Effect of Bivalirudin on Aortic Valve Intervention Outcomes

(BRAVO) Study

A Two-Center Registry Study A Two-Center Registry Study Comparing Bivalirudin and Comparing Bivalirudin and

Unfractionated Heparin in Patients Unfractionated Heparin in Patients Undergoing Balloon Aortic Undergoing Balloon Aortic

ValvuloplastyValvuloplasty

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 non-emergent 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 non-emergent 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.

80 patients excluded:• Emergency indication for BAV• Unclear whether bivalirudin or heparin was

given, or patient given both or neither• anterograde BAV

No vascularClosuren=158

VascularClosure

n=65

No vascularClosure

n=87

VascularClosuren=117

412 pts underwent 503 BAV at Mount

Sinai Medical CenterJanuary 1, 2005 toDecember 31, 2010

96 patients underwent 98BAV at the University of

Miami Medical CenterAugust 11 2010 to

July 28, 2011

428 patients who Underwent

Non-emergent retrograde BAV

Unfractionated heparinN=205

BivalirudinN=223

Methods

Study Medications

• Unfractionated heparin Per local standard practice (50 IU/kg bolus IV with

supplemental boluses to maintain the activated clotting time between 200 to 250 seconds).

• Bivalirudin 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 PointIn-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• 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

• 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)

• 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

Age (mean ± SD) 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

Results. Baseline Characteristics /2Bivalirudin

(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

Number of previous BAVs    

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

Results. Baseline Characteristics /3

Bivalirudin (n=223)

Heparin (n=205) P value

CKD^ 70.8% 69.8% 0.83

Chronic hemodialysis 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

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

Presenting symptoms

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

Baseline INR, median (IQR) 1.1 (1, 1.3) 1.1 (1, 1.3) 0.20

* Evaluated by echocardiography and available in 196 patients.

In-hospital Major Bleeding

4.9%3.6% 3.6%

7.2%

13.2%

10.7%8.8%

13.7%

0%

5%

10%

15%

20%

Major Bleeding(BARC ≥3)

VARC (Life threatening

/Major)

TIMI(Major/Minor)

GUSTO(Moderate,

Severe, Lifethreatening)

Ev

en

t R

ate

s (

%)

Bivalirudin (N=223) Heparin (N=205)

P = 0.003 P = 0.004 P = 0.03 P = 0.03

Non Access Related Bleeding

8

1

2

3

Access

Gastrointestinal

Unclear

BivalirudinHeparin

16

21

5

3

11

Genitourinary

Pericardial

In-hospital Major Adverse Events

6.7%4.9%

11.2%11.2%13.2%

20.0%

0%

5%

10%

15%

20%

25%

MACE Major Bleeding(BARC ≥3)

Net AdverseClinical Events

Eve

nt

Rat

es (

%)

Bivalirudin Heparin

P = 0.003

MACE = composite of all-cause mortality, myocardial infarction, and stroke; NACE = MACE or major bleeding

P=0.01

P = 0.10

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

2.5%

14.9%

10.8%12.0%

0%

5%

10%

15%

20%

Bivalirudin Heparin

Eve

nt

Rat

es (

%)

Preclosure No Preclosure

* Formal interaction testing significant, p-value = 0.03

P=0.02

P=0.54

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: 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 post-BAV 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

AcknowledgementsMount Sinai School of Medicine• 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• Brian O’Neill, MD

• Evan Jacobs, MD

• Vikas Singh, MD

• David Knopf, MS

• Mauricio Cohen, MD