Jaha 121 024425

Journal of the American Heart Association
ORIGINAL RESEARCH
Extended Anticoagulation After Pulmonary

Embolism: A Multicenter Observational
Cohort Analysis
Romain Chopard , MD, PhD; Ida Ehlers Albertsen , MD, PhD; Fiona Ecarnot , PhD; Sebastien Guth, MD;
Matthieu Besutti, MD; Nicolas Falvo, MD; Gregory Piazza , MD, MS*; Nicolas Meneveau , MD, PhD*
BACKGROUND: Pulmonary embolism (PE) has a long-term risk of adverse events, which can be prevented by extended antico-
agulation. We compared clinical characteristics and outcomes between patients treated with 2-year extended anticoagulation
and those who were not, in a population who had completed an initial phase of 3 to 6 months of anticoagulant therapy after
acute PE.
METHODS AND RESULTS: Observational cohort analysis of patients with PE who survived an initial phase of 3 to 6 months antico-
agulation. Primary efficacy outcome was all-cause death or recurrent venous thromboembolism. Primary safety outcome was
major bleeding. In total, 858 (71.5%) patients were treated with and 341 (28.5%) were treated without extended anticoagulant
therapy during the active study period. Age <65 years, intermediate-high or high-risk index PE, normal platelet count, and the
absence of concomitant antiplatelet treatment were independently associated with the prescription of extended anticoagula-
tion. The mean duration of the active phase was 2.1±0.3 years. The adjusted rate of the primary efficacy outcome was 2.1% in
the extended group and 7.7% in the nonextended group (P<0.001) for patients treated with extended anticoagulant therapy.
Rate of bleeding were similar between the extended anticoagulant group and the nonextended group.
Downloaded from http://ahajournals.org by on July 5, 2022
CONCLUSIONS: Extended oral anticoagulation over 2 and a half years after index PE seems to provide a net clinical benefit
compared with no anticoagulation in patients with PE selected to receive extended anticoagulation. Randomized clinical trials
are warranted to explore the potential benefit of extended anticoagulation in patients with PE, especially those with transient
provoking factors but residual risk.
Key Words: extended anticoagulation ■ outcomes ■ pulmonary embolism
P
ulmonary embolism (PE) is becoming increasingly Anticoagulation is the mainstay of PE treatment
recognized as an important source of acute and both in the in-hospital treatment phase and after hos-
chronic morbidity and mortality.1 Patients with in- pital discharge. The purpose of anticoagulant therapy
cident PE carry a long-lasting risk of recurrence, as- is initially to prevent extension of thrombus, but also
sociated with long-term complications.1,2 Patients with to prevent recurrence of venous thromboembolism
PE may develop chronic conditions including thrombo- (VTE), and death.7 Following the acute treatment pe-
embolic pulmonary hypertension, post-thrombotic syn- riod of a minimum of 3 months,8,9 the aim of extended
drome if associated with deep vein thrombosis, post-PE secondary anticoagulation is to prevent VTE recur-
syndrome, which impairs long-term clinical functional rence over the long term. Overall, all direct oral anti-
status, and acute arterial thrombotic events.3–6 coagulants (DOACs) effectively reduce recurrent VTE
Correspondence to: Romain Chopard, MD, PhD, Department of Cardiology, University Hospital Jean Minjoz, 3 Boulevard Fleming, 25000 Besancon, France.
Email: [email protected]
*G. Piazza and N. Meneveau contributed equally.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.121.024425
For Sources of Funding and Disclosures, see page 11.
© 2022 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative
Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use
is non-commercial and no modifications or adaptations are made.
JAHA is available at: www.ahajournals.org/journal/jaha
J Am Heart Assoc. 2022;11:e024425. DOI: 10.1161/JAHA.121.0244251

Chopard et al Extended Anticoagulation After PE
Our institutional review board approved the study. All

CLINICAL PERSPECTIVE patients provided written or oral consent for participa-
tion in the registry. The data that support the findings
What Is New? of this study are available from the corresponding au-
• Extended oral anticoagulation over 2 and a half thor upon reasonable request.
years after index pulmonary embolism provides
a net clinical benefit compared with no antico- Patient Selection
agulation in patients with pulmonary embolism
selected to receive extended anticoagulation.
Patients were eligible for inclusion in the analysis if they
were aged ≥18 years; if they had objectively confirmed,
symptomatic PE (with or without deep vein thrombo-
What Are the Clinical Implications? sis)19,20; and if they had survived an initial phase of 3
• Our results seem to suggest that in patients with
index pulmonary embolism who do not have an
to 6 months of anticoagulant therapy (ie, initial phase).
excess risk of bleeding, extended oral antico- Patients with a contraindication to anticoagulation
agulation may be prescribed up to 2 years and who required implantation of inferior vena cava filter
beyond, regardless of the patient characteris- within 3 to 6 months after the index PE were excluded
tics and clinical context. from the present analysis. Patients with a non-V TE re-
lated life-long indication for anticoagulation (eg, atrial
fibrillation, mechanical heart valve, severe thrombo-
philia) were also excluded. Management was at the
discretion of the physician-in-charge and was in ac-
Nonstandard Abbreviations and Acronyms cordance with the guidelines available at the time of
the study.21,22
CRNMB clinically relevant nonmajor bleeding
DOAC direct oral anticoagulant Data Collection
VKA vitamin K antagonist Research physicians (not involved in the care of the
patients included) prospectively entered data into a
dedicated database for deidentification of personal in-
by about 80% to 90%, with a persisting 2.0% to 6.0% formation and for data validation. Research physicians
risk for clinically relevant nonmajor bleeding (CRNMB) were also asked to ensure that recruitment was con-
in randomized clinical trials (RCTs).10–14 The latest secutive. Patients returned to the participating cent-
evidence-based guidelines recommend that extended ers at 3 to 6 months (after the initial phase), and at
oral anticoagulation of indefinite duration should be least yearly after the index PE for a follow-up visit to
considered for patients with PE with no identifiable risk record clinical status, anticoagulation treatments and
factors or with a minor transient or reversible risk fac- outcomes. If the patients did not attend the hospital
tor.9,15,16 Nevertheless, long-term follow-up data from visit, physicians followed the sequential procedure
unselected populations in daily clinical practice are hereafter: telephone interview with the patient (or fam-
needed to provide insights into the impact of extended ily), consulted the hospitalization records, contacted
anticoagulation after PE.17 the patient’s general practitioner, and consulted the
Using data from a French multicenter prospective national death registry.
nonrandomized registry, we report a comparison of
clinical characteristics and outcomes between patients Study Outcomes and Definitions
treated with 2-year extended anticoagulation and those
Outcomes used were those recommended in regula-
who were not, in a population who had completed 3 to
tory guidelines for studies of extended treatment for
6 months of anticoagulant therapy after acute PE.
VTE diseases.23 The primary efficacy outcome was a
composite of death from any cause or recurrent VTE.
METHODS Secondary efficacy outcomes included: recurrent VTE
or VTE-related death; non-V TE-related cardiovascular
Study Design death, myocardial infarction, or stroke; and recurrent
This is an analysis of a prospectively collected, non- VTE, VTE-related death, myocardial infarction, stroke,
randomized, observational cohort recorded in the or cardiovascular disease-related death. The primary
Burgundy Franche- Comté-France registry from safety outcome was major bleeding.24 Secondary safety
January 2012 to December 2015.18 The registry re- outcomes included CRNMB; major or CRNMB; and a
ceived approval from the national commission for data composite of VTE, VTE-related death, myocardial infarc-
privacy and protection. This study was conducted in tion, stroke, cardiovascular death, or major bleeding. All
accordance with the amended Declaration of Helsinki. suspected outcome events were classified by a central

adjudication committee (S. G. and R. C.). Disagreement anemia (ie, hemoglobin <13 g/dL in men or <12 g/dL in
was resolved by a third author (N.M.). The criteria for women) (+1.5 points); history of bleeding (ie, including
the diagnosis and adjudication of all outcomes and major or nonmajor clinically relevant bleeding event,
their components are described in Data S1.24–26 Risk rectal bleeding, frequent nose bleeding, or hematu-
factors for PE were categorized as transient or revers- ria) (+1.5 points); age >60 years (+1.5 points); and renal
ible, persistent provoked, and no identifiable risk fac- dysfunction (ie, estimated glomerular filtration rate
tor or unprovoked PE.9,15,16,27 Associated cancer was <60 mL/min estimated with the Cockcroft-Gault for-
defined as active or anti-tumor therapy within the last mula) (+1.5 points). Patients with a VTE-BLEED score
6 months, or metastatic state.28 Transient or reversible ≥2 were at high risk of bleeding.30,31
VTE factors included recent surgery (within 90 days),
recent trauma (within 90 days), immobilization (3 days Statistical Analysis
or more), recent hospitalization (within 90 days), preg- We report the study methods and results in accordance with
nancy, postpartum, any infection within 30 days, ex- the Strengthening the Reporting of Observational Studies in
acerbation of inflammatory disease, oral contraceptive Epidemiology guidelines, based on the Recommendations
use, or hormone replacement therapy.29 Persistent risk for Statistical Reporting in Cardiovascular Medicine from
factors included active cancer, inflammatory disease, the American Heart Association.32,33
and antiphospholipid antibody syndrome. Unprovoked Continuous variables are expressed as mean (SD).
PE included factors which did not meet criteria for tran- Categorical variables are expressed as number (per-
sient or persistent provoking factor.9,15,16,27 centage). Unadjusted differences between patients
We also classified patients according to VTE- treated or not with extended anticoagulation were
BLEED for subgroup analyses. The VTE-BLEED score compared using the Chi-square test or Student t-test
includes active cancer (ie, cancer diagnosed within as appropriate. To investigate the independent associ-
6 months before diagnosis of VTE) (excluding basal- ations of various characteristics with the prescription
cell or squamous-cell carcinoma or any cancer that or nonprescription of extended anticoagulation in PE,
required anti-cancer treatment within 6 months before we constructed a multivariable modified Poisson re-
the VTE was diagnosed) (+2 points); male with uncon- gression model.34
trolled hypertension (ie, defined by values of systolic We compared clinical outcomes between patients
blood pressure ≥140 mm Hg at baseline) (+1 point); treated with extended anticoagulation and those not
Figure 1. Study flowchart.

treated using multivariable Cox models. Models were (including sex, age, weight, high bleeding risk accord-
adjusted for baseline characteristics, in-hospital and ing to the VTE-BLEED score [ie, ≥2], prior VTE, risk
initial phase therapies, as well as clinical outcomes factors, cancer, and renal function impairment) with
between index PE and 3 to 6 months that yielded a the use of Breslow- Day tests. We compared rates
P<0.10 by univariable analysis. Results are reported of primary outcomes between patients treated with
as hazard ratios (HR) with associated 95% CI. A DOAC, vitamin K antagonist (VKA) and those who did
P<0.05 was considered significant. The full list of not receive any extended anticoagulation. Finally, we
candidate covariates is given in Table S1. The results performed multiple subgroup analyses across unpro-
of the primary efficacy outcome between patients voked, prior VTE, and cancer-associated PE patients
treated with extended anticoagulation and those based on patients’ bleeding-risk (ie, high versus low
not treated are displayed by Kaplan‒Meier curves. bleeding-risk). We used the family-wise error rate to
The use of multiple imputation was not required, as control the overall false-positive rate for these com-
the rate of missing data was <2% for all covariates parisons by applying Bonferroni correction,36 and we
(Table S1).35 used the unadjusted time-dependent Log-rank test to
To assess the robustness of the findings, we per- compare outcomes.
formed multiple sensitivity analyses for primary efficacy All statistical analyses were performed with SAS
and safety outcomes across relevant subgroups23 version 9.4 (SAS Institute Inc., Cary, NC).
Table 1. Baseline Characteristics and In-Hospital Management Outcomes Between Patients With Pulmonary Embolism
Treated With and Without Extended Anticoagulant Therapy During the Active Study Period (n=1199)
Extended No anticoagulant
All study patients anticoagulation therapy
(n=1199) (n=858) (n=341) P value
Age, y 66.5±17.2 64.4±18.4 67.3±16.7 0.0.1

Female sex (%) 610 (50.1) 453 (52.8) 157 (46.0) 0.03
Weight, kg 78.9±16.9 78.4±18.6 80.2±18.8 0.13
ESC-defined risk stratification of index PE (%) <0.001
Low-risk 253 (21.1) 165 (19.2) 88 (25.8)
Intermediate-low risk 649 (54.1) 458 (53.4) 191 (56.0)

Intermediate-high risk 247 (20.6) 201 (23.4) 46 (13.5)
High-risk 50 (4.2) 34 (4.0) 16 (4.7)
Comorbidities (%)
Chronic pulmonary disease 105 (8.8) 75 (8.7) 30 (8.8) 0.97
Cancer 177 (14.8) 116 (31.5) 61 (17.9) 0.054
Prior VTE 306 (25.5) 270 (88.2) 36 (11.8) <0.001
Transient or reversible risk factor 284 (23.7) 186 (21.7) 98 (28.7) 0. 009
Persistent risk factor 210 (17.5) 146 (17.0) 64 (18.8) 0.47
No identifiable risk factor (unprovoked PE) 705 (58.8) 526 (61.3) 179 (52.5) 0.005
Associated DVT 494 (41.2) 370 (43.1) 124 (36.4) 0.03
Biological data at inclusion
Hemoglobin, g/dL 13.5±3.5 13.6±4.0 13.3±1.9 0.07
Platelet count, ×103/µL 247.6±98.5 246.9±98.9 249.4±97.4 0.70
eGRFMDRD, mmol/L 79.8±28.9 76.9±28.2 81.2±30.8 0.30
Concomitant antiplatelet therapy at inclusion (%) 75 (6.3) 30 (3.5) 45 (13.2) <0.001
VTE BLEED score ≥2 919 (76.5) 671 (78.2) 248 (72.7) 0.12
Adverse outcomes between index PE and 3–6 mo follow-up (%)
Any bleeding 90 (7.5) 58 (6.8) 32 (9.4) 0.11
Major bleeding 57 (4.7) 36 (4.2) 21 (6.2) 0.14
Acute heart failure 23 (1.9) 18 (2.1) 5 (1.5) 0.47
Acute myocardial infarction 8 (0.7) 7 (0.8) 1 (0.3) 0.31
Stroke 5 (0.4) 4 (0.5) 1 (0.3) 0.67
The statistics are shown as mean±SD or n (%). P values are for comparison between extended anticoagulation vs no anticoagulation groups. DVT indicates
deep vein thrombosis; eGRFMDRD, estimated glomerular function calculated with the Modification of Diet in Renal Disease equation; ESC, The European Society
of Cardiology; and VTE, venous thromboembolism.

RESULTS patients with PE who received extended anticoagula-

tion were younger, were more frequently women, and
Study Population more frequently had PE with associated cancer and
A total of 1478 patients were admitted to the participat- deep vein thrombosis, and more severe index PE.
ing centers with a diagnosis of objectively confirmed Patients with PE who received extended anticoagula-
PE between January 2012 and December 2015. tion were less frequently treated with antiplatelet ther-
The mean duration of the initial treatment phase was apy. Rates of adverse events during the initial phase
3.8±0.7 months. Overall, 220 patients (14.9%) died did not differ between 2 groups. The VTE BLEED score
during the initial phase, 4 patients (0.3%) suffered was similar between groups (Table 1). In total, 22.6%
major bleeding that required implantation of an infe- patients with a clear indication for extended anticoagu-
rior vena cava filter with an absolute contraindication to lation as stipulated by the guidelines, including cancer
pursuit of initial anticoagulation, and 15 patients (1.0%) (34.4%) and unprovoked PE (23.4%), did not receive
were lost to follow-up. Among the remaining 1239 pa- anticoagulant therapy. At the end of the initial phase,
tients, 1199 patients (96.8%) had complete follow-up at 33.7% of patients with PE who had transient or revers-
2 years after the 3-to 6-month initial phase and com- ible factors did not receive extended anticoagulation
prise the active study population (mean age, 66.5±17.2; (Table 1). VTE-BLEED-defined high bleeding risk was
610 (50.1%) women) (Figure 1). not associated with the nonprescription of extended
anticoagulation (OR, 0.90; 95% CI, 0.69–1.18).
Age <65 years, intermediate-high, or high-risk index
Patient Characteristics
PE, normal platelet count (ie, >150×103/µL), and the
In total, 858 (71.5%) patients were treated with and 341 absence of concomitant antiplatelet treatment were
(28.5%) were treated without extended anticoagulant independently associated with the prescription of ex-
therapy during the active study period after the initial tended anticoagulation (Figure 2).
phase of 3 to 6 months. Patients who were treated
with extended anticoagulation received DOAC (n=637;
74.2%) or VKA (n=221; 25.8%) (Figure S1). A transient Outcomes
or reversible VTE risk factor was identified in 23.7% of The mean duration of study follow-up was 2.1±0.3 years
patients, a persistent risk factor in 17.5%, and no iden- after the initial phase of 3 to 6 months. During the study
tifiable risk factor was found in 58.8% (Table 1). Overall, period, we observed 143 all-cause deaths (11.9%), as
Figure 2. Factors independently associated with anticoagulant prescription vs nonprescription for the extended treatment
of pulmonary embolism.
*Estimated glomerular function rate >30 mL/min; †platelet count >150×103/µL. PE indicates pulmonary embolism; and RR, relative risk.

well as 74 recurrent VTE (6.2%), 10 myocardial infarc- Adjusted rates of major or CRNMB were similar
tions (0.8%), 19 strokes (1.6%), 24 major bleeding (2.0%), between the extended anticoagulant group and the
and 20 CRNMB (2.5%) (Tables S2 and S3). The abso- no-anticoagulant group (5.1% versus 5.0%, and 4.6%
lute rate of the primary outcome was 9.1% in the group versus 3.0%, respectively) (Table 2). Unadjusted rates
of patients who received extended anticoagulation and of the major bleeding were lower whatever the drug
34.0% in the group who did not (P Log-rank test <0.001) (ie, DOAC or VKA) or DOAC dose used, compared
(Figure 3). Table S4 displays covariates associated with with those observed in the no- anticoagulant group
the occurrence of the primary end point of all-cause (Figure S2).
death or recurrent VTE in univariable and multivariable
analyses. The adjusted rate of all-cause death or recur-
rent VTE was 2.1% (95% CI, 1.2–3.5) in the extended Sensitivity Analyses
group and 7.7% (95% CI, 4.8–12.1) in the nonextended We consistently observed a lower rate of the com-
group, yielding a hazard ratio of 0.23 (95% CI, 0.17–0.31; posite end point of all- cause death or recurrent
P<0.001) (Figure 3). The adjusted rates of all-cause mor- VTE (Figure 4) and similar rates of major bleeding
tality and recurrent VTE were 3.7% (95% CI, 2.1–6.5) and (Figure 5) with extended anticoagulant therapy in all
0.07% (95% CI, 0.02–0.23), respectively, in the extended relevant subgroups. Results were unchanged, re-
anticoagulation group, and 8.0% (95% CI, 4.5– 14.2) gardless of whether VKA or DOAC were prescribed
and 1.0% (95% CI, 0.4–2.3) in the nonextended group for extended anticoagulant therapy (Figures 5 and
(P<0.001, and P<0.001, respectively). Unadjusted rates 6). The unadjusted impact of extended anticoagulant
of the composite outcome of all-cause death or recur- therapy on the primary efficacy and safety outcomes
rent VTE were lower regardless of the drug (ie, DOAC was constant in patients with unprovoked PE, prior
or VKA) or DOAC dose used, compared with those ob- VTE, and associated cancer, whatever their bleeding
served in the nonextended group (Figure S2). risk (Figure S3 and Table S5).
Figure 3. Kaplan–Meier curves for the composite end point, all-cause death, or recurrent venous
thromboembolism, between patients treated with vs without extended anticoagulation.
The primary efficacy rates between patients treated with extended vs without extended anticoagulation
were adjusted for age (per 10 years), weight <60 kg, prior arterial hypertension, prior coronary artery
disease, chronic lung disease, active cancer, systolic blood pressure <100 mm Hg at admission, anemia
at admission (ie, hemoglobin <12 g/dL), thrombocythemia at admission (ie, platelet count <150×103/µL),
renal dysfunction at admission (ie, estimated glomerular function calculated with the Modification of Diet
in Renal Disease equation <60 mL/min), and major bleeding events between index pulmonary embolism
and 3 to 6 months (ie, initial phase) (see Table S4). HR indicates hazard ratio.

Table 2. Clinical Outcomes Between Patients With Pulmonary Embolism Treated With and Without Extended
Anticoagulant Therapy During the Active Study Period (n=1199)
Adjusted rates (%, 95% CI)*
Extended anticoagulation No anticoagulation Hazard ratio (95%

Outcomes (n=858) (n=341) CI) P value
Efficacy outcomes
Recurrent VTE or death from any cause— 2.1% (95% CI, 1.2–3.5) 7.7% (95% CI, 4.8–12.1) 0.23 (0.17–0.31) <0.001
primary efficacy outcome
Recurrent VTE or VTE-related death 0.3% (95% CI, 0.1–0.7) 2.0% (95% CI, 0.9–4.3) 0.12 (0.07–0.21) <0.001
Non-V TE‒related cardiovascular death, 2.1% (95% CI, 1.2–3.5) 8.4% (95% CI, 4.9–14.4) 0.40 (0.29–0.56) <0.001
myocardial infarction, or stroke
Recurrent VTE, VTE-related death, 5.0% (95% CI, 2.5–7.2) 16.8% (95% CI, 8.9–23.0) 0.47 (0.29–0.56) <0.001
myocardial infarction, stroke, or
cardiovascular disease-related death
Safety outcomes
Major bleeding—primary safety outcome 5.1% (95% CI, 2.1–11.9) 5.0% (95% CI, 1.6–13.9) 1.0 (0.57–1.76) 0.98
Clinically relevant nonmajor bleeding 4.6% (95% CI, 1.2–16.8) 3.0% (95% CI, 0.4–15.5) 1.65 (0.67–4.07) 0.27
Major or clinically relevant nonmajor bleeding 5.3% (95% CI, 2.1–13.2) 4.6% (95% CI, 1.4–14.3) 1.14 (0.61–2.11) 0.67
VTE, VTE-related death, myocardial 2.2% (95% CI, 1.0–4.5) 10.3% (95% CI, 5.5–19.1) 0.45 (0.30–0.69) <0.001
infarction, stroke, cardiovascular death, or
major bleeding
VTE indicates venous thromboembolism.

*Rates of outcomes were adjusted with covariates that yielded a P<0.10 by univariable analysis (see Table 1 and Table S4).
only an additional 6 or 12 months treatment/placebo

DISCUSSION duration in patients who had completed initial ther-
Our analysis suggests that extended oral anticoagula- apy for VTE.10–14 The RE- MEDY/active- control study
tion over 2 and a half years after index PE, whether (Secondary Prevention of Venous Thrombo Embolism
by VKA or DOAC, provides a net clinical benefit com- [VTE]) was the sole trial that randomized patients to
pared with no anticoagulation in patients selected by receive dabigatran 150 mg twice daily or warfarin with
providers to receive extended anticoagulation, likely a follow-up of 36 months.10
based on their bleeding risk profile, including factors Similar to our study, other reports have raised the
such as age, renal function, presence of thrombocyto- question of extended anticoagulation duration in PE.
penia or antiplatelet therapy. We observed lower rates First, a nationwide cohort study including 74 000 pa-
of death and recurrent VTE, and an associated similar tients suggested that when extending follow- up to
rate of bleeding in the group of patients treated with 10 years, risk of recurrence of unprovoked and cancer-
long-term anticoagulant therapy. Results were con- related VTE was almost the same, with an absolute risk
sistent across the high-thrombotic-risk subgroup (ie, of 20% for both types of VTE. Above all, the absolute
cancer, unprovoked PE, and prior history of VTE) as risk of recurrence for patients with provoked PE re-
well as in populations at risk of bleeding (ie, women, mains non-negligible, >15% at 10 years.2 Second, in the
elderly patients, renal function impairment, low body PADIS-PE trial (Extended Duration of Oral Anticoagulant
weight, and VTE-BLEED score defined high bleeding Therapy After a First Episode of Idiopathic Pulmonary
risk patients). These findings underscore the crucial Embolism: a Randomized Controlled Trial), 371 pa-
role of anticoagulant therapy for extended secondary tients with unprovoked PE were initially treated with
prevention of PE. They provide additional evidence that warfarin for 6 months. After this period, patients were
may help to clarify the persisting zones of uncertainty randomized to either an additional 18 months of warfa-
in evidence-based guidelines for the long-term man- rin treatment or to placebo.38 During the additional 18-
agement of PE.9,15,16 month treatment period, warfarin was associated with
Existing guidelines were principally derived from higher risk of bleeding compared with placebo (2.2%
5 RCTs that included selected patients with strict in- versus 0.5%; HR, 3.96; 95% CI, 0.44–35.89), but also
clusion and exclusion criteria, which may not entirely a lower risk of recurrent VTE (1.7% versus 13.5%; HR,
reflect the risks and benefits of anticoagulation in the 0.15; 95% CI, 0.05–0.43). However, the benefit of an-
less controlled setting of everyday clinical practice.10–14 ticoagulation in reducing recurrence abated after an-
It was reported that almost one quarter of patients with ticoagulation was discontinued at 18 months, with a
VTE have at least 1 exclusion criterion, making them in- continuous increase in the rate of recurrent VTE in the
eligible for RCTs.37 Moreover, most available RCTs had warfarin group over the subsequent 2-year follow-up

Figure 4. Sensitivity analyses of the composite end point, all-cause death or recurrent venous thromboembolism, across
relevant subgroups.
VTE indicates venous thromboembolism. *P value for interaction; †according to Kearon et al.27
period. Accordingly, at 42 months (18 months treat- extended anticoagulation, and 34.4% versus 43.5% for
ment period plus 24 months follow-up), the risk in the cancer-associated PE, respectively).
warfarin group resembled the risk of the placebo group The choice to introduce extended oral anticoagu-
(17.9% versus 22.1%; HR, 0.69; 95% CI, 0.42–1.12). lation should balance the benefits of preventing recur-
The COMMAND VTE (Contemporary Management rent VTE against the potential harms of bleeding.8,9,15,16
and Outcomes in Patients with Venous Throm bo In the present analysis, it seems that providers may
embolism) multicenter “real-world” registry evaluated have chosen not to prescribe extended anticoagulant
long-term recurrent VTE and bleeding risks between therapy based on clinical factors known to increase
cancer-related, unprovoked, and provoked VTE. In the bleeding risk in the stable anticoagulation setting (ie
landmark analysis, the cumulative 3- year incidence older age, coagulation disturbance with thrombocyto-
of recurrent VTE was lower in patients on anticoag- penia, and concomitant anti-platelet treatment).40–42 In
ulation than in patients off anticoagulation beyond addition to individual decision-making, the VTE-BLEED
1 year in the unprovoked group (on [3.7%] versus off score has been developed to identify patients with PE
[12.2%], P<0.001), but not in the transient risk and can- at high risk of bleeding under chronic anticoagula-
cer groups (respectively, 1.6% versus 2.5%, P=0.30; tion.41 The VTE BLEED score demonstrated good per-
5.6% versus 8.6%, P=0.44).39 Conversely, in our anal- formances in identifying patients with PE at high-risk of
ysis, we observed a clinical benefit of anticoagulation major bleeding in external analyses from randomized
across all subgroups, including cancer-associated PE. and cohort studies (C-index, 0.66 [95% CI, 0.61–0.72],
The numerically higher rates of extended anticoagula- and 0.63 [95% CI, 0.58–0.68], respectively).30,31 In our
tion among patients with PE with associated transient analysis, the VTE-BLEED score was not associated
or reversible factors and cancer observed in our study with the nonprescription of extended anticoagulation.
might explain these differences (33.7% versus 37.3% Individual decision-making may have played a major
for PE with transient or reversible factors not receiving role in the choice of the long-term strategy. Conversely,

Figure 5. Sensitivity analyses of major bleeding across relevant subgroups.

DOAC indicates direct oral anticoagulation; VKA, vitamin K antagonist; and VTE, venous thromboembolism. *P value for interaction;
†
according to Kearon et al.27
several prediction models, either during or after anti- shared similar effects on VTE recurrence and major
coagulation, have tried to identify selected patients at bleeding.49 In addition, DOACs have a rapid onset of
high risk of recurrent VTE who might benefit from ex- action, more predictable pharmacokinetics, and avoid
tended anticoagulation.2,9,43–47 For instance, a scoring the need for routine laboratory monitoring and dose
system developed from a nationwide database includ- adjustments.
ing 11 519 patients showed good calibration and mod- Additional important information on the relationship
est discrimination. Nevertheless, external analyses are between extended anticoagulation and clinical out-
lacking to expand the use of these scoring systems in comes will be provided by 2 ongoing RCTs. The single
individual patients with PE.9 center, randomized trial (HI-PRO [Extended-duration
Finally, our results showing the favourable impact of Low-intensity Apixaban to Prevent Recurrence in
extended anticoagulation were consistent, whichever High-risk Patients with Provoked VTE]) is recruiting
drug was used (ie, VKA or DOAC). Evidence-based 600 patients to compare low-dose apixaban versus
clinical practice guidelines recommend DOACs as the placebo for 12-month prevention of recurrence after
preferred choice for most patients with VTE, except provoked VTE in patients with persistent provoking
those with severe kidney disease and antiphospholipid factors (NCT04168203). The RENOVE (Reduced Dose
syndrome, who may be best treated with VKA.8,9,48 Versus Full-Dose of Direct Oral Anticoagulant After
In a network analysis of 18 221 patients from RCTs, Unprovoked Venous Thromboembolism) study is de-
standard- dose VKA and low/standard- dose DOAC signed to include 2200 participants to demonstrate

Figure 6. Kaplan‒Meier curves for the composite end point, all-cause death or recurrent venous
thromboembolism, between patients treated with extended vitamin K antagonist, direct oral
anticoagulant, or no treated with extended vs without extended anticoagulation.
DOAC indicates direct oral anticoagulant; HR, hazard ratio; and VKA, vitamin K antagonist. The primary
efficacy rates between patients treated with extended vs without extended anticoagulation were adjusted
by age (per 10 years), weight <60 kg, prior arterial hypertension, prior coronary artery disease, chronic
lung disease, active cancer, systolic blood pressure <100 mm Hg at admission, anemia at admission (ie,
hemoglobin <12 g/dL), thrombocythemia at admission (ie, platelet count <150×103/µL), renal dysfunction
at admission (ie, estimated glomerular function calculated with the Modification of Diet in Renal Disease
equation <60 mL/min), and major bleeding events between index pulmonary embolism and 3 to 6 months
(ie, initial phase) (see Table S4).
the noninferiority of reduced doses of rivaroxaban of complete follow-up among survivors of the initial
and apixaban for extended treatment with a mean fol- phase (96.8%), independent adjudication of clinical
low-up period of 24 months (range, 12 to 48 months) outcomes between the index PE and extended fol-
(NCT03285438). low-up, as well as the 2-year follow-up after initial
Our study has some limitations. The main limita- treatment of PE.
tion is the potential for selection bias in the orientation
of patients towards extended anticoagulation ther-
apy by providers, likely based on a more favorable CONCLUSIONS
risk-benefit profile. Despite the use of multivariable Our analysis suggests that extended oral anticoagula-
Poisson regression including several covariates, we tion over 2 and a half years after index PE, whether
did not directly record specific reasons that drove by VKA or DOAC, provides a net clinical benefit com-
providers to prescribe extended anticoagulation or pared with no anticoagulation in patients selected by
not. Our results should therefore be interpreted as a providers to receive extended anticoagulation, likely
pilot study derived from a multicenter cohort popu- based on their bleeding risk profile. Sensitivity analy-
lation, which should be evaluated in RCT. Finally, we ses yielded consistent results across all relevant sub-
were unable to distinguish between major and minor groups, including high bleeding and thrombotic risk
transient risk factors of VTE as recently defined by groups. Randomized clinical trials are warranted to
the international guidelines.9,15,16 The strengths of our explore the potential benefit of extended anticoagula-
analysis include the multicenter design and prospec- tion in patients with PE, especially those with transient
tive inclusion of our cohort population, the high rate provoking factors but residual risk.

ARTICLE INFORMATION Respiratory Society (ERS). Eur Heart J. 2020;41:543–603. doi: 10.1093/
eurheartj/ehz405
Received October 21, 2021; accepted March 28, 2022. 10. Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra
D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ, et al. Extended
Affiliations use of dabigatran, warfarin, or placebo in venous thromboembolism. N
Department of Cardiology, University Hospital Jean Minjoz, Besançon, Engl J Med. 2013;368:709–718. doi: 10.1056/NEJMoa1113697
France (R.C., F.E., S.G., M.B., N.M.); EA3920, University of Burgundy 11. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B, Buller
Franche- Comté, Besançon, France (R.C., F.E., N.M.); F- CRIN, INNOVTE HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, et al.
Network, Saint-Etienne, France (R.C., N.M.); Aalborg Thrombosis Research Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J
Unit, Aalborg University Hospital, Aalborg, Denmark (I.E.A.); Department of Med. 2010;363:2499–2510. doi: 10.1056/NEJMoa1007903
Internal Medicine, University Hospital Dijon-Bourgogne, Dijon, France (N.F.); 12. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari
and Division of Cardiovascular Medicine, Department of Medicine, Brigham A, Raskob GE, Weitz JI; Investigators A-E. Apixaban for extended treat-
and Women’s Hospital, Harvard Medical School, Boston, MA (G.P.). ment of venous thromboembolism. N Engl J Med. 2013;368:699–708.
doi: 10.1056/NEJMoa1207541
Sources of Funding 13. Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J,
The study was supported by grants from Bayer Healthcare SAS (Loos, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H,
France). Bayer Healthcare SAS had no role in the design and conduct of et al. Rivaroxaban or aspirin for extended treatment of venous throm-
the study; collection, management, analysis, and interpretation of the data; boembolism. N Engl J Med. 2017;376:1211–1222. doi: 10.1056/NEJMo
preparation, review, or approval of the manuscript; and decision to submit a1700518
the manuscript for publication. 14. Raskob G, Ageno W, Cohen AT, Brekelmans MPA, Grosso MA, Segers
A, Meyer G, Verhamme P, Wells PS, Lin M, et al. Extended duration of
Disclosures anticoagulation with edoxaban in patients with venous thromboembo-
Dr Albertsen has received speaking fees from Pfizer and Bayer AG. Dr Piazza lism: a post-hoc analysis of the Hokusai-V TE study. Lancet Haematol.
reports research grants from BMS/Pfizer, BSC, Amgen, Bayer, Janssen, 2016;3:e228–236. doi: 10.1016/S2352-3026(16)00023-5
Portola; and Participation on a Data Safety Monitoring Board or Advisory 15. Ortel TL, Neumann I, Ageno W, Beyth R, Clark NP, Cuker A, Hutten BA,
Board for Pfizer, Amgen, Prairie Education Research Cooperative, Agile; Jaff MR, Manja V, Schulman S, et al. American Society of Hematology
Dr Meneveau reports personal fees from Abbott, personal fees from BMS- 2020 guidelines for management of venous thromboembolism: treat-
Pfizer, personal fees from Bayer Healthcare, personal fees from Edwards ment of deep vein thrombosis and pulmonary embolism. Blood Adv.
Lifesciences, personal fees from Terumo, outside the submitted work. The 2020;4:4693–4738. doi: 10.1182/bloodadvances.2020001830
remaining authors have no disclosures to report. 16. Stevens SM, Woller SC, Kreuziger LB, Bounameaux H, Doerschug K,
Geersing G-J, Huisman MV, Kearon C, King CS, Knighton AJ, et al.
Supplemental Material Antithrombotic therapy for VTE disease: second update of the CHEST
Data S1 guideline and expert panel report. Chest. 2021;160:e545–e608. doi:
Tables S1–S5 10.1016/j.chest.2021.07.055
Figures S1–S3 17. Albertsen IE, Piazza G, Sogaard M, Nielsen PB, Larsen TB. Extended
oral anticoagulation after incident venous thromboembolism—a par-
adigm shift? Expert Rev Cardiovasc Ther. 2020;18:201– 208. doi:
10.1080/14779072.2020.1755260
18. Chopard R, Piazza G, Falvo N, Ecarnot F, Besutti M, Capellier G, Schiele

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Supplemental Material
Data S1.
Supplemental Methods
Definition of outcomes:
- Death was classified as related to VTE, related to cardiovascular disease, related to cancer,
related to bleeding, or related to non-cancer, non-cardiovascular causes. VTE was considered as
the cause of death if there was objective documentation or if death could not be attributed to
another documented cause and PE could not be ruled out.
- Recurrent venous thromboembolism included fatal and nonfatal pulmonary embolism and
deep-vein thrombosis. Recurrent VTE was defined as presence of (1) symptoms suggesting
pulmonary embolism, and new defects seen on computed tomography pulmonary angiogram
or ventilation-perfusion scan; or (2) diagnosis of deep vein thrombosis on compression
ultrasonography.
- Any bleeding included clinically relevant non-major (CRNM) bleeding and major bleeding.
- Major bleeding was defined according to the International Society on Thrombosis and
Haemostasis (ISTH) criteria, namely: (1) fatal bleeding and/or (2) symptomatic bleeding in a
critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or
pericardial, or intramuscular with compartment syndrome), and/or (3) bleeding causing a fall in
hemoglobin level of 20 g/L (1.24 mmol/L) or more, or leading to transfusion of two or more
units of whole blood or red cells.24

- Clinically relevant non-major bleeding was acute clinically overt bleeding that consists of: any
bleeding compromising hemodynamics; any bleeding leading to hospitalization; subcutaneous
hematoma larger than 25 cm2, or 100 cm2 if there was a traumatic cause; intramuscular
hematoma documented by ultrasonography; epistaxis that lasted for more than 5 minutes, was
repetitive (i.e., two or more episodes of bleeding more extensive than spots on a handkerchief
within 24 hours), or led to an intervention (e.g., packing or electrocoagulation); gingival
bleeding occurring spontaneously (i.e., unrelated to eating or tooth brushing) or lasting for
more than 5 minutes; hematuria that was macroscopic and was spontaneous or lasted for more
than 24 hours after instrumentation (e.g., catheter placement or surgery) of the urogenital
tract; macroscopic gastrointestinal hemorrhage, including at least one episode of rectal blood
loss, if more than a few spots on toilet paper; hemoptysis, if more than a few speckles in the
sputum and not occurring within the context of PE; or any other bleeding type considered to
have clinical consequences for a patient such as medical intervention, the need for unscheduled
contact (visit or telephone call) with a physician, or temporary cessation of a study drug, or
associated with pain or impairment of activities of daily life. 24
- Acute myocardial infarction was defined as the presence of at least two of the three following
conditions: (1) An appropriate clinical situation suggestive of an MI (e.g., abnormal history,
physical examination, or new electrocardiogram changes); (2) troponin T or I ≥2 × upper limit of
normal (ULN); (3) New, significant (≥0.04 seconds) Q waves in ≥2 contiguous leads. 25
- Acute stroke was defined as a new, focal neurologic deficit of sudden onset, lasting at least 24
hours, not due to a readily identifiable nonvascular cause (i.e., brain tumor, trauma). 26
Table S1. List of candidate covariates for the multivariable models performed in the present analysis after acute pulmonary
embolism.
Covariates Missing data (%) Unvariate analysis
Extended anticoagulation group vs No anticoagulation group
p-value for the primary p-value for the primary
efficacy outcome safety outcome
Age, year 0 - -
Age > 65 years 0.004 0.26

Age > 70 years 0.001 0.67
Age > 75 years <0.001 0.65
Age > 80 years <0.001 0.26
Female sex 0 0.11 0.57
Weight, kg 0.1 - -
Weight < 50 kg 0.24 0.34
Weight < 60 kg 0.04 0.21
BMI, kg/m2 0 - -
BMI > 25 kg/m2 0.67 0.87

BMI > 30 kg/m2 0.56 0.69
BMI > 35 kg/m2 0.30 0.43
BMI < 18 kg/m2 0.21 0.32
Comorbidities
Current smoker 0 0.39 0.24
Hypertension 0 0.05 0.98
Diabetes mellitus 0 0.28 0.43
Dyslipidemia 0 0.54
Chronic pulmonary disease 0 0.006
Coronary artery disease 0 0.08 0.04

Cancer 0 <0.001 0.25
Prior stroke 0 0.88 <0.001
Prior bleeding 1.2 0.40 0.98
Prior VTE 0 0.14 0.78
Neurocognitive disorders 0.3 0.36 0.88
Liver disease 0 0.77 0.28
Excessive Fall Risk 0.4 0.88 0.38
Ethanol abuse 0 0.69 0.08

Recent surgery 0 0.34 0.65
Recent hospitalization 0 0.25 0.24
Thrombophilia 0 0.87 0.15
Pregnancy 0 0.99 0.98
Post-partum period 0 0.99 0.99
Immobility due to sitting (e.g. prolonged car or air travel) 0 0.78 0.65
Bed rest > 3 days 0 0.25 0.67
Varicose veins 0 0.24 0.87
Associated DVT 0 0.11 0.29
Clinical presentation and management of the acute PE event

Syncope 0 0.20 0.82
Arterial oxyhaemoglobin saturation <90% at admission 0 0.25 0. 98
SBP < 90 mmHg at admission 0 0.06 0.01
SBP < 100 mmHg 0 0.001 0.98
Heart rate > 110 b.p.m at admission 0 0.22 0.40
RV dysfunction at admission 0 0.17 0.36
Advanced therapya 0 0.81 0.33
Concomitant anti-thrombotic therapy at admission

Antiplatelet therapy 0 0.19 0.06
Anticoagulation 0 0.32 0.25
Concomitant antiplatelet therapy between index PE and 3 to 0 0.38 0.23
6 months
Adverse outcomes between index PE and 3 to 6 months
Any bleeding 0 0.16 0.007
Major bleeding 0 0.03 0.19
Acute heart failure 0 0.014 0.09
Acute myocardial infarction 0 0.14 0.98
Stroke 0 0.97 0.99

Biological data at inclusion
Hemoglobin (g/dL) 0.6 - -
Anemia with hemoglobin < 10 gl/dL <0.001 0.31
Anemia with hemoglobin < 12 gl/dL <0.001 0.55
Anemia with hemoglobin < 13 g/dL in men and ,12 g/dL in 0.01 0.68
women
Anemia with hemoglobin <13 g/dL in men and < 12 g/dL in 0.02 0.72
women) and hematocrit < 40% in men and < 36% in women
Platelet count (x 103/microliter) 0.7 - -
Thrombocytopenia with platelet count < 50 103/microliter 0.01 0.87
Thrombocytopenia with platelet count < 100 103/microliter <0.001 0.93
Thrombocytopenia with platelet count < 150 103/microliter <0.001 0.98
eGFR 0
eGRFCKD-EPI, mmol/L - -
eGRFMDRD4, mmol/L - -
eGRFCG-BSA, mmol/L - -
eGRFCKD-EPI < 60 mL/min 0.007 0.35
eGRFMDRD4 < 60 mL/min 0.01 0.32

eGRFCG-BSA < 60 mL/min 0.02 0.70
eGRFCKD-EPI < 30 mL/min <0.001 0.88
eGRFMDRD4 < 30 mL/min <0.001 0.65
eGRFCG-BSA < 30 mL/min (%) 0.004 0.65
BMI, body mass index; VTE, venous thromboembolic; DVT, deep vein thrombosis; SBP, systolic blood pressure; eGFR, estimated
glomerular function; CKD-EPI, The Chronic Kidney Disease Epidemiology Collaboration equation; MDRD4, the four variables the
Modification of Diet in Renal Disease equation; CG-BSA, the body surface area-adjusted Cockcroft-Gault equation. a Advanced
therapy included systemic thrombolysis, surgical embolectomy, or extra-corporeal membrane oxygenation.

Table S2. Observed rates of clinical outcomes between pulmonary embolism patients treated
with extended vs without extended anticoagulant therapy during the active study period (n =
1,199).
Extended anticoagulation No anticoagulation
(n = 858) (n = 341)
Death from any cause 76 (8.8%; 95% CI, 6.7-10.9) 67 (19.6%; 95% CI, 15.5-24.2)
Recurrent VTE 11 (1.3%; 95% CI, 0.6-2.3) 63 (18.5%; 95% CI, 14.5-23.0)
Myocardial infarction 2 (0.2%; 95% CI, 0.02-0.8) 8 (2.3%; 95% CI, 1.0-4.5)
Stroke 14 (1.6; 95% CI, 0.9-2.7) 5 (1.5%; 95% CI, 0.5-3.4)
Major bleeding 16 (1.9%; 95% CI, 1.1-3.0) 8 (2.3%; 95% CI, 1.0-4.5)
Clinically relevant non-major 24 (2.8%; 95% CI, 1.8-4.1) 6 (1.8%; 95% CI, 0.7-3.8)
bleeding
VTE, venous thromboembolism; CI, confidence interval.
The statistics are shown as mean ± standard deviation (SD) or N (%, 95% CI)
Table S3. Observed causes of death between pulmonary embolism patients treated with
extended vs without extended anticoagulant therapy during the active study period (n =
1,199).
Cause of death Extended anticoagulation No anticoagulation
(n = 858) (n = 341)
VTE-related 4 (0.5%; 95% CI, 0.1-1.2) 6 (1.8%; 95% CI, 0.7-3.8)
Cardiovascular disease- 2 (0.2%; 95% CI, 0.02-0.8) 2 (0.6%; 95% CI, 0.08-2.1)
related
Cancer-related 35 (4.1%; 95% CI, 2.8-5.6) 35 (10.3%; 95% CI, 7.3-14.0)
Bleeding-related 3 (0.34%; 95% CI, 0.07-1.0) 1 (0.29%; 95% CI, 0.01-1.6
Non-cancer, non 35 (4.1%; 95% Ci, 2.9-5.6) 24 (7.0%; 95% CI, 4.5-10.2)
cardiovascular-related
VTE, venous thromboembolism.

Table S4. Univariable and multivariate predictors of the primary efficacy and safety outcomes
(i.e. recurrent venous thromboembolism or all-cause death) at 2 years in pulmonary
embolism patients treated with vs without extended anticoagulant therapy during the study
period (n = 1,199).
Variable HR (95% CI) p value HR (95% CI) p value
Univariate analysis Multivariate analysis
Primary efficacy outcome:
All-cause death or recurrent VTE
Age, per 10 years 1.09 (1.01-1.16) 0.01 1.26 (1.13-1.41) <0.001
Weight < 60 kg 1.36 (0.99-1.87) 0.051 - -
Prior arterial hypertension 1.33 (1.00-1.77) 0.05 - -

Prior CAD 1.40 (0.95-2.04) 0.08 - -
Chronic lung disease 1.73 (1.15-2.62) 0.008 - -
Cancer 1.39 (0.99-1.95) 0.055 3.45 (2.51-4.73) <0.001
SBP < 100 mmHg at admission 2.14 (1.30-3.52) 0.002 - -
Anemiaa at admission 2.36 (1.76-3.17) <0.001 1.40 (1.01-1.96) 0.04
Thrombocytopeniab at admission 2.0 (1.41-2.80) < 0.001 - -
Renal dysfunctionc at admission 1.48 (1.11-1.99) 0.007 - -
Extended anticoagulation 1.5 (1.04-2.1) 0.03 0.23 (0.17-0.31) <0.001
Major bleeding between index PE 1.82 (1.07-3.09) 0.02 - -

and 3 to 6 months follow-up
Primary safety outcome:
Major bleeding
Prior CAD 1.86 (1.01-3.44) 0.04 - -
Prior stroke 3.37 (1.71-6.65) <0.001 2.88 (1.43-5.79) 0.002
Alcohol use 2.21 (0.88-5.51) 0.08 - -
Major transient or reversible risk 1.80 (1.07-3.3) 0.02 - -
factors
High-risk PE 2.16 (0.86-5.39) 0.09 - -
Extended anticoagulation 1.03 (0.58-1.80) 0.91 1.0 (0.57-1.76) 0.98
Major bleeding or CNRM bleeding 2.55 (1.29-5.03) 0.006 - -

between index PE and 3 to 6
months follow-up
Acute heart failure between index 2.70 (0.84-8.62) 0.09 - -
PE and 3 to 6 months follow-up
CAD, coronary artery disease; SBP, systolic blood pressure; PE, pulmonary embolism; CNRM
Clinically relevant non-major bleeding.
a Defined as a hemoglobin level < 12 g/dL; b Defined as platelet count < 150 x103/microliter; c
Defined as estimated glomerular function calculated with the Modification of Diet in Renal
Disease equation < 60 mL/min.

Table S5. Sub-groups analyses of the unadjusted primary safety outcome rates, major
bleeding, across unprovoked, prior VTE, and cancer-associated PE patients based on patients
bleeding-risk (high and low bleeding-risk).
Extended anticoagulation No anticoagulation p log-rank
n, % (95% CI) n, % (95% CI)
High bleeding-risk
(n=671)*
Unprovoked PE 14 (3.6% [2.2-5.6]) 8 (5.6% [3.8-7.9]) 0.29
(n= 532)
Prior VTE 7 (4.8% [2.1-9.1]) 1 (3.6% [1.4-7.6]) 0.78
(n=174)
Cancer-associated PE 6 (5.2% [2.4-9.7]) 6 (9.8% [5.8-15.3]) 0.22

(n=171)
Low bleeding-risk
(n=671)**
Unprovoked PE 14 (3.9% [2.4-5.9]) 2 (2.1% [1.1-3.7]) 0.20
(n= 532)
Prior VTE 5 (4.0% [1.6-8.1]) 0 (0) 0.56
(n=174)
Cancer-associated PE - - -
(n=171)
PE, pulmonary embolism; VTE, venous thrombo-embolism. *defined by a VTE-BLEED score ≥ 2; **defined by a VTE-
BLEED score < 2. The statistics are shown as mean ± standard deviation (SD) or N (%, 95% CI)
Figure S1. Type of drugs and doses used for anticoagulant therapy in pulmonary embolism patients eligible for extended
treatment (n = 858). The statistics are shown as a frequency (%)

Figure S2. Unadjusted rates of the primary efficacy (i.e. all-cause death or recurrent venous thromboembolism) (A) and safety (i.e.
major bleeding) (B) outcomes in the no-anticoagulant group, in patients treated with vitamin K antagonist or direct anticoagulant
(DOAC), and according to DOAC dosing. The statistics are shown as a frequency (%).
Figure S3. Sub-groups analyses of the unadjusted primary efficacy outcome rates, all-
cause mortality, or recurrent venous thrombo-embolism across unprovoked, prior VTE,
and cancer-associated PE patients based on patients bleeding-risk (high [A] and low [B]
bleeding-risk). High bleeding-risk defined by a VTE-BLEED score ≥ 2; Low bleeding-risk
defined by a VTE-BLEED score < 2.


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Journal of the American Heart Association

Extended Anticoagulation After Pulmonary

Key Words: extended anticoagulation ■ outcomes ■ pulmonary embolism

J Am Heart Assoc. 2022;11:e024425. DOI: 10.1161/JAHA.121.0244251

Our institutional review board approved the study. All

J Am Heart Assoc. 2022;11:e024425. DOI: 10.1161/JAHA.121.0244252

Figure 1. Study flowchart.

J Am Heart Assoc. 2022;11:e024425. DOI: 10.1161/JAHA.121.0244253

Age, y 66.5±17.2 64.4±18.4 67.3±16.7 0.0.1

Intermediate-­low risk 649 (54.1) 458 (53.4) 191 (56.0)

J Am Heart Assoc. 2022;11:e024425. DOI: 10.1161/JAHA.121.0244254

RESULTS patients with PE who received extended anticoagula-

J Am Heart Assoc. 2022;11:e024425. DOI: 10.1161/JAHA.121.0244255

J Am Heart Assoc. 2022;11:e024425. DOI: 10.1161/JAHA.121.0244256

Adjusted rates (%, 95% CI)*

Extended anticoagulation No anticoagulation Hazard ratio (95%

VTE indicates venous thromboembolism.

only an additional 6 or 12 months treatment/placebo

J Am Heart Assoc. 2022;11:e024425. DOI: 10.1161/JAHA.121.0244257

J Am Heart Assoc. 2022;11:e024425. DOI: 10.1161/JAHA.121.0244258

Figure 5. Sensitivity analyses of major bleeding across relevant subgroups.

J Am Heart Assoc. 2022;11:e024425. DOI: 10.1161/JAHA.121.0244259

J Am Heart Assoc. 2022;11:e024425. DOI: 10.1161/JAHA.121.02442510

18. Chopard R, Piazza G, Falvo N, Ecarnot F, Besutti M, Capellier G, Schiele

J Am Heart Assoc. 2022;11:e024425. DOI: 10.1161/JAHA.121.02442511

J Am Heart Assoc. 2022;11:e024425. DOI: 10.1161/JAHA.121.02442512

related to bleeding, or related to non-cancer, non-cardiovascular causes. VTE was considered as

another documented cause and PE could not be ruled out.

or ventilation-perfusion scan; or (2) diagnosis of deep vein thrombosis on compression

critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or

units of whole blood or red cells.24

bleeding compromising hemodynamics; any bleeding leading to hospitalization; subcutaneous

within 24 hours), or led to an intervention (e.g., packing or electrocoagulation); gingival

associated with pain or impairment of activities of daily life. 24

conditions: (1) An appropriate clinical situation suggestive of an MI (e.g., abnormal history,

physical examination, or new electrocardiogram changes); (2) troponin T or I ≥2 × upper limit of

Covariates Missing data (%) Unvariate analysis

Extended anticoagulation group vs No anticoagulation group

p-value for the primary p-value for the primary

efficacy outcome safety outcome

Age > 65 years 0.004 0.26

Age > 70 years 0.001 0.67

Age > 75 years <0.001 0.65

Age > 80 years <0.001 0.26

Female sex 0 0.11 0.57

Weight < 50 kg 0.24 0.34

Weight < 60 kg 0.04 0.21

BMI > 25 kg/m2 0.67 0.87

BMI > 35 kg/m2 0.30 0.43

BMI < 18 kg/m2 0.21 0.32

Current smoker 0 0.39 0.24

Hypertension 0 0.05 0.98

Diabetes mellitus 0 0.28 0.43

Chronic pulmonary disease 0 0.006

Coronary artery disease 0 0.08 0.04

Cancer 0 <0.001 0.25

Prior stroke 0 0.88 <0.001

Prior bleeding 1.2 0.40 0.98

Prior VTE 0 0.14 0.78

J Am Heart Assoc. 2022;11:e024425. DOI: 10.1161/JAHA.121.0244251

J Am Heart Assoc. 2022;11:e024425. DOI: 10.1161/JAHA.121.0244252

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Intermediate-low risk 649 (54.1) 458 (53.4) 191 (56.0)

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J Am Heart Assoc. 2022;11:e024425. DOI: 10.1161/JAHA.121.0244257

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J Am Heart Assoc. 2022;11:e024425. DOI: 10.1161/JAHA.121.0244259

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