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Bivalirudin Reduces Cardiac Mortality in Patients with and Without Major Bleeding

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

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Bivalirudin Reduces Cardiac Mortality in Patients with and Without Major Bleeding

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

  2. 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 JACC2012;60(17SupplB):B16

  3. ' Cardiac Mortality30 days to 3 years* Heparin + GPIIb/IIIa(n=1802) Bivalirudin (n=1800) 6 30-d† HR [95% CI]0.62; [0.40,0.96] P = 0.03 1-yr† HR [95%CI]= 0.57 [0.38, 0.84] P=0.005 5.1% 5 4 2.9% 3.8% CardiacMortality (%) 2.9% 3 3-yr† HR [95%CI]= 0.56 [0.40, 0.80] P=0.001 2 2.1% 1.8% 1 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months *All cause mortality at 3 years was also consistently lower with bivalirudin (5·9% vs7·7%), HR0·75 [0·58–0·97]; p=0·03 †These timepoints were prespecifiedanalyses Stone GW et al NEJM 2008;358:2218-30; Mehran R et al Lancet. 2009;374:1149-59; Stone GW et al. Lancet 2011;377:2193-204

  4. 3-Year Cardiac Mortality • In all patients, multivariable model • Other variables in model: current smoker, female gender, prior MI, # vessels treated, hemoglobin • Stone GW et al. TCT 2012 and JACC2012;60(17SupplB):B16

  5. 3-Year Major Bleeding* Heparin + GPIIb/IIIa(n=1802) Bivalirudin (n=1800) • Stone GW et al. Lancet2011;377:2193-204 • * 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 12 10.5% 10 8 6.9% 6 Major Bleeding, non-CABG (%) Δ=64 major bleeds 3-yr HR [95%CI]= 0.64 [0.51, 0.80] P<0.001 4 2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months

  6. Impact of Major Bleeding • Stone GW et al. TCT 2012 and JACC2012;60(17SupplB):B16 12% No major bleed (n=3296) Major bleed (n=306) 11.6% 10% 8% HR [95%CI] = 5.81 [3.92, 8.62] P<0.001 6% Cardiac mortality (%) 4% 3.3% 2% 0% 0 1 2 3 Years

  7. 3-year Cardiac Mortality • In patients with vs without major bleeding • Stone GW et al. TCT 2012 and JACC2012;60(17SupplB):B16 HR [95%CI] = 5.67 [3.59, 8.96] P<0.0001 Pint = 0.34 HR [95%CI] = 4.62 [2.04, 10.45] P=0.002 27/185 61/1617 7/121 43/1679 P=0.03 % major bleed in patients with cardiac death 14.0% (7/50) 30.7% (27/88)

  8. 3-Year Cardiac Mortality • In patients with vs without major bleeding, according to treatment • Stone GW et al. TCT 2012 and JACC2012;60(17SupplB):B16 HR [95%CI] = 2.56 [1.12, 5.88] P=0.02 HR [95%CI] = 1.47 [1.00, 2.17] P=0.048 Pint = 0.34 27/185 7/121 61/1617 43/1679 # fewer cardiac deaths with bivalirudin ∆ = 20 deaths ∆ = 18 deaths

  9. 3-year Mortality • In patients with major bleeding, according to treatment • *From the time of a major bleed • Stone GW et al. TCT 2012 and JACC2012;60(17SupplB):B16 16% 14.6% 14% 12% HR [95%CI] =0.39 (0.17 - 0.89) P=0.025 Heparin + GPIIb/IIIa (n=185) 10% Bivalirudin (n=121) Cardiac mortality* (%) 8% 5.8% 6% 4% 2% 0% 0 1 2 3 Years UFH + GPIIb/IIIa 185 151 138 86 Bivalirudin 121 104 94 59

  10. 3-Year Cardiac Mortality • In patients with major bleeding, multivariable model • Other variables in model: diabetes, Killip class, LAD treated, hemoglobin, creatinine • Stone GW et al. TCT 2012 and JACC2012;60(17SupplB):B16

  11. Hemoglobin Levels • In patients with major bleeding • Stone GW et al. TCT 2012 and JACC2012;60(17SupplB):B16 P=0.03 P=0.08 ± 1.9 ± 2.3 ± 1.9 ± 2.0 P=0.31 ± 1.7 ± 2.0

  12. RBC Transfusions • Stone GW et al. TCT 2012 and JACC2012;60(17SupplB):B16 Median # units(among patients transfused) UFH + GPIIb/IIIa: 2 [2, 5] Bivalirudin: 3 [2, 5] P=0.10 Number of patients Number of RBC units transfused

  13. 3-year Mortality • In patients without major bleeding* • *KM curve with censoring at time of major bleed • Stone GW et al. TCT 2012 and JACC2012;60(17SupplB):B16 5% 4% 3.8% Heparin + GPIIb/IIIa (n=1802) Bivalirudin (n=1800) 3% 2.6% Cardiac mortality (%) 2% HR [95%CI] = 0.67(0.46 to 1.00) P=0.046 1% 0% 0 1 2 3 Years

  14. 3-Year Cardiac Mortality • In patients without major bleeding*, multivariable model • Stone GW et al. TCT 2012 and JACC2012;60(17SupplB):B16 Other variables in model: current smoker, female gender, prior MI, # vessels treated * patients censored at time of bleed

  15. Acquired thrombocytopenia,*in-hospital Acquired thrombocytopenia (n=404) No thrombocytopenia (n=3053) • Stone GW et al. TCT 2012 and JACC2012;60(17SupplB):B16 • * Nadir platelet count <150,000 in patients w/o baseline thrombocytopenia 10% 8.1% 8% P=0.004 6% HR [95%CI] = 2.76 [1.85, 4.14] P<0.001 13.2% Cardiac mortality (%) 4% 10.1% 3.1% 2% 0% 0 1 2 3 Thrombocytopenia Years

  16. 3-year Cardiac Mortality • In patients with and without in-hospital acquired thrombocytopenia • Stone GW et al. TCT 2012 and JACC2012;60(17SupplB):B16 HR [95%CI] = 4.36 [2.73, 6.95] P<0.0001 Pint = 0.006 HR [95%CI] = 1.44 [0.50, 4.12] P=0.51 28/228 52/1493 4/176 39/1560 % thrombocytopenia in patients with cardiac death 35.0% (28/80) 9.3% (4/43) P=0.002

  17. 3-year Cardiac Mortality • In patients with and without thrombocytopenia, according to treatment • Nadir platelet count <150,000 in patients w/o baseline thrombocytopenia • Stone GW et al. TCT 2012 and JACC2012;60(17SupplB):B16 Pint = 0.006 HR (95%CI) = 5.56 (2.00, 16.67) P=0.0001 HR (95%CI) = 1.41 (0.47 to 1.09) P=0.12 28/228 4/176 52/1493 39/1560

  18. Interaction between major bleeding and acquired thrombocytopenia* • Stone GW et al. TCT 2012 and JACC2012;60(17SupplB):B16 Ptrend <0.0001 P=0.005 P=0.03 14/81 17/205 18/323 74/2848 60.2% (n=74) 14.6% (n=18) 13.8% (n=17) % of 123 cardiac deaths 11.4% (n=14) *Excluding patients with baseline thrombocytopenia

  19. Interaction between major bleeding, thrombocytopenia* and treatment • *Excluding patients with baseline thrombocytopenia Stone GW et al. TCT 2012 and JACC2012;60(17SupplB):B16 Ptrend<0.0001 Ptrend= 0.17 13/50 1/31 12/125 5/80 15/178 3/145 34/1480 40/1368

  20. 3-Year Cardiac Mortality • Multivariable model, including adverse events • Excludes 145 patients with thrombocytopenia at baseline. Other variables in model: current smoker, female gender, prior MI, # vessels treated, hemoglobin • Stone GW et al. TCT 2012 and JACC2012;60(17SupplB):B16

  21. 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

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