AVERT: Apixaban for the Prevention of Venous Thromboembolism in High-Risk Ambulatory Cancer Patients

A study by Marc Carrier and his colleagues published in the New England Journal of Medicine concluded that apixaban therapy resulted in a significantly lower rate of venous thromboembolism as compared to placebo among intermediate-to-high-risk ambulatory patients with cancer who were starting chemotherapy. According to the publication, the investigators also confirmed that the rate of major bleeding episodes was higher with apixaban than with placebo.

 It is already known that patients with active cancer have an increased risk of venous thromboembolism, which results in substantial morbidity, mortality, and health care expenditures. Although parenteral thromboprophylaxis can reduce the risk of venous thromboembolism among ambulatory patients undergoing chemotherapy, it is not routinely recommended in practice guidelines because the absolute risk reduction is modest and parenteral thromboprophylaxis is associated with an increased risk of major bleeding, high cost, and the inconvenience of daily injections. The Khorana score (range, 0 to 6, with higher scores indicating a higher risk of venous thromboembolism) had been validated to identify patients with cancer at elevated risk for this complication and aids in the selection of those who could benefit from thromboprophylaxis. In this study, patients with Khorana score of greater than equal to 2 were included. This umbrella included all ambulatory patients with cancer who were initiating chemotherapy and had an intermediate to- high risk of venous thromboembolism.

Following stratification of patients on the basis of age, sex and center, Marc and his team conducted a randomized, placebo-controlled, double-blind clinical trial assessing the efficacy and safety of apixaban (2.5 mg twice daily) for thromboprophylaxis in ambulatory patients with cancer who were at intermediate-to-high risk for venous thromboembolism (Khorana score, ≥2) and were initiating chemotherapy. The primary efficacy outcome was objectively documented venous thromboembolism over a follow-up period of 6 months. The main safety outcome was a major bleeding episode. Of the 574 patients who underwent randomization, 563 were included in the modified intention-to-treat analysis. The results showed a highly significant reduction in the primary efficacy outcome in the Apixaban arm. It was noted that venous thromboembolism 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). Moreover, the modified intention-to-treat analysis showed that 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). According to the per-protocol analysis, major bleeding occurred in 6 patients (2.1%) in the apixaban group and in 3 patients (1.1%) in the placebo group (hazard ratio, 1.89; 95% CI, 0.39 to 9.24). The secondary outcome, all-cause mortality, was 12.2% in the apixaban group vs. 9.8% in the placebo group (p = not significant).

 The Kaplan-Meir curves showcased no significant between-group difference in overall survival. This probably reflected the fact that many of the enrollees had advanced cancer, which was the most common cause of death. Although prevention of venous thromboembolism would ideally reduce overall mortality, different trial design and a much larger sample would be required to address this question. Addressing some of the possible limitations of the study, the authors acknowledged that the study also comprised of a large proportion of patients with gynecologic, lymphoma, or pancreatic tumors and very few patients with colorectal or prostate cancers. However, this was expected, as these latter tumors were not recognized as posing a high risk of venous thromboembolism according to the Khorana score. However, owing to the sample size, the AVERT investigators had a limited ability to make definitive conclusions about outcomes associated with individual tumor types or individual chemotherapy regimens. Last but not the least, only 5.9% of patients had renal dysfunction as defined by a creatinine clearance of 50 ml or less per minute, so their results could be less applicable to patients with renal dysfunction, who were known to have a higher risk of bleeding than patients with normal renal function.

In conclusion, apixaban at a dose of 2.5 mg twice daily resulted in a significantly lower risk of venous thromboembolism than did placebo among ambulatory patients with cancer who were initiating chemotherapy and had an intermediate to- high risk of venous thromboembolism. Prevention of venous thromboembolism remains an important topic among active cancer patients and optimal treatment remains uncertain. In an accompanying editorial titled ‘Apixaban Helps Prevent Venous Thromboembolism in Patients with Cancer’, Amy Orciari Herman highlighted the important findings in this study. Commenting on the study results, Dr. David Green of NEJM Journal Watch Oncology and Hematology stated, “Recent clinical trials suggest that the new oral factor Xa inhibitors, including apixaban, are effective in the prevention and treatment of cancer-associated venous thromboembolism, with bleeding risks similar to those of low-molecular-weight heparins.”