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Bivalirudin with Provisional GPIIb/IIIa Inhibition – the Data are Clear!

Bivalirudin with Provisional GPIIb/IIIa Inhibition – the Data are Clear!. Gregg W. Stone MD. Columbia University Medical Center Cardiovascular Research Foundation. Bivalirudin vs. Heparin + GPI (n=18,819) 30d TIMI major or minor bleeding by treatment and study . p < 0.0001. p < 0.0001.

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Bivalirudin with Provisional GPIIb/IIIa Inhibition – the Data are Clear!

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  1. Bivalirudin with Provisional GPIIb/IIIa Inhibition – the Data are Clear! Gregg W. Stone MD Columbia University Medical Center Cardiovascular Research Foundation

  2. Bivalirudin vs. Heparin + GPI (n=18,819) 30d TIMI major or minor bleeding by treatment and study p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 58/2993 117/3008 183/4612 306/4603 106/1800 173/1802 347/9405 596/9413 Lincoff AM et al. JAMA 2003;289:853-63 Stone GW et al. NEJM 2006;355:2203-16 Stone GW et al. NEJM 2008;358:2218-30

  3. Bivalirudin vs. Heparin + GPI (n=18,819) Acquired thrombocytopenia (<100,000) by treatment and study p = 0.0003 p = 0.049 p = 0.003 p < 0.0001 20/2868 50/2863 77/4612 103/4603 19/1665 48/1853 116/9145 201/9119 Lincoff AM et al. JAMA 2003;289:853-63 Stone GW et al. NEJM 2006;355:2203-16 Stone GW et al. NEJM 2008;358:2218-30

  4. Bivalirudin vs. Heparin + GPI (n=18,819)Mortality at 1-year by treatment and study Lincoff AM et al. JAMA 2004;292:696-703 Stone GW et al. JAMA 2007;298:2497-506 Mehran R et al. Lancet. 2009;374:1149-59

  5. Bivalirudin vs. Heparin + GPIIb/IIIa N = 127,185 pts undergoing PCI 2003-2006 (Premier Perspective Database, ~1/6th of all US hosps; bival in 26%) In-hospital transfusion Bivalirudin H+GPI Unadjusted (All) Adjusted (All) Adjusted (urgent subgroup) Adjusted (elective subgroup) REPLACE-2** ACUITY** HORIZONS-AMI** ISAR-REACT** 3.0% 4.6% Adjusted HR [95%CI] 0.67 [0.61 - 0.73] 33%  Transfusion 0.1 1 10 **30 days Favors Bival Favors H+GPI Rassen JA et al. EHJ 2010;31:561-72

  6. Bivalirudin vs. Heparin + GPIIb/IIIa N = 127,185 pts undergoing PCI 2003-2006 (Premier Perspective Database, ~1/6th of all US hosps; bival in 26%) In-hospital death Bivalirudin H+GPI Unadjusted (All) Adjusted (All) Adjusted (urgent subgroup) Adjusted (elective subgroup) REPLACE-2** ACUITY** HORIZONS-AMI** ISAR-REACT** 0.8% 2.1% Adjusted HR [95%CI] 0.51 [0.44 – 0.60] 49%  Death 0.1 1 10 **30 days Favors Bival Favors H+GPI Rassen JA et al. EHJ 2010;31:561-72

  7. Bivalirudin vs. Heparin + GPIIb/IIIa Primary PCI in 59,917 STEMI pts 2004-2008 (Premier Perspective Database, ~1/6th of all US hosps) 3:1 propensity adjusted matching Pinto DS et al. Circ CV Qual Outcomes 2012;5:52-61

  8. Anticoagulation Regimens During PCI N = 458,448 PCI pts 2004-2008 at 299 hosps (Premier Perspective Database, ~1/5th of all US hosp discharges; bival in 41%) In-hospital events, propensity adjusted Bleeding + Transfusion Mortality OR (95% CI) OR (95% CI) Comparator OR (95% CI) Comparator OR (95% CI) P Value P Value Bivalirudin monotherapy (n=156,064) Bivalirudin monotherapy (n=156,064) 0.51 (0.48, 0.55) 0.59 (0.54, 0.65) <0.0001 <0.0001 Bivalirudin + GPI (n=33,566) Bivalirudin + GPI (n=33,566) 0.96 (0.87, 1.06) 0.82 (0.72, 0.94) 0.37 0.004 Heparin alone (n=85,870) Heparin alone (n=85,870) 0.71 (0.66, 0.76) 0.88 (0.82, 0.96) <0.0001 0.003 0 1 2 0 1 2 Comparator Better Heparin + GPI Better (n=182,948) Comparator Better Heparin + GPI Better (n=182,948) Wise GR et al. J Interv Cardiol 2012;25:278–88

  9. Bivalirudin vs UFH Monotherapy Meta-analysis Major Bleeding 16 studies (3 rand, 13 reg), 32,492 pts undergoing PCI: Study or subgroup Events Bivalirudin Total Events Heparin Total Odds Ratio M-H, Random, 95% CI Odds Ratio M-H, Random, 95% CI Observational Wolfram 2003 Rha 2005 Chu 2006 Bonello 2009 Lemesle 2009 Lemesle 2009-b Delhaye 2010 Lindsey 2010 Lopes 2010 Schultz 2010 Bangalore 2011 Subtotal (95% CI) 4 1 2 23 10 26 5 6 101 12 38 335 54 216 566 79 1207 267 503 1771 2289 1511 8798 35 2 14 14 20 101 2 26 89 16 78 1543 60 456 333 92 1559 129 861 1365 2505 1551 10414 0.52 [0.18, 1.47] 0.55 [0.05, 6.12] 0.30 [0.07, 1.31] 0.97 [0.49, 1.90] 0.52 [0.21, 3.17] 0.32 [0.21, 0.49] 1.21 [0.23, 6.33] 0.39 [0.16, 0.95] 0.87 [0.65, 1.16] 0.82 [0.39, 1.74] 0.47 [0.32, 0.70] 0.57 [0.42, 0.78] Total Events 228 397 Test for heterogeneity: Tau2=0.11, Chi2=20.84, df=10 (P=0.02),I2=52% Test for overall effect: Z=3.55 (P=0.0004) Randomized Kastrati 2008 Parodi 2010 Patti 2011 Subtotal (95% CI) 12 3 1 2289 363 198 2850 24 8 2 2281 308 203 2792 0.50 [0.25, 0.99] 0.31 [0.08, 1.19] 0.51 [0.05, 5.67] 0.45 [0.25, 0.82] Total Events 16 34 Test for heterogeneity: Tau2=0.00, Chi2=0.37, df=2 (P=0.83),I2=0% Test for overall effect: Z=2.60 (P=0.009) 45%↓ 0.55 [0.43, 0.72] Total (95% CI) 11648 13206 Total Events 244 431 Test for heterogeneity: Tau2=0.08, Chi2=21.99, df=13 (P=0.06),I2=41% Test for overall effect: Z=4.38 (P<0.0001) Test for subgroup differences: Chi2=0.47, df=1 (P=0.49),I2=0% 0.01 0.1 1 10 100 Favors Bivalirudin Favors Heparin Bertrand OF et al. Am J Cardiol 2012;110:599–606

  10. Bivalirudin vs UFH Monotherapy Meta-analysis Mortality 16 studies (3 rand, 13 reg), 32,492 pts undergoing PCI: Study or subgroup Events Bivalirudin Total Events Heparin Total Odds Ratio M-H, Random, 95% CI Odds Ratio M-H, Random, 95% CI Observational Wolfram 2003 Gurm 2005 Rha 2005 Chu 2006 Gurm 2007 Bonello 2009 Lemesle 2009 Lemesle 2009-b Delhaye 2010 Lindsey 2010 Lopes 2010 Schultz 2010 Bangalore 2011 Subtotal (95% CI) 0 3 0 7 3 6 3 48 5 0 12 3 1 335 864 54 216 2051 566 79 1207 267 503 1771 2289 1511 11713 1 4 0 9 7 3 4 124 1 4 18 5 8 1543 801 60 456 3922 333 92 1559 129 861 1365 2505 1551 15137 1.53 [0.06, 37.70] 0.69 [0.15, 3.11] Not estimable 1.66 [0.61, 4.53] 0.82 [0.21, 3.17] 1.18 [0.29, 4.74] 0.87 [0.19, 4.00] 0.48 [0.34, 0.67] 2.44 [0.28, 21.13] 0.19 [0.01, 3.52] 0.51 [0.25, 1.06] 0.66 [0.16, 2.75] 0.12 [0.02, 1.00] 0.62 [0.45, 0.85] Total Events 91 188 Test for heterogeneity: Tau2=0.03, Chi2=11.92, df=11 (P=0.37),I2=8% Test for overall effect: Z=2.98 (P=0.003) Randomized Kastrati 2008 Parodi 2010 Patti 2011 Subtotal (95% CI) 3 1 1 2289 363 198 2850 4 4 0 2281 308 203 2792 0.75 [0.17, 3.34] 0.21 [0.02, 1.89] 3.09 [0.13, 76.33] 0.63 [0.20, 2.01] Total Events 5 8 Test for heterogeneity: Tau2=0.00, Chi2=1.96, df=2 (P=0.38),I2=0% Test for overall effect: Z=0.78 (P=0.44) 42%↓ 0.58 [0.45, 0.75] Total (95% CI) 14563 17929 Total Events 96 196 Test for heterogeneity: Tau2=0.00, Chi2=13.90, df=14 (P=0.46),I2=0% Test for overall effect: Z=4.15 (P<0.0001) Test for subgroup differences: Chi2=0.00, df=1 (P=0.97),I2=0% 0.01 0.1 1 10 100 Favors Bivalirudin Favors Heparin Bertrand OF et al. Am J Cardiol 2012;110:599–606

  11. Impact of Bleeding Avoidance Strategies NCDR CathPCI Registry 2004-2008: PCI in 1,522,935 pts Manual compression alone, closure devices, bivalirudin, or both were used in 35%, 24%, 23%, and 18% of pts, respectively. Major bleeding occurred in 30,429 pts (2.0%) All P<0.001 Risk from NCDR CathPCI bleeding model Marso SP et al. JAMA. 2010;303:2156-64

  12. Impact of Bleeding Avoidance Strategies NCDR CathPCI Registry 2004-2008: PCI in 1,522,935 pts Manual compression alone, closure devices, bivalirudin, or both were used in 35%, 24%, 23%, and 18% of pts, respectively. Propensity-adjusted bleeding Adj OR (95%CI) = 0.77 (0.73 – 0.80) NNT = 148 Adj OR (95%CI) = 0.67 (0.63 – 0.70) NNT = 118 Adj OR (95%CI) = 0.38 (0.35 – 0.42) NNT = 70 23%↓ 33%↓ 62%↓ Marso SP et al. JAMA. 2010;303:2156-64

  13. Impact of Access and Non-Access Site Bleeding after PCI 17,393 pts underwent PCI in REPLACE-2, ACUITY and HORIZONS 925 pts (5.3%) had TIMI major or minor bleeding within 30 days Source of bleeding (absolute rate) 568 (61.4%) non access site related Indeterminate – most likely intraprocedural (catheter exchanges) or baseline anemia with lower transfusion threshold Verheugt FWA et al. JACC Int 2011;4;191-197

  14. Impact of Access and Non-Access Site Bleeding after PCI 17,393 pts underwent PCI in REPLACE-2, ACUITY and HORIZONS 925 pts (5.3%) had TIMI major or minor bleeding within 30 days Time-updated multivariable risk of death within 1-year HR [95%CI] P 3.17 [2.51, 4.00] <0.0001 3.94 [3.07, 5.15] <0.0001 1.82 [1.17, 2.83] 0.008 TIMI Bleed - All TIMI Bleed – Non Access Site TIMI Bleed – Access Site Only 0.1 1 8 Adjusted risk of 1-year mortality Verheugt FWA et al. JACC Int 2011;4;191-197

  15. Impact of Access and Non-Access Site Bleeding after PCI 17,393 pts underwent PCI in REPLACE-2, ACUITY and HORIZONS 925 pts (5.3%) with 30-day TIMI major or minor bleeding Impact of bivalirudin on bleeding according to site Relative Risk P - Value Access site 0.45 <0.0001 Non Access Site 0.62 <0.0001 - Non Access + Access Site 0.31 <0.0001 - Non Access Site Only 0.70 0.08 - Indeterminate 0.75 0.02 Bivalirudin better Hep + GPI better NNT for bivalirudin to prevent 1 non-access site-related TIMI bleed = 71 NNT for bivalirudin to prevent 1 access site-related TIMI bleed = 74

  16. Impact of Access and Non-Access Site Bleeding after PCI 17,393 pts underwent PCI in REPLACE-2, ACUITY and HORIZONS 925 pts (5.3%) with 30-day TIMI major or minor bleeding Impact of bivalirudin on non-access site bleeding Hep + GPI Bivalirudin Relative (%) (%) Risk Intracranial 0.04 0.03 0.66 GI 0.6 0.28 0.44 GU 0.64 0.28 0.44 HEENT 0.33 0.22 0.66 Pulmonary 0.18 0.05 0.31 Other 0.30 0.15 0.49 Indeterminate 1.87 1.40 0.75 All Non - Access Site 3.66 2.27 0.62 0 0.5 1 1.5 2 Bivalirudin better H + GPI better

  17. HORIZONS-AMI: Cardiac Mortality in Pts with Major Bleeding 16% 14.6% 14% 12% HR [95%CI] = 0.39 (0.17 - 0.89) P=0.025 Heparin + GPI (n=185) 10% Bivalirudin (n=121) Cardiac mortality* (%) 8% 5.8% 6% 4% 2% 0% 0 1 2 3 Years UFH + GPI 185 151 138 86 Bivalirudin 121 104 94 59 *From the time of a major bleed

  18. HORIZONS-AMI: Cardiac Mortality in Pts without Major Bleeding* 5% 4% 3.8% Heparin + GPI (n=1802) 3% Bivalirudin (n=1800) 2.6% Cardiac mortality (%) 2% HR [95%CI] = 0.67 (0.46 to 1.00) P=0.046 Adj HR [95%CI] = 0.65 (0.44 to 0.97) P=0.033 1% 0% 0 1 2 3 Years UFH+GPI 1802 1506 1441 957 Bivalirudin 1800 1569 1521 1039 *KM curve with censoring at time of major bleed

  19. HORIZONS-AMI: Multivariable Model for 3-Year Cardiac Mortality, Including Adverse Events Excludes 145 pts with thrombocytopenia at baseline. Other variables in model: current smoker, female gender, prior MI, # vessels treated, hemoglobin

  20. Conclusion: Bivalirudin is the anticoagulant of choice for all PCI procedures Compared to UFH + GPI, bivalirudin reduces mortality across the spectrum of pts undergoing PCI The mortality benefit of bivalirudin can be attributed to a complex interplay of reduced rates of major bleeding (especially non-access site related), thrombocytopenia, and reinfarction, as well as reduced death in pts with these complications These benefits are realized in all PCI pts - including those undergoing radial intervention By reducing major bleeding, bivalirudin is cost-saving

  21. Procedural anticoagulant use during PCI CathPCI Registry (~85% cath labs in the US) 941,248 PCIs between Jan 2010 and June 2011 Dehmer DJ et al. J Am Coll Cardiol 2012;60:2017–31

  22. Bivalirudin in ACS: The Guidelines ACC/AHA Guidelines I • PCI in STEMI and NSTE-ACS • Pts with HIT or HITTS ESC/EACTS Guidelines I • PCI in STEMI and NSTE-ACS Circulation and JACC 2005, 2007, 2009, 2011 EHJ 2010

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