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

Study Overview
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Brief Summary
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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.

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

Conditions
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Severe Aortic Stenosis, Transcatheter Aortic Valve Replacement, Aortic Valve Replacement

Intervention / Treatment
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* Drug: Bivalirudin
* Drug: Unfractionated Heparin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bivalirudin<br>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<br>* Bivalirudin is an anticoagulant that binds directly to thrombin in a bivalent and reversible fashion.<br>* Other names: Angiox;|
| Active Comparator: Unfractionated heparin (UFH)<br>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<br>* Unfractionated heparin is an anticoagulant.<br>* Other names: Heparin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NACE at 48 Hours or Before Hospital Discharge | 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 | 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) | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Transcatheter aortic valve replacement, Aortic valve replacement, Severe aortic stenosis