Download Bivalirudin

Effect of Bivalirudin on
Aortic Valve Intervention Outcomes
(BRAVO) Study
A Two-Center Registry Study
Comparing Bivalirudin and
Unfractionated Heparin in Patients
Undergoing Balloon Aortic
Valvuloplasty
Disclosures
George Dangas
• Research grants from BMS/Sanofi, Eli
Lilly/Daichi Sankyo and The Medicines
Company
• Consultant for Abbott, Astra Zeneca,
Johnson & Johnson, Regado
Background
• With the emergence of new percutaneous therapies for
aortic stenosis in high surgical risk or inoperable patients,
there is renewed interest in balloon aortic valvuloplasty
(BAV) as bridging therapy.
• Given the co-morbidities in this patient group, and the large
sheath sizes required for access in these procedures
(10-13Fr for BAV, 18-24Fr TAVR), bleeding and vascular
complications have become an important concern.
• Bivalirudin is associated with significant reductions in the
rate of both access and non-access site bleeding in
patients undergoing PCI compared to heparin with or
without glycoprotein inhibitors.
• The safety, efficacy, and impact of bivalirudin therapy vs.
heparin in balloon aortic valvuloplasty (BAV) is not known.
OBJECTIVES
• The primary objective was to evaluate the rates
of in-hospital major bleeding in patients with
severe aortic stenosis undergoing nonemergent balloon aortic valvuloplasty with
bivalirudin versus unfractionated heparin
• The secondary objective was to compare the
rates of in-hospital major cardiovascular events
(MACE, death, myocardial infarction, stroke)
and net adverse clinical events (MACE or major
bleeding) in the two patient groups.
Methods
• Retrospective review of all consecutive patients
who underwent BAV at two high volume centers
• Patients who had retrograde BAV with nonemergent indication were compared according to
the use of bivalirudin or heparin, and attempted
preclosure of the large sheath access site
• All adverse events were adjudicated by an
independent Clinical Events Committee, blinded to
the antithrombin agent used, using standardized
definitions from source documents.
Methods
412 pts underwent
503 BAV at Mount Sinai
Medical Center
January 1, 2005 to
December 31, 2010
96 patients underwent 98
BAV at the University of
Miami Medical Center
August 11 2010 to
July 28, 2011
80 patients excluded:
• Emergency indication for BAV
• Unclear whether bivalirudin or heparin was
given, or patient given both or neither
• anterograde BAV
428 patients who
Underwent
Non-emergent
retrograde BAV
Bivalirudin
N=223
No vascular
Closure
n=158
Vascular
Closure
n=65
Unfractionated
heparin
N=205
No vascular
Closure
n=87
Vascular
Closure
n=117
Study Medications
• Unfractionated heparin
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Per local standard practice (50 IU/kg bolus IV
with supplemental boluses to maintain the
activated clotting time between 200 to 250
seconds).
• Bivalirudin
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0.375-0.75mg/kg bolus IV, followed by IV
infusion at 1.75mg/kg/hr
• Patients undergoing procedures of short duration
were given a bolus only at the operator’s discretion
• Reduced dose was used in patients at high risk of
bleeding at the operator’s discretion
Primary End Point
In-hospital major bleeding, defined as: BARC
type ≥3
Bleeding with clinical, laboratory and/or imaging evidence with:
• Any transfusion with overt bleeding
• Overt bleeding plus hemoglobin (Hb) drop ≥3
(provided Hb drop is related to bleeding)
• Cardiac tamponade
• Intracranial hemorrhage, or Intraocular bleed compromising
vision
• Bleeding requiring surgical intervention for control,
intravenous vasoactive drugs
• Bleeding directly causing death with no other explainable
cause.
Mehran R, et al. Circulation 2011;123(23):2736-47
Secondary End Points
In-hospital:
• Bleeding according to VARC*, TIMI, and GUSTO
definitions
• MACE (in-hospital all-cause mortality, myocardial
infarction, and stroke, as per VARC definitions)
• NACE (MACE or major bleeding [BARC type ≥3])
• Vascular Complications (VARC)
• Individual components of MACE
• Transient ischemic attack
• Acute Kidney Injury (VARC)
*Leon M, et al. JACC 2011;57:253-269
Statistical Methods
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Categorical variables are presented as n/N (%), and were compared
using the Pearson’s chi-squared test or Fisher’s exact test.
Continuous variables are presented as mean +/- SD, or median (IQR) for
results with skewed distribution, were compared using Student’s t-test
and Wilcoxon rank-sum test.
Multivariate analysis was performed using logistic regression to
determine the independent predictors of major bleeding. Candidate
variables considered were the use of bivalirudin (vs. heparin), age,
gender, warfarin, frailty, anemia, use of preclosure, PVD, eGFR,
concomitant bleeding, prior BAV, the number of arterial access
sites used and the Euroscore.
Differences in outcomes in the 4 group analysis (bivalirudin vs. heparin,
preclosure vs. manual compression) were compared using the test for
trend for proportion. Formal Interaction Testing was used to determine
the effect of preclosure use on the difference in the primary end point.
The analysis was performed using Stata version 11.2 statistical software
(StataCorp, College Station, Texas) by a dedicated statistician.
Study Organization
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Sponsor
The Mount Sinai Medical Center
Grant Support
The Medicines Company
Principal Investigator
George Dangas, MD, PhD
Mount Sinai co-PI
Annapoorna S. Kini, MD
University of Miami PI
Mauricio Cohen, MD
Medical Lead
Jennifer Yu, MBBS
Data Management
Roxana Mehran, MD (Director),
Usman Baber, MD,
Samantha Sartori, PhD
(Statistical Analysis),
Vanessa Wong (Data Programming)
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Clinical Events Committee
Bruce Darrow, MD (Chair)
Project Management
Samia Ali-Akhtar,
Maria Alu,
Theresa Franklin-Bond
Results. Baseline Characteristics /1
Bivalirudin (n=223)
Heparin (n=205)
P value
84.3 ± 8.2
82.4 ± 9.5
0.03
Male
44.8%
45.9%
0.83
Hypertension
93.3%
89.3%
0.14
Hyperlipidemia
76.2%
67.3%
0.04
Diabetes
34.1%
35.1%
0.82
Smoking history
48.2%
47.3%
0.86
Previous MI
26.9%
26.3%
0.90
CVA
13.9%
19.0%
0.15
Age (mean ± SD)
Results. Baseline Characteristics /2
Bivalirudin
(n=223)
Heparin
(n=205)
P value
AF / Flutter
42.6%
38.5%
0.39
Prior CABG
25.1%
23.9%
0.77
Prior PCI
23.8%
20.7%
0.45
Residual Left Main Disease
9.5%
10.3%
0.77
Residual Coronary Artery Disease
(excluding left main)
42.2%
42.9%
0.87
0
96.2%
90.7%
0.03
1 or more
3.8%
9.3%
Peripheral Arterial Disease
27.8%
20.0%
0.06
COPD
23.3%
22.0%
0.74
Number of previous BAVs
Results. Baseline Characteristics /3
Bivalirudin
(n=223)
Heparin
(n=205)
P value
70.8%
69.8%
0.83
4.0%
3.9%
0.94
Concomitant bleeding
7.6%
3.4%
0.06
Frailty*
13.9%
22.0%
0.03
Hemodynamic instability#
24.7%
19.5%
0.2
Baseline anemia (WHO)
67.3%
63.4%
0.40
Thrombocytopenia (plt < 50)
1.9%
1.0%
0.69
CKD^
Chronic hemodialysis
Logistic Euroscore (mean ± SD)
23.9% ± 18.9% 20.1% ± 16.8%
0.03
^ CKD was defined as CrCl<60mL/min by MDRD formula. *Pt was considered frail if bedbound, dependent for all
ADLs, had moderate or severe dementia, or a nursing home resident. # Hemodynamic instability defined by the
presence of preoperative acute renal failure, or requirement of cardiac massage, inotropic support, intraaortic
balloon pump therapy, non-invasive positive pressure or endotracheal ventilation
Presentation
Bivalirudin
(n=223)
Heparin
(n=205)
P value
Chest pain
29.6%
33.7%
0.37
NYHA Class III/IV
81.2%
82.8%
0.65
Exertional syncope
10.8%
10.2%
0.86
Cardiogenic shock
5.4%
4.4%
0.64
Mod-Severe LV dysfunction*
33.0%
38.7%
0.41
AR > 1+
12.1%
10.5%
0.14
Warfarin
25.6%
17.1%
0.03
1.1 (1, 1.3)
1.1 (1, 1.3)
0.20
Presenting symptoms
Baseline INR, median (IQR)
* Evaluated by echocardiography and available in 196 patients.
In-hospital Major Bleeding
Event Rates (%)
20%
P = 0.003
15%
P = 0.004
P = 0.03
P = 0.03
13.7%
13.2%
10.7%
8.8%
10%
7.2%
4.9%
5%
3.6%
3.6%
0%
Major Bleeding VARC
(Life threatening
(BARC ≥3)
/Major)
Bivalirudin (N=223)
TIMI
(Major/Minor)
Heparin (N=205)
GUSTO
(Moderate,
Severe, Life
threatening)
Non Access Related Bleeding
Bivalirudin
Heparin
2
1
1
8
3
16
11
5
2
3
Access
Gastrointestinal
Unclear
Genitourinary
Pericardial
In-hospital Major Adverse Events
P=0.01
25%
Event Rates (%)
20.0%
20%
P = 0.10
15%
10%
P = 0.003
13.2%
11.2%
6.7%
11.2%
4.9%
5%
0%
MACE
Major Bleeding
Net Adverse
(BARC ≥3)
Clinical Events
Bivalirudin
Heparin
MACE = composite of all-cause mortality, myocardial infarction,
and stroke; NACE = MACE or major bleeding
Subgroup Analysis for Major Bleeding (Barc ≥3) :
Bivalirudin (vs. Heparin) /1
Subgroup Analysis for Major Bleeding (Barc ≥3) :
Bivalirudin (vs. Heparin) /2
Major Bleeding According To
Antithrombin And Use Of Preclosure
20%
P=0.54
Event Rates (%)
14.9%
15%
P=0.02
10.8%
12.0%
10%
5%
2.5%
0%
Bivalirudin
Preclosure
Heparin
No Preclosure
* Formal interaction testing significant, p-value = 0.03
Multivariate Analysis: Independent
Predictors Of Major Bleeding
Other tested covariates which were not included in the final model were:
anemia, use of a closure device, peripheral vascular disease, eGFR,
concomitant bleeding, and the number of arterial access sites used
Limitations
• This was a retrospective review, and while we
attempted to adjudicate all events according to
standardized guidelines, there was small amount
of data which was unavailable and could not be
clarified for the complex subdivisions of the
different standardized definitions utilized
• Selection bias:
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Operators may have given bivalirudin at patients
deemed at higher risk for bleeding
Patients with severe peripheral vascular disease
precluded the use of preclosure of the large sheath
Arterial access site derived selection
Conclusion
• Bivalirudin was associated with
significantly reduced major bleeding postBAV on both univariate and multivariate
analyses
• There was no significant impact on MACE
(non-bleeding related) endpoints; NACE
was significantly lower with bivalirudin
• Bleeding reduction with bivalirudin was
accentuated in patients who had
attempted preclosure with an arteriotomy
closure device
Acknowledgements
Mount Sinai School of Medicine
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Annapoorna S. Kini, MD
Samin K. Sharma, MD
Jennifer Yu, MD
Jason Kovacic, MD
Usman Baber, MD
Chris Varghese, MD
Elliot Elias, MD
Eric Gisnberg, MD
Georgios Vlachojannis, MD, Phd
Avery Clark
Kleanthis Theodoropoulos, MD
Maria Alu, MPH
Phillip Erwin, MD
Prashant Vaishnava, MD
Rajeev Narayan, MD
Rebecca Pinnelas, MD
Robert Pyo, MD
Samia Ali-Akhtar, MS
Shyam Poludasu, MD
Soctrates Kakoulides, MD
Theresa Franklin-Bond, NP
Vanessa Wong
Ziad Sergie, MD
University of Miami
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Brian O’Neill, MD
Evan Jacobs, MD
Vikas Singh, MD
David Knopf, MS
Mauricio Cohen, MD