thrombosis – – H M2 VH –
(DVT/PE)
Arrhythmiaa – M2 M2 M2 M2 M1
QTc ≥ 480 ms – – H H – –
450 ≤ QTc , 480 ms (men); – – M2 M2 – –
460 ≤ QTc , 480 ms
(women)
Prior PI CV toxicity – – – – VH –
Prior IMiD CV toxicity – – – – H –
Cardiac imaging
LVEF , 50% H H H H H H
LVEF 50–54% M2 M2 M2 – M2 M2
LV hypertrophy – – – – M1 –
Cardiac amyloidosis – – – – VH –
Cardiac biomarkers
Elevated baseline cTnb M1 M2 M1 – M2 M2
Elevated baseline NPb M1 M2 M1 – H M2
Age and CVRF
Age ≥ 80 years H H – – – M1
Age 65–79 years M2 M2 – – – M1
Age ≥ 75 years – – H H H M1
Age 65–74 years – – M1 M2 M1 M1
Age ≥ 60 years – – – M1 – –
CVD 10-year risk score – – – H – –
. 20%
Hypertensionc M1 M1 H M2 M1 M2
Chronic kidney diseased M1 M1 M1 M1 M1 M1
Proteinuria – – M1 – – –
DMe M1 M1 M1 M1 M1 M1
Hyperlipidaemiaf – – M1 M1 M1 –
Family history of – – – M1 M1 –
thrombophilia
Continued
ESC Guidelines 19
Current cancer treatment

Dexamethasone . 160 mg/ – – – – M1 –
month
Includes anthracycline – M1g – – – –
before HER2-targeted
therapy
Previous exposure to

Anthracycline H M2h H – H H
Trastuzumab – VH – – – –
RT to left chest or H M2 M1 – M1 M2
mediastinum
Non-anthracycline M1 – – – – –
chemotherapy
Lifestyle risk factors
Current smoker or M1 M1 M1 H M1 M1
© ESC 2022
significant smoking history
Obesity (BMI . 30 kg/m2) M1 M1 M1 M1 M1 M1
AF, atrial fibrillation; BCR-ABL, breakpoint cluster region–Abelson oncogene locus; BMI, body mass index; BNP, B-type natriuretic peptide; BP, blood pressure; CABG, coronary artery
bypass graft; cTn, cardiac troponin; CTRCD, cancer therapy-related cardiac dysfunction; CV, cardiovascular; CVD, cardiovascular disease; CVRF, cardiovascular risk factors; DM, diabetes
mellitus; DVT, deep vein thrombosis; eGFR, estimated glomerular filtration rate; H, high risk; HbA1c, glycated haemoglobin; HER2, human epidermal receptor 2; HF, heart failure; IMiD,
immunomodulatory drugs; LV, left ventricular; LVEF, left ventricular ejection fraction; M, moderate risk; MEK, mitogen-activated extracellular signal-regulated kinase; MI, myocardial
infarction; MM, multiple myeloma; NP, natriuretic peptides (including BNP and NT-proBNP); NT-proBNP, N-terminal pro-B-type natriuretic peptide; PCI, percutaneous coronary
intervention; PE, pulmonary embolism; PH, pulmonary hypertension; PI, proteasome inhibitors; QTc, corrected QT interval; RAF, rapidly accelerated fibrosarcoma; RT,
radiotherapy; TKI, tyrosine kinase inhibitors; ULN, upper limit of normal; VEGFi, vascular endothelial growth factor inhibitors; VH, very high risk; VHD, valvular heart disease.
An expanded version of this table is provided in Supplementary data, Tables S2–S7.
Risk level: Low risk = no risk factors OR one moderate1 risk factor; moderate risk (M) = moderate risk factors with a total of 2–4 points (Moderate 1 [M1] = 1 point; Moderate
[M2] = 2 points); high risk (H) = moderate risk factors with a total of ≥5 points OR any high-risk factor; very-high risk (VH) = any very-high risk factor.
a
AF, atrial flutter, ventricular tachycardia, or ventricular fibrillation.
b
Elevated above the ULN of the local laboratory reference range.
c
Systolic BP . 140 mmHg or diastolic BP . 90 mmHg, or on treatment.
d
eGFR , 60 mL/min/1.73 m2.
e
HbA1c . 7.0% or .53 mmol/mol, or on treatment.
f
Non-high density lipoprotein cholesterol .3.8 mmol/L (.145 mg/dL) or on treatment.
g
High risk if anthracycline chemotherapy and trastuzumab delivered concurrently.
h
Previous malignancy (not current treatment protocol).
Table 5 Anthracycline equivalence dose
Doxorubicin Epirubicin Daunorubicin Mitoxantrone Idarubicina

© ESC 2022
CV toxicity dose ratio 1 0.8 0.6 10.5 5
Isoequivalent dose 100 mg/m2 125 mg/m2 167 mg/m2 9.5 mg/m2 20 mg/m2
This table refers to anthracycline equivalence dose using doxorubicin as a reference. Note that these isoequivalent doses are derived from paediatric CS.
CS, cancer survivors; CV, cardiovascular.
a
Data for idarubicin are based upon an estimated anticancer efficacy ratio, not derived from cardiotoxicity data. The CV toxicity dose ratio provides the value that should be used to
multiply the dose of the anthracycline of interest to convert to isoequivalent doses of doxorubicin; e.g. to convert 125 mg/m2 of epirubicin to doxorubicin isoequivalent, multiply the dose
by 0.8 (125 mg/m2 × 0.8 = 100 mg/m2 of doxorubicin).
calculators (e.g. SMART [Second manifestations of arterial disease] assessment of CV risk, considering that cancer itself may increase
risk score, ADVANCE [Action in Diabetes and Vascular Disease: the likelihood of CVD.19,23,30,31
Preterax and Diamicron-MR Controlled Evaluation] risk score, Baseline risk assessment should be considered by the treating on-
SCORE2 [Systematic Coronary Risk Estimation 2], SCORE2-OP cology or haematology team for all patients diagnosed with cancer
[Systematic Coronary Risk Estimation 2—Older Persons], ASCVD who are scheduled to receive a cancer treatment identified to
[AtheroSclerotic Cardiovascular Disease] risk score, U-Prevent, have a clinically significant level of CRT-CVT, or by a cardiologist if
and lifetime risk calculators) may be considered at baseline for the appropriate. In the case of patients scheduled to receive
20 ESC Guidelines
Patient with cancer
CV risk stratification before anticancer therapy

(Class I)

HFA-ICOS baseline risk assessment
(Class IIa)
HFA-ICOS results
Low risk Moderate risk High/very high risk
Routine oncology follow-up Closer oncology follow-up Cardiologya referral

(Class I)
AND AND AND
Discussion of the risk/benefit
Cardiologya referral if Cardiologya referral if balance of cardiotoxic
CV toxicity develops CV toxicity develops anticancer treatment
(Class I) (Class I) (Class I)
AND AND
Cardiology referral a
Cardioprotective strategies
(Class IIb) (Class IIa)
Communicate the CV toxicity risk assessment results (Class I)

Educate patients regarding risks and protective healthy lifestyle (Class I)
Management of CVRF and CVD according to ESC Guidelines (Class I)
Figure 6 General cardio-oncology approach after Heart Failure Association–International Cardio-Oncology Society cardiovascular toxicity risk assess-
ment. CV, cardiovascular; CVD, CV disease; CVRF, CV risk factors; ESC, European Society of Cardiology; HFA, Heart Failure Association; ICOS,
International Cardio-Oncology Society. aCardio-oncology referral is recommended when available; alternatively, patients should be referred to a spe-
cialized cardiologist with expertise in managing CVD in patients with cancer.
anthracycline chemotherapy, the total planned cumulative anthracy- recommended for patients identified to be at high or very high
cline dose is also relevant, and ≥250 mg/m2 of doxorubicin or risk for CTR-CVT at baseline (Table 4) to institute strategies to miti-
equivalent should be considered higher risk (Table 5).32 gate risk.33 Patients at moderate risk can benefit from closer cardiac
CV risk stratification results should be discussed with the patient monitoring, strict management of traditional CVRF, and selected
and documented in clinical notes. This process will also enable future moderate-risk patients may also benefit from a cardio-oncology re-
validation of these tools. ferral (Figure 6). Low-risk patients can be followed within the oncol-
Cardiology referral (cardio-oncology programme or cardiolo- ogy programme with appropriate referral to cardio-oncology if a
gist with expertise in managing CVD in patients with cancer) is CTR-CVT emerges or new or uncontrolled CVRF appear.
ESC Guidelines 21
Recommendation Table 1 — Recommendations for a prevention includes interventions in patients with prior or active
general approach to cardiovascular toxicity risk CVD or previous CTR-CVT.12
categorization Reviewing traditional risk factors for CVD is recommended.
Where present, the efficacy of treatment and control of these modi-
Recommendations Classa Levelb
fiable risk factors should be determined to ensure optimal control
CV toxicity risk stratificationc before starting during cancer therapy.4,34 Although recent SCORE2 and
potentially cardiotoxic anticancer therapy is
I B SCORE2-OP19 tables are not focused on patients with cancer, risk
recommended in all patients with calculation is recommended for patients with cancer .40 years of

cancer.12,14,19,21,25,28,31 age (unless they are automatically categorized as being at high risk
Communicating the results of the CV toxicity risk or very high risk based on documented CVD, diabetes mellitus
assessment to the patient and other appropriate I C [DM], kidney disease, or a highly elevated single risk factor) as a ref-
healthcare professionals is recommended. erence to optimize CVRF treatment goals.19,31,35 A family history of
The use of HFA-ICOS risk assessment should be premature CVD should be considered because genetic abnormalities
considered to stratify CV toxicity risk in patients associated with CVD may predispose patients with cancer to a high-
IIa C
with cancer scheduled to receive cardiotoxic er risk of CTR-CVT.36–38 Lifestyle factors such as smoking, alcohol
anticancer therapy.12 consumption, sedentary lifestyle, exposure to pollution, and frailty
It is recommended that patients categorized to be are important shared risk factors for both cancer and CVD.
at low CV toxicity risk should proceed to I C Information on prior history of cancer, cardiotoxic cancer therapies,
anticancer therapy without delay. and their respective doses should be collected. Patients should be
In patients categorized at moderate CV toxicity asked about typical cardiac symptoms (e.g. chest pain with activity,
IIb C
risk, cardiology referrald may be considered.e dyspnoea on exertion, orthopnoea, palpitations, and peripheral oe-
Cardiology referrald is recommended in high-risk
dema), which can guide clinical examination and investigations.
and very high-risk patients before anticancer I C Physical examination should document vital signs and look for poten-
therapy.f
tial indicators of undiagnosed CVD such as HF, pericardial disease,
VHD, and arrhythmias.39–42
Discussion of the risk/benefit balance of
The second scenario is secondary prevention in patients with a
cardiotoxic anticancer treatment in high- and very
I C prior history of CVD. These patients with cancer are potentially at
high-risk patients in a multidisciplinary approach
high or very high risk of future CV events,12 and require a more
prior to starting treatment is recommended.
comprehensive clinical evaluation of their CVD, its severity, and
Cardiology referrald is recommended for patients
prior and current treatments. Depending on the type and severity
with cancer and pre-existing CVD or abnormal
of CVD, additional investigations—including resting or stress echo-
© ESC 2022
findings at baseline CV toxicity risk assessmentg I C

cardiography, cardiac magnetic resonance (CMR), nuclear perfusion
who require potentially cardiotoxic anticancer
imaging, and coronary computed tomography angiography (CCTA)
therapy.
—may be indicated to determine risk status. Identifying prior CVD
CV, cardiovascular; CVD, CV disease; ECG, electrocardiogram; GLS, global longitudinal should not automatically be a reason to withhold cancer therapy
strain; HbA1c, glycated haemoglobin; HFA, Heart Failure Association; ICOS,
but considered an opportunity to optimize CV risk prior to and dur-
International Cardio-Oncology Society; LVEF, left ventricular ejection fraction; TTE,
transthoracic echocardiography; ULN, upper limit of normal; VHD, valvular heart ing treatment. Risk/benefit discussions should include the patient,
disease. oncologist or haematologist, and—where available—a specialized
a
Class of recommendation.
b cardio-oncology service.
Level of evidence.
c
Including clinical history and physical examination, ECG, general blood test, HbA1c, Additional factors that add to the complexity of baseline CV risk
lipid profile, and cardiac serum biomarkers and/or TTE (according to cancer drug assessment are the cancer type and prognosis, and type, duration,
type and CV toxicity risk).
d and intensity of cancer treatment (Figure 1).4,12,43 Clinical history,
Cardio-oncology referral is recommended when available; alternatively, the patients
should be referred to a specialized cardiologist with expertise in managing CVD in physical examination features, and treatment-related risk factors
patients with cancer. that contribute to CTR-CVT for various cancer therapies are sum-
e
Without delaying cancer treatments.
f marized in Supplementary data, Table S8. These risk factors should
Unless there is an oncology emergency requiring immediate cancer treatment.
g
Moderate-to-severe pre-existing CVDs or new abnormal findings (baseline cardiac be collected and considered along with baseline ECG, cardiac serum
serum biomarkers . ULN, LVEF ≤ 50%, GLS under normal local values, previously biomarkers, and cardiac imaging tests (summarized in Figure 7) to
undiagnosed moderate-to-severe myocardial, pericardial, or VHDs, abnormal baseline
complete baseline CTR-CVT evaluation.
ECG).
4.3. Electrocardiogram
A baseline 12-lead ECG is a readily available test that can provide im-
4.2. History and clinical examination portant clues to underlying CVD. ECG evidence of chamber enlarge-
A careful clinical history and physical examination is recommended as ment, conduction abnormalities, arrhythmias, ischaemia, or prior
part of the baseline risk assessment. Oncology patients can be di- myocardial infarction (MI), and low voltages should be interpreted
vided into two cohorts with respect to the presence or absence of in the clinical context. A baseline ECG is recommended prior to
pre-existing CVD. A primary prevention strategy can be considered starting a cancer treatment known to cause QTc prolongation.44–49
in patients without previous CVD or CTR-CVT while secondary Measurement of QTc using the Fridericia correction (QTcF) is
22 ESC Guidelines
Baseline clinical CV assessment, physical exam and ECG are recommended

in all cancer patients scheduled for cardiotoxic therapiesa
Patient risk level TTEb NP cTn

Anthracyclines
HER2-targeted therapiesc

Previous
Fluoropyrymidines CVD
VEGFi
All
Second- and third-generation BCR-ABL TKId patients
BTK inhibitors
PIe
RAF and MEK inhibitors
ICI
All other
patients
All
Osimertinib patients
Previous
CAR-T and TIL CVD
All other
patients
Previous
RT to a volume including the heart CVD
All
HSCT patients
Very high Moderate Low Other

Class I Class IIa Class IIb
risk risk risk conditions
Figure 7 Baseline screening recommendations for patients with cancer treated with potentially cardiotoxic drugs. 3D, three-dimensional; ADT, andro-
gen deprivation therapy; AL-CA, amyloid light-chain cardiac amyloidosis; BC, breast cancer; BCR-ABL, breakpoint cluster region-Abelson oncogene locus;
BNP, B-type natriuretic peptide; BTK, Bruton tyrosine kinase; CAR-T, chimeric antigen receptor T cell; CDK, cyclin-dependent kinase; CMR, cardiac mag-
netic resonance; cTn, cardiac troponin; CV, cardiovascular; CVD, cardiovascular disease; ECG, electrocardiogram; GLS, global longitudinal strain; HER2,
human epidermal receptor 2; HSCT, haematopoietic stem cell transplantation; ICI, immune checkpoint inhibitors; LVEF, left ventricular ejection fraction;
MEK, mitogen-activated extracellular signal-regulated kinase; NP, natriuretic peptides (including BNP and NT-proBNP); NT-proBNP, N-terminal
pro-B-type natriuretic peptide; PI, proteasome inhibitors; RAF, rapidly accelerated fibrosarcoma; RT, radiotherapy; TIL, tumour-infiltrating lymphocytes;
TKI, tyrosine kinase inhibitors; TTE, transthoracic echocardiography; VEGFi, vascular endothelial growth factor inhibitors. aIncluding patients scheduled to
receive ADT for prostate cancer, CDK 4/6 inhibitors, endocrine hormone therapy for BC and anaplastic lymphoma kinase inhibitors. bTTE is recom-
mended as the first-line modality for the assessment of cardiac function. 3D echocardiography is recommended to measure LVEF. GLS is recommended
in all patients with cancer having echocardiography, if available. CMR should be considered when echocardiography is unavailable or not diagnostic.
c
Baseline cTn measurement should be considered (Class IIa, Level A) in low- and moderate-risk patients post-anthracycline chemotherapy but prior
to starting HER2-targeted therapies. Baseline NP and cTn measurement may be considered (Class IIb, Level C) in low- and moderate-risk patients.
d
Baseline echocardiography is recommended in patients scheduled to receive dasatinib (Class I, Level C). eNP and cTn measurements are recommended
at baseline in patients with AL-CA (Class I, Level B).
ESC Guidelines 23
recommended.44–48 When baseline QTcF prolongation is recog- A few studies of paediatric and adult patients requiring an-
nized, the correction of reversible causes and the identification of thracycline chemotherapy have reported that patients with can-
genetic conditions that prolong QT is recommended (see Section cer with an increased cTn before treatment were more likely to
6.4.2).45 develop CTRCD.56–58 However, most published studies have
Left atrial enlargement on baseline ECG before ibrutinib has not reported on the prognostic value of baseline cTn measure-
been shown to be a predictor for the development of atrial fibril- ments, possibly due to the low prevalence of patients with pre-
lation (AF) during chemotherapy.50,51 The presence of atrioven- vious CVD or CVRF in these studies.55,59,60 A study of 251
tricular (AV) conduction delays and premature atrial complexes women receiving trastuzumab for early HER2-positive breast

are associated with the development of atrial arrhythmias in pa- cancer (BC) reported that 19% of the patients who developed
tients undergoing autologous haematopoietic stem cell transplant- cardiac dysfunction during trastuzumab therapy had positive ul-
ation (HSCT).52 trasensitive troponin I at baseline (.80 ng/L).61 Furthermore,
baseline high cTnI level was a predictor of lack of recovery des-
pite optimal HF therapy.61 These findings have been confirmed
Recommendation Table 2 — Recommendations for in a subsequent study of 533 patients with BC who had serial
electrocardiogram baseline assessment high-sensitivity cTn (hs-cTn) I and T measurements during tras-
tuzumab therapy.62 Increased baseline cTn (.40 ng/L and
.14 ng/L for hs-cTnI and hs-cTnT, respectively) was associated
An ECG is recommended in all patients starting with a four-fold risk of developing LV dysfunction (LVD).62
cancer therapy as part of their baseline CV risk I C However, given the high proportion of patients with previous
© ESC 2022
assessment. anthracycline exposure in both studies, these elevated cTn levels

In patients with an abnormal baseline ECG,c are not a true baseline as they reflect pre-trastuzumab but post-
I C
referral to a cardiologistd is recommended. anthracycline chemotherapy. It is unclear whether pre-
treatment cTn levels will be predictive of LVD in patients before
AF, atrial fibrillation; CV, cardiovascular; ECG, electrocardiogram; LV, left ventricular;
QTc, corrected QT interval; QTcF, corrected QT interval using Fridericia correction. any treatment, or for those BC patients treated with trastuzu-
a
Class of recommendation. mab without prior anthracyclines.
b
Level of evidence. NP are another potential biomarker for CV risk stratification.
c
Advanced conduction disease (left bundle branch block, right bundle branch block,
second degree heart block, severe first degree heart block with a PR interval Several studies have shown the role of NP measurement at baseline
.300 ms); Q waves in two or more contiguous leads; LV hypertrophy; AF/atrial or NP changes to predict future CTR-CVT.63–65 In patients with mul-
flutter if previously undiagnosed; QTc prolongation using Fridericia correction tiple myeloma (MM), pre-treatment NP may be a predictive marker
formula (QTcF = QT/3√RR) .450 ms for men and .460 ms for women or other
ECG abnormality raising concern. for subsequent CV adverse events. In 109 patients with relapsed MM,
d
Cardio-oncology referral is recommended when available; alternatively, the patients BNP . 100 pg/mL or NT-proBNP . 125 pg/mL levels before initi-
should be referred to a specialized cardiologist with expertise in managing CVD in ation of carfilzomib were associated with an odds ratio of 10.8 for
patients with cancer.
subsequent CV adverse events.66 Therefore, baseline NP measure-
ment is recommended in high- and very high-risk patients and should
be considered in low- and moderate-risk patients before PI
4.4. Cardiac serum biomarkers treatment.
The literature on the use of biomarkers for CTR-CVT risk strati- Baseline elevated values of CV functional peptides (including
fication before cancer therapy is limited, and recommendations NT-proBNP) and hs-cTnT were strongly related to all-cause mortal-
are mostly based on expert opinion.12,43,53–55 Four recent position ity in 555 patients with different types of tumours, suggesting that
papers based on collaboration among the Cardio-Oncology Study the presence of a subclinical myocardial injury might be directly
Group of the HFA of the ESC, the ESC-CCO, and ICOS have sug- linked to disease progression.67 However, in the CARDIOTOX
gested that measurement of cardiac serum biomarkers—cardiac (CARDIOvascular TOXicity induced by cancer-related therapies)
troponin (cTn) I or T and natriuretic peptides (NP) (e.g. B-type registry, in 855 patients treated with a range of oncological treat-
natriuretic peptide [BNP] or N-terminal pro-BNP ments, including radiotherapy (RT), both NT-proBNP and cTn eleva-
[NT-proBNP])—help in baseline CV risk stratification of patients tion at baseline were not associated with the development of severe
scheduled for cancer therapies including anthracyclines, human CTRCD (LVEF , 40% or clinical HF).68
epidermal receptor 2 (HER2)-targeted therapies, vascular endo- There has also been interest in other novel biomarkers for
thelial growth factor (VEGF) inhibitors (VEGFi), proteasome inhi- CTR-CVT risk stratification before cancer treatment; however,
bitors (PI), immune checkpoint inhibitors (ICI), chimeric antigen the literature is limited. Candidates include myeloperoxidase,
receptor T cell (CAR-T) and tumour-infiltrating lymphocytes C-reactive protein, galectin-3, arginine–nitric oxide metabolites,
(TIL) therapies, allowing identification of those who may benefit growth differentiation factor-15, placental growth factor,
from cardioprotective therapy.12,43,53,54 Baseline cardiac serum fms-like tyrosine kinase-1, micro-ribonucleic acids, and immuno-
biomarker measurements are required if the degree of change in globulin E.60,69–71 Currently, there is no evidence to support
the biomarkers is to be used to identify subclinical cardiac injury routine measurement of these novel biomarkers and more re-
during cancer treatment. search is required.
24 ESC Guidelines
Recommendation Table 3 — Recommendation for 4.5. Cardiovascular imaging

cardiac biomarker assessment prior to potentially car- CV imaging has an important role in identifying patients with subclin-
diotoxic therapies
ical CVD, determining the degree of pre-existing cardiac comorbidity
Recommendation Classa Levelb prior to decisions regarding cancer therapy, and serves as a reference
for identification of changes during treatment and long-term follow-
Baseline measurement of NPc and/or cTnd is up.12,54,72–74 Transthoracic echocardiography (TTE) is the preferred
recommended in all patients with cancer at risk of imaging technique for baseline risk stratification as it provides quan-
© ESC 2022
CTRCD if these biomarkers are going to be I C titative assessment of LV and right ventricular (RV) function, cham-

measured during treatment to detect ber dilation, LV hypertrophy, regional wall motion abnormalities,
CTRCD.e,53,55
diastolic function, VHD, pulmonary arterial pressure (PAP), and peri-
cTn, cardiac troponin; CTRCD, cancer therapy-related cardiac dysfunction; NP, cardial disease, which may influence the therapeutic decision.22,72
natriuretic peptides. Suggestions for the components of a baseline echocardiography
a
b
Level of evidence. study are provided in Figure 8.
c
NPs including B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide. Current definitions of CTRCD are based on a reduction of LVEF
d
cTn includes any of troponin I, troponin T, or hs-cTnT. and/or relative changes in global longitudinal strain (GLS) (Table 3).
e
Specific recommendations for baseline cardiac biomarkers in patients with cancer at
low, moderate, high, and very high risk of cancer therapy-related cardiovascular Three-dimensional (3D) echocardiography is the preferred echocar-
toxicity are included in Section 5. diography modality for the assessment of LVEF and cardiac
Right ventricle-right atriuma Left ventricle-left atriuma
TTE TTE
RV dimensions LVV and LV mass

S´ 3D-LVEF (2D-LVEF if
TAPSE 3D not available)
FAC Contrast echo if inadequate
RV-FWLS TTE image quality
RA area GLS
Peak TRV E/e´, LAV
CMR CMR
RVV LVV and LV mass

RVEF LVEF
LS and circumferential strain
if available
Myocardial Characterization
T2w (STIR), T1, T2 maps, LGE
Other parameters
TTE CMR
IVC diameter, and respiratory Valvular and pericardial

changes diseases
Valvular and pericardial
diseases
Figure 8 Recommended transthoracic echocardiography and cardiac magnetic resonance imaging parameters in the evaluation of patients with cancer.
2D, two-dimensional; 3D, three-dimensional; BP, blood pressure; CMR, cardiac magnetic resonance; E, mitral inflow early diastolic velocity obtained by pulsed
wave; e′ , early diastolic velocity of the mitral annulus obtained by tissue doppler imaging; echo, echocardiography; FAC, fractional area change; FWLS, free wall
longitudinal strain; GLS, global longitudinal strain; IVC, inferior vena cava; LAV, left atrial volume; LGE, late gadolinium enhancement; LS, longitudinal strain; LV,
left ventricular; LVEF, left ventricular ejection fraction; LVV, left ventricular volume; RA, right atrial; RV, right ventricular; RVEF, right ventricular ejection fraction;
RVV, right ventricular volume; s′ , systolic velocity of tricuspid annulus obtained by doppler tissue imaging; STIR, short tau inversion recovery; TAPSE, tricuspid
annular plane systolic excursion; TTE, transthoracic echocardiography; TRV, tricuspid regurgitation velocity. aChanges in systemic arterial BP and loading con-
ditions may influence cardiac function measurements.
ESC Guidelines 25
volumes.54,75–79 If 3D echocardiography is not feasible (e.g. unavail- cardiomyopathy), CMR should be considered for further risk
able or poor tracking), the modified two-dimensional (2D) assessment.
Simpson’s biplane method is recommended.80,81 In patients with in- Functional imaging tests for myocardial ischaemia—including
adequate TTE image quality, ultrasound-enhancing contrast agents stress echocardiography, perfusion CMR, or nuclear myocardial per-
should be added to improve evaluation of LV function and volumes fusion imaging—should be performed to assess for ischaemia in
if two or more LV segments are not well visualized.82 Alternatively, in symptomatic patients (stable angina, limiting dyspnoea) if clinical sus-
subjects with poor-quality echocardiography windows, when avail- picion of coronary artery disease (CAD) exists, especially prior to
able, CMR should be considered (Figure 8).14,72,83,84 If TTE and use of cancer therapies associated with vascular toxicity (e.g. fluoro-

CMR are both unavailable for the assessment of LVEF, multigated ac- pyrimidines, VEGFi, breakpoint cluster region–Abelson oncogene lo-
quisition nuclear imaging (MUGA) can be considered as a third-line cus [BCR-ABL], tyrosine kinase inhibitors [TKI]). Alternatively, in
modality. MUGA scans should be avoided whenever possible due patients with low to intermediate pre-test probability of CAD,
to radiation exposure and the inability to obtain other important in- CCTA is a robust alternate modality with high sensitivity to rule
formation (e.g. VHD, PAP, or GLS). out obstructive CAD.100,101
Baseline LVEF and GLS are recommended in all patients evaluated
with TTE before cardiotoxic cancer treatment initiation to stratify
CTR-CVT risk and to identify significant changes during treat- Recommendation Table 4 — Recommendations for
ment.8,64 Changes in loading conditions occur frequently during cardiac imaging modalities in patients with cancer
chemotherapy (e.g. volume increase due to intravenous [i.v.] fluids,
General Classa Levelb
volume loss due to vomiting or diarrhoea, blood pressure [BP] and
heart rate changes with pain or stress) and may affect cardiac vo- Echocardiography is recommended as the
lumes, LVEF, and GLS quantification. Systemic arterial BP measure- first-line modality for the assessment of cardiac I C
4,12,54,94
ment is recommended with all resting TTE as it can influence function in patients with cancer.
cardiac function measurements and should be recorded on the 3D echocardiography is recommended as the
TTE report. A baseline borderline (50–54%) or reduced (,50%) preferred echocardiographic modality to measure I B
LVEF is a risk factor for future CTR-CVT from most cardiotoxic can- LVEF.77–79,89
cer therapies, in particular with anthracyclines or trastuzumab.12,24,74 GLS is recommended in all patients with cancer
Increased baseline indexed LV end-diastolic volume can be a predict- having echocardiography, if I C
or of major CV events (symptomatic HF or cardiac death) during an- available.75,80,81,89,90,92,93,102,103
thracycline chemotherapy in patients with preserved LVEF.85 CMR should be considered for the assessment of
A normal LVEF does not exclude CTRCD and deformation para- cardiac function when echocardiography is IIa C
meters can detect early systolic impairment with sufficient test reli- unavailable or non-diagnostic. 83,104,105
ability.86–89 Determination of GLS using speckle tracking is MUGA may be considered when TTE is not
IIb C
recommended at baseline, using three apical views,90 particularly diagnostic and CMR is not available.106–108
in moderate- and high-risk patients. Baseline GLS can predict
Baseline cardiac imaging prior to potentially cardiotoxic
LVD89–94 in patients receiving anthracyclines and/or trastuzumab.
therapiesc
Strain measurements may be subject to inter-vendor variability95
Baseline comprehensive TTE is recommended in
and serial GLS measurement for each patient is recommended to
© ESC 2022
all patients with cancer at high risk and very high
be performed using the same machine/software. A median GLS I C
risk of CV toxicity before starting anticancer
change of 13.6% predicted a future fall in LVEF with a 95% upper limit
therapy.d,54
of GLS reduction of 15%.93 Using the 15% cut-off improves specifi-
city and is therefore the threshold recommended when monitoring 3D, three-dimensional; CMR, cardiac magnetic resonance; CTR-CVT, cancer
GLS during cancer therapy. Global circumferential strain96 has been therapy-related CV toxicity; CV, cardiovascular; GLS, global longitudinal strain; LVEF,
left ventricular ejection fraction; MUGA, multigated acquisition nuclear imaging; TTE,
reported to identify patients at risk of CTRCD, but data are currently transthoracic echocardiography.
insufficient to recommend its use routinely. Baseline LV diastolic a
b
function may be associated with a small risk of subsequent systolic Level of evidence.
c
Specific recommendations for baseline CV imaging in patients with cancer at low or
dysfunction, especially with anthracyclines and trastuzumab, al- moderate risk of CTR-CVT are included in Section 5.
though the evidence is not consistent.97,98 Chest computed tomog- d
Except asymptomatic patients referred to breakpoint cluster region-Abelson oncogene
raphy (CT) or CMR may be helpful for identifying subclinical CVD locus therapy (BCR-ABL) where baseline TTE should be considered (see Figure 7
and Section 5.5.5).
such as coronary calcium or intracardiac masses on readily available
routine imaging performed for cancer staging.99
In the secondary prevention setting or patients with symptoms or 4.6. Cardiopulmonary fitness assessment
signs of pre-existing CVD, a careful evaluation should begin with a Maximal cardiopulmonary exercise testing (CPET) assesses the inte-
comprehensive TTE.73 This is both to obtain baseline assessment grative capacity of the CV system to transport oxygen and energy
as in the primary prevention setting and to determine the severity substrate to skeletal muscle during exercise,109 described as cardio-
of the underlying CVD. In case of poor-quality or uninterpretable respiratory fitness (CRF). CPET can therefore provide a more global
TTE images, or if a specific CVD is identified (e.g. hypertrophic assessment of CV health than organ-specific tools. CPET-derived
26 ESC Guidelines
CRF—typically measured as the peak rate of oxygen consump- dysfunction.37,126–128 It should be noted that with the advent of
tion110,111 or metabolic equivalents111,112 during exercise—is one immunotherapies, germline genes may not be the only genetic pre-
of the most robust predictors of CV health and longevity,113,114 dispositions to CTR-CVT. A study of patients with ICI-associated
and improves risk classification.115–121 Evidence for CPET pre- myocarditis identified that the selective clonal T-cell populations
treatment is limited to pre-operative risk stratification particularly infiltrating the myocardium were identical to those present in tu-
for patients with lung,122 colon,123 and rectal124 cancers. Whether mours and skeletal muscle, with ribonucleic acid sequencing stud-
CPET performed prior to cardiotoxic cancer therapies is prognostic ies revealing expression of cardiac-specific genes in the tumour,129
of future CV events is unknown. raising the intriguing possibility that somatic mutations in the tu-

mour itself could contribute to CTR-CVT. A list of genetic variants
4.7. Cardiovascular risk evaluation associated with CVD during cancer therapy is provided
before cancer surgery (Supplementary data, Table S9) and has recently been reviewed.38
Cancer surgery remains the primary treatment modality for many Routine use of genetic testing for the assessment of CTR-CVT risk
cancers. Cardio-oncology teams should be involved in pre-operative prior to initiation of cancer therapy is not currently recommended.
CV risk stratification to identify and provide appropriate manage- In the future, a personalized genetic approach may help define indi-
ment and surveillance of the potential risk factors.5 vidual susceptibility to CVD in patients with cancer and more re-
In patients undergoing oncological surgery, peri-operative car- search is required.
diac complications are determined by patient-related risk factors,
the tumour type, concomitant cancer therapies, and the expected
surgical risk. To ensure safe cancer surgery, consultations should 5. Prevention and monitoring of
be directed at: (1) patients with previous significant or symptom-
atic CVD; (2) patients at high and very high CV toxicity risk, ac- cardiovascular complications
cording to baseline HFA-ICOS risk assessment tools,12 when during cancer therapy
adjuvant (post-surgery) cancer treatment is planned; and (3) pa-
tients who have received neoadjuvant (prior to surgery) cancer 5.1. General principles
therapy that is potentially cardiotoxic. Pre-operative clinical evalu- CTR-CVT risk may vary according to cancer type and stage, antic-
ation should not delay surgery. Complementary tests required for ancer drugs, doses, and underlying comorbidities. Certain therapy
the patients included in groups 1 and 2 should be guided by general combinations (drug–drug or drug–radiation) may have a synergis-
ESC Guidelines.125 However, in group 3 patients, the pre- tically toxic effect on the heart, possibly depending on the timing
operative evaluation should be aimed at confirming that no rele- of these therapies (sequential or concomitant) and previous co-
vant events have occurred during CV monitoring (Section 5). morbidities. The pathophysiology of CTR-CVT is out of the scope
Table 6 summarizes factors that could influence peri-operative of this guideline and is extensively reviewed in the ESC
risk during cancer surgery. CardioMed textbook.130
CVD and cancer share common modifiable and non-modifiable
4.8. Genetic testing risk factors (Figure 3).4,131,132 The first step is to optimize lifestyle
Candidate gene and genome-wide association studies have re- CVRF, smoking cessation, restricting alcohol consumption to a max-
sulted in the identification of 40 candidate genes and single nucleo- imum of 100 g per week, and maintaining adequate physical activ-
tide polymorphisms associated with anthracycline-related cardiac ity.30 Exercise prescription seems to be a promising treatment to
Table 6 Factors that could influence peri-operative risk during cancer surgery and preventive strategies
Factors that could influence peri-operative risk during cancer surgery Preventive strategies
Patient-related • Lifestyle risk factors: smoking, obesity, sedentary lifestyle • Optimal management of CVRF and
factors • Poorly controlled CVRF: hypertension, DM CVD (Section 5)
• Pre-existing CVD including CTR-CVT • Optimize VTE and ATE preventive
• Cardiac medications that increase peri-operative bleeding risk (e.g. antiplatelets and strategies (Section 6)
anticoagulants)
• Historical primary malignancy
• Current cancer type, stage and location
Neoadjuvant cancer • Neoadjuvant cardiotoxic cancer treatments (see Section 5; especially anthracycline • Ensure optimal CV monitoring of
therapy chemotherapy and/or trastuzumab, ICI, VEGFi, fluoropyrimidine, and thoracic RT) neoadjuvant therapy (Section 5)
© ESC 2022
• Cancer treatments that increase peri-operative bleeding risk (e.g. VEGFi, BTK • Optimize VTE and ATE preventive
inhibitors) strategies (Section 6)
• Thrombocytopaenia caused by cancer treatment
ATE, arterial thromboembolism; BTK, Bruton tyrosine kinase; CTR-CVT, cancer therapy-related cardiovascular toxicity; CV, cardiovascular; CVD, cardiovascular disease; CVRF,
cardiovascular risk factors; DM, diabetes mellitus; ICI, immune checkpoint inhibitors; RT, radiotherapy; VEGFi, vascular endothelial growth factor inhibitors; VTE, venous
thromboembolism.
ESC Guidelines 27
counteract anticancer treatment side effects and different types of Poor CRF is associated with a higher prevalence of acute and
training can be prescribed during cancer therapy according to a pa- chronic CTR-CVT and exercise positively impacts CRF during
tient’s individual characteristics.133 A healthy lifestyle decreases the chemotherapy, although in a recent meta-analysis, the ability of exer-
risks of cancer, CVD, and transition from diagnosed cancer to subse- cise to prevent CTRCD is unclear.136,137 CVRF must be corrected
quent CVD.134,135 with intensive treatment of arterial hypertension,138 DM,139 and

Primary and secondary cancer-therapy related CV toxicity prevention strategies
Management of CVD and CVRF

Primary vs secondary prevention
according to ESC Guidelines
Baseline CV risk
assessment
In patients at high and very high
1°prevention risk of CTRCD
Minimize the use of cardiotoxic drugs
2°prevention
ACE-I/ARB and beta-blockers
Dexrazoxane/liposomal anthracyclines
(patients treated with anthracyclines)
Statins
1st cancer requiring cardiotoxic cancer therapy

2nd cancer requiring cardiotoxic cancer therapy
CVD
CTR-CVT Class I Class IIa
Figure 9 Primary and secondary cancer therapy-related cardiovascular toxicity prevention. ACE-I, angiotensin-converting enzyme inhibitors; ARB, angio-
tensin receptor blockers; CV, cardiovascular; CVD, cardiovascular disease; CVRF, cardiovascular risk factors; CTR-CVT, cancer therapy-related cardiovascular
toxicity; CTRCD, cancer therapy-related cardiac dysfunction; ESC, European Society of Cardiology.12 Left panel represents examples of five different primary
or secondary prevention strategies definition based on the history of pre-existing CVD and/or prior CTR-CVT. Right panel describes general strategies to
mitigate CTR-CVT risk in patients at high and very high risk of CTRCD.
28 ESC Guidelines
dyslipidaemia,140 and underlying CVD and modifiable comorbidities Pegylated and non-pegylated liposomal doxorubicin164,165,168
should be managed according to appropriate 2021 ESC Guidelines modify pharmacokinetics and tissue distribution without com-
on CVD prevention in clinical practice (Figure 9).19 promising antitumour efficacy. Pegylated and non-pegylated liposo-
Special attention should also be paid to the polypharmacy fre- mal doxorubicin are approved for metastatic BC and pegylated
quently seen in patients with cancer, reducing the use of drugs liposomal doxorubicin is also approved for advanced ovarian can-
that may interfere with cancer therapies to the essential and ac- cer, acquired immune deficiency syndrome-related Kaposi sar-
tively monitoring their CV side effects and drug–drug interac- coma, and MM. In a recent meta-analysis of 19 trials, in both the
tions.141 Electrolyte imbalances such as hypokalaemia and adjuvant and metastatic context, liposomal doxorubicin was re-

hypomagnesaemia should be corrected. The CV risk management ported to be less cardiotoxic than conventional doxorubicin.165
plan should be shared with the cancer specialist team, the pri- Liposomal daunorubicin is also available for acute leukaemia pa-
mary care physician, and the patient to coordinate treatment tients in place of daunorubicin when pre-existing LVD is
strategies. present.164,165
5.2. Primary prevention strategies 5.2.2. Primary prevention of radiation-induced

Primary prevention of CTR-CVT aims to avoid or minimize the de- cardiovascular toxicity
velopment of CV damage due to therapy in patients without Primary prevention of RT-induced damage to the CV system de-
CVD12,142 and requires a multidisciplinary team (MDT) discussion pends on technological advances that allow improved targeting of
between oncologists and cardiologists for complex patients with RT delivery, thereby maintaining or increasing oncological efficacy
cancer with multiple comorbidities.4,21,22,43,143,144 while reducing CTR-CVT.169,170 Modern techniques strive to
minimize the mean heart dose (MHD), either by shaping the
5.2.1. Primary prevention of cancer dose distribution (intensity-modulated RT) or by using respira-
therapy-related cardiovascular toxicity during tory management (gating or breath-hold).171,172 Proton therapy
anthracycline chemotherapy offers the potential to further decrease exposure to surrounding
Neurohormonal therapies during anthracycline chemotherapy (with healthy organs.173 However, complete cardiac avoidance is not
or without subsequent trastuzumab treatment) reduced the risk of always possible due to the proximity of the tumour (e.g. central
significant LVEF decline during follow-up in several small randomized lung tumours, mediastinal lymphomas, irradiation of the internal
controlled trials (RCTs) (Supplementary data, Table S10).145–154 mammary chain in BC). In patients where RT only has a consoli-
Recent meta-analyses including patients with cancer treated with an- dating role and the risk of RT-induced CV injury is very high (e.g.
thracycline chemotherapy and HER2-targeted therapies reported due to baseline risk factors), a MDT is needed to consider the
that renin–angiotensin–aldosterone system blockers, beta-blockers, risk/benefit of RT.171,174
and mineralocorticoid receptor antagonists have a significant benefit There are no proven medical therapies to prevent RT-induced CV
in preventing LVEF reduction, but no statistical differences in the in- toxicity. One component of RT-induced CV toxicity is accelerating
cidence of overt HF or other clinical outcomes were demonstrated pre-existing CAD, and therefore tight control of CVRFs is
(Supplementary data, Table S11).155–160 This may be due, in part, to recommended.
the fact that most trials included patients with a low baseline CTRCD
risk and therefore larger RCTs are needed in high-risk populations.
From the oncological perspective, some strategies that have been Recommendation Table 5 — Recommendations for
primary prevention of cancer therapy-related car-
investigated include managing anthracycline-related toxicity by ad-
diovascular toxicity
justing the infusion time and dose intensity.161 Dexrazoxane and lipo-
somal anthracyclines are currently approved in patients with high and Recommendations Classa Levelb
very high CTRCD risk or who have already received high cumulative
Management of CVRF according to the 2021 ESC
anthracyclines doses.158,162–167 Dexrazoxane is protective against
Guidelines on CVD prevention in clinical practice
anthracycline-induced CTRCD. Currently, dexrazoxane is formally I C
is recommended before,c during, and after cancer
approved in adult patients with advanced or metastatic BC who
therapy.19
have already received a minimum cumulative anthracycline dose of
300 mg/m2 of doxorubicin or equivalent (Table 5; Supplementary Dexrazoxane should be considered in adult
data, Table S12).163 In clinical practice, dexrazoxane infusion (dosage patients with cancer at high and very high CV
IIa B
ratio dexrazoxane/doxorubicin is 10/1; e.g. 500 mg/m2 dexrazoxane toxicity risk when anthracycline chemotherapy is
d,158
per 50 mg/m2 doxorubicin) should be considered (at least 30 min indicated.
prior to each anthracycline cycle) in adult patients with cancer sched- Liposomal anthracyclines should be considered in
uled to receive a high total cumulative anthracycline dose for curative adult patients with cancer at high and very high CV
IIa B
treatment, and in patients with high and very high CTRCD risk (in- toxicity risk when anthracycline chemotherapy is
cluding those with pre-existing HF or low-normal or reduced indicated.e,164,165,168
LVEF) where anthracycline chemotherapy is deemed essential.163 Continued
ESC Guidelines 29
ACE-I or ARB and beta-blockers recommended 5.4. Cardiovascular surveillance during

for HFf should be considered for primary cancer therapies
prevention in high- and very high-risk patients IIa B
A careful clinical evaluation and physical examination is recom-
receiving anthracyclines and/or anti-HER2 mended during cancer treatment to detect early signs and symptoms
therapies.145,150,155–157,159,160,175 of CTR-CVT. ECG monitoring is required in patients at risk of car-
ACE-I or ARB and beta-blockers recommended diac arrhythmias according to specific drug protocols.
for HFf should be considered for primary
prevention in high- and very high-risk patients IIa C
5.4.1. Cardiac serum biomarkers

receiving targeted cancer therapies that may cause
During therapy, NP and cTn should be used for CTRCD screening
HF.g
and diagnosis and they may also serve to guide therapy.55,63,191–194
© ESC 2022
Statins should be considered for primary The release of cTn and NP differ for different cancer treatments.
prevention in adult patients with cancer at high IIa B Therefore, an increase in biomarker level should be interpreted in
and very high CV toxicity risk.h,149,176–185 the patient clinical context (cancer treatment timing and
ACE-I, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; comorbidities).
CV, cardiovascular; CVD, CV disease; CVRF, CV risk factors; ESC, European Society It is important to consider that generally accepted cut-offs and ref-
of Cardiology; HER2, human epidermal receptor 2; HF, heart failure; HFA, Heart
erence values of CV biomarkers have not been established for pa-
Failure Association; ICOS, International Cardio-Oncology Society; MEK,
mitogen-activated extracellular signal-regulated kinase; PI, proteasome inhibitors; tients with cancer or for those who receive cancer therapies. In
RAF, rapidly accelerated fibrosarcoma; VEGFi, vascular endothelial growth factor addition, levels of NP and cTn may differ according to local labora-
inhibitors.
a tories and may be altered by many factors, including age, sex, renal
b
Level of evidence. function, obesity, infections, and comorbidities such as AF and
c
Without delaying cancer treatments. pulmonary embolism (PE).53,63,195–197
d
As per the European Medicine Agency: ≥350 mg/m2 doxorubicin or equivalent; as per the
United States Food and Drug Administration: ≥300 mg/m2 doxorubicin or equivalent.
e
See Section 5.2.1 for specific liposomal doxorubicin type and malignancies. 5.4.2. Cardiac imaging
f
Carvedilol (preferred beta-blocker for CV protection if there is no contraindication),186
Cardiac imaging plays a critical role in clinical decision-making during
bisoprolol, controlled/extended-release metoprolol succinate and nebivolol.
g
VEGFi and bevacizumab, RAF inhibitor, MEK inhibitor, PI, dasatinib, ponatinib, and the cancer process.72,198 Imaging techniques—particularly advanced
osimertinib. echocardiography and CMR—facilitate early diagnosis and manage-
h
According to HFA-ICOS risk assessment tools (Section 4.1; Table 4).
ment of CTR-CVT.22,54,94 The frequency of cardiac imaging monitor-
ing during therapy should be adapted according to the estimated
baseline risk12 and the expected CTR-CVT manifestation.54 The car-
5.3. Secondary prevention strategies diac imaging technique used should be based on local expertise and
Secondary prevention refers to interventions in patients with pre- availability, and the same imaging modality (i.e. 3D-TTE, 2D-TTE,
existing CVD, including prior CTR-CVT, and new emerging CMR) is recommended throughout the entire treatment to decrease
CTR-CVT during cancer therapy. CVD and comorbidities should re- inter-technique variability.94,199,200 Cardiac imaging should be per-
ceive the optimal therapy before and during cancer therapy as dis- formed at any time if patients receiving cardiotoxic therapies present
cussed in previous sections. Regular clinical assessments, physical with new cardiac symptoms.
examinations, and CV investigations (including 12-lead ECG, TTE, New definitions of CTRCD are presented in Section 3.1 Early
and cardiac biomarkers) are recommended in patients receiving spe- recognition of asymptomatic CTRCD allows clinicians to incorp-
cific cardiotoxic cancer therapies, with the frequency of surveillance orate cardioprotective therapy before there is a significant decline
guided by baseline risk and the emergence of new in LVEF, which may or may not be reversible, and also decreases
CTR-CVT.5,12,33,53,54,187–190 the risk of interruptions in cancer therapy, which could otherwise
affect patients’ survival.22,43,72,94 For the diagnosis and manage-
ment of asymptomatic CTRCD during cancer treatment, TTE—in-
Recommendation Table 6 — Recommendation for
secondary prevention of cancer therapy-related car- cluding 3D-LVEF and GLS assessment—is the preferred technique
diovascular toxicity to detect and confirm cardiac dysfunction.72,83,93,102 GLS evalu-
ation is particularly important in patients with low-normal LVEF
Recommendation Classa Levelb to confirm or not asymptomatic myocardial damage.201 It is re-
commended to use the same vendor to analyse GLS during cancer
© ESC 2022
Management of CVD according to applicable ESC

Guidelines is recommended before,c during, and I C
treatment to accurately compare values over time.73 Therefore, a
after cancer therapy.
relative change in GLS has been suggested as the ideal tool to iden-
tify asymptomatic mild CTRCD.1,4,94 Different thresholds have
CVD, cardiovascular disease; ESC, European Society of Cardiology.
a
been considered in the literature in recent years.93,202,203
b
Level of evidence. Currently, a relative GLS decrease of .15% compared with base-
c
Without delaying cancer treatments. line is the recommended threshold as it reflects the 95% upper
30 ESC Guidelines
Anthracycline chemotherapy surveillance protocol
3M 12 M
Baseline C1 C2 C3 C4 C5 C6 post tx post tx

ECG
Low
risk TTEa
cTnb / NPb
ECG
ECG
Moderate TTEa a
TTE
risk
cTnb / NPb
ECG
ECG
High and
very high TTE
TTE
TTE
a
a a
risk
cTn / NP
Figure 10 Cardiovascular toxicity monitoring in patients receiving anthracycline chemotherapy. cTn, cardiac troponin; C, chemotherapy cycle;
ECG, electrocardiogram; M, months; NP, natriuretic peptides; TTE, transthoracic echocardiography; tx, treatment. Biomarker and TTE assessment
should ideally be performed before the corresponding anthracycline cycle (C1–C6). aCardiac magnetic resonance should be considered for the assess-
ment of cardiac function when TTE is unavailable or not diagnostic. In moderate-risk patients, TTE should be considered after a cumulative dose of
≥250 mg/m2 of doxorubicin or equivalent. In low-risk patients, TTE may be considered after a cumulative dose of ≥250 mg/m2 of doxorubicin or equiva-
lent. bMeasurement of NP and/or cTn is recommended in all patients with cancer if these biomarkers are going to be used during treatment monitoring.
cTn and NP monitoring every two cycles during anthracycline chemotherapy and within 3 months after therapy completion may be considered in low-risk
patients (Class IIb, Level C). cTn and NP monitoring every two cycles during anthracycline chemotherapy and within 3 months after therapy completion
should be considered in moderate-risk patients and in low-risk patients receiving a cumulative dose of ≥250 mg/m2 of doxorubicin or equivalent (Class IIa,
Level C).
limit in the meta-analysis of GLS to predict future significant LVEF In patients with poor TTE image quality or when TTE is not diag-
reduction.93 Using the 15% threshold will maximize specificity and nostic, CMR should be considered, including fast strain-encoded
minimize overdiagnosis of CTRCD and guide cardioprotective CMR when available.105,204–206 MUGA can be considered as a third-
therapy.1,4,93 line modality.
ESC Guidelines 31
5.5. Cancer therapy-related Baseline measurement of NP and cTn should be

IIa C
cardiovascular toxicity monitoring considered in low- and moderate-risk patients
211
prior to anthracycline chemotherapy.
protocols
cTn and NP monitoring before every cycle during
5.5.1. Anthracycline chemotherapy
anthracycline chemotherapy and 3 and 12 months
Anthracycline-induced CTRCD is a dose-dependent and cumulative I B
after therapy completion is recommended in high-
process of variable onset that may present with symptomatic or
and very high-risk patients.55,175,211
asymptomatic CTRCD.4
cTn and NP monitoring every two cycles during

Figure 10 summarizes the recommended monitoring protocol
anthracycline chemotherapy and within 3 months
during anthracycline therapy according to baseline CTRCD risk
after therapy completion should be considered in
(Table 4). Clinical assessment combined with cardiac biomarkers IIa C
moderate-risk patients and in low-risk patients
(cTn and NP) and TTE (including 3D-LVEF and GLS when avail-
receiving a cumulative dose of ≥250 mg/m2 of
able) can identify both symptomatic and asymptomatic CTRCD
doxorubicin or equivalent.55,59,212,213
with a reasonably high negative predictive value. This topic has
cTn and NP monitoring every two cycles during
been extensively reviewed in two recent HFA position
© ESC 2022
anthracycline chemotherapy and within 3 months
statements.53,54 Classifying patients based on their risk of IIb C
after therapy completion may be considered in
anthracycline-induced CV toxicity has allowed the early implemen-
low-risk patients.55,59,212,213
tation of personalized preventive strategies (Section 5.2.1).14
Patients with pre-existing CVD should be treated with guideline- cTn, cardiac troponin; NP, natriuretic peptides; TTE, transthoracic echocardiography.
based medical therapy.14,19,207
a
b
Level of evidence.
c
If echocardiography is unavailable or non-diagnostic, follow general cardiac imaging
modalities recommendations (see Section 4.5).
Recommendation Table 7 — Recommendations for
baseline risk assessment and monitoring during an-
thracycline chemotherapy and in the first 12 months
after therapy
5.5.2. HER2-targeted therapies
Recommendations Class a
Level b HER2-targeted therapies are a crucial part of the treatment of
patients with HER2-positive invasive BC in both early and meta-
TTE static settings. In the neoadjuvant and/or adjuvant settings, drugs
Baseline echocardiographyc is recommended in all currently approved are trastuzumab, pertuzumab, trastuzumab
patients with cancer before anthracycline I B emtansine, and neratinib. In the metastatic setting, trastuzumab,
chemotherapy.12,24,208–210 pertuzumab, trastuzumab emtansine, tucatinib, and trastuzumab
In all adults receiving anthracycline chemotherapy, deruxtecan are currently approved.214–216 Trastuzumab can
an echocardiogram is recommended within 12 I B also be used in patients with HER2-overexpressing metastatic
months after completing treatment. 208 gastric adenocarcinomas in combination with platinum-based
In high- and very high-risk patients, chemotherapy and either capecitabine or 5-fluorouracil (5-FU).
echocardiography is recommended every two It is recognized that anti-HER2 therapies may lead to LVD in
I C up to 15–20% of patients and to overt HF if surveillance is
cycles and within 3 months after completing
treatment.24,208–210 missed, or in high- and very high-risk patients.217–220 LV function
surveillance based on LVEF and GLS is recommended prior to
In moderate-risk patients, additional
and every 3 months during HER2-targeted therapies treatment
echocardiography should be considered after a
IIa C surveillance (Figure 11).22 However, this single algorithm has
cumulative dose of ≥250 mg/m2 of doxorubicin
not been tested in low- or high-risk patients and increased fre-
or equivalent.7
quency of assessment (according to local availability) is recom-
In low-risk patients, additional echocardiography
mended in high-risk patients.
may be considered after a cumulative
IIb C The use of cardiac serum biomarkers to identify CTRCD is
dose of ≥250 mg/m2 of doxorubicin or
less well-defined during anti-HER2 treatments.217 Measurement
equivalent.7
of cTn in BC patients after anthracycline-based chemotherapy
Cardiac serum biomarkers but prior to trastuzumab should be considered, as an elevated
Baseline measurement of NP and cTn is cTn identifies patients at higher risk of trastuzumab-induced
recommended in high- and very high-risk patients I B CTRCD. Serial NP measurement was more sensitive than cTn
55,65,211
prior to anthracycline chemotherapy. at predicting subsequent declines in LVEF during trastuzumab
Continued treatment.74
32 ESC Guidelines
HER2-targeted therapy surveillance protocol
3M 12 M
Baseline 3M 6M 9M 12 M
post tx post tx

ECG
Low and
moderate TTEc
riska
e
cTnd / NPd
ECG
High and
very high TTEc
riskb
cTn / NP
Figure 11 Cardiovascular toxicity monitoring in patients receiving human epidermal receptor 2-targeted therapies. cTn, cardiac troponin; CV,
cardiovascular; EBC, early breast cancer; ECG, electrocardiogram; HER2, human epidermal receptor 2; M, months; NP, natriuretic peptides; TTE, trans-
thoracic echocardiography; tx, treatment. This protocol refers to CV toxicity monitoring in patients receiving neoadjuvant or adjuvant anti-HER2 tar-
geted therapies for non-metastatic disease or first year in metastatic disease. Biomarker assessment should ideally be performed before the
corresponding trastuzumab cycle. TTE should be performed in week 2 or 3 of a 3-weekly trastuzumab cycle. aIn low-risk HER2+ EBC patients who
are asymptomatic and with a normal assessment after 3 months, reducing TTE monitoring to every 4 months may be considered (Class IIb, Level C).
In low- and moderate-risk metastatic HER2+ disease, TTE surveillance can be reduced to every 6 months after the first year in asymptomatic patients
with normal TTE assessment (Class I, Level C). bIn high- and very high-risk metastatic HER2+ disease, TTE monitoring every 2–3 cycles may be considered
depending on the absolute risk and local availability. cCardiac magnetic resonance should be considered for the assessment of cardiac function when TTE
is unavailable or not diagnostic. dMeasurement of NP and/or cTn is recommended in all patients with cancer if these biomarkers are going to be used
during treatment monitoring. eBaseline cTn measurement should be considered in low- and moderate-risk patients after anthracycline chemotherapy
but prior to starting anti-HER2 targeted therapies for CV toxicity risk prediction.
For patients requiring adjuvant chemotherapy and Recommendation Table 8 — Recommendations for
anti-HER2-targeted therapy, the use of non-anthracycline chemo- baseline risk assessment and monitoring during hu-
therapy should be considered by the MDT according to man epidermal receptor 2-targeted therapies and in
the first 12 months after therapy
risk of relapse, cardiac risks, and in discussion with the
treating oncologist.217 When anthracycline chemotherapy in the Recommendations Classa Levelb
(neo)-adjuvant setting is necessary, sequential use (anthracyclines
followed by taxanes and anti-HER2 agents) has been shown TTE
to significantly decrease the incidence of CTRCD in several Baseline echocardiographyc is recommended
I B
adjuvant trials, compared with concomitant use in earlier before HER2-targeted therapies in all patients.225
trials.220–224 Continued
ESC Guidelines 33
In patients receiving neoadjuvant or adjuvant is up to 10%.232 Among the several mechanisms responsible for
HER2-targeted therapies, echocardiography is 5-FU-induced myocardial ischaemia are coronary vasospasm and
I B
recommended every 3 months and within 12 endothelial injury.233 Chest pain and ischaemic ECG changes usually
months after completing treatment.225,226 occur at rest (less typically during exercise) within days of drug ad-
In low-risk HER2+ EBC patientsd who are ministration and sometimes persist even after treatment cessation.
asymptomatic and with a normal assessment after CTR-CVT risk markedly increases in patients with cancer with pre-
IIb C
3 months, reducing monitoring to every 4 months existing CAD. Aggressive control of modifiable CVRFs, according to
may be considered. the 2021 ESC Guidelines on CVD prevention in clinical practice,19 is

In high- and very high-risk HER2+ EBC patients,d recommended during and after treatment. A baseline TTE is
more frequent echocardiography monitoringe IIa C recommended in patients with a history of symptomatic CV to
should be considered during treatment. confirm the presence of pre-existing regional wall motion
abnormalities or LVD. Screening for CAD may be considered in
In metastatic HER2+ disease, echocardiography is
selected high- and very high-risk patients before the administration
recommended every 3 months during the first
I C of these drugs and according to local protocols and current
year; if the patient remains asymptomatic without
recommendations.12,234,235
CV toxicity, then surveillance can be reduced to
every 6 months during future treatment.f
In metastatic HER2+ disease patients at high- and
very high-risk, more frequent echocardiography IIb C
baseline risk assessment and monitoring during fluor-
monitoringe may be considered. opyrimidine therapy
Cardiac biomarkers
Baseline NP and cTn measurement are
recommended in high- and very high-risk patients I C Baseline CV risk assessment and evaluation
prior to anti-HER2-targeted therapies.227,228 including BP measurement, ECG, lipid profile,
NP and cTn monitoring every 2–3 cycles during HbA1c measurement, and SCORE2/ I C
c 19
therapy and 3 and 12 months after the end of SCORE2-OP or equivalent is recommended
IIa C
therapy should be considered in high- and very before starting fluoropyrimidines.
high-risk HER2+ EBC patients.d,55 A baseline echocardiogram is recommended in
Baseline cTn measurement should be considered patients with a history of symptomatic CVD I C
in low- and moderate-risk patients before starting fluoropyrimidines.
IIa A
© ESC 2022
post-anthracycline chemotherapy but prior to Screening for CADd may be considered in patients
starting anti-HER2-targeted therapies.55,62 at high and very high risk of CADc before IIb C
NP and cTn monitoring at baseline, every 3 fluoropyrimidines.
© ESC 2022
months, and 12 months after therapy may be BP, blood pressure; CAD, coronary artery disease; CV, cardiovascular; CVD,
IIb C
considered in low- and moderate-risk HER2+ cardiovascular disease; ECG, electrocardiogram; HbA1c, glycated haemoglobin;
SCORE2, Systematic Coronary Risk Estimation 2; SCORE2-OP, Systematic Coronary
EBC patients.d,55
Risk Estimation 2—Older Persons.
a
BC, breast cancer; cTn, cardiac troponin; CV, cardiovascular; EBC, early breast cancer; Class of recommendation.
b
HER2, human epidermal receptor 2; NP, natriuretic peptides; TTE, transthoracic Level of evidence.
c
echocardiography. SCORE2 (,70 years) or SCORE2-OP (≥70 years) CV risk stratification: ,50 years:
a
Class of recommendation. low risk ,2.5%, moderate risk 2.5% to ,7.5%, high risk ≥7.5%; 50–69 years: low risk
b
Level of evidence. ,5%; moderate risk 5% to ,10%; high risk ≥10%; ≥70 years: low risk ,7.5%,
c
If echocardiography is unavailable or non-diagnostic, follow general cardiac imaging moderate risk 7.5% to ,15%, high risk ≥15%.
d
modalities recommendations (see Section 4.5). According to pre-existing CVD and local protocols.234
d
These recommendations are also applicable for HER2+ non-BC patients.
e
Every 2–3 cycles depending on the absolute risk and local availability.
f
Patients at low and moderate risk.
5.5.4. Vascular endothelial growth factor inhibitors
Aberrant activation of kinases plays a critical role in both the devel-
5.5.3. Fluoropyrimidines opment of numerous cancer types and in CV and metabolic homeo-
Fluoropyrimidines such as 5-FU and its oral prodrug capecitabine stasis. Inhibition of the VEGF signalling pathway is achieved with
are mainly used for gastrointestinal (GI) malignancies and advanced either monoclonal antibodies (administered i.v.) against circulating
BC. The most common CTR-CVTs are angina pectoris, VEGF or with small-molecule TKI (taken orally) targeting VEGF re-
ischaemia-related ECG abnormalities, hypertension, Takotsubo syn- ceptors.236 VEGFi are used for the treatment of numerous cancer
drome (TTS), and MI (even in patients with normal coronary arter- types, including renal, thyroid, and hepatocellular carcinomas.
ies),1,4,10,43,229,230 with rarer CTR-CVT including myocarditis, However, their use is associated with a wide array of CV complica-
arrhythmias, and peripheral arterial toxicity (Raynaud’s phenomenon tions including hypertension, HF, QTc prolongation, and acute vascu-
and ischaemic stroke).231 The incidence of myocardial ischaemia var- lar events (Figure 12).131,237–240 It can be challenging to assess the
ies according to the dose, scheduling, and route of administration and prognosis of patients experiencing severe CV side effects because
34 ESC Guidelines
VEGFi-related cardiovascular toxicities
HTN HF QTc VTE ATE MI
Monoclonal antibodies
Aflibercept

Bevacizumaba
Ramucirumaba
VEGF TKI
Axitinib
Cabozantinib
Lenvatinib
Pazopanib
Regorafenib
Sorafenib
Sunitinib
Vandetanib
Very common: ≥10% incidence Uncommon: 0.1% to < 1% incidence
Common: 1% to <10% incidence Rare: <0.1% incidence
Figure 12 Vascular endothelial growth factor inhibitors-related cardiovascular toxicities. ATE, arterial thromboembolism; EMA, European Medicines
Agency; FDA, Food and Drug Administration; HF, heart failure; HTN, hypertension; MedDRA, medical dictionary for regulatory activities; MI, myocardial
infarction; ↑QTc, corrected QT interval prolongation; TKI, tyrosine kinase inhibitors; VEGF, vascular endothelial growth factor; VEGFi, vascular endothe-
lial growth factor inhibitors; VTE, venous thromboembolism. Adverse reactions reported in multiple clinical trials or during post-marketing use are listed
by system organ class (in MedDRA) and frequency. If the frequency is unknown or cannot be estimated from the available data, a blank space has been left.
a
Bevacizumab: hypertension frequency 5–42% (EMA); 60–77% of the patients who received bevacizumab in combination with erlotinib. Pre-existing
hypertension should be adequately controlled before starting treatment. Ramucirumab: hypertension frequency 16–26% (EMA/FDA); in combination
with erlotinib, the incidence of hypertension was 24–45%. Patients with uncontrolled hypertension were excluded from the trials. Figure developed
from EMA prescribing information,252 FDA prescribing information.253
these drugs are often used in patients with advanced cancer. The goal LVD and HF occur in a minority of patients in RCTs,245 but are re-
must be to continue VEGFi treatment for as long as possible with ini- ported more frequently in routine practice246 and are often revers-
tiation or optimization of CV treatment if indicated. ible.247 Acute arterial events (aortic dissection, stroke, arterial
Hypertension is a class effect and is the most reported adverse thrombosis, acute coronary events, vasospasm) and venous
event under VEGFi treatment. It occurs within hours or days, is dose- thromboembolism (VTE) can also complicate treatment with
dependent, and is usually reversed by VEGFi discontinu- VEGFi.248 QTc prolongation has been described with sunitinib, sor-
ation.131,239,241–243 The risk is higher in patients with pre-existing afenib, and vandetanib,249 but it is rarely related to severe arrhythmic
hypertension or CVD, previous anthracycline treatment, advanced events, except with vandetanib.250 Some small-molecule TKI (e.g.
age, history of smoking, hyperlipidaemia, and/or obesity (Table 4).4,244 sorafenib and sunitinib) can cause AF251 and HF.43,129,247
ESC Guidelines 35
A baseline CV risk assessment includes clinical examination, BP recommended for high- and very high-risk patients.14 Patients with
measurement, and an ECG with baseline QTcF measurement (see impaired LV function and/or patients at high or very high risk of de-
Section 4).20 Especially in patients with known hypertension, BP veloping HF should be referred to the cardiologist before starting
should be controlled before VEGFi therapy. A baseline TTE is VEGFi therapy.14

VEGFi surveillance protocol
Baseline 3M 4M 6M 8M 9M 12 M Every
6–12 M
ECGa
Low
risk
TTEb
ECGa
Moderate
risk TTEb
NPc
ECGa
High and
very high TTEb,d
risk
NPc,d
Figure 13 Cardiovascular toxicity monitoring in patients receiving vascular endothelial growth factor inhibitors. ECG, electrocardiogram; M, months;
NP, natriuretic peptides; QTc, corrected QT interval; TTE, transthoracic echocardiography; VEGFi, vascular endothelial growth factor inhibitors. aIn pa-
tients treated with VEGFi at moderate or high risk of QTc prolongation, ECG is recommended (Class I, Level C) monthly during the first 3 months and
every 3–6 months thereafter (Section 6.4). Consider an ECG 2 weeks after starting treatment in high-risk patients and new monitoring in the case of any
dose increase (see Section 6.4.2). bCardiac magnetic resonance should be considered for the assessment of cardiac function when TTE is unavailable or not
diagnostic. cMeasurement of NP is recommended in all patients with cancer if these biomarkers are going to be used during treatment monitoring. dTTE
and NP should be considered at 4 weeks after starting treatment in very high-risk patients.
36 ESC Guidelines
Monitoring during and after treatment is indicated for all patients Echocardiography may be considered every 4
treated with a VEGFi and is based on close clinical follow-up using months during the first year in moderate-risk IIb C
serial ECGs, biomarkers, and echocardiography. Early recognition patients receiving VEGFi or bevacizumab.
and treatment of hypertension are essential to prevent other CV Echocardiography should be considered every 3
complications, especially HF. Home BP monitoring is recommended months during the first year in high- and very
IIa C
daily during the first cycle, after each increase of anticancer therapy high-risk patients receiving a VEGFi or
dose, and every 2–3 weeks thereafter.138,254,255 When treatment bevacizumab.e
with a VEGFi is stopped, a drop in BP must be anticipated and Echocardiography every 6–12 months should be

BP-lowering therapy must be reduced and/or interrupted according- considered in moderate- and high-risk patients
IIa C
ly (Section 6). with cancer who require long-term treatment
In patients at risk of QTc prolongation, regular monitoring of the with a VEGFi.
QTc interval is recommended after a dose increase, whenever other Cardiac biomarker
QT-prolonging agents are added, or if electrolyte imbalances occur
NP may be considered at baseline and then every
(Section 6).
4 months during the first year in moderate-risk IIb C
Patients treated with a VEGFi must also be screened regu-
patients receiving a VEGFi.
larly for symptoms and clinical signs of HF. Regular NP meas-
NP should be considered at baseline, 4 weeks
urement and echocardiography can be useful for the
© ESC 2022
after starting treatment, and them every 3 months
detection of CTRCD, although evidence is weak IIa C
during the first year in high- and very high-risk
(Figure 13).138,254,255
patients receiving a VEGFi.
BP, blood pressure; ECG, electrocardiogram; NP, natriuretic peptides; QTc, corrected
QT interval; QTcF, corrected QT interval using Fridericia correction; VEGFi, vascular
Recommendation Table 10 — Recommendations for endothelial growth factor inhibitors.
a
baseline risk assessment and monitoring during vascu- b
Level of evidence.
lar endothelial growth factor inhibitors c
QTc interval using Fridericia correction (QTcF = QT/3√RR) is the preferred method.
d
Consider an ECG 2 weeks after starting treatment in high-risk patients and new
Recommendations Classa Levelb monitoring in the case of any dose increase (see Section 6.4.2).
e
An additional echocardiography 4 weeks after starting treatment should be considered
BP monitoring in selected high- and very high-risk patients according to local availability, especially if
cardiac biomarker surveillance is not available.
BP measurement is recommended for patients
treated with VEGFi, bevacizumab, or I C
ramucirumab at every clinical visit.
5.5.5. Multitargeted kinase inhibitors targeting
Daily home monitoring of BP for patients treated
BCR-ABL
with VEGFi during the first cycle, after each
I C Chronic myeloid leukaemia (CML) results from aberrant acti-
increase of VEGFi dose, and every 2–3 weeks
vation of ABL1 kinase due to a chromosomal translocation.
thereafter is recommended.
Small-molecule TKIs targeting BCR-ABL—including imatinib,
ECG monitoring bosutinib, dasatinib, nilotinib, and ponatinib—have proven ef-
In patients treated with VEGFi at moderate or fective in the treatment of CML. The toxicities associated
high risk of QTc prolongation, QTcc monitoring is with these TKIs are unique and due to ‘off-target’ effects of
I C
recommended monthly during the first 3 months each drug. Dasatinib is associated with group 1 pulmonary
and every 3–6 months thereafter.d hypertension (PH), HF, and pleural and pericardial effusion,
Echocardiography whereas nilotinib and ponatinib are generally associated
Baseline echocardiography is recommended in
with vascular events (Figure 14).131,256–259 Second-
high- and very high-risk patients treated with I C generation BCR-ABL TKI may induce a QTc prolongation
VEGFi or bevacizumab. (see Section 6.4.2). CV toxicity risk is higher in patients
aged .65 years (relative risk 1.8) and in those with under-
Baseline echocardiography should be considered
in low- and moderate-risk patients treated with a IIa C lying DM (relative risk 2.5), hypertension (relative risk 3.2) or
VEGFi or bevacizumab.
pre-existing CAD (relative risk 2.6). 256–258,260 Before
BCR-ABL TKI therapy, it is critical to define baseline CV tox-
Continued
icity risk with special attention to BP, glucose, and lipids.
ESC Guidelines 37
BCR-ABL TKI-related cardiovascular toxicities
HTN QTc AF HF HG DL Peric-E Pleu-E PH VascTox
1st generation
BCR-ABL TKI

Imatinib
2nd generation
BCR-ABL TKI
Nilotinib
Dasatinib
Bosutinib
3rd generation
BCR-ABL TKI
Ponatinib
Figure 14 Breakpoint cluster region–Abelson oncogene locus tyrosine kinase inhibitor-related cardiovascular toxicities. AF, atrial fibrillation; BCR-ABL,
breakpoint cluster region–Abelson oncogene locus; DL, dyslipidaemia; EMA, European Medicines Agency; FDA, Food and Drug Administration; HF, heart
failure; HG, hyperglycaemia; HTN, hypertension; MedDRA, medical dictionary for regulatory activities; MI, myocardial infarction; PAD, peripheral artery
disease; Peric-E, pericardial effusion; PH, pulmonary hypertension; Pleu-E, pleural effusion; ↑QTc, corrected QT interval prolongation; TKI, tyrosine kinase
inhibitors; VascTox, vascular toxicity (stroke, MI, PAD). Adverse reactions reported in multiple clinical trials or during post-marketing use are listed by
system organ class (in MedDRA) and frequency. If the frequency is unknown or cannot be estimated from the available data, a blank space has been left.261
Figure developed from EMA prescribing information,252 FDA prescribing information.253
38 ESC Guidelines
Second and third generation BCR-ABL TKI surveillance protocol
Every
Baseline 3M 6M 9M 12 M
6–12 M

Physical Bosutinib
examinationa Dasatinib
Nilotinib
BP
Ponatinib
ECG Bosutinib
Dasatinib Nilotinib
Nilotinib Ponatinib
Lipid profile/
HbA1c Ponatinib
Nilotinib Nilotinib Nilotinib

ABI
Ponatinib Ponatinib Ponatinib
TTE Dasatinib
High and very high risk patients Dasatinib

Bosutinib treated with dasatinib or ponatinib Ponatinib
Nilotinib
Ponatinib
Figure 15 Second- and third-generation breakpoint cluster region–Abelson oncogene locus tyrosine kinase inhibitors surveillance protocol. ABI, ankle–
brachial index; BCR-ABL, breakpoint cluster region-Abelson oncogene locus; BP, blood pressure; CV, cardiovascular; ECG, electrocardiogram; HbA1c,
glycated haemoglobin; M, months; TKI, tyrosine kinase inhibitors; TTE, transthoracic echocardiography. aCoronary artery calcium scoring can reclassify
CV risk upwards and downwards in addition to conventional risk factors, and may be considered in men and women with calculated CV risk around
decision thresholds.19
ESC Guidelines 39
Baseline ECG is recommended in all patients and QTc mon- oral inhibitor of BTK, has proven highly effective in chronic
itoring in patients treated with second-generation BCR-ABL lymphocytic leukaemia and related B-cell malignancies including
TKI. Depending on the type of therapy used, specific CV as- mantle cell lymphoma, Waldenström macroglobulinemia, and mar-
sessments should be performed after drug initiation ginal zone lymphomas.262 These disorders are usually diagnosed in
(Figure 15).256 elderly patients in whom frequent comorbidities coexist at diagno-
sis that increase the risk of CTR-CVT.263,264 Ibrutinib has been as-
sociated with bleeding diathesis, infections, and an increased risk of
Recommendation Table 11 — Recommendations for hypertension, AF, and HF.265–267 Ibrutinib may also cause ventricular

baseline risk assessment and monitoring during arrhythmias without prolonging QT.267,268 Acalabrutinib is a second-
second- and third-generation breakpoint cluster re- generation BTK inhibitor with greater BTK selectivity. In a recent
gion–Abelson oncogene locus tyrosine kinase
phase III, randomized, multicentre, open-label, non-inferiority study,
inhibitors
acalabrutinib demonstrated a non-inferior progression-free survival
Recommendations Classa Levelb compared to ibrutinib in patients with previously treated chronic
lymphocytic leukaemia with a lower incidence of symptomatic CV
Baseline CV risk assessmentc is recommended in
events.269 However, grade ≥3 AF (symptomatic AF where urgent
patients who require second- or third-generation I C
intervention is indicated)270 and AF in patients ≥75 years old or with
BCR-ABL TKI.256,261
previous AF history were comparable between groups, as was the
In patients treated with nilotinib or ponatinib, CV risk of CV events in patients with pre-existing CVRFs or CVD.271
risk assessmentc is recommended every 3 months Therefore, we currently do not have enough data to establish different
I C
during the first year and every 6–12 months monitoring strategies in patients treated with these drugs.
thereafter.256,261 Due to the lack of evidence-based recommendations, the manage-
QTcd measurement should be considered at ment of these CV events is challenging.264 Antihypertensive initiation
baseline, at 2 and 4 weeks after starting nilotinib, IIa C has been associated with a lower risk of a major adverse CV events
259
and 2 weeks after any dose increase. (MACE).264 Opportunistic screening for AF by pulse-taking or ECG
Baseline echocardiography should be considered rhythm strip is recommended at every clinical visit during BTK inhibi-
in all patients before starting second- and IIa C tor therapy.272
third-generation BCR-ABL TKI. Due to a higher bleeding risk, ibrutinib should be temporarily
Baseline echocardiography is recommended in
I C
interrupted in patients requiring dual antiplatelet therapy (DAPT)
patients scheduled to receive dasatinib. and 3–7 days before invasive procedures. In case of emergency inter-
Echocardiography should be considered every 3 ventions, platelet transfusion should be considered to minimize
months during the first year in high- and very IIa C bleeding risks.262
high-risk patients receiving dasatinib or ponatinib.
Echocardiography may be considered every 6–12
months in patients who require long-term (.12 IIb C Recommendation Table 12 — Recommendations for
baseline risk assessment and monitoring during
months) ponatinib or dasatinib.
Bruton tyrosine kinase inhibitor therapy
© ESC 2022
Serial assessment of ankle brachial index may be

considered to detect subclinical peripheral IIb C Recommendations Classa Levelb
vascular disease.
BP monitoring and management
BCR-ABL, breakpoint cluster region–Abelson oncogene locus; BP, blood pressure; CV,
cardiovascular; ECG, electrocardiogram; HbA1c, glycated haemoglobin; HFA, Heart
BP measurement is recommended for patients
Failure Association; ICOS, International Cardio-Oncology Society; QTc, corrected treated with BTK inhibitors at every clinical I B
QT interval; QTcF, corrected QT interval using Fridericia correction; TKI, tyrosine visit.264
kinase inhibitors.
a
Class of recommendation. Weekly home monitoring of BP during the first 3
b
Level of evidence. months and every month thereafter should be
c IIa C
Physical examination, BP measurement, ECG, lipid profile, and HbA1c measurement. considered for patients treated with BTK
Coronary artery calcium scoring can reclassify CV disease risk upwards and downwards
in addition to conventional risk factors, and may be considered at baseline in low- and inhibitors.
moderate-risk patients as per HFA-ICOS risk assessment tools.19 Echocardiography
d
QTc interval using Fridericia correction (QTcF = QT/3√RR) is the preferred
method. Baseline echocardiography is recommended in
high-risk patientsc scheduled to receive BTK I C
inhibitors.267,268
5.5.6. Bruton tyrosine kinase inhibitors TTE is recommended in all patients who develop
I C
Bruton tyrosine kinase (BTK) inhibitors are increasingly used to AF during BTK inhibitor therapy.
treat lymphoid malignancies. Ibrutinib, a first-in-class irreversible Continued
40 ESC Guidelines
AF 5.5.7. Multiple myeloma therapies

There are many classes of pharmacotherapy that are approved for
© ESC 2022
Opportunistic screening for AF by pulse-taking or
I the treatment of MM using a range of combinations. These include
ECG rhythm strip is recommended at every C
273 immunomodulatory drugs (IMiD), dexamethasone, PI, and monoclo-
clinical visit during BTK inhibitor therapy.
nal antibodies (e.g. daratumumab). PI—including bortezomib, carfil-
AF, atrial fibrillation; BP, blood pressure; BTK, Bruton tyrosine kinase; DM, diabetes zomib, and ixazomib—have become a mainstay of therapy for
mellitus; ECG, electrocardiogram; HF, heart failure; QTc, corrected QT interval; TTE,
transthoracic echocardiography; VHD, valvular heart disease.
newly diagnosed MM as well as relapsed disease.276,277 Several large
a
Class of recommendation. studies using combination therapy for MM have demonstrated an in-

creased risk of serious CV adverse events.278–281 MM patients being
b
Level of evidence.
c
Male, age ≥ 65 years, previous history of hypertension, DM, QTc ≥ 480 ms, AF, HF,
cardiomyopathy, or severe VHD.263,274,275
treated with PI have a high incidence of coexistent CV comorbidities
Multiple myeloma drugs-related cardiovascular toxicities
HTN HG/DM HF AF MI VTE PH ATE
Alkylating agents
Cyclophosphamide
Melphalan
Immunomodulatory drugs
Lenalidomide
Pomalidomide
Thalidomide
Proteasome inhibitorsa
Bortezomib
Carfilzomib
Monoclonal antibodies
Daratumumab
Elotuzumab
Isatuximab
Figure 16 Multiple myeloma drug-related cardiovascular toxicities. AF, atrial fibrillation; ATE, arterial thromboembolism; DM, diabetes mellitus; EMA,
European Medicines Agency; FDA, Food and Drug Administration; HF, heart failure; HG, hyperglycaemia; HTN, hypertension; MedDRA, medical dictionary
for regulatory activities; MI, myocardial infarction; PH, pulmonary hypertension; VTE, venous thromboembolism. Adverse reactions reported in multiple clinical
trials or during post-marketing use are listed by system organ class (in MedDRA) and frequency. If the frequency is unknown or cannot be estimated from the
available data, a blank space has been left. aIxazomib produces peripheral oedema in up to 18% of patients and hyperglycaemia in combination with lenalidomide
or pomalidomide and dexamethasone. Figure developed from EMA prescribing information,252 FDA prescribing information.253
ESC Guidelines 41
Proteasome inhibitors surveillance protocol
Baseline During therapy
Clinical assessment Clinical assessment

BP at every BP home
Low- BP and ECG
clinical visit monitoring
moderate
risk NP every cycle during the first 6 cycles
NP
under carfilzomib or bortezomiba
TTE TTE every 3 cycles under carfilzomib
BP at every BP home
High and BP and ECG
clinical visit monitoring
very high
risk NP every cycle during the first 6 cycles
NP
under carfilzomib or bortezomiba
TTE TTE every 3 cycles under carfilzomib
BP at every BP home
BP and ECG
Cardiac clinical visit monitoring
amyloidosis
NP and cTn NP and cTn every 3-6 months
TTE and CMR TTE every 3 cycles
Figure 17 Cardiovascular monitoring in patients with multiple myeloma receiving proteasome inhibitors. BP, blood pressure; CMR, cardiac magnetic
resonance; cTn, cardiac troponin; ECG, electrocardiogram; NP, natriuretic peptides; TTE, transthoracic echocardiography. aEvery 2 months for patients
treated with ixazomib.
and increased baseline CV risk.282,283 PI have been associated with a In a safety analysis of patients with MM being treated with carfilzo-
variety of CV toxicities including hypertension, HF,284 acute coron- mib, 7.2% of patients were found to have new HF.284 In another
ary syndromes (ACS),66 arrhythmias,285 PH,286 and VTE study, 23% of patients with MM treated with carfilzomib developed
(Figure 16).287,288 During therapy, cardiac biomarkers and TTE are clinical HF and/or LVD.289 The mechanism is not well understood
important diagnostic and prognostic tools that can inform clinical but is possibly related to PI-induced oxidative stress within myocytes,
decision-making (Figure 17).66 inhibition of the proteasome, or transient endothelial dysfunc-
HF—especially HF with preserved ejection fraction (HFpEF)—is a tion.281,283 Although no studies have yet addressed the optimal
frequent manifestation of cardiac amyloidosis, but it is also an im- follow-up scheme in patients with MM treated with PI, a common
portant adverse effect of PI therapy, especially under carfilzomib. scheme consists of 3–6-monthly visits with ECG, complete blood
42 ESC Guidelines
Risk factors for venous thromboembolic events in patients with multiple myeloma
Patient-related risk factors

Previous VTE
Acute infections
Autoimmune disease
Central venous catheter
Chronic renal disease
Cigarette smoking
CVD
DM
General surgery
History of inherited thrombophilia
Immobilization, surgery, trauma
Obesity (BMI >30 kg/m2)
Myeloma-related risk factors

Advanced disease status
Erythropoietin-stimulating agents
High dexamethasone doses
Hyper-viscosity state
Thalidomide/lenalidomide/ponalidomide
Figure 18 Risk factors for venous thromboembolic events in patients with multiple myeloma. BMI, body mass index; CVD, cardiovascular disease; DM,
diabetes mellitus; VTE, venous thromboembolism.
tests (including NP and cTn) and echocardiography surveillance dur- with a combination of carfilzomib, lenalidomide, and dexametha-
ing PI therapy.290 A recent prospective study of patients with re- sone had higher rates of VTE compared with those treated with
lapsed MM confirmed the utility of NP to assist in risk stratification lenalidomide and dexamethasone (6.6% vs. 3.9%).279
as well as management of CV morbidity during treatment.66 Oncological guidelines recommend the use of aspirin or prophy-
Hypertension, another adverse effect of PI, may also contribute to lactic doses of low-molecular-weight heparins (LMWH) in low-
the development of HFpEF. risk patients receiving thalidomide- or lenalidomide-based regi-
Patients with MM are at elevated risk of thrombosis due to both mens.298 In patients at high risk of VTE, therapeutic doses of
patient- and myeloma-related factors, particularly the combin- LMWH are recommended.299 The role of non-vitamin K antagon-
ation of PI and IMiD (Figure 18).279,287,291–297 In the ASPIRE ist oral anticoagulants (NOAC) in MM patients needs further val-
(Carfilzomib, Lenalidomide, and Dexamethasone vs. idation in larger trials, but recent small studies have confirmed the
Lenalidomide and Dexamethasone for the Treatment of efficacy and safety of low doses of apixaban and rivaroxaban for
Patients with Relapsed Multiple Myeloma) study, patients treated VTE prevention.300–302
ESC Guidelines 43
Recommendation Table 13 — Recommendations for Low doses of apixaban or rivaroxabanf may be

baseline risk assessment and monitoring during mul-
considered as an alternative to LMWH or aspirin
tiple myeloma therapies
in patients with MM with VTE-related risk factorse IIb C
© ESC 2022
a b
Recommendations Class Level (excluding previous VTE) at least during the first 6
months of therapy.300–302
BP monitoring
AL-CA, amyloid light-chain cardiac amyloidosis; BP, blood pressure; cTn, cardiac
BP measurement is recommended for patients troponin; HF, heart failure; LMWH, low-molecular-weight heparins; MM, multiple
I C
treated with PI at every clinical visit. myeloma; NP, natriuretic peptides; PI, proteasome inhibitors; TTE, transthoracic

echocardiography; VTE, venous thromboembolism.
Home monitoring of BP weekly during the first 3 a
months and monthly thereafter should be IIa C b
Level of evidence.
c
Every 2 months for patients treated with oral ixazomib.
considered for patients treated with PI. d
Depending on HF severity and treatment.
e
Cardiac serum biomarkers See Figure 18.295,296,299
f
Low doses of apixaban (2.5 mg twice a day) or rivaroxaban (10 mg once a day).
Measurement of NP is recommended prior to PI
I C
in high- and very high-risk patients.66,303
Measurement of NP should be considered prior
IIa C 5.5.8. Rapidly accelerated fibrosarcoma and
to PI in low- and moderate-risk patients.66
mitogen-activated extracellular signal-regulated
In patients receiving carfilzomib or bortezomib, kinase inhibitor treatment
measurement of NP should be considered at The rapidly accelerated fibrosarcoma (RAF) inhibitors—vemurafenib,
IIa B
baseline and every cycle during the first 6 dabrafenib, and encorafenib—are approved for the treatment of
cycles.c,66 metastatic melanoma with a BRAF V600 mutation. The mitogen-
NP and cTn measurements are recommended at activated extracellular signal-regulated kinase (MEK) inhibitors—
baseline and every 3–6 months in patients with I B trametinib, cobimetinib, binimetinib, and selumetinib—have also
d,290 shown significant clinical activity in melanoma patients whose tu-
AL-CA.
mour contains a BRAF V600 mutation, and are now largely used
TTE in combination with RAF inhibitors. The main CV effects to be con-
Baseline echocardiography, including assessment sidered are hypertension, PE, and CTRCD, which are associated
for AL-CA, is recommended in all patients with I C with all combinations of RAF and MEK inhibitors, and QTc pro-
MM scheduled to receive PI. longation, associated solely with the coadministration of cobimeti-
Echocardiography surveillance every 3 cycles
nib and vemurafenib (Figure 19).12,308,309 RAF inhibitor treatment
IIa B alone or in combination with a MEK inhibitor is associated with an
should be considered in high- and very high-risk
280 increased risk of MI and AF.308
patients receiving carfilzomib.
Patients with cancer with pre-existing CVD have an increased
Echocardiography surveillance every 3 cycles may frequency of CV adverse events during treatment with MEK
be considered in low- and moderate-risk patients IIb C
and RAF inhibitors, and therefore baseline risk stratification is
receiving carfilzomib. recommended.12 Most cardiac complications induced by admin-
Echocardiography surveillance should be istration of MEK and RAF inhibitors seem to be attributable to
considered every 3–6 months in patients with IIa C the MEK inhibitor, with the RAF inhibitor enhancing the toxic
AL-CA treated with PI. d,290 effects of the MEK inhibitor.310–313 Hypertension and LVD
were twice as frequent when MEK and RAF inhibitors were
VTE prophylaxis
coadministered compared with single therapy with RAF inhibitor
Therapeutic doses of LMWH are recommended alone.314
in patients with MM with previous I B CTRCD can manifest any time from the first month of ther-
VTE.296,298,302,304,305 apy to 2 years after the end of the oncological treatment.315
Prophylactic doses of LMWH are recommended Baseline TTE is recommended in patients at moderate to high
in patients with MM with VTE-related risk factorse risk of CTR-CVT. During treatment, it is necessary to monitor
I A
(excluding previous VTE) at least during the first 6 BP at each visit and promote weekly outpatient monitoring dur-
months of therapy.296,304,305
ing the first 3 months and monthly thereafter. In patients treated
with cobimetinib/vemurafenib, an ECG is recommended at 2
Aspirin should be considered as an alternative to
and 4 weeks after initiation of treatment and every 3 months
LMWH in patients with MM with no risk factors
thereafter. In high-risk patients, periodic monitoring of ven-
or one VTE-related risk factore (excluding IIa B
tricular function with echocardiography should be considered
previous VTE) at least during the first 6 months of every 6–12 months.
therapy.296,304–307 CV protective medications (such as angiotensin-converting
Continued enzyme inhibitors [ACE-I], angiotensin receptor blockers [ARB],
44 ESC Guidelines
RAF inhibitor- and MEK inhibitor-related cardiovascular toxicities
HTN HF HG/DM SVT/SBra QTc BLEED VTE/PE

RAF inhibitors
Dabrafenib

Encorafenib
Vemurafenibb
MEK inhibitors
Binimetinib
Cobimetinib
Trametinibb
Figure 19 Rapidly accelerated fibrosarcoma and mitogen-activated extracellular signal-regulated kinase inhibitor-related cardiovascular toxicities. AF, atrial
fibrillation; BLEED, increased bleeding risk; DM, diabetes mellitus; EMA, European Medicines Agency; FDA, Food and Drug Administration; HF, heart failure;
HG, hyperglycaemia; HTN, hypertension; MedDRA, medical dictionary for regulatory activities; MEK, mitogen-activated extracellular signal-regulated kinase;
PE, pulmonary embolism; ↑QTc, corrected QT interval prolongation; RAF, rapidly accelerated fibrosarcoma; SBr, sinus bradycardia; SVT, supraventricular
tachycardia; VTE, venous thromboembolism. Adverse reactions reported in multiple clinical trials or during post-marketing use are listed by system organ class
(in MedDRA) and frequency. If the frequency is unknown or cannot be estimated from the available data, a blank space has been left. aDabrafenib is related with
SBr. Encorafenib is related with SVT. Vemurafenib rarely causes AF. Trametinib is related with bradycardia in some post-marketing reports. bPeripheral oe-
dema is very common. Figure developed from EMA prescribing information,252 FDA prescribing information.253
and beta-blockers) have not been evaluated in patients treated by beta-adrenergic signalling, which also controls the p38 mito-
with MEK and RAF inhibitors but, from a mechanistic perspective, gen-activated protein kinases pathway, associated with cardiotoxic
beta-blockers might prevent CTRCD induced by MEK inhibitors. effects. Beta-blockers might exert their cardioprotective effects
The MEK/ERK pathway has a cardiac protective effect, regulated by reducing p38 signalling.315
Recommendation Table 14 — Recommendations for baseline risk assessment and monitoring during combined rap-
idly accelerated fibrosarcoma and mitogen-activated extracellular signal-regulated kinase inhibitor therapy
BP monitoring at each clinical visit and weekly outpatient monitoring during the first 3 months of treatment and monthly thereafter is
I C
recommended.
In patients treated with cobimetinib/vemurafenib, an ECG is recommended at 2 and 4 weeks after initiation of treatment and every 3
I C
months thereafter.c
Baseline echocardiography is recommended in all high- and very high-risk patients scheduled to receive combined RAF and MEK
I C
inhibitors.
Baseline echocardiography may be considered in low- and moderate-risk patients scheduled to receive combined RAF and MEK
IIb C
© ESC 2022
inhibitors.
Echocardiography should be considered every 4 months during the first year in high- and very high-risk patients receiving combined RAF
IIa C
and MEK inhibitors.
BP, blood pressure; ECG, electrocardiogram; MEK, mitogen-activated extracellular signal-regulated kinase; RAF, rapidly accelerated fibrosarcoma.
a
b
Level of evidence.
c
Consider an ECG and new monitoring in the case of any dose increase (see Section 6.4.2).
ESC Guidelines 45
5.5.9. Immune checkpoint inhibitors tremelimumab), programmed death-1 (PD-1) (nivolumab, ce-
Immunotherapies, which harness the immune system to des- miplimab, pembrolizumab), and programmed death-ligand 1
troy cancer cells, come in different forms but the most widely (PD-L1) (atezolizumab, avelumab, durvalumab) expressed in
used are ICI.316 The immune checkpoints are proteins ex- the cancer cells, with the consequent cytotoxic immune re-
pressed in the T cells that inhibit their activation when they sponse. By blocking these checkpoints from binding with their
contact a body cell. ICI include monoclonal antibodies that partner proteins, ICI inhibit the ‘off’ signal, activating T cells
block the immune brakes or regulators, cytotoxic T and promoting killing of cancer cells. Although their patho-
lymphocyte-associated antigen-4 (CTLA-4) (ipilimumab, physiology is not clearly defined, ICI may also trigger an

Immune checkpoint inhibitors surveillance protocol
Every
Every
Baseline C2 C3 C4 6 M–
3Cc 12 Md
CV assessmenta
ECG
Low
risk TTE
cTn
NP
CV assessmenta
ECG
High
riskb TTE
cTn
NP
Figure 20 Cardiovascular surveillance in patients treated with immune checkpoint inhibitors. BNP, B-type natriuretic peptide; BP, blood pressure; C,
chemotherapy cycle; cTn, cardiac troponin; CV, cardiovascular; CVD, cardiovascular disease; CTRCD, cancer therapy-related cardiac dysfunction;
ECG, electrocardiogram; HbA1c, glycated haemoglobin; ICI, immune checkpoint inhibitors; M, months; NP, natriuretic peptides (including BNP and
NT-proBNP); NT-proBNP, N-terminal pro-B-type natriuretic peptide; TTE, transthoracic echocardiography. aIncluding physical examination, BP,
lipid profile, and HbA1c. bDual ICI, combination ICI-cardiotoxic therapy, ICI-related non-CV events, prior CTRCD or CVD. cEvery three cycles until
completion of therapy to detect subclinical ICI-related CV toxicity. dIn patients who require long-term (.12 months) ICI treatment.
46 ESC Guidelines
overactivation of T cells against non-cancerous tissues, leading Serial ECG and cTn measurements should be
to immune-related adverse events.317 Immune-related CV side considered before ICI doses 2, 3, and 4, and if
effects may lead to life-threatening CV complications such as normal, reduce to every three doses until IIa B
fulminant myocarditis, myopericarditis, cardiac dysfunction, ar- completion of therapy to detect subclinical
rhythmias, or MI, which often results in the discontinuation of ICI-related CV toxicity.333
ICI.318,319 CV assessmentd is recommended every 6–12
The largest case series of 122 patients with ICI-associated months in high-risk patientsc who require
I C
myocarditis had early onset of symptoms (median of 30 days long-term (.12 months) ICI treatment.321–

after initial exposure to ICI), and up to 50% died.320 Late CV 323,335,336
events (.90 days) are less well characterized but generally ex-
© ESC 2022
CV assessmentd may be considered every 6–12
hibit a higher risk of non-inflammatory HF, progressive athero- months in all patients who require long-term IIb C
sclerosis, hypertension, and mortality rates.321 Other CV (.12 months) ICI treatment.
toxicities described during ICI therapy are MI, AV block, supra-
ventricular and ventricular arrhythmias, sudden death, BNP, B-type natriuretic peptide; BP, blood pressure; cTn, cardiac troponin; CTRCD,
cancer therapy-related cardiac dysfunction; CV, cardiovascular; CVD, cardiovascular
Takotsubo-like syndrome, non-inflammatory HF, hypercholes- disease; ECG, electrocardiogram; HbA1c, glycated haemoglobin; ICI, immune
terolaemia, pericarditis, pericardial effusion, ischaemic stroke, checkpoint inhibitors; NP, natriuretic peptides; NT-proBNP, N-terminal pro-B-type
and VTE.322 A meta-analysis including 32 518 patients receiving natriuretic peptide.
a
ICI treatment reported an increased risk of myocarditis, peri- b
Level of evidence.
cardial diseases, HF, dyslipidaemia, MI, and cerebral arterial is- c
Dual ICI, combination ICI-cardiotoxic therapy; ICI-related non-CV events, prior
chaemia.323 Conditions related with high baseline ICI-related CTRCD, or CVD.
d
Physical examination, BP, NP (BNP or NT-proBNP), lipid profile, HbA1c, and ECG.
CV toxicity risk include dual ICI therapy (e.g. ipilimumab and ni-
volumab), combination ICI therapy with other cardiotoxic ther-
apies, and patients with ICI-related non-CV events or prior 5.5.10. Androgen deprivation therapies for
CTRCD or CVD (Figure 20).324,325 All patients on ICI treat- prostate cancer
ment should have an ECG and troponin assay at baseline Androgen deprivation therapy (ADT) is prescribed in 40% of men
(Figure 20).326–329 High-risk patients should additionally have a with prostate cancer as neoadjuvant and/or adjuvant therapy to
TTE evaluation at baseline. Due to the lack of evidence-based RT or for biochemical relapse following prostate cancer surgery.
recommendations, the monitoring of ICI therapy is challenging. Gonadotropin-releasing hormone (GnRH) agonists are the most fre-
Once started on therapy, ECG, cTn, and NP should be quently prescribed ADT. However, GnRH agonists are associated
checked.330–332 In the JAVELIN trial, which assessed avelumab with an increased CV risk and mortality, particularly in patients
plus axitinib vs. sunitinib, no clinical value was observed for on- with prostate cancer aged .60 years.337,338 Baseline risk stratifica-
treatment routine TTE monitoring in asymptomatic patients.333 tion in patients requiring GnRH agonists depends on vascular disease
However, in high-risk patients, and in those with high baseline risk (Figure 21).339,340 No dedicated CV toxicity risk calculators have
cTn levels, TTE monitoring may be considered. In patients been developed for patients receiving ADT. It was the consensus of
who develop ECG abnormalities, new biomarker changes, or the authors to recommend SCORE2 or SCORE2-OP to stratify CV
new cardiac symptoms at any time, prompt cardio-oncology risk in patients receiving ADT without previous CVD.19
evaluation is strongly recommended, including TTE for the The use of GnRH antagonists represents an alternative in the
evaluation of LVEF and GLS, and CMR when myocarditis is sus- treatment of prostate cancer, and preclinical and clinical (HERO
pected (Table 3).334 trial)341 data suggest that GnRH antagonist use is associated with sig-
nificantly lower overall mortality and CV events compared with ago-
nists.342 However, more research is needed in this field. In the
PRONOUNCE trial, no difference in MACE at 1 year was observed
Recommendation Table 15 — Recommendations for between degarelix (a GnRH antagonist) and leuprolide (a GnRH
baseline risk assessment and monitoring during
agonist), although the trial was stopped early.343 Lower CV event
immunotherapy
rates were detected compared with previous studies and all patients
Recommendations Classa Levelb were reviewed by a cardiologist at enrolment (leading to optimal
CVRF management).343
ECG, NP, and cTn measurements are
The main CV effects to be considered are hypertension, DM, ischae-
recommended in all patients before starting ICI I B
333
mic heart disease (IHD) and CTRCD.339,344 ADT is uncommonly asso-
therapy.
ciated with QTc prolongation and rarely causes torsade de pointes
Baseline echocardiography is recommended in (TdP) through blockade of testosterone effects on ventricular repolar-
I B
high-risk patientsc before starting ICI therapy.333 ization.345,346 ECG monitoring and correction of QT prolongation pre-
Baseline echocardiography may be considered in cipitant factors (see Section 6.4.2; Table 9; Supplementary data,
IIb C
all patients before starting ICI therapy. Table S13) is recommended340,347,348 during prostate cancer treatment
Continued if the baseline QTc interval is prolonged.49,339,340,347,349,350
ESC Guidelines 47
Androgen deprivation therapy-related cardiovascular toxicities
HTN HG/DM HF IHD/MI AF QTca

GnRH agonist
Goserelin

Histrelin
Leuprorelin
Triptorelin
GnRH antagonist
Degarelix
Relugolix
1st generation antiandrogens
Bicalutamide
Flutamide
Nilutamide
2nd generation
androgen deprivation therapy
Apalutamide
Darolutamide
Enzalutamide
Androgen metabolism inhibitor
Abirateroneb
Figure 21 Androgen deprivation therapy-related cardiovascular toxicities. ADT, androgen deprivation therapy; AF, atrial fibrillation; DM, diabetes mel-
litus; EMA, European Medicines Agency; FDA, Food and Drug Administration; GnRH, gonadotropin-releasing hormone; HF, heart failure; HG, hypergly-
caemia; HTN, hypertension; IHD, ischaemic heart disease; MedDRA, medical dictionary for regulatory activities; MI, myocardial infarction; ↑QTc,
corrected QT interval prolongation; TdP, torsade de pointes. Adverse reactions reported in multiple clinical trials or during post-marketing use are listed
by system organ class (in MedDRA) and frequency. If the frequency is unknown or cannot be estimated from the available data, a blank space has been left.
a
ADT may prolong the QTc interval. In patients with a history of risk factors for QT prolongation and in patients receiving concomitant medicinal pro-
ducts that might prolong the QT interval, physicians should assess the benefit/risk ratio including the potential for TdP prior to initiating the treatment.
b
Increased risk of QTc prolongation in combination with ADT.49,339,340,349,350 Figure developed from EMA prescribing information,252 FDA prescribing
information.253
48 ESC Guidelines
Recommendation Table 16 — Recommendations for high-dose tamoxifen were found to prolong QTc interval339,340;
baseline risk assessment and monitoring during an- however, no risk data have been published in patients treated with
drogen deprivation therapy for prostate cancer the standard tamoxifen dose used in BC (20 mg/day).
The risks of VTE, hypercholesterolaemia, and CVD should be dis-
cussed with patients, while recognizing that the absolute benefits of
Baseline CV risk assessmentc and estimation of preventing BC recurrence usually outweigh the CV risks.339 In pa-
10-year fatal and non-fatal CVD risk with tients ,70 years old without clinical manifestations of atherosclerot-
SCORE2 or SCORE2-OPd is recommended in I B ic disease, estimation of 10-year fatal and non-fatal CVD risk with

patients treated with ADT without pre-existing SCORE2 (if ≥70 years, SCORE2-OP) is recommended.19
CVD.19,341,342 Cholesterol levels and BP should be monitored regularly in patients
Baseline and serial ECGs are recommended in receiving AI.356 Physical activity and healthy diet are also advised to
patients at risk of QTc prolongation during ADT I B reduce weight and cholesterol levels. Smoking cessation is strongly
therapy.e,339–342 recommended to reduce CV risk (e.g. CAD during AI therapy and
A GnRH antagonist should be considered in VTE during tamoxifen therapy).
patients with pre-existing symptomatic CADf IIa B
who require ADT.341,342
© ESC 2022
Annual CV risk assessmentc is recommended Recommendation Table 17 — Recommendations for
I B
during ADT.19,339,341,342 baseline risk assessment and monitoring during endo-
crine therapy for breast cancer
ACS, acute coronary syndromes; ADT, androgen deprivation therapy; BP, blood
pressure; CAD, coronary artery disease; CCS, chronic coronary syndromes; CV, Recommendations Classa Levelb
cardiovascular; CVD, cardiovascular disease; ECG, electrocardiogram; GnRH,
gonadotropin-releasing hormone; HbA1c, glycated haemoglobin; QTc, corrected QT Baseline CV risk assessmentc and estimation of
interval; SCORE2, Systematic Coronary Risk Estimation 2; SCORE2-OP, Systematic
10-year fatal and non-fatal CVD risk with
Coronary Risk Estimation 2—Older Persons.
a
Class of recommendation. SCORE2 or SCORE2-OPd,e is recommended in I C
b
Level of evidence. BC patients receiving endocrine therapies without
c
BP, lipids, fasting glucose, HbA1c, ECG, and patient education on healthy lifestyle and
pre-existing CVD.19
lifestyle risk factor control is recommended.
d
SCORE2 (,70 years) or SCORE2-OP (≥70 years) CV risk stratification: ,50 years: Annual CV risk assessmentc is recommended
low risk ,2.5%, moderate risk 2.5% to ,7.5%, high risk ≥7.5%; 50–69 years: low during endocrine therapy in BC patients with high
risk ,5%; moderate risk 5% to ,10%; high risk ≥10%; ≥70 years: low risk ,7.5%, I C
moderate risk 7.5% to ,15%, high risk ≥15%.
10-year risk of (fatal and non-fatal) CV events
e
See Table 9. according to SCORE2/SCORE2-OP.d,e
f
CCS and ACS. CV risk assessmentc should be considered every 5
© ESC 2022
years in BC patients with low or moderate
IIa C
10-year risk of (fatal and non-fatal) CV events
5.5.11. Endocrine therapies for breast cancer according to SCORE2/SCORE2-OP.d,e
Endocrine therapy is a common treatment as 65–70% of all early
BC, breast cancer; BP, blood pressure; CV, cardiovascular; CVD, cardiovascular disease;
and metastatic BC patients develop hormone receptor-positive ECG, electrocardiogram; HbA1c, glycated haemoglobin; SCORE2, Systematic
disease.22 Selective oestrogen receptor modulators (tamoxifen, Coronary Risk Estimation 2; SCORE2-OP, Systematic Coronary Risk Estimation 2—
toremifene) or aromatase inhibitors (AI) (letrozole, anastrozole, Older persons.
a
or exemestane) are recommended in early BC (EBC) according b
Level of evidence.
to menopausal status, comorbidities, and the risk of disease relapse. c
BP, lipids, fasting glucose, HbA1c, ECG and patient education on healthy lifestyle and
The use of AI in combination with cyclin-dependent kinase (CDK) lifestyle risk factor control.
d
Or other validated CV risk scores.
4/6 inhibitors is recommended as first- or second-line therapy e
SCORE2 (,70 years) or SCORE2-OP (≥70 years) CV risk stratification: ,50 years:
in patient with hormone receptor-positive/HER2-negative meta- low risk ,2.5%, moderate risk 2.5% to ,7.5%, high risk ≥7.5%; 50–69 years: low
static BC. risk ,5%; moderate risk 5% to ,10%; high risk ≥10%; ≥70 years: low risk ,7.5%,
moderate risk 7.5% to ,15%, high risk ≥15%.19
The use of AI increases the risk of dyslipidaemia, metabolic syn-
drome, hypertension, HF, and MI.339 In the ATAC (‘Arimidex’ and
Tamoxifen Alone or in Combination) trial, anastrozole-treated pa-
tients with pre-existing CAD experienced more CV events (17% 5.5.12. Cyclin-dependent kinase 4/6 inhibitors
vs. 10%) and cholesterol level elevation (9% vs. 5%) than those trea- The use of CDK 4/6 inhibitors (palbociclib, ribociclib, and abemaci-
ted with tamoxifen.351,352 Similarly, HF was significantly more com- clib) in combination with endocrine therapy is approved for the
mon with letrozole compared with tamoxifen in the BIG (Breast treatment of patients with hormone receptor-positive/
International Group) 1–98 trial.353 Longer AI treatment duration HER2-negative metastatic BC. This combination has resulted in im-
was associated with increased odds of developing CVD in two large provements in progression-free survival and, in some trials, overall
meta-analyses.354,355 Significantly increased VTE risk has been con- survival.357–359 CDK 4/6 inhibitors have demonstrated a potential
sistently demonstrated with tamoxifen351,353 and it is not recom- for QT prolongation,339,360 particularly with ribociclib. The phase
mended in patients with thrombotic risks. Toremifene and III trials of ribociclib incorporated routine ECG monitoring.361–368
ESC Guidelines 49
Baseline ECG is recommended and ECGs should be repeated at day crizotinib treatment should have cholesterol levels checked every
14 of the first cycle, before the second cycle, with any dose increase 3–6 months and treated if elevated.
and as clinically indicated.357
In patients who already have, or are at significant risk of develop-
5.5.14. Epidermal growth factor receptor inhibitors
ing, QT prolongation (Section 6.4.2), the risks/benefits for ribociclib
Osimertinib is an oral irreversible, epidermal growth factor receptor
should be discussed by a MDT. Importantly, the use of ribociclib
(EGFR)-TKI approved for patients with non-small cell lung cancer ex-
should be avoided in combination with drugs known to prolong
pressing EGFR mutations. Recent data have shown that osimertinib is
QT interval and/or strong CYP3A inhibitors.357
associated with an increased risk of QTc prolongation, AF, VTE, LVD,

The prescribing information does not recommend ribociclib in
and HF (Figure 22).373,374 A study of 123 patients with EGFR-mutant
combination with tamoxifen due to a higher risk of QTc
non-small cell lung cancer treated with osimertinib reported a 4.9%
prolongation.252,367
incidence of HF or MI and a significant decrease in LVEF ,53% in
11% of patients with TTE surveillance.375 Pre-existing hypertension
and older age are risk factors for LVD and HF (3.9% and 2.6% inci-
dence, respectively).376 LVD and HF were more common during
baseline risk assessment and monitoring during cyclin-
dependent kinase 4/6 inhibitor therapy the first year of therapy.376
Baseline CV risk stratification, ECG and TTE prior to starting osi-
Recommendations Classa Levelb mertinib is recommended. Three-monthly echocardiographic sur-
veillance for new LVD during osimertinib treatment should be
QTcc,d monitoring is recommended at baseline
considered. Close monitoring of magnesium levels is also recom-
and 14 and 28 days in all patients with cancer I A
mended to minimize the risk of osimertinib-induced hypomagnes-
receiving ribociclib.361,365,367,368
aemia and QTc prolongation.
QTcc,d monitoring is recommended in patients
treated with ribociclib with any dose I B
increase. 361,365,367,368
QTcc monitoring should be considered in patients baseline risk assessment and monitoring during ana-
plastic lymphoma kinase and epidermal growth factor
© ESC 2022
treated with palbociclib or abemaciclib who have a

IIa C receptor inhibitors
baseline QTc above the normal rangec or other
conditions that may prolong the QTc interval.e Recommendations Classa Levelb
QTc, corrected QT interval; QTcF, corrected QT interval using Fridericia correction. Baseline CV risk assessmentc is recommended in
a
b patients before ALK inhibitors and EGFR I C
Level of evidence.
c
QT interval using Fridericia correction (QTcF = QT/3√RR) is the preferred method in inhibitors.
patients with cancer. Upper 99% limit of normal for QTc values in the general
Baseline echocardiography is recommended in all
population are 450 ms for men and 460 ms for women.369 I B
d
According to the European Medicines Agency: (1) ribociclib should be interrupted patients with cancer before starting osimertinib.376
when QTcF . 480 ms; (2) if QTcF prolongation resolves to ,481 ms, resume Home BP monitoring should be considered for
treatment at the same dose level; (3) if QTcF ≥ 481 ms recurs, interrupt dose until IIa C
patients treated with brigatinib, crizotinib, or
QTcF resolves to ,481 ms and then resume ribociclib at next lower dose level.
e
See Section 6.4.2 and Table 8. lorlatinib.
Cholesterol profile assessment every 3–6 months
should be considered for patients on crizotinib IIa C
and lorlatinib.
5.5.13. Anaplastic lymphoma kinase inhibitors
Patients with cancer treated with anaplastic lymphoma kinase Echocardiography should be considered every 3
IIa B
(ALK) inhibitors may develop adverse CV events including sinus months in patients during osimertinib therapy.376
© ESC 2022
bradycardia, AV block, QTc prolongation, hypertension, hypergly- ECG should be considered 4 weeks after starting
caemia, and dyslipidaemia.370,371 ACS and HF have rarely been de- therapy and every 3–6 months in patients during IIa C
scribed under crizotinib.372 A baseline ECG is recommended in ALK inhibitor therapy.
patients prior to starting an ALK inhibitor, especially crizotinib, ALK, anaplastic lymphoma kinase; BP, blood pressure; CV, cardiovascular; ECG,
and patients may have an ECG 4 weeks after the start of treatment electrocardiogram; EGFR, epidermal growth factor receptor; HbA1c, glycated
and every 3–6 months thereafter, particularly if the baseline ECG is haemoglobin.
a
abnormal. Home BP monitoring should be considered in patients b
Level of evidence.
treated with brigatinib or lorlatinib. Patients receiving lorlatinib or c
Physical examination, BP measurement, ECG, lipid profile, and HbA1c measurement.
50 ESC Guidelines
ALK inhibitor- and EGFR inhibitor-related cardiovascular toxicities
HTN HG/DM DL HF SBr AF QTc VTE
ALK inhibitors
Alectinib

Brigantinib
Ceritinib
Crizotinib
Lorlatinib
EGFR inhibitors
Osimertiniba
Very common: ≥10% incidence Uncommon: 0.1% to <1% incidence
Figure 22 Anaplastic lymphoma kinase and epidermal growth factor receptor inhibitor-related cardiovascular toxicities. AF, atrial fibrillation; ALK, ana-
plastic lymphoma kinase; DL, dyslipidaemia; DM, diabetes mellitus; EGFR, epidermal growth factor receptor; EMA, European Medicines Agency; FDA,
Food and Drug Administration; HF, heart failure; HG, hyperglycaemia; HTN, hypertension; MedDRA, medical dictionary for regulatory activities;
↑QTc, corrected QT interval prolongation; SBr, sinus bradycardia; VTE, venous thromboembolism. Adverse reactions reported in multiple clinical trials
or during post-marketing use are listed by system organ class (in MedDRA) and frequency. If the frequency is unknown or cannot be estimated from the
available data, a blank space has been left. aOsimertinib increases the risk of hypomagnesaemia. Figure developed from EMA prescribing information,252
FDA prescribing information.253
5.5.15. Chimeric antigen receptor CRS and to distinguish it from other conditions that occur in these
T cell and tumour-infiltrating lymphocytes settings (infections, HF, drug reactions, and PE).378,386 Among adults,
therapies there was a relationship between CRS and CV events. An elevation in
CAR-T therapy is used for the treatment of acute lymphocytic leu- cTn is commonly seen in patients with CRS and is associated with an
kaemia and aggressive B-cell lymphomas.377 Although the reported increased risk for subsequent CV events.378 In a recent retrospective
incidence is variable, there is a growing recognition of the association pharmacovigilance study, CAR-T was associated with tachyarrhyth-
between CAR-T therapy and CTR-CVT, including LVD, HF, cardiac mias (AF the most common, followed by ventricular arrhythmias),
arrhythmias, pericardial effusion, TTS, and cardiac arrest.378–383 The cardiomyopathy, and pleural and pericardial diseases.379 Globally,
majority of the described CV toxicities have been shown to be asso- the fatality rate of CV and pulmonary adverse events was
ciated with the occurrence of cytokine release syndrome 30.9%.378,379,387 Early cardiac evaluation in patients with cTn increase
(CRS).377,384 Baseline CV evaluation including ECG, NP, and cTn is should include NP, ECG, and echocardiography (see Section 6.1.4 for
recommended in all patients. Baseline TTE should also be consid- management).388
ered, especially in patients with pre-existing CVRF and CVD. After Adoptive cellular therapy with TIL has emerged as an effective
receiving CAR-T therapy, patients may develop systemic inflamma- treatment option for unresectable stage III/IV metastatic melanoma.
tory syndromes.385 CRS should be suspected when a patient devel- With TILs, the CV toxicity appears to be related to direct myocardial
ops fever, with or without tachypnoea, tachycardia, hypotension, and vascular toxicity.380 Baseline assessment and CV surveillance in
hypoxia, and/or other end-organ dysfunction hours to days after patients before TIL therapies is the same pathway recommended
treatment.385 A high index of suspicion is necessary to diagnose for CAR-T therapies.
ESC Guidelines 51
Recommendation Table 20 — Recommendations for (1) Modification of cancer management to omit RT. This emphasizes
baseline risk assessment and monitoring in patients the importance of integrating a personalized cardio-oncology
receiving chimeric antigen receptor T cell and tumour- evaluation.402–404
infiltrating lymphocytes therapies
(2) Modification of the dose and volume of RT treatments where
Recommendations Classa Levelb possible. RT protocols should target the minimum volume re-
quired to the minimum dose needed to obtain the desired clin-
Baseline ECG, NP, and cTn are recommended in ical benefit.
all patients with cancer before starting CAR-T and I C
(3) Modification of delivery techniques to reduce cardiac radiation

TIL therapies.388 exposure should lead to a considerable reduction in risk.
A baseline echocardiography is recommended in Modern heart-sparing RT strategies include: the optimal use of
patients with pre-existing CVD before starting I C modern intensity-modulated photon RT technologies; the use
388
CAR-T and TIL therapies. of deep inspiration breath-hold or respiratory-gated techniques
A baseline echocardiography should be in BC,405 lymphoma,406 and lung cancer407; or the use of image-
considered before starting CAR-T and TIL IIa C guided RT to ensure accuracy of delivery and proton beam
therapies.388 therapy.408
© ESC 2022
Measurement of NP, cTn, and echocardiography
are recommended in patients who develop CRS I C The incidence of cardiac events following RT may vary according
of ASTCT ≥ 2.c,378,388 to patient risk factors and synergistic effects of radiation with other
cardiotoxic cancer treatments.12,173
ASTCT, American Society for Transplantation and Cellular Therapy; CAR-T, chimeric
There are no known RT-specific secondary preventative mea-
antigen receptor T cell; CRS, cytokine release syndrome; cTn, cardiac troponin; CVD,
cardiovascular disease; ECG, electrocardiogram; NP, natriuretic peptides; TIL, sures (e.g. drug treatments) to reduce the risk of CV events fol-
tumour-infiltrating lymphocytes. lowing RT. However, given the known importance of
a
b conventional CVRF on the incidence of RT-related events, opti-
Level of evidence.
c
Determine CRS grade according to ASTCT grading: Grade 1: fever; Grade 2: fever mization of modifiable CVRF is recommended in all patients
AND hypotension not requiring vasopressors AND/OR hypoxia requiring low-flow before and after RT.
nasal oxygen; Grade 3: fever AND hypotension requiring one vasopressor +
vasopressin AND/OR hypoxia requiring high-flow nasal cannula or facemask or
non-rebreather mask or Venturi mask; Grade 4: fever AND hypotension requiring
multiple vasopressors, not including vasopressin AND/OR hypoxia requiring positive
airway pressure. baseline risk assessment of patients before radiother-
apy to a volume including the heart

5.5.16. Radiotherapy Baseline CV risk assessmentc and estimation of
RT increases the risk of developing subsequent CVD and periph- 10-year fatal and non-fatal CVD risk with I B
eral artery disease (PAD).173,389–394 There is ongoing debate re- SCORE2 or SCORE2-OPd is recommended.19,389
garding the safest radiation dose, which cardiac substructures
© ESC 2022
Baseline echocardiography should be considered
are most sensitive to RT-induced injury, and the most appropriate in patients with previous CVD before RT to a IIa C
strategies to minimize RT-related CVD.395,396 The heart is consid- volume including the heart.
ered a radiosensitive ‘organ at risk’ during RT and radiation expos-
ure to the heart should be kept as low as reasonably achievable BP, blood pressure; CV, cardiovascular; CVD, cardiovascular disease; ECG,
electrocardiogram; HbA1c, glycated haemoglobin; RT, radiotherapy; SCORE2,
because there is no ‘safe’ dose (Figure 23).389,390 RT-induced CV Systematic Coronary Risk Estimation 2; SCORE2-OP, Systematic Coronary Risk
toxicity risk categorization based on MHD389,397 is recommended Estimation 2—Older Persons.
a
over categorization based on prescribed dose, which may not ac- Class of recommendation.
b
Level of evidence.
curately reflect cardiac radiation exposure (e.g. 35 Gray [Gy] pre- c
BP, lipids, fasting glucose, HbA1c, ECG and patient education on healthy lifestyle and
scribed dose to approximately 70% of the heart is equivalent to lifestyle risk factor control.
d
approximately 25 Gy MHD, whereas 35 Gy prescribed dose to ap- SCORE2 (,70 years) or SCORE2-OP (≥70 years) CV risk stratification: ,50 years:
low risk ,2.5%, moderate risk 2.5% to ,7.5%, high risk ≥7.5%; 50–69 years: low
proximately 40% of the heart is equivalent to approximately 15 Gy risk ,5%; moderate risk 5% to ,10%; high risk ≥10%; ≥70 years: low risk ,7.5%,
MHD). However, MHD is not a perfect metric, and in some pa- moderate risk 7.5% to ,15%, high risk ≥15%.19
tients, a very small portion of the heart might be irradiated to a
very high dose, still conveying a substantial risk despite a low
MHD.398 Therefore, depending on dose distribution and exposure 5.5.17. Haematopoietic stem cell transplantation
of specific cardiac substructures and CVRFs, the cancer treatment HSCT constitutes a potentially curative therapeutic option for many
team may judge the patient to belong to a higher-risk cat- haematological malignancies. Improvements in HSCT techniques and
egory.397,399–401 supportive strategies have markedly decreased treatment-related
Strategies to prevent and attenuate CV complications of RT mortality (Supplementary data, Table S14).409,410 There is a growing
have focused on reducing radiation exposure of the heart and recognition of HSCT-related CV toxicities and HSCT survivors con-
CV substructures during cancer treatment and include the stitute a population at high future CV risk. Several factors contribute
following. to define the risk of HSCT-related CV toxicities, including the HSCT
52 ESC Guidelines
Very high risk High risk

>25 Gy MHDb >15 to 25 Gy MHDb
>15 Gy MHDb + 5 to 15 Gy MHDd
cumulative doxorubicinc cumulative doxorubicinc
≥100 mg/m2 ≥100 mg/m2
RT doses CVa
toxicity risk
5 to 15 Gy MHDd
<5 Gy MHDe +
<5 Gy MHDe
cumulative doxorubicinc
≥100 mg/m2
Moderate risk Low risk
Figure 23 Radiotherapy mean heart dose and associated cardiovascular toxicity risk. CV, cardiovascular; Gy, Gray; MHD, mean heart dose; RT, radio-
therapy. aRT risk categorization based on MHD is recommended over categorization based on prescribed dose, which may not accurately reflect cardiac
radiation exposure. Depending on dose distribution and exposure of specific cardiac substructures (as well as clinical risk factors) the treatment team may
judge the patient to belong to a higher risk category. In addition, a patient may be judged to belong to a lower risk category if only a small part of the heart
was exposed to a relatively low prescribed dose.397,399–401 bOr prescribed RT ≥ 35 Gy to a volume exposing the heart if MHD is not available. Note that
in this case, the limited information about cardiac exposure does not allow one to distinguish between high- and very high-risk categories. cOr equivalent.
d
Or prescribed RT 15–34 Gy to a volume exposing the heart if MHD is not available. eOr prescribed RT , 15 Gy to a volume exposing the heart if MHD
is not available.
type (higher risk after allogeneic HSCT), multiple uncontrolled data, Table S14) and the development of graft vs. host disease
CVRF, pre-existing CV conditions (AF or atrial flutter, sick sinus syn- (GVHD), thrombotic microangiopathy, or sepsis.410,412 In the early
drome, ventricular arrhythmias, CAD, MI, moderate-to-severe VHD, phase following HSCT (,100 days), the most frequent CV event
and HF or LVEF ,50%),411 direct cardiotoxic effects of anticancer is AF, although some patients may experience HF, hypertension,
therapies received prior to and during HSCT (anthracycline- hypotension, pericardial effusion, or VTE.413,414 Late toxicities in-
combined induction regimen, mediastinal RT, total body irradiation, clude DM, dyslipidaemia, metabolic syndrome, hypertension, HF,
or cyclophosphamide-based conditioning regimen) (Supplementary CAD, conductions disorders, and pericardial effusion.410 Acute
ESC Guidelines 53
Cardiovascular surveillance in patients referred for haematopoietic

stem cell transplantation
3M 12 M
Before after after >12 M
HSCT HSCT HSCT (yearly)

CV assessmenta
ECG
Low risk
If new cardiac symptoms
TTE occur at any time
NP If new cardiac symptoms

occur at any time
CV assessmenta
High risk
ECG
Allogenic HSCT
Pre-existing CVD In selected
TTE
Multiple uncontrolled CVRF patients
Cancer treatment historyb
Conditioning schemesc NP
GVHD
CPET In selected
patients
Figure 24 Risk factors and cardiovascular surveillance in patients referred for haematopoietic stem cell transplantation. BNP, B-type natriuretic pep-
tide; BP, blood pressure; CPET, cardiopulmonary exercise testing; CV, cardiovascular; CVD, CV disease; CVRF, cardiovascular risk factors; ECG, elec-
trocardiogram; GVHD, graft vs. host disease; HbA1c, glycated haemoglobin; HSCT, haematopoietic stem cell transplantation; M, months; NP,
natriuretic peptides (including BNP or NT-proBNP); NT-proBNP, N-terminal pro-BNP; TTE, transthoracic echocardiography. aIncluding physical exam-
ination, BP, lipid profile, and HbA1c. bMediastinal or mantle field radiation, alkylating agents, .250 mg/m2 doxorubicin or equivalent. cTotal body irradi-
ation, alkylating agents.
GVHD is associated with thrombosis and inflammatory myocardial

damage (myocarditis, HF, conduction abnormalities, arrhythmias, Recommendation Table 22 — Recommendations for
baseline risk assessment in haematopoietic stem cell
and pericardial effusions), and chronic GVHD has been linked with transplantation patients
increasing risk of hypertension, DM, and dyslipidaemia.415,416
A comprehensive CV evaluation, including NP assessment, ECG, Recommendations Classa Levelb
and TTE, has become a core component of the pre-HSCT assess-
Baseline and serial CV risk assessment (3 and 12
ment409,410 to detect undiagnosed CVD, stratify CTR-CVT risk,
months, then yearly) including BP measurement,
and optimize pre-existing CV conditions.411,417–420 In early surveil- I C
ECG, lipid measurement, and HbA1c is
lance, TTE monitoring is recommended in high-risk HSCT recipients
recommended in HSCT patients.
at 3 and 12 months as LVEF and GLS can decrease after transplant
Echocardiography is recommended in all patients
(see Section 7). Independent factors associated with long-term CVD I C
© ESC 2022
before HSCT.
in HSCT survivors are allogenic HSCT, pre-existing CVD or multiple
Baseline NP measurement should be considered
uncontrolled CVRF, cancer treatment history (mediastinal or man- IIa C
before HSCT.417,418
tle field radiation, alkylating agents, .250 mg/m2 doxorubicin or
equivalent), high-risk conditioning schemes (total body irradiation, BP, blood pressure; CV, cardiovascular; ECG, electrocardiogram; HbA1c, glycated
alkylating agents), and GVHD.410 Figure 24 summarizes strategies haemoglobin; HSCT, haematopoietic stem cell transplantation; NP, natriuretic peptides.
a
for the prevention and attenuation of CV complications in patients b
Level of evidence.
undergoing HSCT.
54 ESC Guidelines
5.5.18. Other cancer treatments (medication, devices) needs to include consideration of a range of
Several other cancer therapies may also induce clinically relevant CV factors including both cancer and CV symptom burden, cancer prog-
events. Cyclophosphamide, cisplatin, ifosfamide, and taxanes (pacli- nosis, ongoing cancer treatment requirements including alternative
taxel and docetaxel) can induce myocardial dysfunction and HF.4 options, possible adverse drug reactions, drug–drug interactions,
Cyclophosphamide CV toxicity is primarily seen in patients receiving and patient preferences. An extensive list of drug–drug interactions
high doses (.140 mg/kg) before HSCT and typically occurs within is provided in Supplementary data, Tables S15–S17.
days of drug administration.410
Platinum-containing chemotherapy (cisplatin, carboplatin, oxali-

platin) may cause vascular disease (vasospasm, MI, and venous and Recommendation Table 23 — Recommendation for
arterial thrombosis). These may occur during treatment and also the management of cardiovascular disease and cancer
therapy-related cardiovascular toxicity in patients re-
contribute to increased long-term risk of CAD in survivors.
ceiving anticancer treatment
Patients with testicular cancer treated with cisplatin have a higher
risk for vascular disease at long-term follow-up.421 The risk of the in- Recommendation Classa Levelb
dividual patient is still hard to predict, but lifestyle interventions, a
A specialist CV assessmentc is recommended for
high degree of clinical suspicion in patients who experience chest
© ESC 2022
optimal diagnostic workup and management of
pain, and close CVRF monitoring is recommended during and after I C
patients with cancer who present with new CV
therapy.422 Cisplatin422 infrequently causes HF; however, because
toxicity during and after cancer treatment.5
it requires the administration of a high i.v. volume to avoid renal tox-
icity, patients with pre-existing CVD may develop symptomatic HF. CV, cardiovascular; CVD, cardiovascular disease.
a
Arsenic trioxide is used to treat some leukaemias and myelomas. Class of recommendation.
b
Level of evidence.
Arsenic trioxide frequently prolongs the QT interval (26–93% of pa- c
Cardio-oncology referral is recommended when available; alternatively, patients should
tients), and life-threatening ventricular tachyarrhythmias have been be referred to a specialized cardiologist with expertise in managing CVD in patients with
reported.45,259 QTc prolongation was observed 1–5 weeks after ar- cancer.
senic trioxide infusion and then returned towards baseline by the end
of 8 weeks. Patients receiving treatment with arsenic trioxide should
be monitored weekly with ECG during the first 8 weeks of therapy.
6.1. Cancer therapy-related cardiac
Electrolyte monitoring is also required as arsenic trioxide may induce dysfunction
hypokalaemia, hypomagnesaemia, and renal dysfunction. Risk factors 6.1.1. Anthracycline chemotherapy-related cardiac
for QT prolongation should be controlled before, during, and after dysfunction
cancer treatment (Section 6.4.2). CTRCD during anthracycline chemotherapy may present clinically or
Several FMS-like tyrosine kinase 3 (FLT3) inhibitors (first-generation: be detected in asymptomatic patients during surveillance (Figure 10;
midostaurin; second-generation: gilteritinib) have been tested for the Table 3).4 The diagnosis of anthracycline chemotherapy-related car-
treatment of acute myeloid leukaemias. Gilterinib-induced differenti- diac dysfunction includes new CV symptoms, new abnormalities in
ation syndrome (fever, dyspnoea, pleuropericardial effusion, pulmon- cardiac function on CV imaging, and/or new increases in cardiac bio-
ary oedema, peripheral oedema, hypotension, renal dysfunction, and markers (Table 3). A MDT discussion is recommended to consider
rash) requires early corticosteroid therapy and haemodynamic moni- the risk/benefit ratio of continuing anthracycline chemotherapy in
toring until resolution of symptoms. Midostaurin and gilterinib may patients who develop new CTRCD.
prolong QTc interval and close electrolyte surveillance and minimizing Discontinuation of anthracycline chemotherapy is recommended
drug–drug interactions are required (see Section 6.4.2; Table 9; in patients with cancer who develop severe symptomatic CTRCD.22
Supplementary data, Tables S15 and S16).423 There are rare exceptions where rechallenge with further anthracy-
cline chemotherapy may be considered after a MDT discussion, using
prevention strategies described below and under close monitoring
6. Diagnosis and management of with each cycle of anthracycline chemotherapy. Temporary interrup-
tion of anthracycline chemotherapy is recommended in patients who
acute and subacute cardiovascular develop moderate symptomatic CTRCD, and in patients who de-
toxicity in patients receiving velop moderate or severe asymptomatic CTRCD. A MDT approach
anticancer treatment regarding interruption vs. continuation of anthracycline chemother-
apy is recommended in patients who develop mild symptomatic
A coordinated MDT is recommended to discuss patients with cancer CTRCD.
who develop acute CV complications of their cancer treatment.5 Guideline-based HF therapy is recommended in patients who de-
Referral to a specialized cardio-oncology service is recommended velop symptomatic CTRCD or asymptomatic moderate or severe
for patients with cancer who present with new CTR-CVT during CTRCD during anthracycline chemotherapy. The use of an ACE-I/
and after cancer treatment.12 The prevention and management of ARB or angiotensin receptor–neprilysin inhibitor, a beta-blocker, a
CVD in patients with cancer should generally follow published ESC sodium–glucose co-transporter 2 inhibitor, and a mineralocorticoid re-
Guidelines for specific CVD. This chapter provides guidance on ceptor antagonist is recommended unless the drugs are contraindi-
the management of CTR-CVT that occur during cancer treatment, cated or not tolerated. Up-titration to target doses as described in
and highlights where management differs for patients with cancer the 2021 ESC Guidelines for the diagnosis and treatment of acute
compared with those without. The decision to initiate CV treatment and chronic HF is recommended.14 ACE-I, ARB, and/or beta-blockers
ESC Guidelines 55
should be considered in mild asymptomatic CTRCD while anthracy- symptomatic CTRCD, or moderate or severe asymptomatic
cline chemotherapy continues uninterrupted (Figure 25).1,14,102,424 CTRCD, after recovery of LV function under HF treatment. If there
The beneficial effects of aerobic exercise before and during anthracy- is a compelling reason to continue anthracycline chemotherapy,
cline chemotherapy have been demonstrated and is recommended three other strategies exist in addition to continuing ACE-I/ARB
for patients with cancer who develop CTRCD.11 and beta-blockers at target doses for HF.14 First, minimizing the
A MDT is recommended to discuss restarting anthracycline dose of anthracycline chemotherapy administered. Second, switch-
chemotherapy in patients who developed mild or moderate ing to liposomal anthracycline preparations. Third, pre-treatment

Management of patients with AC-related cardiac dysfunction
Symptomatic CTRCDa Asymptomatic CTRCDa
Very severe/severe Moderate Mild Severe/moderate Mild
Oncological
strategy
Discontinue Interrupt Interrupt

AC AC MDT approach AC Continue
(Class I) (Class I) regarding interruption (Class I) AC
vs. continuation
with CV monitoring
of AC
AND AND AND (Class I)
(Class I)
MDT b
MDT c
MDTc
CV
strategy
GLS decrease >15%

NP increase
or cTn increase
ACE-I/ARB ACE-I/ARB
HF therapy
and/or BB and/or BB
(Class I)
(Class IIa) (Class IIb)
Figure 25 Management of anthracycline chemotherapy-related cardiac dysfunction. AC, anthracycline chemotherapy; ACE-I, angiotensin-converting
enzyme inhibitors; ARB, angiotensin receptor blockers; BB, beta-blockers; cTn, cardiac troponin; CTRCD, cancer therapy-related cardiac dysfunction;
CV, cardiovascular; GLS, global longitudinal strain; HF, heart failure; LV, left ventricular; LVEF, left ventricular ejection fraction; MDT, multidisciplinary
team; NP, natriuretic peptides. aSee Table 3 (Section 3) for complete definition (symptomatic CTRCD: symptomatic confirmed HF syndrome; asymptom-
atic severe CTRCD: LVEF , 40%; asymptomatic moderate CTRCD: LVEF 40–49%; asymptomatic mild CTRCD: LVEF . 50%). bIn rare exceptions, an-
thracycline chemotherapy may be restarted after recovery of LV function with optimal HF therapy. cA MDT discussion is recommended before restarting
anthracycline chemotherapy after recovery of LV function.
56 ESC Guidelines
with dexrazoxane before each further cycle of anthracycline chemo- Asymptomatic patients who have LVEF ≥ 50%
therapy (Section 5.2.1). and who have developed NP .ULN may be
IIb C
Close cardiac monitoring every 1–2 cycles is recommended in pa- considered for ACE-I/ARB and/or
tients who restart anthracycline chemotherapy following an episode beta-blockers.d,211
of CTRCD and in patients with mild asymptomatic CTRCD while Strategies for restarting anthracycline chemotherapy in
they continue anthracycline chemotherapy. patients with CTRCD
Liposomal anthracyclinee may be considered in
patients with moderate or severe symptomatic or

asymptomatic CTRCDc who require further IIb C
the management of cancer treatment-related cardiac
dysfunction during anthracycline chemotherapy anthracycline chemotherapy to reduce the risk of
further CV toxicity.
Recommendations Classa Levelb Dexrazoxanef may be considered in patients with
moderate or severe symptomatic or
Anthracycline chemotherapy-induced symptomatic CTRCD
© ESC 2022
asymptomatic CTRCDc who require further IIb C
HF therapy is recommended for patients who
anthracycline chemotherapy to reduce the risk of
develop symptomatic CTRCD during I B
further CV toxicity.
anthracycline chemotherapy.c,208,425
Discontinuation of anthracycline chemotherapy is ACE-I, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers;
CTRCD, cancer therapy-related cardiac dysfunction; CV, cardiovascular; GLS, global
recommended in patients who develop I C
longitudinal strain; HF, heart failure; LVEF, left ventricular ejection fraction; NP,
symptomatic severe CTRCD.c natriuretic peptides; ULN, upper limit of normal.
a
Temporary interruption of anthracycline b
Level of evidence.
chemotherapy is recommended in patients who c
See Table 3. Significant fall in GLS = relative reduction .15%.
develop symptomatic moderate CTRCDc and a I C d
Avoid hypotension.
e
See text for specific liposomal doxorubicin type and malignancies (Section 5.2).
multidisciplinary approach regarding the decision f
As per the European Medicines Agency: ≥350 mg/m2 doxorubicin or equivalent; as
to restart is recommended. per the United States Food and Drug Administration: ≥300 mg/m2 doxorubicin or
A multidisciplinary approach regarding equivalent.
interruption vs. continuation of anthracycline

I C
chemotherapy is recommended in patients who 6.1.2. Human epidermal receptor 2-targeted
develop mild symptomatic CTRCD.c therapy-related cardiac dysfunction
Anthracycline chemotherapy-induced asymptomatic The diagnosis of HER2-targeted therapy-related CTRCD can be
CTRCD made using the combination of new CV symptoms, imaging, and
biomarkers. Patients may present with symptomatic CTRCD or
Temporary interruption of anthracycline
may be asymptomatic.426 Early treatment of symptomatic and
chemotherapy and initiation of HF therapy is
I C asymptomatic severe CTRCD (LVEF , 40%), according to the
recommended in patients who develop
2021 ESC Guidelines for the diagnosis and treatment of acute
asymptomatic moderate or severe CTRCD.c,22
and chronic HF,14 is recommended to prevent worsening HF,425
A multidisciplinary approach regarding the
particularly when targeted cancer therapy is continued.427 In pa-
decision when to restart is recommended in all
I C tients who develop CTRCD, a MDT is recommended to guide
patients with moderate or severe asymptomatic
clinical decisions. Temporary interruption is recommended
CTRCD.c,22
in patients who develop moderate or severe symptomatic
Continuation of anthracycline chemotherapy is
CTRCD or severe asymptomatic CTRCD (LVEF , 40%) during
recommended in asymptomatic patients who HER2-targeted therapy. In patients with mild symptomatic
have LVEF ≥ 50% and who have developed a I C
CTRCD, a MDT approach is recommended to continue vs. inter-
significant fall in GLSc or a troponin or a NP
rupt HER2-targeted therapy. In patients with asymptomatic mod-
elevation . ULN. erate CTRCD (LVEF 40–49%), HER2-targeted treatment should
Asymptomatic patients who have LVEF ≥ 50% be continued, and cardioprotective therapy (ACE-I/ARB and beta-
and who have developed a significant fall in GLSc blockers) is recommended with frequent cardiac monitor-
IIa B
should be considered for ACE-I/ARB and/or ing.22,33,189 In patients with asymptomatic mild CTRCD (LVEF ≥
beta-blockers.d,75,93,102 50% with a significant new GLS reduction and/or cardiac biomark-
Asymptomatic patients who have LVEF ≥ 50% er increase), continuing HER2-targeted treatment is recom-
and who have developed a troponin elevation mended and cardioprotective therapy (ACE-I/ARB and/or
IIa B
.ULN should be considered for ACE-I/ARB and/ beta-blockers) should be considered.22,211,428,429
or beta-blockers.d,147,211 Frequent cardiac surveillance with cardiac imaging and cardiac
Continued serum biomarkers is recommended in all patients with CTRCD
ESC Guidelines 57
Management of patients with HER2-targeted therapies related cardiac dysfunction

Symptomatic CTRCDa Asymptomatic CTRCDa
Moderate to very severe Mild Severe Moderate Mild
Oncological
strategy
Anti-HER2 MDT approach Anti-HER2

interruption regarding interruption
(Class I) (Class I) Continue anti-HER2 Continue anti-HER2
interruption
under CV monitoring under CV monitoring
vs. continuation of
(Class IIa) (Class I)
AND anti-HER2 AND
(Class I)c
MDT b,c
MDTb,c
CV
strategy
GLS decrease >15%

cTn and NP increase
ACE-I/ARB
HF therapy
and/or BB
(Class I)
(Class IIa)
Figure 26 Management of human epidermal receptor 2-targeted therapy-related cardiac dysfunction. ACE-I, angiotensin-converting enzyme inhibitors;
ARB, angiotensin receptor blockers; BB, beta-blockers; cTn, cardiac troponin; CTRCD, cancer therapy-related cardiac dysfunction; CV, cardiovascular;
GLS, global longitudinal strain; HER2, human epidermal receptor 2; HF, heart failure; LVEF, left ventricular ejection fraction; MDT, multidisciplinary team;
NP, natriuretic peptides. aSee Table 3 (Section 3) (symptomatic CTRCD: symptomatic confirmed HF syndrome; asymptomatic severe CTRCD: LVEF ,
40%; asymptomatic moderate CTRCD: LVEF 40–49%; asymptomatic mild CTRCD: LVEF . 50%). bFor patients in whom HER2-targeted therapy has
been interrupted, whose signs and symptoms of HF do not resolve and/or LVEF remains ,40%, resumption of HER2-targeted therapy may be considered
if no alternative therapeutic option exists. In advanced cancer that only responds well to trastuzumab, the risk/benefit ratio may warrant continued ther-
apy if other options remain limited.22 cFor patients where HER2-targeted therapy has been interrupted and who have recovered LVEF ≥ 40% and are
now asymptomatic, resumption of HER2-targeted therapy should be considered, supported by HF therapy, and echocardiography and cardiac biomarker
assessment every two cycles for the first four cycles after restarting and then the frequency can be reduced.22
who continue HER2-targeted cancer therapies and in those who serum biomarker measurement every two cycles for the first
restart after an interruption following resolution of HF signs and four cycles after restarting HER2-targeted therapy is recom-
symptoms and recovery of LVEF ≥ 40% (and ideally recovery to mended, and then the frequency can be reduced if cardiac function
LVEF ≥ 50%) (Figure 26).22,33,189 Echocardiography and cardiac and biomarker levels remain stable.
58 ESC Guidelines
Recommendation Table 25 — Recommendations for ACE-I/ARB and/or beta-blockers should be

the management of cancer treatment-related cardiac considered in asymptomatic patients receiving
dysfunction during human epidermal receptor 2-tar-
© ESC 2022
HER2-targeted therapies who have LVEF ≥ 50% IIa B
geted therapies
but develop a new troponin or NP rise while
Recommendations Classa Levelb continuing HER2-targeted therapy.e,22,211,428
ACE-I, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers;

HER2-targeted therapy-induced symptomatic CTRCD
CTRCD, cancer therapy-related cardiac dysfunction; GLS, global longitudinal strain;
HF therapy is recommended for patients who HER2, human epidermal receptor 2; HF, heart failure; LV, left ventricular; LVEF, LV

ejection fraction; NP, natriuretic peptides.
develop symptomatic moderate-to-severe
I B a
CTRCD with LVEF , 50%c during HER2-targeted b
Level of evidence.
treatment.14,61,430,431 c
See Table 3.
d
For patients where HER2-targeted therapy has been interrupted and who have
Temporary interruption of HER2-targeted
recovered LVEF ≥ 40% and are now asymptomatic, resumption of HER2-targeted
treatment is recommended in patients who therapy should be considered supported by HF therapy and echocardiography and
develop moderate or severe symptomatic cardiac biomarkers assessment every two cycles for the first four cycles after
I C restarting and then frequency can be reduced.
CTRCDc and the decision to restart should be e
Avoid hypotension.
based on a multidisciplinary approach after
improvement of LV function and symptoms
resolved.d
6.1.3. Immune checkpoint inhibitor-associated
In patients who develop mild symptomatic myocarditis and non-inflammatory heart failure
CTRCD,c HF therapy and a multidisciplinary Myocarditis is a severe complication of ICI with a high fatality
approach regarding the decision to continue vs. I C
rate that most frequently develops during the first 12 weeks of
interrupt HER2-targeted therapy are treatment, although late cases (after week 20) may occur.386
recommended.d,431,432 Other ICI-related CV toxicities include dyslipidaemia, ACS, vascu-
HER2-targeted therapy-induced asymptomatic CTRCD litis, AV block, supraventricular and ventricular arrhythmias, sud-
Temporary interruption of HER2-targeted den death, TTS, non-inflammatory LVD, pericarditis, pericardial
therapy and initiation of HF therapy is effusion, and ischaemic stroke, with higher risks for myocarditis
I C
recommended in patients who develop (odds ratio 4.42) and dyslipidaemia (odds ratio 3.68)
asymptomatic severe CTRCD.c (Figure 27).323,325
A multidisciplinary approach regarding the The diagnosis of ICI-associated myocarditis is initially based on the
decision to restart HER2-targeted treatment is presence of symptoms, a new increase in troponin (associated with
I C
recommended in patients with severe either CV symptoms or non-CV immuno-related adverse events),
asymptomatic CTRCD.c and new ECG abnormalities (AV or intraventricular conduction dis-
Continuation of HER2-targeted therapy should be orders, bradycardia, tachyarrhythmias) (see Section 3;
considered in patients who develop asymptomatic Table 3).17,434,435 Any abnormal finding should prompt urgent CV im-
IIa B aging and other causes of myocardial injury (e.g. ACS, acute infec-
moderate (LVEF 40–49%) CTRCDc with more
frequent cardiac monitoring.33,189,428,433 tious myocarditis) should be excluded. Treatment with high-dose
methylprednisolone should be promptly initiated in haemodynamic-
Continuation of HER2-targeted therapy is
recommended in patients who develop
ally unstable patients (including those with ventricular arrhythmias
I C [VA] or complete AV block) while awaiting further confirmatory
asymptomatic mild (LVEF ≥ 50%) CTRCDc with
testing.436 TTE and CMR are recommended in all patients with sus-
more frequent cardiac monitoring.428
pected ICI-associated myocarditis. Currently, specific CMR features
ACE-I/ARB and beta-blockers are recommended
for ICI-induced myocarditis are not well described and modified Lake
in patients who develop asymptomatic moderate
I C Louise criteria are recommended (Table 3).18 Cardiac fluorodeoxy-
(LVEF 40–49%) CTRCDc during HER2-targeted
glucose positron emission tomography (PET) may be consid-
treatment.e,189
ered437,438 if CMR is not available or contraindicated, although PET
ACE-I/ARB and/or beta-blockers should be
sensitivity is low and requires a strict 18-h carbohydrate-free
considered in asymptomatic patients receiving
fast.439 Endomyocardial biopsy (EMB) should be considered in cases
HER2-targeted therapies who have LVEF ≥ 50% IIa B
where the diagnosis is suspected but not confirmed non-invasively
but develop a significant fall in GLSc while
(e.g. conflicting results of cardiac imaging and biomarkers or clinically
continuing HER2-targeted therapy.e,22,428
unstable patients).440 All cases of ICI-associated myocarditis should
Continued be classified according to the severity of the myocarditis (fulminant
ESC Guidelines 59
Direct CV Toxicity
Arrhythmias Myocarditis Non-inflammatory HF

Takotsubo syndrome Pericarditis Vascular
Indirect CV Toxicity
Thyroid Adrenal Pituitary
Pancreas Embolism
Figure 27 Direct and indirect immune checkpoint inhibitor-related cardiovascular toxicity. CV, cardiovascular; HF, heart failure.
or non-fulminant, including symptomatic but haemodynamically and Cessation of ICI treatment is recommended in patients with can-
electrically stable patients and incidental cases diagnosed at the same cer with fulminant or non-fulminant ICI-associated myocarditis and
time as other immune-related adverse events) to guide the manage- the patient should be admitted to hospital and a level 2 or 3 bed
ment pathway (Figure 28).331 with continuous ECG monitoring is required. CV complications
Interruption of ICI treatment is recommended in all cases of should be treated as per specific ESC Guidelines (HF,14 tachyarrhyth-
suspected ICI-associated myocarditis (any patient developing mias,441,442 AV block,443 or pericardial effusion444).
new cardiac symptoms, new cardiac arrhythmias, new heart Treatment of both non-fulminant and fulminant ICI-associated
blocks, or new troponin increase who has received an ICI therapy myocarditis with methylprednisolone 500–1000 mg i.v. bolus once
in the past 12 weeks) while investigations are performed. Once daily for the first 3–5 days should be started as soon as possible,
the abnormal findings have resolved, a MDT discussion is recom- once the diagnosis is considered likely, to reduce MACE including
mended to determine the risk/benefit to permanent stopping vs. mortality.386,436 If clinical improvement is observed (cTn reduced
resuming ICI treatment in patients with suspected but not con- by .50% from peak level within 24–72 h and any LVD, AV block,
firmed myocarditis. and arrhythmias resolved), switching to oral prednisolone is
60 ESC Guidelines
Management of patients with a definitive diagnosis of ICI-related myocarditis
Severity (fulminant vs.. non-fulminant)a

Discontinue ICI;; hospital admission; ECG monitoring
(Class I)
Methylprednisolone 500–1000 mg i.v.

v. bolus once daily (minimum 3 days)
a
(Class I)
Haemodynamically unstable
Recoveringb Steroid refractory
fulminant myocarditis
Switching to
Second-line immunosuppression Admission to ICU (level 3)
oral prednisolone (1 mg/kg/day)
a
(Class IIa)
AND AND
Weaning protocol by 10 mg/week
W Optimal CV treatment
with troponin monitoring including MCS
AND
Complete recovery Second-line immunosuppression

(Class I)
Figure 28 Diagnosis and management of immune checkpoint inhibitor-related myocarditis. CMR, cardiac magnetic resonance; CV, cardiovascular;
ECG, electrocardiogram; HF, heart failure; ICI, immune checkpoint inhibitor; ICU, intensive care unit; i.v., intravenous; LGE, late gadolinium enhancement;
LVEF, left ventricular ejection fraction; MCS, mechanical circulatory support. aFulminant: haemodynamic instability, HF requiring non-invasive or inva-
sive ventilation, complete or high-grade heart block, and/or significant ventricular arrhythmia. Non-fulminant: including symptomatic but haemo-
dynamically and electrically stable patients and incidental cases diagnosed at the same time as other immuno-related adverse events. Patients may
have reduced LVEF but no features of severe disease. bRecovering: ongoing improvement in patient clinical symptoms, signs, biomarkers, and imaging
parameters, but not yet normalized, while on tapering doses of immunosuppression. Complete recovery: patients with complete resolution of acute
symptoms, normalization of biomarkers, and recovery of LVEF after discontinuation of immunosuppression. CMR may still show LGE or elevated T1 due
to fibrosis, but any suggestion of acute oedema should be absent.
recommended starting at 1 mg/kg up to 80 mg/day. Although the 5 mg/day, and a final reduction from 5 mg/day in 1-mg per week
most appropriate weaning off protocol is not confirmed, a weekly steps.
reduction of oral prednisolone (most commonly by 10 mg per If the troponin does not reduce significantly (.50% reduction
week) under clinical, ECG, and cTn surveillance should be consid- from peak) and/or AV block, ventricular arrhythmias, or LVD persist
ered (Figure 28). A reassessment of LV function and cTn should be despite 3 days of i.v. methylprednisolone plus cardiac treatments,
considered when the prednisolone dose is reduced to 20 mg/day then steroid-resistant ICI-associated myocarditis is confirmed and
and then continue weaning the prednisolone by 5 mg per week to second-line immunosuppression should be considered.22,445,446
ESC Guidelines 61
There is a lack of data to recommend a specific second-line immunosup- EMB should be considered to confirm the
pression regimen and MDT discussion is recommended. Several agents diagnosis of ICI-associated myocarditis if the IIa C
are currently being investigated with promising results from case series diagnosis is suspected but not confirmed after
including i.v. mycophenolate mofetil, anti-thymocyte globulin (anti-CD3 cardiac imaging and biomarkers.c
Interruption of ICI treatment is recommended in
antibody), i.v. immunoglobulin, plasma exchange, tocilizumab, abatacept
patients with confirmed ICI-associated I C
(CTLA-4 agonist), alemtuzumab (anti-CD52 antibody), and tofacitinib.
myocarditis.
Caution is advised against the use of infliximab for steroid-refractory
Continuous ECG monitoring to assess for new
myocarditis and HF.447,448 Patients with fulminant ICI-associated myo- AV block and tachyarrhythmias during the acute I C

carditis, complicated by haemodynamic and/or electrical instability, re- phase is recommended for all patients with
quire admission to the intensive care unit (ICU) and cardiogenic symptomatic ICI-associated myocarditis.
shock should be managed according to the 2021 ESC Guidelines for Early high-dose corticosteroidsd are
the diagnosis and treatment of acute and chronic HF.14 A single dose recommended in patients with cancer and I C
of i.v. methylprednisolone should be considered in clinically unstable pa- confirmed ICI-associated myocarditis.22,436,454
tients with cancer where ICI-induced myocarditis is suspected at pres- Continuation of high-dose corticosteroids is
recommended for the treatment of ICI-associated
entation but before definitive diagnosis can be confirmed.
myocarditis until resolution of symptoms, LV I C
Following recovery from ICI-associated myocarditis and weaning
systolic dysfunction, conduction abnormalities,
of oral steroid therapy, MDT discussion is recommended to review and significant cTn reduction.e
the decision on whether to restart ICI treatment. This depends on Switching from i.v. to oral prednisolone should be
various factors including the severity of the ICI-associated myocardi- considered after clinical improvement (resolution IIa C
tis (fulminant vs. non-fulminant vs. asymptomatic), alternative oncol- of: symptoms, LV systolic dysfunction, conduction
ogy treatment options, metastatic vs. adjuvant/neoadjuvant abnormalities, and significant cTn reductione).f
indication, and reducing from dual ICI to single ICI treatment if trig- Second-line immunosuppression treatment
should be considered in patients with IIa C
gered by combination ICI treatment.449
steroid-refractory ICI-associated myocarditis.g
Non-inflammatory HF syndromes have also been observed in pa-
Admission to ICU (level 3), treatment with i.v.
tients treated with ICI. These include TTS, non-inflammatory HF or
methylprednisolone, and optimal CV treatment
LVD,450 and post-MI HF.451,452 Non-inflammatory HF is generally a including mechanical support (when indicated) is I C
late event and the diagnostic workflow should be based on defining recommended for patients with ICI-associated
the HF phenotype and excluding myocarditis, TTS, and ACS.14 There fulminant myocarditis.14
is also evidence that vasculitis and CAD can occur after ICI treat- A single dose of i.v. methylprednisoloned should
ment.335 HF treatment as per the 2021 ESC Guidelines for the diagno- be considered in unstableh patients with cancer IIa C
sis and treatment of acute and chronic HF is indicated,14 but there is no where ICI-induced myocarditis is suspected.
indication for immunosuppression if myocarditis has been excluded. A multidisciplinary discussion is recommended
© ESC 2022
Interruption vs. continuing ICI therapy depends on the severity of before restarting ICI treatment in selected I C
patients with previous uncomplicated
the HF syndrome and each case should be reviewed by a MDT.
ICI-associated myocarditis.
Arrhythmias, such as AF, can be seen in patients with ICI therapy with-
out myocarditis (e.g. ICI-associated thyroiditis with thyrotoxicosis, AV, atrioventricular; CMR, cardiac magnetic resonance; cTn, cardiac troponin;
CV, cardiovascular; ECG, electrocardiogram; EMB, endomyocardial biopsy; HF, heart
ICI-associated pericarditis, or ICI-associated severe systemic inflamma-
failure; ICI, immune checkpoint inhibitors; ICU, intensive care unit; i.v., intravenous;
tory syndromes). ICI treatment can be continued after excluding LGE, late gadolinium enhancement; LV, left ventricular; LVD, LV dysfunction; LVEF,
myocarditis. LV ejection fraction.
a
b
Level of evidence.
c
See Table 3 for ICI-related myocarditis definition. EMB should be considered in unstable
Recommendation Table 26 — Recommendations for patients or when CMR is contraindicated.
the diagnosis and management of immune checkpoint d
Early: ≤24 h; high-dose corticosteroids (methylprednisolone 500–1000 mg/day).
e
inhibitor-associated myocarditis Reduction of cTn by .50% from peak level.
f
Complete recovery: Patients with complete resolution of acute symptoms,
normalization of biomarkers, or reduction of cTn by .50% from peak level and
recovery of LVEF after discontinuation of immunosuppression are considered to
cTn, ECG, and CV imaging (echocardiography and have achieved complete recovery. CMR may still show LGE or elevated T1 due to
I B fibrosis but any suggestion of acute oedema should be absent. Incomplete
CMR) are recommended to diagnose
recovery: (1) an increase in symptoms or biomarkers of myocarditis or an inability
ICI-associated myocarditis.320,434,435,453 to taper immunosuppression without a clinical or biomarker flare; (2) patients with
In patients with suspected ICI-associated persistent LVD despite resolution of acute symptoms with immunosuppression.
g
myocarditis, temporary interruption of ICI Steroid refractory: non-resolving or worsening myocarditis (clinical worsening or
I C persistent troponin elevation after exclusion of other aetiologies) despite high-dose
treatment is recommended until the diagnosis is
methylprednisolone (Table 3; Supplementary data, Table S1).
confirmed or refuted. h
Unstable: patients with symptomatic HF, ventricular arrhythmias, new complete
Continued heart block.
62 ESC Guidelines
6.1.4. Chimeric antigen receptor T cell and resting 12-lead ECG, continuous ECG monitoring, TTE, and cTn
tumour-infiltrating lymphocytes therapies and and NP are recommended. Admission to ICU (level 3) is recom-
heart dysfunction mended in severe cases due to the risk of malignant cardiac arrhyth-
Although no large-scale studies on the multiple CV complications mias, circulatory collapse, and multiorgan system failure. In general,
among adults treated with CAR-T therapies exist, small studies the degree of elevation of cytokines correlates with the severity of
and case reports have shown that CV complications represent CRS. C-reactive protein is not specific for CRS and changes in
around 20% of adverse events.378 CV complications are associated C-reactive protein may lag behind clinical changes by ≥12 h. A dra-
with high mortality rates, and are secondary to CRS and immune ef- matic elevation of interleukin-6 is a supportive finding for the diagno-

fector cell-associated neurotoxicity syndrome. The most common sis of CRS. Management of the specific CV complication should
CV complications in patients receiving CAR-T therapies are arrhyth- follow ESC Guidelines, with additional management of the CRS
mias (77.6%), including QTc prolongation, ventricular arrhythmias, (e.g. the anti-interleukin-6 receptor antibody, tocilizumab, and
and AF; HF (14.3%); and MI and VTE (0.5%).455 When suspected, a dexamethasone).381
Diagnosis and management workup in patients with cancer-related Takotsubo syndrome
Clinical evaluation Coronary angiography CMR

ECG (invasive or CCTA) to exclude myocarditis and
AND AND
TTE to exclude ACS myocardial infarction
Cardiac serum biomarkers (Class I) (Class I)
CCU/HDU/ICU admission
ECG monitoring
Avoid QT-prolonging Interruption of the For ICI-related TTS:

drugs AND culprit cancer drug AND methylprednisolone
(Class III) (Class I) (1000 mg i.v.)
Y Recovery of function N
MDT
(Class I) MDT approach regarding
interruption vs resuming
the culprit cancer drug
Consider resuming cancer

treatment under close
monitoring
(Class I)
Figure 29 Diagnosis and management workup in cancer-related Takotsubo syndrome. ACS, acute coronary syndromes; CCTA, coronary computed
tomography angiography; CCU, coronary care unit; CMR, cardiac magnetic resonance; ECG, electrocardiogram; HDU, high-dependency unit; ICI, im-
mune checkpoint inhibitor; ICU, intensive care unit; i.v., intravenous; MDT, multidisciplinary team; N, no TTE, transthoracic echocardiography; TTS,
Takotsubo syndrome; Y, yes.
ESC Guidelines 63
Although CV complications are common with TIL therapies, sur- Recommendation Table 27 — Recommendations for
vival does not appear to be significantly affected. The most frequent the diagnosis and management of Takotsubo syn-
CV events are hypotension that may require treatment with i.v. fluids drome in patients with cancer
and pressors, AF, and to a lesser extent, cTn elevation suggestive of
myocardial damage.380 Further research is needed to define mechan-
isms and potential prevention strategies to help clinicians with the Coronary angiography (invasive or CCTA) is
I C
management of these CV events. recommended to exclude ACS.
CMR is recommended to exclude myocarditis and
I B

MI.458
© ESC 2022
6.1.5. Heart failure during haematopoietic stem cell QT-prolonging drugs are not recommended
III C
transplantation during the acute TTS phase.c
456
CV complications during HSCT, including congestive HF, arterial
ACS, acute coronary syndromes; CMR, cardiac magnetic resonance; CCTA, coronary
events, tamponade, and rhythm disturbances (AF, atrial flutter, and computed tomography angiography; LV, left ventricular; MI, myocardial infarction;
supraventricular tachycardia),457 are uncommon but clinically rele- QTc, corrected QT interval; TTS, Takotsubo syndrome.
a
vant, and should be treated as per specific ESC Guidelines (HF,14 ta- b
Level of evidence.
chyarrhythmias,273,441 pericardial effusion,444 or acute coronary c
Until full recovery and normalization of LV function and QTc.
syndrome458). Studies of treatments during HSCT to prevent both
acute and late CV toxicity are limited.145 ACE-I and beta-blockers
may be effective, but this requires further confirmation.
Outpatient and home-based exercise and education programmes in-
6.2. Coronary artery disease
stituted after HSCT can improve exercise capacity and quality of 6.2.1. Acute coronary syndromes
life,459 and the role of exercise pre-habilitation prior to HSCT is Patients with cancer are at increased risk of CAD because of shared
being investigated.460,461 CVRFs34 and CV toxicity of cancer therapy12 compounded by a
cancer-induced pro-inflammatory and prothrombotic state
(Table 7).467,468,470–473
6.1.6. Takotsubo syndrome and cancer Current knowledge on ACS in patients with cancer is based on
The prevalence of malignant diseases is high in patients with TTS observational data and registries demonstrating that, especially
and is a risk factor for worse outcomes. Malignancy itself, some when diagnosed within 1 year, they are at increased risk for major
cancer treatments (5-FU, ICI, VEGFi), and the stress associated CV events, bleeding, and cardiac and non-cardiac mortality.474–480
with the diagnosis, investigations, and treatment are recognized The proportion of ACS patients with a diagnosis of cancer is rising
triggers or predisposing factors for TTS.462–466 Diagnosis using and constitutes about 3% of large series.475
general TTS criteria is recommended.467,468 Investigations in a pa- Diagnosis of ACS is based on the same principles as in patients
tient with cancer with suspected TTS should include clinical exam- without cancer, including symptoms, an early 12-lead ECG, and serial
ination, ECG, TTE, cardiac biomarkers (cTn and NP), and CMR measurements of hs-cTn for patients presenting with possible
(Figure 29).468,469 Most patients require invasive coronary angiog- non-ST-segment elevation ACS (NSTE-ACS).458 Clinical presenta-
raphy to exclude acute MI. In patients with advanced malignancy or tion can be atypical481 or masked by cancer or therapy-related
significant thrombocytopaenia where invasive coronary angiog- side effects; therefore, diagnostic suspicion should be increased in pa-
raphy is contraindicated, a CCTA is recommended. Cardiac im- tients at high CV risk or treated with vascular cardiotoxic therapies
aging studies should be performed as early as possible when the
diagnosis is suspected as LVD can be transient, and if significant
LVD is detected then repeat imaging to confirm recovery is
Table 7 Cancer treatments that predispose to acute
recommended. coronary syndromes
Interruption of the culprit cancer drug in patients with TTS is re-
Accelerated atherosclerosis ADT (GnRH agonists), ICI, nilotinib,
commended. QT-prolonging drugs should be avoided.467 In cases of
ICI-associated TTS, the role of immunosuppression is unknown and and plaque rupture ponatinib, radiation therapy, VEGFi
if myocardial inflammation is present in a TTS pattern on CMR then Vasospasm Bleomycin, fluoropyrimidines, taxanes,
i.v. methylprednisolone is recommended given the overlap between VEGFi, vinca alkaloids
ICI-induced TTS and ICI-induced myocarditis. Limited information Coronary thrombosis Alkylating agents (cisplatin,
exists regarding the feasibility of ICI rechallenge following TTS and cyclophosphamide), erlotinib, ICI, IMiD
after recovery of LV function. (lenalidomide, thalidomide), monoclonal
© ESC 2022
A MDT discussion is recommended after recovery from the antibodies (VEGFi, anti-CD20), nilotinib,
acute phase of TTS and, if restarting the culprit cancer drug is re- platinum chemotherapy, PI, ponatinib,
quired from an oncology perspective, regular cardiac biomarker VEGFi.
monitoring is recommended (e.g. cTn and NP measured before
ADT, androgen deprivation therapy; GnRH, gonadotropin-releasing hormone; ICI,
every ICI cycle, and TTE if a new rise in cardiac biomarkers occurs) immune checkpoint inhibitors; IMiD, immunomodulatory drugs; PI, proteasome
(Figure 29). inhibitors; VEGFi, vascular endothelial growth factor inhibitors.
64 ESC Guidelines
(Table 7). Echocardiography improves the diagnostic precision in pa- Thrombocytopaenia (platelet count , 100 000/µL) is present in
tients with atypical symptoms and assesses for other cardiac causes about 10% of patients with cancer and may complicate ACS manage-
of chest pain. ment. Based on a small series, coronary angiography can be safely per-
Management of ACS in patients with cancer can be challenging be- formed in these patients when preventative measures to avoid
cause of frailty, increased bleeding risk, thrombocytopaenia, increased bleeding are taken: platelet transfusion before catheterization (for
thrombotic risk, and the possible need for future surgery/interven- platelets ,20 000/µL), radial access, careful haemostasis, and
tions.482 Cancer treatment should be temporarily interrupted, and the use of a lower heparin dose (30–50 U/kg).486 Antiplatelets should
an urgent multidisciplinary approach5 is indicated to plan an individua- not be withheld unless platelet count is ,10 000/µL for aspirin or

lized guideline-based management, taking into account cancer status, ,30 000/µL for clopidogrel. For PCI and CABG, experts advise min-
prognosis, and the patient’s preferences regarding invasive manage- imum platelet counts of 30 000/µL and 50 000/µL, respectively.484
ment. As in patients without cancer, admission to a monitored unit In case of MI with non-obstructive coronary arteries, CMR may be
and initiation of appropriate anti-ischaemic and antithrombotic treat- considered to detect other causes of myocardial injury, especially
ment are indicated, in the absence of contraindications. myocarditis and TTS.
A large retrospective propensity score-matching analysis When acute ischaemia is provoked by cancer therapy, alternative
found that percutaneous coronary intervention (PCI), despite cancer therapies should be considered after a MDT discussion. In the
its lower use, was strongly associated with lower adjusted case of coronary vasospasm secondary to fluoropyrimidines, and in
MACE and all-cause mortality in patients with cancer the absence of an alternative therapy, a rechallenge, although contro-
(Hodgkin and non-Hodgkin lymphomas and breast, lung, colon, versial, can be considered in a monitored unit after exclusion of se-
and prostate cancers).483 Therefore, immediate coronary angi- vere CAD (CT or coronary angiography) and after initiation of
ography and PCI are recommended in patients with cancer prophylactic therapy with long-acting nitrates and calcium channel
and ACS if cancer prognosis is ≥6 months or if they have acute blockers (CCB).487–489
complications of ACS (cardiogenic shock, pulmonary oedema, Following ACS, a review of the cancer medications is recom-
ventricular tachyarrhythmias), where PCI offers palliation of mended, and any cancer drug associated with thrombosis and MI
symptoms.483 When stenting is indicated, third-generation should be stopped. Restarting cancer drugs associated with acute
drug-eluting stents are preferred because of the lower risk of thrombosis and MI after ACS (Table 7) should occur only after a
in-stent thrombosis. Balloon angioplasty is associated with MDT to explore other cancer therapies, with appropriate patient
worse outcome474 and should only be used in case of severe education and consent. Cancer therapies not associated with MI
thrombocytopaenia or need for urgent surgery. Fractional can be restarted once revascularization, where indicated, has been
flow reserve or instantaneous free wave ratio are advised by completed and the patient is stabilized on ACS medical therapy with-
experts484 to avoid unnecessary interventions while intravascu- out complications.
lar ultrasound and optical coherence tomography can be used
to ensure optimal stent apposition and expansion, to avoid
thrombotic complications.485 the management of acute coronary syndromes in pa-
Retrospective data have demonstrated a lower use of invasive tients receiving anticancer treatment
management in patients with cancer with ST-segment elevation MI
(STEMI), with a better outcome for invasively treated pa- Recommendations Classa Levelb
tients.475,480,483 PCI has not demonstrated a mortality benefit in pa-
An invasive strategy is recommended in patients
tients with advanced cancer and NSTE-ACS compared with optimal
with cancer presenting with STEMI or high-risk
medical therapy.479 Therefore, a non-invasive approach can be at- I B
NSTE-ACS with life expectancy ≥6
tempted in low-risk (without signs or symptoms of ongoing ischae-
months.475,479,483
mia or haemodynamic instability) NSTE-ACS patients with poor
A conservative non-invasive strategy should be
cancer prognosis (,6 months).
considered in patients with poor cancer
Due to a potentially higher bleeding risk (especially in patients with
prognosisc (with life expectancy ,6 months) and/ IIa C
active GI cancer),477 the preferred antithrombotic strategy after
or very high bleeding risk presenting with STEMI
drug-eluting stent consists of DAPT with aspirin and clopidogrel in-
or NSTE-ACS.479
stead of newer P2Y12 antagonists. The duration of DAPT should be
A temporary interruption of cancer therapy is
kept as short as possible (1–3 months).458 In patients with need for
recommended in patients where the cancer
therapeutic anticoagulation and antiplatelet therapy, a NOAC and I C
therapy is suspected as a contributing
single oral antiplatelet (preferably clopidogrel) is the default strategy
cause.d,10,490
after a short period of triple antithrombotic therapy (up to 1 week in
hospital).458 Coronary artery bypass graft (CABG) surgery can be A short DAPT strategy should be considered in
patients with cancer with very high bleeding risk IIa C
considered in patients with extensive CAD who are not amenable
with PCI, after MDT discussion and where cancer prognosis is treated with PCI for an ACS.e
.12 months. Continued
ESC Guidelines 65
In patients with cancer, thrombocytopaenia, Recommendation Table 29 — Recommendation for

and ACS, aspirin is not recommended if platelets III C the management of chronic coronary syndromes in
patients receiving anticancer treatment
,10 000/µL.
In patients with cancer, thrombocytopaenia, and Recommendation Classa Levelb
ACS, clopidogrel is not recommended if platelets
III C
,30 000/µL and prasugrel or ticagrelor are not Individualized duration of DAPT is recommended
recommended if platelets ,50 000/µL. in patients with cancer with CCS, following
© ESC 2022
revascularization, based upon thrombotic/ I C
Ticagrelor or prasugrel may be considered in

ischaemic and bleeding risk, type and stage of
© ESC 2022
patients with cancer with low bleeding risk and
IIb C cancer, and current cancer treatment.100,498
excessive thrombotic risk who are treated with
PCI for ACS. CCS, chronic coronary syndromes; DAPT, dual antiplatelet therapy.
a
ACS, acute coronary syndromes; CrCl, creatinine clearance; CV, cardiovascular; DAPT, b
Level of evidence.
dual antiplatelet therapy; GI, gastrointestinal; GU, genitourinary; NSTE-ACS,
non-ST-segment elevation acute coronary syndromes; PCI, percutaneous coronary
intervention; STEMI, ST-segment elevation myocardial infarction; ULN, upper limit of
normal. 6.3. Valvular heart disease
a
Class of recommendation. New or worsening VHD in patients with cancer may be related
b
Level of evidence.
c to coexisting conditions, including CTRCD, ACS, PH, endocarditis,
Related to advanced cancer stage and/or severe irreversible non-CV comorbidities.
d
Anticancer therapies associated with high risk of ACS (very common [.10%]): cardiac tumours, and mechanical prosthetic valve thrombosis.499,500
capecitabine, paclitaxel, cisplatin, carfilzomib, bevacizumab, ramucirumab, aflibercept, Pre-existing severe VHD is associated with an increased risk of
axitinib, sorafenib, pazopanib, cabozantinib, lenvatinib, ponatinib, erlotinib.
e CTRCD,12,501–503 and may also pose a risk for cancer surgery out-
High risk of GI or GU bleeding, significant drug–drug interactions, severe renal
dysfunction (CrCl , 30 mL/min), significant liver disease (alanine aminotransferase/ comes. In patients with mechanical prosthetic valves, the risk of
aspartate aminotransferase .2 × ULN), or significant thrombocytopaenia (platelet thrombosis vs. bleeding should be carefully balanced during chemo-
count , 50 000/µL).
therapy treatment. In patients with severe VHD diagnosed at base-
line assessment, a MDT is required before cancer therapy to
decide the best treatment option. Cardiac surgery is frequently chal-
6.2.2. Chronic coronary syndromes lenging in patients with cancer because of comorbidities, frailty, me-
Several cancer treatments are associated with an increased risk of diastinal fibrosis due to prior RT, impaired wound healing, and the
stable angina and chronic coronary syndromes (CCS).491 5-FU and need for urgent oncology treatment (surgery, chemotherapy, tar-
capecitabine can precipitate effort angina in some cases.4,482,492 geted cancer therapies that effect wound healing). Transcatheter
Platinum-containing chemotherapy-induced ischaemia usually occurs aortic valve implantation (TAVI) may be a viable option for patients
after one of the first three cycles and in patients with underlying with cancer with severe aortic stenosis to limit recovery time and de-
CAD.493 The incidence of cardiac ischaemia is 1–5% with antimicro- lays in starting cancer treatment.504–506
tubule agents, 2–3% with small-molecule VEGF-TKI, and 0.6–1.5% Patients with cancer suspected of new or worsening VHD, such as
with VEGFi monoclonal antibody therapies.492 Nilotinib, ponati- dyspnoea or a new cardiac murmur, or those with fever and positive
nib,494 and ICI335 also accelerate atherosclerosis, which can lead to blood cultures, should be screened for endocarditis and managed ac-
stable angina. cording to the recommendations from the 2021 ESC/European
Patients receiving cancer therapy who present with new stable an- Association for Cardio-Thoracic Surgery (EACTS) Guidelines for
gina should have careful clinical evaluation, with aggressive CVRF the management of VHD,507 while considering the cancer-related
modification and an initial medical management of their symp- prognosis. If valve surgery or percutaneous valve treatment is indi-
toms.484 The diagnosis and management of CAD should follow the cated in a patient receiving cancer treatment, then a MDT is recom-
2019 ESC Guidelines for the diagnosis and management of chronic mended regarding type of valve treatment and periprocedural
coronary syndromes.100 management of cancer treatments.
The management of CCS is similar in patients with and with-
out cancer, in accordance with guideline recommendations.100
However, in the setting of CCS, decisions regarding coronary Recommendation Table 30 — Recommendations for
revascularization should be undertaken by a MDT that includes the management of valvular heart disease in patients
receiving anticancer treatment
cardio-oncology, intervention, and oncology specialists.5 PCI in
patients with cancer is associated with an increased risk of Recommendations Classa Levelb
bleeding, 90-day readmissions for acute MI, in-hospital and long-
term mortality, and the need for repeat revascularization, with In patients with cancer and pre-existing severe
the magnitude of risk depending on both cancer type and VHD, management according to the 2021 ESC/
stage.495,496 The excess bleeding risk should be mitigated by EACTS Guidelines for the management of VHD is I C
keeping the duration of DAPT as short as possible. 497,498 The recommended, taking into consideration cancer
risk is higher in patients with a cancer diagnosis within the pre- prognosis and patient preferences.507
ceding year.477 Continued
66 ESC Guidelines
In patients with cancer developing new VHD may have a limited efficacy if a cancer therapy is the specific cause
during cancer therapy, management according to of the AF.508 Among rate-control drugs, beta-blockers are preferred,
the 2021 ESC/EACTS Guidelines for the especially if the cancer therapies have potential CTRCD risk, where-
I C
as diltiazem and verapamil should be avoided where possible due to
© ESC 2022
management of VHD507 is recommended, taking
into consideration cancer prognosis and patient their drug–drug interactions and negative inotropic effects.508 The
comorbidities. possibility of AF ablation should be discussed in selected patients
with HF/LVD and/or uncontrolled symptoms, taking into consider-
EACTS, European Association for Cardio-Thoracic Surgery; ESC, European Society of
Cardiology; VHD, valvular heart disease.
ation cancer status and prognosis in the context of a MDT

a
Class of recommendation. approach.522
b
Level of evidence. A complex issue in patients with cancer with new AF is risk strati-
fication for stroke/systemic embolism, which according to guidelines,
should be based on the CHA2DS2-VASc score (Congestive heart fail-
6.4. Cardiac arrhythmias ure, Hypertension, Age ≥ 75 years [2 points], Diabetes mellitus,
6.4.1. Atrial fibrillation Stroke [2 points]—Vascular disease, Age 65–74 years, Sex category
AF may occur in patients with cancer in different settings: it may be a [female]).273,523,524 The CHA2DS2-VASc score has not been exten-
marker of cancer type or occult cancer, or it may develop in patients sively validated in patients with cancer.525 In a large cohort of patients
undergoing surgery, chemotherapy, or RT.508,509 All types of cancer with AF, the predictive value of the CHA2DS2-VASc score was lower
show an increased risk of AF compared with the control group, but in patients with cancer than in those without, but a progressive in-
the risk of AF depends on the cancer type and stage.510,511 AF during crease in the risk of ischaemic stroke according to the
a cancer treatment may be caused by a specific therapy or interaction CHA2DS2-VASc score was also found in AF patients with cancer
with a pre-existing substrate in older patients with cancer. (from 0.9% per year to 8.9% per year).519 However, the scope of
During cancer therapy AF may occur with a frequency ranging this score is not to identify high-risk patients, but rather to identify
from 2% to 16%, according to a variety of factors,4,490,508,512–514 low-risk individuals in whom anticoagulation can be avoided. A study
and may present either as first-diagnosed AF or as recurrence of par- based on the Danish healthcare system data set found that
oxysmal AF. The risk of developing AF is greater in patients older CHA2DS2-VASc scores of 0 and 1 in patients with recent cancer
than 65 years and/or with pre-existing CVD.4,509,512,515 Cancer sur- were linked with higher risk of stroke/thromboembolism at 2 years
gery is associated with a variable rate of AF occurrence, with the than in patients without recent cancer.526 This concept should be
highest incidence reported for lung surgery, ranging from 6% to considered in defining the risk/benefit ratio of anticoagulation in indi-
32%, but with occurrence also in cases of non-thoracic surgery vidual patients with cancer. Therefore, the decision for anticoagula-
(e.g. 4–5% after colectomy).509 tion in patients with an active malignancy should take into account
Many anticancer drugs have been associated with an increased risk the enhanced thrombotic and/or bleeding risk and other risk predic-
of AF both in terms of incident and recurrent AF (Supplementary tion scores used for general AF populations.509 For bleeding risk as-
data, Table S18).251 AF may occur shortly after treatment516 or sessment, the HAS-BLED (Hypertension, Abnormal renal and liver
weeks or months after starting treatment.517,518 The pathophysi- function, Stroke, Bleeding Labile international normalized ratio,
ology of AF associated with cancer is complex and has been exten- Elderly, Drugs or alcohol) score may be considered. A proposed ap-
sively reviewed elsewhere (Figure 30).509 proach to anticoagulation therapy in cancer, based on the acronym T
In patients with cancer, the occurrence of AF is associated with a (thrombotic risk), B (bleeding risk), I (interactions among drugs), P
two-fold higher risk of systemic thromboembolism/stroke and a six- (patient access and preferences), is outlined in Figure 31.519,527
fold increase in the risk of HF.4,509,512 The coexistence of cancer in- Long-term anticoagulation is recommended in adult patients with
creases the risk of all-cause mortality, major bleeding, and intracranial CHA2DS2-VASc score ≥2 in men or ≥3 in women and must be con-
haemorrhage in patients with AF. The association between cancer sidered also when the score is 1 in men and 2 in women.273 The clin-
and ischaemic stroke differs between cancer types, and in some ical pattern of AF (i.e. first detected, paroxysmal, persistent,
types, the risk of bleeding seems to exceed the thromboembolic long-standing persistent, permanent, post-operative) should not in-
risk.519 The management of AF in patients with cancer should follow fluence the indication of thromboprophylaxis.273 The same approach
the 2020 ESC Guidelines for the diagnosis and management of atrial can be proposed for patients with cancer and AF, also considering
fibrillation273 and the ‘ABC pathway’ (Atrial fibrillation Better Care) that the CHA2DS2-VASc score likely underestimates their thrombo-
approach should be applied (A: Anticoagulation to avoid stroke/sys- embolic risk.530 In the specific setting of cancer, decision-making on
temic embolism, B: Better symptom control with rate- and/or long-term oral anticoagulation should also consider the cancer-
rhythm-control drugs and interventions, and C: Comorbidities and related type, stage, prognosis and the potentially changing thrombo-
CVRF management, including lifestyle changes).273,520 embolic or bleeding risk.508,509 The use of vitamin K antagonists
The acute management of AF in patients with cancer should con- (VKA) in cancer is limited by their drawbacks in this setting; however,
sider electrical cardioversion in cases of haemodynamic instability,521 they remain the only indicated anticoagulants in patients with mod-
while in others, the alternative between rate and rhythm control has erate to severe mitral stenosis or a mechanical prosthetic valve.
several important considerations specific to patients with cancer. LMWH constitute a viable short-term anticoagulation option, par-
Drugs for rhythm control may lead to QT-interval prolongation,369 ticularly in hospitalized patients with a recent cancer diagnosis, ad-
frequently have drug–drug interactions with cancer therapies, or vanced cancer disease, or during some cancer treatments (e.g.
ESC Guidelines 67
Pathophysiology of AF associated with cancer

Ageing
Anticancer CV and metabolic

treatmentsa comorbiditiesb
AF
in cancer
Inflammation
Hypoxia
Cancer
ANS imbalance
surgery
Paraneoplastic
manifestations
Cancer
invasion
Figure 30 Pathophysiology of atrial fibrillation associated with cancer. AF, atrial fibrillation; ANS, autonomic nervous system; CV, cardiovascular; DM,
diabetes mellitus; HF, heart failure; IHD, ischaemic heart disease; VHD, valvular heart disease. aSupplementary data, Table S18. bObesity, hypertension,
DM, CVDs (HF, VHD, IHD, cardiomyopathies, cardiac amyloidosis), thyroid diseases, obstructive sleep apnoea, chronic obstructive pulmonary disease,
chronic kidney disease, autonomic dysfunction, alcohol consumption, genetic predisposition.
patients receiving myelosuppressive chemotherapy or with recent Events in Atrial Fibrillation], ENGAGE AF-TIMI 48 [Effective
active bleeding). However, LMWH efficacy for stroke or systemic Anticoagulation with Factor Xa Next Generation in Atrial
embolism prevention in AF has not been established and their Fibrillation–Thrombolysis in Myocardial Infarction 48]) and obser-
use is only based on their proven efficacy and safety in VTE. The vational data suggest better safety and at least similar effectiveness
use of a NOAC for AF has not been evaluated in a dedicated of the NOAC when compared with VKA in patients with AF and
RCT in patients with cancer. However, secondary analyses of sem- active cancer.531–538 NOAC use in cancer is limited by drug–drug
inal NOAC trials using direct factor Xa inhibitors (ROCKET AF interactions,508 severe renal dysfunction, increased risk of bleeding
[Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition in patients with unoperated or residual GI or genitourinary (GU)
Compared with Vitamin K Antagonism for Prevention of malignancies, or impaired GI absorption.
Stroke and Embolism Trial in Atrial Fibrillation], ARISTOTLE Left atrial appendage (LAA) occluder devices are used in very se-
[Apixaban for Reduction in Stroke and Other Thromboembolic lected patients with cancer in clinical practice. The potential
68 ESC Guidelines
Structured approach to anticoagulation for AF in patients with cancer
Assess Thromboembolic risk: Long-term anticoagulation

according to CHA2DS2-VASc score
Cancer-related risk (cancer type and stage, cancer treatment) ≥2 (men) or ≥3 (women) (Class I)
T CHA2DS2-VASc score for risk stratification (Class IIa)a 1 (men) or 2 (women) (Class IIa)
0 (men) or 1 (women) (Class IIb)

Assess Bleeding risk:
Thrombocytopaenia
GI/GU cancer, GI comorbidities, or GI toxicity
B Recent or evolving intracranial lesions
Active bleeding or recent major bleeding
Severe renal dysfunction (eGFR <30 mL/min/1.73 m2)
Bleeding risk scores (e.g., HAS-BLED)
Assess drug-drug Interactions (P-glycoprotein, CYP3A4):
I Anticancer agents
Supportive therapies
P Assess Patient preferences and drug availability
Thromboembolic and
Very high bleeding riskb Y No anticoagulation bleeding risk reassessment
(Class I)
N
Type of anticoagulant LAA oclusionc

treatment (Class IIb)
Moderate/severe mitral stenosis VKA

Y
or mechanical prosthetic valve (Class IIa)
Patients suitable NOAC

Y
for NOACd (Class IIa)
LMWH
N
(Class IIa)
Figure 31 Structured approach to anticoagulation for atrial fibrillation in patients with cancer. AF, atrial fibrillation; CHA2DS2-VASc, Congestive heart
failure, Hypertension, Age ≥ 75 years (2 points), Diabetes mellitus, Stroke (2 points)—Vascular disease, Age 65–74 years, Sex category (female); CrCl,
creatinine clearance; eGFR, estimated glomerular filtration rate; GI, gastrointestinal; GU, genitourinary; HAS-BLED, Hypertension, Abnormal renal and
liver function, Stroke, Bleeding Labile international normalized ratio, Elderly, Drugs or alcohol; LA, left atrial; LAA, left atrial appendage; LMWH,
low-molecular-weight heparins; N, no; NOAC, non-vitamin K antagonist oral anticoagulant; VKA, vitamin K antagonists; Y, yes. aIn selected patients, car-
diac imaging parameters related to increased thromboembolic risk should be considered (LAA thrombus, severely dilated left atrium, severely impaired
LA strain528). bVery high bleeding risk: active or recent major bleeding (,1 month previously); recent/evolving intracranial lesions; platelet count ,25
000/µL. According to the International Society on Thrombosis and Haemostasis,529 major bleeding is defined as a fall in haemoglobin level ≥2 g/dL and/or
transfusion of ≥2 units of red blood cells and/or fatal bleeding and/or bleeding in a critical area (intracranial, intraspinal, intraocular, pericardial,
intra-articular, intramuscular with compartment syndrome, or retroperitoneal). cPercutaneous left appendage closure may be considered in pa-
tients with a life expectancy of .1 year who are at high thromboembolic and bleeding risk and in whom anticoagulation is contraindicated. dConditions
favouring LMWH: unoperated GI/GU cancer; GI comorbidities or toxicity; severe renal dysfunction (CrCl , 15 mL/min); NOAC major drug–drug
interactions, platelet count ,50 000/µL.
ESC Guidelines 69
complications related to the implant—including device-related throm- Long-term anticoagulation should be considered
bosis—and the lack of prospective data in the setting of patients with for stroke/systemic thromboembolism
prevention in patients with cancer with AF and a
cancer have to be taken into consideration for this option. In a recent IIa C
CHA2DS2-VASc score = 1 (men) or = 2
retrospective analysis of patients referred to LAA occlusion the risk of (women) as per the 2020 ESC Guidelines for the
in-hospital ischaemic stroke/transient ischaemic attack was higher in diagnosis and management of atrial fibrillation.273
patients with active cancer than in those with no cancer or prior his- Patients with cancer,c AF, and CHA2DS2-VASc
tory of cancer. The rate of in-hospital composite outcome (in-hospital score 0 (men) or 1 (women) may have a higher
thrombotic risk than patients without cancer and IIb C
death, ischaemic stroke/transient ischaemic attack, systemic embolism,
may be considered for therapeutic anticoagulation

bleeding requiring blood transfusion, pericardial effusion/cardiac tam-
after consideration of the bleeding risk.526
ponade treated with pericardiocentesis or surgically, and removal of Thromboembolic and bleeding risk reassessment
embolized device) and 30-day/180-day readmission outcomes were is recommended during follow-up in patients with I C
not significantly different between the groups.539 cancer with AF.d,273
The onset of AF may be related to transient factors, such as the NOAC should be considered for stroke
peri-operative period or the effect of drugs known to facilitate AF prevention in preference to LMWH and VKA
(excluding patients with mechanical heart valves IIa B
onset. The traditional assumption that in these cases, AF may occur
or moderate-to-severe mitral stenosis) in patients
as an isolated event without recurrence may not be valid as the oc- without a high bleeding risk, significant drug–drug
currence of AF may often be related to a pre-existing atrial substrate interactions, or severe renal dysfunction.531–537
with vulnerability to AF.540 Post-operative AF has been associated LMWH should be considered in patients with
with a four- to five-fold risk of AF recurrence in the following 5 years, active cancere and AF who are not suitable for IIa C
NOACf.525
along with a comparable long-term thromboembolic risk with AF not
LAA occlusion may be considered for stroke
related to surgery.273,540,541 Anticoagulation therapy yielded a simi-
prevention in patients with cancer with AF and IIb C
larly lower risk of thromboembolic events and all-cause death in contraindications for long-term anticoagulation
both groups.541 In the absence of direct evidence, anticoagulation with a life expectancy .12 months.273,539
to prevent thromboembolic events should be considered in patients Antiplatelet therapy or prophylactic LMWH are
at risk for stroke with AF after cancer surgery considering the antici- not recommended for stroke or systemic III C
thromboembolism prevention in AF with
pated net clinical benefit and informed patient preferences.273
cancer.273
Similarly, in patients with AF apparently related to transient factors
Heart rate control strategy, preferably with
© ESC 2022
—such as chemotherapy, other drugs, or electrolyte disturbances beta-blockers, should be considered in patients IIa C
—a careful clinical assessment of the propensity to further develop who develop well-tolerated AF while they are
AF is recommended, with need to revisit the risk/benefit ratio of receiving active cancer treatmentg.
long-term prescription of anticoagulation after a period of 3 months. 5-FU, 5-fluorouracil; AF, atrial fibrillation; BMI, body mass index; CHA2DS2-VASc,
In patients with cancer and newly detected or recurrence of AF, de- Congestive heart failure, Hypertension, Age .75 years (2 points), Diabetes mellitus,
cision making on anticancer treatment requires a cardio-oncology MDT Stroke (2 points)—Vascular disease, Age 65–74 years, Sex category (female); CrCl,
creatinine clearance; eGFR, estimated glomerular filtration rate; EGFR, epidermal
management,5 taking into account that neither the presence nor the risk growth factor receptor; ESC, European Society of Cardiology; HF, heart failure; LAA,
of AF constitutes contraindications to anticancer treatment.508,517 left atrial appendage; LMWH, low-molecular-weight heparins; LV, left ventricular;
MM, multiple myeloma; NOAC, non-vitamin K antagonist oral anticoagulants; VKA,
vitamin K antagonists.
a
Recommendation Table 31 — Recommendations for b
Level of evidence.
the management of atrial fibrillation in patients re- c
Factors that may increase thromboembolic risk in patients with cancer including
ceiving anticancer treatment comorbidities (proteinuria . 150 mg/24 h, eGFR , 45 mL/min/1.73 m2, BMI ≥ 30 kg/m2,
thrombophilia), cancer type (pancreatic, gastric, ovarian, brain, lung, MM), cancer stage
(metastatic disease) anticancer therapies: alkylating agents, aflibercept, bevacizumab,
anthracyclines, capecitabine, 5-FU, gemcitabine, methotrexate, EGFR inhibitors,
CHA2DS2-VASc score should be considered for bleomycin, axitinib, lenvatinib, pazopanib, sorafenib, sunitinib, carfilzomib, irinotecan,
risk stratification for stroke/systemic taxanes, tasonermin, tretinoin.
d
IIa C Stroke and bleeding risk may change during both cancer treatment and the course of the
thromboembolism taking into account that it may
underlying disease; reassessment is important to inform treatment decisions and address
underestimate the actual thromboembolic
potentially modifiable bleeding risk factors.
risk.519,526 e
Patients receiving cancer treatment, patients diagnosed with cancer in the past 6 months,
Long-term anticoagulation is recommended for and patients with progressive or advanced disease.
f
stroke/systemic thromboembolism prevention in High bleeding risk, severe renal dysfunction (CrCl , 15 mL/min); NOAC major drug–drug
patients with cancer with AF and a interactions.
I C g
CHA2DS2-VASc score ≥2 (men) or ≥3 (women) Asymptomatic or mild symptomatic patients without HF signs or symptoms or
as per the 2020 ESC Guidelines for the diagnosis deterioration of LV function. The optimal heart rate target in AF patients is unclear. A
resting heart rate ,110 bpm (i.e. lenient rate control) should be considered as the
and management of atrial fibrillation.273
initial heart rate target for rate control therapy. A review of rate vs. rhythm strategy
Continued should be made at the end of cancer treatment.273
70 ESC Guidelines
6.4.2. Long corrected QT interval and ventricular Table 9 Classification of corrected QT interval pro-
arrhythmias longation induced by cancer drug therapy
VA are not common during cancer, although their incidence in-
Classification Drugs
creases in patients with advanced cancer and CV comorbid-
ities.49,259,516,542 Mechanisms proposed to explain cancer High risk: QTcF prolongation ≥ 10 ms and risk • Aclarubicin
therapy-induced VA include: (1) direct effects of cancer drugs on of TdP • Arsenic trioxide
the activity/expression of ionic channels that regulate the ventricular • Glasdegib
action potential,4,369,442,516,542,543 and (2) a permanent arrhythmo- • Nilotinib

genic substrate created by cancer and systemic inflammation caused • Oxaliplatin
by cancer, pre-existing CV comorbidities, and/or a new • Pazopanib
CTR-CVT.4,9,259,369,442,516,542,543 • Ribociclib
Treatment of cancer therapy-induced VA should follow general • Sunitinib
clinical guidelines.22,442,544 In patients with asymptomatic self- • Toremifene
• Vandetanib
terminating VA, drug discontinuation is not required unless they
have additional CVRF or persistent ECG abnormalities.270 Moderate risk: QTcF prolongation ≥ 10 ms • Abarelix
and low or no risk of TdP (or uncertain) • Belinostat
Symptomatic VA require cancer drug dose reduction or discontinu-
• Brigantinib
ation and patients should be referred to the cardiologist for evalu-
• Carbozantinib
ation and treatment.4,442
• Ceritinib
Recurrent symptomatic life-threatening VA require urgent inter-
• Crizotinib
vention.4,270,442,544 The administration of class IA, IC, and III anti-
• Dovitinib
arrhythmic drugs is limited by the risk of drug–drug interactions
• Entrectinib
and QTc prolongation. Beta-blockers and class IB drugs are less likely • Eribulin
to cause drug interactions or QTc prolongation. Beta-blockers are • Gilteritinib
the preferred choice if the cancer drug is also associated with • Ivosidenib
CTRCD. Amiodarone is the antiarrhythmic drug of choice in patients • Lapatinib
with structural heart disease and haemodynamic instability. • Lenvatinib
• Osimertinib
Table 8 Risk factors for drug-induced QT prolonga- • Panobinostat
tion and torsade de pointes • Rucaparib
• Selpercatinib
Correctable Non-correctable • Sorafenib
• Tipiracil/
QT-prolonging drugsa Acute myocardial ischaemia trifluridine
• Antiarrhythmics Age . 65 years • Vemurafenib
• Antibiotics Baseline QTc interval Low risk: QTcF prolongation , 10 msa • ADT
• Antidepressants prolongationb
• Afatinib
• Antifungals Family history of sudden death • Axitinib
• Antiemetics (congenital LQTS or genetic • Binimetinib
• Antihistamines polymorphism) • Bortezomib
• Antipsychotics Female sex • Bosutinib
• Loop diuretics Impaired renal function (for • Carfilzomib
• Opioids (methadone) renally excreted drugs) • Dabrafenib
Bradyarrhythmia Liver disease (for hepatically • Dasatinib
Electrolyte imbalance/ excreted drugs) • Encorafenib
abnormalities Personal history of syncope or • Midostaurin
• Hypokalaemia (≤3.5 mEq/L) drug-induced TdP • Pertuzumab
• Hypomagnesaemia Pre-existing CVD (CAD, HF, LV • Ponatinib
(≤1.6 mEq/L) hypertrophy) • Romidepsin
© ESC 2022
• Hypocalcaemia (≤8.5 mEq/L) • Quizartinib

© ESC 2022
Inadequate dose adjustment of • Tamoxifen

renal or hepatic cleared • Vorinostat
QT-prolonging drugs
ADT, androgen deprivation therapy; QTcF, corrected QT interval using Fridericia
CAD, coronary artery disease; CVD, cardiovascular disease; HF, heart failure; LQTS, correction; TdP, torsade de pointes.
a
long QT syndrome; LV, left ventricular; QTc, corrected QT interval; TdP, torsade de ADT may prolong the QTc interval (GnRH agonist, GnRH antagonist, bicalutamide,
pointes. flutamide, apalutamide, darolutamide, enzalutamide, and abiraterone) (see Figure 21).
a
See https://www.crediblemeds.org. Developed from EMA prescribing information,252 FDA prescribing information,253
b
QTc using Fridericia correction (QTcF = QT/3√RR) is recommended in patients with and AZCERT.547
cancer.
ESC Guidelines 71
Decisions on the use of antiarrhythmic drugs or device therapy (car- ,500 ms.442 Although the incidence of QTc prolongation
dioverter defibrillators, catheter ablation) should consider life ex- ≥500 ms and TdP is low during cancer therapy, QTc prolongation
pectancy, quality of life, and complication risks.349 to levels that require closer monitoring (QTc ≥ 480 ms) is more
Most cancer therapy-induced VA are related to a prolongation of common (Table 9).4,9,22,45,48,49,259,369,516,543,546 Changes in the QT
QTc leading to the development of TdP.259,516,542 Risk factors for interval of .60 ms from baseline should not routinely affect treat-
QTc prolongation and TdP are summarized in Table 8.4,22,45,48,516,543 ment decisions if the QTc remains ,500 ms.1 Cardiology consult-
The upper 99% limits of normal for QTc values in the general ation is advised in patients with an abnormal baseline QTc interval,
population are 450 ms for men and 460 ms for women.545 patients treated with drugs that prolong the QT interval, those

Although there is no threshold of QTc prolongation at which TdP who develop new cardiac symptoms (syncope or pre-syncope, rapid
can occur, a QTc ≥ 500 ms is associated with a two- to three-fold palpitations or QTc prolongation with new-onset bradycardia, high
higher risk for TdP, while TdP rarely occurs when QTc is degree of heart block), and/or those with known inherited arrhythmia
QTc monitoring before a r treat e t t c ro o a t ca cer r a
Baseline 12-lead ECG: QTcF

Correct baseline risk factors for QTc prolongationb
Avoid/stop concomitant QTc prolonging drugsb
Ensure K+ >4.0 mmol/L, Mg2+ >2.0 mg/dL (>1.10 mmol/L) and normal values of corrected Ca2+
≤480 ms QTcF value >480 ms
Start therapy Cardio-oncology evaluation

ECG monitoringc Correct reversible causesb
QTcF value QTcF value
>480 ms and TdP or >480 ms and

≤480 ms ≥500 ms ≥500 ms
<500 ms sustained VA <500 ms
Correct Drug Drug

reversible withhold interruption
QTcF monitoring causesb Correct Correct Consider
Alternative
according to drug- Weekly ECG reversible reversible alternative
treatment
specific protocol monitoring causesb causesb treatment
(Class I) (Class I) (Class I)
ECG after any QTcF value

dose increase of QTc-
prolonging drug Resume treatment at the same
(class I) ≤480 ms or reduced dose according
to drug-specific protocol
Consider restarting treatment
>480 ms and
If QTcF <500 ms at reduced dose
<500 ms
Continue treatment at same or (Class IIb)
reduced dose according to MDT to discuss alternative
drug-specific protocol ≥500 ms cancer treatments
(Class I) (Class I)
Figure 32 Corrected QT interval monitoring before and during treatment with corrected QT interval-prolonging anticancer drugs. Ca2+ , calcium; ECG,
electrocardiogram; K+, potassium; MDT, multidisciplinary team; Mg2+, magnesium; QTc, corrected QT interval; QTcF, corrected QT interval using
Fridericia correction; TdP, Torsade de pointes; VA, ventricular arrhythmias. QT interval using Fridericia correction (QTcF = QT/3√RR) is recommended in
patients with cancer. Upper 99% limits of normal for QTc values in the general population are 450 ms for men and 460 ms for women.369 aTable 9.
b
Table 8 and https://www.crediblemeds.org. cECG monitoring at baseline, once steady-state anticancer drug levels have been achieved, after each dose modi-
fication, or any treatment interruption .2 weeks; monthly for the first 3 months, and then periodically during treatment depending on patient-specific risk
factors and cancer treatment.
72 ESC Guidelines
disorders.4,45,48,442,544 The challenges for the cardio-oncology teams Restarting QTc-prolonging cancer therapy
are to identify patients more susceptible to developing VA, determine
A multidisciplinary discussion is recommended
whether a VA is directly due to CTR-CVT, individualize the treatment
before restarting QTc-prolonging drugs in
strategy, and optimize clinical monitoring during treatment. I C
patients who have developed significant QTcF
Figure 32 shows the algorithm for the management of QTc pro-
prolongation, to discuss alternative cancer
longation during cancer therapy. In patients with cancer, the
treatments.4,22,259,349,442,546
Fridericia formula is recommended and has demonstrated less error
In patients who experienced significant QTcF
than other correction methods such as Bazzett at both high and low
prolongation, restarting the culprit

heart rates.44 In patients treated with QTc-prolonging drugs, serum
QTc-prolonging cancer treatment may be IIb C
electrolytes and other risk factors should be closely monitored and
considered, ideally at a reduced dose according to
corrected, and concomitant QT-prolonging drugs avoided if pos-
each drug recommendation.45,259,349,442,546,549
sible.4,22,45,369,543 For selected cancer drugs, there are specific manu-
Weekly ECG monitoring during the first 4–6
facturer recommendations for ECG monitoring during treatment,
© ESC 2022
weeks and then monthly thereafter is
dosage adjustments, or discontinuation of therapy in case of QTc I C
recommended in patients with cancer after
prolongation.548
restarting QTc-prolonging cancer therapy.549
Although there are no recommendations, patients with cancer
with QTc prolongation associated with severe bradycardia or sinus ECG, electrocardiogram; QTc, corrected QT interval; QTcF, corrected QT interval
pauses may benefit from isoprenaline infusion or temporary pa- using Fridericia correction; TdP, torsade de pointes.
a
cing. Despite present restrictions, the improved prognosis for b
Level of evidence.
many malignancies is increasing the number of patients with cancer c
See https://www.crediblemeds.org and Table 8.
who are candidates for an implantable cardioverter defibrillator
(ICD), particularly when life expectancy is .1 year (including pa-
tients who experienced resuscitated sudden cardiac death or se- 6.4.3. Bradyarrhythmias
vere VA from a QTc-prolonging drug with no alternative AV conduction disease can be caused by ICI in the presence or ab-
treatment available). sence of myocarditis. If the PR interval increases (new first-degree
heart block) in patients treated with ICI, serial ECG monitoring is re-
commended, and if PR prolongation to .300 ms develops, the pa-
tient should be hospitalized under close ECG monitoring and i.v.
methylprednisolone is recommended.550
the management of long corrected QT interval and IMiD (thalidomide, pomalidomide)285 and ALK inhibitors (crizoti-
ventricular arrhythmias in patients receiving antican- nib, alectinib, brigatinib, or ceritinib)551 are associated with sinus
cer treatment bradycardia. Holter ECG monitoring is recommended to exclude
significant sinus pauses in symptomatic patients. In asymptomatic pa-
Recommendations Classa Levelb tients with normal LV function, sinus bradycardia is usually well tol-
How to manage QTc prolongation in patients with cancer
erated and treatment can continue. If patients are symptomatic
(syncope, pre-syncope of reduced exercise tolerance from chrono-
Discontinuation of QTc-prolonging cancer
tropic incompetence) then a trial of cancer drug withdrawal to con-
therapy is recommended in patients who develop
I C firm causation with the symptoms is recommended. A MDT
TdP or sustained ventricular tachyarrhythmias
discussion is needed to analyse risks/benefits of alternative cancer
during treatment.549
therapies vs. restarting the culprit cancer therapy at a lower dose
Temporary interruption of QTc-prolonging
with heart rate monitoring. In selected cases, when no cancer treat-
cancer therapy is recommended in patients who
ment alternative is available, pacing is indicated.
develop asymptomatic QTcF ≥ 500 ms and an I C
ECG should be repeated every 24 h until
6.5. Arterial hypertension
resolution of the QTcF prolongation.549
Arterial hypertension in patients with cancer may be caused by their
Immediate withdrawal of any offending drug and cancer treatments (e.g. VEGFi, second- and third-generation
correction of electrolyte abnormalities and other BCR-ABL TKI, brigatinib, ibrutinib, fluoropyrimidines, cisplatin, abir-
I C
risk factorsc is recommended in patients with
aterone, bicalutamide, enzalutamide), non-cancer drugs (e.g. corti-
cancer who develop QTcF ≥ 500 ms.349,442,546 costeroids, non-steroidal anti-inflammatory drugs), and other
Weekly ECG monitoring is recommended in factors including stress, pain, excessive alcohol consumption, renal
asymptomatic patients with cancer with QTcF impairment, untreated sleep apnoea, obesity, and reduced exer-
I C
480–500 ms who are treated with a cise.552 In all patients with cancer with new hypertension assessment,
QTc-prolonging cancer therapy.349,442,546 correction of these other factors is important before considering
A 12-lead ECG is recommended after any dose interruption of a cancer treatment.
increase of QTc-prolonging cancer I C Untreated hypertension344 is a confirmed risk factor of HF during
therapy.270,442,544 treatment with anthracyclines,553 ibrutinib,264 and VEGFi.554 Given
Continued that many of the cancer therapies that cause hypertension also cause
ESC Guidelines 73
CTRCD, treatment of hypertension with ACE-I or ARB as first-line In patients with resistant cancer therapy-related hypertension,
therapy is recommended to reduce the risk of CTRCD. spironolactone, oral or transdermal nitrates, and/or hydralazine
Combination therapy with an ACE-I or ARB and a dihydropyridine should be considered. In patients with cancer with evidence of
CCB is recommended in patients with cancer with systolic BP ≥ high sympathetic tone, stress, and/or pain, beta-blockers including
160 mmHg and diastolic BP ≥ 100 mmHg due to the more rapid on- carvedilol or nebivolol should be considered. Diuretics, preferably
set of BP control with the combination compared with ACE-I/ARB spironolactone, may be considered in patients with cancer with
monotherapy (Figures 33 and 34). hypertension and evidence of increased fluid retention, with moni-
If severe hypertension is diagnosed (systolic BP ≥ 180 mmHg or toring of BP, electrolytes, and renal function.

diastolic BP ≥ 110 mmHg), the competing cancer and CV risks The decisions to initiate BP treatment and BP targets during the
should be evaluated by a MDT, and any cancer therapy associated management of cancer-drug induced hypertension depend upon
with hypertension should be deferred or temporarily withheld until the context of the cancer and prognosis (Figure 34). CS should be
the BP is controlled to values ,160 mmHg (systolic BP) and treated according to the 2018 ESC/European Society of
,100 mmHg (diastolic BP). Culprit cancer therapy can be restarted Hypertension (ESH) Guidelines for the management of arterial
once BP is controlled, with consideration for dose reduction. hypertension.138
Recommended threshold for asymptomatic hypertension treatment

in different!clinical!scenarios
Home CS Curable cancer Metastatic cancer Metastatic cancer Metastatic cancer

BP mmHg during treatment Prognosis >3 years Prognosis 1–3 years Prognosis <1 year
160+ Treat Treat Treat Treat Treat
Consider
140–159 Treat Treat Treat May treat
treatment
Consider
135–139 Treat May treat May treat None
treatment
130–134 May treat None None None None
<130 None None None None None
Figure 33 Recommended threshold for asymptomatic hypertension treatment in different clinical scenarios. BP, blood pressure; CS, cancer survivors.
74 ESC Guidelines
Treatment of arterial hypertension in patients with cancer
Hypertension caused by cancer therapy
Systolic BP ≥160 mmHg and diastolic BP ≥100 mmHg BP target during cancer therapy

Y N
ACE-I or ARB ACE-I or ARB

BP target <140 mmHg systolic and
(Class I) (Class I)
<90 mmHg diastolic
AND (Class I)
Dihydropyridine CCB OR
Dihydropyridine CCB
(Class I)
as second-line therapy
in patients with BP target <130 mmHg systolic and <80 mmHg
uncontrolled BP diastolic if well tolerated
(Class I) (Class IIb)
OR
If resistant hypertension : a In selected asymptomatic patients with

metastatic cancer systolic BP 140–160 mmHg,
Beta-blockersb
and diastolic BP 90–100 mmHg
Spironolactone
(Class IIb)
Oral or transdermal nitrates and/or hydralazine
(Class IIa)
Figure 34 Treatment of arterial hypertension in patients with cancer. AF, atrial fibrillation; ACE-I, angiotensin-converting enzyme inhibitors; ARB, angio-
tensin receptor blockers; BP, blood pressure; CCB, calcium channel blockers; HF, heart failure; MI, myocardial infarction; N, no; VEGFi, vascular endothelial
growth factor inhibitors; Y, yes. aResistant hypertension is defined as BP being uncontrolled despite treatment with optimal or best-tolerated doses of three
or more drugs including a diuretic, and confirmed by ambulatory and home BP monitoring. bConsider beta-blockers (nebivolol or carvedilol are preferred in
patients on VEGFi) at any treatment step, when there is a specific indication for their use, e.g. HF, angina, post-MI, or AF.

the management of arterial hypertension in patients Cancer therapy-induced arterial hypertension treatment
receiving anticancer treatment ACE-I or ARB are the first-line antihypertensive
drugsc recommended for BP management in I B
patients with cancer.555–557
General Dihydropyridine CCB are recommended as
second-line antihypertensive drugs for patients I C
Effective treatment of cancer therapy-induced
with cancer with uncontrolled BP.
arterial hypertension to prevent cancer treatment
I C Combination therapy with ACE-I or ARB and
interruption and CV complications is
recommended. dihydropyridine CCB is recommended in patients
I C
with cancer with systolic BP ≥ 160 mmHg and
A BP target ,140 mmHg systolic and ,90 mmHg
I C diastolic BP ≥ 100 mmHg.
diastolic is recommended during cancer therapy.
© ESC 2022
Diltiazem and verapamil are not recommended to

A BP target ,130 mmHg systolic and ,80 mmHg
treat arterial hypertension in patients with cancer III C
diastolic may be considered during cancer therapy IIb C
due to their drug–drug interactions.d
provided that the treatment is well tolerated.
In selected asymptomatic patients with metastatic ACE-I, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers;
BP, blood pressure; CCB, calcium channel blockers; CV, cardiovascular.
cancer, a systolic BP 140–160 mmHg and diastolic
IIb C a
BP 90–100 mmHg treatment threshold may be b
Level of evidence.
c
considered provided there is ongoing BP monitoring. Unless contraindicated.
d
In selected patients with cancer, who are intolerant to multiple other antihypertensive
The competing cancer and CV risk evaluation is
drugs, diltiazem and verapamil may be considered with close monitoring of drug–drug
recommended if the systolic BP is ≥180 mmHg or interactions.
diastolic BP ≥110 mmHg, and any cancer therapy
associated with hypertension should be deferred I C
or temporarily withheld until the BP is controlled
to values ,160 mmHg (systolic) and
,100 mmHg (diastolic).
Continued
ESC Guidelines 75
6.6. Thrombosis and thromboembolic Cancer confers a five-fold higher risk of VTE and cancer-associated
VTE represents 30% of all VTE cases.559,560 The risk of VTE varies
events
in the course of cancer, with the highest risk occurring in the period
Thromboembolic events that develop during cancer and its treat-
following cancer diagnosis, during hospitalization and chemotherapy,
ment encompass both VTE and arterial thromboembolism (ATE)
and upon development of metastatic disease.561,562 Unprovoked
and are collectively referred to as cancer-associated thrombosis.
VTE may be the first clinical sign of a malignancy, followed by a 5%
Cancer-associated thrombosis is determined by the prothrombotic
incidence of cancer diagnosis during the subsequent 12 months.563
milieu induced by cancer, the prothrombotic properties of certain
The risk factors for VTE in cancer are summarized in
anticancer and adjunctive therapies, and patient-related risk

Figure 35.564,565 Patients with symptoms or signs suggestive of
factors, including demographics, genetic predisposition, and
VTE, such as unilateral lower limb oedema or unexplained dyspnoea,
comorbidities.513
should be screened with lower-extremity venous ultrasonography
6.6.1. Venous thromboembolism or contrast-enhanced CT for DVT and CT pulmonary angiography
VTE, including deep vein thrombosis (DVT) and PE, is the for PE, according to the 2019 ESC Guidelines for the diagnosis and
second-leading cause of death in patients with malignancies.558 management of acute pulmonary embolism recommendations566
Risk factors for VTE in patients with cancer
Patient-related factors
Ageing
Comorbiditiesa
Sex (female)
Hereditary coagulation defectsb
Performance status
Prior VTE history
Cancer-related factors
Cancer type
Genetic characteristics (JAK2 or K-ras mutations)
Histology (adenocarcinoma)
Initial period after diagnosis
Primary site (pancreas, stomach, ovaries,
brain, lung, myeloma)
Stage (advanced, metastatic)
Treatment-related factors
Cancer therapyc
Central venous catheters
Hospitalization
Major surgery
Figure 35 Risk factors for venous thromboembolism in patients with cancer. ATE, arterial thromboembolism; BMI, body mass index; CrCl, creatinine
clearance; IMiD, immunomodulatory drugs; PI, proteasome inhibitors; VTE, venous thromboembolism. aAcute infection, chronic kidney disease (CrCl ,
45 mL/min), pulmonary disease, obesity (BMI ≥ 30 kg/m2), ATE. bFactor V Leiden, prothrombin gene mutation. cChemotherapy (carboplatin, cyclophos-
phamide, anthracyclines, antimetabolites, irinotecan, taxanes, tasonermin), anti-angiogenic agents (bevacizumab, axitinib, lenvatinib, pazopanib, sorafenib,
sunitinib), IMiD (thalidomide, lenalidomide), PI (carfilzomib), hormonal therapy, erythropoiesis-stimulating agents.
76 ESC Guidelines
and the second consensus document on diagnosis and management 6.6.3. Intracardiac thrombosis
of acute deep vein thrombosis.567 Intracardiac thrombus in patients with malignancies may result from
the prothrombotic properties of cancer and its treatment and the
6.6.2. Arterial thromboembolism use of central venous catheters. Thrombus is the most common in-
Cancer carries a two-fold higher risk of ATE, including MI and ischae- tracardiac mass and it can occur within any cardiac chamber. Right
mic stroke.568 ATE risk is higher in men, with advanced age, and in atrial thrombi are often related to a venous catheter where the
patients with lung or kidney cancer. Pathologies related to ATE in line has inappropriately advanced into the right atrium.
cancer include ischaemic stroke induced by AF or RT-induced ca- Intraventricular thrombi usually occur in the setting of CTRCD.

rotid artery disease, embolization by tumour cells or non-bacterial LAA thrombi are most commonly associated with AF, which may
thrombotic endocarditis, disseminated intravascular coagulation- also be related to cancer or its therapy.
related peripheral microcirculatory thromboembolism, paradoxical Patients with systemic embolization should be screened for car-
cerebral embolism in the course of VTE, and cerebral sinus diac origin of thrombus initially with TTE and/or transoesophageal
thrombosis.569 echocardiography.528 CMR is more sensitive and specific than TTE
Structured approach to anticoagulation for VTE in patients with cancer
Assess Thromboembolic risk:

Patient-related factors
T Cancer-related factors
Treatment-related factors
Assess Bleeding risk:
Thrombocytopaenia
Thromboembolic and GI/GU cancer, GI comorbidities, or GI toxicity
bleeding risk reassessment B Recent or evolving intracranial lesions
(Class I)
Active bleeding or recent major bleeding
Severe renal dysfunction (eGFR <30 mL/min/1.73 m2)
Assess drug-drug Interactions (P-glycoprotein, CYP3A4):

I Anticancer agents
Supportive therapies
P Assess Patient preferences
No anticoagulation Y Very high bleeding riska
LMWH Conditions favouring

Y
(Class I) LMWH over NOACb
Patient’s preference
NOAC or LMWH
(Class I)
Figure 36 Structured approach to anticoagulation for venous thromboembolism in patients with active cancer. CrCl, creatinine clearance; eGFR, es-
timated glomerular filtration rate; GI, gastrointestinal; GU, genitourinary; LMWH, low-molecular-weight heparins; N, no; NOAC, non-vitamin K antag-
onist oral anticoagulants; VTE, venous thromboembolism; Y, yes. aVery high bleeding risk: active or recent major bleeding (,1 month); recent/
evolving intracranial lesions; platelet count ,25 000/µL. According to the International Society on Thrombosis and Haemostasis,529 major bleeding is
defined as: fall in haemoglobin level ≥ 2 g/dL, transfusion of ≥2 units of red blood cells, fatal bleeding, or bleeding in a critical area (intracranial, intraspinal,
intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal). bConditions favouring LMWH: unoper-
ated GI/GU cancer; GI comorbidities or toxicity; severe renal dysfunction (CrCl , 15 mL/min); NOAC major drug–drug interactions, platelet
count , 50 000/µL.
ESC Guidelines 77
for detecting intracardiac thrombi and late gadolinium enhancement In VTE relapse under anticoagulation, the patient should be investi-
(LGE) CMR with the long inversion time technique is currently con- gated for treatment adherence, cancer progression or relapse, while a
sidered the gold standard.570,571 different anticoagulation strategy should be endorsed (e.g. replacement
of NOAC with LMWH). The management of patients with VTE and a
platelet count ,25 000/µL should be individualized by a MDT.299
6.6.4. Anticoagulation therapy
The duration of anticoagulation in patients with catheter-
Patients with cancer frequently have both an increased thrombotic risk
associated thrombosis depends upon whether the catheter is re-
and an increased bleeding risk associated with certain cancer locations
moved or remains in situ. If removed, then anticoagulation should
(e.g. GI, intracranial), thrombocytopaenia, and other coagulation de-

continue for a minimum of 3 months and until follow-up cardiac im-
fects (secondary to bone marrow invasion, cancer therapies, or cancer
aging confirms resolution of the thrombus. If the catheter remains in
itself) and associated comorbidities (e.g. renal or hepatic dysfunction,
situ, then long-term therapeutic anticoagulation should continue.
GI toxicities). Several anticancer agents are further characterized by
drug–drug interactions with anticoagulants. All these factors may ren-
der anticoagulation in cancer quite challenging. A proposed approach Recommendation Table 34 — Recommendations for
to anticoagulation therapy in cancer-associated venous thrombosis, the management of venous thromboembolism in pa-
based on the TBIP acronym (Thromboembolic risk, Bleeding risk, tients receiving anticancer treatment
drug–drug Interactions, Patient preferences), is outlined in Figure 36.527
6.6.4.1. Treatment and secondary prevention of venous Apixaban, edoxaban, or rivaroxabanc are
thromboembolism recommended for the treatment of symptomatic
I A
Several large RCTs and meta-analyses have shown that LMWH de- or incidental VTE in patients with cancer without
crease the risk of recurrent VTE by 40% compared to VKA, with a contraindications.d,578–581,584,585
similar risk of major bleeding.572–576 However, VKA are character- LMWH are recommended for the treatment of
ized by an unpredictable anticoagulation effect and low time in thera- symptomatic or incidental VTE in patients with
I A
peutic range in patients with malignancies due to multiple drug–drug cancer with platelet count .50 000/µL.298,299,578–
581,584,585
interactions, GI toxicity, malnutrition, and liver dysfunction.577
NOAC have been assessed as potential alternatives to LMWH for In patients with cancer with platelet counts of
cancer-associated VTE, based on RCTs that compared edoxaban, rivar- 25 000–50 000/µL, anticoagulation with half-dose
IIb C
oxaban or apixaban to dalteparin.578–583 The totality of evidence de- LMWH may be considered after a
rived by these trials and subsequent meta-analyses584–586 shows that multidisciplinary discussion.591
NOAC are non-inferior to dalteparin in reducing the risk of VTE recur- Prolongation of anticoagulation therapy beyond 6
rence. The risk of major bleeding was similar, although NOAC were as- months should be considered in selected patients
IIa A
sociated with an increased risk of clinically relevant non-major bleeding, with active cancere including metastatic
particularly in patients with luminal GI and GU malignancies.586 As a re- disease.589,590
sult, edoxaban, rivaroxaban, and apixaban are recommended for the Catheter-associated VTE
treatment of VTE (DVT and PE) in patients with cancer without any Duration of anticoagulation in patients with
of the following bleeding risk factors: unoperated GI or GU malignan-
© ESC 2022
cancer with a catheter-associated VTE is
cies, history of recent bleeding or within 7 days of major surgery, signifi- I C
recommended for a minimum of 3 months and
cant thrombocytopaenia (platelet count , 50 000/µL), severe renal continuing longer if the catheter remains in situ.
dysfunction (creatinine clearance (CrCl , 15 mL/min), or GI comorbid-
ities.582,586 In addition, drug–drug interactions between NOAC, cancer CrCl, creatinine clearance; GI, gastrointestinal; GU, genitourinary; LMWH,
low-molecular-weight heparins; ULN, upper limit of normal; VTE, venous
therapies, and other concomitant treatments should be checked.587 thromboembolism.
There are also concerns about NOAC in patients with GI toxicity a
b
such as vomiting or those having undergone gastrectomy or extensive Level of evidence.
c
Drugs are listed in alphabetical order
intestine resection, as well as those with severely impaired renal func- d
High risk of GI or GU bleeding, GI absorption concerns, significant drug–drug
tion. Shared decision-making considering informed patient preferences interactions, severe renal dysfunction (CrCl , 15 mL/min), significant liver disease
should guide the choice of anticoagulation. (alanine aminotransferase/aspartate aminotransferase . 2 × ULN), or significant
thrombocytopaenia (platelet count , 50 000/µL). In addition, patients with primary
Incidentally encountered proximal DVT or PE should be treated in brain tumours or brain metastases and acute leukaemia were excluded from the
the same manner as symptomatic VTE as they bear similar rates of seminal apixaban trial.580
e
recurrence and mortality.588 Patients receiving cancer treatment, patients diagnosed with cancer in the past 6
months, and patients with progressive or advanced disease.
The minimal duration of anticoagulation is 6 months and extended
anticoagulation is suggested in the presence of active malignancy,
metastatic disease, or chemotherapy use. Cohort studies have
shown that extended LMWH therapy beyond 6 and up to 12 months 6.6.4.2. Primary prevention of venous thromboembolism
is safe in cancer-associated VTE.589,590 However, patients with can- Patients undergoing surgery and those who are hospitalized or in
cer are also at high risk of bleeding during anticoagulant treatment prolonged bed rest require thromboprophylaxis with low-dose an-
and a periodic assessment of the risk/benefit ratio should performed. ticoagulation.298,299,592–594 The ENOXACAN (Enoxaparin and
78 ESC Guidelines
Cancer) II study showed favourable outcomes with LMWH as pri- 6.7. Bleeding complications
mary thromboprophylaxis for 4 weeks after major abdominal or pel- Bleeding complications are more common in patients with cancer
vic cancer surgery.595 For ambulatory patients, VTE risk should be than in patients without cancer. This may be directly related to the
individually determined and proposed scores such as the Khorana tumour itself, or indirectly related to chemotherapy- or
or the COMPASS-CAT (prospective COmparison of Methods for RT-induced weakening of mucosal barriers.530
thromboembolic risk assessment with clinical Perceptions and
AwareneSS in real-life patients—Cancer Associated Thrombosis)
score may be useful.596,597 Further trials and a meta-analysis have 6.7.1. High-risk patients

shown that LMWH significantly reduced the incidence of symptomatic GI and GU cancers are associated with a significant excess bleeding
VTE in ambulatory patients with cancer receiving chemotherapy with risk compared with other solid tumours.603 Thrombocytopaenia
acceptable safety.598–600 Two randomized, placebo-controlled, and platelet dysfunction due to haematological malignancies or
double-blind clinical trials have assessed the role of NOAC in primary bone marrow suppression can exacerbate bleeding. Other bleed-
prevention of VTE in high-risk ambulatory patients receiving systemic ing risk factors include advancing age, renal or hepatic impair-
cancer therapy (Khorana score ≥ 2).601,602 Over a follow-up period of ment, metastatic disease, low body mass index, and treatment
180 days, apixaban (2.5 mg twice a day)601 therapy resulted in a signifi- with ibrutinib, VEGFi, cetuximab, or bevacizumab.578,603–605
cantly lower rate of VTE, although the rate of major bleeding episodes Gastric protection with routine proton pump inhibitor use
was higher than with placebo. Rivaroxaban (10 mg once a day)602 should be considered in all patients with cancer on DAPT606,607
treatment resulted in a non-significantly lower incidence of VTE or or anticoagulation.530
death due to VTE with low bleeding risk (no significant differences
with placebo). Further data on the use of NOAC in this setting are
warranted. Consideration of such therapy should be accompanied 6.7.2. Antiplatelet therapy
by a discussion with the patient about the relative benefits and harms, Antiplatelet therapy, in particular DAPT, increases the risk of bleed-
cancer prognosis, drug cost, and duration of prophylaxis. ing in patients with cancer.477 Following ACS and/or PCI, the risk of
bleeding is approximately 1.6-fold greater in patients with cancer
than in those without.477,605 The risk is greatest in those diagnosed
Recommendation Table 35 — Recommendations for with cancer in the preceding year, whereas more remote cancers
venous thromboembolism prophylaxis during antican-
cer treatment carry lower excess risk.477 The PRECISE-DAPT (PREdicting bleeding
Complications In patients undergoing Stent implantation and
Recommendation Classa Levelb subsEquent Dual Anti Platelet Therapy) score appears not to per-
form well for predicting bleeding in patients with cancer.477 In order
Extended prophylaxis with LMWH for 4 weeks
to reduce bleeding risk, the duration and intensity of DAPT should be
post-operatively is recommended for patients
minimized477,607 and triple therapy avoided whenever possible. At
with cancer undergoing major open or I B
the same time, DAPT—if indicated—should not be withheld without
laparoscopic abdominal or pelvic surgery with low
good reason. A recent expert consensus statement suggests reduced
bleeding risk and high VTE risk.c,298,299,595
platelet count thresholds for CV therapies, recommending aspirin
Prophylactic LMWH for the primary prevention initiation for platelet counts .10 000/µL and DAPT initiation (with
of VTE is indicated in hospitalized patients with aspirin and clopidogrel) for platelet counts .30 000/µL.608 In pa-
cancer or those with prolonged bedrest or I B
tients with platelet counts ,50 000/µL, clopidogrel is preferred
reduced mobility in the absence of bleeding or over prasugrel or ticagrelor, and glycoprotein IIb/IIIa inhibitors
other contraindications.298,299,592,594 should be avoided.608 To reduce peri-procedural bleeding, PCI
For ambulatory patients with cancer at high risk of should preferably be undertaken via the radial approach484 and
thrombosis receiving systemic therapy,d primary prophylactic platelet transfusion may be considered for patients
thromboprophylaxis with a NOAC (apixaban or with platelet count ,20 000/µL.609
IIb B
rivaroxaban) or LMWH may be considered,
provided there are no significant
contraindications.e,298,593,594,601,602 6.7.3. Management of bleeding
A discussion with the patient about the relative Basic principles of bleeding management should be followed with
benefits and harms, cancer prognosis, drug cost, control of the bleeding source whenever possible. Platelet transfu-
© ESC 2022
and duration of treatment is recommended prior I C sions for significant thrombocytopaenia and withholding and reversal
to prophylactic anticoagulation for the primary of anticoagulation for life-threatening bleeding may be needed as in
prevention of VTE. the general population.530,610 Antifibrinolytic agents, such as tranex-
amic acid or e-aminocaproic acid, can be considered. Non-specific
LMWH, low-molecular-weight heparins; NOAC, non-vitamin K antagonist oral
anticoagulants; VTE, venous thromboembolism. support of haemostasis using coagulation factor concentrates and
a
Class of recommendation. specific reversal agents may be needed for patients on a NOAC
b
c
Level of evidence. with life-threatening bleeding.530 Recombinant activated factor VII
Reduced mobility, obesity, VTE history.
d
Locally advanced or metastatic pancreas or lung cancer or Khorana score ≥ 2. or activated prothrombin complex concentrates should be avoided
e
Risk factors for bleeding, significant drug–drug interactions, or severe renal dysfunction. in patients with recent thrombosis.
ESC Guidelines 79
6.8. Peripheral artery disease complicating cancer management. Other group 4 PH due to pulmon-
There is growing evidence that cancer therapy affects the vascula- ary artery obstructions includes angiosarcoma and other malignant
ture. A recent meta-analysis showed a significantly increased arterial tumours (e.g. renal carcinoma, uterine carcinoma, germ cell tumours
stiffness after anthracycline and non-anthracycline treatment.611 of the testis).618
Paraneoplastic acral vascular syndrome was described after initiation PH with unclear and/or multifactorial mechanisms (group 5) in-
of nivolumab, with first symptoms 3 weeks after initiation of ther- cludes several conditions that may be complicated by complex and
apy.612 Raynaud phenomenon has been associated with the use of sometimes overlapping pulmonary vascular involvement. Tumoral
bleomycin, cyclophosphamide, platinum compounds, vinca alkaloids, PH includes pulmonary tumour micro-embolism and pulmonary tu-

and fluoropyrimidines.491 Usual treatment of Raynaud’s includes mour thrombotic microangiopathy.619 Multiple causes of PH have
non-pharmacological measures to help prevent an episode (avoid- been described in patients with chronic myeloproliferative disorders.
ance of provoking factors such as cold temperature, vasoconstricting In chronic myelogenous leukaemia, spleen enlargement and anaemia
drugs) and a long-acting dihydropyridine CCB (amlodipine, can give rise to hyperkinetic syndrome. In polycythaemia vera and es-
modified-release nifedipine). sential thrombocythemia, there is an increased risk of VTE and
Treatment with nilotinib or ponatinib may be associated with an chronic thromboembolic PH. Moreover, formation of a blood clot
increased risk of vascular adverse events, including arterial stiffness within the hepatic veins can lead to Budd–Chiari syndrome and sub-
and PAD development.494 In a subgroup of patients, these events sequent porto-PH. Pulmonary extramedullary haematopoiesis com-
are severe or even life-threatening.613 Although the exact mechan- plicating idiopathic or secondary myelofibrosis may also contribute
isms remain unknown, we recommend screening for pre-existing to dyspnoea and PH.620
PAD and for vascular risk factors such as DM in all patients before Symptoms of PH are non-specific, such as shortness of breath and
and during nilotinib or ponatinib therapy. Pooled data from three fatigue. In later stages, symptoms of right-sided HF may develop. An
clinical trials showed arterial occlusive disease to be related to ECG should be performed and examined for RV hypertrophy, but a
dose intensity in ponatinib-treated patients,614 but PAD was not ad- normal ECG does not exclude PH. Echocardiography is the first
dressed separately. If rapidly progressive PAD occurs with second- choice for assessing PH probability in patients who develop symp-
generation TKI, it may be advisable to switch to an alternative lower- toms and/or signs suggestive of PH during cancer treatment.
risk TKI (e.g. imatinib). Platelet aggregation inhibitors or anticoagula- When peak tricuspid regurgitation velocity (TRV) is ≤2.8 m/s
tion and statins should be considered. Despite lack of evidence, all (equating to an estimated systolic PAP [sPAP] of ≤35 mmHg)
risk factors should be corrected.615 and no other signs of PH are present, then the probability of PH
is low. In the absence of a tricuspid regurgitant jet, other echocar-
diography signs may increase suspicion of PH (e.g. RV/LV basal
diameter ratio . 1, RV outflow tract acceleration time , 105 ms,
inferior vena cava diameter . 21 mm with decreased inspiratory col-
management of peripheral artery disease during antic-
ancer treatment lapse).620 Baseline TTE should be considered in patients receiving
cancer drugs that can cause PH; however, a right-heart catheter-
Recommendation Classa Levelb ization is required for definitive diagnosis of PH and to support
PAH treatment decisions. In the DASISION (DASatinib vs. Imatinib
In patients who develop new symptomatic PAD, a
Study In treatment-Naïve chronic myeloid leukemia patients) trial,
© ESC 2022
multidisciplinary approach regarding the decision

I C 5% of patients randomized to dasatinib were diagnosed with
to continue vs. interrupt culprit cancer therapyc is
PH, compared with 0.4% of those randomized to imatinib.621 In
recommended.
patients who develop PH, dasatinib treatment should be inter-
PAD, peripheral artery disease; VEGFi, vascular endothelial growth factor inhibitors.
a
rupted and an alternative TKI should be used.616
b Overall management of PH in oncology patients should be based
Level of evidence.
c
VEGFi, nilotinib, ponatinib, platins, etc. on the 2022 ESC/European Respiratory Society (ERS) Guidelines for
the diagnosis and treatment of pulmonary hypertension.620 Referral
to a PH centre is recommended for multidisciplinary management
6.9. Pulmonary hypertension with the oncology team. In patients with CML treated with drugs
All five groups of the PH classification can be observed in patients causing PH-induced PAH, discontinuation of the potential culprit
with cancer. Several cancer drugs can cause group 1 PH (pulmonary therapy is recommended if there is a high probability of new PH
arterial hypertension [PAH]), including carfilzomib, bosutinib, dasati- (peak TRV . 3.4 m/s, equating to an estimated sPAP of
nib,616 ponatinib, interferon alpha, and alkylating agents (e.g. mitomy- ≥50 mmHg) until the diagnosis is confirmed or ruled out by a right-
cin C and cyclophosphamide, which mostly cause pulmonary heart catheterization. In CML patients on dasatinib, an alternative
veno-occlusive disease).617 PH associated with left heart disease BCR-ABL TKI is recommended if they develop symptomatic PAH
(group 2) is related to drugs causing HF (e.g. anthracyclines). PH as- or an asymptomatic increase in peak TRV .3.4 m/s. Dasatinib
sociated with lung disease (group 3) is related to drugs and therapies dose reduction and close monitoring of peak TRV with TTE every
causing pulmonary fibrosis (e.g. bleomycin, thoracic radiation). The 4 weeks should be considered in CML patients who develop new
most common pulmonary vascular disease complicating cancer is asymptomatic peak TRV ranging from 2.9 to 3.4 m/s.620 If peak
VTE, which can cause chronic thromboembolic PH (group 4). Of TRV remains normal or mildly elevated on serial monitoring, then da-
note, central venous catheters are important causes of group 4 PH satinib can continue, with reduced TTE monitoring to every 3
80 ESC Guidelines
months. If peak TRV continues to rise, then right-heart catheteriza- with standard therapy or after discontinuation of the treatment.444
tion should be performed, dasatinib treatment should be stopped, Cancer treatment interruption should be discussed with the
and PAH drugs should be considered if PAH is confirmed. cardio-oncology team. Treatment with anti-inflammatory drugs
(e.g. ibuprofen) and colchicine, in the absence of contraindications,
is recommended as it reduces the rate of recurrence requiring re-
Recommendation Table 37 — Recommendations for peat intervention.623 Low-to-moderate doses of steroids are only in-
the management of pulmonary hypertension during dicated for resistant cases except ICI-related pericarditis.444
anticancer treatment
ICI-associated pericarditis has a median time of onset of 30 days in

Recommendations Classa Levelb retrospective surveillance studies and is associated with a poor prog-
nosis, especially in case of concomitant myocarditis.444,624
Right-heart catheterization and discontinuation of In patients with severe ICI-associated pericarditis with moderate or
dasatinib is recommended in patients who severe effusion, ICI discontinuation and high-dose steroids (methylpred-
I C
develop symptomatic or asymptomatic increase in nisolone 1 mg/kg/day) with or without colchicine are recommended, as
peak TRV .3.4 m/s. well as pericardiocentesis in case of cardiac tamponade.624,625 In case of
Dasatinib dose reduction and close monitoring of refractory pericarditis, immunosuppressive drugs should be considered.
peak TRV with echocardiography should be For uncomplicated ICI-related pericarditis, the ICI might be continued
considered in patients who develop new IIa C and colchicine or non-steroidal anti-inflammatory drugs could be con-
asymptomatic peak TRV ranging from 2.9 to sidered.326,444 For patients requiring ICI discontinuation, restarting ICI
3.4 m/s. can be considered in a MDT discussion after resolution of pericardial
In patients with confirmed dasatinib-induced disease and under close monitoring.
© ESC 2022
PAHc or new asymptomatic peak TRV .3.4 m/s,

I C
an alternative BCR-ABL inhibitor is recommended 6.10.2. Pericardial effusion
after peak TRV recovery to ,2.8 m/s. Pericardial effusions are often observed as an incidental finding in pa-
BCL-ABL, breakpoint cluster region–Abelson oncogene locus; PAH, pulmonary arterial
tients with cancer. Cancer therapy is the cause of a pericardial effu-
hypertension; TRV, tricuspid regurgitation velocity. sion in ,30% of cases, although this may increase with the expanding
a
b
Class of recommendation. use of ICI in cancer. Malignancy-related pericardial effusions caused
Level of evidence.
c
Definite diagnosis of PAH requires a right-heart catheterization.
by direct (lung, oesophageal, breast) or metastatic invasion (haem-
atological malignancies, ovarian, melanoma) or by lymph node ob-
struction are generally associated with poor prognosis.
6.10. Pericardial diseases Clinical presentation depends on the size of the effusion and the
Pericarditis and pericardial effusion can be related to a wide range of speed of its growth.444 Malignancy-related pericardial effusions
cancer treatments including chest radiation, cytotoxic therapies (an- make up .30% of patients presenting with cardiac tamponade626
thracyclines, bleomycin, cyclophosphamide, cytarabine), targeted and usually develop slowly, resulting in larger pericardial effusions
therapies (all-trans retinoic acid, arsenic trioxide, dasatinib), and at the time of diagnosis compared with non-malignant pericardial ef-
immune-based therapies (interleukin-2, interferon-αICI). A combin- fusions. Management consists of determination of the cause and
ation of therapies may have a synergistic effect on the pericardium. evaluation of the haemodynamic impact. Small-to-medium-sized ef-
These therapy-induced complications must be differentiated from fusions (.4 and ,20 mm) can be monitored with a reassessment
progressive cancer (local invasion, metastatic involvement, or medias- 7–14 days after initial diagnosis and at further 4–6-weekly inter-
tinal lymphatic drainage obstruction) and non-cancer-related causes vals.444,627 In unstable patients with signs of tamponade, immediate
such as infection, especially in immune-compromised patients.622 A echocardiographic-guided percutaneous pericardiocentesis is pre-
careful history and clinical examination are of help to determine the ferred over surgical pericardiotomy to minimize potential complica-
cause. TTE plays a central role in diagnosis and management. CT tions.628 In patients with cardiac tamponade due to malignant
and CMR can provide additional information on pericardial inflamma- pericardial effusions, colchicine may be useful to improve clinical out-
tion and constrictive physiology. The principles for the diagnosis and comes and reduce the rate of repeat intervention.623 Drainage of a
management should follow the 2015 ESC Guidelines for the diagnosis pericardial effusion related to ICI is rarely required629 and corticos-
and management of pericardial diseases,444 but there are some specific teroids should be considered.630 Intrapericardial instillation of
issues to consider in patients with cancer.482 cytostatic/sclerosing agents, colchicine,623 and radiation for
radiation-sensitive tumours can reduce recurrence after drainage.
6.10.1. Pericarditis The creation of a pleuropericardial or pleuroperitoneal window
The diagnosis of pericarditis in patients with cancer follows the same with balloon pericardiotomy or surgery should be considered in
principles as in those without, but symptoms can be atypical.444 case of recurrent malignant pericardial effusions after emergency
Acute pericarditis caused by radiation has become rare due to lower pericardiocentesis.444
doses and improved radiation techniques. It occurs within days to A surgical pericardial window should be considered if the percu-
weeks after treatment and is usually self-limiting, but can evolve to- taneous approach is not feasible and in stable patients with large
wards constrictive pericarditis many years later (Section 8.6). (≥20 mm) or rapidly expanding malignant pericardial effusions prior
Pericarditis caused by conventional cancer therapies often resolves to the development of cardiac tamponade.
ESC Guidelines 81
Recommendation Table 38 — Recommendations for continue on long-term oncology therapies, e.g. women with oestro-
the management of pericardial diseases in patients re- gen receptor-positive early invasive BC. In this example, the
ceiving anticancer treatment end-of-therapy risk assessment refers to the timepoint from the
last anthracycline or trastuzumab dose.
High-risk patients can be identified at completion of their cardio-
General toxic cancer therapies by their clinical characteristics, history of
Diagnosis and management of acute pericarditis in CTR-CVT during treatment, and by elevated cardiac biomarkers
patients with cancer based on the 2015 ESC and/or abnormal CV imaging at follow up.53,54,92 Cardiac serum bio-

Guidelines for the diagnosis and management of markers (NP and cTn) are useful given their high negative predictive
I C
pericardial diseases is recommended and a value for future CV events.197,631 In a prospective study of 2625 adult
multidisciplinary discussion is needed before patients with cancer that assessed LVEF after anthracycline-based
interrupting cancer therapy.444 chemotherapy, the overall incidence of CTRCD was 9%; 98% of
A surgical pericardial window should be
cases could be detected within 12 months after chemotherapy and
considered if the percutaneous approach is not
the median time from chemotherapy to CTRCD detection was
IIa C 3.5 months (interquartile range 3–6 months).208 The response to
feasible or in cases of recurrent malignant
pericardial effusions.
ACE-I treatment declined when the interval between the end of
chemotherapy and CTRCD detection lengthened; complete LVEF
Intrapericardial instillation of cytostatic or
IIb C recovery was not observed in patients where treatment was delayed
sclerosing agents may be considered for
by .6 months.425
prevention of recurrence.
Measurement of cTn after completion of anthracycline chemo-
Diagnosis and management of ICI-associated pericarditis
therapy during the end-of-treatment assessment should be consid-
Multimodality CV imaging (echocardiography, ered. Rises in cTnI after anthracycline chemotherapy identify
CMR + CT), ECG and measurement of cardiac patients at risk of future cardiac dysfunction who then benefit
biomarkers are recommended to confirm the
I C from CV protection.4 Educating patients with cancer of their poten-
diagnosis, assess the haemodynamic tial increased CVD risk and supporting them to make appropriate
consequences of pericardial disease, and rule out healthy lifestyle choices is recommended. CS should also be advised
associated myocarditis. to promptly report early signs and symptoms of possible CVD and
Prednisolone and colchicine are recommended inform medical teams of their previous cardiotoxic cancer therapies.
for patients with ICI-associated I C CVRF including hypertension, DM, and dyslipidaemia correlate with
pericarditis.326,624,625,630 the probability of future CV events in CS and should be well con-
Interruption of ICI treatment in patients with trolled after completion of cancer therapy.31,632,633
confirmed ICI-associated pericarditis with
I C
moderate-to-severe pericardial effusion is 7.2. Which cancer survivors require
cardiovascular surveillance in the first
© ESC 2022
recommended.
A multidisciplinary discussion is recommended
I C year after cancer treatment?
before restarting ICI treatment.
The end-of-treatment risk assessment ideally identifies those high-risk
CMR, cardiac magnetic resonance; CT, computed tomography; CV, cardiovascular; CS, who require long-term CV surveillance, based on the following
ECG, electrocardiogram; ESC, European Society of Cardiology; ICI, immune criteria (Table 10):
checkpoint inhibitors.
a
Class of recommendation. (1) Baseline high or very high risk based on HFA-ICOS risk assess-
b
Level of evidence.
ment tools12 (Section 4).
(2) Cardiotoxic cancer therapy with a high risk of long-term CV
complications7,21 (Section 8).
7. End-of-cancer therapy (3) Moderate or severe CTR-CVT diagnosed during cancer treat-
ment (Table 3).68
cardiovascular risk assessment (4) New abnormalities in cardiac function detected by echocardiog-
raphy, new elevated cardiac serum biomarkers, or newly CV
7.1. Cardiovascular evaluation during the symptoms detected at the end-of-therapy assessment (3 or 12
first year after cardiotoxic anticancer months after treatment).68,208
therapy
End-of-cancer therapy CV risk assessment covers the first 12 The timing of the first CV assessment after cardiotoxic cancer
months after the last cardiotoxic cancer treatment. These recom- treatment depends on the risk defined by baseline CV assessment,
mendations are where cardiotoxic cancer therapy has been success- the type of cancer therapy, and whether CTR-CVT was diagnosed
fully completed with good long-term prognosis. These during treatment.
recommendations are not indicated when cancer therapies are dis- In asymptomatic high-risk patients (Table 10), echocardiography
continued due to cancer progression and prognosis is poor, or and cardiac serum biomarkers are recommended at 3 and 12 months
where end-of-life care is indicated. Selected patients with cancer after completion of cancer therapy.53,54,59,61,68,148,208,425 In
82 ESC Guidelines
Table 10 Risk factors for future cardiovascular dis- 7.3. Management of cancer
ease at the end-of-cancer therapy cardiovascular risk
assessment therapy-related cardiac dysfunction at
the end-of-therapy assessment
High-risk conditions During this end-of-treatment assessment, a review of cardioprotec-
High- and very-high baseline CV toxicity risk based on HFA-ICOS
tive medications initiated during cancer therapy to treat CTRCD is
assessment
recommended (Figure 37). In selected patients with asymptomatic
mild or moderate CTRCD who have fully recovered with normal
Specific anticancer treatment proven to have a high risk of long-term CV
TTE and cardiac serum biomarkers, a trial of weaning off CV

complicationsa
medication should be considered after MDT discussion. This is
Doxorubicinb ≥ 250 mg/m2
most common after asymptomatic mild or moderate CTRCD sec-
RT . 15 Gy MHDc
ondary to trastuzumab, particularly in younger otherwise healthy
Both doxorubicinb ≥ 100 mg/m2 and RT 5–15 Gy MHDd
HER2+ BC survivors with no exposure to anthracycline chemother-
High-risk HSCT patientse
apy. Further assessment of cardiac function with TTE and cardiac
Moderate or severe CTR-CVT during cancer treatment (especially
serum biomarkers is recommended following withdrawal of CV
CTRCD), ICI-related myocarditis, cardiac arrhythmias, or severe vascular
medication in patients with previous CTRCD to ensure cardiac func-
toxicities (ACS, stroke, PVD)
tion remains normal.
New CV symptoms or new asymptomatic abnormalities in © ESC 2022 Continuing long-term CV medication is generally recommended
echocardiography and/or cardiac serum biomarkers at the end of therapy in patients with moderate and severe symptomatic or severe asymp-
assessment tomatic CTRCD due to the high rate of recurrent HF. Long-term
ACS, acute coronary syndromes; CTRCD, cancer therapy-related cardiac dysfunction; treatment is also recommended in CS with mild or moderate
CTR-CVT, cancer therapy-related cardiovascular toxicity; CV, cardiovascular; CVD, CTRCD who fail to recover normal LV function at their
cardiovascular disease; CVRF, cardiovascular risk factors; GVHD, graft vs. host end-of-therapy assessment (Figure 37).
disease; Gy, Gray; HFA, Heart Failure Association; HSCT, haematopoietic stem cell
transplantation; ICI, immune checkpoint inhibitors; ICOS, International
Cardio-Oncology Society; MHD, mean heart dose; PVD, peripheral vascular disease;
RT, radiotherapy. 7.4. Cardiopulmonary exercise testing
a
RT risk categorization based on MHD is recommended over categorization based on and fitness during the end-of-therapy
prescribed dose, which may not accurately reflect cardiac radiation exposure.
Depending on dose distribution and exposure of specific cardiac substructures (as assessment
well as clinical risk factors), the treatment team may judge the patient to belong to a CRF impairment is a strong predictor of patient outcome following
higher risk category. In addition, a patient may be judged to belong to a lower risk
category if only a small part of the heart is exposed to a relatively high prescribed
cancer treatment and an intervention target in CS. Low CRF is asso-
dose (i.e. RT to left breast or left chest wall only). ciated with poor quality of life, increased morbidity, reduced exercise
b
c
Or doxorubicin equivalent. cardiac function and worse CVD risk profile, and is a robust inde-
Or prescribed RT ≥ 35 Gy to a volume exposing the heart if MHD is not available.
d
Or prescribed RT 15–34 Gy to a volume exposing the heart if MHD is not available.
pendent predictor of all-cause, cancer-related, and CVD-related
e
High-risk HSCT patients: allogenic HSCT; pre-existing CVD or multiple uncontrolled mortality in CS.119,120 Recent evidence suggests the risk of
CVRF; cancer treatment history (mediastinal or mantle field radiation, alkylating CVD-related mortality in CS decreases by 14% per 1 metabolic
agents, .250 mg/m2 doxorubicin or equivalent); conditioning schemes (total body
irradiation, alkylating agents); development of GVHD.
equivalent (3.5 mL O2/kg/min) increase in CRF.120
CPET may be considered for CS with exertional limitation, who
may have substantial benefit from cardiac rehabilitation. Eligible pa-
tients include those treated with higher doses of anthracycline
chemotherapy and/or RT to a volume including the heart, high CV
asymptomatic moderate-risk patients (according to CV toxicity
toxicity risk at baseline, patients who developed CTRCD during can-
baseline risk stratification), echocardiography and cardiac serum bio-
cer therapy, and those identified with new abnormalities in LV func-
markers should be considered within 12 months after completion of
tion at their end-of-therapy assessment.11 CPET can be an objective
cancer therapy.53,54,59,61,68,148,208 In asymptomatic low-risk patients
tool in the diagnosis of decreased physical capacity and identify CV vs.
(according to CV toxicity baseline risk stratification), echocardiog-
non-CV causes.635
raphy and cardiac serum biomarkers may be considered within 12
months after completion of cancer therapy.634
All patients started on CV therapies (ACE-I/ARB/angiotensin 7.5. The role of cardiac rehabilitation
receptor-neprilysin inhibitors, beta-blockers, mineralocorticoid re- Exercise is a potent multitargeted therapy that prevents and
ceptor antagonists, sodium-glucose co-transporter 2 inhibitors, anti- treats multiple competing mechanisms of CTR-CVT in CS, includ-
hypertensive medications, antiarrhythmic medications, antiplatelet ing CRF impairment,636 CV injury, and pre-existing and new
therapies, statins) for any CTR-CVT (especially CTRCD) should CVRF.137 Prescribing exercise facilitates the delivery of therapeut-
have a clinical assessment, ECG, echocardiography, and cardiac ser- ic exercise that is individualized to a person’s fitness level and sys-
um biomarkers (if LV systolic dysfunction/HF is a potential risk) at 3, tematically progressed to optimize physiological adaptation.637
6, and 12 months after completing cancer treatment. A MDT-based Current evidence demonstrates that supervised exercise therapy
approach to palliative and end-of-life care for patients with cancer (including high-intensity interval training [HIIT]) is safe and well
with HF or other CTR-CVT should be focused on symptom relief tolerated,638 attenuates CTR-CVT risk, and improves CRF.
according to general ESC Guidelines. Furthermore, HIIT reduces CVRF460 and CV risk639 in patients
ESC Guidelines 83
Patients who develop CTRCD during cancer treatment and are being started on HF therapy
CTRCD

Mild or moderate Severe and very severe
Continue HF therapy
Recovery N Partial or nonea
(Class I)
Fullb
MDT to consider
weaning HF therapyc
Patient risk
High riskd Low riske
Continue Consider weaning

HF therapy HF therapy
(Class I) (Class IIa)
Figure 37 Management of cancer therapy-related cardiac dysfunction after cancer therapy. CTRCD, cancer therapy-related cardiac dysfunction; CV,
cardiovascular; GLS, global longitudinal strain; HF, heart failure; HFA, Heart Failure Association; ICOS, International Cardio-Oncology Society; LV, left
ventricular; LVEF, left ventricular ejection fraction; MDT, multidisciplinary team; N, no; Y, yes. aPartial or no recovery: patients who do not
meet all of the criteria for full recovery. bFull recovery: no signs or symptoms of HF + LVEF . 50% + GLS within normal range or similar to baseline
measurements + cardiac serum biomarkers within the normal range or similar to baseline measurements cThe CTRCD trajectory of each patient is
unique and dynamic and withdrawal of HF therapy requires a MDT to consider several key points that help to stratify patients into low- or high-risk
categories. Key points to consider during a MDT discussion are: HFA-ICOS baseline CV toxicity risk assessment, pre-existing indications for
CV medication, class of cancer treatment causing CTRCD (generally reversible vs. generally irreversible), magnitude and duration of CTRCD before re-
covery, intensity of HF therapy needed to recover LV function, family history of cardiomyopathy or known cardiomyopathy gene carrier (see Section 4.8).
d
See Table 10. eLow-risk patient characteristics: low to moderate baseline CV toxicity risk (HFA-ICOS risk assessment), no pre-existing indications
for CV medication, cancer treatment generally associated with reversible myocardial damage, asymptomatic mild CTRCD, early cardiac function recovery
(3–6 months) under HF therapy, no family history of cardiomyopathy.
with cancer in the pre-, active-, and post-treatment settings. may not be feasible in elderly and frail patients.642 Dedicated
HIIT-related benefits on CRF, physical activity behaviour, fatigue, cardio-oncology rehabilitation programmes are currently under
and quality of life persist months post-intervention.640,641 HIIT development.11
84 ESC Guidelines
© ESC 2022
ECG follow-up is recommended in patients who
end-of-cancer therapy cardiovascular risk assessment I
developed QT lengthening or LQTS during cancer C
a b therapy.646
Recommendations Class Level
CPET, cardiopulmonary exercise testing; CS, cancer survivors; CTRCD, cancer
Educating and supporting patients with cancer to therapy-related cardiac dysfunction; CV, cardiovascular; CVD, cardiovascular disease;
make appropriate healthy lifestyle choices is I C CVRF, cardiovascular risk factors; DM, diabetes mellitus; ECG, electrocardiogram;
recommended.c ESC, European Society of Cardiology; LQTS, long QT syndrome; TKI, tyrosine kinase
inhibitors.
Education is recommended for patients with a

cancer regarding recognition for early signs and I C b
Level of evidence.
c
symptoms of CVD. Including regulation of hypertension, DM, dyslipidaemia, smoking cessation, weight loss
in case of obesity, and an adequate amount of exercise.
CVRF assessment is recommended during the d
High-risk patients: see Table 10.
e
first year after cancer therapyc,12,22,31,632,643 and Moderate- or low-risk patients: according to CV toxicity baseline risk stratification.
I B f
Cardio-oncology referral is recommended when available; alternatively, the patient
thereafter according to the 2021 ESC Guidelines
should be referred to a cardiologist with expertise in managing CVD in patients with
on CVD prevention in clinical practice.19 cancer.
In asymptomatic high-risk patients,d
echocardiography and cardiac serum biomarkers
I B
are recommended at 3 and 12 months after
completion of cancer
8. Long-term follow-up and
therapy.53,54,59,61,68,148,208,425 chronic cardiovascular
In asymptomatic moderate-risk patients,e complications in cancer survivors
echocardiography and cardiac serum biomarkers
IIa B
should be considered within 12 months after 8.1. Cancer survivors
completion of cancer therapy.53,54,59,61,68,148,208 8.1.1. Adult survivors of childhood and adolescent
In asymptomatic low-risk patients,e cancer
echocardiography and cardiac serum biomarkers The survival of children and adolescents with cancer has increased
IIb C
may be considered within 12 months after considerably in recent decades, with 5-year survival rates currently
completion of cancer therapy.634 exceeding 80%.647 However, the long-term health effects in the
Cardiology referralf is recommended in patients growing population of childhood and adolescent CS are a major con-
with cancer with new cardiac symptoms or new cern.648 CTR-CVT, as a consequence of treatment with anthracy-
asymptomatic abnormalities in echocardiography I C clines, mitoxantrone, and/or chest-directed RT can manifest as
and/or cardiac serum biomarkers at the end of CTRCD but also as VHD, CAD, arrhythmias, autonomic dysfunc-
therapy assessment.11 tion, pericardial disease, and premature CV mortality, depending
In selected patients with exercise intolerance on the type of cardiotoxic treatment.643,649
persisting at 12 months after cancer treatment CTRCD is one of the most frequent late effects in childhood CS
and with normal resting echocardiogram and who received cardiotoxic cancer treatment and contributes to sig-
IIb C
cardiac biomarkers, exercise stress nificant morbidity and non-cancer-related mortality later in life.650
echocardiography and/or CPET may be The cumulative incidence of CTRCD varies depending on the diag-
considered. nostic criteria applied and the population studied and ranges from
Targeted cardiac rehabilitation should be 4.8% to 10.6% at 40–45 years of age.651 RT to a field involving the
IIa B
considered in CS with high CV risk.638–640 heart increases the risk of CTRCD and valvular and vascular
Long-term continuation of cardiac medication is complications.652
recommended in patients who develop severe I C Follow-up of paediatric CS according to the International Late
CTRCD during cancer therapy. Effects of Childhood Cancer Guideline Harmonization Group is re-
CV follow-up and treatment optimization is commended.653 This includes risk stratification based upon the total
recommended in patients who developed cumulative dose of anthracycline chemotherapy and MHD delivered
I C
TKI-mediated hypertension during cancer (Table 11). Annual review of CVRF and education to promote a
therapy.644,645 healthy lifestyle is recommended. The frequency of CV review
CV follow-up and treatment optimization is
with TTE depends upon risk. A CV review should be considered
recommended in patients who developed vascular I C every 5 years for moderate-risk childhood and adolescent adult CS
toxicities during cancer therapy.10,237
and every 2 years for high-risk childhood and adolescent adult CS.
A recent retrospective analysis has shown that quantification of
Continued
LVEF .5 years after cancer diagnosis improves long-term childhood
ESC Guidelines 85
Table 11 Risk categories for asymptomatic adults who are childhood and adolescent cancer survivors
Risk category RT dosea (Gy MHD) Total cumulative doxorubicinb Combination therapy
dose (mg/m2)
RT dosea (Gy MHD) Total cumulative doxorubicinb
dose (mg/m2)
Very high risk .25c ≥400 .15c ≥100

c
High risk .15 to 25 250–399 5–15d ≥100
© ESC 2022
Moderate risk 5–15d 100–249 ,5e ≥100
e
Low risk ,5 ,100 –
Gy, Gray; MHD, mean heart dose; RT, radiotherapy.

a
RT risk categorization based on MHD is recommended over categorization based on prescribed dose, which may not accurately reflect cardiac radiation exposure. Depending on dose
distribution and exposure of specific cardiac substructures (as well as clinical risk factors), the treatment team may judge the patient to belong to a higher risk category. In addition, a
patient may be judged to belong to a lower risk category if only a small part of the heart is exposed to a relatively high prescribed dose.
b
Or doxorubicin equivalent.
c
Or prescribed RT ≥ 35 Gy to a volume exposing the heart if MHD is not available. Note that in this case, the limited information about cardiac exposure does not allow one to distinguish
between high- and very high-risk categories.
d
Or prescribed RT 15–34 Gy to a volume exposing the heart if MHD is not available.
e
Or prescribed RT , 15 Gy to a volume exposing the heart if MHD is not available.
CS risk stratification. A LVEF of 40–49% is associated with an almost 8.1.2. Adult cancer survivors
eight-fold increased risk for LVEF ,40% at 10-year follow-up com- Long-term cancer survivorship care is an advancing field of research.
pared with patients with a preserved LVEF (≥50%).654 Lifelong sur- Many survivors will experience several cancer- and treatment-related
veillance for high-risk survivors is recommended.7 late effects throughout their lives, including CTR-CVT. Besides affect-
ing their physical and psychosocial health status, these might reduce
Recommendation Table 40 — Recommendations for life expectancy and quality of life. This is relevant in some cancer types,
cardiovascular surveillance in asymptomatic adults when CVD risk—especially CTRCD risk—exceeds cancer mortal-
who are childhood and adolescent cancer survivors ity.658,659 The risk of fatal heart disease is increased more than two-
fold in survivors of several solid cancers and lymphoma compared
with the general population.660–662
Education of adults who are childhood and CV risk assessment at the end of therapy (Section 7) identifies CS
adolescent CS treated with anthracyclines, who require long-term cardiology follow-up beyond the first 12
mitoxantrone, and/or RT to a volume including I B months after completing their cancer treatment. Asymptomatic
the heart and their healthcare providers regarding CS with new or persisting abnormalities at their end-of-therapy as-
their increased CV risk is recommended.655–657 sessment will be identified as at high risk for future CV events and
Annual screening for modifiable CVRFc is require long-term surveillance.
recommended in adults who are childhood and Specific cancer treatments carry the highest risk of long-term CV
adolescent CS treated with anthracyclines, I C toxicity including anthracycline chemotherapy and RT where the
mitoxantrone, and/or RT to a volume including heart is within the RT treatment volume. Progressive RT-related
the heart. CV toxicity typically develops 5–10 years after the initial treatment,
CV assessmentd is recommended in female and may cause CAD and HF at an incidence up to six-fold higher than
childhood and adolescent CS prior to pregnancy I C in the general population. An increased CV mortality compared with
or in the first trimester. the general population has been attributed to radiation-associated
Echocardiography surveillance should be heart disease in Hodgkin lymphoma, non-Hodgkin lymphoma, BC,
considered every 2 years in adults who are IIa B and patients with lung cancer.663–665 The incidence and progression
high-risk childhood and adolescente CS.7 of the radiation-related CV complications depends on the dose to
the CV tissue and on concomitant cancer therapies and patient char-
© ESC 2022
Echocardiography surveillance should be

considered every 5 years in adults who are IIa B acteristics, such as pre-existing CVD, CVRF, and age.389,400
moderate-risk childhood and adolescente CS.7,654 Late CV complications are also observed in CS who required HSCT.
The incidence of HF increases up to 14.5% in women 15 years after
BP, blood pressure; CS, cancer survivors; CV, cardiovascular; CVRF, cardiovascular risk HSCT. Risk factors for CVD following HSCT include age, anthracycline
factors; DM, diabetes mellitus; ECG, electrocardiogram; HbA1c, glycated haemoglobin;
RT, radiotherapy; TTE, transthoracic echocardiography. dose, chest radiation exposure, hypertension, DM, and smoking.666
a
Class of recommendation. Long-term follow-up surveillance, based on CV toxicity risks
b
Level of evidence. (Table 12), includes patient education and CVRF optimization. An an-
c
Obesity, sedentary lifestyle, cigarette smoking, alcohol intake, unhealthy diet,
dyslipidaemia, hypertension, DM. nual clinical CV risk assessment is recommended for all adult CS to
d
BP, lipids, fasting glucose, HbA1c, ECG, and TTE. optimize CVRF control, promote a healthy lifestyle, and symptom re-
e
See Table 11. view. This can be done in collaboration with primary care or a
86 ESC Guidelines
Table 12 Risk categories for asymptomatic adult can- early risk, particularly in the first 2 years.61,667,668 Annual CV assess-
cer survivors ment with clinical examination, ECG, and NP measurement is recom-
mended in CS. TTE should be considered at years 1, 3, and 5 after
Risk categorya Patient characteristics
completion of cardiotoxic cancer therapy and every 5 years thereafter
Very high risk • Very high baseline CV toxicity risk in asymptomatic very high- and early high-risk adult CS.
pre-treatment In adult CS with late high CTR-CVT risk (e.g. young adults with
• Doxorubicinb ≥ 400 mg/m2 Hodgkin lymphoma or sarcomas who received a high total cumula-
• RT . 25 Gy MHDc tive anthracycline dose or patients treated with high-dose radiation

• RT . 15–25 Gy MHDc + doxorubicinb to a field involving the heart, e.g. Mantle RT) there is a progressive
≥100 mg/m2 risk of CTRCD.661,669 Annual CV assessment with clinical examin-
Early high risk • High baseline CV toxicity risk ation, ECG, and NP measurement is recommended, starting 5 years
(,5 years after • Symptomatic or asymptomatic after the end of treatment, provided the end-of-therapy assessment
therapy) moderate-to-severe CTRCD during at 12 months is normal. TTE should also be considered every 5 years,
treatment as well as non-invasive screening for CAD (Section 8.3) and carotid
• Doxorubicinb 250–399 mg/m2 disease (Section 8.5) according to local protocols.670
• High-risk HSCTd The long-term effects of CTRCD caused by trastuzumab and
Late high risk • RT . 15–25 Gy MHDc other targeted cancer therapies (e.g. TKI) beyond 10 years are un-
• RT 5–15 Gy MHDe + doxorubicinb known. Currently, there is no recommendation for lifelong surveil-
≥100 mg/m2 lance in these CS unless they have another indication.
• Poorly controlled CVRF CV assessment with clinical examination, ECG, echocardiography,
Moderate risk • Moderate baseline CV toxicity risk
and NP measurement every 5 years should be considered in asymp-
• Doxorubicinb 100–249 mg/m2
tomatic adult CS at moderate risk of future CTR-CVT and a normal
• RT 5–15 Gy MHDe
end-of-therapy CV assessment.
• RT , 5 Gy MHDf + doxorubicinb ≥ 100 mg/
m2 Recommendation Table 41 — Recommendations for
Low risk cardiovascular surveillance in asymptomatic adult can-
• Low baseline CV toxicity risk and normal
cer survivors
end-of-therapy cardiac assessment
• Mild CTRCD during therapy but recovered by Recommendations Classa Levelb
© ESC 2022
the end of cancer therapy

Annual CV risk assessment,c including ECG and
• RT , 5 Gy MHDf
NP, and CVRF management is recommended in
• Doxorubicinb , 100 mg/m2 I B
CS who were treated with a potentially
CTRCD, cancer therapy-related cardiac dysfunction; CV, cardiovascular; CVD, cardiotoxic cancer drug or RT.d,631–633,671,672
cardiovascular disease; CVRF, cardiovascular risk factors; GVHD, graft vs. host
disease; Gy, Gray; HSCT, haematopoietic stell cell transplantation; MHD, mean heart CV toxicity risk restratificatione is recommended
dose; RT, radiotherapy. References:397,399,400,673,674 5 years after therapy to organize long-term I C
a
RT risk categorization based on MHD is recommended over categorization based on
follow-up.
prescribed dose, which may not accurately reflect cardiac radiation exposure.
Depending on dose distribution and exposure of specific cardiac substructures (as well Echocardiography at years 1, 3, and 5 after
as clinical risk factors), the treatment team may judge the patient to belong to a higher completion of cardiotoxic cancer therapy and
risk category. In addition, a patient may be judged to belong to a lower risk category in IIa C
every 5 years thereafter should be considered in
case only a small part of the heart is exposed to a relatively high prescribed dose.
b
Or equivalent. asymptomatic very high- and early high-risk adult
c
Or prescribed RT ≥ 35 Gy to a volume exposing the heart if MHD is not available. Note CS.f
that in this case, the limited information about cardiac exposure does not allow one to
distinguish between high- and very high-risk categories. Echocardiography should be considered in
d
High-risk HSCT patients: allogenic HSCT; pre-existing CVD or multiple uncontrolled asymptomatic late high-risk adult CSf starting at 5
IIa C
CVRF; cancer treatment history (mediastinal or mantle field radiation, alkylating agents, years after radiation to a volume including the
.250 mg/m2 doxorubicin or equivalent); conditioning schemes (total body irradiation,
alkylating agents); development of GVHD. heart and then every 5 years.
e
Or prescribed RT 15–34 Gy to a volume exposing the heart if MHD is not available. Echocardiography may be considered every 5
f
Or prescribed RT , 15 Gy to a volume exposing the heart if MHD is not available.
IIb C
years in asymptomatic moderate-risk adult CS.f
Non-invasive screening for CADg should be
specialist in CV medicine with expertise in CVRF management. CS at considered every 5–10 years in asymptomatic
IIa C
high or very high risk of future CVD can be divided into those at high patients who received .15 Gy MHD,d starting at
early risk (within 5 years of completing cancer therapy) and those at 5 years after radiation.
high late risk (.30 years from completing treatment). The timing and Carotid ultrasound imaging should be considered
frequency of other complementary tests depends upon the risk for every 5 years in asymptomatic patients with a
IIa C
CTR-CVT (Figure 38). history of head/neck RT, starting at 5 years after
CS with a high or very high baseline risk and patients with abnormal radiation and every 5–10 years thereafter.
LV function at the end-of-therapy assessment have a high or very high Continued
ESC Guidelines 87
Renal artery ultrasound should be considered in 8.2. Myocardial dysfunction and heart
© ESC 2022
patients with a history of abdominal and pelvic
IIa C failure
radiation who present with worsening renal HF treatment in CS should follow the current 2021 ESC Guidelines
function and/or systemic hypertension. for the diagnosis and treatment of acute and chronic HF.14
BP, blood pressure; CAD, coronary artery disease; CMR, cardiac magnetic resonance; Treatment with ACE-I/ARB and/or beta-blockers is recommended
CS, cancer survivors; CT, computed tomography; CTR-CVT, cancer therapy-related for both symptomatic and asymptomatic CS who have LVEF ,
cardiovascular toxicity; CV, cardiovascular; CVD, cardiovascular disease; CVRF,
50% detected on CV assessment.14,61,208,675 In CS with mild asymp-
cardiovascular risk factors; ECG, electrocardiogram; HbA1c, glycated haemoglobin;
tomatic CTRCD detected on CV assessment (LVEF . 50% but new

MHD, mean heart dose; NP, natriuretic peptides; RT, radiotherapy.
a
Class of recommendation. fall in GLS and/or cardiac serum biomarker increase), treatment with
b
Level of evidence.
c ACE-I/ARB and/or beta-blockers may be considered.
Clinical review, BP, lipid profile, HbA1c.
d
RT risk categorization based on MHD is recommended over categorization based on
prescribed dose (≥35 Gy to a volume exposing the heart if MHD is not available).
e
Restratification includes evaluation of new or pre-existing CVRF and CVD (including
CTR-CVT).
f
See Table 12.
g
Stress echocardiography, cardiac CT, stress CMR, single-photon emission CT stress
test, according to local protocol.234
Long-term surveillance in asymptomatic CS
Annual CV risk
Low assessmenta
risk
Cardiology referralb
if new CV TTE every 5 years in
symptoms develop adults who are childhood
Moderate
and adolescent CS
risk
TTE every 5 years in
CV toxicity risk adult CS
re-stratificationc
at 5 years
TTE every 2 years in
adults who are childhood
High and and adolescent CS
very high
risk
Patient education and
TTE at years 1, 3, and 5 after
CVRF optimization
cardiotoxic cancer therapy and
every 5 years thereafter in adult CS
Figure 38 Long-term follow-up in cancer survivors. BP, blood pressure; CAD, coronary artery disease; CS, cancer survivors; CTR-CVT, cancer
therapy-related cardiovascular toxicity; CV, cardiovascular; CVD, cardiovascular disease; CVRF, cardiovascular risk factors; ECG, electrocardiogram;
HbA1c, glycated haemoglobin; NP, natriuretic peptides; TTE, transthoracic echocardiography. aClinical review, BP, lipid profile, HbA1c, ECG, NP. In
selected patients, non-invasive screening for CAD and carotid or renal diseases every 5–10 years, starting at 5 years after radiation may be considered.
b
Cardio-oncology referral is recommended when available; alternatively, the patient should be referred to a specialized cardiologist with expertise in
managing CVD in patients with cancer. cRestratification includes evaluation of new or pre-existing CVRF and CVD (including CTR-CVT).
88 ESC Guidelines
Recommendation Table 42 — Recommendations for mammary artery viability, venous access, and sternal wound healing
adult cancer survivors who develop cancer is recommended in CS with RT-induced CAD where CABG is con-
therapy-related cardiac dysfunction late after cardio- sidered. PCI with drug-eluting stents may be considered over CABG
toxic cancer therapy
in CS with RT-induced severe left main or three-vessel disease, with a
Recommendations Classa Levelb high SYNTAX (SYNergy between percutaneous coronary interven-
tion with TAXus and cardiac surgery) score (.22), in whom the
ACE-I/ARB and/or beta-blockers are planned PCI is technically feasible given the increased complications
recommended in adult CS with moderate I C
associated with CABG after mediastinal RT.

asymptomatic CTRCD.c,208,425,675–678 Screening for CAD should be considered in high-risk patients who
© ESC 2022
ACE-I/ARB and/or beta-blockers may be have received chest RT to a treatment volume including the heart.
considered in adult CS with mild asymptomatic IIb C Screening should take the form of functional imaging and/or CCTA be-
d
CTRCD. ginning at 5 years post-RT.234,484 The natural history of RT-related vas-
ACE-I, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers;
culopathy is different to atherosclerosis and may accelerate rapidly.173
CS, cancer survivors; CTRCD, cancer therapy-related cardiac dysfunction; GLS, Functional cardiac imaging should be considered in asymptomatic CS
global longitudinal strain; LVEF, left ventricular ejection fraction. with pre-existing CAD or when new significant CAD is detected on
a
b
Level of evidence.
anatomical imaging. In asymptomatic patients with inducible ischaemia
c
New LVEF reduction by ≥10 percentage points to an LVEF of 40–49% OR new LVEF secondary to RT-induced CAD, a MDT is recommended to discuss re-
reduction by ,10 percentage points to an LVEF of 40–49% AND either new relative vascularization needs according to the location of the RT-induced CAD,
decline in GLS by .15% from baseline OR new rise in cardiac biomarkers.
d
LVEF ≥ 50% and new relative decline in GLS by .15% from baseline AND/OR new
the ischaemia burden, LV function, arrhythmia burden, time since treat-
rise in cardiac biomarkers. ment, time since previous normal review (if available), concomitant
valvular disease, risks of surgical or percutaneous revascularization,
medical options, and patient preference.173
8.3. Coronary artery disease Platinum-based chemotherapies are now recognized to cause
Any vascular location within the RT treatment volume is at increased CAD in CS. Cisplatin-based chemotherapy for testicular cancer is
risk for both accelerated atherosclerosis and RT-related vasculopa- associated with a 1.5–7-fold increased risk of developing
thy.173,392 RT to the chest (e.g. treatment of Hodgkin lymphoma, CAD.421,493,685 Testicular CS who received platinum-based chemo-
early-stage BC, lung and oesophageal cancer, and for some patients therapy should have their CVRF tightly controlled and be educated
receiving infradiaphragmatic irradiation if the apex of the heart is to report any new chest pain or cardiac symptoms to their doctor
within the treatment volume) increases the risk of CAD. The latency promptly. The role of screening for CAD in patients who received
between RT and the appearance of CAD varies from a few years to platinum-based chemotherapy is unknown.
several decades, depending upon the presence or absence of pre- Aggressive risk-factor modification and CV diagnostic work-up
existing atherosclerosis and the age of the patient at the time of strongly enhance survival.5,672 Medical therapy with aspirin and sta-
RT. This is a serious complication for young CS with a good progno- tins for primary/secondary prevention, and beta-blockers and ni-
sis and long-life expectancy (e.g. BC and Hodgkin lymphoma).389,390 trates for symptom control, are recommended in CS.686,687
Patients treated for mediastinal Hodgkin lymphoma have shown an
increased risk of CAD as a first cardiac event.400 RT-induced CAD
depends on the location of the RT treatment volume and most com- Recommendation Table 43 — Recommendations for
monly affects either the proximal left anterior descending or the adult cancer survivors with coronary artery disease
right coronary arteries. RT-related vasculopathy is progressive and
typically manifests in severe, diffuse, long, smooth and concentric
angiographic lesions.679,680 Asymptomatic radiation-induced CAD detected during
The risk and severity of CAD increases with radiation dose, larger surveillance
volume exposed, younger age at time of treatment (,25 years),390 Non-invasive stress testingc is recommended in
time from treatment, smoking,400 the presence of other typical asymptomatic CS with new moderate or severe
CVRF, type of radiation source, and concurrent metabolic risk I C
radiation-induced CAD detected on CCTA to
factors.493 RT accelerates pre-existing atherosclerosis leading to in- guide ischaemia-directed management.635,688
creased ACS risk within 10 years of treatment.681
A MDT discussion is recommended for clinical
Patients with RT-induced CAD undergoing PCI with bare-metal
decision-making in patients with radiation-induced
stent or balloon angioplasty have an increased risk of all-cause and I C
CAD and inducible ischaemia or severe left main
CV mortality.682 Conversely, after PCI with a drug-eluting stent,
CAD.
there is no difference in target lesion revascularization or cardiac
Symptomatic CAD
mortality between patients with and without prior chest RT.683
Surgical revascularization in patients with prior RT may be compli- Pre-operative assessment of LIMA and RIMA
cated by poor tissue healing (skin and sternum), RT-induced injury to viability, venous access, and sternal wound healing
I C
the left and right internal mammary arteries (LIMA and RIMA, re- is recommended in CS with radiation-induced
spectively), inadequate target coronary vessels, and increased CAD where CABG is considered.
sternotomy-related pain.684 Pre-operative assessment of internal Continued
ESC Guidelines 89
PCI may be considered in CS with TAVI should be considered for patients with
© ESC 2022
radiation-induced CAD with severe left main or symptomatic severe aortic stenosis caused by
IIa B
© ESC 2022
three-vessel disease with a high SYNTAX score IIb B radiation at intermediate surgical
(.22) in whom the procedure is technically risk.504,506,693,694,696,697
682,689,690
feasible.
CS, cancer survivors; EuroSCORE, European System for Cardiac Operative Risk
CABG, coronary artery bypass graft; CAD, coronary artery disease; CCTA, coronary Evaluation; MDT, multidisciplinary team; STS PROM, Society of Thoracic Surgeons–
computed tomography angiography; CS, cancer survivors; LIMA, left internal Predicted Risk of Mortality; TAVI, transcatheter aortic valve implantation; VHD,
mammary artery; MDT, multidisciplinary team; PCI, percutaneous coronary valvular heart disease.

a
intervention; RIMA, right internal mammary artery; SYNTAX, SYNergy between Class of recommendation.
b
percutaneous coronary intervention with TAXus and cardiac surgery. Level of evidence.
c
a
Class of recommendation. Surgical risks include: vascular access, sternal and skin wound healing, concomitant
b
Level of evidence. cardiac disease, radiation-induced lung and thoracic vessels disease, aortic
c
According to local protocols and Non-invasive imaging in coronary syndromes: calcification, STS PROM/EuroSCORE II.
recommendations of the European Association of Cardiovascular Imaging and the
American Society of Echocardiography, in collaboration with the American Society of 8.5. Peripheral artery disease and stroke
Nuclear Cardiology, Society of Cardiovascular Computed Tomography, and Society Peripheral arterial and cerebrovascular disease in CS can be due to
for Cardiovascular Magnetic Resonance recommendations.234
the continuum of vascular disease pre-existing before, or developing
during or after cancer therapy. Cancer therapies such as cisplatin,
BCR-ABL inhibitors, and RT can have a direct long-lasting effect on
the vasculature. Approximately 30% of CML patients on nilotinib
8.4. Valvular heart disease may develop PAD, which is clinically recognized 2–4 years after
VHD can appear in CS at any point in time but typically occurs the start of therapy.698 The disease process may progress even after
10 or more years after cancer treatment. 691 Chest RT is the discontinuation of nilotinib. Long-term vascular effects, generally as-
main risk factor in CS, in particular at higher dose ranges, which sociated with vascular reactivity, can also be seen in patients treated
can cause either stenosis or regurgitation, or both. 391 with ponatinib, cisplatin, and bleomycin.699,700 Accelerated vascular
The reported incidences of valvular regurgitation are up to aging, inflammation, fibrosis, and atherosclerosis are characteristic
40% of CS survivors who received high-dose chest RT to a vol- consequences of RT.701 Up to 30% of patients may develop signifi-
ume involving the heart, with ,10% presenting with clinically cant carotid artery stenoses (.70%) after head/neck radiation.702,703
significant VHD.670 Vascular disease can also be an indirect consequence of cancer and
Prognosis and management depend on the extent and severity of its therapy, e.g. via reduction in physical activity, hyperlipidaemia, DM,
VHD, as it does in patients without cancer.692 TAVI should be con- obesity, hypothyroidism, and/or kidney disease. These CVRF-related
sidered for patients with symptomatic RT-induced severe aortic effects are mostly additive to the direct treatment-related effects.
stenosis at intermediate surgical risk.504,506,693,694 Similar strategies Promoting vascular health and preventing vascular disease in CS is re-
with percutaneous mitral valve repair or replacement can be consid- commended.672 This should be in line with the 2021 ESC Guidelines
ered.695 Importantly, commonly used calculators such STS PROM on CVD prevention in clinical practice.19
(Society of Thoracic Surgeons–Predicted Risk of Mortality) or
EuroSCORE (European System for Cardiac Operative Risk 8.6. Pericardial complications
Evaluation) II507 may underestimate the surgery-related risk in CS, The risk of long-term pericardial complications after cancer
and especially those who develop RT-induced VHD, due to addition- drug-induced acute pericarditis, caused by anthracyclines, cyclophos-
al RT-related risk factors such as pericardial calcification, aortic calci- phamide, cytarabine, and bleomycin, is unknown but generally con-
fication, increased bleeding risk, impaired skin healing, and RT-related sidered low. Long-term dasatinib treatment may lead to pericardial
pulmonary fibrosis. A Heart Team with cardiac surgeons, interven- effusion and pericarditis. The incidence of long-term ICI-associated
tional cardiologists, and cardio-oncology specialists should review pericardial complications is low.10
each case to guide appropriate treatment. The Heart Team recom- RT-induced chronic pericardial diseases can appear months to
mendation should be discussed with the patient, who can then make decades after the initial RT and constrictive pericarditis is the most
an informed treatment choice. serious.173,392 Incidence is difficult to determine, and many cases
are initially asymptomatic.704 Five-yearly echocardiographic surveil-
lance for pericardial constriction in CS following RT-induced acute
pericarditis may be considered. The absolute risk is considerably re-
Recommendation Table 44 — Recommendations for duced with modern radiation protocols,704 but a high rate of pericar-
adult cancer survivors with valvular heart disease
dial effusion has still been reported in patients with lung (grade ≥ 2,
.40%705) and oesophageal cancer (.25%706) treated with RT.
Pericardial disease has been less investigated than other
A MDT approach is recommended to discuss and RT-induced CVD, and clear protocols for post-therapy surveillance
I C
define the surgical riskc in CS with severe VHD. are lacking.707,708 In CS with chronic pericardial effusions following
Continued RT, cardiac imaging can assess for evidence of inflammation,
90 ESC Guidelines
constriction, or tamponade.709 Percutaneous balloon pericardiot- standardized risk-based screening and management of these condi-
omy or pericardial window creation should be used in selected cases tions according to general ESC Guidelines is recommended19 to im-
for large or growing chronic effusions if haemodynamic compromise prove long-term outcomes in CS.672
develops. Management of these conditions should follow general Increasing numbers of patients with cancer are already overweight
guideline recommendations.14,444 or obese at cancer diagnosis,717 and additional weight gain is a fre-
quent complication of anticancer treatments.718 Obesity is asso-
ciated with metabolic syndrome, worsening CVRF, and cancer.
Increasing evidence indicates that being overweight increases the
adult cancer survivors with pericardial complications

risk of cancer recurrence and reduces the likelihood of disease-free
Recommendation Classa Levelb survival and overall survival among those diagnosed with cancer.719–
724
There is also growing evidence to support intentional weight loss
Patients with acute pericarditis during RT to a
post-treatment in CS, which may result in improved prognosis and
volume including the heart are at higher risk of
survival.719 Dietary patterns characterized by a high intake of vegeta-
© ESC 2022
developing chronic constrictive pericarditis, hence IIb C
bles/fruits and whole grains has been shown to be associated with re-
echocardiography surveillance every 5 years may
duced mortality and cancer recurrence when compared with a high
be considered.
intake of refined grains, processed and red meats, and high-fat dairy
RT, radiotherapy. products.725–727
a
Class of recommendation. The identification and treatment of hyperlipidaemia in CS is asso-
b
Level of evidence.
ciated with a profound impact on outcomes.182,183 There is a benefit
for CS from an all-cause mortality perspective as well as for decreas-
8.7. Arrhythmias and autonomic disease ing cancer recurrence.728–730
Arrhythmias, conduction disease, and autonomic disease are com- Several studies have demonstrated the therapeutic benefits of ex-
mon complications in CS. Conduction disease after thoracic RT is ercise during primary anticancer treatment,731,732 and exercise is re-
typically associated with other CTR-CVT.710 It may include AV commended during and after anticancer treatment.11,733 For CS,734
block, bundle branch block, and sick sinus syndrome that should aerobic exercise results in improved survival.735 Based on current
be monitored and treated according to the 2021 ESC Guidelines guidelines, patients undergoing anticancer therapy and long-term
on cardiac pacing and cardiac resynchronization therapy.443 CS should be encouraged to exercise for at least 150 min per
Patients who require valve replacement after thoracic RT have a week.736
high risk of post-operative AV block requiring permanent pace-
maker therapy.711 Supraventricular and ventricular arrhythmias
are more common in patients after thoracic RT,712 possibly due 8.9. Pregnancy in cancer survivors
to RT-induced myocardial fibrosis. A common long-term complica- Improvements in the treatment of cancer have led to an increasing
tion after HSCT is supraventricular arrhythmia including AF and at- number of female paediatric and adolescent CS who experience
rial flutter,457 particularly in CS treated with anthracyclines or with pregnancy many years after their oncological treatments.
new CVRF or CV toxicity. Approximately 60% of them will have been previously exposed to
Autonomic dysfunction is an emerging but poorly understood anthracycline chemotherapy or chest RT and they have a 15-fold in-
complication observed in CS, and is most frequently observed as a crease in their lifetime risk of developing HF.737 As young CS enter
late complication after thoracic RT. Orthostatic hypotension, pos- their reproductive years and contemplate pregnancy, it is important
tural orthostatic tachycardia syndrome, inappropriate sinus tachy- to understand the impact of cancer and its treatment on fertility,
cardia, and loss of circadian heart rate variability can occur.713,714 pregnancy outcomes, and CV health. There are limited data available
Physicians caring for these patients should consider referral for auto- regarding CV risk in pregnancy following cancer treatments. The
nomic evaluation. In addition, the perception of angina pain may be overall incidence of LVD or HF associated with pregnancy in female
impaired,714 making the diagnosis of post-radiation CAD challenging. adult CS varies according to the studied population. In a single insti-
Evidence-based pharmacological treatment strategies are based on tution report including 337 female CS treated with cardiotoxic ther-
studies of patients with other autonomic dysfunction aetiologies apies, 58 (17%) had a subsequent pregnancy.738 Cardiac events,
(e.g. DM or infiltrative diseases) and the reported effectiveness is defined as LVEF , 50% on two TTE or new CAD, were identified
generally poor.714 in 17 patients.738 Patients with cardiac events were likely to be
younger at cancer diagnosis, received a higher cumulative dose of an-
thracycline, and had a longer delay (in years) from cancer treatment
8.8. Metabolic syndrome, lipid to first pregnancy compared with pregnant women with no cardiac
abnormalities, diabetes mellitus, and event.738 In a recent meta-analysis of six studies, the weighted risk of
hypertension pregnancy-associated LVD or HF in CS treated with anthracyclines
There is a growing understanding about shared CVRF that may be was 1.7% with no reported maternal cardiac deaths.739 Major risk
responsible for cancer development or progression and premature factors for CV events during pregnancy in CS include CTRCD (inci-
CV morbi-mortality.34 Modifiable CVRF continue to be underdiag- dence 28%; 47.4-fold higher odds),739 younger age at cancer diagno-
nosed and undertreated in CS, especially hypertension,715 obesity, sis,738,740 longer time from cancer treatment to first pregnancy, and
DM, metabolic syndrome,716 and dyslipidaemia. Early diagnosis via cumulative anthracycline dose.738
ESC Guidelines 91
Management by an expert MDT (the pregnancy heart team) is re- predominant in adults, rhabdomyomas in children).744 Malignant pri-
commended for all CS with CTRCD who are considering preg- mary tumours most commonly consist of sarcomas (approximately
nancy.739,741,742 The risk of HF in CS without CTRCD is low, 65%) or lymphomas (approximately 25%).745 Cardiac metastases
although vigilance remains important for potential maternal cardiac (from melanoma, lymphoma, leukaemia, breast, lung, and oesopha-
complications. geal cancers) are much more common than primary cardiac tumours
(Figure 39).746 Presenting symptoms are paraneoplastic (fever, weak-
ness, fatigue), thromboembolic, haemodynamic (due to compression
Recommendation Table 46 — Recommendations for or obstruction from the tumour) or arrhythmic.747,748
cardiovascular monitoring in cancer survivors during

The diagnostic pathway should be based on knowledge about
pregnancy
tumour type epidemiology, imaging features, and usually the
Recommendations Classa Levelb requirement for a histopathological diagnosis. This topic has been
extensively reviewed in ESC CardioMed,749 and here we
In high-risk female CS, pre-pregnancy counselling summarize the main recommendations for differential diagnosis
and management during pregnancy and around and management. Differential diagnosis should exclude cardiac
I C
delivery by a multidisciplinary pregnancy heart thrombi or the presence of chemotherapy catheters. Imaging must
team is recommended. assess the possibilities of cardiac surgery, and may include: (1) echo-
A baseline CV evaluation including history, cardiography (initial approach using TTE or transoesophageal
physical examination, ECG, NP, and echocardiography)748,750; (2) CMR (for cardiac tumour tissue char-
echocardiography is recommended in female CS I C acterization)751,752; and (3) CT and PET (to distinguish malignant
with a history of CTRCD who are considering from benign lesions and assess for non-cardiac metastatic disease
pregnancy. or primary cancers) (Figure 40).753,754
A baseline CV evaluation including history, Myxomas are primarily treated with surgery with a good progno-
physical examination, ECG, and echocardiography sis. Malignant tumours are associated with a poor prognosis and evi-
should be considered in all female CS who IIa C dence of the best treatment is lacking. Complete surgical resection is
received potentially cardiotoxic cancer therapy often impossible and adjuvant RT, systemic chemotherapy, and/or
and are considering pregnancy. debulking palliative surgery are needed.755 Cardiac aggressive B-cell
A CV evaluation including echocardiography is lymphomas require histopathological diagnosis (often obtained via
recommended at 12 weeks of pregnancy in female analysis of pericardial effusion, EMB, or direct surgical biopsy) and
CS who are either high-risk or who received I C are treated with chemotherapy, possibly followed by RT
potentially cardiotoxic cancer therapy and did not (Table 13).756
have a baseline CV assessment.
A second CV evaluation including 9.2. Pregnant patients with cancer
© ESC 2022
echocardiography should be considered at 20 The diagnosis of cancer during pregnancy is uncommon (1 in every
IIa C
weeks of pregnancy in high-risk female CSc who 1000 pregnant women is diagnosed with cancer), with BC, melan-
received potentially cardiotoxic cancer therapy. oma, and cervical cancer being the most frequent diagnoses.757
Chemotherapy is generally not applied during the first trimester
CS, cancer survivors; CTRCD, cancer therapy-related cardiac dysfunction; CV,
cardiovascular; ECG, electrocardiogram, NP, natriuretic peptides. due to the high risk of foetal congenital abnormalities (up to 20%)
a
Class of recommendation. and cytotoxic chemotherapies have different risk profiles during
b
c
Level of evidence. the second or third trimesters.758,759 Furthermore, chemotherapy
See Tables 11 and 12.
administration is usually not given beyond week 34 of gestation to
provide a 3-week window between the last cycle and delivery.757
Supplementary data, Table S19 summarizes the chemotherapies
8.10. Pulmonary hypertension for pregnant patients with cancer.760,761
Long-term clinical evaluation may be considered in patients who de- Cardiac assessment prior to chemotherapy in pregnant women
velop PH during therapy (Section 6). In patients with new exertional with cancer should consist of clinical history, physical examination,
dyspnoea, fatigue, or angina, a TTE is recommended to assess the ECG, cardiac biomarker assessment and TTE (Figure 41).741
probability of PH. As TTE alone is not enough to confirm the diagnosis Baseline and follow-up TTE should be interpreted in the context
of PH, CS diagnosed with high PH probability require a right-heart of physiological haemodynamic alterations during pregnancy. In nor-
catheterization to confirm the diagnosis. PH should be treated accord- mal pregnancy, increase in stroke volume, heart rate, and pre-load
ing to general guidelines with referral to a specialist PH service.620 blood volume, and decrease in systemic vascular resistance, lead to
an increase in cardiac output from the first trimester to 80–85%
above baseline by the third trimester.762–764 An increase in LV
9. Special populations mass and LV and RV volumes is observed in the third trimester.
During normal pregnancy, LVEF is usually unchanged and can be
9.1. Cardiac tumours used for CTRCD monitoring. Although NP and cTn may be slightly
Cardiac tumours are classified as either benign or malignant.743 Over elevated during normal pregnancy (NT-proBNP , 300 ng/L, BNP ,
90% of primary cardiac tumours are benign (myxomas are 100 pg/mL,14 and hs-cTnT765,766), serial evaluation may be useful for
92 ESC Guidelines
Pulmonary artery Left atrium
Sarcoma Lipoma
Metastasis
Myxoma
Right atrium Sarcoma

Lipoma
Lymphoma
Metastasis
Myxoma
Sarcoma
Pulmonary veins
Lung tumours
Right ventricle Sarcoma
Fibroma
Lipoma
Lymphoma
Metastasis Valves
Rhabdomyoma
Fibroelastoma
Metastasis
Inferior cava vein
Leiomyoma
Renal tumour
Left ventricle
Pericardium
Fibroma
Lipo-sarcoma Lipoma
Lipoma Lymphoma
Lymphoma Metastasis
Mesothelioma Rhabdomyoma
Metastasis Sarcoma
Figure 39 Location of primary and secondary cardiac tumours.
close CTRCD monitoring during cancer treatment with the higher TTE during treatments with potential CTRCD risk should be advised
cut-off NP levels for pregnancy. (e.g. every 4–8 weeks or every two cycles for a 3-weekly anthracycline
The topic of CVD during pregnancy has been extensively re- chemotherapy cycle). The management of clinical HF or asymptomatic
viewed in the 2018 ESC Guidelines for the management of CVD LVD during pregnancy is fully described in the 2018 ESC Guidelines for
during pregnancy.741 Here we focus on specific recommendations the management of CVD during pregnancy.741
in pregnant women with cancer receiving anthracycline
chemotherapy.
9.2.2. Venous thromboembolism and pulmonary
embolism
9.2.1. Left ventricular dysfunction and heart failure Pregnant patients with cancer have an increased risk of
Medical history evaluating signs and symptoms of HF should be per- developing VTE, especially when hospitalized. 767–769
formed at every clinical visit of pregnant women with cancer receiv- Identified risks for VTE in pregnant patients include having a
ing anthracycline chemotherapy. More frequent CV evaluations with history of BC or previous chemotherapy in the past 6 months.
ESC Guidelines 93
Diagnostic algorithm for cardiac masses
Non-invasive assessment of single or multiple cardiac masses
Echocardiographya CTb CMRc PETd

Consider cardiac mass biopsy if malignant primary
tumour suspected or diagnosis uncertain on imaginge
Tumour Thrombus, vegetation, structural
Type
Secondary tumour Benign primary Malignant primary

(metastasis)f tumour tumour
Leukaemias Angioma, lipoma, papillary Lymphoma

Lymphomas fibroelastoma Sarcoma
Melanomas Myxoma
Solid tumours: breast, lung,
and oesophageal cancers
Figure 40 Diagnostic algorithm for cardiac masses. CMR, cardiac magnetic resonance; CT, computed tomography; PET, positron emission tomog-
raphy; TTE, transthoracic echocardiography. aTTE/transoesophageal echocardiography: location, size, and haemodynamic disturbances. Contrast echo-
cardiography to assess vascularization. bIdentify primary extra-cardiac malignancy. Reveal extra-cardiac changes. Staging of malignant lesions. cTissue
characterization (fat infiltration, necrosis, haemorrhage, calcification, and vascularization). Exclude thrombus. dDistinguish malignant vs. benign lesions.
Staging of malignant lesions. eMass biopsy of suspected primary malignant cardiac tumours and/or biopsy of extracardiac masses if detected and safer
to biopsy. f20–30 times more likely than primary tumours.
Table 13 Management strategies and surgery indications for symptomatic and asymptomatic patients with benign
and malignant cardiac tumours
Classification Management strategies Surgery indications
Benign Asymptomatic MDT discussion is required considering: tumour type, If left-sided and endocardial: even if small and incidental, a
tumours location, size, growth rate, and likelihood of embolism. MDT is needed to consider the indication for surgical
Anticoagulation should be considered for left-sided removal due to the embolic risk
tumours or right-sided tumours associated with an
intracardiac shunt, according to the individual’s embolic and
bleeding risk
Symptomatic Non-surgical management for: Surgical resection is indicated in all other cases.
• Rhabdomyomas (possible spontaneous regression) For large, benign, unresectable, symptomatic cardiac
• Intramural haemangioma (possible response to tumours (obstruction, severe HF, or malignant
corticosteroids) arrhythmias), heart transplantation may be indicated in
• Unresectable cases: if antiarrhythmic therapy is sufficient some cases
Malignant Asymptomatic Histopathological diagnosis is required If primary cardiac sarcoma, a complete surgical resection
tumours may increase survival
© ESC 2022
Symptomatic Chemotherapy and/or RT are the only therapeutic options Secondary cardiac tumours may also be treated with
for secondary cardiac tumours. palliative cardiac surgery
If primary cardiac lymphoma: chemotherapy
HF, heart failure; MDT, multidisciplinary team; RT, radiotherapy.

94 ESC Guidelines
Cardiac monitoring protocol for pregnant women receiving

anthracycline-based chemotherapy

1st trimester Anthracycline chemotherapy Follow-up
Baseline Week Week Every Week Delivery 12 M

12 20 4–8 W 34
Every visit
Physical examination
ECG
TTE
cTn/NP
Figure 41 Cardiac monitoring protocol for pregnant women receiving anthracycline-based chemotherapy. cTn, cardiac troponin; ECG, electrocardio-
gram; M, months; NP, natriuretic peptides; TTE, transoesophageal echocardiography; W, week.
Recommendations for the diagnosis and treatment of PE during preg- morbidity and/or mortality due to VTE. 770 LMWH have be-
nancy are the same as in the general 2018 ESC Guidelines for the man- come the drug of choice for the prophylaxis and treatment
agement of CVD during pregnancy741 and 2019 ESC Guidelines for the of VTE in pregnant patients. 741 The recommendation for
diagnosis and management of acute pulmonary embolism.566 thromboprophylaxis should be individualized, weighing the
Determination of VTE risk score and the use of thrombo- risks of bleeding vs. thromboembolism in pregnant patients
prophylaxis protocols may be useful to prevent maternal with cancer.
ESC Guidelines 95
Recommendation Table 47 — Recommendations for syndrome require both tricuspid and pulmonary valve surgery.783
cardiovascular assessment and monitoring of pregnant Administration of i.v. somatostatin analogues (e.g. octreotide) is re-
women with cancer commended to avoid a peri-operative carcinoid crisis. The infusion
should be started on the morning of the procedure (up to 12 h pre-
operatively), continued throughout the procedure (surgery, pre-
Management by an expert MDT (the pregnancy operative coronary angiography, pacemaker implantation), and post-
heart team) in an expert centre is recommended
I C operatively for at least 48 h following valve surgery or until stable if a
for pregnant women with cancer who require carcinoid crisis is triggered post-operatively.772

cardiotoxic cancer therapy.741 The optimal choice of valve prosthesis is still a matter of debate
Cardiac assessment prior to cardiotoxic cancer due to the balance of risk of both accelerated bioprosthetic valve de-
therapy in pregnant women is recommended and generation vs. bleeding risks in patients with extensive liver metasta-
I C
consists of clinical history, physical examination, ses requiring therapeutic anticoagulation for mechanical valves.784,785
ECG, and echocardiography.741 Complications include AV block, requiring pacemaker implantation
Monthly or bimonthly CV evaluation, including in 25% of patients.786 Frequently, the reduced RV function does
TTE, should be considered during cardiotoxic IIa C not improve despite tricuspid valve replacement and HF persists.787
cancer therapyc in pregnant women with cancer. Thrombus formation on the tricuspid bioprosthesis can occur, espe-
cially during the first 3 months post-operatively, and oral anticoagu-
© ESC 2022
cTn may be considered at baseline and during
anthracycline chemotherapy in pregnant women IIb C lation with VKA may be considered. Persistent serotonin elevation
with cancer. can cause recurrent bioprosthesis valve fibrosis. Valve-in-valve trans-
catheter intervention has been reported in bioprosthetic valve failure
cTn, cardiac troponin; CV, cardiovascular; ECG, electrocardiogram; MDT,
multidisciplinary team; TTE, transthoracic echocardiography.
in metastatic carcinoid heart disease; however, future research is
a
Class of recommendation. needed to define its role.783,788,789
b
c
Level of evidence. In patients with left-sided carcinoid valvular involvement, closure
For patients receiving anthracycline-based chemotherapy.
of interatrial shunts should be considered, although only sparse
data exist for this approach.
9.3. Carcinoid valvular heart disease
Carcinoid tumours represent rare neuroendocrine malignancies ori-
ginating from the enterochromaffin cells (Figure 42).771 Carcinoid Recommendation Table 48 — Recommendations for
syndrome is a rare cause of acquired VHD including mainly right- carcinoid valvular heart diseases
sided valvular lesions, but also left-sided involvement, pericardial ef-
fusion, and myocardial metastases.772 Coronary artery vasospasm Recommendations Classa Levelb
and paroxysmal atrial or ventricular tachycardias may rarely occur Echocardiographyc is recommended for the
due to sympathetic stimulation. Cardiac metastases are reported detection of carcinoid cardiac involvement in all
with an incidence of 3.8% on the ventricles, confirmed by PET-CT patients with carcinoid syndrome and elevated NP
scans.773,774 Data from the SEER (Surveillance, Epidemiology, and levels and/or clinical signs of carcinoid heart I B
End Results) registry identified that approximately 20% of patients disease, and for surveillance every 3 or 6 months
with neuroendocrine malignancies develop carcinoid syndrome depending on the severity of cardiac involvement
(7.6–32.4%), which is associated with shorter survival (4.7 years and clinical status.772,790,791
compared with 7.1 years in patients without carcinoid syndrome)
NP should be considered for screening and
and poor quality of life.775 It is estimated that 20–50% of these pa- IIa B
surveillance of carcinoid heart disease every 6
tients present cardiac involvement, especially of the right-sided car-
months.777–780
diac valves.771 In the presence of a patent foramen ovale, interatrial
A MDT discussion for optimal medial
shunt, primary bronchial neuroendocrine tumour, or extensive liver
management to prevent carcinoid crisis is
metastases, humoral substances directly enter the systemic circula- I C
recommended before any invasive or surgical
tion, causing left-sided valvular involvement in up to one-third of
cardiac procedure.
cases.776
Valve replacement surgery is recommended in
NP should be considered for screening and surveillance of patients
symptomatic patients with severe carcinoid
at risk of carcinoid cardiac involvement and TTE is recommended in I C
tricuspid or pulmonary VHD and an expected
patients with NT-proBNP . 260 pg/mL or clinical signs or symp-
survival ≥12 months.d,783,785
toms.777–780 In asymptomatic patients with NT-proBNP , 260 pg/
Valve replacement surgery should be considered
mL, repeat clinical and NP assessment should be considered every
in patients with asymptomatic severe carcinoid
6 months.
tricuspid or pulmonary VHD, progressive RV IIa C
Survival has improved in carcinoid tumours, with the use of som-
dysfunction/dilatation, and an expected survival
atostatin analogues and surgical techniques in liver metastasis.
≥12 months.d,772
However, right HF still represents a major cause of death.781,782
Many patients with severe tricuspid regurgitation due to carcinoid Continued
96 ESC Guidelines
Valve replacement or repair surgery is 9.4. Amyloid light-chain cardiac
© ESC 2022
recommended in symptomatic patients with
I C amyloidosis
severe carcinoid mitral or aortic VHD and an Amyloid light-chain amyloidosis is a plasma cell dyscrasia, which
expected survival ≥12 months.783,785 is typically treated with therapies very similar to those used in
MDT, multidisciplinary team; NP, natriuretic peptides; RV, right ventricular; VHD, MM, including PI-based therapy.792 It can occur in conjunction
valvular heart disease. with myeloma or independently as a light-chain protein-
a
b producing disorder. Amyloid light-chain amyloidosis is a systemic
Level of evidence.
c disease 793,794 and it is critical to have a high degree of suspicion for

Including saline contrast infusion at baseline to rule out patent foramen ovale.
d
With controlled serotonin concentrations. the diagnosis of cardiac involvement (amyloid light-chain cardiac
amyloidosis [AL-CA]) because a combination of specialized tests
is needed to make an accurate diagnosis (Figure 43).290,793,795,796
Carcinoid heart disease: clinical features and diagnostic tests
Clinical features Diagnostic and pronostic tools
Flushing CMR
Pleural
effusion
Broncho- TTE
constriction
Ascites
Circulating serotonin
Diarrhoea
NP
Peripheral
oedema
Urinary 5HIAA
Figure 42 Carcinoid heart disease: clinical features and diagnostic tests. 5HIAA, 5-hydroxyindoleacetic acid; CMR, cardiac magnetic resonance; NP,
natriuretic peptides; TTE, transthoracic echocardiography.
ESC Guidelines 97
Non-invasive diagnosis of AL-CA
Clinical features n e tigation
Skin

Bruising
CV Laboratorya
AF/flutter
Dyspnoea
HFpEF or unexplained
ECGb
right HF
Hypotension or syncope
Peripheral oedema
TTEc
Nerves
Orthostatic hypotension
Peripheral polyneuropathy ECHO score ≥8d
Polyneuropathy
Kidney
Characteristic echo findingse
Proteinuria
Renal impairment
CMRf
GI
Constipation /diarrhoea
Macroglossia
Malabsorption/weight
loss/nausea
Figure 43 Non-invasive diagnosis of amyloid light-chain cardiac amyloidosis. a′ , late diastolic velocity of mitral annulus obtained by tissue Doppler im-
aging; AF, atrial fibrillation; AL-CA, amyloid light-chain cardiac amyloidosis; CMR, cardiac magnetic resonance; CV, cardiovascular; E, mitral inflow early
diastolic velocity obtained by pulsed wave; e′ , early diastolic velocity of mitral annulus obtained by tissue doppler imaging; ECG, electrocardiogram; echo,
echocardiography; ECV, extracellular volume fraction; GI, gastrointestinal; GLS, global longitudinal strain; HF, heart failure; HFpEF, heart failure with pre-
served ejection fraction; IVS, interventricular septum; LGE, late gadolinium enhancement; LV, left ventricular; LVEDD, left ventricular end diastolic diam-
eter; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PW, left ventricular posterior wall; s′ , systolic velocity of tricuspid annulus obtained by
Doppler tissue imaging; SPEP, serum protein electrophoresis; TAPSE, tricuspid annular plane systolic excursion; TTE, transthoracic echocardiography;
UPEP, urine protein electrophoresis. Individually, the clinical manifestations and findings on cardiac testing for AL-CA are non-specific. Integration of
all clinical and diagnostic findings is necessary when assessing the likelihood of the diagnosis. aDisproportionately high NT-proBNP; persisting elevated
troponin levels; abnormal free light-chain levels (AL-CA); positive SPEP and/or UPEP (AL-CA). bDisproportionally low QRS voltage; early conduction
system disease; pseudo-infarct pattern. cUnexplained LV thickness ≥ 12 mm + 1 or 2 characteristic echo findings or ECHO score ≥ 8; idiopathic peri-
cardial effusion. dECHO score: relative LV wall thickness (IVS + PW/LVEDD) . 0.6 (3 points), Doppler E/e′ . 11 (1 point); TAPSE ≤ 19 mm (2 points);
GLS ≥ −13% (1 point); systolic longitudinal strain apex to base ratio.2.9 (3 points). eCharacteristic echocardiography findings: grade ≥ 2 diastolic dys-
function; reduced s′ , e′ , and a′ velocities (,5 cm/s); decreased GLS to ≥−15%. fDiffuse subendocardial or transmural LGE; elevated native T1 values;
abnormal gadolinium kinetics (myocardial nulling preceding or coinciding with the blood pool); ECV ≥ 0.40% (strongly supportive).
98 ESC Guidelines
Cardiac serum biomarkers are an essential step in the diagnostic Recommendation Table 49 — Recommendations for
and prognostic assessments for these patients.797–799 AL-CA has amyloid light-chain cardiac amyloidosis diagnosis and
been extensively reviewed in a recent position paper from the monitoring
Working Group on Myocardial and Pericardial Diseases.290
The classical non-invasive definition of AL-CA is based on clinical
suspicion, biomarkers, TTE, CMR, and nuclear scintigraphy criteria Echocardiography, NP, and cTn are
(Figure 43). Persistent troponin elevation and disproportionately recommended for the diagnosis of AL-CA in I B
high NT-proBNP (generally .300 ng/L in the absence of renal fail- patients with plasma cell dyscrasia.290,820 822

ure or AF) to ventricular function parameters on TTE is a charac- CMR is recommended in patients with suspected
I A
teristic red flag for AL-CA.800 A decrease in GLS with a AL-CA.290,803,804
distinctive apical sparing pattern (preserved GLS values in the LV EMB should be considered in patients with
apical region) is considered specific for cardiac amyloidosis, al- suspected AL-CA involvement if CMR is not IIa C
though it is not helpful to distinguish between amyloid light-chain diagnostic.290
and transthyretin amyloidosis.801 Additionally, GLS ≥ −15% may
© ESC 2022
Admission with inpatient ECG monitoring should be
serve as an independent prognostic factor of poor overall survival considered for high-risk patients with AL-CA IIa C
in patients with AL-CA.802 CMR with LGE and parametric imaging requiring PI during their first cycle of therapy.c,808,811
has emerged as a new non-invasive gold-standard for diagnosis

AL-CA, amyloid light-chain cardiac amyloidosis; CMR, cardiac magnetic resonance; cTn,
(Figure 43).803,804 Nuclear scintigraphy can differentiate transthyre- cardiac troponin; ECG, electrocardiogram; EMB, endomyocardial biopsy; HFA, Heart
tin amyloidosis from AL-CA supported by the presence of mono- Failure Association; ICOS, International Cardio-Oncology Society; NP, natriuretic
clonal protein.290 EMB should be considered in patients with peptides; PI, proteasome inhibitors.
a
suspected AL-CA involvement if CMR is not diagnostic.290 A rare b
Level of evidence.
condition that may coexist with AL-CA is light-chain deposition dis- c
According to baseline evaluation using HFA-ICOS PI risk assessment tools (see
ease, which frequently associates extensive renal involvement and Section 4).
poor prognosis.799
Recently, a staging system for AL-CA has demonstrated the prog-
nostic impact of cTnT and NT-proBNP levels.797 Heart progression 9.5. Cardiac implantable electronic
criteria are defined by NT-proBNP progression (.30% and devices
.300 ng/L increase), cTnT progression (≥33% increase) or ejection RT can cause malfunction of cardiac implantable electronic de-
fraction decrease (≥10% decrease).805–807 However, evaluating a vices (CIEDs).443,823 The risk of RT-induced CIED malfunction
cardiac response to treatment using a decrease in NT-proBNP levels generally increases with the radiation dose,824,825 although the
and New York Heart Association class improvement is still strongest predictor of malfunction is the magnitude of
challenging. exposure to neutron emission from high-energy photon RT, conven-
AL-CA frequently results in HF, major cardiac arrhythmias, ortho- tionally defined as a beam energy .10 megavolts (MV).824,826,827
static hypotension, sudden cardiac death, and an increased risk of ar- Non-neutron-producing treatment is therefore preferable in pa-
terial and venous thrombosis.808–810 Beta-blockers, ACE-I, ARB, or tients with a CIED.826
angiotensin receptor-neprilysin inhibitor may not be well tolerated RT-induced CIED malfunction can manifest in: (1) transient inter-
because of hypotension.290 The management of AF is very complex ference, with inappropriate triggering during the irradiation only; (2)
in this population. Amiodarone is the preferred antiarrhythmic treat- a reset, reverting to backup settings, recoverable with device repro-
ment and digitalis should be used with caution. Anticoagulation is re- gramming; and, rarely (3) permanent damage to the device due to
commended in all AL-CA patients with AF independent of the direct CIED irradiation.826,827
CHA2DS2-VASc score due to the high prothrombotic risk unless The clinical consequences of a CIED malfunction include the inhib-
there is a contraindication.290 Currently, the guidelines for implanted ition of pacing and inappropriate pacing at maximum sensor rate.826
devices, including pacemakers and ICDs, do not provide specific re- The clinical effects of device malfunction are greatest when the pa-
commendations for AL-CA and decisions should be individualized tient is pacing-dependent. Theoretically, oversensing might lead to
after a MDT discussion.811 inappropriate ICD shocks, although this has not been reported in
Optimal systemic therapy for AL-CA is rapidly changing, and the the literature.826
efficacy of certain combination therapies continues to im- More recent registries have reported minimal or no adverse ef-
prove.812,813 Autologous HSCT for AL-CA is not universally utilized fects of RT on CIED malfunction.827,828 Nevertheless, as it is not pos-
but is a viable treatment option.814 Therapies for AL-CA are evolv- sible to predict the behaviour of a CIED within or close to an RT
ing, and daratumumab and PI show promise for improved out- treatment volume, general recommendations should be followed
comes.792,815–817 Clinical observations, but no RCT evidence, to minimize patient risk (Figures 44–46).188,824,825
suggest the potential role of doxycycline to improve survival in pa- Patients with a CIED should be reviewed by their cardiologist/
tients with AL-CA.818,819 electrophysiologist to assess the risk of CIED malfunction and
ESC Guidelines 99
Assessing risk of RT to CIED

Patient
Pacing-
Pacing- dependent or
independent frequent ICD
CIED in the RT Dose region
therapies

treatment and risk
volume category
Risk areas
<5 Gy
YES
≥5 Gy
<10 Gy or
neutrons <10 MV
NO
≥10 Gy or
neutrons ≥10 MV
Low risk Medium risk High risk
Figure 44 Risk stratification in patients with a cardiac implantable electronic device undergoing radiotherapy. CIED, cardiac implantable electronic de-
vice; Gy, Gray; ICD, implantable cardioverter defibrillator; MV, megavolt; RT, radiotherapy.
patients should be informed of the potential risks of RT.443 For pa- adequate tumour treatment. The photon beam energy should
tients with rate-adaptive pacemakers, consideration should be given be kept ,10 MV as the risk of device malfunction/damage in-
to temporary deactivation of the sensor during RT. Although inacti- creases above this threshold. If higher doses are needed or if
vation of antitachycardia therapies in patients with ICDs is recom- the CIED cannot be kept out of the beam, consideration should
mended in several publications, by either reprogramming or be given to removing and relocating the CIED away from the
application of a magnet to ICDs, it is infrequently performed in clin- beam, although this will only very rarely be necessary. The main
ical practice.826 reason for device relocation is to allow adequate RT treatment
CIEDs should not be placed directly in the RT treatment vol- of the tumour, but consideration should also be given to possible
ume and the cumulative dose should not exceed 2 Gy to a pace- RT-induced CIED malfunction/damage with consequent need for
maker or 1 Gy to an ICD.827 If the CIED is situated in the path CIED replacement.826 However, CIED explant and resiting carries
of the planned radiation beam, it could also interfere with significant risks, including the risk of infection, which may be of
100 ESC Guidelines
Risk stratification of patients with CIED undergoing thoracic RT
Y CIED in the RT treatment volume N
MDTa Consider RT type and dose

(Figure 46)

Leave device in situ
Consider moving CIED OR Reduce radiation energy to minimize exposure to neutrons
Limit cumulative dose
Maximum cumulative
incident dose of >5 Gy
N Y
Pacing dependent or
frequent ICD therapies
N Y
Low-risk patients High-risk patients
CIED evaluation: CIED evaluation:

Before RTb
Before RTb (Class I) ECG and/or pulse oximetry monitoring and external pacing available
during RT sessions
Audio-visual monitoring Weekly during RT
(Class I)
CIED check-up after completing RT

(Class I)
Figure 45 Management of patients with a cardiac implantable electronic device located in the radiotherapy treatment beam. CIED, cardiac implantable
electronic device; ECG, electrocardiogram; Gy, Gray; ICD, implantable cardioverter defibrillator; MDT, multidisciplinary team; N, no; RT, radiotherapy; Y,
yes. aMultidisciplinary discussion must consider: (1) whether the CIED is interfering with the RT dose delivered to the tumour; (2) whether the
RT is interfering with CIED function (aim to not exceed 2 Gy to permanent pacemaker and 1 Gy to ICD); (3) risks of moving the CIED: infection (es-
pecially in immunocompromised patients), procedural complications (e.g. bleeding with thrombocytopaenia); for younger patients with good prognosis,
consider long-term effects of losing an access site (lead extraction/RT-induced thrombosis). bIf last CIED check .3 months earlier.
particular importance in patients receiving chemotherapy or conjunction with the patient. Device relocation is not recom-
those who are immunosuppressed. For most patients in whom mended for CIEDs receiving a maximum cumulative incident
definitive tumour treatment is planned, the risk/benefit ratio will dose of ,5 Gy, where the risk is considered negligible.826,828
usually favour device relocation, whereas for patients receiving There should be continuous visual and voice contact with the pa-
palliative RT or with significant comorbidities, relocation could tient during each treatment fraction. CIEDs should be periodically
be avoided.826 These decisions should be made by a MDT in checked in patients with ICDs, especially those receiving .10 MV
ESC Guidelines 101
Management of patients with CIED located outside the RT treatment volume
RT type and dose

Non-neutron-generating RT Neutron-generating RT
or dose <2 Gy or dose ≥ 2 Gy
<10 MV photons or ≥10 MV photons or

2–9 Gy ≥10 Gy
Pacing-dependent or
Pacing-dependent frequent ICD therapies
N Y N Y
Low-risk patients High-risk patients Low-risk patients High-risk patients High-risk patients
CIED evaluation: CIED evaluation: CIED evaluation: CIED evaluation:
Before RTa (Class I) Before RTa Before RTa (Class I) Before RTa

ECG and/or pulse ECG and/or pulse
Audio-visual monitoring oximetry monitoring and Audio-visual monitoring oximetry monitoring and
external pacing available external pacing available
during RT sessions during RT sessions
Weekly during RT Weekly during RT
(Class I) (Class I)
CIED check-up after completing radiotherapy

(Class I)
Figure 46 Management of patients with a cardiac implantable electronic device located outside the radiotherapy treatment volume. CIED, cardiac
implantable electronic device; ECG, electrocardiogram; Gy, Gray; ICD, implantable cardioverter defibrillator; MV, megavolt; N, no; RT, radiotherapy;
Y, yes. aIf last CIED check .3 months earlier.
photon beam energy.827,829 For patients receiving electron or kV of CIED reset is potentially significant.824,830 The CIED should be re-
photon beam RT, CIED evaluation appears largely unnecessary.827 checked within 2 weeks of completion of RT treatment. Systematic
For patients treated with proton beam RT, special consideration remote CIED monitoring may be helpful to optimize the patient’s
should be paid to the neutron component of the beam, as the risk surveillance.831
102 ESC Guidelines

risk stratification and monitoring for patients with cardiac
10. Patient information,
implantable electronic devices undergoing radiotherapy communication, and
Recommendations Classa Levelb self-management
Risk stratification including planned radiation type Collaboration between different healthcare professionals and pa-
and energy, dose to CIED, the patient’s device tients is of paramount importance for the most effective manage-
I C
type, and pacing dependence is recommended ment of patients with cancer and CVD. Appropriate language and

prior to starting treatment.824,825,827,828 communication should be used to allow patients to receive clear
In patients undergoing RT, a CIED check is and accurate information about their condition, and play an active
recommended in all patients before and after role in managing their treatment.11
I C
completing RT, and during RT according to The first goal of this process is to raise the patient’s awareness of
individual risk.824,826 the possible presence or development of a CVD, either during can-
In patients with a CIED undergoing RT at high risk cer or after having some oncological therapy. Patients should under-
stand that cancer and CVD share many CVRF and reducing risk is
© ESC 2022
of arrhythmia and/or device dysfunction, ECG
I C
monitoring and/or pulse oximetry are vital for the prevention of cancer, cancer relapse, and the develop-
recommended during every RT session.827,829,831 ment or worsening of a CVD during or after treatment. Patients
should be informed—at the end of chemotherapy—that a persona-
CIED, cardiac implantable electronic device; ECG, electrocardiogram; RT, radiotherapy.
a lized follow-up plan and regular CV controls are needed to detect
b
Level of evidence. potential reversible stages of CV toxicities. Education, counselling,
and support to promote healthy lifestyle and to treat modifiable
Interaction between healthcare professionals and patients with cancer
Appropriate language
and communication
Information Education, counselling, and support
Raise awareness Recognition and Don’t stop

Appropriate lifestyle
of possible CVD report of early CV cardioprotective therapy
with cancer modification
symptoms and signs without medical advice
Understand shared Active treatment Regular CV follow-up Timely EoL and
risk factors for
cancer and CVD of CVRF (also if asymptomatic) DNR discussion
Consider specific psychologic and social conditions
Aid of digital health tools or information leaflets
Figure 47 Patient information, communication, and self-management. CV, cardiovascular; CVD, cardiovascular disease; CVRF, cardiovascular risk fac-
tors; DNR, do not resuscitate; EoL, end of life.
ESC Guidelines 103
CVRF should be offered to patients with cancer, in order to reduce Moreover, cancer and medical associations have also developed an in-
the burden of complications during and after anticancer therapy. creasing interest in cardio-oncology. Important roles of these scientific
Patients should receive guidance to recognize and to report signs societies are clinical research, education, and advocacy. The ESC-CCO
and symptoms of CVD, in order to receive prompt and effective treat- strategic plan and mission include improvement of prevention, diagno-
ment, ideally without interfering with their cancer treatment. Patients sis, treatment, and management of CTR-CVT and enhancement of the
should also be advised not to stop cardioprotective therapies without standard of care for patients with cancer (Figure 48).
medical guidance, even if they recover their cardiac function. To help
in this complex task, leaflets specifically designed for this context may

be used,832,833 eventually with the aid of digital tools (Figure 47). 12. Key messages
This is the first ESC cardio-oncology Guideline and contains 272 new
11. The role of scientific societies recommendations. The key messages from this guideline are:
in the promotion and • A guiding principle of cardio-oncology is integration, and
development of cardio-oncology cardio-oncology providers must have knowledge of the broad
in modern medicine scope of cardiology, oncology, and haematology. Communication
between different healthcare professionals is critical to optimize
Cardio-oncology is a subspecialty that has seen huge development and the care of patients with cancer and CVD.
growth in recent years with the formation—in almost all national and • Cardio-oncology programmes facilitate cancer treatment by min-
international societies—of cardio-oncology working groups. imizing unnecessary cancer therapy interruptions and CTR-CVT
The role of scientific societies in the promotion and

development of cardio-oncology
Research
Basic and translational Appropriate
research resources
Clinical research Communication
Long-term survivorship Knowledge
programmes Organization
Education Advocacy
Cardio-
oncology
Communication Political strategies

strategies against cancer and CVD
Community Engagement Community level
Healthcare authorities International level
Healthcare professionals National level
Patients Regional level
Figure 48 The role of scientific societies in the promotion and development of cardio-oncology. CVD, cardiovascular disease.
104 ESC Guidelines
across the entire continuum of cancer care. In patients who de- and worldwide. Strategic investments in cardio-oncology care
velop CTR-CVT, a MDT discussion is required to balance the networks and cardio-oncology services provision are needed to
risk/benefit of cancer treatment discontinuation. meet the projected increased clinical demand in the near fu-
• There is a new international definition of CTR-CVT (Table 3). ture,834 and to facilitate research, training, and educational activ-
• CV toxicity risk is a dynamic variable. This guideline is structured to ities. A dedicated training core curriculum for a minimum of
provide a personalized approach to care based upon the baseline 1-year medical training is urgently needed. It may include: (1)
CV toxicity risk. A baseline CV risk assessment is recommended knowledge of the broad scope of cardiology, oncology, and
for all patients with cancer scheduled to receive a potentially car- haematology; (2) CV competencies for CTR-CVT prevention,

diotoxic anticancer therapy. This enables the oncology team to surveillance, and management of patients with cancer in dedicated
consider CV risk while making cancer treatment choices, educating outpatients’ cardio-oncology clinics; (3) inpatient consultative
patients regarding their CV risk, and personalizing CV surveillance services; and (4) dedicated time to achieve competences in CV im-
and follow-up strategy. aging, HF, and vascular cardiology.
• Primary prevention of CV toxicity from cancer therapy aims to Collaboration between healthcare providers, clinical and basic in-
avoid or minimize the development of CTR-CVT in patients with- vestigators, healthcare authorities, regulatory bodies, advocacy
out CVD. groups, and patients’ associations is needed to address future needs
• Secondary prevention refers to interventions in patients with pre- (see Section 11).
existing CVD, including prior or new CTR-CVT. A MDT is recom- As this Guideline was developed, it became clear that there is a sig-
mended when patients with cancer have complex CVD that may nificant lack of RCT to guide decision-making, with many recommen-
impact on their cancer treatment. dations supported by level of evidence C. This is complicated by the
• Defining and delivering an appropriate prevention and surveillance fast-moving pace of new oncology treatment developments against a
plan for potential CV complications is recommended. Optimal background of dynamic CV toxicity likelihood. Therefore, large num-
management of CVRF and pre-existing CVD is mandatory to facili- bers of patients and longer follow-up are required to provide suffi-
tate cancer therapy and to improve patients’ prognosis. cient statistical power and definitive answers. In the future, the
• Detailed monitoring pathways during cancer therapy—including following strategies and areas of research are priorities:
3D echocardiography, GLS, and cardiac biomarkers—are pro-
vided to detect CV toxicity based upon specific cancer therapies • New trial designs focusing upon the ‘at-risk’ cancer patient
and baseline CV toxicity risk. populations.
• Treatment recommendations for CTRCD during and after cancer • Validating current HFA-ICOS risk assessment tools and surveil-
therapy depend upon CTRCD severity and symptoms. New guid- lance algorithms.
ance on continuing trastuzumab in BC patients who develop • Assessment of new technologies for the detection of early
asymptomatic moderate CTRCD (LVEF 40–49%) while starting CTRCD, broadening the biomarker panel and recognizing the spe-
cardioprotective medication is provided. cific patterns in early myocardial damage.
• Use of a structured algorithm to guide decisions regarding anticoa- • Refining CV risk scores (e.g. EuroSCORE II, SCORE2,
gulation management in patients with cancer presenting with AF SCORE2-OP, CHA2DS2-VASc, HAS-BLED, SYNTAX) for appli-
or VTE encompassing the TBIP assessment is encouraged. cation in cancer populations.
• After cancer treatment is completed, the focus of the • Optimal treatment of steroid-resistant ICI CV toxicity and long-
cardio-oncology team shifts to coordination of long-term follow- term CV effects of ICI therapy.
up. This starts with an ‘end-of-treatment’ assessment in the first • Selection criteria for modern percutaneous structural (TAVI,
year after treatment, reviewing patients with cancer who have re- Mitraclip, LAA occluder devices) and electrophysiological (abla-
ceived cardiotoxic anticancer therapies to reassess their CV tox- tion) CV therapies in patients with active cancer.
icity risk and guide long-term surveillance planning. • Patient-specific predictive algorithms for QTc prolongation with
• A new algorithm (Figure 37) is provided to guide weaning off of CV cancer drugs.
medication in CS. • Assessment of genetic profiles in more specific CTRCD risk
• Patients with cancer, CS, and the patient’s family/carers should re- prediction.
ceive guidance to promote healthy lifestyle and recognize and re- • Identification of the cancer patient populations with mild or mod-
port signs and symptoms of CVD, to receive prompt and effective erate CTRCD during treatment who can safely wean off long-term
treatment, without interfering with their cancer treatment. CV medication.
• Patients must receive psychological support when needed and • Optimal modalities for screening long-term survivor populations
clear and accurate information about their condition to play an ac- for the complications of anthracycline chemotherapy and medias-
tive role in managing their treatment and increase adherence to tinal radiation.
cancer and CV treatments. • Creation of large cardio-oncology registries to collect ‘big data’ on
large patient populations.
• Application of artificial intelligence and other new data analytics to
13. Future needs identify new patients with cancer at risk and new parameters that
can predict risk of CTR-CVT, response to specific cardioprotec-
There are a low number of dedicated cardio-oncology services and tive interventions, and long-term risk and safety to wean off CV
most patients are reviewed in general cardiology clinics in Europe therapies initiated during cancer treatment.
ESC Guidelines 105
14. Gaps in evidence • Personalized medicine and use of big data and artificial intelligence
tools.
Cancer and CVD are the two major public health problems with great
economic and social impact. In addition, CTR-CVT are associated with Cardiovascular toxicity risk stratification
an excess of both CV and oncological mortality, especially when they limit
patients’ ability to complete effective treatments. However, the intersec- • Development of CV toxicity risk prediction tools including both
tion of cancer and CVD has only recently gained wider interest and many treatment- and patient-related risk factors.
areas with lack of evidence need to be addressed in future research. • Validated prospective CV toxicity risk scores based on clinical

outcomes.
Role of cardio-oncology services and cardio-oncology • Further research on the role of genetics in CV toxicity risk
care networks stratification.
• Robust evidence on the impact of dedicated cardio-oncology pro- • Validation of CPET parameters for CV outcomes in patients with
grammes and cardio-oncology rehabilitation on the prognosis of cancer.
patients with cancer and survivors.
• Specification of roles of different healthcare professionals (includ- Prevention, diagnosis, and management of CTR-CVT
ing nurses and pharmacists) in cardio-oncology teams.
• Cardio-oncology care networks to improve the management of • Raise awareness of the benefits of minimizing CV risk in patients
patients with cancer and to discuss difficult cases. with cancer in order to reduce the risk of CTR-CVT.
• Cardio-oncology team support and involvement in oncology trials • More data on new technologies (biomarkers, advanced echocardi-
design (including patients’ representatives). ography, CMR, etc.) and genetic profiles for the detection of early
• Understand how to engage patients with cancer in their own CV CV toxicity.
care (inclusion of digital tools). • Prospective studies showing the impact on outcomes and/or qual-
ity of life (and frailty) of early CTR-CVT diagnosis and treatment.
Research, education, and training in cardio-oncology • Further evidence from prospective RCTs to define when cardio-
• Consensus about CV toxicity definitions used in oncology trials. protective medications improve patients’ outcomes.
• Define standards for CV toxicity monitoring in oncology trials to • Further research on the potential for aerobic exercise to reduce
avoid unexpected CV toxicities when new drugs are approved for CTR-CVT.
clinical use. • RCTs of (new) CV therapies in patients with different types of
• Relevant model systems to allow high-throughput screening of CTR-CVT.
new cancer treatments for CV toxicity.
• Improved knowledge on CV toxicity mechanisms of new targeted Long-term cancer survivorship programmes
cancer therapies and ICI and optimal treatment of CV toxicities.
• Improved knowledge on the effects of radiation to specific cardiac • Development of optimal CV follow-up programmes after treat-
substructures and the interactions between cardiotoxic systemic ment for cancer (research on risk stratification, efficacy, and fre-
therapy and RT. quency of screening protocols).
• Further research into the underlying mechanisms that connect • Best screening strategies for RT-induced CAD.
CVD and cancer, such as a genetic predisposition to CV toxicity. • Further research on CV preventive strategies for long-term CS.
15. ‘What to do’ and ‘what not to do’ messages from the Guidelines
Recommendation Table 1 for a general approach to cardiovascular toxicity risk categorization

CV toxicity risk stratification before starting potentially cardiotoxic anticancer therapy is recommended in all patients with
I B
cancer.
Communicating the results of the CV toxicity risk assessment to the patient and other appropriate healthcare professionals is
I C
recommended.
It is recommended that patients categorized as low CV toxicity risk should proceed with anticancer therapy without
I C
delay.
Cardiology referral is recommended in high-risk and very high-risk patients before anticancer therapy. I C
Discussion of the risk/benefit balance of cardiotoxic anticancer treatment in high- and very high-risk patients in a multidisciplinary
I C
approach prior to starting treatment is recommended.
Cardiology referral is recommended for patients with cancer and pre-existing CVD or abnormal findings at baseline CV toxicity risk
I C
assessment who require potentially cardiotoxic anticancer therapy.
Continued
106 ESC Guidelines
Recommendation Table 2 for electrocardiogram baseline assessment
An ECG is recommended in all patients starting cancer therapy as part of their baseline CV risk assessment. I C
In patients with an abnormal baseline ECG, referral to a cardiologist is recommended. I C
Recommendation Table 3 for cardiac biomarker assessment prior to potentially cardiotoxic therapies
Baseline measurement of NP and/or cTn is recommended in all patients with cancer at risk of CTRCD if these biomarkers are going to
I C

be measured during treatment to detect CTRCD.
Recommendation Table 4 for cardiac imaging modalities in patients with cancer
General
Echocardiography is recommended as the first-line modality for the assessment of cardiac function in patients with cancer. I C
3D echocardiography is recommended as the preferred echocardiographic modality to measure LVEF. I B
GLS is recommended in all patients with cancer having echocardiography, if available. I C
Baseline cardiac imaging prior to potentially cardiotoxic therapies

Baseline comprehensive TTE is recommended in all patients with cancer at high risk and very high risk of CV toxicity before starting
I C
anticancer therapy.
Recommendation Table 5 for primary prevention of cancer therapy-related cardiovascular toxicity
Management of CVRF according to the 2021 ESC Guidelines on CVD prevention in clinical practice is recommended before, during, and
I C
after cancer therapy.
Recommendation Table 6 for secondary prevention of cancer therapy-related cardiovascular toxicity
Management of CVD according to applicable ESC Guidelines is recommended before, during, and after cancer therapy. I C
Recommendation Table 7 for baseline risk assessment and monitoring during anthracycline chemotherapy and in the first 12 months
after therapy
TTE
Baseline echocardiography is recommended in all patients with cancer before anthracycline chemotherapy. I B
In all adults receiving anthracycline chemotherapy, an echocardiogram is recommended within 12 months after completing treatment. I B
In high- and very high-risk patients, echocardiography is recommended every two cycles and within 3 months after completing
I C
treatment.
Cardiac serum biomarkers
Baseline measurement of NP and cTn is recommended in high- and very high-risk patients prior to anthracycline chemotherapy. I B
cTn and NP monitoring before every cycle during anthracycline chemotherapy and 3 and 12 months after therapy completion is
I B
recommended in high- and very high-risk patients.
Recommendation Table 8 for baseline risk assessment and monitoring during HER2-targeted therapies and in the first 12 months
after therapy
TTE
Baseline echocardiography is recommended before HER2-targeted therapies in all patients. I B
In patients receiving neoadjuvant or adjuvant HER2-targeted therapies, echocardiography is recommended every 3 months and within
I B
12 months after completing treatment.
In metastatic HER2+ disease, echocardiography is recommended every 3 months during the first year; if the patient remains
I C
asymptomatic without CV toxicity, then surveillance can be reduced to every 6 months during future treatment.
Cardiac biomarkers
Baseline NP and cTn measurement are recommended in high- and very high-risk patients prior to anti-HER2-targeted therapies. I C
Continued
ESC Guidelines 107
Recommendation Table 9 for baseline risk assessment and monitoring during fluoropyrimidine therapy
Baseline CV risk assessment and evaluation including BP measurement, ECG, lipid profile, HbA1c measurement, and SCORE2/SCORE2-
I C
OP or equivalent is recommended before starting fluoropyrimidines.
A baseline echocardiogram is recommended in patients with a history of symptomatic CVD before starting fluoropyrimidines. I C
Recommendation Table 10 for baseline risk assessment and monitoring during VEGFi
BP monitoring

BP measurement is recommended for patients treated with VEGFi, bevacizumab, or ramucirumab at every clinical visit. I C
Daily home monitoring of BP for patients treated with VEGFi during the first cycle, after each increase of VEGFi dose, and every 2–3
I C
weeks thereafter is recommended.
ECG monitoring
In patients treated with VEGFi at moderate or high risk of QTc prolongation, QTc monitoring is recommended monthly during the first
I C
3 months and every 3–6 months thereafter.
Echocardiography
Baseline echocardiography is recommended in high- and very high-risk patients treated with VEGFi or bevacizumab. I C
Recommendation Table 11 for baseline risk assessment and monitoring during second- and third-generation BCR-ABL tyrosine
kinase inhibitors
Baseline CV risk assessment is recommended in patients who require second- or third-generation BCR-ABL TKI. I C
In patients treated with nilotinib or ponatinib, CV risk assessment is recommended every 3 months during the first year and every 6–12
I C
months thereafter.
Baseline echocardiography is recommended in patients scheduled to receive dasatinib. I C
Recommendation Table 12 for baseline risk assessment and monitoring Bruton tyrosine kinase inhibitor therapy
BP monitoring and management
BP measurement is recommended for patients treated with BTK inhibitors at every clinical visit. I B
Echocardiography
Baseline echocardiography is recommended in high-risk patients scheduled to receive BTK inhibitors. I C
TTE is recommended in all patients who develop AF during BTK inhibitor therapy. I C
AF
Opportunistic screening for AF by pulse-taking or ECG rhythm strip is recommended at every clinical visit during BTK inhibitor therapy. I C
Recommendation Table 13 for baseline risk assessment and monitoring during multiple myeloma therapies
BP monitoring
BP measurement is recommended for patients treated with PI at every clinical visit. I C
Cardiac serum biomarkers
Measurement of NP is recommended prior to PI in high- and very high-risk patients. I C
NP and cTn measurements are recommended at baseline and every 3–6 months in patients with AL-CA. I B
TTE
Baseline echocardiography, including assessment for AL-CA, is recommended in all patients with MM scheduled to receive PI. I C
Continued
108 ESC Guidelines
VTE prophylaxis
Therapeutic doses of LMWH are recommended in patients with MM with previous VTE. I B
Prophylactic doses of LMWH are recommended in patients with MM with VTE-related risk factors (excluding previous VTE) at least
I A
during the first 6 months of therapy.
Recommendation Table 14 for baseline risk assessment and monitoring during combined RAF and MEK inhibitor therapy
BP monitoring at each clinical visit and weekly outpatient monitoring during the first 3 months of treatment and monthly thereafter is
I C

recommended.
In patients treated with cobimetinib/vemurafenib, an ECG is recommended at 2 and 4 weeks after initiation of treatment and every 3
I C
months thereafter.
Baseline echocardiography is recommended in all high- and very high-risk patients scheduled to receive combined RAF and MEK
I C
inhibitors.
Recommendation Table 15 for baseline risk assessment and monitoring during immunotherapy
ECG, NP, and cTn measurements are recommended in all patients before starting ICI therapy. I B
Baseline echocardiography is recommended in high-risk patients before starting ICI therapy. I B
CV assessment is recommended every 6–12 months in high-risk patients who require long-term (.12 months) ICI treatment. I C
Recommendation Table 16 for baseline risk assessment and monitoring during androgen deprivation therapy for prostate cancer
Baseline CV risk assessment and estimation of 10-year fatal and non-fatal CVD risk with SCORE2 or SCORE2-OP is recommended in
I B
patients treated with ADT without pre-existing CVD.
Baseline and serial ECGs are recommended in patients at risk of QTc prolongation during ADT therapy. I B
Annual CV risk assessment is recommended during ADT. I B
Recommendation Table 17 for baseline risk assessment and monitoring during endocrine therapy for breast cancer
Baseline CV risk assessment and estimation of 10-year fatal and non-fatal CVD risk with SCORE2 or SCORE2-OP is recommended in
I C
BC patients receiving endocrine therapies without pre-existing CVD.
Annual CV risk assessment is recommended during endocrine therapy in BC patients with high 10-year risk of (fatal and non-fatal) CV
I C
events according to SCORE2/SCORE2-OP.
Recommendation Table 18 for baseline risk assessment and monitoring during cyclin-dependent kinase 4/6 inhibitor therapy
QTc monitoring is recommended at baseline and 14 and 28 days in all patients with cancer receiving ribociclib. I A
QTc monitoring is recommended in patients treated with ribociclib with any dose increase. I B
Recommendation Table 19 for baseline risk assessment and monitoring during ALK and EGFR inhibitors
Baseline CV risk assessment is recommended in patients before ALK inhibitors and EGFR inhibitors. I C
Baseline echocardiography is recommended in all patients with cancer before starting osimertinib. I B
Recommendation Table 20 for baseline risk assessment and monitoring in patients receiving chimeric antigen receptor T cell
and tumour-infiltrating lymphocytes therapies
Baseline ECG, NP, and cTn are recommended in all patients with cancer before starting CAR-T and TIL therapies. I C
A baseline echocardiography is recommended in patients with pre-existing CVD before starting CAR-T and TIL therapies. I C
Measurement of NP, cTn, and echocardiography are recommended in patients who develop CRS of ASTCT ≥ 2. I C
Continued
ESC Guidelines 109
Recommendation Table 21 for baseline risk assessment of patients before radiotherapy to a volume including the heart
Baseline CV risk assessment and estimation of 10-year fatal and non-fatal CVD risk with SCORE2 or SCORE2-OP is recommended. I B
Recommendation Table 22 for baseline risk assessment in haematopoietic stem cell transplantation patients
Baseline and serial CV risk assessment (3 and 12 months, then yearly) including BP measurement, ECG, lipid measurement, and HbA1c is
I C
recommended in HSCT patients.
Echocardiography is recommended in all patients before HSCT. I C

Recommendation Table 23 for the management of cardiovascular disease and cancer therapy-related cardiovascular toxicity in
patients receiving anticancer treatment
A specialist CV assessment is recommended for optimal diagnostic workup and management of patients with cancer who present with
I C
new CV toxicity during and after cancer treatment.
Recommendation Table 24 for the management of cancer treatment-related cardiac dysfunction during anthracycline
chemotherapy
Anthracycline chemotherapy-induced symptomatic CTRCD
HF therapy is recommended for patients who develop symptomatic CTRCD during anthracycline chemotherapy. I B
Discontinuation of anthracycline chemotherapy is recommended in patients who develop symptomatic severe CTRCD. I C
Temporary interruption of anthracycline chemotherapy is recommended in patients who develop symptomatic moderate CTRCD and
I C
a multidisciplinary approach regarding the decision to restart is recommended.
A multidisciplinary approach regarding interruption vs. continuation of anthracycline chemotherapy is recommended in patients who
I C
develop mild symptomatic CTRCD.
Anthracycline chemotherapy-induced asymptomatic CTRCD
Temporary interruption of anthracycline chemotherapy and initiation of HF therapy is recommended in patients who develop
I C
asymptomatic moderate or severe CTRCD.
A multidisciplinary approach regarding the decision when to restart is recommended in all patients with moderate or severe
I C
asymptomatic CTRCD.
Continuation of anthracycline chemotherapy is recommended in asymptomatic patients who have LVEF ≥ 50% and who have
I C
developed a significant fall in GLS or a troponin or a NP elevation .ULN.
Recommendation Table 25 for the management of cancer treatment-related cardiac dysfunction during HER2-targeted therapies
HER2-targeted therapy-induced symptomatic CTRCD
HF therapy is recommended for patients who develop symptomatic moderate-to-severe CTRCD with LVEF , 50% during HER2-
I B
targeted treatment.
Temporary interruption of HER2-targeted treatment is recommended in patients who develop moderate or severe symptomatic CTRCD
I C
and the decision to restart should be based on a multidisciplinary approach after improvement of LV function and symptoms resolved.
In patients who develop mild symptomatic CTRCD, HF therapy and a multidisciplinary approach regarding the decision to continue vs.
I C
interrupt HER2-targeted therapy are recommended.
HER2-targeted therapy-induced asymptomatic CTRCD
Temporary interruption of HER2-targeted therapy and initiation of HF therapy is recommended in patients who develop asymptomatic
I C
severe CTRCD.
A multidisciplinary approach regarding the decision to restart HER2-targeted treatment is recommended in patients with severe
I C
asymptomatic CTRCD.
Continuation of HER2-targeted therapy is recommended in patients who develop asymptomatic mild (LVEF ≥ 50%) CTRCDc with
I C
more frequent cardiac monitoring.
ACE-I/ARB and beta-blockers are recommended in patients who develop asymptomatic moderate (LVEF 40–49%) CTRCDc during
I C
HER2-targeted treatment.
Recommendation Table 26 for the diagnosis and management of immune checkpoint inhibitor-associated myocarditis
cTn, ECG, and CV imaging (echocardiography and CMR) are recommended to diagnose ICI-associated myocarditis. I B
In patients with suspected ICI-associated myocarditis, temporary interruption of ICI treatment is recommended until the diagnosis is
I C
confirmed or refuted.
Continued
110 ESC Guidelines
Interruption of ICI treatment is recommended in patients with confirmed ICI-associated myocarditis. I C
Continuous ECG monitoring to assess for new AV block and tachyarrhythmias during the acute phase is recommended for all patients
I C
with symptomatic ICI-associated myocarditis.
Early high-dose corticosteroids are recommended in patients with cancer and confirmed ICI-associated myocarditis. I C
Continuation of high-dose corticosteroids is recommended for the treatment of ICI-associated myocarditis until resolution of
I C
symptoms, LV systolic dysfunction, conduction abnormalities, and significant cTn reduction.

Admission to ICU (level 3), treatment with i.v. methylprednisolone, and optimal CV treatment including mechanical support (when
I C
indicated) is recommended for patients with ICI-associated fulminant myocarditis.
A multidisciplinary discussion is recommended before restarting ICI treatment in selected patients with previous uncomplicated ICI-
I C
associated myocarditis.
Recommendation Table 27 for the diagnosis and management of Takotsubo syndrome in patients with cancer
Coronary angiography (invasive or CCTA) is recommended to exclude ACS. I C
CMR is recommended to exclude myocarditis and MI. I B
QT-prolonging drugs are not recommended during the acute TTS phase. III C
Recommendation Table 28 for the management of acute coronary syndromes in patients receiving anticancer treatment
An invasive strategy is recommended in patients with cancer presenting with STEMI or high-risk NSTE-ACS with life expectancy ≥6
I B
months.
A temporary interruption of cancer therapy is recommended in patients where the cancer therapy is suspected as a contributing cause. I C
In patients with cancer, thrombocytopaenia and ACS, aspirin is not recommended if platelets ,10 000/µL. III C
In patients with cancer, thrombocytopaenia and ACS, clopidogrel is not recommended if platelets ,30 000/µL and prasugrel or
III C
ticagrelor are not recommended if platelets ,50 000/µL.
Recommendation Table 29 for the management of chronic coronary syndromes in patients receiving anticancer treatment
Individualized duration of DAPT is recommended in patients with cancer with CCS, following revascularization, based upon thrombotic/
I C
ischaemic and bleeding risk, type and stage of cancer, and current cancer treatment.
Recommendation Table 30 for the management of valvular heart disease in patients receiving anticancer treatment
In patients with cancer and pre-existing severe VHD, management according to the 2021 ESC/EACTS Guidelines for the management
I C
of VHD is recommended, taking into consideration cancer prognosis and patient preferences.
In patients with cancer developing new VHD during cancer therapy, management according to the 2021 ESC/EACTS Guidelines for the
I C
management of VHD is recommended, taking into consideration cancer prognosis and patient comorbidities.
Recommendation Table 31 for the management of atrial fibrillation in patients receiving anticancer treatment
Long-term anticoagulation is recommended for stroke/systemic thromboembolism prevention in patients with cancer with AF and a
I C
CHA2DS2-VASc score ≥2 (men) or ≥3 (women) as per the 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation.
Thromboembolic and bleeding risk reassessment is recommended during follow-up in patients with cancer with AF. I C
Antiplatelet therapy or prophylactic LMWH are not recommended for stroke or systemic thromboembolism prevention in AF with
III C
cancer.
Recommendation Table 32 for the management of long QTc and ventricular arrhythmias in patients receiving anticancer treatment
How to manage QTc prolongation in patients with cancer
Discontinuation of QTc-prolonging cancer therapy is recommended in patients who develop TdP or sustained ventricular
I C
tachyarrhythmias during treatment.
Temporary interruption of QTc-prolonging cancer therapy is recommended in patients who develop asymptomatic QTcF ≥ 500 ms
I C
and an ECG should be repeated every 24 h until resolution of the QTcF prolongation.
Immediate withdrawal of any offending drug and correction of electrolyte abnormalities and other risk factors is recommended in
I C
patients with cancer who develop QTcF ≥ 500 ms.
Weekly ECG monitoring is recommended in asymptomatic patients with cancer with QTcF 480–500 ms who are treated with a QTc-
I C
prolonging cancer therapy.
Continued
ESC Guidelines 111
A 12-lead ECG is recommended after any dose increase of QTc-prolonging cancer therapy. I C
Restarting QTc-prolonging cancer therapy

A multidisciplinary discussion is recommended before restarting QTc-prolonging drugs in patients who have developed significant QTcF
I C
prolongation, to discuss alternative cancer treatments.
Weekly ECG monitoring during the first 4–6 weeks and then monthly thereafter is recommended in patients with cancer after
I C
restarting QTc-prolonging cancer therapy.

Recommendation Table 33 for the management of arterial hypertension in patients receiving anticancer treatment
General
Effective treatment of cancer therapy-induced arterial hypertension to prevent cancer treatment interruption and CV complications is
I C
recommended.
A BP target ,140 mmHg systolic and ,90 mmHg diastolic is recommended during cancer therapy. I C
The competing cancer and CV risk evaluation is recommended if the systolic BP is ≥180 mmHg or diastolic BP ≥110 mmHg, and any
cancer therapy associated with hypertension should be deferred or temporarily withheld until the BP is controlled to values I C
,160 mmHg (systolic) and ,100 mmHg (diastolic).
Cancer therapy-induced arterial hypertension treatment
ACE-I or ARB are the first-line antihypertensive drugs recommended for BP management in patients with cancer. I B
Dihydropyridine CCB are recommended as second-line antihypertensive drugs for patients with cancer with uncontrolled BP. I C
Combination therapy with ACE-I or ARB and dihydropyridine CCB is recommended in patients with cancer with systolic
I C
BP ≥ 160 mmHg and diastolic BP ≥ 100 mmHg.
Diltiazem and verapamil are not recommended to treat arterial hypertension in patients with cancer due to their drug–drug
III C
interactions.
Recommendation Table 34 for the management of venous thromboembolism in patients receiving anticancer treatment
Apixaban, edoxaban, or rivaroxaban are recommended for the treatment of symptomatic or incidental VTE in patients with cancer
I A
without contraindications.
LMWH are recommended for the treatment of symptomatic or incidental VTE in patients with cancer with platelet count .50 000/µL. I A
Catheter-associated VTE
Duration of anticoagulation in patients with cancer with a catheter-associated VTE is recommended for a minimum of 3 months and
I C
continuing longer if the catheter remains in situ.
Recommendation Table 35 for venous thromboembolism prophylaxis during anticancer treatment
Extended prophylaxis with LMWH for 4 weeks post-operatively is recommended for patients with cancer undergoing major open or
I B
laparoscopic abdominal or pelvic surgery with low bleeding risk and high VTE risk.
Prophylactic LMWH for the primary prevention of VTE is indicated in hospitalized patients with cancer or those with prolonged bed
I B
rest or reduced mobility in the absence of bleeding or other contraindications.
A discussion with the patient about the relative benefits and harms, cancer prognosis, drug cost, and duration of treatment is
I C
recommended prior to prophylactic anticoagulation for the primary prevention of VTE.
Recommendation Table 36 for management of peripheral artery disease during anticancer treatment
In patients who develop new symptomatic PAD, a multidisciplinary approach regarding the decision to continue vs. interrupt
I C
culprit cancer therapy is recommended.
Recommendation Table 37 for the management of pulmonary hypertension during anticancer treatment
Right-heart catheterization and discontinuation of dasatinib is recommended in patients who develop symptomatic or asymptomatic
I C
increase in peak TRV . 3.4 m/s.
In patients with confirmed dasatinib-induced PAH or new asymptomatic peak TRV . 3.4 m/s, an alternative BCR-ABL inhibitor is
I C
recommended after peak TRV recovery to ,2.8 m/s.
Recommendation Table 38 for the management of pericardial diseases in patients receiving anticancer treatment
General
Diagnosis and management of acute pericarditis in patients with cancer based on the 2015 ESC Guidelines for the diagnosis and
I C
management of pericardial diseases is recommended and a multidisciplinary discussion is needed before interrupting cancer therapy.
Continued
112 ESC Guidelines
Diagnosis and management of ICI-associated pericarditis

Multimodality CV imaging (echocardiography, CMR + CT), ECG and measurement of cardiac biomarkers are recommended to
I C
confirm the diagnosis, assess the haemodynamic consequences of pericardial disease, and rule out associated myocarditis.
Prednisolone and colchicine are recommended for patients with ICI-associated pericarditis. I C
Interruption of ICI treatment in patients with confirmed ICI-associated pericarditis with moderate-to-severe pericardial effusion is
I C
recommended.

A multidisciplinary discussion is recommended before restarting ICI treatment. I C
Recommendation Table 39 for end-of-cancer therapy cardiovascular risk assessment
Educating and supporting patients with cancer to make appropriate healthy lifestyle choices is recommended. I C
Education is recommended for patients with cancer regarding recognition for early signs and symptoms of CVD. I C
CVRF assessment is recommended during the first year after cancer therapy and thereafter according to the 2021 ESC Guidelines on
I B
CVD prevention in clinical practice.
In asymptomatic high-risk patients, echocardiography and cardiac serum biomarkers are recommended at 3 and 12 months after
I B
completion of cancer therapy.
Cardiology referral is recommended in patients with cancer with new cardiac symptoms or new asymptomatic abnormalities in
I C
echocardiography and/or cardiac serum biomarkers at the end of therapy assessment.
Long-term continuation of cardiac medication is recommended in patients who develop severe CTRCD during cancer therapy. I C
CV follow-up and treatment optimization is recommended in patients who developed TKI-mediated hypertension during cancer
I C
therapy.
CV follow-up and treatment optimization is recommended in patients who developed vascular toxicities during cancer therapy. I C
ECG follow-up is recommended in patients who developed QT lengthening or LQTS during cancer therapy. I C
Recommendation Table 40 for cardiovascular surveillance in asymptomatic adults who are childhood and adolescent cancer
survivors
Education of adults who are childhood and adolescent CS treated with anthracyclines, mitoxantrone, and/or RT to a volume including
I B
the heart and their healthcare providers regarding their increased CV risk is recommended.
Annual screening for modifiable CVRF is recommended in adults who are childhood and adolescent CS treated with anthracyclines,
I C
mitoxantrone, and/or RT to a volume including the heart.
CV assessment is recommended in female childhood and adolescent CS prior to pregnancy or in the first trimester. I C
Recommendation Table 41 for cardiovascular surveillance in asymptomatic adult cancer survivors

Annual CV risk assessment, including ECG and NP, and CVRF management is recommended in CS who were treated with a potentially
I B
cardiotoxic cancer drug or RT.
CV toxicity risk restratification is recommended 5 years after therapy to organize long-term follow-up. I C
Recommendation Table 42 for adult cancer survivors who develop cancer therapy-related cardiac dysfunction late after cardiotoxic
cancer therapy
ACE-I/ARB and/or beta-blockers are recommended in adult CS with moderate asymptomatic CTRCD. I C
Recommendation Table 43 for adult cancer survivors with coronary artery disease
Asymptomatic radiation-induced CAD detected during surveillance
Non-invasive stress testing is recommended in asymptomatic CS with new moderate or severe radiation-induced CAD detected on
I C
CCTA to guide ischaemia-directed management.
A MDT discussion is recommended for clinical decision-making in patients with radiation-induced CAD and inducible ischaemia or
I C
severe left main CAD.
Continued
ESC Guidelines 113
Symptomatic CAD
Pre-operative assessment of LIMA and RIMA viability, venous access, and sternal wound healing is recommended in CS with radiation-
I C
induced CAD where CABG is considered.
Recommendation Table 44 for adult cancer survivors with valvular heart disease
A MDT approach is recommended to discuss and define the surgical risk in CS with severe VHD. I C
Recommendation Table 46 for cardiovascular monitoring in cancer survivors during pregnancy

In high-risk female CS, pre-pregnancy counselling and management during pregnancy and around delivery by a multidisciplinary
I C
pregnancy heart team is recommended.
A baseline CV evaluation including history, physical examination, ECG, NP, and echocardiography is recommended in female CS with a
I C
history of CTRCD who are considering pregnancy.
A CV evaluation including echocardiography is recommended at 12 weeks of pregnancy in female CS who are either high-risk or who
I C
received potentially cardiotoxic cancer therapy and did not have a baseline CV assessment.
Recommendation Table 47 for cardiovascular assessment and monitoring of pregnant women with cancer
Management by an expert MDT (the pregnancy heart team) in an expert centre is recommended for pregnant women with cancer who
I C
require cardiotoxic cancer therapy.
Cardiac assessment prior to cardiotoxic cancer therapy in pregnant women is recommended and consists of clinical history, physical
I C
examination, ECG, and echocardiography.
Recommendation Table 48 for carcinoid valvular heart diseases
Echocardiography is recommended for the detection of carcinoid cardiac involvement in all patients with carcinoid syndrome and
elevated NP levels and/or clinical signs of carcinoid heart disease, and for surveillance every 3 or 6 months depending on the severity of I B
cardiac involvement and clinical status.
A MDT discussion for optimal medial management to prevent carcinoid crisis is recommended before any invasive or surgical cardiac
I C
procedure.
Valve replacement surgery is recommended in symptomatic patients with severe carcinoid tricuspid or pulmonary VHD and an
I C
expected survival ≥12 months.
Valve replacement or repair surgery is recommended in symptomatic patients with severe carcinoid mitral or aortic VHD and an
I C
expected survival ≥12 months.
Recommendation Table 49 for amyloid light-chain cardiac amyloidosis diagnosis and monitoring
Echocardiography, NP, and cTn are recommended for the diagnosis of AL-CA in patients with plasma cell dyscrasia. I B
CMR is recommended in patients with suspected AL-CA. I A
Recommendation Table 50 for risk stratification and monitoring for patients with cardiac implantable electronic devices undergoing
radiotherapy
Risk stratification including planned radiation type and energy, dose to CIED, the patient’s device type, and pacing dependence is
I C
recommended prior to starting treatment.
In patients undergoing RT, a CIED check is recommended in all patients before and after completing RT, and during RT according to
I C
© ESC 2022
individual risk.
In patients with a CIED undergoing RT at high risk of arrhythmia and/or device dysfunction, ECG monitoring and/or pulse oximetry are
I C
recommended during every RT session.
3D, three-dimensional; ACE-I, angiotensin-converting enzyme inhibitors; ACS, acute coronary syndromes; ADT, androgen deprivation therapy; AF, atrial fibrillation; AL-CA, amyloid light-chain
cardiac amyloidosis; ALK, anaplastic lymphoma kinase; ARB, angiotensin receptor blocker; ASTCT, American Society for Transplantation and Cellular; AV, atrioventricular; BC, breast cancer; BCR-
ABL, breakpoint cluster region–Abelson oncogene locus; BP, blood pressure; BTK, Bruton tyrosine kinase; CABG, coronary artery bypass graft; CAD, coronary artery disease; CAR-T, chimeric
antigen receptor T cell; CCB, calcium channel blockers; CCS, chronic coronary syndromes; CCTA, coronary computed tomography angiography; CHA2DS2-VASc, Congestive heart failure,
Hypertension, Age .75 years (2 points), Diabetes mellitus, Stroke (2 points)—Vascular disease, Age 65–74 years, Sex category (female); CIED, cardiac implantable electronic device; CMR,
cardiac magnetic resonance; CRS, cytokine release syndrome; CT, computed tomography; cTn, cardiac troponin; CTRCD, cancer therapy-related cardiac dysfunction; CS, cancer survivors;
CV, cardiovascular; CVD, cardiovascular disease; CVRF, cardiovascular risk factors; DAPT, dual antiplatelet therapy; EACTS, European Association for Cardio-Thoracic Surgery; ECG,
electrocardiogram; EGFR, epidermal growth factor receptor; ESC, European Society of Cardiology; GLS, global longitudinal strain; HbA1c, glycated haemoglobin; HER2, human epidermal
receptor 2; HF, heart failure; HSCT, haematopoietic stem cell transplantation; ICI, immune checkpoint inhibitors; ICU, intensive care unit; i.v., intravenous; LIMA, left internal mammary
artery; LMWH, low-molecular-weight heparins; LQTS, long QT syndrome; LV, left ventricular; LVEF, left ventricular ejection fraction; MDT, multidisciplinary team; MEK, mitogen-activated
extracellular signal-regulated kinase; MI, myocardial infarction; MM, multiple myeloma; NP, natriuretic peptides; NSTE-ACS, non-ST-segment elevation acute coronary syndromes; PAD,
peripheral artery disease; PAH, pulmonary arterial hypertension; PI, proteasome inhibitors; QTc, corrected QT interval; QTcF, corrected QT interval using Fridericia correction; RAF, rapidly
accelerated fibrosarcoma; RIMA, right internal mammary artery; RT, radiotherapy; SCORE2, Systematic Coronary Risk Estimation 2; SCORE2-OP, Systematic Coronary Risk Estimation 2—
Older Persons; STEMI, ST-segment elevation myocardial infarction; TdP, torsade de pointes; TIL, tumour-infiltrating lymphocytes; TKI, tyrosine kinase inhibitors; TTE, transthoracic
echocardiography; TTS, Takotsubo syndrome; TRV, tricuspid regurgitation velocity; ULN, upper limit of normal; VEGFi, vascular endothelial growth factor inhibitors; VHD, valvular heart
disease; VTE, venous thromboembolism.
a
b
Level of evidence.
114 ESC Guidelines
16. Quality indicators for Department, Institut Jules Bordet, Brussels, Belgium; Rudolf
A. de Boer, Cardiology, University Medical Center Groningen,
cardio-oncology Groningen, Netherlands; Susan F. Dent, Department of
Medicine, Duke Cancer Institute, Durham, NC, United States of
Quality indicators (QIs) are tools that may be used to evaluate care
America; Dimitrios Farmakis, Medical School, University of
quality, including structural, process, and outcomes of care.835 They
Cyprus, Nicosia, Cyprus; Sofie A. Gevaert, Cardiology, Ghent
may also serve as a mechanism for enhancing adherence to guideline
University Hospital, Ghent, Belgium; Diana A. Gorog, Postgraduate
recommendations, through associated quality improvement initia-
Medicine, University of Hertfordshire, Hatfield, United Kingdom, and
tives and the benchmarking of care providers.836,837 As such, the

National Heart and Lung Institute, Imperial College, London, United
role of QIs in improving care and outcomes for CVD is increasingly
Kingdom, and Cardiology Department, East and North
recognized by healthcare authorities, professional organizations,
Hertfordshire NHS Trust, Stevenage, United Kingdom; Joerg
payers, and the public.835
Herrmann, Department of Cardiovascular Diseases, Mayo Clinic,
The ESC understands the need for measuring and reporting qual-
Rochester, MN, United States of America; Daniel Lenihan,
ity and outcomes of CV care and has established methods for the de-
Cardio-Oncology, International Cardio-Oncology Society, Tampa, FL,
velopment of the ESC QIs for the quantification of care and
United States of America, and Cardiology, Saint Francis Healthcare,
outcomes for CVD.835 These methods were used to develop QIs
Cape Girardeau, MO, United States of America; Javid Moslehi,
pertinent to cardio-oncology in parallel with the writing of this
Section of Cardio-Oncology & Immunology, Cardiovascular
Clinical Practice Guideline document and through the collaboration
Research Institute, University of California, San Francisco (UCSF),
with patient representatives and domain experts. The QIs, alongside
San Francisco, CA, United States of America; Brenda Moura,
their measurement specifications and development process will be
Cardiology Department, Armed Forces Hospital, Porto, Portugal,
published separately.
and Faculty of Medicine, University of Porto, Porto, Portugal; Sonja
S. Salinger, Clinic for Cardiovascular Disease, University Clinical
17. Supplementary data Center, Nis, Serbia, and Medical Faculty, University of Nis, Nis,
Serbia; Richard Stephens (United Kingdom), ESC Patient Forum,
Supplementary data is available at European Heart Journal online. Sophia Antipolis, France; Thomas M. Suter, Department of
Cardiology, Inselspital, Bern University Hospital, University of Bern,
18. Data availability statement Bern, Switzerland; Sebastian Szmit, Department of Pulmonary
Circulation, Thromboembolic Diseases and Cardiology, Centre of
No new data were generated or analysed in support of this research. Postgraduate Medical Education, Otwock, Poland, and Institute of
Hematology and Transfusion Medicine, Transfusion Medicine,
19. Author information Warsaw, Poland; Juan Tamargo, Pharmacology and Toxicology,
Universidad Complutense, Madrid, Spain; Paaladinesh
Author/Task Force Member Affiliations: Liam S. Couch, Thavendiranathan, Department of Medicine, Division of
King’s College London BHF Centre, the Rayne Institute, St Cardiology, Ted Rogers Program in Cardiotoxicity Prevention, Peter
Thomas’ Hospital, King’s College London, London, United Munk Cardiac Center, Toronto General Hospital, University Health
Kingdom; Riccardo Asteggiano, Cardiology, LARC Network, University of Toronto, Toronto, Canada; Carlo
(Laboratorio Analisi Ricerca Clinica), Turin, Italy, and School of G. Tocchetti, Cardio-Oncology Unit, Department of Translational
Medicine, Insubria University, Varese, Italy; Marianne C. Aznar, Medical Sciences, Federico II University, Naples, Italy, and Center for
Division of Cancer Sciences, Faculty of Biology, Medicine and Basic and Clinical Immunology Research (CISI), Federico II
Health, University of Manchester, Manchester, United Kingdom; University, Naples, Italy, and Interdepartmental Center for Clinical
Jutta Bergler-Klein, Department of Cardiology, Medical and Translational Research (CIRCET), Federico II University, Naples,
University of Vienna, Vienna, Austria; Giuseppe Boriani, Italy; Peter van der Meer, Cardiology, University Medical Center
Cardiology Division, Department of Biomedical, Metabolic and Groningen, Groningen, Netherlands; Helena J.H. van der Pal,
Neural Sciences, University of Modena and Reggio Emilia, Princess Máxima Center for Pediatric Oncology, Princess Máxima
Policlinico di Modena, Modena, Italy; Daniela Cardinale, Center for Pediatric Oncology, Utrecht, Netherlands.
Cardioncology Unit, European Institute of Oncology—I.R.C.C.S.,
Milan, Italy; Raul Cordoba, Department of Hematology,
Fundacion Jimenez Diaz University Hospital, Madrid, Spain, and 20. Appendix
Cancer Research Group, Health Research Institute IIS-FJD, Madrid,
Spain; Bernard Cosyns, Cardiology, Centrum voor Hart en ESC Scientific Document Group
Vaatziekten (CHVZ), Universitair Ziekenhuis Brussel (UZB), Includes Document Reviewers and ESC National Cardiac Societies.
Brussels, Belgium, and In Vivo Molecular and Cellular (ICMI)
Center, Vrij Universiteit Brussel, Brussels, Belgium; David Document Reviewers: Patrizio Lancellotti (CPG Review
J. Cutter, Nuffield Department of Population Health, University Coordinator) (Belgium), Franck Thuny (CPG Review Coordinator)
of Oxford, Oxford, United Kingdom, and Oxford Cancer Centre, (France), Magdy Abdelhamid (Egypt), Victor Aboyans (France),
Oxford University Hospitals NHS Foundation Trust, Oxford, Berthe Aleman (Netherlands), Joachim Alexandre (France), Ana
United Kingdom; Evandro de Azambuja, Medical Oncology Barac (United States of America), Michael A. Borger (Germany),
ESC Guidelines 115
Ruben Casado-Arroyo (Belgium), Jennifer Cautela (France), Jolanta Society of Cardiology, Aatif Benyass; Netherlands: Netherlands
Čelutkienė (Lithuania), Maja Cikes (Croatia), Alain Cohen-Solal Society of Cardiology, Olivier Manintveld; North Macedonia:
(France), Kreena Dhiman (United Kingdom), Stéphane Ederhy North Macedonian Society of Cardiology, Marijan Bosevski;
(France), Thor Edvardsen (Norway), Laurent Fauchier (France), Norway: Norwegian Society of Cardiology, Geeta Gulati;
Michael Fradley (United States of America), Julia Grapsa (United Poland: Polish Cardiac Society, Przemysław Leszek; Portugal:
Kingdom), Sigrun Halvorsen (Norway), Michael Heuser (Germany), Portuguese Society of Cardiology, Manuela Fiuza; Romania:
Marc Humbert (France), Tiny Jaarsma (Sweden), Thomas Kahan Romanian Society of Cardiology, Ruxandra Jurcut; Russian
(Sweden), Aleksandra Konradi (Russian Federation), Konstantinos Federation: Russian Society of Cardiology, Yury Vasyuk; San

C. Koskinas (Switzerland), Dipak Kotecha (United Kingdom), Marino: San Marino Society of Cardiology, Marina Foscoli;
Bonnie Ky (United States of America), Ulf Landmesser (Germany), Serbia: Cardiology Society of Serbia, Dragan Simic; Slovakia:
Basil S. Lewis (Israel), Ales Linhart (Czech Republic), Gregory Slovak Society of Cardiology, Miroslav Slanina; Slovenia:
Y. H. Lip (United Kingdom), Maja-Lisa Løchen (Norway), Slovenian Society of Cardiology, Luka Lipar; Spain: Spanish
Katarzyna Malaczynska-Rajpold (United Kingdom), Marco Metra Society of Cardiology, Ana Martin-Garcia; Sweden: Swedish
(Italy), Richard Mindham (United Kingdom), Marie Moonen Society of Cardiology, Laila Hübbert; Switzerland: Swiss Society
(Belgium), Tomas G. Neilan (United States of America), Jens of Cardiology, Reto Kurmann; Syrian Arab Republic: Syrian
Cosedis Nielsen (Denmark), Anna-Sonia Petronio (Italy), Eva Cardiovascular Association, Ahmad Alayed; Tunisia: Tunisian
Prescott (Denmark), Amina Rakisheva (Kazakhstan), Joe-Elie Salem Society of Cardiology and Cardio-Vascular Surgery, Leila Abid;
(France), Gianluigi Savarese (Sweden), Marta Sitges (Spain), Jurrien Turkey: Turkish Society of Cardiology, Cafer Zorkun; Ukraine:
ten Berg (Netherlands), Rhian M. Touyz (Canada/United Ukrainian Association of Cardiology, Elena Nesukay; United
Kingdom), Agnieszka Tycinska (Poland), Matthias Wilhelm Kingdom of Great Britain and Northern Ireland: British
(Switzerland), Jose Luis Zamorano (Spain) Cardiovascular Society, Charlotte Manisty, Uzbekistan:
Association of Cardiologists of Uzbekistan, Nigora Srojidinova.
ESC National Cardiac Societies actively involved in the review
process of the 2022 ESC Guidelines on cardio-oncology: Algeria: ESC Clinical Practice Guidelines (CPG) Committee: Colin
Algerian Society of Cardiology, Nadia Laredj; Armenia: Armenian Baigent (Chairperson) (United Kingdom), Magdy Abdelhamid
Cardiologists Association, Parounak Zelveian; Austria: Austrian (Egypt), Victor Aboyans (France), Sotiris Antoniou (United
Society of Cardiology, Peter P. Rainer; Azerbaijan: Azerbaijan Kingdom), Elena Arbelo (Spain), Riccardo Asteggiano (Italy),
Society of Cardiology, Fuad Samadov; Belarus: Belorussian Andreas Baumbach (United Kingdom), Michael A. Borger
Scientific Society of Cardiologists, Uladzimir Andrushchuk; (Germany), Jelena Čelutkienė (Lithuania), Maja Cikes (Croatia),
Belgium: Belgian Society of Cardiology, Bernhard L. Gerber; Jean-Philippe Collet (France), Volkmar Falk (Germany), Laurent
Bosnia and Herzegovina: Association of Cardiologists of Fauchier (France), Chris P. Gale (United Kingdom), Sigrun
Bosnia and Herzegovina, Mirsad Selimović; Bulgaria: Bulgarian Halvorsen (Norway), Bernard Iung (France), Tiny Jaarsma
Society of Cardiology, Elena Kinova; Croatia: Croatian Cardiac (Sweden), Aleksandra Konradi (Russian Federation), Konstantinos
Society, Jure Samardzic; Cyprus: Cyprus Society of Cardiology, C. Koskinas (Switzerland), Dipak Kotecha (United Kingdom), Ulf
Evagoras Economides; Czechia: Czech Society of Cardiology, Landmesser (Germany), Basil S. Lewis (Israel), Ales Linhart (Czech
Radek Pudil; Denmark: Danish Society of Cardiology, Kirsten Republic), Maja-Lisa Løchen (Norway), Richard Mindham (United
M. Nielsen; Egypt: Egyptian Society of Cardiology, Tarek Kingdom), Jens Cosedis Nielsen (Denmark), Steffen E. Petersen
A. Kafafy; Estonia: Estonian Society of Cardiology, Riina Vettus; (United Kingdom), Eva Prescott (Denmark), Amina Rakisheva
Finland: Finnish Cardiac Society, Suvi Tuohinen; France: French (Kazakhstan), Marta Sitges (Spain), Rhian M. Touyz (Canada/United
Society of Cardiology, Stéphane Ederhy; Georgia: Georgian Kingdom).
Society of Cardiology, Zurab Pagava; Germany: German Cardiac
Society, Tienush Rassaf; Greece: Hellenic Society of Cardiology,
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European Heart Journal (2022) 00, 1–133 ESC GUIDELINES

2022 ESC Guidelines on cardio-oncology

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Table of contents 6.1. Cancer therapy-related cardiac dysfunction ............................... 54

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Figure 20 Cardiovascular surveillance in patients treated with

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CCU Coronary care unit ESC-CCO European Society of Cardiology Council of

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Table 1 Classes of recommendations

Definition Wording to use

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Class IIa Weight of evidence/opinion is in Should be considered

Class IIb Usefulness/efficacy is less well May be considered

Class III Evidence or general agreement that the Is not recommended

Table 2 Levels of evidence

Level of Data derived from multiple randomized clinical trials

Level of Data derived from a single randomized clinical trial

Level of Consensus of opinion of the experts and/or small studies,

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Baseline During cardiotoxic

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Cardio-Oncology Care Pathways

New cancer During cancer First year after Long term

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Annual CVRF assessmente

Assessment at 3 Annual CVRF

Cardiology referrald if new CV signs/symptoms or CTR-CVT develop

Class 1 Class 1Ia Class 1Ib

Baseline CV toxicity risk assessment checklist

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ECG, TTE, and

Clinical assessment Complementary tests

Clinical severity of CTR-CVT

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3. Cancer therapy-related (HF), myocarditis, vascular toxicities, hypertension, cardiac arrhyth-

Table 3 Cancer therapy-related cardiovascular toxicity deﬁnitions

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Coronary epicardial Vasospastic angina

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Baseline cardiovascular toxicity risk assessment

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ECG Physical and metabolic Pre-existing CVD or

New, untreated or TTE

Check and correct Refer to Refer to cardiologistg

Consider primary vs secondary preventive strategies according to CV toxicity risk,

Baseline CV toxicity Anthracycline HER2-targeted VEGF BCR-ABL Multiple RAF and

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Current cancer treatment

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Table 5 Anthracycline equivalence dose

Doxorubicin Epirubicin Daunorubicin Mitoxantrone Idarubicina

Patient with cancer

CV risk stratification before anticancer therapy

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