Clinical trial NCT01651780: Open-label, Randomized Trial in Participants Undergoing TAVR to Determine Safety & Efficacy of Bivalirudin vs UFH
Official title: Effect of Bivalirudin on Aortic Valve Intervention Outcomes 2/3 (BRAVO 2/3)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Severe Aortic Stenosis
Transcatheter Aortic Valve Replacement
Aortic Valve Replacement
Keywords: Transcatheter aortic valve replacement
Aortic valve replacement
Severe aortic stenosis
Lead sponsor: The Medicines Company
Sponsor class: INDUSTRY
First posted: 2012-07-27
Enrollment: 803
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The objective of this study is to assess the safety and efficacy of using bivalirudin instead of unfractionated heparin (UFH) in transcatheter aortic valve replacements (TAVR). The primary hypothesis of BRAVO 3 was that bivalirudin would reduce major bleeding compared with heparin in TAVR procedures. Results for all participants enrolled into the randomized trial (BRAVO 3) are presented.


Eligibility criteria: Inclusion Criteria:

* Males and females, ≥18 years of age
* High risk (Euroscore ≥18, or considered inoperable) for surgical aortic valve replacement
* Undergoing TAVR via transfemoral arterial access
* Provide written informed consent before initiation of any study related procedures

Exclusion Criteria:

* Any known contra-indication to the use of bivalirudin (except presence of severe renal impairment \[glomerular filtration rate (GFR) \<30 milliliters (mL)/minute\] since these participants will be included in the trial or UFH
* Refusal to receive blood transfusion
* Mechanical valve (any location) or mitral bioprosthetic valve
* Extensive calcification of the common femoral artery, or minimal luminal diameter \<6.5 millimeters (mm)
* Use of elective surgical cut-down for transfemoral access
* Concurrent performance of percutaneous coronary intervention with TAVR
* International normalized ratio (INR) ≥2 on the day of TAVR procedure or known history of bleeding diathesis
* History of hemorrhagic stroke, intracranial hemorrhage, intracerebral mass or aneurysm, or arteriovenous malformation
* Severe left ventricular dysfunction (left ventricular ejection fraction \<15%)
* Severe aortic regurgitation or mitral regurgitation (4+)
* Hemodynamic instability (for example, requiring inotropic or intra-aortic balloon pump support) within 2 hours of the procedure
* Dialysis dependent
* Administration of thrombolytics, glycoprotein IIb/IIIa inhibitors, or warfarin in the 3 days prior to the procedure
* Acute myocardial infarction, major surgery, or any therapeutic cardiac procedure (other than balloon aortic valvuloplasty) within 30 days
* Percutaneous coronary intervention within 30 days
* Upper gastrointestinal or genitourinary bleed within 30 days
* Stroke or transient ischemic attack within 30 days
* Any surgery or biopsy within 2 weeks
* Administration of:

  * UFH within 30 minutes of the procedure
  * Enoxaparin within 8 hours of the procedure
  * Fondaparinux or other low-molecular-weight heparins (LMWHs) within 24 hours of the procedure
  * Dabigatran, rivaroxaban, or other oral anti-Xa or antithrombin agent within 48 hours of the procedure
  * Thrombolytics, glycoprotein IIb/IIIa inhibitor, or warfarin within 72 hours of the procedure
* Absolute contraindications or allergy that cannot be pre-medicated to iodinated contrast
* Contraindications or allergy to aspirin or clopidogrel
* Known or suspected pregnant women or nursing mothers. Women of child-bearing potential will be asked if they are pregnant and will be tested for pregnancy
* Previous enrollment in this study
* Treatment with other investigational drugs or devices within the 30 days preceding enrollment or planned use of other investigational drugs or devices before the primary endpoint of this study has been reached

Primary outcomes:
measure: Major Bleeding (BARC ≥3b) at 48 Hours or Before Hospital Discharge
timeFrame: at 48 hours or discharge, whichever occurs first
measure: Net Adverse Clinical Events (NACE) at up to 30 Days
timeFrame: up to 30 days after procedure
Secondary outcomes:
measure: NACE at 48 Hours or Before Hospital Discharge
timeFrame: at 48 hours or before hospital discharge, whichever occurred earlier
measure: Major Adverse Cardiac Events (MACE) Including Death, Non-fatal MI, and Stroke
timeFrame: at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days)
measure: Major Bleeding According to Additional Scales (VARC, TIMI, GUSTO, ACUITY/HORIZONS)
timeFrame: at 48 hours or hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) follow-up
measure: Transient Ischemic Attack
timeFrame: at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days)
measure: Acute Kidney Injury
timeFrame: at 48 hours or hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) follow-up
measure: Major Vascular Complications
timeFrame: at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days)
measure: Acquired Thrombocytopenia
timeFrame: at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days)
measure: New Onset Atrial Fibrillation/Flutter
timeFrame: at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days)
measure: Timing Effect on Bleeding Event Rate up to 48 Hours or Hospital Discharge
timeFrame: Up to 48 hours after procedure or at hospital discharge (but also includes any subsequent hospitalizations)
measure: Bleeding BARC 3a, BARC Types 1 or 2, and TIMI Minor
timeFrame: at 48 hours or hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) follow-up
Other outcomes:
Locations:
city: Montreal
country: Canada
facility: Montreal Heart Institute
state: Quebec
city: Vancouver
country: Canada
facility: St. Paul´s Hospital Providence Health Care
city: Toulouse
country: France
facility: Clinique Pasteur, Unité de Cardiologie Interventionnelle
state: Cedex 3
city: Toulouse
country: France
facility: CHU de Toulouse
state: Cedex 9
city: Besançon
country: France
facility: CHU Jean Minjoz, Service de Cardiologie
city: Bron
country: France
facility: Centre Hospitalier de Lyon
city: Lille
country: France
facility: Department of Cardiology, CHRU Lille
city: Massy
country: France
facility: Institut Hospitalier Jacques Cartier
city: Rouen
country: France
facility: Service de Cardiologie, Centre Hospitalo-Universitaire, Hôpital Charles-Nicolle
city: Jena
country: Germany
facility: University Heart Centre, Clinic of Inner Medicine 1 Cardiology
state: Lobeda Ost
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
city: Bremen
country: Germany
facility: Klinikum links der Weser Bremen
city: Essen
country: Germany
facility: Elisabeth-Krankenhaus Essen
city: Freiburg
country: Germany
facility: Freiburg University
city: Hamburg
country: Germany
facility: Asklepios St. Georg Hamburg
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Leipzig
country: Germany
facility: Universität Leipzig - Herzzentrum GmbH
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg-Universitat Mainz
city: Munich
country: Germany
facility: LMU Munich, Klinikum der Universität München
city: München
country: Germany
facility: Deutsches Herzzentrum München
city: Siegburg
country: Germany
facility: Helios Heart Center Siegburg
city: Catania
country: Italy
facility: Ferraroto Hospital, University of Catania
city: Milano
country: Italy
facility: Ospedale San Raffaele U.O. Cardiologia Interventistica
city: Pisa
country: Italy
facility: Azienda Ospedaliero-Universitaria Pisana
city: Roma
country: Italy
facility: Azienda Ospedaliera San Camillo-Forlanini
city: Roma
country: Italy
facility: Policlinico Umberto I, Università La Sapienza
city: Nieuwegein
country: Netherlands
facility: St. Antonius Ziekenhuis
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
city: Basel
country: Switzerland
facility: Cardiology University Hospital Basel
city: Bern
country: Switzerland
facility: Universitätsklinik Bern
city: Brighton
country: United Kingdom
facility: The Royal Sussex County Hospital
state: East Sussex
city: London
country: United Kingdom
facility: Hammersmith Hospital
Study officials:
affiliation: Hôpital Privé Jacques Cartier
name: Thierry Lefevre, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Bonn
name: Eberhardt Grube, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Zena and Michael A. Wiener Cardiovascular Institute
name: George D Dangas, MD, PhD
role: STUDY_DIRECTOR
affiliation: The Medicines Company
name: Prodromos Anthopoulos, MD
role: STUDY_DIRECTOR
References:
citation: Van Belle E, Hengstenberg C, Lefevre T, Kupatt C, Debry N, Husser O, Pontana F, Kuchcinski G, Deliargyris EN, Mehran R, Bernstein D, Anthopoulos P, Dangas GD; BRAVO-3 MRI Study Investigators. Cerebral Embolism During Transcatheter Aortic Valve Replacement: The BRAVO-3 MRI Study. J Am Coll Cardiol. 2016 Aug 9;68(6):589-599. doi: 10.1016/j.jacc.2016.05.006. Epub 2016 May 18.
citation: Dangas GD, Lefevre T, Kupatt C, Tchetche D, Schafer U, Dumonteil N, Webb JG, Colombo A, Windecker S, Ten Berg JM, Hildick-Smith D, Mehran R, Boekstegers P, Linke A, Tron C, Van Belle E, Asgar AW, Fach A, Jeger R, Sardella G, Hink HU, Husser O, Grube E, Deliargyris EN, Lechthaler I, Bernstein D, Wijngaard P, Anthopoulos P, Hengstenberg C; BRAVO-3 Investigators. Bivalirudin Versus Heparin Anticoagulation in Transcatheter Aortic Valve Replacement: The Randomized BRAVO-3 Trial. J Am Coll Cardiol. 2015 Dec 29;66(25):2860-2868. doi: 10.1016/j.jacc.2015.10.003. Epub 2015 Oct 15.