Net clinical benefit of dabigatran vs. warfarin in venous thromboembolism: analyses from RE-COVER®, RE-COVER™ II, and RE-MEDY™
J Thromb Thrombolysis
Net clinical benefit of dabigatran vs. warfarin in venous thromboembolism: analyses from RE-COVER®, RE-COVER™ II, and RE-MEDY™
Martin Feuring 0 1 2 3 4 5 6 7
Sam Schulman 0 1 2 3 4 5 6 7
Henry Eriksson 0 1 2 3 4 5 6 7
Ajay J. Kakkar 0 1 2 3 4 5 6 7
Sebastian Schellong 0 1 2 3 4 5 6 7
Stefan Hantel 0 1 2 3 4 5 6 7
Elke Schueler 0 1 2 3 4 5 6 7
Jörg Kreuzer 0 1 2 3 4 5 6 7
Samuel Z. Goldhaber 0 1 2 3 4 5 6 7
0 Department of Medicine, Sahlgrenska University Hospital- Östra , Gothenburg , Sweden
1 Department of Medicine, McMaster University and Thrombosis and Atherosclerosis Research Institute , Hamilton, ON , Canada
2 Martin Feuring
3 Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School , Boston, MA , USA
4 Accovion GmbH , Eschborn , Germany
5 Medical Division 2, Municipal Hospital Dresden- Friedrichstadt , Dresden , Germany
6 Thrombosis Research Institute and University College London , London , UK
7 fees from Boehringer Ingelheim , Merck, Bristol-Myers Squibb, and Medscape
The direct oral anticoagulants, e.g., dabigatran etexilate (DE), are effective and well tolerated treatments for venous thromboembolism (VTE). Net clinical benefit (NCB) is a useful concept in weighing potential benefits against potential harm of comparator drugs. The NCB of DE vs. warfarin in VTE treatment was compared. Posthoc analyses were performed on pooled data from the 6-month RE-COVER® and RE-COVER™ II trials, and data from the RE-MEDY™ trial (up to 36 months), to compare the NCB of DE (150 mg twice daily) and warfarin [target international normalized ratio (INR) 2.0-3.0]. Patients (≥18 years old) had symptomatic proximal deep vein thrombosis and/or pulmonary embolism. NCB was the composite of cardiovascular endpoints (non-fatal events of recurrent VTE, myocardial infarction, stroke or systemic embolism), all-cause death, and bleeding outcomes, all weighted equally. A broad definition of NCB included major bleeding events (MBE) and clinically relevant nonmajor bleeding events as bleeding outcomes, while a narrow definition included just MBE. The pooled dataset totalled 5107 patients from RE-COVER/RE-COVER II and 2856 patients from RE-MEDY. When NCB was narrowly defined, NCB was similar between DE and warfarin. When broadly defined, NCB was superior with DE vs. warfarin [RE-COVER/RE-COVER II, hazard ratio (HR) 0.80; 95% confidence interval (CI), 0.68-0.95 and RE-MEDY, HR 0.73; 95% CI 0.59-0.91]. These findings were unaffected by warfarin time in therapeutic range. The NCB of DE was similar or superior to warfarin, depending on the NCB definition used, regardless of the quality of INR control.
Venous thromboembolism; Warfarin; Dabigatran etexilate; Anticoagulant
Published online: 16 February 2017 © The Author(s) 2017. This article is published with open access at Springerlink.com
Boehringer Ingelheim GmbH & Co. KG,
55216 Ingelheim am Rhein, Germany
Introduction
The direct oral anticoagulants (DOACs) are effective and
usually well tolerated for treating venous thromboembolism
(VTE) [
1–7
]. In pooled analyses from the RE-COVER®
and RE-COVER™ II trials in patients with acute VTE,
dabigatran etexilate (DE) at a fixed dose of 150 mg twice
daily was as effective as warfarin [dose adjusted to achieve
international normalized ratio (INR) between 2 and 3] for
the treatment of acute VTE. For prevention of recurrent
VTE, DE was associated with a significantly lower risk of
clinically relevant, major or non-major, bleeding and of any
bleeding events [
6
]. In the RE-MEDY™ trial of extended
anticoagulation, DE was non-inferior to warfarin for the
prevention of recurrent VTE, with a significantly lower risk
of major or clinically relevant non-major bleeding [
8
].
DVT deep vein thrombosis, PE pulmonary embolism, SD standard deviation
aREMEDY included 567 patients in the dabigatran group, and 606 patients in the warfarin group, that rolled over from RE-COVER and
RECOVER II
bResults of objective testing for initial symptomatic DVT/PE performed locally. If a patient had more than one event, the last event prior to
randomization was classified as the qualifying event
cThese were diagnosed with DVT or PE initially but refuted on subsequent local examination
The benefit–risk balance of DE compared with
warfarin in VTE treatment and prevention of recurrence
can be further understood by assessing the net clinical
benefit (NCB) [
9
]. NCB weighs potential benefits (e.g.,
reduced risk of VTE or stroke) vs. potential harm (e.g.,
risk of bleeding). Thus, NCB quantifies both clinical
efficacy and safety outcomes. NCB is particularly useful in
the assessment of multiple endpoints affecting mortality
and morbidity [e.g., VTE, myocardial infarction (MI),
stroke, major bleeding events (MBEs), clinically
relevant non-major bleeding events (CRNMBEs)] and for
facilitating the comparison of the benefit–risk balance of
anticoagulants.
The effectiveness and safety of warfarin depends on the
time in therapeutic range (TTR) with an INR between 2.0
and 3.0 [
10
]. Analysis of the NCB of dabigatran compared
with that of warfarin at high TTRs will determine whether
the comparative NCB is affected when INR is tightly
controlled.
Post-hoc analyses were performed on pooled data from
RE-COVER and RE-COVER II, as well as data from
REMEDY, to compare the NCB of DE with that of warfarin
overall, and in relation to mean TTR for warfarin at each
center (cTTR). Broad and narrow definitions of NCB were
used: MBEs plus CRNMBEs as bleeding outcomes and
MBEs as the only bleeding outcome, respectively.
Methods
Study population and trial design
The study designs, populations and outcomes of the
RECOVER, RE-COVER II, and RE-MEDY trials have been
published [
5, 6, 8
]. In all three trials, patients aged ≥18
years with objectively confirmed symptomatic proximal
deep vein thrombosis or pulmonary embolism were
eligible for inclusion.
In RE-COVER and RE-COVER II, patients were
randomized to warfarin or warfarin–placebo plus parenteral
anticoagulation for ≥5 days until the INR was ≥2 on two
consecutive measurements. Parenteral therapy was then
discontinued and patients continued warfarin (therapeutic
INR range 2.0–3.0) or received DE 150 mg twice daily
for 6 months (double-dummy treatment period).
In RE-MEDY, patients who had been treated for 3–12
months with an approved anticoagulant (or were
participating in RE-COVER or RE-COVER II) were
randomized to DE 150 mg twice daily or warfarin (INR range
2.0–3.0) for 6–36 months.
a
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n
e
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c
n
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2
0
b
14
12
) 10
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Broad NCB: composite
cardiovascular endpoint*,
all-cause death and
MBEs/CRNMBEs
HR 0.73 (95% CI 0.59, 0.91)
P-value for superiority: 0.0058
For this post-hoc analysis, NCB was evaluated as the
composite of cardiovascular endpoints (the components being
non-fatal events of recurrent VTE, MI, stroke or systemic
embolism), all-cause death, and bleeding outcomes, which
were all weighted equally. The bleeding outcomes either
included MBEs alone (narrow definition of NCB) or MBEs
plus CRNMBEs (broad definition of NCB). MBEs and
CRNMBEs were defined according to the International
Society on Thrombosis and Haemostasis criteria (MBEs)
[
11
], and as previously defined for the phase 3 dabigatran
studies (CRNMBEs) [
6
]. All events were evaluated from
the beginning of the parenteral phase of anticoagulation
treatment until the end of the post-treatment period
(RECOVER and RE-COVER II) or from randomization to the
end of the planned treatment period (RE-MEDY).
HR 0.80 (95% CI 0.68, 0.95) HR 1.02 (95% CI 0.81, 1.27)
P-value for superiority: 0.0088 P-value for superiority: 0.8926
Dabigatran
308/2554 Warfarin
The pooled dataset from RE-COVER and RE-COVER
II included 2553 patients randomized to DE and 2554
patients randomized to warfarin [
6
]. The RE-MEDY
dataset consisted of 1430 and 1426 patients randomized to DE
and warfarin, respectively [
8
]. Patient characteristics were
generally similar between DE and warfarin groups in the
pooled RE-COVER/RE-COVER II dataset and in
REMEDY (Table 1).
Net clinical benefit
When NCB was defined to include MBEs as the only
bleeding outcome (narrow definition), NCB was similar
between DE and warfarin (RE-COVER/RE-COVER II, HR
1.02; 95% CI 0.81–1.27 and RE-MEDY, HR 1.05; 95% CI
0.75–1.46) (Fig. 1a, b).
When MBEs plus CRNMBEs were included as
bleeding outcomes (broad definition), NCB was superior with
DE compared with warfarin [RE-COVER/RE-COVER II,
hazard ratio (HR) 0.80; 95% CI 0.68–0.95 and RE-MEDY,
HR 0.73; 95% CI 0.59–0.91] (Fig. 1a, b).
In subgroups divided according to cTTR, the NCB (both
definitions) with DE was similar to warfarin, regardless of
warfarin cTTR in both the RE-COVER/RE-COVER II and
the RE-MEDY analyses, with no trends observed, whether
CRNMBEs were included as bleeding outcomes or not.
This result was observed when centers were grouped into
quintiles (Tables 2, 3) and when they were grouped into
tertiles (data not shown), according to their mean TTR (INR
2–3) and overall number of patients. As only centers with
≥1 patient with available TTR are included, these cTTR
data are limited to 5055 patients vs. the 5107 patients in the
study overall for the RE-COVER/RE-COVER II analysis,
and 2813 patients vs. the 2856 patients in the study overall
for the RE-MEDY analysis.
Discussion
Phase 3 trials have shown DE to be as effective as
warfarin for the treatment of acute VTE and for the extended
treatment of VTE, with a lower risk of bleeding [5, 6,
HR obtained from Cox Model with treatment, center TTR and treatment by center TTR interaction
stratified by study
CI confidence interval, CRNMBE clinically relevant non-major bleeding event, HR hazard ratio, INR
international normalized ratio, TTR time in therapeutic range
*P value for treatment by center TTR interaction: 0.0815
**P value for treatment by center TTR interaction: 0.3896
aCenters grouped into five categories according to their mean TTR (INR 2–3) and overall number of
patients (quintiles). Only centers with at least one patient with available TTR (INR 2–3) were included
8]. Whereas clinical trials tend to treat benefits and risks
as separate entities, evaluation of the NCB can provide a
clearer representation of the benefit–risk balance of a
treatment overall by analyzing efficacy and safety as a collective
outcome.
The inclusion of CRNMBEs in the evaluation of NCB
provides a comprehensive reflection of anticoagulant safety
outcomes encountered in real-world clinical practice [
9
].
This is because CRNMBEs, which include bleeding
leading to hospitalization or requiring surgical treatment, could
adversely affect prognosis and can also result in reduced
patient adherence to, and persistence with, necessary
anticoagulant therapy [
12, 13
].
Although NCBs of DE and warfarin were similar when
the NCB included only MBEs as the bleeding outcome,
the NCB of DE was superior to that of warfarin when
CRNMBEs were also included in the calculation.
It was surprising that the analysis of NCB stratified by
cTTR showed that quality of warfarin control did not
influence the relative benefits of dabigatran and warfarin for the
treatment and secondary prevention of VTE. This was true
when either the broad or the narrow NCB definitions were
used.
Study strengths and limitations
RE-COVER, RE-COVER II and RE-MEDY were
randomized, double-blind studies with central adjudication
of outcome events. RE-MEDY is the only study so far of
a DOAC with warfarin as the comparator in the extended
treatment of VTE. The NCB definitions included
clinically relevant cardiovascular endpoints (including stroke
and systemic embolism) and all-cause mortality, as well as
bleeding.
One limitation is that the endpoints included in the NCB
definition do not have an equal impact on morbidity and
mortality, but were weighted equally in this analysis.
Furthermore, in analyses on the association of clinical effects
of DE with quality of warfarin control (cTTR), limited data
were presented, as these were dependent on the availability
Including CRNMBE* Dabigatran Excluding CRNMBE** Warfarin
aCenters grouped into five categories according to their mean TTR (INR 2–3) and overall number of
patients (quintiles). Only centers with at least one patient with available TTR (INR 2–3) were included
of patient INR measurements. Finally, this was a post-hoc
analysis.
These analyses of safety and efficacy data support
previous assessments of the benefit–risk balance of DE vs.
warfarin [
5, 6, 8
].
Conclusion
The NCB of DE is superior to that of warfarin when the
NCB definition includes MBEs plus CRNMBEs (typical of
the safety outcomes arising in real-world clinical practice).
This applies to both the initial treatment and the extended
treatment of VTE. The NCB of DE is similar to warfarin
when NCB includes only MBEs as the bleeding outcome.
These results indicate a positive impact of DE, in
comparison with warfarin, on the clinical outcome of patients
treated for acute VTE or for secondary VTE prevention in
clinical practice settings, regardless of the quality of INR
control.
Acknowledgements The RE-COVER and RE-MEDY studies
were funded by Boehringer Ingelheim. The authors meet criteria for
authorship as recommended by the International Committee of
Medical Journal Editors, were fully responsible for all content and editorial
decisions, and were involved at all stages of manuscript development.
The authors received no compensation related to the development of
the manuscript. Medical writing support was provided by Keith Day,
PhD. and was funded by Boehringer Ingelheim for these services.
Compliance with ethical standards
Conflict of interest Martin Feuring, Stefan Hantel and Jörg Kreutzer
are employees of Boehringer Ingelheim. Sam Schulman reports
receiving consulting fees from Boehringer Ingelheim and grant support from
Bayer Healthcare. Henry Eriksson reports receiving consultant fees
and lecture fees from Boehringer Ingelheim, Pfizer, Bayer Healthcare,
Leo Pharma, and Bristol-Meyers Squibb. Ajay Kakkar reports
receiving consultancy fees/honoraria from Bayer AG, Boehringer Ingelheim,
Daiichi Sankyo, and Hanssen Pharma. Sebastian Schellong reports
receiving speaker fees and consulting honoraria from Bayer Healthcare,
Boehringer Ingelheim, GlaxoSmithKline, and consulting fees from
Sanofi Aventis. Elke Schueler is a consultant for Boehringer
Ingelheim. Samuel Goldhaber reports receiving clinical research support
from Bristol-Myers Squibb, and Boehringer Ingelheim, and consulting
Ethical approval All procedures performed in studies involving
human participants were in accordance with the ethical standards of
the institutional and/or national research committee and with the 1964
Helsinki declaration and its later amendments or comparable ethical
standards.
Informed consent Informed consent was obtained from all
individual participants included in the study.
Research involving human and animal rights This article does not
contain any studies with animals performed by any of the authors.
Open Access This article is distributed under the terms of the
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