In the trial by Agnelli et al., how did oral apixaban compare to subcutaneous dalteparin for the prevention of recurrent venous thromboembolism?
Agnelli et al. assessed whether oral apixaban would be noninferior to subcutaneous dalteparin for the prevention of recurrent venous thromboembolism in patients with cancer without increasing the risk of major bleeding. Read the NEJM Original Article here.
Q: What therapeutic agents are currently recommended for the treatment of cancer-associated venous thromboembolism?
A: Major guidelines recommend the use of low-molecular-weight heparin for the treatment of cancer-associated venous thromboembolism and have recently added the use of edoxaban or rivaroxaban.
Q: Did the trial by Agnelli et al. include patients with a large variety of cancer types?
A: The trial included patients with predominantly advanced active cancer and acute symptomatic venous thromboembolism. Patients with a large variety of cancer types, including approximately one third that occurred at gastrointestinal sites, were included in the trial, which was consistent with the cancer distribution in the general population. Cancers associated with high thromboembolic risk, such as lung and colorectal cancers, were well represented. No anticancer therapy was excluded, which led to the inclusion of patients receiving a broad array of cytotoxic and biologic therapies.
Morning Report Questions
Q: In the trial by Agnelli et al., how did oral apixaban compare to subcutaneous dalteparin for the prevention of recurrent venous thromboembolism?
A: The authors found that oral apixaban was noninferior to subcutaneous dalteparin for the treatment of recurrent venous thromboembolism in patients with cancer. The primary outcome of recurrent venous thromboembolism occurred in 32 of 576 patients (5.6%) in the apixaban group and in 46 of 579 patients (7.9%) in the dalteparin group (hazard ratio, 0.63; 95% confidence interval [CI], 0.37 to 1.07; P<0.001 for noninferiority; P=0.09 for superiority). Major bleeding occurred in 22 patients (3.8%) in the apixaban group and in 23 patients (4.0%) in the dalteparin group (hazard ratio, 0.82; 95% CI, 0.40 to 1.69; P=0.60). In patients younger than 65 years of age, apixaban was seen to be more effective than dalteparin at preventing recurrent venous thromboembolism. The apparent decrease in efficacy with increasing age that was shown in the subgroup analysis should be considered as hypothesis generating and warrants attention in future studies.
Q: Describe some of the limitations of the trial by Agnelli et al.
A: First, it was an open-label trial to avoid the use of parenteral placebo for 6 months. However, the numbers of suspected recurrences of venous thromboembolism were similar in the two treatment groups, and all suspected trial outcome events were centrally adjudicated in a blinded manner. Second, gastrointestinal bleeding was not a prespecified trial outcome; however, after the publication of results of studies of other direct anticoagulants, such bleeding emerged as a relevant safety outcome. Third, patients with brain tumors, known cerebral metastases, or acute leukemia were not enrolled for safety reasons, so the results cannot be extrapolated to these patient groups. Finally, as in the large majority of studies regarding the treatment of venous thromboembolism, the sample size of the trial was powered for the primary outcome (recurrent venous thromboembolism) and was not powered to make definitive conclusions about bleeding.
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