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

March 9, 2017 updated by: The Medicines Company

Effect of Bivalirudin on Aortic Valve Intervention Outcomes 2/3 (BRAVO 2/3)

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
803

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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:
  • Angiox
  • AngioMAX
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 Names:
  • Heparin

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
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.
at 48 hours or discharge, whichever occurs first
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.
up to 30 days after procedure

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
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.
at 48 hours or before hospital discharge, whichever occurred earlier
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.
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)
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
at 48 hours or hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) follow-up
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.
at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days)
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.
at 48 hours or hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) follow-up
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.
at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days)
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.
at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days)
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.
at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days)
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.
Up to 48 hours after procedure or at hospital discharge (but also includes any subsequent hospitalizations)
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.
at 48 hours or hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) follow-up

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
The Medicines Company

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • 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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 1, 2012

Primary Completion (ACTUAL)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 1, 2015

Study Completion (ACTUAL)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 1, 2015

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 24, 2012

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 26, 2012

First Posted (ESTIMATE)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 27, 2012

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 7, 2017

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 9, 2017

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • TMC-BIV-11-02
  • 2012-000632-26 (EUDRACT_NUMBER)

Drug and device information, study documents

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Cookie Settings

We use cookies to ensure that we give you the best experience on our website. For more details carefully read our Privacy and Cookies Policy. ...>>>You can change your preferences or withdraw your consent at any time by deleting the cookies from your website or computer as described in the policy. Please accept it and choose your preferences by ticking the corresponding boxes in the "Manage Settings" section below. Please carefully read our Terms of Service before you proceed with using any part of this website.
«Manage Settings