Seminar

Acute coronary syndromes

Brian A Bergmark, Njambi Mathenge, Piera A Merlini, Marilyn B Lawrence-Wright, Robert P Giugliano

Although substantial progress has been made in the diagnosis and treatment of acute coronary syndromes, Lancet 2022; 399: 1347–58
cardiovascular disease remains the leading cause of death globally, with nearly half of these deaths due to ischaemic TIMI Study Group,
heart disease. The broadening availability of high-sensitivity troponin assays has allowed for rapid rule-out algorithms Cardiovascular Division,
Brigham and Women’s
in patients with suspected non-ST-segment elevated myocardial infarction (NSTEMI). Dual antiplatelet therapy is Hospital, (B A Bergmark MD,
recommended for 12 months following an acute coronary syndrome in most patients, and additional secondary R P Giugliano MD) and Division
prevention measures including intensive lipid-lowering therapy (LDL-C <1·4 mmol/L), neurohormonal agents, and of Cardiology
lifestyle modification, are crucial. The scientific evidence for diagnosis and management of acute coronary syndromes (N Mathenge MD),
Massachusetts General
continues to evolve rapidly, including adapting to the COVID-19 pandemic, which has impacted all aspects of care. Hospital, Harvard Medical
This Seminar provides a clinically relevant overview of the pathobiology, diagnosis, and management of acute School, Boston, MA, USA;
coronary syndromes, and describes key scientific advances. 4th Division of Cardiology,
Cardiocenter De Gasperis,
ASST GOM Niguarda and
Epidemiology Type 2 myocardial infarction, which results from Bicocca University, Milan, Italy
Although substantial progress has been made in the myocardial oxygen supply versus demand mismatch (P A Merlini MD); Division of
diagnosis and treatment of acute coronary syndromes, unrelated to acute atherothrombosis, tends to have a Cardiology, Department of
cardiovascular disease remains the leading cause of higher mortality rate than Type 1 myocardial infarction.10 Medicine, The University of the
West Indies at Mona, Kingston,
death worldwide, with nearly half of these deaths due to Although data are scarce concerning targeted treatments Jamaica
ischaemic heart disease.1,2 Globally, 12% of disability- for Type 2 myocardial infarction, intensive lipid- (M B Lawrence-Wright MD)
adjusted life-years lost annually are attributable to lowering might reduce incidence.11 Correspondence to:
ischaemic heart disease.2–4 Marked global variation in The previous paradigm of coronary atherosclerotic Robert P Giugliano, TIMI Study
rates of revascularisation and long-term mortality plaque rupture as the singular cause of STEMI or Group, Brigham and Women’s
Hospital, Harvard Medical
following acute coronary syndromes exist (panel).5–7 non-ST-segment elevation acute coronary syndrome School, 60 Fenwood Road,
The proportion of acute coronary syndromes that are (NSTEACS) has been disrupted in recent years, with Suite 7022, Boston, MA 02115,
ST-segment elevation myocardial infarction (STEMI) is intracoronary imaging studies showing acute coronary USA
decreasing in high-income countries (HIC),8 likely in syndrome at times to be caused by plaque erosion rather [email protected]

part due to secular trends in patient risk profiles, than rupture, or, less commonly, a calcific nodule
including declining rates of smoking in western Europe leading to thrombus formation.12,13 Two particular
and North America, and in part related to increasingly scenarios of interest are: 1) the presence of a clinically
widespread use of high-sensitivity troponin (hsTn) assays diagnosed myocardial infarction with no obstructive
to diagnose non-STEMI (NSTEMI). Nonetheless, rates of coronary artery disease identified on angiography
in-hospital mortality in patients with STEMI complicated (referred to as MINOCA); and 2) spontaneous coronary
by shock remain high, particularly in the setting of artery dissection (SCAD).
cardiac arrest.9
Myocardial infarction with no obstructive coronary
Pathobiology artery disease
At the least severe end of the acute coronary syndrome MINOCA, which is seen in a minority of acute coronary
spectrum is unstable angina, in which clinical syndrome cases and with a predominance in women
symptoms suggest acute coronary syndrome, but there compared with men (14·9% vs 3·5%, odds ratio [OR] 4·84;
is no biochemical evidence of myocardial infarction. 95% CI 3·29–7·13),14 carries significant diagnostic and
Type 1 myocardial infarction, which is caused by therapeutic uncertainty. The HARP-MINOCA study,
atherothrombotic coronary artery disease, is further which enrolled 170 women with MINOCA, showed that
classified as NSTEMI or STEMI based on ECG findings the combined use of intracoronary optical coherence
and is defined by the 4th Universal Definition of tomography (OCT) and cardiac MRI resulted in
Myocardial Infarction (UDMI) as requiring a rise or fall
in cardiac troponin (cTn) level (or another biomarker
if cTn is not available), or both, accompanied by Search strategy and selection criteria
clinical evidence of ischaemia (ie, symptoms, ECG We searched MEDLINE and Embase for “acute coronary
changes, supportive ECG or other imaging findings, syndrome”, “STEMI”, “NSTEMI”, and “NSTEACS” for articles
or evidence of coronary thrombus).10 Beyond athero­ published since inception through May 1, 2021. We also
sclerosis, myocardial injury and infarction can result reviewed recent major society guidelines as well
from numerous other processes, including Takotsubo as presentations from the European Society of Cardiology,
cardiomyopathy, myocarditis, and supply versus demand American Heart Association, and American College
mismatch. A framework for defining these events is of Cardiology scientific congresses from the past 5 years.
provided in the 4th UDMI.10 It is important to note that

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Panel: Acute coronary syndromes

Summary • The timing of invasive coronary angiography in NSTEMI
Cardiovascular disease is the leading cause of death globally, is determined by clinical risk stratification: very high-risk
with nearly half of these deaths due to ischaemic heart patients (eg, haemodynamic instability, refractory chest
disease. The proportion of acute coronary syndromes that discomfort, life-threatening arrhythmia) warrant
are ST-segment elevation myocardial infarction (STEMI) emergent (<2 h) angiography; patients at high risk
is decreasing and the broadening availability of high- (eg, elevated clinical risk score or dynamic ECG changes)
sensitivity troponin assays has allowed for so-called rapid should undergo catheterisation within 24 h; and patients
rule-out algorithms in patients with suspected non-STEMI at low risk should be submitted to a selective invasive
(NSTEMI). Dual antiplatelet therapy is recommended strategy
for 12 months following acute coronary syndrome in most • In STEMI, emergent revascularisation, ideally by
patients, and additional secondary prevention measures percutaneous coronary intervention when available,
including intensive lipid-lowering therapy, neurohormonal is the immediate clinical priority with goal of first medical
agents, and lifestyle modification, are crucial. contact to device time of <60–90 min
• Dual antiplatelet therapy, ideally with ticagrelor
Despite important scientific progress in the management of
or prasugrel in addition to low dose aspirin, is
acute coronary syndromes, marked racial and sex-based
recommended for 12 months following acute coronary
disparities exist. Furthermore, the burden of cardiovascular
syndrome in most patients
disease is extensive in low-income and middle-income
• Secondary prevention with intensive lipid-lowering
countries, with increasing population risk factor exposure
therapy, antithrombotic therapy, neurohormonal agents,
and structural impediments to acute coronary syndrome
and lifestyle modification (including cardiac rehabilitation)
diagnosis and treatment. This Seminar aims to provide
is critical after acute coronary syndrome
a clinically relevant overview of the pathobiology, diagnosis,
• Marked racial and sex-based disparities exist in the
and management of acute coronary syndromes, and describe
prevention, diagnosis, and management of acute coronary
major recent scientific advances.
syndromes
Fast facts • The burden of cardiovascular disease is extensive in
• Cardiovascular disease remains the leading cause of death low-income and middle-income countries, with increasing
globally population risk factor exposure, structural impediments
• The proportion of acute coronary syndromes that are to acute coronary syndrome diagnosis and treatment, and
STEMI is decreasing in high-income countries high rates of mortality at younger ages
• Myocardial infarction with no obstructive coronary artery • COVID-19 has complicated diagnosis and treatment
disease and spontaneous coronary artery dissection are two of acute coronary syndromes globally, as COVID-19 can
commonly encountered clinical scenarios with evolving cause direct or indirect myocardial inflammation and
evidence bases to guide management injury; it predisposes patients to arterial and venous
• High-sensitivity troponin (hsTn) assays have allowed for the thrombotic events; and it causes societal and health-care
adoption of rapid rule-out algorithms for NSTEMI, system disruptions
which are now endorsed by major society guidelines

identification of a mechanism for the myocardial in the subtended myocardial territory. Fewer than 5% of
infarction in 85% of patients, with an ischaemic aetiology, all ACS is caused by SCAD, but proportions are higher in
typically plaque rupture in a mild atherosclerotic lesion certain populations, such as women who are pregnant
(type 1 myocardial infarction), seen in 64%.15 For patients or post-partum.16 Optimal management of SCAD is
with MINOCA, guidelines recommend establishing a uncertain given the absence of randomised trials, but for
diagnosis where possible, directing further testing and patients with low-risk anatomy, non-obstructive lesions,
therapy according to an established diagnosis, and treating and resolution of symptoms, conservative medical man­
with standard secondary preventative measures if the age­ment and aggressive secondary prevention, including
diagnosis remains unclear.8 blood pressure control, is generally preferred.8 The
possibility of a primary vascular syndrome such as fibro­
Spontaneous coronary artery dissection muscular dysplasia should be considered in these patients.
Spontaneous coronary artery dissection (SCAD) refers to
an intimal tear (or less commonly vasa vasorum Diagnosis
haemorrhage) leading to creation of a false lumen in the Diagnosis of acute coronary syndrome relies on clinical
arterial wall in the absence of a clear mechanical cause presentation, ECG findings, and biochemical evidence of
(eg, trauma or catheter manipulation).8 Ensuing myocardial injury. The immediate initial branchpoint for
compression of the vessel lumen can result in ischaemia a patient with possible acute coronary syndrome is, of

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course, the presence or absence of diagnostic ST-segment

Women Men <40 years Men >40 years
elevations on the 12-lead ECG (table 1). Diagnosis of
NSTEACS, which encompasses unstable angina and Leads V2-V3 >1·5 mm >2·5 mm >2 mm
NSTEMI, has evolved significantly with the development Other leads >1 mm >1 mm >1 mm
of high-sensitivity troponin (hsTn) assays and is ST elevation is measured at the J-point and should be present in at least two
discussed in the next section. Adjunctive diagnostic contiguous leads. Assess right-sided leads (V3R and V4R) in inferior myocardial
infarction and assess posterior leads (V7-V9) in suspected posterior myocardial
tools, such as ECG or cardiac MRI, can help detect infarction (ST depressions in V1-V3).
regional wall motion abnormalities and other evidence of
myocardial ischemia in patients with suspected ACS.10 Table 1: ECG criteria for the diagnosis of ST-elevation myocardial infarction

Physical examination
Concern for NSTEACS
Although physical examination findings are not generally
specific for the diagnosis of acute coronary syndromes,
careful patient evaluation is critical for immediate High-sensitivity troponin drawn at presentation

risk assessment, recognition of impending haemo-

dynamic collapse, and identification of mechanical 0h Very low* Low Intermediate High
complications of myocardial infarction. Tachycardia, a
narrow pulse pressure, hypotension, and signs of No significant Significant No significant Significant
1h
congestion (eg, pulmonary oedema) or inadequate increase increase increase increase
perfusion (eg, cool extremities) are all indicators of high
clinical risk. The Killip classification stratifies patients
with acute coronary syndromes based on the degree of Rule-out Consider additional testing Rule-in
clinical heart failure, ranging from no evidence of
congestion (Class I) to cardiogenic shock (Class IV), and Figure 1: Approach to non-ST elevation acute coronary syndromes using a rapid rule-out strategy.
strongly predicts mortality.17 Mechanical complications of General scheme for a 0 h/1 h rapid rule-out algorithm for patients with suspected NSTEACS. High-sensitivity
troponin concentration thresholds are assay-specific. NSTEACS=non-ST-segment elevation acute coronary
myocardial infarction are typically accompanied by syndrome. *And symptom duration at least 3 h.
abrupt haemodynamic deterioration along with a loud
holosystolic murmur in the left parasternal region in the
case of acute ventricular septal rupture, an oftentimes soft change between samples (figure 1). Based on these
systolic murmur in the case of acute mitral regurgitation, criteria, patients can be ruled-out of having NSTEMI with
and signs of tamponade in the case of free wall rupture.18 very low rates of 30-day major adverse cardiovascular
events (MACE), ruled-in for NSTEMI and managed
Evaluation and management of suspected NSTEACS accordingly or fall in an intermediate group where further
The evaluation of suspected acute coronary syndromes is observation and investigation might be warranted based
challenging given the time-sensitivity, potential under- on overall clinical assessment. A 0 h/1 h algorithm is
lying life-threatening pathology, and often non-specific endorsed by the 2020 European Society of Cardiology
findings on initial assessment. The ECG in NSTEACS ESC guidelines.8 The specific concentrations for the hsTn
may show T-wave inversions or ST-segment depressions, thresholds are assay specific.8
but these findings are commonly absent and are not
necessary for diagnosis. Elevated concentration of a Timing of coronary angiography in NSTEACS
circulating marker of myocardial necrosis such as cardiac Immediate therapy for patients with NSTEACS includes
troponin I or T (cTnI or cTnT) or creatine kinase- administration of a loading dose of aspirin and systemic
myocardial band (CK-MB) differentiates NSTEMI from anticoagulation.8 The optimal timing of catheterisation in
unstable angina and is typically marked by an early NSTEACS continues to be debated. Clinical risk stratifi­
rise, peak, and then fall in biomarker concentration.10 cation is the major determinant of timing, with very high-
risk patients (eg, haemodynamic instability, refractory
High-sensitivity troponin assays chest discomfort, life-threatening arrhythmia) warranting
cTn assays are sensitive and reasonably specific and are emergent (<2 h) angiography, patients at high risk (eg,
therefore preferred over other biomarkers, including Global Registry of Acute Coronary Events [GRACE] score
CK-MB, for the diagnosis of NSTEMI.8 hsTn assays have >140) undergoing catheterisation within 24 h, and patients
improved test characteristics relative to standard cTn at low risk being submitted to a selective invasive strategy
assays and are more sensitive early after symptom onset. (figure 2). Increasing evidence, such as the VERDICT
As such, they have allowed for the adoption of so-called trial,25 has reinforced the importance of early catheterisation
rapid rule-out treatment algorithms.8,19–24 These algorithms in the highest-risk patients and generally supports the safety
rely on hsTn measurement at presentation (0 h) and at a of delayed catheterisation in lower-risk patients. P2Y12
second time point 1–3 h later, with attention both to the inhibitor pretreatment before catheterisation is now
absolute concentration as well as the magnitude of recommended against as a routine strategy in patients

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haemodynamically stable STEMI found a significantly

Established or high concern for non-ST-segment elevation acute coronary syndrome
lower rate of cardiovascular death in patients assigned to
complete revascularisation.40
Low or intermediate clinical risk High clinical risk Very high cinical risk What does this mean for clinicians caring for patients
• No high-risk features • No very high-risk features • Haemodynamic instability with recent STEMI? Providers should anticipate planned
• TIMI Risk Score ≤3 • TIMI Risk Score >4 • Ventricular arrhythmia
• GRACE Score ≤140 • GRACE Score >140 • Acute heart failure due to
staged revascularisation procedures in many patients
• Dynamic ECG changes acute coronary syndrome discharged after STEMI. These subsequent procedures
• Medically refractory angina or heighten the importance of antiplatelet therapy
anginal equivalent
adherence and can create further need for follow-up
visits and renal function assessment. They do have the
Delayed or selective invasive Early invasive strategy Immediate invasive strategy additional benefit of more touchpoints in the system,
strategy (>24 h) (<24 h) (<2 h) however, which provide further opportunities for
optimisation of the secondary prevention regimen.
Figure 2: Risk stratification for timing of invasive angiography in non-ST segment elevation acute coronary Importantly, the COMPLETE trial findings cannot
syndrome necessarily be extended to patients with acute myocardial
Selection of non-ST-segment elevation acute coronary syndrome treatment strategy and timing according to
initial risk stratification. GRACE=Global Registry of Acute Coronary Events. TIMI=thrombolysis in myocardial
infarction (STEMI or NSTEMI) complicated by shock. In
infarction. the CULPRIT-SHOCK trial,41 706 patients with acute
myocardial infarction with shock and significant non-
with NSTEACS and a planned early invasive strategy.8 culprit coronary lesions were randomised to multivessel
Non-invasive anatomical assessment via coronary PCI at the time of the index procedure or to culprit lesion-
computed tomography angiography (CCTA) might be only PCI. Patients assigned to immediate multivessel PCI
expanded in the future.26–29 had higher rates of renal failure and death than did those
assigned to culprit lesion-only PCI. Based on the
Evaluation and management of STEMI CULPRIT-SHOCK trial, routine immediate non-culprit
For patients who manifest ST-segment elevation diagnostic lesion PCI is not recommended in these patients.8
for STEMI, emergent reperfusion therapy remains the Whether staged revascularisation after resolution of the
imme­ diate priority, as emphasised in the most recent shock and concomitant end-organ injury may be beneficial
European and American guidelines.30–32 The latest data is not currently known.
continue to reinforce the association between prompt
(<90 min) reperfusion and more favourable long-term Antiplatelet therapy
clinical outcomes.33 Patients presenting to a percutaneous Antiplatelet therapy is a critical component of the medical
coronary intervention (PCI)-capable hospital should regimen in the acute phase of acute coronary syndromes
undergo immediate coronary angio-graphy with a goal of as well as for secondary prevention following stabilisation
first medical contact-to-device time of less than (table 2). Previous randomised trials have shown that
60–90 min.30,32 For patients presenting to a non-PCI centre, treatment with aspirin plus a P2Y12 inhibitor for at
transfer to PCI should be executed if the anticipated time least 12 months following acute coronary syndromes
to PCI will be 120 min or less. Alternatively, if PCI within reduces ischaemic events,42 with additional benefit seen
this timeframe is not possible, fibrinolysis should be with the 3rd generation P2Y12 inhibitors ticagrelor and
admini­ stered if not contraindicated, and a pharmaco- prasugrel compared to clopidogrel.43,44 These reductions
invasive approach should be considered in which initial in ischaemic events come at a cost of increased bleeding,
fibrinolytic therapy is followed by invasive angiography but with an overall favourable net outcome in the pivotal
within 24 h.34 trials. As such, DAPT has typically been recommended
for 12 months following acute coronary syndromes in
Non-culprit lesions patients not meeting criteria for high bleeding risk (see
About half of patients with STEMI have obstructive Bleeding Risk below), with ticagrelor and prasugrel
coronary disease outside the infarct-related artery, and the generally preferred over clopidogrel.8,30,32
presence of flow-limiting non-infarct-related artery lesions The approach to antiplatelet therapy in the setting of
portends a worse prognosis.35 The COMPLETE trial36 of ACS is evolving, however. The major areas of recent new
4041 patients with hemodynamically stable STEMI and at clinically relevant data are: 1) choice of agent; 2) early
least one other significant non-culprit lesion found that aspirin cessation; and 3) strategy in patients with an
patients randomised to complete revascularisation of all indication for an anticoagulant.
lesions within 45 days resulted in a lower rate of
cardiovascular death or myocardial infarction compared Choice of P2Y12 antagonist
with culprit-only PCI. The COMPLETE trial built upon The large randomised trials evaluating prasugrel
several smaller trials suggesting potential benefit with (TRITON-TIMI 38)43 and ticagrelor (PLATO)44 in acute
complete revasculari­sation37–39 and a meta-analysis of coronary syndromes compared each agent with
complete versus culprit-only revascularisation in clopidogrel. As such, until recently, there have been

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scant randomised trial data comparing the 3rd generation

Route Loading dose Maintenance dose Dose reduction Notes
P2Y12 inhibitors to each other. The ISAR-REACT 5 trial,45
which was a randomised, open-label comparison of Clopidogrel Oral 300–600 mg 75 mg daily NA ··

prasugrel versus ticagrelor in 4018 patients with acute Ticagrelor Oral 180 mg 90 mg BID NA Long-term dose
(>12 months after
coronary syndromes and a planned invasive strategy, ACS) is 60 mg BID
provides the only major randomised comparison of Prasugrel Oral 60 mg 10 mg daily 5 mg daily for Avoid if patient has
these agents. There was a higher rate of the composite patients had stroke or TIA; use
primary end point (death, myocardial infarction, or <60 kg or with caution if age
>75 years >75 years
stroke) at 1 year among patients randomised to ticagrelor
Cangrelor IV 30 µg/kg bolus 4 µg/kg/min (2 h or NA ··
(9·3 vs 6·9%; hazard ratio [HR] 1·36, 95% CI 1·09–1·70)
duration of PCI,
with no significant difference in major bleeding. There whichever is longer)
were critical limitations to this trial, however, including
ACS=acute coronary syndrome. BID=twice per day. IV=intravenous. NA=not applicable. PCI=percutaneous coronary
an open-label design and frequent loss to follow-up. intervention. TIA=transient ischaemic attack.
Nonetheless, the 2020 ESC NSTEACS guidelines provide
Table 2: P2Y12 inhibitors
a Class IIa, Level of Evidence B recommendation for
prasugrel over ticagrelor in patients with NSTEACS who
undergo PCI and are eligible for prasugrel (no prior Early aspirin cessation
stroke or transient ischaemic attack).8 As noted Several trials have investigated early aspirin cessation
previously, these guidelines recommend against routine after PCI. The TWILIGHT trial53 randomised 7119 patients
P2Y12 inhibitor loading before catheteri-sation, regardless (65% of whom had NSTEACS) who had undergone PCI
of agent chosen, in patients with NSTEACS planned for followed by 3 months of treatment with aspirin and
an invasive strategy.8 The intravenous P2Y12 inhibitor ticagrelor to either ticagrelor monotherapy or to continued
cangrelor is an additional option in the acute phase for DAPT with aspirin and ticagrelor. Patients assigned to
patients undergoing PCI who have not been pretreated ticagrelor monotherapy had lower rates at 1 year of the
with an oral P2Y12 inhibitor and who are not receiving a primary bleeding endpoint. There was no difference in
glycoprotein IIb/IIIa inhibitor.8,46 rates of ischaemic events such as myocardial infarction
The potential utility of genetic or platelet function and stroke between treatment arms, although the trial
testing to guide P2Y12 inhibitor choice has also been a was not powered to assess these outcomes. Although
topic of renewed interest. Clopidogrel is a prodrug which TWILIGHT and other related trials54–57 have been
requires biotransformation by the hepatic CYP450 underpowered individually to study the effect of early
enzyme into its active metabolite. Variations in the aspirin discontinuation on ischaemic events, a meta-
CYP2C19 locus impact the metabolism of clopidogrel analysis including data from more than 32 000 patients
and it was established over a decade ago that CYP2C19 found no increased risk of MACE with early
loss of function carriers who are treated with clopidogrel discontinuation of aspirin, including in the 16 898 patients
after acute coronary syndromes are at higher risk with acute coronary syndromes.58
for MACE than are patients with typical clopidogrel It remains important to keep in mind, however, that
metabolism.47,48 Nevertheless, genotype and platelet trials of early aspirin cessation were not designed to
function-guided treatment strategies have not found evaluate the effect of these strategies on the endpoints the
widespread clinical uptake or been supported over medications are intended to influence (eg, myocardial
clinical judgement alone in major society guidelines. As infarction, stent thrombosis, stroke) and that scarce
such, clinical assessment of ischaemic and bleeding risk information is available beyond 1 year. Furthermore,
remains the cornerstone of agent selection. reconciling these findings with separate previous trials
This question was revisited in the POPular Genetics showing benefit with extended-duration (>12 months)
trial.49 Among 2488 patients undergoing primary PCI for ticagrelor, prasugrel, or clopidogrel on top of aspirin
STEMI, a genotype-guided strategy with de-escalation to therapy is not straightforward. Nonetheless, the trial data
clopidogrel in subjects without loss of function CYP2C19 in aggregate suggest there might not be a major ischaemic
alleles was non-inferior to standard therapy for ischemic risk in most patients with a strategy of de-escalation to
outcomes and had a significantly lower rate of bleeding.50 P2Y12 inhibitor monotherapy after 3 months of DAPT and
Conversely, in the TAILOR-PCI trial51 of 5302 patients the most recent NSTEACS guidelines allow for
undergoing PCI for acute coronary syndromes or stable consideration of such a strategy in patients at high risk
coronary disease, a point-of-care genetic testing strategy for bleeding.8
had no effect on clinical outcomes at 12 months. Of note, although scarce data exist to-date, a strategy of
Nonetheless, this is a topic of heightened current interest early single antiplatelet therapy (SAPT) with aspirin alone
and further evidence paired with evolution in point-of- rather than a P2Y12 inhibitor might be a consid­eration in
care genetic or platelet function testing could lead to some patients. In the MASTER DAPT trial,59 among
clinically validated guided platelet inhibition strategies 4434 patients with high bleeding risk undergoing PCI
moving forward.52 with drug-eluting stents, one month of DAPT was non-

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inhibitor (typically clopidogrel) until 1 year, at which

Acute coronary syndromes in a patient with an indication for oral anticoagulant
point DOAC monotherapy can be considered.8 The
duration of triple antithrombotic therapy might be
High ischaemic risk Typical risk High bleeding risk extended to 1 month in patients with high ischaemic risk
• Multivessel coronary artery • No high ischaemic risk or • Recent or recurrent severe
disease high bleeding risk features bleeding
and acceptable bleeding risk. A general approach to
• Left main or other complex • Thrombocytopenia antithrombotic therapy after ACS in patients with an
percutaneous coronary • Anaemia indication for anticoagulation is shown in figure 3.
intervention • Cirrhosis
• Prior stent thrombosis • Malignancy
• Diabetes • Significant chronic kidney Bleeding risk
• Significant chronic kidney disease
disease
Central to the risk versus benefit considerations of anti-
thrombotic strategies following acute coronary syndromes
is a determination of a patient’s risk for clinically
Oral anticoagulant + dual Oral anticoagulant + dual Oral anticoagulant + dual significant bleeding. The ESC recommends considering
antiplatelet therapy antiplatelet therapy antiplatelet therapy use of the PRECISE-DAPT scale, with a score of 25 or
Up to 1 month 1 week (or hospital discharge) 1 week (or hospital discharge)
more considered to indicate high bleeding risk, or the
ARC-HBR criteria.8 To-date, no high-quality randomised
Oral anticoagulant + single Oral anticoagulant + single Oral anticoagulant + single data support the use of any specific bleeding scale in
antiplatelet therapy antiplatelet therapy antiplatelet therapy determining antithrombotic strategy.
Through 12 months Through 12 months Through 6 months

Secondary prevention
Oral anticoagulant alone Oral anticoagulant alone Oral anticoagulant alone Secondary prevention in patients who have had an acute
coronary syndrome is crucial and includes several non-
Figure 3: Approach to antithrombotic therapy in patients with an indication for oral anticoagulation who
pharmacological interventions such as diet and exercise
have undergone percutaneous coronary intervention for acute coronary syndromes. guidance, smoking cessation, and cardiac rehabilitation
The strategy for antithrombotic therapy is guided by assessment of each patient’s risk for ischaemic events and for (figure 4).8,30 Beta blockade and renin angiotensin
bleeding. aldosterone system (RAAS) modification are long-
standing secondary prevention therapies. With respect
inferior to at least 3 months of DAPT in terms of net to recent evolution in secondary prevention medical
adverse clinical events. Approximately 30% of patients in therapy, there is important new evidence guiding lipid-
the SAPT arm were treated with aspirin alone after lowering and anti-inflammatory agents.
1 month of DAPT.
Lipid-lowering therapy
Concomitant anticoagulant therapy Reducing the concentration of circulating atherogenic
Approximately 8–10% of patients undergoing PCI have lipoproteins has a major effect on the risk of adverse
atrial fibrillation or another indication for an cardiovascular events in numerous clinical settings.67
oral anticoagulant.60 Understandably, the use of triple Whereas the prior evidence base for LDL-cholesterol
antithrombotic therapy in the form of DAPT plus an (LDL-C) lowering after acute coronary syndromes was
oral anticoagulant has raised concern for excessive primarily for statins and ezetimibe,68 additional classes of
bleeding risk in these patients. agents are now providing promising new data.
Several trials have tested various strategies of dual Two monoclonal antibodies against PCSK9, evolocumab
versus triple antithrombotic therapy, the majority of and alirocumab, which reduce LDL-C by 50–70%, have
which have incorporated asymmetric comparisons; for shown major reductions in cardiovascular events in
example, a direct oral anticoagulant (DOAC)-based dual high-risk patients, including within 12 months of
antit­hrombotic therapy regimen versus warfarin-based acute coronary syndromes occurring.69–71 The safety and
triple antithrombotic therapy.61–63 A meta-analysis of these feasibility of in-hospital initiation of evolocumab was
randomised trials found lower rates of bleeding with investigated in the EVOPACS trial,72 which randomised
DOAC dual antithrombotic therapy than vitamin K patients with acute coronary syndromes and elevated
agonist triple antithrombotic therapy, but with LDL-C treated with atorvastatin to evolocumab or placebo
numerically greater rates of myocardial infarction and and found rapid attainment of guideline-recommended
stent thrombosis not meeting statistical signifi­ LDL-C levels in the evolocumab arm. A recommended
cance.63 A single, large, symmetric randomised step-wise approach is to treat all patients with acute
comparison between a DOAC (apixaban) and vitamin K coronary syndromes with high-intensity statin therapy.73
agonist in this setting found lower rates of bleeding with ESC guidelines recommend that patients in whom an
the DOAC.60 The 2020 ESC NSTEACS guidelines LDL-C concentration of less than 1·4 mmol/L is not
recommend 1 week of triple antithrombotic therapy (or achieved in 4–6 weeks should be treated additionally with
until hospital discharge) as a default strategy followed by ezetimibe and that if the patient remains above this
dual antithrombotic therapy with a DOAC plus P2Y12 LDL-C goal on the high-intensity statin and ezetimibe, a

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PCSK9 inhibitor should be added.8 Furthermore, if the

Secondary prevention after acute coronary syndromes
current acute coronary event occurred within 2 years of a
previous acute coronary syndrome event, an LDL-C goal
<40 mg/dL (<1 mmo/L) might be considered.8 American Lipid-lowering Antithrombotic Anti-inflammatory Neurohormonal
therapy8,70 therapy 8,35,36 agents8,35,36
society guidelines have endorsed a treatment LDL-C • Specific anti-
• High intensity statin • General strategy of inflammatory • β Blocker
threshold of 70 mg/dL (1·8 mmol/L) for high risk therapy in all DAPT for at least therapies are not Initiate within
patients, above which the addition of non-statin therapy is patients 12 months in most currently 24 h if no
• If LDL-C not patients recommended contraindication and
recommended to further reduce LDL-C.74 <1.4 mmol/L in • Consider long-term • Some data support continue for at least
4–6 weeks, add DAPT in high colchicine 0·5 mg 3 years
Targeting inflammation ezetimibe then ischaemic risk daily following acute • ACEi /ARB
PCKS9i as needed patients coronary syndrome72 Greatest benefit with
Inflammation appears to contribute to the increased • Consider bempedoic • Consider early aspirin • Additional targeted heart failure with
risk of recurrent events across vascular territories acid where approved cessation in high anti-inflammatory LVEF <40%, or
• Additional agents bleeding risk patients agents are under anterior STEMI
following acute coronary syndrome,74 but identifying under investigation • Generally avoid triple investigation • Aldosterone
safe and effective anti-inflammation therapy has been therapy antagonist
challenging. Anti-inflammatory treatment with Heart failure with
LVEF <40%
colchicine after acute coronary syndrome has recently
shown some promise, however. Patients within 30 days
of a myocardial infarction randomised to colchicine Lifestyle modification
Cardiac rehabilitation Dietary guidance
0·5 mg daily had a 23% lower risk of MACE compared Smoking cessation Exercise programme
to placebo-treated patients in the COLCOT trial,75 and
similar findings were observed among patients with Figure 4: Secondary prevention after acute coronary syndromes
chronic coronary syndrome in the LoDoCo2 trial.76 Even Bempedoic acid is a novel oral inhibitor of cholesterol synthesis which was approved by the European Medicines
so, there were numerically higher rates of non- Agency and the US Food and Drug Administration in 2020 for lipid-lowering, though clinical efficacy to reduce
cardiovascular death among colchicine-treated patients cardiovascular events is not yet proved.64 Numerous additional targets for lipid-lowering therapy, including
ANGPTL3, lipoprotein(a), APOC3, lipoprotein lipase, and others, are in development.65,66 ACEi=angiotensin
in these trials and a separate trial of colchicine in converting enzyme inhibitor. ACS=acute coronary syndrome. ARB=angiotensin receptor blocker. DAPT=dual
patients with acute coronary syndrome, COPS,77 found a antiplatelet therapy. HF=heart failure. LVEF=left ventricular ejection fraction. PCSK9i=proprotein covertase
significantly increased risk of death with colchicine. To- subtilisin/kexin type 9 inhibitor. STEMI=ST-segment elevation myocardial infarction.
date, no major society guidelines recommend colchicine
following acute coronary syndrome. heart failure hospitalisation after a first myocardial
infarction. There were statistically significant contribu­
Disparities in health-care access and outcomes tions from pre-existing comorbidities and myocardial
Entrenched racial disparities impact the recognition, infarction characteristics to these relationships,
management, and outcomes of acute coronary emphasising the complex and important associations
syndrome. According to the Heart Disease and Stroke underlying the unequal long-term outcomes after acute
Statistics 2022 Update,3,4 which compiles epidemiological coronary syndrome.82
data from multiple sources, Black men and women in An analysis of racial representation in 460 acute
the USA continue to have higher rates of incident coronary syndrome trials, many of which were multi-
myocardial infarction than do White men or women national, found that on average 3·7% of participants
across all age groups, with a nearly two times higher rate were Black and that this proportion had not changed
for Black men than White men aged 75–84 years significantly from 2001 to 2018.83 Addressing these long-
(16 vs 9 per 1000 person-years).3,4 Despite this, Black standing inequities in all aspects of cardiovascular
patients evaluated for chest pain are less likely than disease, from risk exposure to diagnosis, treatment,
other patients to have an ECG ordered in the emergency outcomes, and representation in clinical studies, is
department (adjusted odds ratio [aOR] 0·82; 95% CI crucially important.84
0·69–0·99),78 have a 30% longer wait time in the
emergency department for symptoms suggestive of Acute coronary syndrome in women
acute coronary syndrome,4,79 are less likely to receive Sex-based disparities in the evaluation and management
mechanical circulatory support in myocardial infarction of acute coronary syndrome are also pervasive. Women
complicated by shock (0·84; 0·79–0·89),80 are less likely with STEMI tend to present later after symptom onset
to be referred to cardiac rehabilitation after a myocardial than men,85 and among patients who have sought
infarction (0·70; 0·53–0·93),4 and have higher rates of medical attention for symptoms before acute coronary
heart failure or death following myocardial infarction.4,81 syndrome onset, women are more likely to have been
In an analysis from the REGARDS registry,82 3-year reassured that the symptoms were not cardiac in nature
outcomes after myocardial infarction were compared for (53·4% vs 36·4%; p<0·001).86 Chest pain appears to be
Black versus White patients. Black patients had a more present in approximately 90% of patients with an acute
than 40% higher adjusted risk than White patients of myocardial infarction regardless of sex,14 although
cardio-vascular death, myocardial infarction, stroke, or women tend to present with more diverse symptoms.87

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Importantly, commonly recommended hsTn concen­ study, found smoking to be one of the most significant
tration thresholds for NSTEMI diagnosis might be less modifiable risk factors for acute myocardial infarction,
sensitive in women than in men.88 accounting for approximately 36% of the population
Women with acute coronary syndrome are less likely attributable risks of acute coronary syndrome globally.96
than men to undergo revascularisation (adjusted OR for However, tobacco use has particularly marked regional
PCI 0·68; 95% CI 0·66–0·70; CABG 0·40; 95% CI variation, accounting for more than 15% of lost
0·39–0·44).86 When PCI for acute coronary syndrome is disability-adjusted life-years (DALYs) in some countries
performed, radial access is less commonly used in in Asia and eastern Europe but very few lost DALYs in
women and older women have higher rates of significant sub-Saharan Africa.95 Furthermore, social determinants
post-procedural bleeding than do older men.89,90 of health such as education level, socioeconomic status,
In terms of secondary prevention, women are less dietary patterns, alcohol consumption, and physical
likely than men to receive statins, angiotensin converting activity levels, are increasingly associated with cardio­
enzyme inhibitors, or angiotensin receptor blockers at vascular disease risk in LMICs, with notable regional
time of discharge (p=0·01).91,92 These differences in variation.7 Although cardiovascular disease accounts for
secondary prevention regimens might contribute to the a smaller portion of the relative disease burden in
lesser observed reductions in recurrent myocardial LMIC as compared with HIC at present, the absolute
infarction rates over time in women than in men.93 disease burden is extensive in these countries, is more
likely to occur at younger ages, is expected to grow
Acute coronary syndrome in older patients rapidly given rising risk factor prevalence, and
Elderly patients comprise an increasing proportion of soberingly, is associated with significantly higher
patients with acute coronary syndrome in HIC, morbidity and mortality.95,97–99
accounting for approximately one-third of patients with Impediments to the diagnosis and treatment of acute
acute myocardial infarction and two-thirds of deaths coronary syndrome exist at every step in LMIC, from
following myocardial infarction.94 Older patients might be symptom recognition to availability of an appropriate
more likely to have atypical symptoms of acute coronary health-care facility, transportation, and access to
syndrome than younger patients and are often at disease-specific health-care personnel, medications,
heightened risk for both ischaemic and bleeding events.8,94 medical equipment, and secondary prevention
Furthermore, less than 10% of people enrolled in trials of measures.6,100 Additionally, increasing health-care costs
acute coronary syndrome are 75 years or older, indicating and limited insurance coverage penetration lead to
an important gap in clinical evidence for this population.94 magnified patient and health-system-centred barriers
The open-label POPular AGE trial49 randomised to diagnosis and management of acute coronary
1002 patients who were at least 70 years old with syndrome worldwide, particularly in LMIC.101,102 There
NSTEACS to clopidogrel versus ticagrelor or prasugrel are crucial disparities in access to specialised health-
and found a significantly lower rate of bleeding with care system professionals and cardiovascular care
clopidogrel with no increase in ischaemic events. The resource capacity in LMIC compared with HIC.97 For
2020 ESC NSTEACS guidelines recommend that the example, the majority of countries in sub-Saharan Africa
same diagnostic and interventional strategies should be have fewer than five physicians per 10 000 people and
applied to older patients as well as their younger nearly a fifth of these countries had no registered
counterparts and that the choice of antithrombotic agent cardiologists according to recent surveys.103 In an
and secondary prevention measures should take into analysis of 196 acute coronary syndrome admissions to
account renal function and specific contraindications.8 Kenyatta National Hospital in Nairobi, Kenya, only 5%
Ongoing studies, such as the SENIOR-RITA trial of of patients with STEMI received reperfusion therapy
coronary angiography versus medical therapy in patients and the rate of in-hospital mortality was 17%.103 In the
75 years or older with NSTEMI, might add important Caribbean, similar acute myocardial infarction in-
evidence to guide clinical management of acute coronary hospital mortality rates have been reported. In an
syndrome in these older patients.8 analysis of 3794 admissions to the University Hospital
of the West Indies in Jamaica, acute coronary syndrome
Acute coronary syndrome worldwide accounted for 8% of all medical admissions and there
Vast disparities in acute coronary syndrome exist was an impatient acute myocardial infarction mortality
globally, from risk factor prevalence to acute coronary rate of 19%.104 A recent consensus document endorsed
syndrome incidence, treatment availability, and long- by several professional societies in Africa, Asia, and the
term outcomes.7 Whereas aggregate risk factor exposure Americas outlined management strategies for STEMI
appears to have been relatively stable from 2010 to 2019 in resource-limited settings along with directions
on a global scale, there have been important increases forward.6 This work addressing the large and growing
in hyperlipidaemia, hyperglycaemia, high body-mass burden of acute coronary syndrome in LMIC is complex
index, hypertension, and air pollution exposure in and is essential to the health and development of these
LMIC during this timeframe.95 The INTERHEART countries.

1354 www.thelancet.com Vol 399 April 2, 2022

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COVID-19 Janssen, Daiichi-Sankyo, and Philips, outside the submitted work.

The global spread of the novel coronavirus SARS-CoV-2 and RPG reports grants from Amgen, Ionis, Daiichi-Sankyo, and Anthos;
honoraria for Continuing Medical Education Programmes and lectures
its associated clinical disease, COVID-19, has impacted the from Amgen, Centrix, Daiichi Sankyo, Dr. Reddy’s Laboratories, Medical
management of acute coronary syndrome worldwide. Education Resources, Medscape, Menarini, Pfizer, SAJA Pharmaceuticals,
COVID-19 has complicated acute coronary syndrome Servier, and Voxmedia; and consultant fees from Amarin, Amgen, Bayer,
diagnosis and treatment for several reasons: 1) COVID-19 CryoLife, Daiichi Sankyo, Esperion, Gilead, Hengrui, Inari, Pfizer,
PhaseBio Pharmaceuticals, St Luke’s Hospital (Kansas City, MO, USA),
can cause direct or indirect myocardial inflammation or and Sanofi Aventis. All other authors declare no competing interests.
injury,105 which creates diagnostic uncertainty in patients
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