Bivalirudin vs Heparin and GPIs in STEMI Patients Having PCI
Background In the HORIZONS-AMI (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction) trial, 3,602 patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) treated with bivalirudin had lower bleeding and mortality rates, but higher acute stent thrombosis rates compared with heparin + a glycoprotein IIb/IIIa inhibitor (GPI). Subsequent changes in primary PCI, including the use of potent P2Y12 inhibitors, frequent radial intervention, and pre-hospital medication administration, were incorporated into the EUROMAX (European Ambulance Acute Coronary Syndrome Angiography) trial, which assigned 2,218 patients to bivalirudin versus heparin ± GPI before primary PCI.
Objectives The goal of this study was to examine the outcomes of procedural anticoagulation with bivalirudin versus heparin ± GPI for primary PCI, given the evolution in primary PCI.
Methods Databases from HORIZONS-AMI and EUROMAX were pooled for patient-level analysis. The Breslow-Day test evaluated heterogeneity between trials.
Results A total of 5,800 patients were randomized to bivalirudin (n = 2,889) or heparin ± GPI (n = 2,911). The radial approach was used in 21.3% of patients, prasugrel/ticagrelor was used in 18.1% of patients, and GPI was used in 84.8% of the control group. Bivalirudin compared with heparin ± GPI resulted in reduced 30-day rates of major bleeding (4.2% vs. 7.8%; relative risk [RR]: 0.53; 95% confidence interval [CI]: 0.43 to 0.66; p < 0.0001), thrombocytopenia (1.4% vs. 2.9%, RR: 0.48; 95% CI: 0.33 to 0.71; p = 0.0002), and cardiac mortality (2.0% vs. 2.9%; RR: 0.70; 95% CI: 0.50 to 0.97; p = 0.03), with nonsignificantly different rates of reinfarction, ischemia-driven revascularization, stroke, and all-cause mortality. Bivalirudin resulted in increased acute (<24 h) stent thrombosis rates (1.2% vs. 0.2%; RR: 6.04; 95% CI: 2.55 to 14.31; p < 0.0001), with nonsignificantly different rates of subacute stent thrombosis. Composite net adverse clinical events were lower with bivalirudin (8.8% vs. 11.9%; RR: 0.74; 95% CI: 0.63 to 0.86; p < 0.0001). There was no significant heterogeneity between the 2 trials for these outcomes, and results were consistent across major subgroups.
Conclusions Despite increased acute stent thrombosis, primary PCI with bivalirudin improved 30-day net clinical outcomes, with significant reductions in major bleeding, thrombocytopenia, and transfusions compared with heparin ± GPI, results that were consistent with evolution in PCI technique and pharmacotherapy. (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction [HORIZONS-AMI]; NCT00433966) (European Ambulance Acute Coronary Syndrome Angiography [EUROMAX]; NCT01087723)
Primary percutaneous coronary intervention (PCI) with stent implantation is the standard of care for acute ST-segment elevation myocardial infarction (STEMI) when delivered in a timely fashion. Restoring and maintaining patency of the infarct artery during and after primary PCI require judicious use of adjunctive antithrombotic and antiplatelet agents, given tradeoffs between efficacy and safety. In the large-scale, prospective, randomized HORIZONS-AMI (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction) trial (which concluded enrollment in 2007), among 3,602 patients treated with aspirin and clopidogrel, bivalirudin, a direct thrombin inhibitor, reduced major hemorrhagic complications and all-cause mortality compared with unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor (GPI). These results emerged as early as 30 days and were sustained for 3 years. However, acute (<24 h) stent thrombosis was more common with bivalirudin, although rates of stent thrombosis at 30 days and 3 years were not significantly different with bivalirudin than with heparin + GPI. Clinical practice has since evolved; specifically, the potent platelet P2Y12 receptor inhibitors prasugrel and ticagrelor have been introduced, reducing reinfarction and stent thrombosis in patients undergoing primary PCI; the radial artery is increasingly used for vascular access, reducing bleeding complications; and medications are often first administered at nontertiary referral hospitals or during ambulance transport. Given this evolution, whether results with bivalirudin have remained consistent over time is unknown.
In the EUROMAX (European Ambulance Acute Coronary Syndrome Angiography) trial, the outcomes of bivalirudin compared with a heparin-based control group during primary PCI in 2,218 patients were examined in a contemporary multicenter, prospective, randomized trial (last patient enrolled in June of 2013) in which radial artery access and potent P2Y12 inhibitors were encouraged. Antithrombotic agents were administered to patients before arrival at the hospital for PCI, and GPI use was optional in the heparin control arm, reflecting European practice. Therefore, we combined the databases from the HORIZONS-AMI and EUROMAX trials and performed a pre-specified patient-level analysis to derive insight into the frequency and timing of adverse events after bivalirudin compared with heparin ± GPI from a large pooled population of randomized patients and to examine outcomes among clinically relevant subgroups.
Abstract and Introduction
Abstract
Background In the HORIZONS-AMI (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction) trial, 3,602 patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) treated with bivalirudin had lower bleeding and mortality rates, but higher acute stent thrombosis rates compared with heparin + a glycoprotein IIb/IIIa inhibitor (GPI). Subsequent changes in primary PCI, including the use of potent P2Y12 inhibitors, frequent radial intervention, and pre-hospital medication administration, were incorporated into the EUROMAX (European Ambulance Acute Coronary Syndrome Angiography) trial, which assigned 2,218 patients to bivalirudin versus heparin ± GPI before primary PCI.
Objectives The goal of this study was to examine the outcomes of procedural anticoagulation with bivalirudin versus heparin ± GPI for primary PCI, given the evolution in primary PCI.
Methods Databases from HORIZONS-AMI and EUROMAX were pooled for patient-level analysis. The Breslow-Day test evaluated heterogeneity between trials.
Results A total of 5,800 patients were randomized to bivalirudin (n = 2,889) or heparin ± GPI (n = 2,911). The radial approach was used in 21.3% of patients, prasugrel/ticagrelor was used in 18.1% of patients, and GPI was used in 84.8% of the control group. Bivalirudin compared with heparin ± GPI resulted in reduced 30-day rates of major bleeding (4.2% vs. 7.8%; relative risk [RR]: 0.53; 95% confidence interval [CI]: 0.43 to 0.66; p < 0.0001), thrombocytopenia (1.4% vs. 2.9%, RR: 0.48; 95% CI: 0.33 to 0.71; p = 0.0002), and cardiac mortality (2.0% vs. 2.9%; RR: 0.70; 95% CI: 0.50 to 0.97; p = 0.03), with nonsignificantly different rates of reinfarction, ischemia-driven revascularization, stroke, and all-cause mortality. Bivalirudin resulted in increased acute (<24 h) stent thrombosis rates (1.2% vs. 0.2%; RR: 6.04; 95% CI: 2.55 to 14.31; p < 0.0001), with nonsignificantly different rates of subacute stent thrombosis. Composite net adverse clinical events were lower with bivalirudin (8.8% vs. 11.9%; RR: 0.74; 95% CI: 0.63 to 0.86; p < 0.0001). There was no significant heterogeneity between the 2 trials for these outcomes, and results were consistent across major subgroups.
Conclusions Despite increased acute stent thrombosis, primary PCI with bivalirudin improved 30-day net clinical outcomes, with significant reductions in major bleeding, thrombocytopenia, and transfusions compared with heparin ± GPI, results that were consistent with evolution in PCI technique and pharmacotherapy. (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction [HORIZONS-AMI]; NCT00433966) (European Ambulance Acute Coronary Syndrome Angiography [EUROMAX]; NCT01087723)
Introduction
Primary percutaneous coronary intervention (PCI) with stent implantation is the standard of care for acute ST-segment elevation myocardial infarction (STEMI) when delivered in a timely fashion. Restoring and maintaining patency of the infarct artery during and after primary PCI require judicious use of adjunctive antithrombotic and antiplatelet agents, given tradeoffs between efficacy and safety. In the large-scale, prospective, randomized HORIZONS-AMI (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction) trial (which concluded enrollment in 2007), among 3,602 patients treated with aspirin and clopidogrel, bivalirudin, a direct thrombin inhibitor, reduced major hemorrhagic complications and all-cause mortality compared with unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor (GPI). These results emerged as early as 30 days and were sustained for 3 years. However, acute (<24 h) stent thrombosis was more common with bivalirudin, although rates of stent thrombosis at 30 days and 3 years were not significantly different with bivalirudin than with heparin + GPI. Clinical practice has since evolved; specifically, the potent platelet P2Y12 receptor inhibitors prasugrel and ticagrelor have been introduced, reducing reinfarction and stent thrombosis in patients undergoing primary PCI; the radial artery is increasingly used for vascular access, reducing bleeding complications; and medications are often first administered at nontertiary referral hospitals or during ambulance transport. Given this evolution, whether results with bivalirudin have remained consistent over time is unknown.
In the EUROMAX (European Ambulance Acute Coronary Syndrome Angiography) trial, the outcomes of bivalirudin compared with a heparin-based control group during primary PCI in 2,218 patients were examined in a contemporary multicenter, prospective, randomized trial (last patient enrolled in June of 2013) in which radial artery access and potent P2Y12 inhibitors were encouraged. Antithrombotic agents were administered to patients before arrival at the hospital for PCI, and GPI use was optional in the heparin control arm, reflecting European practice. Therefore, we combined the databases from the HORIZONS-AMI and EUROMAX trials and performed a pre-specified patient-level analysis to derive insight into the frequency and timing of adverse events after bivalirudin compared with heparin ± GPI from a large pooled population of randomized patients and to examine outcomes among clinically relevant subgroups.
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