News:Apixaban causes increased bleeding, but reduced ischemic events in patients with recent acute coronary syndrome: Results of the APPRAISE-1 Trial

September 2, 2008 By Alexandra M. Palmer [mailto:apalmer@perfuse.org]

The goal of this trial was 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 (Aspirin ≤165 mg/d, Clopidogrel per MD discretion) and 2) to determine the optimal dose of Apixaban for further investigation. Major bleeding was defined as bleeding with a fall in hemoglobin of ≥2 g/dl, or bleeding with transfusion of ≥2 units of PRBC or whole blood, or bleeding that occurs in a critical location (i.e. brain or spine), or bleeding that causes death.

The APPRAISE-1 trial was a phase 2, randomized, double-blind, placebo-controlled, parallel arm study that enrolled 1,715 patients from Europe (n=1,305) and North America (n=410). Phase A of the study randomized 547 patients to 10 mg Apixaban daily (Apixaban 10 mg QD, n=184), 2.5 mg Apixaban twice daily (Apixaban 2.5 mg BID, n=179), and placebo (n=184). In phase B, 1168 patients were randomized to Apixaban 10 mg QD (n=134), Apixaban 2.5 mg BID (n=138), placebo (n=427), Apixaban 10 mg BID (n=248), and Apixaban 20 mg QD (n=221). All patients received the study drug for 6 months. The latter two groups (10 mg BID and 20 mg QD, n=469) were discontinued prematurely from the study due to excess bleeding.

The inclusion criteria selected patients age 18-90 years with recent ACS (≤7 days) and at least one additional risk factor such as age ≥65 years, diabetes mellitus, or prior MI within the past 12 months. The primary safety endpoint was International Society of Thrombosis and Haemostasis (ISTH) major or clinically relevant non-major (CRNM) bleeding. The secondary efficacy endpoint included cardiovascular (CV) death, MI, severe recurrent ischemia, or ischemic stroke. The duration of follow-up was a mean of 6 months.

Compared to placebo, Apixaban treatment was associated with increased bleeding among patients with a recent ACS according to the ISTH major or CRNM and Thrombolysis in Myocardial Infarction (TIMI) bleeding definitions. According to the ISTH major or CRNM definition, bleeding occurred in 7.9% of patients receiving Apixaban 10 mg QD (n=315), 5.7% in the Apixaban 2.5 mg BID arm (n=315) and 3.0% in the placebo group (n=599). HR: 2.45, 95% CI: 1.31 to 4.61, p = 0.005 for Apixaban 10 mg QD vs. placebo and HR: 1.78, 95% CI: 0.91 to 3.48, p = 0.09 for Apixaban 2.5 mg BID vs. placebo. 1.0%, 0.0%, 0.3% of patients being administered Apixaban 10 mg QD (n=315), Apixaban 2.5 mg BID (n=315) and placebo (n=599), respectively, experienced major bleeding by the TIMI definition.

When bleeding was stratified by Clopidogrel status, the study drug was still associated with increased bleeding. Patients taking Clopidogrel: 9.1% bleeding for Apixaban 10 mg QD (n=241), 7.0% for Apixaban 2.5 mg BID (n=230), 3.1% for placebo (n=453); No Clopidogrel: 4.1%, 2.4%, 2.7% bleeding for Apixaban 10 mg QD (n=74), Apixaban 2.5 mg BID (n=85) and placebo (n=146) respectively.

The secondary endpoints of CV death, MI, severe recurrent ischemia, or ischemic stroke were most prevalent in the placebo group (6.0%, 7.6%, and 8.7% in the Apixaban 10 mg QD n=318, Apixaban 2.5 mg BID n=317 and placebo groups n=611, respectively, HR 0.61, 95% CI 0.35 to 1.04, p = 0.07 for Apixaban 10 mg QD vs. placebo and HR 0.73, 95% CI 0.44 to 1.19, p = 0.21 for Apixaban 2.5 mg BID vs. placebo) while CV death alone occurred most frequently in the Apixaban 2.5 mg BID group (1.3% Apixaban 10 mg QD n = 318, 3.5% Apixaban 2.5 mg BID n = 317, 1.8% placebo n = 611).

When secondary endpoints were stratified by Clopidogrel status, placebo was associated with the most ischemic events. Patients taking Clopidogrel: 4.9% for Apixaban 10 mg QD (n=243), 5.6% for Apixaban 2.5 mg BID (n=232), 6.5 % for placebo (n=462); No Clopidogrel: 9.3%, 12.9%, 15.4% for Apixaban 10 mg QD (n=75), Apixaban 2.5 mg BID (n=85) and placebo (n=149) respectively.

APPRAISE-1 represents the first trial to combine anticoagulation with a direct factor Xa inhibitor in the treatment of patients with a recent ACS already receiving antiplatelet therapy. Overall, the results suggest that administration of Apixaban on top of current antiplatelet therapy for 6 months post-ACS leads to increased bleeding in a dose-dependent fashion and reduced ischemic events. Similar outcomes were found among patients taking Aspirin or Aspirin + Clopidogrel.

APPRAISE-1 was supported by Bristol-Myers Squibb.