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Progress in High Risk ACS/PCI

Progress in High Risk ACS/PCI. Advanced Cardiovascular Interventions, London January 27, 2011 Efthymios N. Deliargyris , MD, FACC, FESC, FSCAI European Medical Director The Medicines Company. My Conflicts of Interest are. The Medicines Company (employee). 16.5%. 14.0%. 11.9%. 10.3%.

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Progress in High Risk ACS/PCI

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  1. Progress in High Risk ACS/PCI Advanced Cardiovascular Interventions, London January 27, 2011 Efthymios N. Deliargyris, MD, FACC, FESC, FSCAIEuropean Medical DirectorThe Medicines Company

  2. My Conflicts of Interest are The Medicines Company (employee)

  3. 16.5% 14.0% 11.9% 10.3% 11.8% 9.9% 8.3% 7.0% Heparin Heparin outcomes by risk strata • Results in pre-specified increasing high-risk patients • Henry J Inv Cardiol. 2002;14(suppl B):19B-29B Bittl JA et al. Am Heart J. 2001;142:952-59 Hemorrhage Death, MI, URV UA, on prior heparin & <14 days post-MI n = 241 UA & on prior heparin n = 1,006 <14 days Post MI n = 741 Unstable angina n = 2,806 % of patients with events at 7 days

  4. 10.5% 8.1% 14.3% 6.5% 10.7% 10.3% Cleveland Clinic Meta-analysis • EPIC, EPILOG, CAPTURE, RAPPORT, IMPACT-II, EPISTENT, BAT • Data on file. The Medicines Company Bleeding Death, MI, revasc High dose heparin (n = 2,151) Low dose heparin with GPI (n = 7,629) Low dose heparin (n = 4,578) 15 10 5 0 5 10 % of patients with events at 7 days

  5. Mortality & GPIIb/IIIa inhibition • 6 month cumulative death rates in PCI trials • Karvouni JACC 2003; 41: 26-32 Risk ratio for death (95% CI) Study Year #Pts EPIC 1994 2099 CAPTURE 1997 1265 EPILOG 1997 2792 RAPPORT 1998 483 RESTORE 1998 2141 ERASURE 1999 225 EPISTENT 1999 1603 ISAR 2 2000 401 ESPRIT 2001 2064 ADMIRAL 2001 300 Tamburino 2002 107 CADILLAC-P 2002 1036 CADILLAC-P 2002 1046 Petronio 2002 89 Overall 15651 0.79 (0.64-0.97) p-value = 0.048 0.1 1 10 Control better Treatment better

  6. Meta-analysis of GPIIb/IIIa trials in primary PCI • RAPPORT, ISAR-2, CADILLAC, ADMIRAL • Kandzari, Am Heart J 2004;147:457–62.) Placebo Better Abciximab better

  7. Bivalirudin Trials Ischemic* and Bleeding Outcomes • *Ischemic endpoints: death, MI, and revascularization • Lincoff AM et al. JAMA. 2003;289:853-863. 2 Stone GW et al. NEJM. 2006;355:2203-2216. 3 Stone GW. NEJM 2008;358:2218-30 Bivalirudin Heparin + GP IIb/IIIa 10% 10% 10% P<.001 P=.32 P=.23 8.3% 7.8% 8% 8% 8% 7.3% P=.95 7.0% P<.001 6.2% P<.001 5.7% 5.5% 6% 6% 6% 5.4% 30 day events (%) 4.9% 4.2% 4% 4% 4% 3.0% 2.4% 2% 2% 2% 0% 0% 0% Ischemia Bleeding Ischemia Bleeding Ischemia Bleeding HORIZONS-AMI3 N=3,602 UFH ± GP IIb/IIIavs Bivalirudin(primary PCI) REPLACE-21 N=6,002 UFH +GP IIb/IIIavs Bivalirudin (Urgent/elective PCI) ACUITY2 N=9,215 UFH + abciximabvs Bivalirudin +GPIIb/IIIa (ACS)

  8. HORIZONS-AMI • Three-year all cause mortality Bivalirudin alone (n=1800) 10 Heparin + GPIIb/IIIa (n=1802) 9 7.7% 8 7 5.9% 6 All-Cause Mortality (%) 5 4 3-yr HR [95%CI] 3 0.75 [0.58, 0.97] 2 p-value = 0.03 1 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months

  9. HORIZONS: • 1 year mortality CADILLAC Risk Score • * Subset of patients in HORIZONS-AMI with CADILLAC risk score data • Parodi G, et al JACC Interv 2010;3:796–802 RR 0.53 P=0.01 1-year mortality (%) RR 1.0 P=0.99 RR 0.34 P=0.09 N=1522 N=531 N=437

  10. 1 year bleeding by risk category and treatment – CADILLAC Risk Score • Parodi G, et al JACC Interv 2010;3:796–802 P=0.135 P=0.281 1-year bleeding rates (%) P=0.0005 N=1522 N=531 N=437

  11. High Risk Analysis Populations: • Bivalirudin vs. Heparin + GP IIb/IIIa • All patients (ITT) REPLACE-2N = 5,986 ACUITY N = 9,215 HORIZONS N = 3,602 N = 18,803 • All patients with DAPT at any time before angiography REPLACE-2N = 5,052 ACUITY N = 5,716 HORIZONS N = 3,490 N = 14,258 Risk Factors included in the stratification model: 1) Age>65, 2) Diabetes, 3) Hypertension, 4) Creatinineclearance<60mg/mL, 5) LVEF<35%, 6)NSTEMI, 7)STEMI, 8)Previous MI and 9) hematocrit<36.

  12. Pooled analysis, 1-year mortality • DAPT Population (n=14,258*) • † fixed model ‡random effects model • Data on File, The Medicines Company Heparin + GPIIb/IIIa better Bivalirudin better

  13. 30-day and 1-year Mortality: Low vs. High Risk • DAPT Population (n=14,258) • Data on File, The Medicines Company Low Risk = 8082 High Risk = 6176 Heparin + GPIIb/IIIa better Bivalirudin better

  14. 1-year mortality, ≥ 3 risk factors(n=6,176) • Data on file, The Medicines Company. • *DAPT population 7.1% 4.9% 1-year death (%)

  15. 1-year mortality by High Risk Subgroups • Consistent effect in all subsets • Data on File, The Medicines Company Bivalirudin better Heparin + GPIIb/IIIabetter

  16. 1-year mortality, LVEF <35 • (n=682, overall 1 year mortality rate of 12%) • Data on file, The Medicines Company. • *DAPT population 16.9% 1-year death (%) 7.8%

  17. 1-year mortality by LVEF • Consistent effect in REPLACE-2, ACUITY, HORIZONS • *DAPT population • Data on File, The Medicines Company Bivalirudin better Heparin + GPIIb/IIIabetter

  18. Progress in High Risk ACS/PCIConclusions • Indirect and unpredictable thrombin inhibition by UFH provides inadequate ischemic protection in high risk ACS • The addition of GPI’s improves ischemic protection at the cost of increased bleeding – modest if any mortality benefit • Bivalirudin trials have consistently demonstrated equivalent efficacy to GPI+UFH with reduced bleeding • HORIZONS showed mortality benefit with bivalirudin out to 3 years, especially in high risk patients • In a pooled analysis set (n=14,258, DAPT treated patients): • 20% reduction in all-cause 1-year mortality • Greater efficacy in high risk population (>3RF’s) LVEF<35%, STEMI, Cr Clear<60 mg/mL, age>65 - Pronounced mortality benefit in low LVEF patients is an intriguing finding requiring further study

  19. 3.3% 5.8% Bivalirudin 16.5% 14.0% Heparin 4.1% 7.4% Bivalirudin 11.9% 10.3% Heparin 2.4% 4.9% Bivalirudin 11.8% 9.9% Heparin 3.8% 6.1% Bivalirudin 8.3% 7.0% Heparin Heparin Heparin vs. BivalirudinOutcomes by risk strata B•A•T • Results in pre-specified increasing high-risk patients Hemorrhage Death, MI, revasc UA, on UFH & <14 days post-MI n = 241 UA & on prior heparin n = 1,006 <14 days Post-MI n = 741 Unstable angina n = 2,806 % of patients with events at 7 days Bittl JA et al. Am Heart J. 2001;142:952-59 Henry J Inv Cardiol. 2002;14(suppl B):19B-29B

  20. ACS/PCI Risk Stratification • 1Boersma E, et al. Circulation2000;101:2557-67; 2Madan P, et al. Am Heart J2008;155:1068-74; 3Antman EM, et al. JAMA2000;284:835-42; 5Eagle KA, et al. JAMA2004;291:2727-33; 6Addala S, et al. Am J Cardiol2004;93:629–32; 7Halkin A, et al. J Am CollCardiol 2005;45:1397–1405

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