A tale of two studies: Prescribe Pradaxa 'with caution'? Or rely on FDA's safety backing?

One drug. Two new safety studies promoted on the same day. Two different conclusions. That's the situation with Pradaxa, the Boehringer Ingelheim anticoagulant that's drawn scrutiny for reports of serious bleeding--and prompted safety reviews in the U.S. and EU.

Boehringer rolled out a press release about one study, published in Circulation and masterminded by the FDA. Its conclusion: No difference in bleeding risk between Pradaxa (dabigatran) and the older remedy it seeks to replace, warfarin. The study examined records on 134,000 Medicare patients with atrial fibrillation to come to that conclusion.

The company didn't, however, tout the results of the other study, published in JAMA Internal Medicine. The study authors came to the opposite conclusion: Doctors should prescribe Pradaxa with caution, because of "a higher incidence of major bleeding" when compared with warfarin. Pradaxa patients had a 30% greater risk of any bleeding, 58% greater risk of major bleeding, and an 85% higher risk of gastrointestinal bleeding, the study found.

Rates of major bleeding were 9% for Pradaxa patients, compared with 6% in warfarin patients, according to the study. But though Pradaxa patients were more likely to have gastrointestinal bleeding--a finding the FDA replicated in its study--they were less likely to experience bleeding in the brain. The FDA study concurred with the latter figure as well, with a reduction of risk of about 65% compared with warfarin.

The JAMA study covered a fraction of the number of patients as the FDA study, but, according to the JAMA authors, it did one key thing that the FDA study didn't: It accounted for differences between the warfarin patients and the Pradaxa patients that would otherwise bias the results.

Rita Redberg

The JAMA study findings "give us cause for concern because it appears that the bleeding risk for dabigatran is higher than for warfarin and significantly greater than originally appeared at the time of the FDA approval," journal editor-in-chief Dr. Rita Redberg, said in an accompanying commentary (as quoted by HealthDay). The FDA study, on the other hand, said that the risks found were no greater than those exhibited in the RELY trial that supported Pradaxa's approval.

One thing that has been pointed out over and over is that Pradaxa, unlike warfarin, has no quick-acting, well-proven antidote. Neither do its warfarin-replacement counterparts Eliquis (Pfizer ($PFE) and Bristol-Myers Squibb ($BMY)) and Xarelto (Bayer and Johnson & Johnson ($JNJ)). Those antidotes are under development now, with new data recently backing up their effectiveness; in fact, Boehringer won breakthrough status from the FDA for its antibleeding agent.

What makes Pradaxa worth using? The JAMA study authors say that the lower risk of intracranial bleeding is one big reason. It's "arguably more serious than GI bleeding," the study authors said, "so this agent is still clinically useful." The FDA study found that Pradaxa cut the risk of stroke by 20%, along with that 66% decrease in brain-bleed risk.

Boehringer cited the FDA study for its own case that Pradaxa is a better alternative than warfarin. "This is the largest and most rigorous postmarketing study of Pradaxa in routine clinical practice and supports the positive risk/benefit profile of Pradaxa," SVP of regulatory affairs said in a statement. "Patient safety is of utmost importance and we are pleased to see these findings further support the value of Pradaxa as a treatment option."

- check out the JAMA study announcement
- read the release on the Circulation study
- get more from Heartwire
- see the HealthDay story

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