The RECOVER Trial Dabigatran Versus Warfarin in the Treatment of Acute Venous Thromboembolism

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The RE-COVER TrialDabigatran Versus Warfarin in
the Treatment of Acute Venous Thromboembolism

• Schulman S, Kearon C, Kakkar AK, et al.
  N Engl J Med 20093612342-52,
• December 10, 2009
• Dennis Nguyen
• GIM Journal Club December 22, 2009

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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

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Background

• As described in Virchows triad, development of
  venous thrombosis depends on 3 factors
• Venous stasis
• Activation of clotting cascade (thrombophilia)
• Endothelial injury

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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

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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.

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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.

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Dabigatran
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Objective

• Comparison between dabigatran (at single fixed
  dose) and warfarin for the treatment of acute
  venous thromboembolism

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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

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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

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Methods

• Exclusion Criteria
• Symptoms present gt 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 gt 2x
  upper limit
• Estimated CrCl lt 30
• Life expectancy lt 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)

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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

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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

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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 lt
  0.025 was considered significant.
• Cox proportional hazards model used to calculate
  hazard ratio Kaplan-Meier estimator used to
  calculate differences in risk

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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 lt 6 months
• Dabigatran 101 patients (7.9)
• Warfarin 97 patients (7.7)
• Mean time of exposure to drug was hence 163-164
  days

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Results
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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 lt
  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

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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

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Results
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Results

• Other adverse effects
• No significantly different rates of patients who
  died, had an acute coronary syndrome, had an
  elevation of AST or ALT gt 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)

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Results

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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

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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
  dabigatrans significantly higher rates of
  dyspepsia (also there is an ongoing
  nonstatistically significant trend towards GI
  hemorrhage)
• Possibly due to drugs enhanced absorption with
  higher acidity (core of tablet contains tartaric
  acid)

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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

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Discussion

• Other strengths
• Well powered study
• Double-blinded, prospective study
• Backed by solid history of similar phase III
  trials demonstrating efficacy

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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

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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.

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Clinical practice implications

• There doesnt appear to be any overwhelming
  evidence suggesting the use of dabigatran over
  warfarin for the outpatient treatment of VTE.
  More likely itll 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

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Happy Holidays!
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Resources

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• www.cadth.ca/media/cdr/complete/cdr_complete_Prada
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