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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 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 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 • • • • • 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 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: 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 • • • • • • • • • • • • • • • • • • • • • • • 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