Article
Reference
Oral rivaroxaban for the treatment of symptomatic pulmonary
embolism
BÜLLER, Harry R, et al.
Abstract
A fixed-dose regimen of rivaroxaban, an oral factor Xa inhibitor, has been shown to be as
effective as standard anticoagulant therapy for the treatment of deep-vein thrombosis, without
the need for laboratory monitoring. This approach may also simplify the treatment of
pulmonary embolism.
BÜLLER, Harry R, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary
embolism. The New England journal of medicine, 2012, vol. 366, no. 14, p. 1287-97
DOI : 10.1056/NEJMoa1113572
PMID : 22449293
Available at:
http://archive-ouverte.unige.ch/unige:26316
Disclaimer: layout of this document may differ from the published version.
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original article
Oral Rivaroxaban for the Treatment
of Symptomatic Pulmonary Embolism
The EINSTEIN–PE Investigators*
The members of the writing committee
(Harry R. Büller, M.D., Martin H. Prins,
M.D., Anthonie W.A. Lensing, M.D., Hervé
Decousus, M.D., Barry F. Jacobson, M.D.,
Erich Minar, M.D., Jaromir Chlumsky, M.D.,
Peter Verhamme, M.D., Phil Wells, M.D.,
Giancarlo Agnelli, M.D., Alexander Cohen,
M.D., Scott D. Berkowitz, M.D., Henri
Bounameaux, M.D., Bruce L. Davidson,
M.D., Frank Misselwitz, M.D., Alex S. Gal-
lus, M.D., Gary E. Raskob, Ph.D., Sebas-
tian Schellong, M.D., and Annelise Segers,
M.D.) take responsibility for the content
and integrity of this article. Address re-
print requests to Dr. Büller at the Depart-
ment of Vascular Medicine, Academic
Medical Center, F4-275, Meibergdreef 9,
1105 AZ Amsterdam, the Netherlands, or
at h.r.buller@amc.uva.nl.
The affiliations of the writing committee
members are listed in the Appendix.
* The investigators participating in the
EINSTEIN–Pulmonary Embolism (PE)
Study and the study committees are
listed in the Supplementary Appendix,
available at NEJM.org.
This article (10.1056/NEJMoa1113572) was
published on March 26, 2012, at NEJM.org.
N Engl J Med 2012;366:1287-97.
Copyright © 2012 Massachusetts Medical Society.
Abstr act
Background
A fixed-dose regimen of rivaroxaban, an oral factor Xa inhibitor, has been shown to
be as effective as standard anticoagulant therapy for the treatment of deep-vein throm-
bosis, without the need for laboratory monitoring. This approach may also simplify
the treatment of pulmonary embolism.
Methods
In a randomized, open-label, event-driven, noninferiority trial involving 4832 patients
who had acute symptomatic pulmonary embolism with or without deep-vein throm-
bosis, we compared rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg
once daily) with standard therapy with enoxaparin followed by an adjusted-dose vita-
min K antagonist for 3, 6, or 12 months. The primary efficacy outcome was symp-
tomatic recurrent venous thromboembolism. The principal safety outcome was major
or clinically relevant nonmajor bleeding.
Results
Rivaroxaban was noninferior to standard therapy (noninferiority margin, 2.0;
P = 0.003) for the primary efficacy outcome, with 50 events in the rivaroxaban group
(2.1%) versus 44 events in the standard-therapy group (1.8%) (hazard ratio, 1.12;
95% confidence interval [CI], 0.75 to 1.68). The principal safety outcome occurred
in 10.3% of patients in the rivaroxaban group and 11.4% of those in the standard-
therapy group (hazard ratio, 0.90; 95% CI, 0.76 to 1.07; P = 0.23). Major bleeding was
observed in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the
standard-therapy group (hazard ratio, 0.49; 95% CI, 0.31 to 0.79; P = 0.003). Rates of
other adverse events were similar in the two groups.
Conclusions
A fixed-dose regimen of rivaroxaban alone was noninferior to standard therapy
for the initial and long-term treatment of pulmonary embolism and had a poten-
tially improved benefit–risk profile. (Funded by Bayer HealthCare and Janssen Phar-
maceuticals; EINSTEIN-PE ClinicalTrials.gov number, NCT00439777.)
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P
ulmonary embolism is a common dis-
ease, with an estimated annual incidence of
70 cases per 100,000 population.
1,2
The con-
dition usually leads to hospitalization and may
recur; it can be fatal.
3
For half a century, the standard therapy for
most patients with pulmonary embolism has been
the administration of heparin, overlapped and fol-
lowed by a vitamin K antagonist.
4,5
This regimen
is effective but complex.
5-9
Recently developed oral
anticoagulants that are directed against factor Xa
or thrombin overcome some limitations of stan-
dard therapy, including the need for injection and
for regular dose adjustments on the basis of labo-
ratory monitoring.
5,10,11
Current data suggest that rivaroxaban, an oral
direct inhibitor of factor Xa, is effective and safe
for the prevention of venous thromboembolism
after major orthopedic surgery, for the prevention
of stroke in patients with atrial fibrillation, and
in the treatment of acute coronary syndromes.
12-14
The EINSTEIN program evaluated the concept of
using rivaroxaban alone for anticoagulant thera-
py for acute deep-vein thrombosis and pulmonary
embolism, replacing both heparin and vitamin K
antagonists.
15,16
This single-drug approach, start-
ing with an increased dose for 3 weeks, appeared
to be successful in treating deep-vein thrombo-
sis. Here we report the findings for this regimen
in patients with pulmonary embolism.
Methods
Study Design and Organization
The EINSTEIN–PE study was a randomized,
open-label trial of the efficacy and safety of riva-
roxaban as compared with standard therapy con-
sisting of enoxaparin and a vitamin K antagonist
in patients who had acute symptomatic pulmo-
nary embolism with or without deep-vein throm-
bosis. The trial was sponsored by Bayer Health-
Care and Janssen Pharmaceuticals.
The steering committee had final responsibil-
ity for the study design, clinical protocol, study
oversight, data verification, and analyses. The pro-
tocol, which is available with the full text of this
article at NEJM.org, was approved by the institu-
tional review board at each center, and written
informed consent was obtained from all patients.
The trial sponsor collected and maintained all the
data. A central committee whose members were
unaware of the study-group assignments adjudi-
cated the results of all baseline lung-imaging tests
and all suspected outcome events. An independent
data and safety monitoring board periodically re-
viewed the study outcomes. The writing commit-
tee wrote the manuscript, made the decision to
submit the manuscript for publication, and vouch-
es for the accuracy and completeness of the data
as well as the fidelity of this report to the study
protocol.
Patients
Patients were eligible if they were of legal age and
had an acute, symptomatic pulmonary embolism
with objective confirmation, with or without symp-
tomatic deep-vein thrombosis. Patients were in-
eligible if they had received a therapeutic dose of
low-molecular-weight heparin, fondaparinux, or
unfractionated heparin for more than 48 hours
or if they had received more than a single dose of
a vitamin K antagonist before randomization; if
thrombectomy had been performed, a vena cava
filter placed, or a fibrinolytic agent administered
for treatment of the current episode; or if they
had any contraindication listed in the local label-
ing of enoxaparin, warfarin, or acenocoumarol.
Other criteria for ineligibility were another indi-
cation for a vitamin K antagonist; a creatinine
clearance below 30 ml per minute; clinically sig-
nificant liver disease (e.g., acute hepatitis, chronic
active hepatitis, or cirrhosis) or an alanine amino-
transferase level that was more than three times
the upper limit of the normal range; bacterial
endocarditis; active bleeding or a high risk of bleed-
ing contraindicating anticoagulant treatment;
a systolic blood pressure of more than 180 mm Hg
or a diastolic blood pressure of more than 110
mm Hg; childbearing potential without proper
contraceptive measures, pregnancy, or breast-feed-
ing; concomitant use of a strong inhibitor of cy-
tochrome P-450 3A4
(
CYP3A4) (e.g., a protease
inhibitor for human immunodeficiency virus in-
fection or systemic ketoconazole) or a CYP3A4
inducer (e.g., rifampin, carbamazepine, or pheny-
toin); participation in another experimental phar-
macotherapeutic program within 30 days; or a
life expectancy of less than 3 months.
Randomization and Treatment Regimens
Randomization was performed with the use of a
computerized voice-response system and was strat-
ified according to country and the intended treat-
ment duration (3, 6, or 12 months). The intended
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Oral Rivaroxaban for Symptomatic Pulmonary Embolism
n engl j med 366;14 nejm.org april 5, 2012
1289
duration of treatment was determined by the treat-
ing physician before randomization.
Patients who were assigned to the rivaroxaban
group were given 15 mg twice daily for the first
3 weeks, followed by 20 mg once daily. Patients
who were assigned to the standard-therapy group
received enoxaparin at a dose of 1.0 mg per kilo-
gram of body weight twice daily and either war-
farin or acenocoumarol, started within 48 hours
after randomization. Enoxaparin was discontinued
when the international normalized ratio (INR)
was 2.0 or more for 2 consecutive days and the
patient had received at least 5 days of enoxaparin
treatment. The dose of the vitamin K antagonist
was adjusted to maintain an INR of 2.0 to 3.0. The
INR was determined at least once a month.
The use of nonsteroidal antiinflammatory
drugs and antiplatelet agents was discouraged.
Aspirin administered at a dose of no more than
100 mg per day, clopidogrel at a dose of 75 mg per
day, or both were allowed.
Surveillance and Follow-up
We followed the patients for the intended treatment
period and assessed them at fixed intervals that
were identical in the two study groups, using a
checklist to elicit information on symptoms and
signs of recurrent venous thromboembolism,
bleeding, and adverse events. Patients were in-
structed to report to the study center immediately
if any of these symptoms or signs occurred. In
the case of suspected venous thromboembolism,
the protocol required objective testing.
Outcome Assessment
The primary efficacy outcome was symptomatic
recurrent venous thromboembolism, which was
defined as a composite of fatal or nonfatal pulmo-
nary embolism or deep-vein thrombosis on the
basis of criteria that have been described previ-
ously.
9
Death was classified as due to pulmonary
embolism, bleeding, or other established diagno-
ses. Pulmonary embolism was considered the cause
of death if there was objective documentation of
the condition or if death could not be attributed
to a documented cause and pulmonary embolism
could not be confidently ruled out.
The principal safety outcome was clinically rel-
evant bleeding, which was defined as a composite
of major or clinically relevant nonmajor bleeding,
as described previously.
9
Bleeding was defined as
major if it was clinically overt and associated with
a decrease in the hemoglobin level of 2.0 g per
deciliter or more, if bleeding led to the transfu-
sion of 2 or more units of red cells, or if bleed-
ing was intracranial or retroperitoneal, occurred
in another critical site, or contributed to death.
Clinically relevant nonmajor bleeding was defined
4833 Patients underwent randomization
2420 Were assigned to receive
rivaroxaban
2413 Were assigned to receive
standard therapy
1 Was excluded because of
invalid informed consent
2419 Were included in the intention-to-
treat analysis
2413 Were included in the intention-to-
treat analysis
7 Did not receive rivaroxaban
8 Did not receive standard
therapy
2412 Were included in safety analysis 2405 Were included in safety analysis
Figure 1. Enrollment and Outcomes.
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Table 1. Demographic and Clinical Characteristics of the Patients.*
Characteristic
Rivaroxaban
(N = 2419)
Standard Therapy
(N = 2413)
Mean age — yr 57.9±7.3 57.5±7.2
Male sex — no. (%) 1309 (54.1) 1247 (51.7)
Weight — no. (%)
≤50 kg 38 (1.6) 43 (1.8)
>50 to 100 kg 2034 (84.1) 2010 (83.3)
>100 kg 345 (14.3) 359 (14.9)
Missing data 2 (<0.1) 1 (<0.1)
Creatinine clearance — no. (%)
<30 ml/min 4 (0.2) 2 (<0.1)
30 to <50 ml/min 207 (8.6) 191 (7.9)
50 to <80 ml/min 637 (26.3) 593 (24.6)
≥80 ml/min 1555 (64.3) 1617 (67.0)
Missing data 16 (0.7) 10 (0.4)
Diagnostic method — no. (%)
Spiral computed tomography 2114 (87.4) 2076 (86.0)
Ventilation–perfusion lung scanning 284 (11.7) 326 (13.5)
Pulmonary angiography 20 (0.8) 10 (0.4)
Missing data 1 (<0.1) 1 (<0.1)
Anatomical extent of pulmonary embolism — no. (%)
Limited: ≤25% of vasculature of a single lobe 309 (12.8) 299 (12.4)
Intermediate 1392 (57.5) 1424 (59.0)
Extensive: multiple lobes and >25% of entire pulmonary vasculature 597 (24.7) 576 (23.9)
Not assessable 121 (5.0) 114 (4.7)
Concurrent symptomatic deep-vein thrombosis — no. (%) 606 (25.1) 590 (24.5)
Hospitalized — no. (%) 2156 (89.1) 2160 (89.5)
Admitted to intensive care unit — no. (%) 311 (12.9) 289 (12.0)
Time from onset of symptoms to randomization — days
Median 4.0 4.0
Interquartile range 2.0–8.0 2.0–9.0
Cause of pulmonary embolism — no. (%)†
Unprovoked 1566 (64.7) 1551 (64.3)
Recent surgery or trauma 415 (17.2) 398 (16.5)
Immobilization 384 (15.9) 380 (15.7)
Estrogen therapy 207 (8.6) 223 (9.2)
Active cancer 114 (4.7) 109 (4.5)
Known thrombophilic condition — no. (%) 138 (5.7) 121 (5.0)
Previous venous thromboembolism — no. (%) 455 (18.8) 489 (20.3)
* Plus–minus values are means ±SD. There were no significant differences between the two study groups. Percentages
may not total 100 because of rounding.
† Patients could have multiple causes of pulmonary embolism.
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