MD Conference Express AHA 2011 - (Page 14)

n C L I N I C A L T R I A L H I G H L I G H T S was given as a loading dose (40 mg) at least 1 hour prior to revascularization, followed by a maintenance dose (2.5 mg daily). The primary efficacy endpoint was the composite of cardiovascular (CV) death, MI, stroke, hospitalization for ischemia, or urgent revascularization. The secondary efficacy endpoint was the composite of CV death, MI, or stroke. Safety-related endpoints included the composite of moderate and severe GUSTO bleeding and clinically significant TIMI bleeding. The mean age of participants was 64 years, 28% was female, 31.4% had DM, 29% prior had MI, and 94% had elevated cardiac biomarkers at baseline. The majority of participants were from western Europe. Concomitant antiplatelet therapy consisted of aspirin (~97% of patients) and thienopyridine (~87%). The majority of patients (88%) underwent angiography, with 58% having subsequent PCI and 10% CABG. Follow-up in the trial was terminated early (median follow-up of 502 days) after a review by the data safety monitoring board. Treatment with vorapaxar did not significantly reduce the primary endpoint compared with placebo (18.5% vs 19.9%; HR, 0.92; 95% CI, 0.85 to 1.01; p=0.07). Although the primary endpoint was neutral, there was a reduction in the secondary endpoint, a composite of death from CV causes, MI, or stroke with vorapaxar compared with placebo (14.7% vs 16.4%; HR, 0.89; 95% CI, 0.81 to 0.98; p=0.02), which was primarily driven by a reduction in spontaneous MI (11.1% vorapaxar vs 12.5% placebo; HR, 0.88; 95% CI, 0.79 to 0.98; p=0.02). The individual rates of CV death, stroke, and hospitalization for ischemia, urgent revascularization, stent thrombosis, and all-cause mortality were not significantly different between the two groups. Treatment with vorapaxar was associated with increased bleeding compared with placebo, including the primary safety endpoint of GUSTO moderate/severe bleeding (7.2% vs 5.2%; HR, 1.35; 95% CI, 1.16 to 1.58; p<0.001) as well as ICH (1.1% vs 0.2%; HR, 3.39; 95% CI, 1.78 to 6.45; p<0.001). The excess bleeding with vorapaxar occurred early and continued to accrue over time. Clinically significant TIMI, severe GUSTO, and major TIMI bleeding were also significantly (p<0.001) higher for the patients who were randomized to vorapaxar. Fatal bleeds were low and not different between the two groups. Rates of nonhemorrhagic adverse events were similar in the two groups. There was an interaction between GUSTO moderate or severe bleeding with vorapaxar and thienopyridine therapy at randomization (p=0.04), with no significant hazard with vorapaxar for patients who were not taking thienopyridines (HR, 0.95; 95% CI, 0.65 to 1.40) but a significant hazard for those who were taking thienopyridines (HR, 1.45; 95% CI, 1.23 to 1.71). In addition, patients with lower body weight had higher rates of bleeding (p-interaction=0.03), Overall, these results show that vorapaxar, as administered in this trial (40-mg loading dose and 2.5 mg daily), was not associated with a reduction in ischemic events and was associated with increased bleeding, with significant interactions for concomitant thienopyridine therapy and low body weight. Whether PAR-1 blockade improves outcomes with different medication strategies or in other patient populations with coronary artery disease requires further study. Further reading: Tricoci P et al. N Engl J Med 2011. ISAR-REACT 4 – Bivalirudin Similar to Abciximab/Heparin in Reducing Ischemic Outcomes in NSTEMI and Has Significantly Less Bleeding Written by Rita Buckley A strategy of intravenous (IV) abciximab (a glycoprotein [GP] IIb/IIIa inhibitor) plus unfractionated heparin (UFH), compared with bivalirudin, an IV direct thrombin inhibitor, failed to improve clinical outcomes and increased the risk of bleeding in patients with acute non-ST-segment elevation myocardial infarction (NSTEMI) who were undergoing percutaneous coronary intervention (PCI), according to Adnan Kastrati, MD, Deutsches Herzzentrum, Technische Universitat, Munich, Germany, who presented the results of the ISAR-REACT 4 trial [NCT00373451]. The ISAR-REACT 4 Trial was designed to assess whether abciximab, added to UFH, was superior to bivalirudin in patients with NSTEMI. The primary outcome measure was a composite of death, large recurrent myocardial infarction, urgent target vessel revascularization (UTVR), or major bleeding in 30 days. Secondary efficacy endpoints were a composite of death, any MI (new Q waves or CKMB elevation >3 times above the upper limit of normal), or UTVR within 30 days. The primary safety endpoint was major bleeding within 30 days. The study was designed with a sample size of 1700 patients to achieve 80% power (twosided alpha of 0.05) to detect a 30% reduction in the primary endpoint, assuming a 10.7% event rate in those who were assigned to abciximab/UFH compared with a 15.3% event rate in the bivalirudin group, based on prior trials. 14 January 2012 www.mdconferencexpress.com  http://www.mdconferencexpress.com http://www.mdconferencexpress.com

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