Open-label, Randomized Trial in Participants Undergoing TAVR to Determine Safety & Efficacy of Bivalirudin vs UFH (BRAVO 2/3)
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| ClinicalTrials.gov Identifier: NCT01651780 |
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Recruitment Status :
Completed
First Posted : July 27, 2012
Results First Posted : February 27, 2017
Last Update Posted : April 7, 2017
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Sponsor:
The Medicines Company
Information provided by (Responsible Party):
The Medicines Company
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Severe Aortic Stenosis Transcatheter Aortic Valve Replacement Aortic Valve Replacement | Drug: Bivalirudin Drug: Unfractionated Heparin | Phase 3 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 803 participants |
| 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) |
| Study Start Date : | October 2012 |
| Actual Primary Completion Date : | June 2015 |
| Actual Study Completion Date : | June 2015 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Supravalvular aortic stenosis
MedlinePlus related topics:
Blood Thinners
| Arm | Intervention/treatment |
|---|---|
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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.
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Drug: Bivalirudin
Bivalirudin is an anticoagulant that binds directly to thrombin in a bivalent and reversible fashion.
Other Names:
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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.
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Drug: Unfractionated Heparin
Unfractionated heparin is an anticoagulant.
Other Name: Heparin |
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.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| 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
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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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01651780
Locations
Show 33 study locations
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 |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | The Medicines Company |
| ClinicalTrials.gov Identifier: | NCT01651780 |
| Other Study ID Numbers: |
TMC-BIV-11-02 2012-000632-26 ( EudraCT Number ) |
| First Posted: | July 27, 2012 Key Record Dates |
| Results First Posted: | February 27, 2017 |
| Last Update Posted: | April 7, 2017 |
| Last Verified: | March 2017 |
| Product Manufactured in and Exported from the U.S.: | Yes |
Keywords provided by The Medicines Company:
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Transcatheter aortic valve replacement Aortic valve replacement Severe aortic stenosis |
Additional relevant MeSH terms:
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Aortic Valve Stenosis Heart Valve Diseases Heart Diseases Cardiovascular Diseases Ventricular Outflow Obstruction Heparin Calcium heparin Bivalirudin |
Anticoagulants Fibrinolytic Agents Fibrin Modulating Agents Molecular Mechanisms of Pharmacological Action Antithrombins Serine Proteinase Inhibitors Protease Inhibitors Enzyme Inhibitors |