The RE-COVER Trial

Dabigatran Versus Warfarin in

the Treatment of Acute Venous
Thromboembolism
Schulman S, Kearon C, Kakkar AK, et al.
N Engl J Med 2009;361:2342-52,
December 10, 2009

Dennis Nguyen
GIM Journal Club December 22, 2009
 Background
 Venous Thromboembolism affects 1-2 out of 1000 adults
annually
 3rd most common cause of vascular death after MI and
stroke
 Each year in the US, approximately 200,000 people
develop venous thrombosis
 Of those cases, 50,000 are complicated by pulmonary
embolism
 Background
 As described in Virchow’s triad, development of
venous thrombosis depends on 3 factors:
– Venous stasis
– Activation of clotting cascade (thrombophilia)
– Endothelial injury
 Background
 Wells Criteria traditionally used in guiding clinical
decision-making in patients presenting with
symptoms concerning for DVT

 Modified Wells criteria now used to simplify risk

stratification and subsequent management
 Background
 Standard of treatment for venous thromboembolism is
rapidly acting parenteral anticoagulation (generally IV
heparin or SQ enoxaparin) for 5-7 days followed by a
minimum of 3-6 months of oral vitamin K antagonist
(warfarin).
 Warfarin is a direct factor II, V, IX, and X inhibitor
 Well proven in its use for treatment of venous
thromboembolism but continually limited by numerous
interactions with foods and other drugs, as well as small
therapeutic window requiring frequent monitoring of
INR.
 Background
 Dabigatran
– Orally available, direct inhibitor of thrombin (free and fibrin-
bound)
– Administered in fixed doses without need for monitoring
– Majority of drug is renally exreted
– Quick onset of action, peak plasma concentration after 1-2 hours
– Half-life 12-17 hours
 RE-MODEL 2007 – similar safety and efficacy to enoxaparin for
prevention of thromboembolism after knee surgery
 RE-LY 2009 – superior safety and similar efficacy (110mg BID) or
similar safety and superior efficacy (150mg) when compared with
warfarin for prevention of stroke in patients with a.fib.
Dabigatran
 Objective
 Comparison between dabigatran (at single fixed
dose) and warfarin for the treatment of acute
venous thromboembolism
 Methods
 Study Design
– Double-blind, double-dummy, prospective,
randomized phase III trial

– Similar to RE-LY trial, Boehringer Ingelheim

funded, designed, conducted this study and
analyzed the data
 Methods
 Study Population
– From April 2006 through November 2008, patients
were recruited from 228 clinical centers in 29
countries

 Inclusion Criteria
– Acute DVT or pulmonary embolism
 Diagnosed by compression US, venography of leg veins and V/Q scan of
lungs, angiography, or spiral CT of pulmonary arteries.

– Age 18 and up
– 6 months of anticoagulation needed as treatment
– Written informed consent

*Note: no weight restrictions

 Methods
 Exclusion Criteria
– Symptoms present > 14 days
– PE with hemodynamic instability or requiring thrombolytics
– Another indication for warfarin therapy
– Recent unstable cardiovascular disease
– High risk of bleeding
– Liver disease with aminotransferase level > 2x upper limit
– Estimated CrCl < 30
– Life expectancy < 6 months
– Contraindication to heparin or to radiographic contrast material
– Pregnancy or risk of becoming pregnant
– Requirement for long-term antiplatelet therapy (baby ASA ok)
 Methods
 Assignment
– Single-dummy phase:
 Patients were randomly assigned to receive warfarin or warfarin
placebo, which were adjust to achieve a true or sham INR of 2 to 3
(achieved with a point-of-care coagulometer that programmed in
conjunction with randomization schedule)
– Double-dummy phase:
 Dabigatran (150mg PO BID) or dabigatran placebo was initiated
and parenteral anticoagulation stopped after 5 days and true/sham
INR in therapeutic range for 2 consecutive days
 Dabigatran and warfarin-like placebo or warfarin and dabigatran-
like placebo were given for 6 months
 Methods
 Monitoring
– Follow-up occurred at 7 days then monthly for 6 months.
Additional follow-up 30 days post-study.
 Primary outcome (efficacy)
– Recurrent symptomatic, objectively confirmed venous
thromboembolism and related deaths
 Verified by same diagnostic testing used for initial diagnosis
 Safety end points
– Bleeding events (major and minor), acute coronary syndromes,
other adverse events leading to discontinuation of study drug,
and abnormal liver-function tests

*all suspected outcome events and deaths were classified by blinded

central adjudication committees
 Methods
 Statistical analyses
– Non-inferiority trial to test 6 months of dabigatran versus
standard warfarin treatment of venous thromboembolism
– Non-inferiority margins established from 4 trials comparing
efficacy of warfarin versus no anticoagulation (i.e. discontinuing
after 4-6 weeks compared to continuing it for 3-6 months)
– In this trial, non-inferiority was established if the hazard ratio
was less than 2.75 and absolute increase in risk was less than
3.6%. P-value < 0.025 was considered significant.
– Cox proportional hazards model used to calculate hazard ratio;
Kaplan-Meier estimator used to calculate differences in risk
 Results
 Study Population
– 1274 patients in dabigatran group and 1265 in warfarin group
– No significant differences in characteristics between study groups
– Both groups received mean of 10 days parenteral anticoagulation
– Mean of 16 INR values drawn over the 6 month study period
– INR in therapeutic range for 60% of the time (compared to 64% in
recent RE-LY trial)
– Study drug stopped prematurely:
 Dabigatran – 204 patients (16%)
 Warfarin – 183 patients (14.5%)
– Observation time for efficacy < 6 months:
 Dabigatran – 101 patients (7.9%)
 Warfarin – 97 patients (7.7%)
– Mean time of exposure to drug was hence 163-164 days
Results
 Results
 Efficacy
– Primary outcome
 Recurrent or fatal venous
thromboembolism
– Dabigatran – 30 patients
(2.4%)
– Warfarin – 27 patients
(2.1%)

 Dabigatran was non-inferior

to warfarin (p < 0.001) with
respect to hazard ratio (1.10,
95% CI, 0.65 to 1.84) and
difference in risk
(0.4%, 95% CI, -0.8 to 1.5)

– Superiority of dabigatran was

tested for and not reached
 Results
 Safety
– No significant difference in major
bleeding
 Dabigatran – 20 patients (1.6%)
 Warfarin – 24 patients (1.9%)

– Significantly less clinically relevant (+

major bleeding) and total bleeding
events in dabigatran group
 Dabigatran – 5.6% and 16.1%
respectively
 Warfarin - 8.8% and 21.9%
Results
 Results
 Other adverse effects
– No significantly different rates of patients who died, had an
acute coronary syndrome, had an elevation of AST or ALT > 3x
upper normal limit of normal were found between the study
groups
– Rate of dyspepsia was significantly higher in dabigatran (2.9%)
than for the warfarin group (0.6%)
Results
 Discussion
 In parallel with recent trials demonstrating the
efficacy of dabigatran, the RE-COVER trial shows
similar efficacy for dabigatran compared to
warfarin for treatment of acute venous
thromboembolism
 Discussion
 Consistent with the RE-LY trial results, dabigatran seems
to avoid the hepatotoxic effects of its sister drug
ximelagatran (which had previously shown noninferiority
compared to warfarin for treatment of VTE with similar
major bleeding rates

 Also consistent with the RE-LY trial is dabigatran’s

significantly higher rates of dyspepsia (also there is an
ongoing nonstatistically significant trend towards GI
hemorrhage)
– Possibly due to drug’s enhanced absorption with higher acidity
(core of tablet contains tartaric acid)
 Discussion

 Unlike the RE-LY trial, the rate of myocardial infarction

was not significantly higher in dabigatran in this study.
However, it is most likely due to the fact that unstable
CV patients or patients with other indications for
warfarin were excluded from the trial
 Discussion
 Other strengths
– Well powered study
– Double-blinded, prospective study
– Backed by solid history of similar phase III trials demonstrating
efficacy
 Discussion
 Other weaknesses
– No specific mention of direct cost of the study drugs
– According to the Canadian Expert Drug Advisory Committee, the
daily cost of dabigatran ($7.85) is substantially greater than
warfarin (approximately $0.40)
– No reliable way to judge adherence to dabigatran therapy other
than pill counting (whereby 80% was considered adherence)
– Extensive exclusion factors and narrow racial distribution limit
widespread applicability of results
 Summary
 Non-inferiority trial comparing dabigatran 150mg PO BID
versus Warfarin adjusted to INR 2-3 for treatment of
acute venous thromboembolism

 Dabigatran proved to be non-inferior while having

similar major bleeding risk and less total episodes of
bleeding

 Dabigatran is associated with more adverse affects,

especially GI-related.
 Clinical practice implications
 There doesn’t appear to be any overwhelming evidence suggesting
the use of dabigatran over warfarin for the outpatient treatment of
VTE. More likely it’ll come down to individual preferences, long-
term cost-analysis studies.

 Dabigatran may be a useful in patients who are less likely to be able

to adhere to a schedule that requires frequent visits to a Coumadin
Clinic

 However, due to its twice daily dosing and GI-related side effects
compliance may be a greater issue with dabigatran than warfarin

 Patients who are particularly bothered by mild bleeding episodes

may benefit from switching to dabigatran
Happy Holidays!
 Resources
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