Apixaban for Prevention of Acute Ischemic Events 2 - APPRAISE-2

Description:

Apixaban is a novel oral anti Xa antagonist, with demonstrated safety and efficacy, as compared with agents such as warfarin in patients with atrial fibrillation and enoxaparin in patients undergoing orthopedic surgery. The phase II APPRAISE-1 trial noted that in patients with recent acute coronary syndrome (ACS), apixaban, in the background of dual antiplatelet therapy with aspirin and clopidogrel, was associated with reduced ischemic events, but increased bleeding, especially with doses higher than 10 mg daily.

The current trial is a phase III trial to assess the safety and efficacy of apixaban in patients with recent ACS and at high risk for recurrent ischemic events.

Contribution to the Literature: The APPRAISE-2 trial showed that apixaban 5 mg twice daily, in the background of dual antiplatelet therapy, is associated with increased bleeding without a significant improvement in ischemic outcomes in patients with recent ACS and high-risk features for recurrent ischemic events.

Study Design

  • Blinded
  • Parallel
  • Placebo Controlled
  • Randomized

Patient Populations:

  • ACS within the previous 7 days, with symptoms of ischemia lasting 10 minutes or more with the patient at rest, with either elevated biomarkers or electrocardiogram changes
  • Hemodynamically stable
  • On dual antiplatelet therapy
  • At least two of the following high-risk features:
    • Diabetes mellitus
    • Age ≥65 years
    • MI within 5 years
    • Cerebrovascular accident
    • Peripheral arterial disease
    • CHF/EF ≤40%
    • Impaired renal function
    • No revascularization

      Number of enrollees: 7,392
      Duration of follow-up: 8 months (median)
      Mean patient age: 67
      Percentage female: 32%

    Exclusions:

    • Severe hypertension
    • Severe renal dysfunction
    • Active bleeding or high risk of bleeding
    • Known coagulopathy
    • Ischemic stroke within 7 days
    • New York Heart Association class IV symptoms
    • History of intracranial hemorrhage
    • Hemoglobin <9 g/dl
    • Platelet count <100,000 mm3
    • Ongoing treatment with parenteral or oral anticoagulant
    • Treatment with aspirin >325 mg daily or strong inhibitor of CYP3A4
    • Life expectancy ≤6 months
    • Acute pericarditis
    • Acute hepatobiliary disease
    • Pregnant, breastfeeding women

    Primary Endpoints:

    • Efficacy: Cardiovascular (CV) death/MI/ischemic stroke
    • Safety: TIMI major bleeding

    Secondary Endpoints:

    • Efficacy:
      • CV death/MI/ischemic stroke/unstable angina
      • CV death/MI/ischemic or hemorrhagic stroke/fatal bleeding
      • CV death/MI/ischemic stroke or hemorrhagic stroke
      • CV death
      • MI
      • Stroke
      • Stent thrombosis
    • Safety:
      • TIMI major or minor bleeding
      • ISTH bleeding
      • GUSTO bleeding

    Drug/Procedures Used:

    Patients were randomized to receive either apixaban 5 mg twice daily (2.5 mg twice daily if creatinine clearance was ≤40 ml/min) or matching placebo.

    Concomitant Medications:

    Aspirin (97%), dual antiplatelet therapy: aspirin + P2Y12 receptor antagonist (81%), angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (79%), beta-blocker (76%), statin (84%), proton pump inhibitor (24%)

    Principal Findings:

    A total of 7,392 patients were randomized, 3,705 to apixaban and 3,687 to placebo. The trial has initially aimed to enroll 10,800 patients, but had to be terminated early after preliminary analyses demonstrated significantly increased bleeding with apixaban, without a concurrent reduction in ischemic events. Baseline characteristics were fairly similar between the two arms. About 48% had diabetes mellitus, 10% had history of prior stroke, 40% had congestive heart failure (CHF) or ejection fraction (EF) <40%, and 29% had evidence of renal insufficiency. Presentation was ST-segment elevation myocardial infarction (STEMI) in 39%, non-STEMI (NSTEMI) in 42%, and unstable angina in about 18% of the patients; 55% did not undergo revascularization for their index ACS event, and 44% underwent percutaneous coronary intervention.

    The median time to randomization after initial ACS event was 6 days, and the median time of initiation of apixaban after discontinuation of parenteral antithrombotics (used in 81%) was 2 days. Median exposure time to apixaban was 175 days, and to placebo was 185 days.

    The primary efficacy endpoint of CV death, MI, or ischemic stroke over a median follow-up of 8 months was similar between the apixaban and placebo arms (7.5% vs. 7.9%, hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.80-1.11, p = 0.51). Rates of all-cause mortality (4.2% vs. 3.9%, p = 0.51), MI (4.9% vs. 5.3%, p = 0.51), ischemic stroke (0.6% vs. 0.9%, p = 0.14), and stent thrombosis (0.9% vs. 1.3%, p = 0.15) were similar between the two arms. The primary safety endpoint of Thrombolysis In Myocardial Infarction (TIMI) major bleeding was significantly higher in the apixaban arm, as compared with placebo (1.3% vs. 0.5%, HR 2.59, 95% CI 1.50-4.46, p = 0.001). Similarly, TIMI major or minor bleeding was also increased with apixaban (2.2% vs. 0.8%, p < 0.001).

    Other definitions of bleeding such as International Society on Thrombosis and Hemostasis (ISTH) major bleeding (2.7% vs. 1.1%, p < 0.001) and Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) severe bleeding (1.3% vs. 0.3%, p = 0.001) all demonstrated significantly higher rates with apixaban. Intracranial bleeding was higher with apixaban (0.3% vs. 0.1%, p = 0.03), and all fatal bleeds were numerically higher (0.1% vs. 0, p = NS).

    Baseline antiplatelet monotherapy vs. dual therapy: At baseline, 16.3% were on aspirin alone; the rest were on dual antiplatelet therapy. The primary endpoint for apixaban vs. placebo for aspirin monotherapy at baseline was 12.21 vs. 13.21 per 100 person-years (PY), and for dual antiplatelet therapy at baseline: 13.22 vs. 14.24 per 100 PY (p > 0.05 for both). TIMI major bleeding was increased in both strata (1.48 vs. 0.25 per 100 PY, 2.58 vs. 1.02 per 100 PY; p < 0.05 for both).

    Rates of premature discontinuation were higher in the apixaban arm (23.5% vs. 20.5%, p = 0.02). Serious adverse events were similar between the two arms (24.3% vs. 24.3%).

    Interpretation:

    The results of the APPRAISE-2 trial indicate that apixaban 5 mg twice daily, in the background of dual antiplatelet therapy, is associated with increased bleeding, without significant improvement in ischemic outcomes over a median follow-up of 8 months. One limitation of the current trial is that the majority of the patients did not undergo revascularization after their index ACS event, even though more than 80% presented with either STEMI or NSTEMI. Reasons for this are likely due to their high-risk features, but it somewhat limits the generalizability of these results.

    Apixaban is a novel oral anti Xa anticoagulant, with a mechanism of action similar to other agents such as rivaroxaban. A similar dose-dependent increase in bleeding in ACS patients had been noted with rivaroxaban in the phase II ATLAS ACS-TIMI 46 trial, although apixaban is the first drug in its class to be tested in a phase III ACS trial; a phase III ACS trial with rivaroxaban is ongoing.

    References:

    Hess CN, James S, Lopes RD, et al. Apixaban Plus Mono Versus Dual Antiplatelet Therapy in Acute Coronary Syndromes: Insights From the APPRAISE-2 Trial. J Am Coll Cardiol 2015;66:777-87.

    Alexander JH, Lopes RD, James S, et al.; on behalf of the APPRAISE-2 Investigators. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011;Jul 24:[Epub ahead of print].

    Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Anticoagulation Management and ACS, Acute Heart Failure, Interventions and ACS, Interventions and Vascular Medicine

    Keywords: Myocardial Infarction, Acute Coronary Syndrome, Stroke, Morpholines, Warfarin, Peripheral Arterial Disease, Pyrazoles, Ticlopidine, Orthopedics, Hemostasis, Stents, Percutaneous Coronary Intervention, Renal Insufficiency, Thrombosis, Enoxaparin, Heart Failure, Pyridones, Diabetes Mellitus


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