Fallout from Bleeding Less Severe in Patients on Dabigatran Compared with Warfarin

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Patients with atrial fibrillation (A-fib) or venous thromboembolism (VTE) who experience major bleeding on the direct thrombin inhibitor dabigatran require a shorter intensive care stay and show a trend for lower mortality than do similar patients on warfarin, according to a review of comparative trials published online September 30, 2013, ahead of print in Circulation.

Researchers led by Sam Schulman, MD, of HHS-General Hospital (Ontario, Canada), reviewed bleeding reports from 27,419 patients who were enrolled in 5 phase III trials comparing dabigatran and warfarin at treatment durations of 6 to 36 months.

In all, 1,121 major bleeding events occurred in 1,034 patients. Major bleeds per year were lower in patients taking dabigatran compared with warfarin (RR 0.80; 95% CI 0.69-0.93).

There were fewer intracranial bleeds on dabigatran (52 vs. 90; P < 0.001) as well as intramuscular bleeds (11 vs. 20; P = 0.002), while GI bleeding was more common with the direct thrombin inhibitor than with warfarin (361 vs. 151; P < 0.001).

Bleeding on Dabigatran Associated with Aspirin, NSAIDs

Patients with major bleeding during treatment with dabigatran were older (75.3 years) and had lower creatinine clearance (median 53 mL/min) than those with major bleeding during treatment with warfarin (mean 71.8 years; 62 mL/min). Also, a larger proportion of patients who experienced bleeding on dabigatran had received concomitant treatment with aspirin (30.9% vs. 24.6% on warfarin; P = 0.026) or an NSAID (12.9% vs. 8.4% on warfarin; P = 0.023).

Blood transfusion was used more often in dabigatran-treated patients with major bleeding compared with warfarin-treated patients (59.2% vs. 49.9%; P = 0.002), while fresh frozen plasma was used more often in warfarin-treated patients (30.2% vs. 19.8%; P < 0.001).

Based on the RE-LY database, mean length of stay in the intensive care unit was shorter for dabigatran patients than warfarin patients after bleeding (1.6 nights vs. 2.7 nights; P = 0.01).

Crude mortality in the 5 studies at 7 and 30 days after the onset of the first major bleeding event among dabigatran- and warfarin-treated patients was 5.3% vs. 8.4% (P = 0.045) and 9.1% vs. 13.0% (P = 0.057). Kaplan-Meier analysis showed a trend for a reduction in mortality risk with dabigatran vs. warfarin during 30 days from bleeding (P = 0.052). On multivariable adjustment, dabigatran also showed trends for reduced 30-day mortality compared with warfarin, both in the combined dabigatran 110 mg and 150 mg group (OR 0.66; 95% CI 0.44-1.00; P = 0.051) and in the individual dosage groups (110 mg, OR 0.65; 95% CI 0.38-1.11; 150 mg, OR 0.68; 95% CI 0.42-1.08).

All-cause mortality for bleeding events restricted to the on-treatment period only in the 5 trials was 4.8% in the dabigatran group and 7.7% in the warfarin group (P = 0.062) at 7 days and 8.1% and 12.6%, respectively, at 30 days (P = 0.018). Thirty-day mortality and bleeds on treatment also showed a reduction in the dabigatran group (adjusted OR 0.62; 95% CI 0.40-0.96; P = 0.03).

High-Risk Patients More Likely on Dabigatran

The study authors stress that one of the most important findings of the analysis was that patients with major bleeding on dabigatran were older, had worse renal function, and more often had concomitant treatment with aspirin or an NSAID than those with warfarin.

“This implies that when bleeding occurs with dabigatran, the patient is usually at higher risk compared to patients with major bleeding events on warfarin and raises the possibility that some of these bleeds might be avoidable by using a lower dose of dabigatran, as also recommended in some treatment guidelines,” they note. Furthermore, “avoidance of concomitant medication with aspirin and [NSAID] agents might also reduce the risk and severity of bleeding,” they add.

The main clinical implication, Dr. Schulman and colleagues observe, is that dabigatran offers “an alternative to warfarin with similar or superior efficacy, carrying similar or lower risk for major bleeding events (especially intracranial hemorrhage), that can be managed satisfactorily with simple measures [resulting in] a trend to lower mortality after such bleeding events compared to warfarin. . . . Whether the management of bleeding on dabigatran can be further improved by a specific antidote remains to be evaluated.”

Study Details

Data were pooled from trials including patients with A-fib (RE-LY) or VTE (RE-COVER, RE-COVER II, RE-MEDY, and RE-SONATE).


Majeed A, Hwang H-G, Connolly SJ, et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation. 2013;Epub ahead of print.



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  • The study was funded by a grant from Boehringer Ingelheim.
  • Dr. Schulman reports receiving honoraria from Boehringer Ingelheim, Bayer, and Merck.