Table 2. Trials of combined... | American Society of Hematology

Table 2.

Trials of combined antithrombotic therapy for atherosclerotic disease

Name	APPRAISE-2	ATLAS ACS 2-TIMI 51	COMPASS	VOYAGER
Total patients	7392	15 526	27 395	6564
Population	Patients with recent ACS and additional risk factors for recurrent ischemic events	Patients with recent ACS	Patients with stable CAD or PAD	Patients with PAD undergoing revascularization
Treatments	• Apixaban 5 mg twice daily • Placebo All patients received standard antiplatelet therapy (usually DAPT)	• Rivaroxaban 2.5 mg twice daily • Rivaroxaban 5 mg twice daily • Placebo All patients received standard antiplatelet therapy (usually DAPT)	• Rivaroxaban 2.5 mg twice daily + aspirin 100 mg daily • Rivaroxaban 5 mg twice daily • Aspirin 100 mg daily	• Rivaroxaban 2.5 mg twice daily • Placebo All patients received aspirin therapy
Notable exclusion criteria	Severe hypertension, CrCl < 20 mL/min, active bleeding, recent ischemic stroke, NYHA class IV heart failure, prior intracranial bleeding, anemia (Hg <9 g/dL), thrombocytopenia, ongoing use of anticoagulation or aspirin >325 mg daily	Thrombocytopenia, anemia (Hg <10 g/dL), CrCl <30 mL/min	High risk of bleeding, recent stroke, severe heart failure, estimated glomerular filtration rate <15 mL/min, use of dual antiplatelet therapy, or anticoagulation use	Unstable clinical condition, high risk for bleeding, or long-term use of clopidogrel (beyond 6 mo)
Efficacy outcome	• Apixaban, 13.2 per 100-patient-years • Placebo, 14.0 per 100 patient-years HR 0.95 (95% CI, 0.80-1.11) Composite of cardiovascular death, MI, ischemic stroke	• Rivaroxaban 2.5 mg, 9.1% • Rivaroxaban 5 mg, 8.8% • Placebo, 10.7% Rivaroxaban 2.5 mg vs placebo, HR 0.84 (95% CI, 0.72-0.97) Rivaroxaban 5 mg vs placebo, HR 0.85 (95% CI, 0.73-0.98) Composite of cardiovascular death, MI, ischemic stroke	• Rivaroxaban 2.5 mg + aspirin, 4.1% • Rivaroxaban 5 mg, 4.9% • Aspirin, 5.4% Rivaroxaban + aspirin vs aspirin, HR 0.76 (95% CI, 0.66-0.86) Rivaroxaban vs aspirin, HR 0.90 (95% CI, 0.79-1.03) Composite of cardiovascular death, MI, ischemic stroke	• Rivaroxaban 2.5 mg, 17.3% • Placebo, 19.9% HR 0.85 (95% CI, 0.76-0.96) Composite of acute limb ischemia, major amputation for vascular causes, MI, cardiovascular death
Primary safety outcome	• Apixaban, 2.4 per 100 patient-years • Placebo, 0.9 per 100 patient-years HR 2.59 (95% CI, 1.50-4.46) TIMI major bleeding	• Rivaroxaban 2.5 mg, 1.8% • Rivaroxaban 5 mg, 2.4% • Placebo, 0.6% Rivaroxaban 2.5 mg vs placebo, HR 3.46 (95% CI, 2.08-5.77) Rivaroxaban 5 mg vs placebo, HR 4.47 (95% CI, 2.71-7.36) TIMI major bleeding not related to coronary artery bypass graft	• Rivaroxaban 2.5 mg + aspirin, 3.1% • Rivaroxaban 5 mg, 2.8% • Aspirin, 1.9% Rivaroxaban + aspirin vs aspirin, HR 1.70 (95% CI, 1.40-2.05) Rivaroxaban vs aspirin, HR 1.51 (95% CI, 1.25-1.84) Modified ISTH major bleeding (including all bleeding leading to an acute care facility presentation or hospitalization)	• Rivaroxaban 2.5 mg, 2.65% • Placebo, 1.87% HR 1.43 (95% CI, 0.97-2.10) TIMI major bleeding • Rivaroxaban 2.5 mg, 5.94% • Placebo, 4.06% HR 1.42 (95% CI, 1.10-1.84) ISTH major bleeding
Intracranial bleeding	• Apixaban, 0.6 per 100 patient-years • Placebo, 0.2 per 100 patient-years HR 4.06 (95% CI, 1.15-14.38)	• Rivaroxaban 2.5 mg, 0.4% • Rivaroxaban 5 mg, 0.7% • Placebo, 0.2% Rivaroxaban 2.5 mg vs placebo, HR 2.83 (95% CI, 1.02-7.86) Rivaroxaban 5 mg vs placebo – HR 3.74 (95% CI, 1.39-10.07)	• Rivaroxaban 2.5 mg + aspirin, 0.3% • Rivaroxaban 5 mg, 0.5% • Aspirin, 0.3% Rivaroxaban + aspirin vs aspirin, HR 1.16 (95% CI, 0.67-2.00) Rivaroxaban vs aspirin, HR 1.80 (95% CI, 1.09-2.96)	• Rivaroxaban 2.5 mg, 0.40% • Placebo, 0.52% HR 0.78 (95% CI, 0.38-1.61)

Name	APPRAISE-2	ATLAS ACS 2-TIMI 51	COMPASS	VOYAGER
Total patients	7392	15 526	27 395	6564
Population	Patients with recent ACS and additional risk factors for recurrent ischemic events	Patients with recent ACS	Patients with stable CAD or PAD	Patients with PAD undergoing revascularization
Treatments	• Apixaban 5 mg twice daily • Placebo All patients received standard antiplatelet therapy (usually DAPT)	• Rivaroxaban 2.5 mg twice daily • Rivaroxaban 5 mg twice daily • Placebo All patients received standard antiplatelet therapy (usually DAPT)	• Rivaroxaban 2.5 mg twice daily + aspirin 100 mg daily • Rivaroxaban 5 mg twice daily • Aspirin 100 mg daily	• Rivaroxaban 2.5 mg twice daily • Placebo All patients received aspirin therapy
Notable exclusion criteria	Severe hypertension, CrCl < 20 mL/min, active bleeding, recent ischemic stroke, NYHA class IV heart failure, prior intracranial bleeding, anemia (Hg <9 g/dL), thrombocytopenia, ongoing use of anticoagulation or aspirin >325 mg daily	Thrombocytopenia, anemia (Hg <10 g/dL), CrCl <30 mL/min	High risk of bleeding, recent stroke, severe heart failure, estimated glomerular filtration rate <15 mL/min, use of dual antiplatelet therapy, or anticoagulation use	Unstable clinical condition, high risk for bleeding, or long-term use of clopidogrel (beyond 6 mo)
Efficacy outcome	• Apixaban, 13.2 per 100-patient-years • Placebo, 14.0 per 100 patient-years HR 0.95 (95% CI, 0.80-1.11) Composite of cardiovascular death, MI, ischemic stroke	• Rivaroxaban 2.5 mg, 9.1% • Rivaroxaban 5 mg, 8.8% • Placebo, 10.7% Rivaroxaban 2.5 mg vs placebo, HR 0.84 (95% CI, 0.72-0.97) Rivaroxaban 5 mg vs placebo, HR 0.85 (95% CI, 0.73-0.98) Composite of cardiovascular death, MI, ischemic stroke	• Rivaroxaban 2.5 mg + aspirin, 4.1% • Rivaroxaban 5 mg, 4.9% • Aspirin, 5.4% Rivaroxaban + aspirin vs aspirin, HR 0.76 (95% CI, 0.66-0.86) Rivaroxaban vs aspirin, HR 0.90 (95% CI, 0.79-1.03) Composite of cardiovascular death, MI, ischemic stroke	• Rivaroxaban 2.5 mg, 17.3% • Placebo, 19.9% HR 0.85 (95% CI, 0.76-0.96) Composite of acute limb ischemia, major amputation for vascular causes, MI, cardiovascular death
Primary safety outcome	• Apixaban, 2.4 per 100 patient-years • Placebo, 0.9 per 100 patient-years HR 2.59 (95% CI, 1.50-4.46) TIMI major bleeding	• Rivaroxaban 2.5 mg, 1.8% • Rivaroxaban 5 mg, 2.4% • Placebo, 0.6% Rivaroxaban 2.5 mg vs placebo, HR 3.46 (95% CI, 2.08-5.77) Rivaroxaban 5 mg vs placebo, HR 4.47 (95% CI, 2.71-7.36) TIMI major bleeding not related to coronary artery bypass graft	• Rivaroxaban 2.5 mg + aspirin, 3.1% • Rivaroxaban 5 mg, 2.8% • Aspirin, 1.9% Rivaroxaban + aspirin vs aspirin, HR 1.70 (95% CI, 1.40-2.05) Rivaroxaban vs aspirin, HR 1.51 (95% CI, 1.25-1.84) Modified ISTH major bleeding (including all bleeding leading to an acute care facility presentation or hospitalization)	• Rivaroxaban 2.5 mg, 2.65% • Placebo, 1.87% HR 1.43 (95% CI, 0.97-2.10) TIMI major bleeding • Rivaroxaban 2.5 mg, 5.94% • Placebo, 4.06% HR 1.42 (95% CI, 1.10-1.84) ISTH major bleeding
Intracranial bleeding	• Apixaban, 0.6 per 100 patient-years • Placebo, 0.2 per 100 patient-years HR 4.06 (95% CI, 1.15-14.38)	• Rivaroxaban 2.5 mg, 0.4% • Rivaroxaban 5 mg, 0.7% • Placebo, 0.2% Rivaroxaban 2.5 mg vs placebo, HR 2.83 (95% CI, 1.02-7.86) Rivaroxaban 5 mg vs placebo – HR 3.74 (95% CI, 1.39-10.07)	• Rivaroxaban 2.5 mg + aspirin, 0.3% • Rivaroxaban 5 mg, 0.5% • Aspirin, 0.3% Rivaroxaban + aspirin vs aspirin, HR 1.16 (95% CI, 0.67-2.00) Rivaroxaban vs aspirin, HR 1.80 (95% CI, 1.09-2.96)	• Rivaroxaban 2.5 mg, 0.40% • Placebo, 0.52% HR 0.78 (95% CI, 0.38-1.61)

CrCl, creatinine clearance; Hg, hemoglobin; ISTH, International Society on Thrombosis and Haemostasis; PAD, peripheral artery disease; TIMI, Thrombolysis in Myocardial Infarction; TT, triple therapy.

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