Gregg W. Stone, Tim Clayton, Roxana Mehran, Efthymios N. Deliargyris, Jayne Prats, Stuart J. Pocock TCT 2012; JACC 2012;60(17SupplB):B16 The HORIZONS-AMI Trial Bivalirudin Reduces Cardiac Mortality in Patients with and Without Major Bleeding

Background ● In the HORIZONS-AMI trial, treatment with bivalirudin compared to heparin + a GPIIb/IIIa inhibitor in patients 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 Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16

Cardiac Mortality 30 days to 3 years* ' Bivalirudin (n=1800)Heparin + GPIIb/IIIa (n=1802) Stone GW et al NEJM 2008;358: ; Mehran R et al Lancet. 2009;374: ; Stone GW et al. Lancet 2011;377: d † HR [95% CI] 0.62; [0.40,0.96] P = % 2.9% * All cause mortality at 3 years was also consistently lower with bivalirudin (5·9% vs 7·7%), HR 0·75 [0·58–0·97]; p=0·03 † These timepoints were prespecified analyses

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 Creatinine (per 0.1 mg/dL)1.11 (1.06 to 1.16)<0.001 Killip class (1.62 to 3.60) <0.001 LAD PCI1.68 (1.16 to 2.45) Diabetes, medically treated1.54 (1.06 to 2.23)0.02 Bivalirudin (vs UFH+GPIIb/IIIa)0.57 (0.40 to 0.81) Year Cardiac Mortality Other variables in model: current smoker, female gender, prior MI, # vessels treated, hemoglobin Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16 ●In all patients, multivariable model

yr HR [95%CI]= 0.64 [0.51, 0.80] P< % 10.5% Major Bleeding, non-CABG (%) Months 369 Δ=64 major bleeds 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: Bivalirudin (n=1800) Heparin + GPIIb/IIIa (n=1802)

HR [95%CI] = 5.81 [3.92, 8.62] P< % 11.6% Years Cardiac mortality (%) 12% No major bleed (n=3296) Major bleed (n=306) 10% 8% 6% 4% 2% 0% 0123 Impact of Major Bleeding Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16

% major bleed in patients with cardiac death 14.0% (7/50) 30.7% (27/88) P=0.03 HR [95%CI] = 4.62 [2.04, 10.45] P=0.002 HR [95%CI] = 5.67 [3.59, 8.96] P< /12143/167927/18561/1617 P int = year Cardiac Mortality Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16 ●In patients with vs without major bleeding

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 ∆ =  20 deaths∆ =  18 deaths # fewer cardiac deaths with bivalirudin P int = Year Cardiac Mortality Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16 ●In patients with vs without major bleeding, according to treatment

HR [95%CI] = 0.39 ( ) P= % 2% 4% 6% 8% 10% 12% 14% 16% Cardiac mortality* (%) Bivalirudin UFH + GPIIb/IIIa 0123 Years Heparin + GPIIb/IIIa (n=185) Bivalirudin (n=121) 5.8% 14.6% 3-year Mortality *From the time of a major bleed Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16 ●In patients with major bleeding, according to treatment

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+GPIIb/IIIa)0.32 (0.14 to 0.78) Year Cardiac Mortality Other variables in model: diabetes, Killip class, LAD treated, hemoglobin, creatinine Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16 ●In patients with major bleeding, multivariable model

± 1.9 ± 2.3 P=0.03 ± 1.9 ± 2.0 ± 1.7 ± 2.0 P=0.08 P=0.31 Hemoglobin Levels Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16 ●In patients with major bleeding

Median # units (among patients transfused) UFH + GPIIb/IIIa: 2 [2, 5] Bivalirudin: 3 [2, 5] P=0.10 Number of RBC units transfused Number of patients RBC Transfusions Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16

0% 1% 2% 3% 4% 5% 0123 HR [95%CI] = 0.67 (0.46 to 1.00) P=0.046 Cardiac mortality (%) Years Heparin + GPIIb/IIIa (n=1802) Bivalirudin (n=1800) 2.6% 3.8% 3-year Mortality *KM curve with censoring at time of major bleed Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16 ●In patients without major bleeding*

Risk factorHazard ratio (95% CI)P-value LMS PCI10.57 ( <0.001 LAD PCI1.72 ( ) 0.02 Age (per 5 years)1.29 ( )<0.001 Killip class ( ) <0.001 S. creatinine (per 0.1 mg/dl)1.14 ( )<0.001 WBC (per 10 9 cells/L)1.08 ( )0.009 Diabetes, insulin treated1.92 ( )0.047 Hemoglobin (per g/dl)0.86 ( )0.03 Bivalirudin (vs UFH+GPIIb/IIIa)0.65 ( )0.035 Other variables in model: current smoker, female gender, prior MI, # vessels treated * patients censored at time of bleed 3-Year Cardiac Mortality Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16 ●In patients without major bleeding*, multivariable model

13.2% 10.1% P= % 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 Acquired thrombocytopenia,* in-hospital * Nadir platelet count <150,000 in patients w/o baseline thrombocytopenia Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16

HR [95%CI] = 1.44 [0.50, 4.12] P=0.51 HR [95%CI] = 4.36 [2.73, 6.95] P< /17639/156028/22852/ % (4/43) 35.0% (28/80) P=0.002 % thrombocytopenia in patients with cardiac death P int = year Cardiac Mortality Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16 ●In patients with and without in-hospital acquired thrombocytopenia

HR (95%CI) = 5.56 (2.00, 16.67) P= HR (95%CI) = 1.41 (0.47 to 1.09) P=0.12 4/17639/156028/22852/1493 P int = year Cardiac Mortality Nadir platelet count <150,000 in patients w/o baseline thrombocytopenia Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16 ●In patients with and without thrombocytopenia, according to treatment

P trend < /8117/20518/32374/2848 P=0.005 P=0.03 % of 123 cardiac deaths 11.4% (n=14) 14.6% (n=18) 13.8% (n=17) 60.2% (n=74) Interaction between major bleeding and acquired thrombocytopenia* Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16 *Excluding patients with baseline thrombocytopenia

P trend < /5012/12515/17840/13681/315/803/14534/1480 P trend = 0.17 Interaction between major bleeding, thrombocytopenia* and treatment *Excluding patients with baseline thrombocytopenia Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16

3-Year Cardiac Mortality Excludes 145 patients with thrombocytopenia at baseline. Other variables in model: current smoker, female gender, prior MI, # vessels treated, hemoglobin 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 (1.41 to 3.35)<0.001 LAD PCI1.68 (1.13 to 2.50) 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+GPIIb/IIIa)0.54 (0.38 to 0.79)0.002 Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16 ●Multivariable model, including adverse events

Conclusions ● In HORIZONS-AMI, treatment with bivalirudin rather than UFH + GPIIb/IIIa resulted in a marked reduction in cardiac mortality in patients with STEMI undergoing primary PCI –~Half of the reduction in cardiac deaths with bivalirudin occurred in patients without major bleeding ● In addition to reducing major bleeding, bivalirudin reduced the occurrence of thrombocytopenia, which contributed to the improved survival in patients with and without major bleeding ● The adverse effects of major bleeding and thrombocytopenia are mitigated in patients treated with bivalirudin rather than UFH + GPIIb/IIIa, and bivalirudin was strongly associated with reduced cardiac mortality even after accounting for bleeding and thrombocytopenia – further studies are required to identify the non-hematolgic benefits of bivalirudin Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16