title: Bivalirudin Versus Heparin Anticoagulation in Transcatheter Aortic Valve Replacement: The Randomized BRAVO-3 Trial.
abstract: BACKGROUND
  Anticoagulation is required during transcatheter aortic valve replacement (TAVR) procedures. Although an optimal regimen has not been determined, heparin is mainly used. Direct thrombin inhibition with bivalirudin may be an effective alternative to heparin as the procedural anticoagulant agent in this setting.
  
  
  OBJECTIVE
  The goal of this study was to determine whether bivalirudin offers an alternative to heparin as the procedural anticoagulant agent in patients undergoing TAVR.
  
  
  METHODS
  A total of 802 patients with aortic stenosis were randomized to undergo transfemoral TAVR with bivalirudin versus unfractionated heparin during the procedure. The 2 primary endpoints were major bleeding within 48 h or before hospital discharge (whichever occurred first) and 30-day net adverse clinical events, defined as the combination of major adverse cardiovascular events (all-cause mortality, myocardial infarction, or stroke) and major bleeding.
  
  
  RESULTS
  Anticoagulation with bivalirudin versus heparin did not meet superiority because it did not result in significantly lower rates of major bleeding at 48 h (6.9% vs. 9.0%; relative risk: 0.77; 95% confidence interval [CI]: 0.48 to 1.23; p = 0.27) or net adverse cardiovascular events at 30 days (14.4% vs. 16.1%; relative risk: 0.89; 95% CI: 0.64 to 1.24; risk difference: -1.72; 95% CI: -6.70 to 3.25; p = 0.50); regarding the latter, the prespecified noninferiority hypothesis was met (pnoninferiority < 0.01). Rates of major adverse cardiovascular events at 48 h were not significantly different (3.5% vs. 4.8%; relative risk: 0.73; 95% CI: 0.37 to 1.43; p = 0.35). At 48 h, the bivalirudin group had significantly fewer myocardial infarctions but more acute kidney injury events than the heparin group; at 30 days, these differences were no longer significant.
  
  
  CONCLUSIONS
  In this randomized trial of TAVR procedural pharmacotherapy, bivalirudin did not reduce rates of major bleeding at 48 h or net adverse cardiovascular events within 30 days compared with heparin. Although superiority was not shown, the noninferiority hypothesis was met with respect to the latter factor. Given the lower cost, heparin should remain the standard of care, and bivalirudin can be an alternative anticoagulant option in patients unable to receive heparin in TAVR. (International, Multi-center, Open-label, Randomized Controlled Trial in Patients Undergoing TAVR to Determine the Treatment Effect [Both Safety and Efficacy] of Using Bivalirudin Instead of UFH [BRAVO-2/3]; NCT01651780).
authors.affiliation: The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: george.dangas@mountsinai.org.
authors.forename: George D
authors.initials: GD
authors.lastname: Dangas
authors.affiliation: Institut Cardio Vasculaire Paris Sud, Hôpital Privé Jacques Cartier, Massy, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lefèvre
authors.affiliation: LMU Munich, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kupatt
authors.affiliation: Clinique Pasteur, Toulouse, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Tchetche
authors.affiliation: University Heart Center, Hamburg, Germany, and Asklepios Clinics St. Georg, Hamburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schäfer
authors.affiliation: CHU Rangueil, Toulouse, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dumonteil
authors.affiliation: St. Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: John G
authors.initials: JG
authors.lastname: Webb
authors.affiliation: San Raffaele Hospital, Milan, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Colombo
authors.affiliation: Department of Cardiology, Bern University Hospital, Bern, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Windecker
authors.affiliation: St. Antonius Ziekenhuis, Nieuwegein, the Netherlands.
authors.forename: Jurriën M
authors.initials: JM
authors.lastname: Ten Berg
authors.affiliation: Sussex Cardiac Centre-Brighton & Sussex University Hospitals NHS Trust, Brighton, East Sussex, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Hildick-Smith
authors.affiliation: The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Roxana
authors.initials: R
authors.lastname: Mehran
authors.affiliation: Helios Heart Center Siegburg, Siegburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Boekstegers
authors.affiliation: Universität Leipzig, Herzzentrum, Leipzig, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Linke
authors.affiliation: CHU de Rouen, Rouen, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Tron
authors.affiliation: Department of Cardiology and INSERM UMR 1011, University Hospital, and CHRU Lille, Lille, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Van Belle
authors.affiliation: Institut de Cardiologie de Montreal, Montreal, Quebec, Canada.
authors.forename: Anita W
authors.initials: AW
authors.lastname: Asgar
authors.affiliation: Klinikum links der Weser Bremen, Bremen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Fach
authors.affiliation: Cardiology University Hospital Basel, Basel, Switzerland.
authors.forename: Raban
authors.initials: R
authors.lastname: Jeger
authors.affiliation: Policlinico Umberto I, Rome, Italy.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Sardella
authors.affiliation: Universitätsmedizin Mainz, Mainz, Germany.
authors.forename: Hans Ulrich
authors.initials: HU
authors.lastname: Hink
authors.affiliation: Deutsches Herzzentrum München, Technische Universität München, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Husser
authors.affiliation: Universitaetsklinikum Bonn, Bonn, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Grube
authors.affiliation: The Medicines Company, Parsippany, New Jersey.
authors.forename: Efthymios N
authors.initials: EN
authors.lastname: Deliargyris
authors.affiliation: The Medicines Company, Zurich, Switzerland.
authors.forename: Ilknur
authors.initials: I
authors.lastname: Lechthaler
authors.affiliation: The Medicines Company, Parsippany, New Jersey.
authors.forename: Debra
authors.initials: D
authors.lastname: Bernstein
authors.affiliation: The Medicines Company, Zurich, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Wijngaard
authors.affiliation: The Medicines Company, Zurich, Switzerland.
authors.forename: Prodromos
authors.initials: P
authors.lastname: Anthopoulos
authors.affiliation: DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany, and Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hengstenberg
mesh_terms: D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects; D000991:Antithrombins / Q000008:administration & dosage / Q000009:adverse effects; D001024:Aortic Valve Stenosis / Q000175:diagnosis / Q000601:surgery*; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D005060:Europe / Q000453:epidemiology; D005260:Female; D005500:Follow-Up Studies; D006493:Heparin / Q000008:administration & dosage* / Q000009:adverse effects; D006629:Hirudins / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D015994:Incidence; D008297:Male; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000009:adverse effects; D019106:Postoperative Hemorrhage / Q000139:chemically induced / Q000453:epidemiology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D012189:Retrospective Studies; D015996:Survival Rate / Q000639:trends; D013923:Thromboembolism / Q000517:prevention & control*; D065467:Transcatheter Aortic Valve Replacement; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D006629:Hirudins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D006493:Heparin; C074619:bivalirudin
keywords: anticoagulation; bivalirudin; major bleeding; transcatheter aortic valve replacement