(Circulation. 1999;99:1277.)
© 1999 American Heart Association, Inc.
Cardiovascular News |
FDA Panel Votes Against Approval for Bivalirudin
From the Department of Cardiology, Temple University, Philadelphia, Pa.
Correspondence to Ileana Piña, MD, Cardiology, Parkinson Pavilion, 9th Floor, Temple University, 3401 N Broad St, Philadelphia, PA 19140-5103.
The Cardiovascular and Renal Advisory Panel of the Food and Drug Administration (FDA) met on October 22 and 23, 1998, to discuss guidelines for evaluation of drugs for heart failure and to consider the anticoagulant bivalirudin.
Bivalirudin is a 20-amino-acid peptide that acts as a direct thrombin inhibitor and is active against bound and circulating thrombin. The discussion centered around 2 large multicenter trials (with identical designs) that compared the safety and efficacy of bivalirudin and heparin in 4672 patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA). The trials were powered to demonstrate the superiority of bivalirudin over heparin for a primary composite end point of "procedural failure," defined as death, myocardial infarction (MI) during hospitalization, need for revascularization, or angiographic evidence of established or impending abrupt vessel closure. Despite the large number of patients, neither study, nor the 2 combined, demonstrated a significant difference between bivalirudin and heparin for the primary end point. A substudy of post-MI patients in 1 of the 2 trials had a significantly lower rate of procedural failure with bivalirudin compared with heparin, but this was not shown in the second trial. Because post-MI patients composed only 15% of all patients entered, the Advisory Panel did not feel that this finding was sufficient to demonstrate superiority of bivalirudin over heparin in this population.
Bivalirudin use led to fewer and less severe bleeding events in both trials, although this was not a primary end point. Although heparin use has become standard in PTCA, no well-controlled trials demonstrating its effectiveness in this setting have been performed, and it is in fact not labeled for this indication. In addition, there is no standard regimen or accepted schedule of heparin administration during PTCA. In the submitted trials, the patients on heparin tended to have longer clotting times, which may have increased bleeding and prolonged hospitalization. In addition, the dosing regimen of heparin was amended in both trials, which the committee felt was further evidence of uncertainty in standardization of heparin administration.
Because the large trials designed to demonstrate superiority of bivalirudin over heparin failed to reach this primary end point and because the lower bleeding rate with bivalirudin may have reflected the heparin regimen used, the panel, in a split vote, recommended against approval for bivalirudin.
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  D. M. Roden and R. Temple The US Food and Drug Administration Cardiorenal Advisory Panel and the Drug Approval Process Circulation, April 5, 2005; 111(13): 1697 - 1702. [Full Text] [PDF]
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 H. Van Aken, C. Bode, H. Darius, C. Diehm, A. Encke, D. C. Gulba, S. Haas, W. Hacke, W. Puhl, M. Quante, et al. State-of-the-Art Review: Anticoagulation: The Present and Future Clinical and Applied Thrombosis/Hemostasis, July 1, 2001; 7(3): 195 - 204. [Abstract] [PDF]
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