Expert Review:

Management and Outcomes of Major Bleeding during Treatment with Dabigatran or Warfarin

Background
Anticoagulants are important in preventing systemic embolization in patients with atrial fibrillation and preventing pulmonary embolism in patients with venous thromboembolism. However, the risk and management of bleeding complications are a matter of concern. When patients present with major bleeding due to warfarin use, rapid reversal of anticoagulation is desirable, particularly if the bleeding is life threatening. Several products are available to assist, with treatment, often combining vitamin K with one of prothrombin complex concentrate, fresh frozen plasma (FFP), or recombinant factor VIIa. Vitamin K is given to sustain the effects of the other products because of the relatively short half-lives of the latter.

The new oral anticoagulant dabigatran has predictable pharmacokinetic and pharmacodynamic profiles and is an alternative to warfarin. Major and life­threatening bleeding (eg, intracerebral hemorrhage) requires aggressive treatment in the intensive care unit, withdrawal of the anticoagulant, mechanical compression of the bleeding site if accessible, fluid replacement and blood transfusion as appropriate, and interventional procedures. The half­life of dabigatran after multiple doses is approximately 14 to 17 hours and is not dose­dependent5. It is recommended that patients with severe hemorrhage resulting from dabigatran should receive supportive therapy, including transfusion of FFP, transfusion of packed red blood cells, or surgical intervention if appropriate6. However, transfusion of FFP is debatable because there is no evidence to support its use in this situation. While FFP may be useful in cases of coagulation factor depletion, it does not effectively reverse inhibition of coagulation factors7.

Knowledge Gap
It has previously been reported that the risk of clinically relevant bleeding is lower with dabigatran than with warfarin8,9. However, evidence concerning the efficacy of the recommended management approaches and outcomes in bleeding patients is limited.

Aim of the Study
The objective of this study was to describe the management of major bleeding and outcomes after bleeding in large phase III trials evaluating the efficacy and safety of long-term (at least 6 months) dabigatran compared with warfarin.

Methods
This is a post-hoc analysis of phase III trials comparing the management and outcomes of major bleeding events in patients taking dabigatran with major bleeding events in patients taking warfarin. It was based on pooled patient-level data from the AF trial RE-LY and the VTE-prevention trials RECOVER, RECOVER II, RE-MEDY and RESONATE, which encompassed 1121 major bleeds. The trials had durations of six to 36 months and included 27,419 patients. For the meta-analysis’ purposes, major bleeds included only those developing within three days of the last dose of oral anticoagulant

Results
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).
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).
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 non-steroidal anti-inflammatory drugs (12.9% vs. 8.4% on warfarin; p = 0.023).
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 gastrointestinal bleeding was more common with the direct thrombin inhibitor than with warfarin (361 vs. 151; p < 0.001).
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).

Conclusion
The overall resources required to manage bleeding were not greater with dabigatran and the prognosis after a major bleeding was not worse than after a warfarin-associated bleed. More frequent transfusion with red cells was counterbalanced by shorter stay by approximately one day in the intensive care unit and less frequent transfusion of plasma.

Clinical Impact:
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 (drug discontinuation, transfusion of red cell concentrates) with a trend to lower mortality after such bleeding events compared to warfarin. The overall safety profile of dabigatran is favorable. Whether the management of bleeding on dabigatran can be further improved by a specific antidote remains to be evaluated.

Corresponding author from original paper
Sam Schulman, MD. Thrombosis Service HHS-General Hospital. 237 Barton Street East Hamilton, ON, L8L 2X2 Canada
Tel: 1-905-5270271, ext 44479
Fax: 1-905-5270271
E-mail: schulms@mcmaster.ca

Citation: Majeed A. Circulation 2013. DOI: 10.1161/CIRCULATIONAHA.113.002332

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