Reduction in Cardiac Mortality With Bivalirudin in Patients With and Without Major Bleeding: The HORIZONS-AMI Trial
What is the extent to which the reduction in cardiac mortality after primary percutaneous coronary intervention (PCI) with bivalirudin compared to unfractionated heparin (UFH) + a glycoprotein IIb/IIIa inhibitor (GPI) can be attributed to reduced bleeding?
A total of 3,602 ST-segment elevation myocardial infarction (STEMI) patients undergoing primary PCI were randomized to bivalirudin vs. UFH + GPI. Three-year cardiac mortality was analyzed in patients with and without major bleeding. To investigate the effect of bivalirudin after accounting for adverse events that bivalirudin is known to reduce (including thrombocytopenia and reinfarction, as well as major bleeding), each event was entered into a time-updated covariate-adjusted Cox model.
Bivalirudin compared to UFH + GPI resulted in lower 3-year rates of major bleeding (6.9% vs. 10.5%; hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.51-0.80; p < 0.0001) and cardiac mortality (2.9% vs. 5.1%; HR, 0.56; 95% CI, 0.40-0.80; p = 0.001). Three-year cardiac mortality was reduced in bivalirudin-treated patients with major bleeding (20 fewer deaths with bivalirudin; 5.8% vs. 14.6%; p = 0.025), and without major bleeding (18 fewer deaths with bivalirudin; 2.6% vs. 3.8%; p = 0.048). In a fully-adjusted multivariable model accounting for major bleeding and other adverse events, bivalirudin was still associated with a 43% reduction in 3-year cardiac mortality (adjusted HR, 0.57; 95% CI, 0.39-0.83; p = 0.003).
The authors concluded that bivalirudin reduces cardiac mortality in patients with STEMI undergoing primary PCI, an effect which can only partly be attributed to prevention of bleeding.
This study reported that while bivalirudin resulted in a 36% relative (3.6% absolute) reduction in major bleeding, this outcome did not fully account for the survival benefit of bivalirudin. Among patients with major bleeding, a smaller proportion of bivalirudin-treated than UFH + GPI-treated patients died, an effect not explainable by less severe bleeding or fewer blood transfusions. Furthermore, bivalirudin was strongly associated with reduced cardiac mortality even in nonbleeders, and even after accounting for all adverse events known to be reduced by bivalirudin (bleeding, thrombocytopenia, and reinfarction). Additional mechanistic studies are required to identify the nonhematologic benefits of bivalirudin in patients undergoing PCI.
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