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

Phase 3

Completed

Conditions: Transcatheter Aortic Valve Replacement
Aortic Valve Replacement
Severe Aortic Stenosis

Interventions: Drug: Bivalirudin
Drug: Unfractionated Heparin

Registration Number: NCT01651780

Lead Sponsor: The Medicines Company

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 803

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Bivalirudin	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.
Unfractionated heparin (UFH)	Unfractionated Heparin	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.

Primary Outcome Measures

Name	Time	Method
Major Bleeding (BARC ≥3b) at 48 Hours or Before Hospital Discharge	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	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

Name	Time	Method
New Onset Atrial Fibrillation/Flutter	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.
Bleeding BARC 3a, BARC Types 1 or 2, and TIMI Minor	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.
Acute Kidney Injury	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.
NACE at 48 Hours or Before Hospital Discharge	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 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	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	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.
Major Vascular Complications	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	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.
Timing Effect on Bleeding Event Rate up to 48 Hours or Hospital Discharge	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.
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)	The percentage of participants reporting a MACE overall and the individual components of MACE (including death, non-fatal MI, and stroke) are presented.

Trial Locations

Locations (33): Montreal Heart Institute
🇨🇦
Montreal, Quebec, Canada
St. Paul´s Hospital Providence Health Care
🇨🇦
Vancouver, Canada
Centre Hospitalier de Lyon
🇫🇷
Bron, 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
Asklepios St. Georg Hamburg
🇩🇪
Hamburg, Germany
Universität Leipzig - Herzzentrum GmbH
🇩🇪
Leipzig, Germany
Deutsches Herzzentrum München
🇩🇪
München, Germany
Helios Heart Center Siegburg
🇩🇪
Siegburg, Germany
Ospedale San Raffaele U.O. Cardiologia Interventistica
🇮🇹
Milano, Italy
Azienda Ospedaliera San Camillo-Forlanini
🇮🇹
Roma, Italy
Policlinico Umberto I, Università La Sapienza
🇮🇹
Roma, Italy
St. Antonius Ziekenhuis
🇳🇱
Nieuwegein, Netherlands
Universitätsklinik Bern
🇨🇭
Bern, Switzerland
Cardiology University Hospital Basel
🇨🇭
Basel, Switzerland
The Royal Sussex County Hospital
🇬🇧
Brighton, East Sussex, United Kingdom
Hammersmith Hospital
🇬🇧
London, United Kingdom
CHU de Toulouse
🇫🇷
Toulouse, Cedex 9, France
Clinique Pasteur, Unité de Cardiologie Interventionnelle
🇫🇷
Toulouse, Cedex 3, France
CHU Jean Minjoz, Service de Cardiologie
🇫🇷
Besançon, France
Department of Cardiology, CHRU Lille
🇫🇷
Lille, France
Institut Hospitalier Jacques Cartier
🇫🇷
Massy, France
Elisabeth-Krankenhaus Essen
🇩🇪
Essen, Germany
Freiburg University
🇩🇪
Freiburg, Germany
Universitätsklinikum Hamburg-Eppendorf
🇩🇪
Hamburg, Germany
Medizinische Hochschule Hannover
🇩🇪
Hannover, Germany
Universitätsmedizin der Johannes Gutenberg-Universitat Mainz
🇩🇪
Mainz, Germany
LMU Munich, Klinikum der Universität München
🇩🇪
Munich, Germany
Ferraroto Hospital, University of Catania
🇮🇹
Catania, Italy
Azienda Ospedaliero-Universitaria Pisana
🇮🇹
Pisa, Italy
University Medical Center Utrecht
🇳🇱
Utrecht, Netherlands