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

The Medicines Company

Status and phase: Completed; Phase 3

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

Treatments: Drug: Unfractionated Heparin; Drug: Bivalirudin

Study type: Interventional

Funder types: Industry

Identifiers

NCT01651780

TMC-BIV-11-02

2012-000632-26 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 803 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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803 participants in 2 patient groups

Bivalirudin

Experimental group

Description:

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.

Treatment:

Drug: Bivalirudin

Unfractionated heparin (UFH)

Active Comparator group

Description:

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.

Treatment:

Drug: Unfractionated Heparin