October 20, 2010 (Silver Spring, Maryland)— Late Tuesday, Boehringer Ingelheim announced that the US FDA has approved dabigatran (Pradaxa) for the prevention of stroke and systemic embolism in patients with atrial fibrillation .
As previously reported by heartwire , an advisory panel in September voted 9 to 0 to recommend that the oral antithrombin be approved. The drug will be available in two doses: 150 mg twice daily and, for a small subset with severe renal impairment, 75 mg twice daily. Debates about the approved dosing have already begun (see the discussion in the heartwire forum).
In the large the 18 000-patient Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) study, on which the drug's approval is primarily based, investigators compared dabigatran 110 mg twice daily and 150 mg twice daily against a conventional warfarin regimen. The 75-mg twice-daily dose, now approved by the FDA, was not studied in RE-LY.
During the advisory committee meeting in September, there were discussions about dosing, with some panelists arguing in favor of approving just the 150-mg dose, while others wanted a lower dose approved for selected patients at special risk for bleeding complications, such as the very elderly. In RE-LY, the 150-mg dose was superior to standard warfarin therapy, whereas the 110-mg twice-daily dose was comparable to warfarin in effectiveness. As a result, some panel members felt the 110-mg twice-daily dose shouldn't be part of the approval.
In an email to heartwire , advisory panel member Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA) said the 75-mg twice-daily dose will be recommended for individuals with poor renal function, while the 150-mg twice-daily dose will be reserved for patients with creatinine clearance 15 to >30 mL/min.
"The 110-mg dose, while associated with reduced bleeding, had a 12% higher incidence of ischemic stroke," said Kaul. "In my opinion, it would not offer much of an advantage over warfarin and would likely be an ineffective alternative."
Asked about the approved doses, FDA spokesperson Sandy Walsh said that FDA reviewers felt the data strongly support the 150-mg dose, noting that it was superior to warfarin on the primary end point and similar in terms of bleeding rates. In reviewing the data, FDA officials noted, like Kaul, there were numerically more ischemic strokes in the dabigatran 110-mg arm when compared with warfarin, and this dose was only statistically noninferior to warfarin in terms of efficacy.
"Moreover, if we accept the validity of the post hoc analysis showing that the 150-mg dose is statistically superior to the 110-mg dose in preventing stroke, it could be argued that it wouldn’t even be ethical to use the lower dose," said Walsh, in explanation of the FDA decision. "The data in favor of a 110-mg dose were suggestive, but not entirely convincing."
With the absence of the 110-mg dose, FDA officials felt that treatment options were limited for patients with severe renal insufficiency. Pharmacokinetic data from RE-LY and other studies led them to conclude that a dosing regimen of 75 mg twice daily is appropriate for patients with a creatinine clearance 15 to 30 mL/min, a dose already made by Boehringer Ingelheim and currently marketed in the European Union.
As with other approved anticlotting drugs, bleeds, both life-threatening and fatal, were among the most common adverse reactions reported by patients treated with dabigatran in studies, an FDA press release notes. Other side effects, including gastrointestinal symptoms, dyspepsia, stomach pain, nausea, heartburn, and bloating also were reported.
Dabigatran was approved with a medication guide that details the risk of serious bleeding for patients.
On the whole, however, the cardiology community has expressed few major reservations about the RE-LY trial. And for a generation, it has longed for an oral antithrombin that's at least as safe and effective as warfarin but is more consistent in its effects and doesn't require cumbersome anticoagulation monitoring.