title: 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.
abstract: BACKGROUND
  After an acute coronary syndrome, patients remain at risk of recurrent events. Apixaban, an oral direct factor Xa inhibitor, is a novel anticoagulant that may reduce these events but also poses a risk of bleeding.
  
  
  RESULTS
  Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) was a phase 2, double-blind, placebo-controlled, dose-ranging study. Patients (n=1715) with recent ST-elevation or non-ST-elevation acute coronary syndrome were randomized to 6 months of placebo (n=611) or 1 of 4 doses of apixaban: 2.5 mg twice daily (n=317), 10 mg once daily (n=318), 10 mg twice daily (n=248), or 20 mg once daily (n=221). Nearly all patients received aspirin; 76% received clopidogrel. The primary outcome was International Society of Thrombosis and Hemostasis major or clinically relevant nonmajor bleeding. A secondary outcome was cardiovascular death, myocardial infarction, severe recurrent ischemia, or ischemic stroke. At the recommendation of the Data Monitoring Committee, the 2 higher-dose apixaban arms were discontinued because of excess total bleeding. Compared with placebo, apixaban 2.5 mg twice daily (hazard ratio, 1.78; 95% confidence interval, 0.91 to 3.48; P=0.09) and 10 mg once daily (hazard ratio, 2.45; 95% confidence interval, 1.31 to 4.61; P=0.005) resulted in a dose-dependent increase in major or clinically relevant nonmajor bleeding. Apixaban 2.5 mg twice daily (hazard ratio, 0.73; 95% confidence interval, 0.44 to 1.19; P=0.21) and 10 mg once daily (hazard ratio, 0.61; 95% confidence interval, 0.35 to 1.04; P=0.07) resulted in lower rates of ischemic events compared with placebo. The increase in bleeding was more pronounced and the reduction in ischemic events was less evident in patients taking aspirin plus clopidogrel than in those taking aspirin alone.
  
  
  CONCLUSIONS
  We observed a dose-related increase in bleeding and a trend toward a reduction in ischemic events with the addition of apixaban to antiplatelet therapy in patients with recent acute coronary syndrome. The safety and efficacy of apixaban may vary depending on background antiplatelet therapy. Further testing of apixaban in patients at risk of recurrent ischemic events is warranted.
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, DUMC Box 3850, Durham, NC 27715, USA. john.h.alexander@duke.edu
authors.forename: John H
authors.initials: JH
authors.lastname: Alexander
authors.forename: Richard C
authors.initials: RC
authors.lastname: Becker
authors.forename: Deepak L
authors.initials: DL
authors.lastname: Bhatt
authors.forename: Frank
authors.initials: F
authors.lastname: Cools
authors.forename: Filippo
authors.initials: F
authors.lastname: Crea
authors.forename: Mikael
authors.initials: M
authors.lastname: Dellborg
authors.forename: Keith A A
authors.initials: KA
authors.lastname: Fox
authors.forename: Shaun G
authors.initials: SG
authors.lastname: Goodman
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harrington
authors.forename: Kurt
authors.initials: K
authors.lastname: Huber
authors.forename: Steen
authors.initials: S
authors.lastname: Husted
authors.forename: Basil S
authors.initials: BS
authors.lastname: Lewis
authors.forename: Jose
authors.initials: J
authors.lastname: Lopez-Sendon
authors.forename: Puneet
authors.initials: P
authors.lastname: Mohan
authors.forename: Gilles
authors.initials: G
authors.lastname: Montalescot
authors.forename: Mikhail
authors.initials: M
authors.lastname: Ruda
authors.forename: Witold
authors.initials: W
authors.lastname: Ruzyllo
authors.forename: Freek
authors.initials: F
authors.lastname: Verheugt
authors.forename: Lars
authors.initials: L
authors.lastname: Wallentin
mesh_terms: D054058:Acute Coronary Syndrome / Q000150:complications / Q000188:drug therapy*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001241:Aspirin / Q000627:therapeutic use; D000077144:Clopidogrel; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D065427:Factor Xa Inhibitors; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000517:prevention & control; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000008:administration & dosage* / Q000633:toxicity; D011728:Pyridones / Q000008:administration & dosage* / Q000633:toxicity; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D065427:Factor Xa Inhibitors; D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin