George Dangas (New York, USA) and others report in JACC: Cardiovascular Interventions that heparin should continue to be the first-line anticoagulant for transcatheter aortic valve implantation (TAVI) procedures because it is not associated with a significantly increased risk of bleeding compared with bivalirudin (Angiomax, The Medicines Company).
According to Dangas (The Zena and Michael A Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, USA) and his fellow authors, in randomised trials and clinical practice, unfractionated heparin has been used as the “empiric procedural anticoagulation regimen for TAVI”. However, they add that the evidence base for using heparin in this setting is based on expert clinical consensus rather than “evidence from randomised trials”. “The rapid expansion of TAVI procedures worldwide necessitates dedicated clinical investigation in the field of periprocedural pharmacology in an attempt to build a robust evidence base, derive appropriate practice guidelines and further improve clinical outcomes,” Dangas et al comment.
Therefore in BRAVO 3 (Effect of bivalirudin on aortic valve intervention outcomes 3), the authors aimed to determine if bivalirudin was a good alternative to heparin as a procedural anticoagulation during TAVI, noting that the drug “has reduced major bleeding while providing stable effective anticoagulation in the setting of percutaneous coronary intervention compared to other regimens.”
In the study, high-risk or inoperable 802 patients undergoing TAVI were randomised to receive heparin (398) or bivalirudin (404) during TAVI. The co-primary endpoints were major bleeding within 48 hours or before hospital discharge (whichever came first) and the rate of net adverse cardiovascular events—a composite of major adverse cardiac events (all-cause mortality, myocardial infarction, or stroke) and major bleeding—within 30 days. The primary hypothesis was,
Dangas et al write, that “bivalirudin would reduce major bleeding compared with heparin in TAVI procedures to a similar extent with that observed in coronary intervention trials”. Clinical follow-up was performed at days one and two, on day of hospital discharge, and at 30 days post procedure. At 30 days, data were available for 97.5% (394) of the bivalirudin group and for 97.5% (388) of the heparin group.
The authors report that: “After 48 hours of the TAVI procedure, major bleeding (Bleeding Academic Research Consortium, BARC ≥3b) occurred in 6.9% of the bivalirudin-treated patients vs. 9% of the heparin-treated patients (p=0.27); the superiority hypothesis was not met.” They add that the reason why BRAVO 3 failed to find a difference in major bleeding between groups when studies in the PCI setting have found a difference “likely reflect the substantial differences between coronary and TAVI patient populations and the respective procedures as considerable larger arterial sheath/catheter sizes are used in TAVI.” Furthermore, the authors say that the sample size limitation may have affected the results “despite the attempt to overcome this by using an adaptive trial design”.
However, Dangas told Cardiovascular News that “there was no negative safety signal with bivalirudin (all adverse event rates were numerically lower) despite the absence of an immediate antidote, such as protamine sulfate for excessive heparin action.” There were no significant differences between bivalirudin and heparin in terms of net adverse cardiovascular events at 30 days (14.4% vs. 16.1%, respectively; p
In JACC: Cardiovascular Interventions, Dangas et al call the higher rate of kidney injury with bivalirudin “an unexpected finding” and say that no “plausible biological mechanism exists” for the finding, commenting that it did not appear to affect mortality “even in patients with advanced kidney disease at baseline”. Dangas notes that the lower periprocedural myocardial infarction rate with bivalirudin “may reflect a more effective thrombin inhibtion during TAVI”. He added “In this respect, a dedicated MRI substudy is underway, evaluating the brain embolisation phenomena with the two treatments and will be presented in 2016.”
Concluding their report, the authors say: “Given the lower cost, heparin should remain the standard of care and bivalirudin could be an alternative anticoagulant for minority of patients who cannot receive heparin in TAVI procedures.”
Thierry Lefèvre (Institut Cardiovasculaire Paris Sud, Hôpital Privé Jacques Cartier, Massy, France) presented the results of BRAVO 3 during a late-breaking trial session at the 2015 Transcatheter Cardiovascular Therapeutics (TCT) meeting (11–15 October, San Francisco, USA).