Major Bleeds Less Daunting With Dabigatran Than Warfarin in Meta-Analysis

October 04, 2013

DALLAS, TX — Major bleeding complications from dabigatranetexilate (Pradaxa, Boehringer Ingelheim) in trials of atrial fibrillation (AF) and venous thromboembolism (VTE) prevention tended to be less critical and more manageable than those attributed to the warfarin comparator, suggests a new meta-analysis, published online September 30, 2013 in Circulation[1]. The worst major bleeds, for example, tended to be gastrointestinal with dabigatran and the more daunting intracranial hemorrhage (ICH) on warfarin.

At the same time, major bleeding events in the meta-analysis were no more common with the newer oral anticoagulant and were in higher-risk patients.

"Patients who had a major bleeding event on dabigatran treatment were older and had worse renal function and more often concomitant treatment with aspirin or a nonsteroidal anti-inflammatory agent than those with warfarin," according to the authors, led by Dr Ammar Majeed (Karolinska University Hospital, Stockholm, Sweden).

Many patients who are on anticoagulants are also on aspirin, but don't necessarily need it.

That, they write, "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." In the meta-analysis of five phase 3 trials, the 110-mg twice-daily dosage compared with 150 mg twice daily—which were both tested in one of the included trials, RE-LY —was less associated with bleeding-related hospitalization or nights in the ICU.

The meta-analysis 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 in >27 000 patients. For the meta-analysis' purposes, major bleeds included only those developing within three days of the last dose of oral anticoagulant.

Avoid Unnecessary Antiplatelets

The analysis also questions the scale of concomitant aspirin use, according to senior author Dr Sam Schulman (McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton, ON). "We should do everything we can to minimize the risk of bleeding," he said to heartwire . "I think most important is to avoid unnecessary [dabigatran] combination with other antithrombotic agents. Many patients who are on anticoagulants are also on aspirin but don't necessarily need it."

Aspirin use in the current analysis was mainly in RE-LY, he said. "It was used all of the time in 20% [of patients], and up to 40% had some antiplatelet agent at least part of the time." And among those with major bleeding events, the combination of aspirin and an oral anticoagulation was more likely for dabigatran than for warfarin (p=0.026).

When they had major bleeds, [they] didn't run to their investigators to be treated, they went to the nearest emergency room.

In RE-LY, drops in hemoglobin levels from baseline to bleeding were significantly greater with dabigatran vs warfarin (p=0.02), probably because patients who received the newer drug were more likely to have GI bleeds (p<0.001), while those on warfarin had more ICH (p<0.001). Although more blood is lost with GI bleeds, they can be managed with endoscopy and red blood cell infusions, for example, whereas blood isn't lost with an ICH, but it can be devastating clinically, observed Schulman. Major bleeds with warfarin, compared with dabigatran, were only two-thirds as likely to be treated with blood transfusions (p<0.001).

The imbalance of GI bleeds and ICH "is also reflected in the fact that dabigatran patients in our study had a significantly shorter stay in the intensive-care unit," he said (mean 4.3 nights vs 6.6 for warfarin, p=0.01). Their 30-day mortality following the first major bleed also trended lower, a 32% drop with dabigatran vs warfarin (p=0.057).

Bleeding Management

Although antidotes for other oral anticoagulants are in early developmental stages, "for warfarin we have vitamin K and prothrombin complex concentrate (PCC), but they aren't used very much," Schulman said. In the current analysis, vitamin K was used to treat warfarin-related bleeding in only 31% of cases.

"That's surprising," he said. It's defensible to say that dabigatran stacked up so well against warfarin because warfarin recipients weren't optimally managed, "but this is the reality worldwide. These patients [in the trials], when they had major bleeds, didn't run to their investigators to be treated, they went to the nearest emergency room."

Majeed reported no conflicts of interest. Schulman disclosed receiving honoraria from Boehringer Ingelheim, Bayer, and Merck. Disclosures for the coauthors are listed in the paper.


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