SAN FRANCISCO – The reversible direct thrombin inhibitor bivalirudin, compared with unfractionated heparin, did not reduce the rate of major bleeding at 48 hours after transcatheter aortic valve replacement, in the randomized, open label, phase IIIb BRAVO 3 trial.
Bivalirudin, which has a half-life of 25 minutes, has been shown to reduce major bleeding in the setting of percutaneous coronary intervention when compared with other regimens, but its safety and efficacy as compared with that of unfractionated heparin was unknown. In BRAVO 3 (The effect of BivaliRudin on Aortic Valve Intervention Outcomes trial), the rate of major bleeding at 48 hours, defined as Bleeding Academic Research Consortium (BARC) 3b or greater, was 6.9% in 404 patients treated with bivalirudin vs. 9.0% in 398 patients treated with heparin (relative risk, 0.77), Dr. Thierry Lefevre reported at the Transcatheter Cardiovascular Therapeutics annual meeting.
Dr. Thierry Lefevre
Further, the rate of net adverse clinical outcomes (NACE), including all-cause mortality, myocardial infarction, stroke, and major bleeding at up to 30 days was 14.4% in the bivalirudin group vs. 16.1% in the heparin group (relative risk, 0.89), Dr. Lefevre of Institut Hospitalier Jacques Cartier, Massy, France, said at the meeting, which was sponsored by the Cardiovascular Research Foundation.
The differences on both measures failed to meet statistical significance. With respect to bleeding at 48 hours, bivalirudin did not meet superiority, and with respect to cardiovascular events at 30 days, the prespecified noninferiority hypothesis was met.
No difference was seen between the groups for secondary endpoints, including bleeding defined according to various other bleeding scales and other BARC types.
The findings were published simultaneously in the Journal of the American College of Cardiology (J Am Coll Cardiol. 2015;Oct 15. doi: 10.1016/j.jacc.2015.10.003).
Heparin should remain the standard of care, especially given its lower cost compared to the cost of bivalirudin, Dr. Lefevre said.
However, Dr. Lefevre noted, major bleeding remains an important concern in transcatheter aortic valve replacement (TAVR), and “bivalirudin may be used as an alternative to heparin during TAVR in patients who cannot be treated with UFH.”
BRAVO III participants were adults with aortic stenosis who were at high surgical risk and who were scheduled for TAVR via transfemoral access. They were enrolled at 31 centers in seven countries throughout Europe and North America.
Those randomized to the bivalirudin group received an initial bolus of 0.75 mg/kg followed by a continuous infusion at a rate of 1.75 mg/kg per hour in those with an estimated glomerular filtration rate (eGFR) of 60 mL/min or greater, 1.4 mg/kg per hour in those with eGFR of 30-59 mL/min, and 1.0 mg/kg per hour in those with eGFR lower than 30 mL/min.
Heparin dosing and administration included a recommended target activated clotting time of greater than 25 seconds. Protamine was used for reversal at the end of the procedure based on standard local institution practice.
Session moderator Dr. Ajay J. Kirtane said that “one of the reasons this trial is exciting is that there has been a hypothesis that bivalirudin could reduce bleeding compared to heparin alone in PCI patients. While this is a much bigger access site, you don’t necessarily see these trends. On the other hand, when you have a bigger access site there is potential for increased signal, but this study is still somewhat underpowered.”
The Medicines Company provided funding for the BRAVO 3 trial to the Icahn School of Medicine at Mount Sinai, New York. Dr. Lefevre disclosed ties with Boston Scientific, Directflow, Edwards, Symetis and Medtronic.