ARISTOTLE

The randomized, double-blind, double-dummy Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE] trial evaluated apixaban for the treatment of patients with AF and at least 1 additional risk factor for stroke [Lopes RD et al. Am Heart J 2010]. A total of 18,201 patients were randomly assigned to treatment with apixaban (5 mg, oral, BID; n=9120) or warfarin (target INR 2–3; n=9081). The primary outcome was stroke or systemic embolism (SE). The primary safety outcome was ISTH major bleeding.

The primary outcome of stroke or SE was significantly reduced in patients treated with apixaban compared with warfarin (1.27% vs 1.60% per year; HR, 0.79) [Granger CB et al. N Engl J Med 2011]. The rates of hemorrhagic stroke were significantly lower with apixaban than with warfarin (0.24% vs 0.47% per year; HR, 0.51; p<0.001). Ischemic or uncertain stroke and SE rates were not significantly different between arms. All-cause death rates were lower for patients treated with apixaban compared with those treated with warfarin (3.52% vs 3.94%; HR, 0.89; p=0.047).

ISTH major bleeding occurred significantly less often in patients randomized to apixaban compared with warfarin (2.13% vs 3.09% per year; HR, 0.69; p<0.001), a difference that was largely driven by a reduction in intracranial hemorrhage (ICH; 0.33% vs 0.80% per year; HR, 0.42; p<0.001). Major bleeding or clinically relevant non-major bleeding was significantly less in patients treated with apixaban compared with warfarin (4.07% vs 6.01% per year; HR, 0.68; p<0.001; Table 1).

PALLAS Trial

The aim of the Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy [PALLAS; Connolly SJ et al. N Eng J Med 2011] trial was to demonstrate the efficacy of dronedarone for preventing major cardiovascular (CV) events or unplanned CV hospitalization or all-cause death in patients with permanent AF and additional risk factors. Investigators randomly assigned 3236 patients to treatment with dronedarone (400 mg BID) or placebo with a follow-up of 3.5 months.

The study was terminated early because of safety concerns with dronedarone. The first coprimary outcome (stroke, SE, myocardial infarction [MI], or CV death) occurred in more patients treated with dronedarone compared with placebo (43 vs 19, respectively; HR, 2.29; p=0.002). The second coprimary outcome of unplanned hospitalization for CV causes or death also occurred in significantly more dronedarone-treated patients than placebo-treated patients (127 vs 67, respectively; HR, 1.95; p<0.001). Adverse events (AEs), serious AEs, and discontinuations because of AEs occurred more frequently with dronedarone versus placebo (p<0.001). Dronedarone restored sinus rhythm at 4 months in significantly more patients than placebo (p=0.001). At 1 month, dronedarone patients had significantly decreased heart rates (p<0.001) and systolic blood pressures (p=0.003) versus placebo patients.

ATLAS ACS 2-TIMI 51 Trial

The Rivaroxaban in Combination With Aspirin Alone or with Aspirin and a Thienopyridine in Patients with Acute Coronary Syndromes [ATLAS ACS 2-TIMI 51] trial evaluated the efficacy and safety of rivaroxaban added to standard care in patients with recent ACS [Mega JL et al. N Engl J Med 2012]. A total of 15,526 patients were randomly assigned to treatment with rivaroxaban 2.5 mg BID (n=5174) or 5.0 mg BID (n=5176) or placebo (n=5176) plus standard care for a mean of 13 months.

The primary endpoint of CV death, MI, or stroke occurred in 8.9% of rivaroxaban (both doses combined) patients versus 10.7% of placebo patients (HR, 0.84; p=0.008). The very low dose 2.5-mg rivaroxaban group demonstrated significantly lower rates of CV death (2.7% vs 4.1%; HR, 0.66; p=0.002) and all-cause death (2.9% vs 4.5%; HR, 0.68; ITT p=0.002) compared with placebo-treated patients. These benefits were not observed in the 5-mg rivaroxaban group.

The combined rivaroxaban group compared with placebo treated patients had significantly higher rates of bleeding (noncoronary artery bypass graft TIMI major bleeding [2.1% vs 0.6%; HR, 3.96; p<0.001]; TIMI minor bleeding [1.3% vs 0.5%; p=0.003]; TIMI bleeding requiring medical attention [14.5% vs 7.5%; p<0.001]; ICH [0.6% vs 0.2%; p=0.009]). The very low dose 2.5-mg rivaroxaban group had significantly less bleeding compared with the 5.0-mg rivaroxaban group TIMI minor bleeding (0.9% vs 1.6%; p=0.046), TIMI bleeding requiring medical attention (12.9% vs 16.2%; p<0.001), and fatal bleeding (0.1% vs 0.4%; p=0.04).

Vorapaxar

Vorapaxar, the first oral thrombin receptor (PAR-1) antagonist was evaluated versus placebo in patients with ACS in the Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients with Acute Coronary Syndrome [TRACER; Tricoci P et al. N Engl J Med 2012]. No significant difference was observed for the primary endpoint of CV death, MI, stroke, hospitalization for ischemia, or urgent revascularization in patients treated with vorapaxar or placebo (18.5% vs 19.9%, respectively; HR, 0.92; p=0.072). Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) moderate or severe bleeding was significantly higher for patients treated with vorapaxar compared with placebo (7.2% vs 5.2%, respectively; HR, 1.35; p<0.001).

In the Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients with Atherosclerosis [TRA 2°P-TIMI 50; Morrow DA et al. N Engl J Med 2012], the primary endpoint (composite of CV death, MI, or stroke) occurred less frequently in patients treated with vorapaxar compared with placebo (9.3% vs 10.5%, respectively; HR, 0.87; p<0.001). When compared with placebo treatment, patients treated with vorapaxar had significantly more moderate or severe bleeding (2.5% vs 4.2%; HR, 1.66; p<0.001) and ICH (0.5% vs 1.0%; p<0.001).

Duration of Dual Antiplatelet Therapy Post Stenting

The Synergy Between Stent and Drugs to Avoid Ischemic Recurrences After Percutaneous Coronary Intervention [PRODIGY; Valgimigli M et al. Circulation 2012] trial assessed 6 versus 24 months of dual antiplatelet therapy (DAPT) with aspirin and clopidogrel after coronary stenting. At 2 years, the primary composite endpoint (death, MI, or stroke) rates were 10.1% with 6-month treatment versus 10.0% with 24-month treatment (p=0.91). Patients receiving long-term DAPT had twice the risk of bleeding (HR, 2.17; 95% CI, 1.44 to 3.22; p=0.00018) and transfusion (HR, 0.50; 95% CI, 0.26 to 0.98; p=0.041).