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FDA Rejects Lepirudin for New Indication
Lepirudin, the anticoagulant approved for heparin-induced thrombocytopenia, is considered "nonapprovable" by the Food and Drug Administration for treating adults with acute coronary syndromes.
In a statement, Aventis Pharmaceuticals announced that the company had received a "nonapprovable" letter from the FDA for this indication.
The drug will continue to be marketed for heparin-induced thrombocytopenia (HIT) and associated thromboembolic disease. The company is maintaining an "open dialogue" with the FDA about this issue, the statement said.
Lepirudin, which is recombinant hirudin, a specific thrombin inhibitor, is marketed as Refludan.
In May, the FDA's Cardiology and Renal Drugs Advisory Committee voted 74 that the data on lepirudin did not provide adequate evidence of its effectiveness for the proposed indication.
Those who voted in favor cited the need for more treatments in this area as one of the reasons for supporting approval.
Aventis had filed an application for approval of the following indication: "anticoagulation in adult patients with acute coronary syndromes (unstable angina/acute MI without ST elevation," followed by the statement: "In this setting, Refludan has been shown to decrease the rate of CV death, new MI, or refractory angina (combined triple end point)."
The votes followed a presentation and discussion of the data from the Organization to Assess Strategies for Ischemic Syndromes (OASIS)-1 and OASIS-2 studies.
OASIS-1, a study designed to identify a beneficial dose, compared different doses of lepirudin to heparin in 909 patients with unstable angina or non--Q-wave MI.
Treatment with a medium dose of lepirudin was found to have a significant benefit at 7 days over heparin in the combined end point of cardiovascular death, MI, refractory angina, and severe angina.
These results led to the testing of the medium dose in the pivotal trial, OASIS-2, a multinational double-blind study that compared lepirudin to heparin in more than 10,000 patients, with unstable angina or suspected acute MI without ST elevation.
Patients were given a bolus of either heparin or lepirudin, followed by an infusion for 72 hours.
At 7 days, there was a benefit of lepirudin over heparin on the combined end point of cardiovascular death or new MI, but the difference was only nominally significant.
The secondary combined end point of the study--cardiovascular death, MI, and refractory angina at 7 days--was also better for lepirudin, but again the result was only nominally significant.
The panel also voted 7-4 that based on data from the two trials presented, the benefits of lepirudin did not exceed its risks for this indication.
Of particular concern was that there were more bleeding events and ischemic strokes in lepirudin-treated subjects.