APixaban for PRevention of Acute ISchemic Events 2 (2010)


Prevention of cardiovascular events after ACS

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Determine if apixaban is superior to placebo for preventing cardiovascular death, non-fatal myocardial infarction or ischemic stroke in post-ACS patients

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Trial design

Randomized, double-blind phase III study
Active treatment: apixaban 5 mg p.o. twice daily in addition to mono or dual antiplatelet therapy (either ASA or ASA plus clopidogrel). This dose was considered to be safe according to the results of the preceding APPRAISE-1 study
Control treatment: placebo in addition to mono or dual antiplatelet therapy

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Primary efficacy endpoint: composite of cardiovascular death, myocardial infarction, or ischemic stroke
Primary safety endpoint: major bleeding, according to the Thrombolysis in Myocardial Infarction (TIMI) definition
Secondary endpoints: ischemic or hemorrhagic stroke, unstable angina, stent thrombosis, minor bleeding, fatal bleeding

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Trial participants

The study was designed to include approximately 10,800 patients ≥18 years with an acute coronary syndrome (myocardial infarction, with or without ST-segment elevation, or unstable angina) within the previous 7 days and with symptoms of myocardial ischemia and at least two additional risk factors for recurrent ischemic events (e.g. diabetes mellitus, PAD, age > 65 years). After recruitment of 7392 patients the trial was terminated prematurely because of an increase in major bleeding events with apixaban, which was not offset by clinically meaningful reductions in ischemic events

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Efficacy outcome: With a median follow-up of 241 days, the primary outcome occurred in 279 of the 3705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 of the 3687 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban 0.95; p=0.51).
Safety outcome: In the on-treatment analysis, the primary safety outcome of major bleeding occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patient-years) and in 18 of the 3642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient-years) (hazard ratio with apixaban 2.59; p=0.001). Among the patients receiving apixaban, as compared with those receiving placebo, there were more events of fatal bleeding (5 vs. 0), intracranial bleeding (12 vs. 3), ISTH major or clinically relevant non-major bleeding (117 vs. 45), and total bleeding (679 vs. 305)

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The addition of the oral factor Xa inhibitor apixaban to standard antiplatelet therapy (ASA or ASA plus clopidogrel) in high-risk patients after an acute coronary syndrome resulted in a significant increase in bleeding events, including increases in events of fatal and intracranial bleeding, without a significant reduction in recurrent ischemic events

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Alexander JH, Lopes RD, James S, Kilaru R, He Y, Mohan P, Bhatt DL, Goodman S, Verheugt FW, Flather M, Huber K, Liaw D, Husted SE, Lopez-Sendon J, De Caterina R, Jansky P, Darius H, Vinereanu D, Cornel JH, Cools F, Atar D, Leiva-Pons JL, Keltai M, Ogawa H, Pais P, Parkhomenko A, Ruzyllo W, Diaz R, White H, Ruda M, Geraldes M, Lawrence J, Harrington RA, Wallentin L, for the APPRAISE-2 Investigators. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011;365:699-708

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Corresponding author

John H. Alexander, MD, MHS, Duke Clinical Research Institute, Duke University Medical Center, DUMC Box 3850, Durham, NC 27715, e-mail:

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