AVERT

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Carrier M,et al. "Apixaban to Prevent Venous Thromboembolism in Patients with Cancer". New England Journal of Medicine. 2018. :.
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Clinical Question

In ambulatory patients with cancer who are initiating chemotherapy and who are at intermediate-to-high risk for venous thromboembolism, does apixaban reduce the risk of venous thromboembolism?

Bottom Line

Apixaban significantly reduces the risk of venous thromboembolism in ambulatory cancer patients, but the risk of major bleeding episodes is also significantly higher.

Major Points

Patients with active cancer have an increased risk of venous thromboembolism (VTE), but determining who may benefit from thromboprophylaxis has been difficult, especially given the burdensome and costly nature of parenteral therapy. Low-molecular-weight heparin has been studied for thromboprophylaxis for cancer patients, but the efficacy has not reached statistical significance[1]. Multiple recent studies have investigated the use of oral factor Xa inhibitors in treatment of cancer-associated VTE[2][3] and have demonstrated lower rates of major bleeding than parenteral therapy. The AVERT trial[4] was a randomized, placebo-controlled, double-blind clinical trial that evaluated the efficacy of low dose apixaban for thromboprophylaxis in cancer patients identified at intermediate-to-high risk of VTE utilizing the validated Khorana score[5] [6]. The trial demonstrated that low dose apixaban was effective in significantly lowering the risk of VTE from 10.2% to 4.2%, albeit with a concomitant increase in risk of major bleeding from 1.1% to 2.1%.

Guidelines

As of January 2018, no guidelines reflect the findings of this trial.

Design

  • Multicenter, double-blind, placebo-controlled, randomized trial
  • N=574
    • Apixaban (n=291)
    • Standard (n=283)
  • Setting: 13 centers in Canada
  • Enrollment: Februrary 2014 to April 2018
  • Mean follow-up: 183 days
  • Analysis: Modified intention-to-treat
  • Primary outcome: Objectively documented proximal deep-vein thrombosis or pulmonary embolism

Population

Inclusion Criteria

  • Newly diagnosed cancer or progression of known cancer after previous complete or partial remission
  • Initiating chemotherapy with a planned duration of at least 3 months
  • Khorana score of 2 or higher
  • 18 years of age or older

Exclusion Criteria

  • Conditions associated with increased risk of clinically significantly bleeding
  • Hepatic disease with coagulopathy
  • Cancer diagnosis of only basal-cell or squamous-cell skin carcinoma, acute leukemia, or myeloproliferative neoplasm
  • Planned stem cell transplantation
  • Life expectancy less than 6 months
  • Chronic kidney disease with GFR less than 30 ml per minute per 1.73 square meter of body-surface area
  • Platelet count less than 50,000 per cubic millimeter

Baseline Characteristics

From the apixaban group:

  • Mean age: 61.2 years
  • Male sex: 41.6%
  • Weight: 80.0 kg
  • Creatinine clearance >50 ml/min: 94.5%
  • Tumor type:
    • Brain: 4.8%
    • Bladder: 0.3%
    • Lung: 10.7%
    • Testicular: 0.7%
    • Stomach: 8.6%
    • Pancreatic: 12.7%
    • Lymphoma: 26.1%
    • Myeloma: 2.4%
    • Gynecologic: 25.4%
    • Colon: 1.0%
    • Prostate: 0%
    • Other: 7.2%
  • Khorana score:
    • 2: 63.9%
    • 3: 26.8%
    • 4: 8.9%
    • 5: 0.3%
    • 6: 0%
  • Components of Khorana score besides tumor type:
    • Prechemotherapy leukocyte count >11,000/cubic mm: 28.5%
    • Hemoglobin <10 g/dl or use of red-cell growth factors: 22.7%
    • Pre-chemotherapy platelet count ≥250,000/cubic mm: 40.9%
    • Body-mass index ≥35: 24.7%
  • Concomitant antiplatelet medication: 23.0%
  • ECOG performance status score:
    • 0 or 1: 85.3%
    • ≥2: 14.7%
  • Previous venous thromboembolism: 3.1%

Interventions

  • Randomized to apixaban 2.5 mg PO BID or placebo
    • First dose of apixaban or placebo administered within 24 hours of the first dose of chemotherapy
  • Patients were followed for up to 210 days or death

Outcomes

Comparisons are apixaban vs. placebo.

Primary Outcomes

Venous thromboembolism
4.2% vs. 10.2% (HR 0.41; 95% CI 0.26-0.65; P<0.001)
Major bleeding episode
3.5% vs. 1.8% (HR 2.00; 95% CI 1.01-3.95; P=0.046)

Secondary Outcomes

Death from any cause
12.2% vs. 9.8% (HR 1.29; 95% CI 0.98-1.71)
Clinically relevant nonmajor bleeding
7.3% vs. 5.5% (HR 1.28; 95% CI 0.89-1.84)
Venous thromboembolism during the treatment period
1.0% vs. 7.3% (HR 0.14; 95% CI 0.05-0.42)
Major bleeding episode during the treatment period
2.1% vs. 1.1% (HR 1.89; 95% CI 0.39-9.24)

Subgroup Analysis

  • Major bleeding was mostly associated with patients with gastrointestinal or gynecologic cancers
  • No cases of fatal bleeding

Criticisms

  • Low rate of renal insufficiency with creatinine clearance <50 ml or less per minute
  • No mortality benefit demonstrated

Funding

  • Canadian Institutes of Health Research
  • Bristol-Myers Squibb-Pfizer Alliance

Further Reading

  1. Khorana AA et al. Dalteparin thromboprophylaxis in cancer patients at high risk for venous thromboembolism: A randomized trial. Thromb. Res. 2017. 151:89-95.
  2. Raskob GE et al. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N. Engl. J. Med. 2018. 378:615-624.
  3. Young AM et al. Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D). J. Clin. Oncol. 2018. 36:2017-2023.
  4. Carrier M et al. Apixaban to Prevent Venous Thromboembolism in Patients with Cancer. N. Engl. J. Med. 2018. :.
  5. Ay C et al. Prediction of venous thromboembolism in cancer patients. Blood 2010. 116:5377-82.
  6. Khorana AA et al. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008. 111:4902-7.