The Effect of BivaliRudin on
Aortic Valve Intervention
Outcomes 3 Trial
(BRAVO 3)
Thierry Lefèvre for the BRAVO 3 Study group
Disclosure Statement of Financial Interest
Within the past 12 months, I or my spouse/partner have had a financial
interest/arrangement or affiliation with the organization(s) listed below.
• Grant/Research Support
• Consulting Fees/Honoraria
• Major Stock Shareholder/Equity
• Royalty Income
• Ownership/Founder
• Intellectual Property Rights
• Other Financial Benefit
• Boston Sci, Directflow, Edwards,
Symetis, Medtronic,
Background
 Major bleeding remains an important concern in
TAVR.
 In daily practice, UFH has been the empiric
procedural anticoagulation regimen for TAVR.
 While reversal of heparin with protamine can be
used, practice patterns vary, with guideline
statements based on expert consensus rather than
on evidence from randomized trials.
3
Background
 Bivalirudin is a reversible direct thrombin inhibitor
with a half-life of 25 minutes, and has reduced major
bleeding in the setting of PCI compared to other
regimens.
 The safety and efficacy of bivalirudin compared with
UFH in TAVR is unknown
4
Objectives and Study Hypothesis
Objectives:
To assess the safety and efficacy of bivalirudin vs.
UFH in Transcatheter Aortic Valve Replacement.
Study Hypothesis:
 Bivalirudin will reduce bleeding rates compared to
UFH, and will improve the overall clinical outcomes of
TAVR patients (superiority hypothesis)
 Bivalirudin will be non-inferior to UFH in preventing
intra- and peri-procedural events in patients
undergoing TAVR (non-inferiority hypothesis)
5
5
Trial Organization and Committees
Executive Committee
•
•
•
•
•
•
•
•
•
•
•
•
•
•
George D Dangas, Icahn School of Medicine at Mount Sinai, New York, NY, USA (Chair, Mount Sinai)
Eberhard Grube, University Hospital, Bonn, Germany (Co-Principal Investigator)
Thierry Lefèvre, Hôpital Privé Jacques Cartier, Massy, France (Co-Principal Investigator)
Antonio Colombo, San Raffaele Hospital, Milan, Italy
Christian Hengstenberg, Deutsches Herzzentrum München, München, Germany
Christian Kupatt, LMU Munich, Munich, Germany
David Hildick-Smith, Sussex Cardiac Centre – Brighton & Sussex University Hospitals NHS Trust, Brighton, Sussex, UK
John G Webb, St. Paul's Hospital, Providence Health Care, Vancouver, BC, Canada
Jurriën M ten Berg, St. Antonius Ziekenhuis, Nieuwegein, Netherlands
Efthymios N Deliargyris, The Medicines Company, Parsippany, NJ, USA
Nicolas Dumonteil CHU Rangueil, Toulouse, France
Prodromos Anthopoulos, The Medicines Company, Zurich, Switzerland
Roxana Mehran, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Stephan Windecker, Department of Cardiology, Bern University Hospital, Bern, Switzerland
Data Safety Monitoring Board
•
•
•
•
•
•
Michel Bertrand (France)
Gregory Dehmer (Texas A&M School of Medicine, Temple, Texas, USA)
Arie Pieter Kappetein (Thoraxcenter, Erasmus MC, Rotterdam Department of Thoracic Surgery, Rotterdam, Netherlands)
Germano DiSciascio (Campus Biomedico, University of Rome, Rome, Italy)
Stuart Pocock (London School of Hygiene & Tropical Medicine, UK)
Timothy Clayton (London School of Hygiene & Tropical Medicine, UK)
6
Statistical Methods
 The original sample size assumed an estimated
rate of major bleeding of 19% in the control group
and a relative risk reduction of 47% in the
experimental group so that a sample size of 261
Pts per arm would be needed for an 80% power to
detect a significant bleeding reduction at an alpha
level < 0.05.
 The study was also powered to show non-inferiority
for 30-day net adverse cardiovascular events with a
margin of 8.0% difference in event rates.
7
Statistical Methods
 BRAVO 3 had an adaptive sample size design and
after interim analysis, the data safety monitoring
board issued a recommendation to continue the trial
unmodified until the predefined maximum of 800
patients were enrolled.
 The primary data analysis was performed according
to the intention-to-treat principle.
8
Bravo 3 Study Flow
Phase III b
Open label,
randomized
802 high-risk TAVR in
7 countries / 31 sites
Sites in EU
and North
America
R
1:1
BIVALIRUDIN
(bolus 0.75 mg/kg + infusion 1.75 or
1.4 or 1.0 mg/kg/h)
Unfractionated Heparin*
(Recommended ACT ≥ 250)
Co-Primary Endpoints
• BARC ≥ 3b major bleeding†, at 48 hours or hospital discharge whichever occurs earlier
• Net Adverse Clinical Events [NACE] (Death, MI, stroke and major bleeding) up to 30 days.
*Heparin dosing and protamine use left at discretion of the operator
†Bleeding evaluated also according TIMI, GUSTO, ACUITY and VARC scales
9
Dangas et al, BRAVO-3 Investigators; JACC 2015; in press (online 10/15/2015)
9
UFH:
Dose and Mode of Administration
 Weight-adjusted bolus of UFH, when the valve
procedure is initiated, repeated doses as necessary
to maintain the ACT ≥ 250 sec, and possible reversal
with protamine at the end of the procedure according
to institutional practice..
10
10
Bivalirudin:
Dose and Mode of Administration
 0.75 mg/kg bolus preferably through the valve delivery sheath after
successful access and valve sheath insertion,
plus
 1.75 mg/kg/hr continuous intravenous infusion until successful valve
treatment is achieved in patients with normal renal function
or
 1.4 mg/kg/hr continuous intravenous infusion until successful valve
treatment is achieved in patients with moderate renal impairment
(GFR of 30-59 mL/min),
or
 1.0 mg/kg/hr continuous intravenous infusion until successful valve
treatment is achieved in patients with severe renal impairment
(GFR < 30 mL/min).
11
11
Inclusion Criteria
1. ≥ 18 years of age
2. High risk (Euroscore ≥18, or considered inoperable)
for SAVR
3. Undergoing TAVR via transfemoral arterial access
4. Provide written informed consent before initiation of
any study related procedures
12
12
Exclusion Criteria
1. Contraindication to bivalirudin or
2.
3.
4.
5.
6.
7.
8.
9.
unfractionated heparin
Refusal to receive blood transfusion
Mechanical valve (any location) or mitral
bioprosthetic valve
Use of elective surgical cut-down for
transfemoral access
Extensive calcification of the common
femoral artery or minimal luminal
diameter<6.5mm
Concurrent performance of PCI with
TAVR
INR ≥ 2 on day of TAVR or known history
of bleeding diathesis
History of hemorrhagic stroke,
intracranial hemorrhage, intracerebral
mass or aneurysm, or AVM
Administration of thrombolytics,
glycoprotein IIb/IIIa inhibitors, or warfarin
in the 3 days prior to the procedure
10. Acute MI, major surgery or any
11.
12.
13.
14.
15.
16.
therapeutic cardiac procedure (other
than BAV) within 30 days
PCI within 30 days
Upper GI or GU bleed within 30 days
Stroke or TIA within 30 days
Administration of: UFH within 30
minutes of the procedure OR
Enoxaparin within 8 hours of the
procedure OR Fondaparinux or other
LMWHs within 24 hours of the
procedure OR Dabigatran, rivaroxaban
or other oral anti-Xa or antithrombin
agent within 48 hours of the procedure,
OR Thrombolytics, GPI or warfarin
within 72 hours of the procedure
Absolute contraindications or allergy to
iodinated contrast that cannot be premedicated
Contraindications or allergy to aspirin or
clopidogrel
13
13
Recruiting Sites
Vancouver
Canada
2/75
UK
2/18
Netherlands
2/20
Germany
12/353
Montreal
Ranking
1
2
3
4
5
6
7
8
9
10
Investigator
Hengstenberg
Tchetche
Boekstegers
Webb
Linke
Dumonteil
Tron
Schäfer
Asgar
Van Belle
Country
Germany
France
Germany
Canada
Germany
France
France
Germany
Canada
France
Enrollment
88
60
51
41
41
38
38
38
34
33
France
6/214
Switzerland
2/47
Italy
5/76
14
14
Baseline Characteristics (I)
Bivalirudin
(N=404)
Heparin
(N=398)
Age – yr
82.3 ± 6.5
82.3 ± 6.5
Female sex – no. (%)
195 (48.3)
196 (49.2)
Logistic EuroSCORE – (%)
17.2 ± 10.7
16.9 ± 9.9
Diabetes mellitus – no. (%)
125 (30.9)
114 (28.6)
47/125 (37.6)
40/114 (35.1)
Chronic kidney disease (stage 4 or 5) – no. (%)
18 (4.5)
22 (5.5)
Peripheral artery disease – no. (%)
60 (14.9)
59/397 (14.9)
Prior stroke/transient ischemic attack – no./total no. (%)
45 (11.1)
38 (9.5)
Chronic obstructive pulmonary disease – no. (%)
68 (16.8)
87 (21.9)
Insulin treatment – no./total no. (%)
15
Dangas, Lefèvre et al, BRAVO-3 Investigators; JACC 2015; in press (online 10/15/2015)
Baseline Characteristics (II)
Bivalirudin
(N=404)
Heparin
(N=398)
209 (51.7)
196/397 (49.4)
Prior myocardial infarction, no./total no. (%)
63/400 (15.8)
53/394 (13.5)
Prior atrial fibrillation, no./total no. (%)
158/403 (39.2)
139/397 (35.0)
11/391 (2.8)
9/381 (2.4)
Previous CABG – no. (%)
61 (15.1)
56 (14.1)
Balloon aortic valvuloplasty – no. (%)
29 (7.2)
31/397 (7.8)
Left ventricular ejection fraction (%)
53.9 ± 12.8
53.4 ± 12.9
Hematocrit (%)
37.51 ± 4.87
38.06 ± 4.53
Hemoglobin (g/dl)
12.49 ± 1.74
12.68 ± 1.60
217.73 ± 73.91
217.18 ± 71.44
276/402 (68.7)
272/397 (68.5)
266/276 (96.4)
266/273 (97.4)
135/402 (33.6)
115/397 (29.0)
130/135 (96.3)
114/115 (99.1)
Coronary artery disease – no. (%)
Prior ventricular tachycardia, no./total no. (%)
Platelet count (x 109/L)
Antiplatelet medications as prior maintenance therapy
Aspirin, no./total no. (%)
≤160 mg, no./total no. (%)
P2Y12 inhibitor, no./total no. (%)
Clopidogrel, no./total no. (%)
16
Dangas, Lefèvre et al, BRAVO-3 Investigators; JACC 2015; in press (online 10/15/2015)
Procedural Data (I)
Bivalirudin
(N=404)
Heparin
(N=398)
393 (97.3)
388 (97.5)
Balloon expandable
251/391 (64.2)
249/391 (63.7)
Self expandable
140/391 (35.8)
142/391 (36.3)
35.0 (24, 50)
36.0 (24, 49)
<18
128/393 (32.6)
127/390 (32.6)
18
216/393 (55.0)
208/390 (53.3)
>18
49/393 (12.5)
55/390 (14.1)
7/397 (1.8)
3/393 (1.0)
4/396 (1.0)
3/393 (0.8)
359/396 (90.7)
367/393 (93.4)
33/396 (8.3)
23/393 (5.9)
Procedural success – no. (%)
Valve type – no./total no. (%)
Duration of procedure, median (IQR), min
Size of TAVR system (Fr) – no./total no. (%)
Embolic protection device used – no./total no. (%)
Closure technique used for TAVR access site
Not attempted – no./total no. (%)
Successful deployment – no./total no. (%)
Attempted but failed – no./total no. (%)
17
Dangas, Lefèvre et al, BRAVO-3 Investigators; JACC 2015; in press (online 10/15/2015)
Procedural Data (II)
Bivalirudin
(N=404)
Heparin
(N=398)
325/401 (81.0)
313/395 (79.2)
16/395 (4.1)
12/393 (3.1)
Prostar – no./total no. (%)
175/397 (44.1)
179/392 (45.7)
Proglide – no./total no. (%)
198/397 (49.9)
198/392 (50.5)
152/402 (37.8)
142/397 (35.8)
≤6 h
118/152 (77.6)
111/142 (78.2)
>6 h
34/152 (22.4)
31/142 (21.8)
Valvuloplasty performed pre-TAVR – no./total no. (%)
Additional TAVR device used – no./total no. (%)
Device used to close TAVR access site
Antiplatelet therapies – no./total no. (%)
Prior loading dose of P2Y12 inhibitor
Post procedure – no./total no. (%)
Aspirin
343/401 (85.5)
348/397 (87.7)
P2Y12 inhibitor
299/401 (74.6)
296/397 (74.6)
111/400 (27.8)
119/397 (30.0)
≤48 h – no./total no. (%)
31/400 (7.8)
39/397 (9.8)
>48 h to <30 days – no./total no. (%)
90/400 (22.5)
91/397 (22.9)
Post-procedural oral anticoagulant therapy
* Vitamin K antagonist (50/797, 6.2%), dabigatran (6/797, 0.8%), rivaroxaban (4/797, 0.1%), or fondaparinux (10/797, 1.2%).
18
Dangas, Lefèvre et al, BRAVO-3 Investigators; JACC 2015; in press (online 10/15/2015)
Clinical Outcomes (ITT)
Bivalirudin
(N=404)
Heparin
(N=398)
Relative risk
Major bleeding (BARC ≥3b) at 48 h/PRE-D/C
28 (6.9%)
36 (9.0%)
0.77 (0.48-1.23)
0.27
Net adverse cardiovascular events 30 days
58 (14.4%)
64 (16.1%)
0.89 (0.64-1.24)
0.50
(95% Ci)
P value
Co-primary endpoints
19
Dangas, Lefèvre et al, BRAVO-3 Investigators; JACC 2015; in press (online 10/15/2015)
Clinical Outcomes (ITT)
Bivalirudin
(N=404)
Heparin
(N=398)
Relative risk
Major bleeding (BARC ≥3b) at 48 h/PRE-D/C
28 (6.9%)
36 (9.0%)
0.77 (0.48-1.23)
0.27
Net adverse cardiovascular events 30 days
58 (14.4%)
64 (16.1%)
0.89 (0.64-1.24)
0.50
Mortality
6 (1.5%)
7 (1.8%)
0.85 (0.29-2.49)
0.76
Net adverse cardiovascular events
36 (8.9%)
50 (12.6%)
0.71 (0.47-1.06)
0.09
VARC (life-threatening or major)
88 (21.8%)
78 (19.6%)
1.11 (0.85-1.46)
0.45
TIMI (major)
16 (4.0%)
26 (6.5%)
0.61 (0.33-1.11)
0.10
GUSTO (severe/life-threatening)
15 (3.7%)
13 (3.3%)
1.14 (0.55-2.36)
0.73
105 (26.0%)
97 (24.4%)
1.07 (0.84-1.35)
0.60
(95% CI)
P value
Co-primary endpoints
Secondary endpoints at 48 h
ACUITY/HORIZONS (major)
20
Dangas, Lefèvre et al, BRAVO-3 Investigators; JACC 2015; in press (online 10/15/2015)
48-h Major bleeding (BARC >3b)
Bivalirudin
Heparin
9.1%
Event Rate
7.0%
Log rank p = 0.50
Days from Randomization Date
Patients at risk:
Bivalirudin
Heparin
404
398
384
371
381
367
381
366
381
365
378
364
378
364
375
361
375
361
375
361
375
360
374
360
373
358
21
Dangas, Lefèvre et al, BRAVO-3 Investigators; JACC 2015; in press (online 10/15/2015)
Net Adverse Clinical Events
100
90
80
60
50
40
Log rank p = 0.62
0
30
Heparin
15.6%
14.4%
12
10
8
6
4
2
0
70
Event Rate
Bivalirudin
18
16
14
5
10
15
20
25
30
20
10
0
0
Patients at risk:
Bivalirudin
Heparin
5
10
15
20
25
30
329
319
270
261
Days from Randomization Date
404
398
354
344
349
341
342
336
337
332
22
Dangas, Lefèvre et al, BRAVO-3 Investigators; JACC 2015; in press (online 10/15/2015)
22
Clinical Outcomes – 48 hours (cont ..)
Bivalirudin
(N=404)
Heparin
(N=398)
Relative risk
BARC 3a
63 (15.6)
53 (13.3)
1.17(0.84-1.64)
0.36
BARC types 1 and 2
84 (20.8)
84 (21.1)
0.99 (0.75-1.29)
0.91
TIMI minor
67 (16.6)
57 (14.3)
1.16 (0.84-1.60)
0.38
MACE – no. (%)
14 (3.5)
19 (4.8)
0.73 (0.37-1.43)
0.35
Death
6 (1.5)
7 (1.8)
0.84 (0.29-2.49)
0.76
Myocardial infarction
0 (0.0)
5 (1.3)
NA
0.03
Stroke†
8 (2.0)
8 (2.0)
0.99 (0.37-2.60)
0.98
0
0
NA
NA
44 (10.9)
26 (6.5)
1.67 (1.05-2.65)
0.03
Stage 1
33 (8.2)
22 (5.5)
1.48 (0.88-2.49)
0.14
Stage 2
6 (1.5)
2 (0.5)
2.96 (0.60-14.56)
0.29
Stage 3
5 (1.2)
2 (0.5)
2.46 (0.48-12.62)
0.45
Major vascular complications – no. (%)
35 (8.7)
36 (9.0)
0.96 (0.61-1.49)
0.85
New onset atrial fibrillation/flutter – no. (%)
13 (3.2)
10 (2.5)
1.28 (0.57-2.89)
0.55
(95% CI)
P value
Minor bleeding – no. (%)
Transient ischemic attack
Acute kidney injury – no. (%)
23
Dangas, Lefèvre et al, BRAVO-3 Investigators; JACC 2015; in press (online 10/15/2015)
23
Secondary Endpoints @ 30 Days
Bivalirudin
(N=404)
Heparin
(N=398)
Relative risk
Major bleeding (BARC ≥3b) – no. (%)
36 (8.9)
42 (10.6)
0.84 (0.55, 1.29)
0.43
MACE – no. (%)
31 (7.7)
32 (8.0)
0.95 (0.59, 1.53)
0.85
Mortality
19 (4.7)
19 (4.8)
0.99 (0.53, 1.83)
0.96
Myocardial infarction
2 (0.5)
7 (1.8)
0.28 (0.06, 1.35)
0.11
Stroke†
14 (3.5)
11 (2.8)
1.25 (0.58, 2.73)
0.57
0
0
NA
NA
76 (18.8)
55 (13.8)
1.36 (0.99, 1.87)
0.06
Stage 1
60 (14.9)
46 (11.6)
1.28 (0.90, 1.84)
0.17
Stage 2
10 (2.5)
5 (1.3)
1.97 (0.68, 5.71)
0.20
Stage 3
6 (1.5)
5 (1.3)
1.18 (0.36, 3.84)
0.78
Major vascular complications – no. (%)
37 (9.2)
38 (9.5)
0.96 (0.62, 1.48)
0.85
New onset atrial fibrillation/flutter – no. (%)
22 (5.4)
16 (4.0)
1.35 (0.72, 2.54)
0.34
Thrombocytopenia – no. (%)
67 (16.6)
69 (17.3)
0.96 (0.70, 1.30)
0.78
Transient ischemic attack – no. (%)
Acute kidney injury – no. (%)
(95% CI)
P value
24
Dangas, Lefèvre et al, BRAVO-3 Investigators; JACC 2015; in press (online 10/15/2015)
Conclusion
 In patients undergoing transfemoral TAVR with severe
symptomatic aortic stenosis, procedural anticoagulation
with bivalirudin did not significantly reduce the primary
outcomes of major bleeding at 48 h or net adverse cardiac
events at 30 days compared with heparin.
 Despite not achieving superiority, non-inferiority was met
and no safety concern was identified.
 Bivalirudin can be the alternative anticoagulant during
TAVR in patients who cannot be treated with heparin.
25
Thank You to the
BRAVO 3 Investigators !
Country
Investigator
Enrollment
Sites/pts.
recruited
Canada
Webb
Asgar
41
34
2/75
France
Tchetche
Dumonteil
Tron
Van Belle
Lefèvre
Meneveau
Country
Italy
Hengstenberg
Boekstegers
Linke
Schäfer
Hambrecht
Kupatt
Werner
Hink
Widder
Ferrari
Naber
Enrollment
Sites/pts.
recruited
Colombo
Sardella
Violini
De Carlo
Tamburino
28
21
11
8
8
5/76
16
4
2/20
Jeger
Windecker
26
21
2/47
Hildick-Smith
Mikhail
14
4
2/18
60
6/214
38
38
Dangas,
Lefèvre et al, BRAVO-3 Investigators;
33
Netherlands
Ten Berg
JACC 2015; in press (online
10/15/2015)
29
Stella
16
Switzerland
Germany
Investigator
88
51
41
38
32
28
25
21
18
8
3
12/353
United
Kingdom
26
Back - Up Slides
Non-inferiority Results
 After 30 days, net adverse cardiovascular events
occurred in 14.4% of the bivalirudin-treated patients and
in 16.1% of heparin-treated patients (risk difference –
1.72, 95% CI –6.70 to 3.25; relative risk 0.89, 95% CI
0.64–1.24; p=0.50); the prespecified non-inferiority
hypothesis was met: pnon-inferiority<0.01).
 The risk difference data observed (upper limit of 95%
confidence interval of 3.25%) would also be significant for
an absolute non-inferiority margin of 4% (i.e. smaller
margin that the prespecified 8%)
28
Dangas, Lefèvre et al, BRAVO-3 Investigators; JACC 2015; in press (online 10/15/2015)
28
Bivalirudin
Age
>80 yr
≤80 yr
Genger
Male
Female yr
Estimated GFR
≥ 60 ml/min
< 60 ml/min
Diabetes mellitus
Yes
No
Valve type
Balloon expandable
Self expanding
EuroSCORE
? 15 (median)
< 15 (median)
Anemia
Yes
No
Ejection fraction
≥ 50%
< 50%
Peripheral artery dis.
Yes
No
COPD
Yes
No
Coronary artery dis.
Yes
No
Clopidogrel loading
Yes
No
Sheath size
≥ 18 Fr.
< 18 Fr.
Heparin
Int.
P value P value
No./total no. (%) No./total no. (%)
Relative Risk
20/268 (7.5)
8/136 (5.9)
23/267 (8.6)
13/131 (9.9)
0.87 [0.49, 1.54]
0.59 [0.25, 1.38]
0.62
0.22
0.47
14/209 (6.7)
14/195 (7.2)
18/202 (8.9)
18/196 (9.2)
0.75 [0.38, 1.47]
0.78 [0.40, 1.53]
0.40
0.47
0.47
13/181 (7.2)
15/223 (6.7)
17/183 (9.3)
19/215 (8.8)
0.77 [0.39, 1.54]
0.76 [0.40, 1.46]
0.46
0.41
0.98
10/125 (8.0)
18/279 (6.5)
13/114 (11.4)
23/284 (8.1)
0.70 [0.32, 1.54]
0.80 [0.44, 1.44]
0.37
0.45
0.79
19/251 (7.6)
20/249 (8.0)
15/142 (10.6)
0.94 [0.52, 1.72]
0.54 [0.24, 1.24]
0.85
0.14
0.29
8/140 (5.7)
17/207 (8.2)
11/195 (5.6)
19/203 (9.4)
17/195 (8.7)
0.88 [0.47, 1.64]
0.65 [0.31, 1.35]
0.68
0.24
0.54
23/289 (8.0)
5/107 (4.7)
27/296 (9.1)
9/100 (9.0)
0.87 [0.51, 1.49]
0.52 [0.18, 1.50]
0.61
0.22
0.39
21/288 (7.3)
7/115 (6.1)
28/284 (9.9)
8/112 (7.1)
0.74 [0.43, 1.27]
0.85 [0.32, 2.27]
0.27
0.75
0.80
3/60 (5.0)
25/344 (7.3)
9/59 (15.3)
27/338 (8.0)
0.33 [0.09, 1.15]
0.91 [0.54, 1.53]
0.06
0.72
0.13
6/68 (8.8)
22/336 (6.5)
6/87 (6.9)
30/311 (9.6)
1.28 [0.43, 3.79]
0.68 [0.40, 1.15]
0.66
0.15
0.30
13/209 (6.2)
15/195 (7.7)
19/196 (9.7)
17/201 (8.5)
0.64 [0.33, 1.26]
0.91 [0.47, 1.77]
0.20
0.78
0.47
11/152 (7.2)
17/250 (6.8)
14/142 (9.9)
22/255 (8.6)
0.73 [0.34, 1.56]
0.79 [0.43, 1.45]
0.42
0.44
0.88
20/265 (7.5)
8/128 (6.3)
23/263 (8.7)
12/127 (9.4)
0.86 [0.49, 1.53]
0.66 [0.28, 1.56]
0.61
0.34
0.62
0.01
0.1
Favors
Bivalirudin
1
Favors
Heparin
Outcomes
according to
prespecified
subgroups (i)
Major bleeding
(BARC ≥3b) events
at 48 h
COPD=chronic
obstructive lung
disease
GFR= glomerular
filtration rate.
10
Dangas, Lefèvre et al, BRAVO-3 Investigators; JACC 2015; in press (online 10/15/2015)
Bivalirudin
Age
> 80 yr
≥ 80 yr
Gender
Male
Female
Estimated GFR
≥ 60 ml/min
< 60 ml/min
Diabetes mellitus
Yes
No
Valve type
Balloon expandable
Self expanding
EuroSCORE
≥ 15 (median)
< 15 (median)
Anemia
Yes
No
Ejection fraction
≥ 50%
< 50%
Peripheral artery dis.
Yes
No
COPD
Yes
No
Coronary artery dis.
Yes
No
Clopidogrel loading
Yes
No
Sheath size
≥ 18 Fr.
< 18 Fr.
Heparin
Int.
P value P value
No./total no. (%)
No./total no. (%)
Relative Risk
42/268 (15.7)
16/136 (11.8)
42/267 (15.7)
22/131 (16.8)
1.00 [0.67, 1.48]
0.70 [0.39, 1.27]
0.99
0.24
0.34
31/209 (14.8)
27/195 (13.8)
30/202 (14.9)
34/196 (17.3)
1.00 [0.63, 1.59]
0.80 [0.50, 1.27]
0.10
0.34
0.50
23/181 (12.7)
35/223 (15.7)
28/183 (15.3)
36/215 (16.7)
0.83 [0.50, 1.39]
0.94 [0.61, 1.44]
0.48
0.77
0.73
16/125 (12.8)
42/279 (15.1)
22/114 (19.3)
42/284 (14.8)
0.66 [0.37, 1.20]
1.02 [0.69, 1.51]
0.17
0.93
0.24
34/251 (13.5)
23/140 (16.4)
35/249 (14.1)
27/142 (19.0)
0.96 [0.62, 1.49]
0.86 [0.52, 1.43]
0.87
0.57
0.74
34/207 (16.4)
24/195 (12.3)
36/203 (17.7)
28/195 (14.4)
0.93 [0.60, 1.42]
0.86 [0.52, 1.42]
0.72
0.55
0.83
46/289 (15.9)
12/107 (11.2)
48/296 (16.2)
16/100 (16.0)
0.98 [0.68, 1.42]
0.70 [0.35, 1.41]
0.92
0.31
0.41
39/288 (13.5)
19/115 (16.5)
45/284 (15.8)
18/112 (16.1)
0.85 [0.58, 1.27]
1.03 [0.57, 1.85]
0.44
0.93
0.61
8/60 (13.3)
50/344 (14.5)
10/59 (16.9)
54/338 (16.0)
0.79 [0.33, 1.85]
0.91 [0.64, 1.30]
0.58
0.60
0.76
13/68 (19.1)
45/336 (13.4)
12/87 (13.8)
52/311 (16.7)
1.39 [0.68, 2.84]
0.80 [0.55, 1.16]
0.37
0.24
0.18
28/209 (13.4)
30/195 (15.4)
34/196 (17.3)
30/201 (14.9)
0.77 [0.49, 1.22]
1.03 [0.65, 1.64]
0.27
0.90
0.39
21/152 (13.8)
37/250 (14.8)
22/142 (15.5)
42/255 (16.5)
0.89 [0.51, 1.55]
0.90 [0.60, 1.35]
0.68
0.61
0.99
41/265 (15.5)
17/128 (13.3)
44/263 (16.7)
18/127 (14.2)
0.92 [0.63, 1.37]
0.94 [0.51, 1.73]
0.69
0.84
0.97
0.01
0.1
Favors
Bivalirudin
1
Favors
Heparin
Outcomes
according to
prespecified
subgroups (ii)
Net Adverse
Clinical Events
at 30 days
COPD=chronic
obstructive lung
disease
GFR= glomerular
filtration rate.
10
Dangas, Lefèvre et al, BRAVO-3 Investigators; JACC 2015; in press (online 10/15/2015)
30-Day Major bleeding (BARC >3b)
100
12
90
10
80
8
Heparin
10.4%
9.0%
70
Event Rate
Bivalirudin
6
Log rank p = 0.50
60
4
50
2
40
0
0
30
5
10
15
20
25
30
20
10
0
0
Patients at risk:
Bivalirudin
Heparin
5
10
15
20
25
30
340
332
278
269
Days from Randomization Date
404
398
364
353
357
351
353
347
348
344
Dangas et al, BRAVO-3 Investigators; JACC 2015; in press (online 10/15/2015)
31