Clinical Pearls & Morning Reports
Published February 20, 2019
The use of direct oral anticoagulants as thromboprophylactic agents in patients with cancer can offer important advantages over parenteral agents, including route of administration, convenience, and cost. A previous small, phase 2 trial involving 125 patients suggested that the oral factor Xa inhibitor apixaban may be safe and effective. Carrier et al. conducted the Apixaban for the Prevention of Venous Thromboembolism in High-Risk Ambulatory Cancer Patients (AVERT) trial to assess the efficacy of apixaban thromboprophylaxis in ambulatory patients with cancer at intermediate-to-high risk for venous thromboembolism. Read the latest NEJM Original Article here.
Q: What is the Khorana score?
A: The Khorana score, based on type of cancer, body-mass index, and hematologic variables (range, 0 to 6, with higher scores indicating a higher risk of venous thromboembolism) has been validated to identify patients with an elevated risk of venous thromboembolism and may help select those who could benefit from prophylaxis. Patients who have a solid tumor and a Khorana score of 2 or higher have an estimated risk of symptomatic thrombosis of 9.6% during the first 6 months of chemotherapy. Inclusion in the AVERT trial required a Khorana score of 2 or higher.
Q: Is apixaban effective among ambulatory patients with cancer who are starting chemotherapy and are at intermediate-to-high risk for venous thromboembolism?
A: The AVERT trial showed that thromboprophylaxis with apixaban resulted in a significantly lower rate of venous thromboembolic complications than placebo among ambulatory patients with cancer who were starting chemotherapy and had a Khorana score of 2 or higher. The primary efficacy outcome was the first episode of objectively documented major venous thromboembolism (proximal deep-vein thrombosis or pulmonary embolism) within the first 180 days after randomization. The primary efficacy outcome occurred in 12 of 288 patients (4.2%) in the apixaban group and in 28 of 275 patients (10.2%) in the placebo group (hazard ratio, 0.41; 95% confidence interval [CI], 0.26 to 0.65; P<0.001).
A: In the modified intention-to-treat analysis, major bleeding occurred in 10 patients (3.5%) in the apixaban group and in 5 patients (1.8%) in the placebo group (hazard ratio, 2.00; 95% CI, 1.01 to 3.95; P=0.046). The trial showed no significant between-group difference in overall survival. This probably reflects the fact that many of the patients had advanced cancer, which was the most common cause of death. Although prevention of venous thromboembolism would ideally reduce overall mortality, a different trial design and a much larger sample would be required to address this question.
A: The AVERT trial had a high proportion of patients with gynecologic, lymphoma, or pancreatic tumors and very few patients with colorectal or prostate cancers. However, this is expected, because these latter tumors are not recognized as posing a high risk of venous thromboembolism according to the Khorana score. Owing to the sample size, the trial has limited ability to make definitive conclusions about outcomes associated with individual tumor types or individual chemotherapy regimens. Only 5.9% of patients had renal dysfunction as defined by a creatinine clearance of 50 ml or less per minute, so the results may be less applicable to patients with renal dysfunction, who are known to have a higher risk of bleeding than patients with normal renal function.