AVERT

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Carrier M, et al. "Apixaban to Prevent Venous Thromboembolism in Patients with Cancer". The New England Journal of Medicine. 2018. E-pub 2018-12-04:1-8.
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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

Prophylactic apixaban reduces the risk of venous thromboembolism in ambulatory cancer patients while increasing major bleeding episodes.

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 its efficacy is not well established.[1] Recent studies have investigated the use of oral factor Xa inhibitors in treatment of acute cancer-associated VTE (e.g., edoxaban in the Hokusai VTE Cancer Trial and rivaroxaban in SELECT-D). The role of these agents for primary prevention in high-risk adults is unknown.

Published in 2019, the Apixaban for the Prevention of Venous Thromboembolism in High-Risk Ambulatory Cancer Patients (AVERT) trial randomized 574 patients with cancer and an elevated risk for VTE (calculated by a Khorana score ≥2[2][3]) to apixaban 2.5 mg PO BID or placebo. At 180 days, the incidence of VTE was lower in the apixaban group than the placebo group (4.2% vs. 10.2%; NNT=17) at the cost of increased major bleeding (3.5% vs. 1.8%; NNH=59). Consistent with bleeding in other DOAC cancer VTE trials, bleeding episodes clustered in patients predominantly with gastrointestinal malignancies.

Guidelines

As of January 2019, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, double-blind, placebo-controlled, randomized trial
  • N=574 ambulatory patients with active malignancy
    • Apixaban (n=291)
    • Placebo (n=283)
  • Setting: 13 centers in Canada
  • Enrollment: 2014-2018
  • Mean follow-up: 183 days
  • Analysis: Modified intention-to-treat
  • Primary outcome: Objectively documented proximal DVT or PE

Population

Inclusion Criteria

  • Age ≥18 years
  • 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 ≥2

Exclusion Criteria

  • Increased risk of bleeding
  • Liver disease with with coagulopathy
  • BCC, SCC, acute leukemia, or MPN
  • Planned stem cell transplantation
  • Life expectancy <6 months
  • CKD (GFR <30 ml/min/1.73 m2)
  • Platelet count <50,000/mm3

Baseline Characteristics

From the apixaban group:

  • Demographics: Age 61 years, 42% male
  • Weight: 80.0 kg
  • Creatinine clearance >50 ml/min: 94%
  • Tumor type: Brain 5%, bladder 0.3%, lung 11%, testicular 1%, stomach 9%, pancreatic 13%, lymphoma 26%, myeloma 2%, gynecologic 25%, colon 1%, prostate 0%, other 7%
  • Khorana score:
    • 2: 64%
    • 3: 27%
    • 4: 9%
    • 5: 0.3%
    • 6: 0%
  • Components of Khorana score besides tumor type:
    • Prechemotherapy leukocyte count >11,000/mm3: 28%
    • Hemoglobin <10 g/dl or use of RBC growth factors: 23%
    • Pre-chemotherapy platelet count ≥250,000/mm3: 41%
    • BMI ≥35: 25%
  • Concomitant antiplatelet medication: 23.0%
  • ECOG performance status score:
    • 0 or 1: 85%
    • ≥2: 15%
  • Previous venous thromboembolism: 3%

Interventions

  • Randomized to an arm:
    • Apixaban - 2.5 mg PO BID
    • 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
  • No routine radiology screening

Outcomes

Comparisons are apixaban vs. placebo.

Primary Outcomes

Proximal DVT or PE
4.2% vs. 10.2% (HR 0.41; 95% CI 0.26-0.65; P<0.001; NNT=17)
Major bleeding episode
ISTH definition: Overt bleeding with drop in hgb ≥2g/dL, leading to ≥2 units pRBC transfused, bleeding in a critical site, or contributing to death.
3.5% vs. 1.8% (HR 2.00; 95% CI 1.01-3.95; P=0.046; NNH=59)

Secondary Outcomes

All-cause mortality
35 (12.2%) vs. 27 (9.8%) (HR 1.29; 95% CI 0.98-1.71)
Cancer: 31 vs. 23
Sepsis: 3 vs. 1
Medically-assisted death: 0 vs. 2
Kidney failure: 0 vs. 1
Stroke: 1 vs. 0
Clinically relevant non-major bleeding
7.3% vs. 5.5% (HR 1.28; 95% CI 0.89-1.84; NNH=56)
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 inclusion of distal DVT in the outcome. Patients with malignancy and symptomatic distal DVT may be treated with anticoagulation. This may have led to attenuation of the VTE and bleeding outcomes.

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. Ay C et al. Prediction of venous thromboembolism in cancer patients. Blood 2010. 116:5377-82.
  3. Khorana AA et al. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008. 111:4902-7.