December 12, 2012

ATLANTA Despite the fact that there is no specific reversal agent for dabigatran (Pradaxa, Boehringer Ingelheim), outcomes after major bleeding on the drug are not worse than for warfarin and might actually be better, new data suggest.

These new data come out at the same time as more reports surfaced of lawsuits against Boehringer Ingelheim alleging the drug contributed to deaths from bleeding. A Bloomberg news report notes that the company is facing more than 150 such suits in the US [1]. The company says the lawsuits are "without merit," and it will defend every case.

The data suggesting bleeding outcomes are not worse with dabigatran were presented at the American Society of Hematology (ASH) 2012 Annual Meeting. Senior author Dr Sam Schulman (McMaster University, Hamilton, ON), commented to heartwire : "We found that patients who had a major bleed on dabigatran had a lower 30-day mortality rate than those who had a major bleed on warfarin."

He added: "There has been some concern about bleeding with dabigatran, given the lack of a specific reversal agent, but doctors need to see these data to be reassured that this drug is not dangerous." Noting that dabigatran has a much shorter half-life than warfarin, he said: '"If the drug is stopped and the blood is replaced, bleeding on dabigatran seems to be manageable."

But Schulman said a reversal agent would still be desirable for situations where a patient has overdosed or has suddenly gone into renal failure, where concentrations of dabigatran are very high. Boehringer Ingelheim is developing a monoclonal-antibody reversal agent that is currently in early clinical trials.

For the current study, Schulman and colleagues looked at how patients with major bleeding are managed and what their outcomes were in all the phase 3 trials in which dabigatran was taken for six months to two years and compared with warfarin.

They accessed all the reports of major bleeding defined as such by an independent adjudication committee but excluded bleeds that occurred more than three days after stopping the drug, as it could be argued that they may not be drug related.

1034 Major Bleeds Analyzed

The five studies examined included a total of 26 000 patients (including 18 000 from RE-LY), and there were 1034 major bleeds analyzed. There were more major bleeds on dabigatran (627) than warfarin (407), as there were more patients on dabigatran in the trials, Schulman noted. "This study was not about the incidence of major bleeding with the two drugs. Rather, it addressed how the bleeds were managed and what outcome resulted," he commented.

Results showed that dabigatran-associated bleeding were more likely to be treated with red blood cells, whereas patients with major bleeds on warfarin were more likely to be given plasma. Overall, the use of blood products was the same.

In terms of outcomes, patients who had a major bleed on dabigatran had a lower 30-day mortality rate than those who had a major bleed on warfarin--HR 0.55 (95% CI 0.36–0.85).

Hospitalizations for bleeding were the same in both groups, as was the mean length of hospital stay, at eight days. However, patients who bled on dabigatran had fewer nights in intensive care than those who bled on warfarin (1.9 vs 3.2).

In addition, there was a trend toward fewer surgeries to stop bleeding with dabigatran bleeds--10.7%, vs 14% for warfarin bleeds.

There was no difference in neurological function between the two groups as measured by the modified Rankin scale after intracranial hemorrhage.

Persistence Better on Dabigatran vs Warfarin

In another study presented at the ASH meeting, persistence rates were higher for dabigatran than for warfarin in newly diagnosed AF patients.

The study, led by Kevin Francis (Trinity Partners Consultants, Waltham, MA), analyzed insurance-claim data from the US Department of Defense to identify patients who received either dabigatran or warfarin between October 2010 and June 2012.

Results showed that during this time, 1775 newly diagnosed, treatment-naive patients were started on warfarin and 3370 were started on dabigatran. Persistence rates at six months were 64% for dabigatran vs 41% for warfarin, and at one year the corresponding figures were 50% vs 24%.

Of those who discontinued, 9.4% switched from warfarin to dabigatran, and 5.9% switched from dabigatran to warfarin. With both agents, patients with a low risk of stroke were more likely to discontinue therapy.

Trinity Partners is a consultant for Boehringer Ingelheim. Schulman consults for Boehringer Ingelheim, Bayer, Sanofi, GlaxoSmithKline, and AstraZeneca.

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