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Open-label, Randomized Trial in Participants Undergoing TAVR to Determine Safety & Efficacy of Bivalirudin vs UFH (BRAVO 2/3)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
The Medicines Company
ClinicalTrials.gov Identifier:
NCT01651780
First received: July 24, 2012
Last updated: March 9, 2017
Last verified: March 2017
  Purpose
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.

Condition Intervention Phase
Severe Aortic Stenosis Transcatheter Aortic Valve Replacement Aortic Valve Replacement Drug: Bivalirudin Drug: Unfractionated Heparin Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Effect of Bivalirudin on Aortic Valve Intervention Outcomes 2/3 (BRAVO 2/3)

Resource links provided by NLM:


Further study details as provided by The Medicines Company:

Primary Outcome Measures:
  • Major Bleeding (BARC ≥3b) at 48 Hours or Before Hospital Discharge [ Time Frame: at 48 hours or discharge, whichever occurs first ]

    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.

  • Net Adverse Clinical Events (NACE) at up to 30 Days [ Time Frame: up to 30 days after procedure ]
    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.


Secondary Outcome Measures:
  • NACE at 48 Hours or Before Hospital Discharge [ Time Frame: at 48 hours or before hospital discharge, whichever occurred earlier ]
    NACE at 48 hours or before hospital discharge is the composite of major adverse cardiovascular events (MACE) + major bleeding (BARC type ≥3b). The composite of MACE is defined as all-cause mortality, 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.

  • Major Adverse Cardiac Events (MACE) Including Death, Non-fatal MI, and Stroke [ Time Frame: at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) ]
    The percentage of participants reporting a MACE overall and the individual components of MACE (including death, non-fatal MI, and stroke) are presented.

  • Major Bleeding According to Additional Scales (VARC, TIMI, GUSTO, ACUITY/HORIZONS) [ Time Frame: at 48 hours or hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) follow-up ]

    Percentage of participants with major bleeding according to the following scales:

    • Valve Academic Research Consortium (VARC)=life threatening, disabling bleeding, or major bleeding
    • Thrombolysis in Myocardial Infarction (TIMI)=major bleeding
    • Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)=severe or moderate
    • Acute Catheterization and Urgent Intervention Triage StrategY (ACUITY)/Harmonizing Outcomes with RevasculariZatiON and Stents (HORIZONS)=major bleeding

  • Transient Ischemic Attack [ Time Frame: at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) ]
    The percentage of participants reporting transient ischemic attack is presented.

  • Acute Kidney Injury [ Time Frame: at 48 hours or hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) follow-up ]
    The percentage of participants reporting acute kidney injury is presented.

  • Major Vascular Complications [ Time Frame: at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) ]
    The percentage of participants reporting a major vascular complications as defined by VARC is presented.

  • Acquired Thrombocytopenia [ Time Frame: at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) ]
    The percentage of participants reporting acquired thrombocytopenia is presented.

  • New Onset Atrial Fibrillation/Flutter [ Time Frame: at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) ]
    The percentage of participants reporting new onset atrial fibrillation/flutter is presented.

  • Timing Effect on Bleeding Event Rate up to 48 Hours or Hospital Discharge [ Time Frame: Up to 48 hours after procedure or at hospital discharge (but also includes any subsequent hospitalizations) ]
    The effect of timing on bleeding event rates (the percentage of participants with an incidence of major bleeding) is presented.

  • Bleeding BARC 3a, BARC Types 1 or 2, and TIMI Minor [ Time Frame: at 48 hours or hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) follow-up ]
    The percentage of participants with moderate bleeding as defined by BARC 3a and minor bleeding as defined as BARC type 1 and 2 and TIMI minor is presented.


Enrollment: 803
Study Start Date: October 2012
Study Completion Date: June 2015
Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.
Drug: Bivalirudin
Bivalirudin is an anticoagulant that binds directly to thrombin in a bivalent and reversible fashion.
Other Names:
  • AngioMAX
  • Angiox
Active Comparator: 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.
Drug: Unfractionated Heparin
Unfractionated heparin is an anticoagulant.
Other Name: Heparin

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01651780

Locations
Canada, Quebec
Montreal Heart Institute
Montreal, Quebec, Canada, H1T 1C8
Canada
St. Paul´s Hospital Providence Health Care
Vancouver, Canada, V6Z1Y6
France
Clinique Pasteur, Unité de Cardiologie Interventionnelle
Toulouse, Cedex 3, France, 31076
CHU de Toulouse
Toulouse, Cedex 9, France, 31059
CHU Jean Minjoz, Service de Cardiologie
Besançon, France, 25000
Centre Hospitalier de Lyon
Bron, France, 69500
Department of Cardiology, CHRU Lille
Lille, France, 59037
Institut Hospitalier Jacques Cartier
Massy, France, 91300
Service de Cardiologie, Centre Hospitalo-Universitaire, Hôpital Charles-Nicolle
Rouen, France, 76031
Germany
University Heart Centre, Clinic of Inner Medicine 1 Cardiology
Jena, Lobeda Ost, Germany, 07747
Universitätsklinikum Bonn
Bonn, Germany, 53105
Klinikum links der Weser Bremen
Bremen, Germany, 28277
Elisabeth-Krankenhaus Essen
Essen, Germany, 45257
Freiburg University
Freiburg, Germany, 79106
Asklepios St. Georg Hamburg
Hamburg, Germany, 20099
Universitätsklinikum Hamburg-Eppendorf
Hamburg, Germany, 20246
Medizinische Hochschule Hannover
Hannover, Germany, 30625
Universität Leipzig - Herzzentrum GmbH
Leipzig, Germany, 04289
Universitätsmedizin der Johannes Gutenberg-Universitat Mainz
Mainz, Germany, 55131
LMU Munich, Klinikum der Universität München
Munich, Germany, 81377
Deutsches Herzzentrum München
München, Germany, 80636
Helios Heart Center Siegburg
Siegburg, Germany, 53721
Italy
Ferraroto Hospital, University of Catania
Catania, Italy, 95123
Ospedale San Raffaele U.O. Cardiologia Interventistica
Milano, Italy, 20132
Azienda Ospedaliero-Universitaria Pisana
Pisa, Italy, 56124
Azienda Ospedaliera San Camillo-Forlanini
Roma, Italy, 00151
Policlinico Umberto I, Università La Sapienza
Roma, Italy
Netherlands
St. Antonius Ziekenhuis
Nieuwegein, Netherlands, 3435
University Medical Center Utrecht
Utrecht, Netherlands, 3584 CX
Switzerland
Cardiology University Hospital Basel
Basel, Switzerland, CH-4031
Universitätsklinik Bern
Bern, Switzerland, 3010
United Kingdom
The Royal Sussex County Hospital
Brighton, East Sussex, United Kingdom, BN2 5BE
Hammersmith Hospital
London, United Kingdom, W12 0HS
Sponsors and Collaborators
The Medicines Company
Investigators
Principal Investigator: Thierry Lefevre, MD Hôpital Privé Jacques Cartier
Principal Investigator: Eberhardt Grube, MD University Hospital, Bonn
Study Director: George D Dangas, MD, PhD The Zena and Michael A. Wiener Cardiovascular Institute
Study Director: Prodromos Anthopoulos, MD The Medicines Company
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: The Medicines Company
ClinicalTrials.gov Identifier: NCT01651780     History of Changes
Other Study ID Numbers: TMC-BIV-11-02
2012‐000632‐26 ( EudraCT Number )
Study First Received: July 24, 2012
Results First Received: January 9, 2017
Last Updated: March 9, 2017

Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by The Medicines Company:
Transcatheter aortic valve replacement
Aortic valve replacement
Severe aortic stenosis

Additional relevant MeSH terms:
Aortic Valve Stenosis
Heart Valve Diseases
Heart Diseases
Cardiovascular Diseases
Ventricular Outflow Obstruction
Calcium heparin
Bivalirudin
Heparin
Hirudins
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 18, 2017