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

NCT01651780 | Completed Phase 3 Results DMC

• 2 other identifiers: TMC-BIV-11-022012-000632-26
• Study Type: interventional
• Target: 803
• Locations: 7 countries
• Sites: 33

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

Keywords

Transcatheter aortic valve replacement; Aortic valve replacement; Severe aortic stenosis

Outcome Measures

Primary Outcomes (2)

• Major Bleeding (BARC ≥3b) at 48 Hours or Before Hospital Discharge

  Major bleeding (Bleeding Academic Research Consortium \[BARC\] type ≥3b) was defined as follows: * Bleeds that were evident clinically, or by laboratory or imaging results, which resulted in surgical intervention or administration of IV vasoactive drugs; overt bleeds with a hemoglobin drop of at least 5 grams per deciliter (g/dL); and bleeding that caused cardiac tamponade. * BARC 3c includes intracranial or intraocular bleeds that compromised vision. * BARC type 4 (Coronary Artery Bypass Grafting \[CABG\]-related bleeding) includes perioperative intracranial bleeding within 48 hours, bleeds that result in reoperation following closure of sternotomy for the purpose of controlling bleeding, bleeds that result in treatment with transfusion of ≥5 units of whole blood or packed red blood cells within a 48 hour period; and chest tube output ≥2 liters (L) within a 24-hour period. * BARC type 5, fatal bleeding, describes bleeds that directly result in death with no other cause.

  at 48 hours or discharge, whichever occurs first

• Net Adverse Clinical Events (NACE) at up to 30 Days

  The net adverse cardiac events (NACE) at 30 days is the composite of major adverse cardiovascular events (MACE) + major bleeding (BARC type ≥3b). The composite of MACE is defined as all-cause mortality, myocardial infarction (MI), and stroke. A participant was defined to have a composite event if the participant experienced at least 1 of the components. If the participant did not have any of the components, then he or she did not have the composite endpoint. If a participant had more than 1 of the components, he or she was only counted once in the determination of the total number of participants experiencing the composite endpoint.

  up to 30 days after procedure

Secondary Outcomes (10)

• NACE at 48 Hours or Before Hospital Discharge

  at 48 hours or before hospital discharge, whichever occurred earlier

• Major Adverse Cardiac Events (MACE) Including Death, Non-fatal MI, and Stroke

  at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days)

• Major Bleeding According to Additional Scales (VARC, TIMI, GUSTO, ACUITY/HORIZONS)

  at 48 hours or hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) follow-up

• Transient Ischemic Attack

  at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days)

• Acute Kidney Injury

  at 48 hours or hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) follow-up

Study Arms (2)

Bivalirudin

EXPERIMENTAL

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.

Drug: Bivalirudin

Unfractionated heparin (UFH)

ACTIVE COMPARATOR

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.

Drug: Unfractionated Heparin

Interventions

Bivalirudin DRUG

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

Also known as: AngioMAX, Angiox

Bivalirudin

Unfractionated Heparin DRUG

Unfractionated heparin is an anticoagulant.

Also known as: Heparin

Unfractionated heparin (UFH)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• The Medicines Company: lead

Study Sites (33)

Montreal Heart Institute

Montreal, Quebec, H1T 1C8, Canada

Location

St. Paul´s Hospital Providence Health Care

Vancouver, V6Z1Y6, Canada

Location

Clinique Pasteur, Unité de Cardiologie Interventionnelle

Toulouse, Cedex 3, 31076, France

Location

CHU de Toulouse

Toulouse, Cedex 9, 31059, France

Location

CHU Jean Minjoz, Service de Cardiologie

Besançon, 25000, France

Location

Centre Hospitalier de Lyon

Bron, 69500, France

Location

Department of Cardiology, CHRU Lille

Lille, 59037, France

Location

Institut Hospitalier Jacques Cartier

Massy, 91300, France

Location

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

Rouen, 76031, France

Location

University Heart Centre, Clinic of Inner Medicine 1 Cardiology

Jena, Lobeda Ost, 07747, Germany

Location

Universitätsklinikum Bonn

Bonn, 53105, Germany

Location

Klinikum links der Weser Bremen

Bremen, 28277, Germany

Location

Elisabeth-Krankenhaus Essen

Essen, 45257, Germany

Location

Freiburg University

Freiburg im Breisgau, 79106, Germany

Location

Asklepios St. Georg Hamburg

Hamburg, 20099, Germany

Location

Universitätsklinikum Hamburg-Eppendorf

Hamburg, 20246, Germany

Location

Medizinische Hochschule Hannover

Hanover, 30625, Germany

Location

Universität Leipzig - Herzzentrum GmbH

Leipzig, 04289, Germany

Location

Universitätsmedizin der Johannes Gutenberg-Universitat Mainz

Mainz, 55131, Germany

Location

LMU Munich, Klinikum der Universität München

Munich, 81377, Germany

Location

Deutsches Herzzentrum München

München, 80636, Germany

Location

Helios Heart Center Siegburg

Siegburg, 53721, Germany

Location

Ferraroto Hospital, University of Catania

Catania, 95123, Italy

Location

Ospedale San Raffaele U.O. Cardiologia Interventistica

Milan, 20132, Italy

Location

Azienda Ospedaliero-Universitaria Pisana

Pisa, 56124, Italy

Location

Azienda Ospedaliera San Camillo-Forlanini

Roma, 00151, Italy

Location

Policlinico Umberto I, Università La Sapienza

Roma, Italy

Location

St. Antonius Ziekenhuis

Nieuwegein, 3435, Netherlands

Location

University Medical Center Utrecht

Utrecht, 3584 CX, Netherlands

Location

Cardiology University Hospital Basel

Basel, CH-4031, Switzerland

Location

Universitätsklinik Bern

Bern, 3010, Switzerland

Location

The Royal Sussex County Hospital

Brighton, East Sussex, BN2 5BE, United Kingdom

Location

Hammersmith Hospital

London, W12 0HS, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 27208464 DERIVED

• 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.

  PMID: 26477635 DERIVED

MeSH Terms

Conditions

Aortic Valve Stenosis

Interventions

bivalirudin; Heparin

Condition Hierarchy (Ancestors)

Aortic Valve Disease; Heart Valve Diseases; Heart Diseases; Cardiovascular Diseases; Ventricular Outflow Obstruction

Intervention Hierarchy (Ancestors)

Glycosaminoglycans; Polysaccharides; Carbohydrates

Results Point of Contact

• Title: Global Health Science Center
• Organization: The Medicines Company

800-388-1183

Study Officials

• Thierry Lefevre, MD

  Hôpital Privé Jacques Cartier

  PRINCIPAL INVESTIGATOR

• Eberhardt Grube, MD

  University Hospital, Bonn

  PRINCIPAL INVESTIGATOR

• George D Dangas, MD, PhD

  The Zena and Michael A. Wiener Cardiovascular Institute

  STUDY DIRECTOR

• Prodromos Anthopoulos, MD

  The Medicines Company

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 24, 2012
• First Posted: July 27, 2012
• Study Start: October 1, 2012
• Primary Completion: June 1, 2015
• Study Completion: June 1, 2015
• Last Updated: April 7, 2017
• Results First Posted: February 27, 2017

Record last verified: 2017-03

Locations

CA (2); IT (5); CH (2); GB (2); FR (7); DE (13); NL (2)