APPRAISE-1

APixaban for PRevention of Acute Ischemic and Safety Events 1 (2009)

Condition

Prevention of acute ischemic events in patients with ACS

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Objective

(1) To evaluate the effect on bleeding of 4 doses of apixaban vs. placebo given over 26 weeks in patients with a recent ACS receiving current evidence based care (ASA ≤165 mg/d in all patients, clopidogrel per MD discretion)
(2) To determine the optimal dose of apixaban for further investigation

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Trial design

Randomized, double-blind phase II study
Active treatment: apixaban 2.5 mg twice daily (n=317) or apixaban 10 mg once daily (n=318) or apixaban 10 mg twice daily (n=248) or apixaban 20 mg once daily (n=221) in addition to mono or dual antiplatelet therapy
Control treatment: placebo in addition to mono or dual antiplatelet therapy (n=611)

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Endpoints

Primary endpoint (safety): major and/or clinically relevant non-major bleeding according to the ISTH definitions
Secondary endpoint (efficacy): composite of cardiovascular death, myocardial infarction, severe recurrent ischemia, or  ischemic stroke

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Trial participants

1715 patients between 18 and 90 years of age with a recent (<7 days) ST-elevation or non-ST-elevation ACS; clinically stable, receiving evidence based care, with ≥1 additional risk factor for recurrent ischemic events and not scheduled for an invasive procedure

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Results

Primary endpoint (safety): At the recommendation of the data monitoring committee, the two higher-dose apixaban arms (10 mg twice daily and 20 mg once daily) were discontinued because of excess total bleeding. 1229 patients (315 apixaban 2.5 mg twice daily, 315 apixaban 10 mg once daily, 599 placebo) were included in the safety analysis. 5.7% of patients receiving apixaban 2.5 mg twice daily, 7.9% in the apixaban 10 mg once daily arm and 3.0% in the placebo group experienced an increase in major or clinically relevant non-major bleeding. When bleeding was stratified by clopidogrel status, the study drug was still associated with increased bleeding. Patients taking clopidogrel: 7.0% bleeding for apixaban 2.5 mg twice daily (n=230), 9.1% for apixaban 10 mg once daily (n=241), 3.1% for placebo (n=453); no clopdogrel: 2.4% bleeding for apixaban 2.5 mg twice daily (n=85), 4.1% for apixaban 10 mg once daily (n=74), and 2.7% for placebo (n=146)
Secondary endpoint (efficacy): 1246 patients (317 apixaban 2.5 mg twice daily, 318 apixaban 10 mg once daily, 611 placebo) were included in the efficacy analysis. There were no significant differences in the incidence of the efficacy endpoint of cardiovascular death, myocardial infarction, severe recurrent ischemia or ischemic stroke between the apixaban 2.5 mg twice daily group (7.6%), the apixaban 10 mg once daily group (6.0%), and the placebo group (8.7%). The reduction in ischemic events was less evident in patients taking ASA plus clopidogrel than in those taking ASA alone

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Summary

Safety: Apixaban treatment was associated with a dose dependent increase in major or clinically relevant non-major bleeding
Efficacy: There was a trend in reduction of clinically important ischemic events (statistically non-significant)
Dosage range: A total daily dose of between 5 and 10 mg apixaban appears safe and effective in ACS patients

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Reference

APPRAISE Steering Committee and Investigators. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome. Results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation 2009;119:2877-2885

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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 john.h.alexander@duke.edu

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