Dabigatran - Goodbye to coumadin?

Motivation: After even a few months in the wards, I think that all of us learn that coumadin/warfarin inspires mixed emotions.  With too little drug, you don't get the proven benefits.  And, with too much, there is chance of bleeding - even to death.  This summer, while in the neuro service, I saw a man on coumadin die from intraventricular hemorrhage.  The problem with coumadin is that its metabolism is affected by so many environmental variables that steady anti-coagulation is hard to maintain.  Recently, the FDA approved dabigatran, which is a direct inhibitor of thrombin, for anti-coagulation in atrial fibrillation.  It is expected that in the future, dabigatran can be substituted for most cases of anticoagulation.   But, what is the data to justify replacing good old coumadin?

Paper(s): Two primary studies for dabigatran: (1) Trial RE-COVER: Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. Schulman, S. et. al. NEJM, 2009 (361): 2342-2352.  (2) Trial RE-LY: Dabigatran versus Warfarin in Patients with Atrial Fibrillation. Stuart, J. et. al. NEJM, 2009 (361): 1139-1151.

Links: RE-COVER: http://www.nejm.org/doi/full/10.1056/NEJMoa0906598#t=article; RE-LY: http://www.nejm.org/doi/full/10.1056/NEJMoa0905561#t=article

Methods: For the RE-COVER study, 2,539 patients were recruited from 228 clinical centers in 29 countries and, in a blinded way, randomized to a fixed dose of dabigatran (150 mg bid) or warfarin adjusted to INR of 2.0-3.0.  Patients were essentially adults with symptomatic deep vein thrombosis who did not have pulmonary embolism with hemodynamic instability.  The primary end-point was symptomatic venous thromboembolism (VTE) or death from VTE.  For the RE-LY study, 18,113 patients were recruited from 951 clinical centers in 44 countries and randomized to a fixed dose of dabigatran (110 mg bid or 150 mg bid) or warfarin adjusted to INR of 2.0-3.0.  In the study, patients essentially had to have atrial fibrillation plus one more condition: previous stroke/TIA, heart failure, or older age (65-74) with diabetes, HTN, or CAD.  The primary end-point was stroke or systemic embolism.

Results:
RE-COVER:  In the primary end-point of symptomatic or deadly VTE, 2.4% in the dabigatran group had such events while 2.1% in the warfarin group (difference not significant).  There was no difference in overall mortality.  In the warfarin group, INR was therapeutic for only 66% of the time. In terms of safety, there were equivalent rates for any bleeding events or for major bleeds (1.6% in dabigatran vs. 1.9% in coumadin).  Patients in dabigatran were marginally more likely to experience any adverse event (9.0% vs. 6.8%, p=0.05).  Follow-up was for six months and essentially complete (>98%).

RE-LY: For the primary end-point of stroke or systemic embolism, the 150 mg dose of dabigatran was superior to coumadin (rate of 1.11% vs. 1.69% per year, p<0.001).  The 110 mg dose of dabigatran was equivalent to coumadin (rate of stroke or embolism: 1.53% vs. 1.69%, p=0.34).  Rates of hemorrhagic stroke were lower in the 150 mg group compared to warfarin (0.10% vs. 0.38%, p<0.001).  Similar trend was found in the 110 mg group.  Overall rates of mortality were not significantly different though there was a slight trend of lower mortality in the 150 mg group (3.64% vs. 4.13%, p=0.051).

Follow-up was essentially complete in all patients for two years.  In the warfarin group, INR was therapeutic only 64% of the time.  In terms of safety, rate of MI was higher in the 150 mg group compared to warfarin (0.74% vs. 0.53%, p = 0.048).  Same trend held for 110 mg group.  Overall, life-threatening bleeds were lower in both dabigatran group compared to warfarin, but rates of major GI bleeds were higher in the 150 mg dabigatran group compared to warfarin (1.51% vs. 1.02%, p<0.001).  In the 110 mg group, rates of GI bleeding were comparable.

Conclusion: Overall, both studies were well done with good follow-up and clinically relevant end-points chosen.  The RE-COVER trial satisfactorily showed, I think, that dabigatran was equivalent to warfarin in terms of preventing complications of thromboembolism.  Another interesting result from this trial was that even though warfarin was not therapeutic 1/3 of the time in the trial, the missed target did not seem to make any difference for thromboembolic events or bleeding events when compared with dabigatran, which presumably has pretty constant anti-coagulation all of the time.  The RE-LY also provided many interesting results.  On one hand, 150 mg dose of dabigatran proved to be superior to coumadin (and 110 mg dose) for preventing embolic events from atrial-fibrillation.  On the other hand, the side-effect of dabigatran is a mixed bag.  While it has lower rates of potentially deadly intraventricular hemorrhage and life-threatening bleeds, dabigatran had higher rates of MI and GI bleeds - not altogether benign either.  There is no good explanation for why dabigatran has higher rates of MI.  Finally, dabigatran is estimated to cost about five times more than coumadin.  What this does for our health care spending with 30 million prescriptions for warfarin each year is an open issue.  In conclusion, I think dabigatran is a definite first choice for patients with atrial-fibrillation or DVT with poor follow-up in INR clinics and good first-choice alternative in other patients with atrial fibrillation, who can afford the drug and understand the varying side-effect profile.