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 347/9405596/9413106/1800173/1802183/4612306/460358/2993117/3008 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. p = 0.0003 Bivalirudin vs. Heparin + GPI (n=18,819) Acquired thrombocytopenia (<100,000) by treatment and study p = 0.049p = 0.003p < 0.0001116/9145201/911919/166548/185377/4612103/460320/286850/2863 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 (n=9406) H+GPI (n=9413) Adjusted HR [95%CI] PREPLACE-21.9%(56/2994)2.4%(72/3008) 0.78 (0.55 to 1.10) 0.16 ACUITY3.7%(170/4612)3.9%(178/4603) 0.96 (0.77 to 1.18) 0.67 HORIZONS-AMI3.4%(61/1800)4.8%(86/1802) 0.71 (0.51 to 0.98) 0.038 Pooled3.1%(287/9406)3.6%(336/9413) 0.84 (0.72 to 0.99) 0.035 Bivalirudin vs. Heparin + GPI (n=18,819) 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. Rassen JA et al. EHJ 2010;31:561-72 N = 127,185 pts undergoing PCI 2003-2006 ( (Premier Perspective Database, ~1/6 th of all US hosps; bival in 26%) Bivalirudin vs. Heparin + GPIIb/IIIa In-hospital transfusion BivalirudinH+GPI 3.0%4.6% Adjusted HR [95%CI] 0.67 [0.61 - 0.73] 33%  Transfusion Favors BivalFavors H+GPI **30 days Unadjusted (All) Adjusted (All) Adjusted (urgent subgroup) Adjusted (elective subgroup) REPLACE-2** ACUITY** HORIZONS-AMI** ISAR-REACT** 0.1101

6. N = 127,185 pts undergoing PCI 2003-2006 ( (Premier Perspective Database, ~1/6 th of all US hosps; bival in 26%) Bivalirudin vs. Heparin + GPIIb/IIIa In-hospital death BivalirudinH+GPI 0.8%2.1% Adjusted HR [95%CI] 0.51 [0.44 – 0.60] 49%  Death **30 days Unadjusted (All) Adjusted (All) Adjusted (urgent subgroup) Adjusted (elective subgroup) REPLACE-2** ACUITY** HORIZONS-AMI** ISAR-REACT** 0.1101 Favors BivalFavors H+GPI Rassen JA et al. EHJ 2010;31:561-72

7. Pinto DS et al. Circ CV Qual Outcomes 2012;5:52-61 Primary PCI in 59,917 STEMI pts 2004-2008 ( (Premier Perspective Database, ~1/6 th of all US hosps) Bivalirudin vs. Heparin + GPIIb/IIIa 3:1 propensity adjusted matching In-hospital outcomes Bivalirudin(N=5,329) UFH + GPI (N=15,987) OR (95% CI) P value Bleeding6.9%10.5% 0.52 (0.41, 0.66) <0.0001 Transfusion5.9%7.6% 0.75 (0.66–0.86) <0.0001 Bleeding + transf 1.6%3.0% 0.63 (0.56–0.71) <0.0001 Death3.2%4.0% 0.80 (0.67– 0.95) 0.01 Length of stay (days) 4.3 ± 4.5 4.5 ± 4.4 -<0.0001 Total cost (median) $14,462$15,772-<0.0001

8. N = 458,448 PCI pts 2004-2008 at 299 hosps (Premier Perspective Database, ~1/5 th of all US hosp discharges; bival in 41%) Wise GR et al. J Interv Cardiol 2012;25:278–88 Bleeding + Transfusion In-hospital events, propensity adjusted Mortality Comparator Better Heparin + GPI Better (n=182,948) 021 0.71 (0.66, 0.76) Heparin alone (n=85,870) <0.0001 0.96 (0.87, 1.06) Bivalirudin + GPI (n=33,566) 0.37 0.51 (0.48, 0.55) Bivalirudin monotherapy (n=156,064) <0.0001 OR (95% CI)Comparator P Value Comparator Better Heparin + GPI Better (n=182,948) 021 0.88 (0.82, 0.96) Heparin alone (n=85,870) 0.003 0.82 (0.72, 0.94) Bivalirudin + GPI (n=33,566) 0.004 0.59 (0.54, 0.65) Bivalirudin monotherapy (n=156,064) <0.0001 OR (95% CI)Comparator P Value Anticoagulation Regimens During PCI OR (95% CI) OR (95% CI)

9. 16 studies (3 rand, 13 reg), 32,492 pts undergoing PCI: Bivalirudin vs UFH Monotherapy Meta-analysis Major Bleeding Bertrand OF et al. Am J Cardiol 2012;110:599–606 Study or subgroupEvents Odds Ratio M-H, Random, 95% CI Total Bivalirudin Events Heparin 0.01 Favors Bivalirudin 0.1110100 Favors Heparin Total Events 244 431 Test for heterogeneity: Tau 2 =0.08, Chi 2 =21.99, df=13 (P=0.06),I 2 =41% Test for overall effect: Z=4.38 (P<0.0001) Test for subgroup differences: Chi 2 =0.47, df=1 (P=0.49),I 2 =0% Total (95% CI) Observational Randomized Kastrati 2008 Parodi 2010 Patti 2011 Subtotal (95% CI) 0.55 [0.43, 0.72] 11648 Total Events 16 34 Test for heterogeneity: Tau 2 =0.00, Chi 2 =0.37, df=2 (P=0.83),I 2 =0% Test for overall effect: Z=2.60 (P=0.009) 12 3 1 0.50 [0.25, 0.99] 0.31 [0.08, 1.19] 0.51 [0.05, 5.67] 0.45 [0.25, 0.82] 2289 363 198 2850 24 8 2 Total Events 228 397 Test for heterogeneity: Tau 2 =0.11, Chi 2 =20.84, df=10 (P=0.02),I 2 =52% Test for overall effect: Z=3.55 (P=0.0004) 4 1 2 23 10 26 5 6 101 12 38 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] 335 54 216 566 79 1207 267 503 1771 2289 1511 8798 35 2 14 20 101 2 26 89 16 78 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) Total 13206 2281 308 203 2792 1543 60 456 333 92 1559 129 861 1365 2505 1551 10414 45%↓

10. 16 studies (3 rand, 13 reg), 32,492 pts undergoing PCI: Bivalirudin vs UFH Monotherapy Meta-analysis Mortality Bertrand OF et al. Am J Cardiol 2012;110:599–606 Study or subgroupEvents Odds Ratio M-H, Random, 95% CI Total Bivalirudin Events Heparin 0.01 Favors Bivalirudin 0.1110100 Favors Heparin Total Events 96 196 Test for heterogeneity: Tau 2 =0.00, Chi 2 =13.90, df=14 (P=0.46),I 2 =0% Test for overall effect: Z=4.15 (P<0.0001) Test for subgroup differences: Chi 2 =0.00, df=1 (P=0.97),I 2 =0% Total (95% CI) Observational Randomized Kastrati 2008 Parodi 2010 Patti 2011 Subtotal (95% CI) 0.58 [0.45, 0.75] 1456317929 Total Events 5 8 Test for heterogeneity: Tau 2 =0.00, Chi 2 =1.96, df=2 (P=0.38),I 2 =0% Test for overall effect: Z=0.78 (P=0.44) 311311 0.75 [0.17, 3.34] 0.21 [0.02, 1.89] 3.09 [0.13, 76.33] 0.63 [0.20, 2.01] 2289 363 198 2850 440440 Total Events 91 188 Test for heterogeneity: Tau 2 =0.03, Chi 2 =11.92, df=11 (P=0.37),I 2 =8% Test for overall effect: Z=2.98 (P=0.003) 0 3 0 7 3 6 3 48 5 0 12 3 1 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] 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 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) Total 2281 308 203 2792 1543 801 60 456 3922 333 92 1559 129 861 1365 2505 1551 15137 42%↓

11. 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%) Impact of Bleeding Avoidance Strategies Marso SP et al. JAMA. 2010;303:2156-64 All P<0.001 Risk from NCDR CathPCI bleeding model

12. 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 Impact of Bleeding Avoidance Strategies Marso SP et al. JAMA. 2010;303:2156-64 23%↓ 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 33%↓ 62%↓

13. Impact of Access and Non-Access Site Bleeding after PCI 17,393 pts underwent PCI in REPLACE-2, ACUITY and HORIZONS 568(61.4%) non access site related 925 pts (5.3%) had TIMI major or minor bleeding within 30 days Source of bleeding (absolute rate) 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 Adjusted risk of 1-year mortality TIMI Bleed - All TIMI Bleed – Non Access Site TIMI Bleed – Access Site Only 0.181 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 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 RiskP-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 0.700.08 - Indeterminate 0.750.02 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 Intracranial0.040.030.66 GI0.60.280.44 GU0.640.280.44 HEENT0.330.220.66 Pulmonary0.180.050.31 Other0.300.150.49 Indeterminate1.871.400.75 All Non - Access Site 3.662.270.62 Bivalirudin better H + GPI better 00.511.52

17. HORIZONS-AMI: Cardiac Mortality in Pts with Major Bleeding 0.39 (0.17 - 0.89) HR [95%CI] = 0.39 (0.17 - 0.89) P=0.025 0% 2% 4% 6% 8% 10% 12% 14% 16% Cardiac mortality* (%) 1211049459Bivalirudin 18515113886UFH + GPI 0123 Years Heparin + GPI (n=185) Bivalirudin (n=121) 5.8% 5.8% 14.6% *From the time of a major bleed

18. 0% 1% 2% 3% 4% 5% 1800156915211039Bivalirudin 180215061441957UFH+GPI 0123 0.67 (0.46 to 1.00) HR [95%CI] = 0.67 (0.46 to 1.00) P=0.046 *KM curve with censoring at time of major bleed HORIZONS-AMI: Cardiac Mortality in Pts without Major Bleeding* Cardiac mortality (%) Years Heparin + GPI (n=1802) Bivalirudin (n=1800) 2.6% 2.6% 3.8% 0.65 (0.44 to 0.97) Adj HR [95%CI] = 0.65 (0.44 to 0.97) P=0.033

19. HORIZONS-AMI: Multivariable Model for 3-Year Cardiac Mortality, Including Adverse Events Risk factorHazard ratio (95% CI)P-value Age (per 5 years)1.34 (1.23 to 1.46)<0.001 WBC (per 10 9 cells/L)1.15 (1.09 to 1.21)<0.001 S. creatinine (per 0.1 mg/dl)1.10 (1.05 to 1.16)<0.001 Killip class 2-42.17 (1.41 to 3.35)<0.001 LAD PCI1.68 (1.13 to 2.50) 0.007 Diabetes, medically treated1.50 (1.01 to 2.23)0.045 Major bleeding2.97 (1.88 to 4.69)<0.001 Acquired thrombocytopenia2.10 (1.36 to 3.24)0.001 Bivalirudin (vs UFH+GPI)0.54 (0.38 to 0.79)0.002 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 1.Compared to UFH + GPI, bivalirudin reduces mortality across the spectrum of pts undergoing PCI 2.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 3.These benefits are realized in all PCI pts - including those undergoing radial intervention 4.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. ESC/EACTS Guidelines PCI in STEMI and NSTE-ACSPCI in STEMI and NSTE-ACS I Bivalirudin in ACS: The Guidelines ACC/AHA Guidelines PCI in STEMI and NSTE-ACSPCI in STEMI and NSTE-ACS Pts with HIT or HITTSPts with HIT or HITTS I EHJ 2010 Circulation and JACC 2005, 2007, 2009, 2011