1. Gregg W. Stone, Tim Clayton, Roxana Mehran, Efthymios N. Deliargyris, Jayne Prats, Stuart J. Pocock Bivalirudin Reduces Cardiac Mortality in Patients with and Without Major Bleeding The HORIZONS-AMI Trial

2. Background In the HORIZONS-AMI trial, treatment with bivalirudin compared to heparin + a GPIIb/IIIa inhibitor in pts with STEMI undergoing primary PCI resulted in markedly reduced rates of cardiac mortality, which is usually attributed to decreased bleeding Whether the reduction in mortality with bivalirudin can be fully ascribed to reduced bleeding is unknown

3. HORIZONS-AMI: 3-Year Cardiac Mortality * Intracranial intraocular, retroperitoneal, access site bleed requiring intervention/surgery, hematoma ≥5 cm, hgb ↓ ≥3g/dL with or ≥4g/dL w/o overt source; reoperation for bleeding; or blood product transfusion 1611 1568 16601689 1670 6 1800 Bivalirudin alone 0 2 3 4 5 1 0 121518212427303336 1098 180216431043 Months 369 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Number at risk Heparin+GPIIb/IIIa 1633 1593 1574 1525 Stone GW et al. Lancet 2011; Stone GW et al. Lancet 2011;377:2193-204 Cardiac Mortality (%) 2.9% 5.1% P=0.001 3-yr HR [95%CI]= 0.56 [0.40, 0.80] Δ=38 cardiac deaths

4. HORIZONS-AMI: Multivariable Model for 3-Year Cardiac Mortality (all pts) Risk factorHazard ratio (95% CI)P-value Age (per 5 years)1.31 (1.21 to 1.43)<0.001 WBC (per 10 9 cells/L)1.12 (1.07 to 1.18)<0.001 S. creatinine (per 0.1 mg/dl)1.11 (1.06 to 1.16)<0.001 Killip class 2-42.41 (1.62 to 3.60) <0.001 LAD PCI1.68 (1.16 to 2.45) 0.007 Diabetes, medically treated1.54 (1.06 to 2.23)0.02 Bivalirudin (vs UFH+GPI)0.57 (0.40 to 0.81)0.001 Other variables in model: current smoker, female gender, prior MI, # vessels treated, hemoglobin

5. HORIZONS-AMI: 3-Year Major Bleeding* * Intracranial intraocular, retroperitoneal, access site bleed requiring intervention/surgery, hematoma ≥5 cm, hgb ↓ ≥3g/dL with or ≥4g/dL w/o overt source; reoperation for bleeding; or blood product transfusion Stone GW et al. Lancet 2011; Stone GW et al. Lancet 2011;377:2193-204 Δ=64 major bleeds

6. HORIZONS-AMI: Impact of Major Bleeding HR [95%CI] = 5.81 [3.92, 8.62] P<0.001 3.3% 11.6% Years Cardiac mortality (%) 12% No bleed Bleed No major bleed (n=3296) Major bleed (n=306) 3296 306 10% 8% 6% 4% 2% 0% 0123 3043 255 2944 232 1996 145

7. HR [95%CI] = 4.62 [2.04, 10.45] P=0.002 HORIZONS-AMI: 3-year Cardiac Mortality in Pts with vs without Major Bleeding HR [95%CI] = 5.67 [3.59, 8.96] P<0.0001 7/12143/167927/18561/1617 % major bleed in pts with cardiac death 14.0% (7/50) 30.7% (27/88) P=0.03P=0.03 P int = 0.34

8. 27/1857/12161/161743/1679 HR [95%CI] = 2.56 [1.12, 5.88] P=0.02 HR [95%CI] = 1.47 [1.00, 2.17] P=0.048 HORIZONS-AMI: 3-Year Cardiac Mortality in pts with and without Major Bleeding According to Treatment ∆ =  20 deaths∆ =  18 deaths # fewer cardiac deaths with bivalirudin P int = 0.34

9. HORIZONS-AMI: Mortality in Patients 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

10. HORIZONS-AMI: Multivariable Model for 3-Year Cardiac Mortality in Pts With Major Bleeding Risk factorHR (95% CI)P-value Age (per 5 years)1.33 (1.13 to 1.56)0.001 WBC (per 10 9 cells/L)1.23 (1.12 to 1.36)<0.001 Bivalirudin (vs UFH+GPI)0.32 (0.14 to 0.78)0.006 Other variables in model: diabetes, Killip class, LAD treated, hemoglobin, creatinine

11. HORIZONS-AMI: Frequency and Severity of Major Bleeding UFH + GPI N=1,802 Bivalirudin N=1,800 P Deaths* (H+GPI, Biv) Intracranial bleeding4 (0.2%) -1, 0 Intraocular bleeding0 (0%)1 (<0.1%)-0, 0 Drop in hgb ≥3 g/dl with overt source50 (2.8%)35 (1.9%)0.103, 4 Drop in hgb ≥4 g/dl without an overt source88 (4.9%)53 (2.9%)0.00318, 2 Drop in hgb ≥5 g/dl without an overt source44 (2.4%)28 (1.6%)0.0611, 1 Reoperation for bleeding3 (0.2%)1 (<0.1%)0.321, 1 Blood product transfusion89 (4.9%)60 (3.3%)0.0216, 4 Retroperitoneal bleeding10 (0.6%)9 (0.5%)0.824, 0 Access site requiring intervention/surgery7 (0.4%)4 (0.2%)0.370, 0 Hematoma ≥5 cm at puncture site48 (2.7%)24 (1.3%)0.0045, 1 Total (≥1 major bleed)185 (10.3%)121 (6.7%) 0.000127, 7 *In pts with that type of major bleed

12. HORIZONS-AMI: Hemoglobin Levels in Pts with Major Bleeding ± 1.9 ± 2.3 P=0.03 ± 1.9 ± 2.0 ± 1.7 ± 2.0 P=0.08 P=0.31

13. HORIZONS-AMI: RBC Transfusions Median # units (among pts transfused) UFH + GPI: 2 [2, 5] Bivalirudin: 3 [2, 5] P=0.10 Number of RBC units transfused Number of pts

14. 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: Mortality in Pts without Major Bleeding* Cardiac mortality (%) Years Heparin + GPI (n=1802) Bivalirudin (n=1800) 2.6% 2.6% 3.8%

15. HORIZONS-AMI: Multivariable Model for 3-Year Cardiac Mortality in Pts Without Major Bleeding* Risk factorHazard ratio (95% CI)P-value LMS PCI10.57 (3.76 to 29.70<0.001 LAD PCI1.72 (1.10 to 2.69) 0.02 Age (per 5 years)1.29 (1.16 to 1.43)<0.001 Killip class 2-42.86 (1.82 to 4.51) <0.001 S. creatinine (per 0.1 mg/dl)1.14 (1.08 to 1.20)<0.001 WBC (per 10 9 cells/L)1.08 (1.02 to 1.14)0.009 Diabetes, insulin treated1.92 (1.01 to 3.65)0.047 Hemoglobin (per g/dl)0.86 (0.76 to 0.98)0.03 Bivalirudin (vs UFH+GPI)0.65 (0.44 to 0.97)0.035 Other variables in model: current smoker, female gender, prior MI, # vessels treated *Pts censored at time of bleed

16. HORIZONS-AMI: Incidence and Impact of In-hospital Acquired Thrombocytopenia* * Nadir platelet count <150,000 in pts w/o baseline thrombocytopenia 13.2% 10.1% P=0.004 3.1% 8.1% HR [95%CI] = 2.76 [1.85, 4.14] P<0.001 Thrombocytopenia Years Cardiac mortality (%) Acquired thrombocytopenia (n=404) No thrombocytopenia (n=3053) 0 10% 8% 6% 4% 2% 0% 123 3053 404 2832 341 2726 330 1833 217 No thromb Thromb

17. HR [95%CI] = 1.44 [0.50, 4.12] P=0.51 HORIZONS-AMI: 3-year Cardiac Mortality in Pts with vs without In-hospital Acquired Thrombocytopenia HR [95%CI] = 4.36 [2.73, 6.95] P<0.0001 4/17639/156028/22852/1493 9.3% (4/43) 35.0% (28/80) P=0.002P=0.002 % thrombocytopenia in pts with cardiac death P int = 0.006

18. HORIZONS-AMI: 3-year Cardiac Mortality in Pts with vs without Acquired Thrombocytopenia* According to Treatment HR (95%CI) = 5.56 (2.00, 16.67) P=0.0001 Nadir platelet count <150,000 in pts w/o baseline thrombocytopenia HR (95%CI) = 1.41 (0.47 to 1.09) P=0.12 4/17639/156028/22852/1493 P int = 0.006

19. HORIZONS-AMI: Interaction Between Major Bleeding and Acquired Thrombocytopenia* *Excluding pts with baseline thrombocytopenia P trend <0.0001 14/8117/20518/32374/2848 P=0.005P=0.005 P=0.03P=0.03 % of 123 cardiac deaths 11.4% (n=14) 14.6% (n=18) 13.8% (n=17) 60.2% (n=74)

20. P trend <0.0001 13/5012/12515/17840/13681/315/803/14534/1480 P trend = 0.17 *Excluding pts with baseline thrombocytopenia HORIZONS-AMI: Interaction Between Major Bleeding, Thrombocytopenia* and Treatment

21. 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

22. Conclusions 1.In HORIZONS-AMI, treatment with bivalirudin rather than UFH + GPI resulted in a marked reduction in cardiac mortality in pts with STEMI undergoing primary PCI  ~Half of the reduction in cardiac deaths with bivalirudin occurred in pts without major bleeding 2.In addition to reducing major bleeding, bivalirudin reduced the occurrence of thrombocytopenia, which contributed to the improved survival in pts with and without major bleeding 3.The adverse effects of major bleeding and thrombocytopenia are mitigated in pts treated with bivalirudin rather than UFH + GPI, and bivalirudin was strongly associated with reduced cardiac mortality even after accounting for bleeding and thrombocytopenia – further studies are required to identify the non-hematologic benefits of bivalirudin