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

• Sponsor: The Medicines Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01651780
• Collaborator: (none)
• Enrollment: 803
• Locations: 33
• Arms: 2
• Duration (Months): 32
• Patients Per Site: 24.3
• Patients Per Site Per Month: 0.8

Study Details

Study Description

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 Design

• Study Type: Interventional
• 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: Oct 1, 2012
• Actual Primary Completion Date: Jun 1, 2015
• Actual Study Completion Date: Jun 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
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: AngioMAX Angiox
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

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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

1. 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.

2. 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.

3. 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

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

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

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: The Medicines Company
• ClinicalTrials.gov Identifier: NCT01651780
• Other Study ID Numbers: TMC-BIV-11-02; 2012-000632-26
• First Posted: Jul 27, 2012
• Last Update Posted: Apr 7, 2017
• Last Verified: Mar 1, 2017

• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by The Medicines Company: Transcatheter aortic valve replacement; Aortic valve replacement; Severe aortic stenosis
• Additional relevant MeSH terms: Aortic Valve Stenosis; Heparin; Calcium heparin; Bivalirudin

Study Results

Participant Flow

Arm/Group Title	Bivalirudin	Unfractionated Heparin (UFH)
Arm/Group Description	Bivalirudin administered as a bolus and intravenous (IV) infusion during transcatheter aortic valve replacement (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.	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.
Period Title: Overall Study
STARTED	405	398
Intent-To-Treat (ITT) Population	404	398
Received at Least 1 Dose of Study Drug	393	394
BRAVO 2 Feasibility Cohort	65	0
COMPLETED	394	388
NOT COMPLETED	11	10

Baseline Characteristics

Arm/Group Title	Bivalirudin	Unfractionated Heparin (UFH)	Total
Arm/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.	The dose of UFH adhered to the standard institutional practice. An ACT target ≥250 seconds was recommended. All wires, catheters, and sheaths were to be flushed with heparinized saline.	Total of all reporting groups
Overall Participants	404	398	802
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	82.3 (6.5)	82.3 (6.5)	82.3 (6.5)
Sex: Female, Male (Count of Participants)
Female	195 48.3%	196 49.2%	391 48.8%
Male	209 51.7%	202 50.8%	411 51.2%
Region of Enrollment (participants) [Number]
Canada	36 8.9%	38 9.5%	74 9.2%
Netherlands	10 2.5%	10 2.5%	20 2.5%
Italy	37 9.2%	39 9.8%	76 9.5%
United Kingdom	8 2%	10 2.5%	18 2.2%
France	108 26.7%	106 26.6%	214 26.7%
Switzerland	25 6.2%	22 5.5%	47 5.9%
Germany	180 44.6%	173 43.5%	353 44%

Outcome Measures

1. Primary Outcome

Title	Major Bleeding (BARC ≥3b) at 48 Hours or Before Hospital Discharge
Description	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.
Time Frame	at 48 hours or discharge, whichever occurs first

Outcome Measure Data

Analysis Population Description

Participants in the ITT population.

Arm/Group Title	Bivalirudin	Unfractionated Heparin (UFH)
Arm/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.	The dose of UFH adhered to the standard institutional practice. An ACT target ≥250 seconds was recommended. All wires, catheters, and sheaths were to be flushed with heparinized saline.
Measure Participants	404	398
Number [percentage of participants]	6.9 1.7%	9 2.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bivalirudin, Unfractionated Heparin (UFH)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	If non-inferiority was confirmed, then superiority analysis was pursued.
Statistical Test of Hypothesis	p-Value	0.2692
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.48 to 1.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Net Adverse Clinical Events (NACE) at up to 30 Days
Description	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.
Time Frame	up to 30 days after procedure

Outcome Measure Data

Analysis Population Description

Participants in the ITT population.

Arm/Group Title	Bivalirudin	Unfractionated Heparin (UFH)
Arm/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.	The dose of UFH adhered to the standard institutional practice. An ACT target ≥250 seconds was recommended. All wires, catheters, and sheaths were to be flushed with heparinized saline.
Measure Participants	404	398
Number [percentage of participants]	14.4 3.6%	16.1 4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bivalirudin, Unfractionated Heparin (UFH)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	If non-inferiority was confirmed, then superiority analysis was pursued.
Statistical Test of Hypothesis	p-Value	0.4967
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; 0.64 to 1.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	NACE at 48 Hours or Before Hospital Discharge
Description	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.
Time Frame	at 48 hours or before hospital discharge, whichever occurred earlier

Outcome Measure Data

Analysis Population Description

Participants in the ITT population.

Arm/Group Title	Bivalirudin	Unfractionated Heparin (UFH)
Arm/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.	The dose of UFH adhered to the standard institutional practice. An ACT target ≥250 seconds was recommended. All wires, catheters, and sheaths were to be flushed with heparinized saline.
Measure Participants	404	398
Number [percentage of participants]	8.9 2.2%	12.6 3.2%

4. Secondary Outcome

Title	Major Adverse Cardiac Events (MACE) Including Death, Non-fatal MI, and Stroke
Description	The percentage of participants reporting a MACE overall and the individual components of MACE (including death, non-fatal MI, and stroke) are presented.
Time Frame	at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days)

Outcome Measure Data

Analysis Population Description

Participants in the ITT population.

Arm/Group Title	Bivalirudin	Unfractionated Heparin (UFH)
Arm/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.	The dose of UFH adhered to the standard institutional practice. An ACT target ≥250 seconds was recommended. All wires, catheters, and sheaths were to be flushed with heparinized saline.
Measure Participants	404	398
MACE at 48 hours or before hospital discharge	3.5 0.9%	4.8 1.2%
Death at 48 hours or before hospital discharge	1.5 0.4%	1.8 0.5%
MI at 48 hours or before hospital discharge	0 0%	1.3 0.3%
Stroke at 48 hours or before hospital discharge	2 0.5%	2 0.5%
MACE at up to 30 days	7.7 1.9%	8 2%
Death at up to 30 days	4.7 1.2%	4.8 1.2%
MI at up to 30 days	0.5 0.1%	1.8 0.5%
Stroke at up to 30 days	3.5 0.9%	2.8 0.7%

5. Secondary Outcome

Title	Major Bleeding According to Additional Scales (VARC, TIMI, GUSTO, ACUITY/HORIZONS)
Description	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
Time Frame	at 48 hours or hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) follow-up

Outcome Measure Data

Analysis Population Description

Participants in the ITT population.

Arm/Group Title	Bivalirudin	Unfractionated Heparin (UFH)
Arm/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.	The dose of UFH adhered to the standard institutional practice. An ACT target ≥250 seconds was recommended. All wires, catheters, and sheaths were to be flushed with heparinized saline.
Measure Participants	404	398
VARC at 48 hours or before hospital	21.8 5.4%	19.6 4.9%
TIMI at 48 hours or before hospital	4 1%	6.5 1.6%
GUSTO at 48 hours or hospital discharge	13.9 3.4%	11.6 2.9%
ACUITY/HORIZONS at 48 hours or hospital discharge	26 6.4%	24.4 6.1%
VARC at 30 days	26.5 6.6%	24.6 6.2%
TIMI at 30 days	5.7 1.4%	7.3 1.8%
GUSTO at 30 days	16.3 4%	14.6 3.7%
ACUITY/HORIZONS at 30 days	33.4 8.3%	29.6 7.4%

6. Secondary Outcome

Title	Transient Ischemic Attack
Description	The percentage of participants reporting transient ischemic attack is presented.
Time Frame	at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days)

Outcome Measure Data

Analysis Population Description

Participants in the ITT population.

Arm/Group Title	Bivalirudin	Unfractionated Heparin (UFH)
Arm/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.	The dose of UFH adhered to the standard institutional practice. An ACT target ≥250 seconds was recommended. All wires, catheters, and sheaths were to be flushed with heparinized saline.
Measure Participants	404	398
at 48 hours or before hospital discharge	0 0%	0 0%
at up to 30 days (±7 days) follow-up	0 0%	0 0%

7. Secondary Outcome

Title	Acute Kidney Injury
Description	The percentage of participants reporting acute kidney injury is presented.
Time Frame	at 48 hours or hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) follow-up

Outcome Measure Data

Analysis Population Description

Participants in the ITT population.

Arm/Group Title	Bivalirudin	Unfractionated Heparin (UFH)
Arm/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.	The dose of UFH adhered to the standard institutional practice. An ACT target ≥250 seconds was recommended. All wires, catheters, and sheaths were to be flushed with heparinized saline.
Measure Participants	404	398
at 48 hours or before hospital discharge	10.9 2.7%	6.5 1.6%
at up to 30 days (±7 days) follow-up	18.8 4.7%	13.8 3.5%

8. Secondary Outcome

Title	Major Vascular Complications
Description	The percentage of participants reporting a major vascular complications as defined by VARC is presented.
Time Frame	at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days)

Outcome Measure Data

Analysis Population Description

Participants in the ITT population.

Arm/Group Title	Bivalirudin	Unfractionated Heparin (UFH)
Arm/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.	The dose of UFH adhered to the standard institutional practice. An ACT target ≥250 seconds was recommended. All wires, catheters, and sheaths were to be flushed with heparinized saline.
Measure Participants	404	398
at 48 hours or before hospital discharge	8.7 2.2%	9 2.3%
at up to 30 days (±7 days) follow-up	9.2 2.3%	9.5 2.4%

9. Secondary Outcome

Title	Acquired Thrombocytopenia
Description	The percentage of participants reporting acquired thrombocytopenia is presented.
Time Frame	at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days)

Outcome Measure Data

Analysis Population Description

Participants in the ITT population.

Arm/Group Title	Bivalirudin	Unfractionated Heparin (UFH)
Arm/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.	The dose of UFH adhered to the standard institutional practice. An ACT target ≥250 seconds was recommended. All wires, catheters, and sheaths were to be flushed with heparinized saline.
Measure Participants	404	398
at 48 hours or before hospital discharge	16.6 4.1%	17.3 4.3%
at up to 30 days (±7 days)	24 5.9%	23.1 5.8%

10. Secondary Outcome

Title	New Onset Atrial Fibrillation/Flutter
Description	The percentage of participants reporting new onset atrial fibrillation/flutter is presented.
Time Frame	at 48 hours or before hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days)

Outcome Measure Data

Analysis Population Description

Participants in the ITT population.

Arm/Group Title	Bivalirudin	Unfractionated Heparin (UFH)
Arm/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.	The dose of UFH adhered to the standard institutional practice. An ACT target ≥250 seconds was recommended. All wires, catheters, and sheaths were to be flushed with heparinized saline.
Measure Participants	404	398
at 48 hours or before hospital discharge	3.2 0.8%	2.5 0.6%
at up to 30 days (±7 days) follow-up	5.4 1.3%	4 1%

11. Secondary Outcome

Title	Timing Effect on Bleeding Event Rate up to 48 Hours or Hospital Discharge
Description	The effect of timing on bleeding event rates (the percentage of participants with an incidence of major bleeding) is presented.
Time Frame	Up to 48 hours after procedure or at hospital discharge (but also includes any subsequent hospitalizations)

Outcome Measure Data

Analysis Population Description

Participants in the ITT population with an incidence of major bleeding. Participants were categorized as "First half of study site's enrolled participants" (Bivalirudin, N=173; UFH, N=173) and "Second half of study site's enrolled participants" (Bivalirudin, N=171; UFH, N=165). Only sites with >20 participants are included in this analysis.

Arm/Group Title	Bivalirudin: First Half of Study Site's Enrolled Participants	Bivalirudin: Second Half of Study Site's Enrolled Participants	UFH: First Half of Study Site's Enrolled Participants	UFH: Second Half of Study Site's Enrolled Participants
Arm/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. This includes the first half of the site's enrolled participants, and only sites with more than 20 participants are included in this analysis.	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. This includes the second half of the site's enrolled participants, and only sites with more than 20 participants are included in this analysis.	The dose of UFH adhered to the standard institutional practice. An ACT target ≥250 seconds was recommended. All wires, catheters, and sheaths were to be flushed with heparinized saline. This includes the first half of the site's enrolled participants, and only sites with more than 20 participants are included in this analysis.	The dose of UFH adhered to the standard institutional practice. An ACT target ≥250 seconds was recommended. All wires, catheters, and sheaths were to be flushed with heparinized saline. This includes the second half of the site's enrolled participants, and only sites with more than 20 participants are included in this analysis.
Measure Participants	173	171	173	165
Number [percentage of participants]	6.4 1.6%	6.4 1.6%	11.6 1.4%	8.5 NaN

12. Secondary Outcome

Title	Bleeding BARC 3a, BARC Types 1 or 2, and TIMI Minor
Description	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.
Time Frame	at 48 hours or hospital discharge, whichever occurred earlier, and at up to 30 days (±7 days) follow-up

Outcome Measure Data

Analysis Population Description

Participants in the ITT population.

Arm/Group Title	Bivalirudin	Unfractionated Heparin (UFH)
Arm/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.	The dose of UFH adhered to the standard institutional practice. An ACT target ≥250 seconds was recommended. All wires, catheters, and sheaths were to be flushed with heparinized saline.
Measure Participants	404	398
BARC 3a at 48 hours or hospital discharge	15.6 3.9%	13.3 3.3%
BARC types 1 and 2 at 48 hours or discharge	20.8 5.1%	21.1 5.3%
TIMI minor at 48 hours or hospital discharge	16.6 4.1%	14.3 3.6%
BARC 3a at 30 days	18.8 4.7%	17.3 4.3%
BARC types 1 and 2 at 30 days	27.7 6.9%	25.6 6.4%
TIMI minor at 30 days	21.3 5.3%	19.3 4.8%

Adverse Events

Arm/Group Title	Bivalirudin		Unfractionated Heparin (UFH)
Arm/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.		The dose of UFH adhered to the standard institutional practice. An ACT target ≥250 seconds was recommended. All wires, catheters, and sheaths were to be flushed with heparinized saline.
All Cause Mortality
	Bivalirudin		Unfractionated Heparin (UFH)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Bivalirudin		Unfractionated Heparin (UFH)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	112/393 (28.5%)		116/394 (29.4%)
Cardiac disorders
Atrioventricular block complete	46/393 (11.7%)		34/394 (8.6%)
Bundle branch block left	7/393 (1.8%)		10/394 (2.5%)
Bradycardia	2/393 (0.5%)		7/394 (1.8%)
Cardiac arrest	2/393 (0.5%)		7/394 (1.8%)
Atrioventricular block second degree	2/393 (0.5%)		6/394 (1.5%)
Atrioventricular block first degree	3/393 (0.8%)		4/394 (1%)
Atrioventricular block	2/393 (0.5%)		4/394 (1%)
Ventricular tachycardia	4/393 (1%)		1/394 (0.3%)
Cardiac failure acute	1/393 (0.3%)		3/394 (0.8%)
Aortic valve incompetence	1/393 (0.3%)		1/394 (0.3%)
Cardiac tamponade	1/393 (0.3%)		1/394 (0.3%)
Cardiogenic shock	0/393 (0%)		2/394 (0.5%)
Coronary artery occlusion	0/393 (0%)		2/394 (0.5%)
Ventricular fibrillation	1/393 (0.3%)		1/394 (0.3%)
Ventricular tachyarrhythmia	1/393 (0.3%)		1/394 (0.3%)
Bifascicular block	1/393 (0.3%)		0/394 (0%)
Bradyarrhythmia	1/393 (0.3%)		0/394 (0%)
Cardiac perforation	0/393 (0%)		1/394 (0.3%)
Cardio-respiratory arrest	1/393 (0.3%)		0/394 (0%)
Cardiopulmonary failure	1/393 (0.3%)		0/394 (0%)
Coronary artery stenosis	0/393 (0%)		1/394 (0.3%)
Ischaemic cardiomyopathy	0/393 (0%)		1/394 (0.3%)
Low cardiac output syndrome	0/393 (0%)		1/394 (0.3%)
Pericardial effusion	1/393 (0.3%)		0/394 (0%)
Sick sinus syndrome	1/393 (0.3%)		0/394 (0%)
Supraventricular tachycardia	1/393 (0.3%)		0/394 (0%)
Bundle branch block	2/393 (0.5%)		0/394 (0%)
Cardiac failure	6/393 (1.5%)		10/394 (2.5%)
Gastrointestinal disorders
Retroperitoneal haemorrhage	1/393 (0.3%)		1/394 (0.3%)
Abdominal hernia	0/393 (0%)		1/394 (0.3%)
Abdominal pain	0/393 (0%)		1/394 (0.3%)
Gastric haemorrhage	1/393 (0.3%)		0/394 (0%)
Gastritis	0/393 (0%)		1/394 (0.3%)
Intestinal infarction	0/393 (0%)		1/394 (0.3%)
Intestinal ischaemia	1/393 (0.3%)		0/394 (0%)
Umbilical hernia, obstructive	1/393 (0.3%)		0/394 (0%)
General disorders
Death	1/393 (0.3%)		1/394 (0.3%)
Device leakage	1/393 (0.3%)		1/394 (0.3%)
Thrombosis in device	2/393 (0.5%)		0/394 (0%)
Device dislocation	0/393 (0%)		1/394 (0.3%)
General physical health deterioration	1/393 (0.3%)		0/394 (0%)
Hyperthermia	1/393 (0.3%)		0/394 (0%)
Multi-organ failure	0/393 (0%)		1/394 (0.3%)
Non-cardiac chest pain	1/393 (0.3%)		0/394 (0%)
Pyrexia	1/393 (0.3%)		0/394 (0%)
Sudden death	1/393 (0.3%)		0/394 (0%)
Hepatobiliary disorders
Cholecystitis acute	0/393 (0%)		1/394 (0.3%)
Immune system disorders
Anaphylactic shock	1/393 (0.3%)		0/394 (0%)
Infections and infestations
Pneumonia	2/393 (0.5%)		2/394 (0.5%)
Bronchopneumonia	0/393 (0%)		2/394 (0.5%)
Sepsis	1/393 (0.3%)		1/394 (0.3%)
Bronchitis	0/393 (0%)		1/394 (0.3%)
Infection	0/393 (0%)		1/394 (0.3%)
Intervertebral discitis	1/393 (0.3%)		0/394 (0%)
Klebsiella infection	0/393 (0%)		1/394 (0.3%)
Pneumonia viral	1/393 (0.3%)		0/394 (0%)
Postoperative wound infection	0/393 (0%)		1/394 (0.3%)
Pseudomonas infection	1/393 (0.3%)		0/394 (0%)
Septic encephalopathy	1/393 (0.3%)		0/394 (0%)
Urinary tract infection	0/393 (0%)		1/394 (0.3%)
Injury, poisoning and procedural complications
Cardiac valve replacement	3/393 (0.8%)		0/394 (0%)
Cardiac valve rupture	0/393 (0%)		2/394 (0.5%)
Fall	0/393 (0%)		2/394 (0.5%)
Pneumothorax traumatic	1/393 (0.3%)		0/394 (0%)
Vascular procedure complication	1/393 (0.3%)		0/394 (0%)
Metabolism and nutrition disorders
Diabetes mellitus inadequate control	0/393 (0%)		1/394 (0.3%)
Hyperglycaemia	1/393 (0.3%)		0/394 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer	0/393 (0%)		2/394 (0.5%)
Bladder cancer	1/393 (0.3%)		0/394 (0%)
Gastric cancer	0/393 (0%)		1/394 (0.3%)
Nervous system disorders
Ischaemic stroke	3/393 (0.8%)		0/394 (0%)
Carotid artery stenosis	0/393 (0%)		1/394 (0.3%)
Cerebrovascular accident	0/393 (0%)		1/394 (0.3%)
Cognitive disorder	0/393 (0%)		1/394 (0.3%)
Haemorrhage intracranial	0/393 (0%)		1/394 (0.3%)
Haemorrhagic stroke	1/393 (0.3%)		0/394 (0%)
Loss of consciousness	0/393 (0%)		1/394 (0.3%)
Myasthenia gravis	1/393 (0.3%)		0/394 (0%)
Syncope	1/393 (0.3%)		0/394 (0%)
Psychiatric disorders
Confusional state	1/393 (0.3%)		0/394 (0%)
Panic attack	0/393 (0%)		1/394 (0.3%)
Renal and urinary disorders
Renal failure acute	0/393 (0%)		2/394 (0.5%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/393 (0.5%)		1/394 (0.3%)
Pleural effusion	2/393 (0.5%)		0/394 (0%)
Respiratory failure	1/393 (0.3%)		1/394 (0.3%)
Chronic obstructive pulmonary	1/393 (0.3%)		0/394 (0%)
Pleurisy	1/393 (0.3%)		0/394 (0%)
Pneumothorax	0/393 (0%)		1/394 (0.3%)
Pulmonary embolism	0/393 (0%)		1/394 (0.3%)
Surgical and medical procedures
Intestinal anastomosis	1/393 (0.3%)		0/394 (0%)
Vascular disorders
Hypotension	2/393 (0.5%)		1/394 (0.3%)
Peripheral ischaemia	0/393 (0%)		2/394 (0.5%)
Aortic dissection	1/393 (0.3%)		0/394 (0%)
Circulatory collapse	1/393 (0.3%)		0/394 (0%)
Femoral artery dissection	1/393 (0.3%)		0/394 (0%)
Haemodynamic instability	0/393 (0%)		1/394 (0.3%)
Hypertensive crisis	0/393 (0%)		1/394 (0.3%)
Peripheral arterial occlusive disease	1/393 (0.3%)		0/394 (0%)
Peripheral artery thrombosis	1/393 (0.3%)		0/394 (0%)
Phlebitis	1/393 (0.3%)		0/394 (0%)
Shock	0/393 (0%)		1/394 (0.3%)
Other (Not Including Serious) Adverse Events
	Bivalirudin		Unfractionated Heparin (UFH)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	73/393 (18.6%)		70/394 (17.8%)
Cardiac disorders
Bundle branch block left	15/393 (3.8%)		16/394 (4.1%)
General disorders
Pyrexia	12/393 (3.1%)		19/394 (4.8%)
Musculoskeletal and connective tissue disorders
Back pain	13/393 (3.3%)		9/394 (2.3%)
Psychiatric disorders
Confusional state	14/393 (3.6%)		10/394 (2.5%)
Vascular disorders
Hypertension	19/393 (4.8%)		16/394 (4.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.