Open-label, Randomized Trial in Participants Undergoing TAVR to Determine Safety & Efficacy of Bivalirudin vs UFH

NCT ID: NCT01651780

Last Updated: 2017-04-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 803 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-10-31
• Study Completion Date: 2015-06-30

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.

Conditions

Severe Aortic Stenosis; Transcatheter Aortic Valve Replacement; Aortic Valve Replacement

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Bivalirudin

Bivalirudin administered as a bolus and intravenous (IV) infusion during TAVR. It was recommended that the bolus (0.75 milligrams per kilogram \[mg/kg\]) be directly administered through the valve delivery sheath immediately following its successful delivery via percutaneous femoral access. Systemic IV administration of the bolus dose was also acceptable. The bivalirudin IV infusion was initiated immediately after the bolus administration. All wires, catheters, and sheaths were to be flushed with heparinized saline.

Group Type: EXPERIMENTAL

Bivalirudin

Intervention Type: DRUG

Bivalirudin is an anticoagulant that binds directly to thrombin in a bivalent and reversible fashion.

Unfractionated heparin (UFH)

The dose of UFH adhered to the standard institutional practice. An activated clotting time (ACT) target ≥250 seconds was recommended. All wires, catheters, and sheaths were to be flushed with heparinized saline.

Group Type: ACTIVE_COMPARATOR

Unfractionated Heparin

Intervention Type: DRUG

Unfractionated heparin is an anticoagulant.

Interventions

Bivalirudin

Bivalirudin is an anticoagulant that binds directly to thrombin in a bivalent and reversible fashion.

Intervention Type: DRUG

Unfractionated Heparin

Unfractionated heparin is an anticoagulant.

Intervention Type: DRUG

Other Intervention Names

AngioMAX; Angiox; Heparin

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The Medicines Company

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Thierry Lefevre, MD

Role: PRINCIPAL_INVESTIGATOR

Hôpital Privé Jacques Cartier

Eberhardt Grube, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Bonn

George D Dangas, MD, PhD

Role: STUDY_DIRECTOR

The Zena and Michael A. Wiener Cardiovascular Institute

Prodromos Anthopoulos, MD

Role: STUDY_DIRECTOR

The Medicines Company

Locations

Montreal Heart Institute

Montreal, Quebec, Canada

St. Paul´s Hospital Providence Health Care

Vancouver, , Canada

Clinique Pasteur, Unité de Cardiologie Interventionnelle

Toulouse, Cedex 3, France

CHU de Toulouse

Toulouse, Cedex 9, France

CHU Jean Minjoz, Service de Cardiologie

Besançon, , France

Centre Hospitalier de Lyon

Bron, , France

Department of Cardiology, CHRU Lille

Lille, , France

Institut Hospitalier Jacques Cartier

Massy, , France

Service de Cardiologie, Centre Hospitalo-Universitaire, Hôpital Charles-Nicolle

Rouen, , France

University Heart Centre, Clinic of Inner Medicine 1 Cardiology

Jena, Lobeda Ost, Germany

Universitätsklinikum Bonn

Bonn, , Germany

Klinikum links der Weser Bremen

Bremen, , Germany

Elisabeth-Krankenhaus Essen

Essen, , Germany

Freiburg University

Freiburg im Breisgau, , Germany

Asklepios St. Georg Hamburg

Hamburg, , Germany

Universitätsklinikum Hamburg-Eppendorf

Hamburg, , Germany

Medizinische Hochschule Hannover

Hanover, , Germany

Universität Leipzig - Herzzentrum GmbH

Leipzig, , Germany

Universitätsmedizin der Johannes Gutenberg-Universitat Mainz

Mainz, , Germany

LMU Munich, Klinikum der Universität München

Munich, , Germany

Deutsches Herzzentrum München

München, , Germany

Helios Heart Center Siegburg

Siegburg, , Germany

Ferraroto Hospital, University of Catania

Catania, , Italy

Ospedale San Raffaele U.O. Cardiologia Interventistica

Milan, , Italy

Azienda Ospedaliero-Universitaria Pisana

Pisa, , Italy

Azienda Ospedaliera San Camillo-Forlanini

Roma, , Italy

Policlinico Umberto I, Università La Sapienza

Roma, , Italy

St. Antonius Ziekenhuis

Nieuwegein, , Netherlands

University Medical Center Utrecht

Utrecht, , Netherlands

Cardiology University Hospital Basel

Basel, , Switzerland

Universitätsklinik Bern

Bern, , Switzerland

The Royal Sussex County Hospital

Brighton, East Sussex, United Kingdom

Hammersmith Hospital

London, , United Kingdom

Countries

Canada; France; Germany; Italy; Netherlands; Switzerland; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 27208464 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26477635 (View on PubMed)

Other Identifiers

2012-000632-26

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

TMC-BIV-11-02

Identifier Type: -

Identifier Source: org_study_id