Archief Roodbont

April 13, 2011 (Silver Spring, Maryland) — Few saw it coming: the FDA's surprise decision not to approve the 110-mg dose of dabigatran (Pradaxa, Boehringer Ingelheim) when it approved the 150-mg dose last fall. At the time, an FDA spokesperson told heartwire : "It could be argued that it wouldn't even be ethical to use the lower dose. . . . The data in favor of a 110-mg dose were suggestive but not entirely convincing."

Now, in a perspective published online April 13, 2011 in the New England Journal of Medicine, three FDA officers offer a full explanation and some numbers for that decision [1].

"There were certainly reasons why we might have approved both doses," Drs B Nhi Beasley, Ellis F Unger, and Robert Temple (FDA Center for Drug Evaluation and Research) concede. "Ultimately, the FDA's decision to approve only the 150-mg strength was based on our inability to identify any subgroup in which use of the lower dose would not represent a substantial disadvantage."

Speaking with heartwire , RE-LY principal investigator Dr Stuart J Connolly (McMaster University, Hamilton, ON) disagreed, calling the FDA perspective an "apology" for a bad decision.

"I just think that they're wrong; they should have approved the lower dose. I don't think what they're saying is incorrect--they couldn't find a subgroup in the RE-LY study--but I do think that there are patients where the 110-mg dose makes perfect sense,"

An After-the-Fact Explanation

As previously reported by heartwire , the pivotal RE-LY trial showed that both the 150-mg and the 110-mg doses were noninferior to warfarin. The higher dose was significantly better than both the lower dose and warfarin for the primary end point of stroke or systemic embolism but caused more bleeding than the lower dose (at a rate similar to warfarin). By contrast, the lower dose was superior to warfarin for major bleeding.

As such, write Beasley et al, both doses met the "evidentiary standards for safety and efficacy," and, they acknowledge, patients and doctors "value choices that allow treatment to be individualized."

Indeed, these two issues were hashed out at length during the FDA advisory committee discussions of dabigatran's approvability.

Would Benefits Outweigh Risks in High-Risk Patients?

But the question the FDA zeroed in on was whether the 110-mg dose provided a meaningful option for the kinds of patients who, in theory, could benefit from less bleeding: namely, patients at high risk of bleeding, elderly patients, or patients with impaired renal function.

The high-risk-for-bleeding group was the simplest: according to the FDA's analysis, 57% of patients in RE-LY who had a major bleed during the study resumed taking their study drug or never stopped taking it in the first place. And rates of additional bleeds were no different among the three groups. While "exploratory," these numbers "do not support the strategy of transitioning patients to the lower dose," Beasley et al conclude.

Older patients made up 40% of the RE-LY population: in this group, the rate of stroke was slightly lower in the higher-dabigatran-dose group than in the 110-mg group, but the rate of bleeding was higher.

Major Events in Patients >75 Years

"If stroke or systemic embolism and major hemorrhage were considered equally undesirable, these rates would indicate similar benefit/risk assessments for the two doses," they write. But since most people "would agree" that stroke/systemic embolism is a worse outcome than bleeding, the risk/benefit balance falls in favor of the higher dose in this group, they conclude.

Impaired-Renal-Function Group

The impaired-renal-function group was identified as the most likely to derive benefit from a lower dose, because dabigatran is cleared primarily by the kidney. According to the analysis of RE-LY patients with moderate renal impairment (creatinine clearance >30 to 50 mL/min) cited by Beasley et al, the rate of stroke in the higher-dose group was actually half that of the lower-dose group, while bleeding rates were no different.

Major Events in Patients With Moderate Renal Impairment

Where the FDA made an exception, however, was for patients with severe renal impairment--a group excluded from RE-LY. It was for these patients that the agency opted to approve the surprise, untested, 75-mg dose. This decision, they explain, "was based not on efficacy and safety data, but on pharmacokinetic and pharmacodynamic modeling."

But that 75-mg dose is only for this renal subgroup. "What's needed is [a reduced dose for] those patients in whom the bleeding risk is considered to be sufficiently high that they wouldn't want to use the 150-mg dose," Connolly said. "Without the 110-mg dose available, there are, I think, a lot of patients who now will not receive dabigatran at all--these are patients for whom warfarin was not being used because the bleeding risk was considered to be high, or patients who have some bleeding on the dabigatran 150-mg dose for whom there is no alternative available."

Connolly acknowledged the concern raised by the FDA authors--that if physicians had access to two doses, they might try to "play it safe" by giving the lower dose more than absolutely necessary.

"What's clear is that they don't trust physicians to make rational choices about the use of the two doses," he said. "The point that they're missing is that physicians have a lot more information at their disposal when they're encountering a patient than what is in the RE-LY database, including an appreciation of the patient's own values, a lot more information about the patient's bleeding risk, and other information about the patient's history that just isn't in the RE-LY database."

Of note, Health Canada approved both the 110-mg dose and the 150-mg dose for the prevention of stroke and systemic embolism in AF patients last October. A 75-mg dose (as well as a 110-mg dose) is already on the market in the European Union, where dabigatran was approved in 2008 for the prevention of venous thromboembolism in patients undergoing hip or knee replacement. On Thursday, a spokesperson for Boehringer Ingelheim told heartwire that the company "continues to believe that there is a place for the 110-mg dose in reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation" and that it "will continue to discuss the 110-mg dose with the FDA as we remain committed to providing clinicians with appropriate options for the treatment of patients."

Last week, a RE-LY substudy presented at the American College of Cardiology 2011 Scientific Sessions suggested that the 110-mg dose was less effective than the higher dose in patients with permanent atrial fibrillation, although investigators cautioned against overinterpreting this finding.