Apixaban for Prevention of Acute Ischemic and Safety Events - APPRAISE

Jun 02, 2009
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Bristol-Myers Squibb
Date Presented:
01/01/2008
Date Published:
01/01/2009
Date Updated:
06/02/2009
Original Posted Date:
06/02/2009
References

Description:

The goal of the trial was to evaluate the impact of bleeding from various doses of apixaban, an oral direct factor Xa inhibitor, compared with placebo, in patients with a recent acute coronary syndrome (ACS).

Hypothesis:

This dose-finding study would determine the optimal dose of apixaban for further study.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patients Enrolled: 1,715
Mean Follow Up: 6 months
Mean Patient Age: Median 61 years
Female: 27

Patient Populations:

  • Stable patients 18-90 years of age recovering from an ACS in the last 7 days
  • At least one additional risk factor for recurrent ischemia: ≥65 years of age; elevated cardiac biomarkers and dynamic electrocardiographic changes; diabetes; MI in the last 12 months; prior stroke, transient ischemic attack, or carotid artery stenosis; peripheral vascular disease; history of congestive heart failure or left ventricular ejection fraction <40%; non-revascularized multi-vessel disease; mild to moderate renal insufficiency

Exclusions:

  • Planned revascularization
  • Uncontrolled hypertension
  • Severe renal insufficiency
  • Current bleeding or excess risk for bleeding
  • Acute pericarditis or pericardial effusion
  • Stroke in the last 3 months
  • New York Heart Association class IV heart failure
  • Thrombocytopenia (<100,000/mm3) or anemia (<10 g/dl)
  • Indication for chronic anticoagulation, nonsteroidal anti-inflammatory drugs, or high-dose aspirin

Primary Endpoints:

  • Major bleeding according to the ISTH definition: two or more g/dl decrease in hemoglobin, transfusion of two or more units of red blood cells, bleeding in a critical location, or bleeding that results in death
  • CRNM bleeding did not meet the definition for ISTH bleeding, although it resulted in the need for medical or surgical intervention

Secondary Endpoints:

Cardiovascular death, MI, recurrent ischemia, or stroke

Drug/Procedures Used:

Patients recovering from a recent ACS were randomized to 6 months of apixaban 20 mg daily (n = 221), apixaban 10 mg twice daily (n = 248), apixaban 10 mg daily (n = 318), apixaban 2.5 mg twice daily (n = 317), or placebo (n = 611).

Concomitant Medications:

The use of concomitant medications during the trial (apixaban 10 mg group representative of entire group) was 99.7% for aspirin, 77.5% for clopidogrel, 92.1% for beta-blockers, 82.9% for angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, and 87.9% for statins.

Principal Findings:

A total of 1,715 patients were randomized. At baseline (apixaban 10 mg daily group representative of entire group), the median age was 61 years, 27% were women, diabetes was 22%, and recent myocardial infarction (MI) was 5.7%. The index event was ST-elevation MI in 67% and recent percutaneous coronary intervention (PCI) in 65%.

The study arms with the two highest doses of apixaban were terminated early due to excess bleeding. The rate of major bleeding (International Society of Thrombosis and Hemostasis [ISTH] definition) plus clinically relevant nonmajor (CRNM) bleeding was 7.9% in the 10 mg daily apixaban group, 5.7% in the 2.5 mg twice daily apixaban group, and 3.0% in the placebo group (p = 0.005 for higher dose compared with placebo and p = 0.09 for lower dose compared with placebo). ISTH major/CRNM bleeding was increased more among patients taking clopidogrel compared with patients not on clopidogrel. Major bleeding according to the Thrombosis In Myocardial Infarction (TIMI) definition was 1.0% in the 10 mg daily apixaban group, 0% in the 2.5 mg twice daily apixaban group, and 0.3% in the placebo group.

Cardiovascular death, MI, recurrent ischemia, or stroke was 6.0% in the 10 mg daily apixaban group, 7.6% in the 2.5 mg twice daily apixaban group, and 8.7% in the placebo group (p = 0.07 for higher dose compared with placebo and p = 0.21 for lower dose compared with placebo). Any serious adverse event was 22.9% in the 10 mg apixaban group, 23.2% in the 5 mg apixaban group, and 20.9% in the placebo group.

Interpretation:

This dose-finding study revealed that bleeding is increased among patients with a recent ACS with escalated doses of apixaban on a backgroud of aspirin and clopidogrel therapy. In fact, the two arms that studied the highest doses of apixaban were terminated early due to excess bleeding. Bleeding was evident with the liberal definition defined in the study; however, it also appeared to be true according to TIMI major bleeding. Major bleeding was potentiated among patients who received clopidogrel. Although not powered to examine efficacy, the 10 mg daily dose of apixaban demonstrated the lowest incidence of cardiovascular death, MI, recurrent ischemia, or stroke. Serious adverse events were similar between the arms.

Accumulating data highlights that bleeding is an important adverse prognosticator. Current guidelines recommend treatment of ACS patients with aspirin and clopidogrel; therefore, apixaban will need to be carefully scrutinized given an increased risk for bleeding on this background therapy. There are ongoing phase III trials studying the role of factor Xa inhibitors in the setting of atrial fibrillation and thromboembolic disease, which will also help define the efficacy and safety of these agents.

References:

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;May 26:[Epub ahead of print].

Safety of the Factor Xa Inhibitor, Apixaban, in Combination With Antiplatelet Therapy After Acute Coronary Syndromes: Results From the APPRAISE-1 Dose Guiding Trial. Presented by Dr. John Alexander at the European Society of Cardiology Congress, Munich, Germany, August/September 2008.

Keywords: Myocardial Infarction, Acute Coronary Syndrome, Stroke, Ischemic Attack, Transient, Ticlopidine, Pyrazoles, Peripheral Vascular Diseases, Percutaneous Coronary Intervention, Renal Insufficiency, Thrombosis, Heart Failure, Stroke Volume, Factor Xa, Pyridones, Carotid Stenosis, Diabetes Mellitus


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