In the randomized, placebo-controlled AVERT trial, investigators assessed the safety and efficacy of apixaban thromboprophylaxis in patients with cancer considered to be at intermediate- to high-risk of developing a venous thromboembolism (VTE). While the direct oral anticoagulant resulted in a lower rate of VTE, it was associated with a higher rate of major bleeding episodes than placebo.
Marc Carrier, MD, from the University of Ottawa and Ottawa Hospital Research Institute, and coauthors reported their findings in the New England Journal of Medicine.
“The treatment of VTE with therapeutic anticoagulation is challenging in patients with cancer because it often involves daily injections of low-molecular-weight heparin and is associated with a high risk of thrombosis recurrence and serious bleeding complications,” the authors wrote. These results suggest that apixaban can be considered in this population, offering “important advantages over parenteral agents, including route of administration, convenience, and cost.”
AVERT enrolled patients who had a newly diagnosed cancer or progressive cancer following complete or partial remission and who were initiating a new course of chemotherapy. All participants had an increased risk of VTE (defined as a Khorana score ≥2). Patients were excluded if they had conditions putting them at increased risk for clinically significant bleeding; hepatic disease associated with coagulopathy; renal insufficiency; or a diagnosis of basal-cell or squamous-cell skin carcinoma, acute leukemia, or myeloproliferative neoplasm.
After stratifying for age, sex, and participating center, the investigators randomized 574 participants to receive thromboprophylaxis with either apixaban 2.5 mg twice daily (n=291) or placebo (n=283). The treatment period was 180 days and the first dose of study drug was administered within 24 hours after the initiation of chemotherapy.
Participants’ baseline characteristics were well balanced, the authors reported. The mean age was 61 years and the most common types of primary cancers were gynecologic (25.8%), lymphoma (25.3%), and pancreatic (13.6%).
The median duration of treatment was 157 days in the apixaban group (interquartile range [IQR] = 78-168) and 155 days in the placebo group (IQR=83-168), and the median duration of follow-up was 183 days in each group (range not reported). “The rate of adherence to the trial regimen was high in both groups, at 83.6 percent in the apixaban group and 84.1 percent in the placebo group,” the researchers noted.
Three patients in the apixaban group and eight in the placebo group did not receive treatment, leaving 288 and 275 patients in each group, respectively.
During follow-up, the primary efficacy endpoint (defined as major VTE [including proximal deep-vein thrombosis or pulmonary embolism] within the first 180 days after randomization) occurred in 12 apixaban-treated patients (4.2%) and 28 placebo-treated patients (10.2%; TABLE). This translated to a significantly lower risk of VTE with apixaban (hazard ratio [HR] = 0.41; 95% CI 0.26-0.65; p<0.001).
In the modified intention-to-treat analysis, which included all randomized patients who had received at least one dose of apixaban or placebo, major bleeding (the primary safety endpoint) occurred in 10 apixaban-treated patients (3.5%) and five placebo-treated patients (1.8%; HR=2.00; 95% CI 1.01-3.95; p=0.046). Most episodes of VTE were grade 2 in severity, meaning the episode required treatment but was not considered to be a clinical emergency (n=8 [80%] in the apixaban group and n=3 [60%] in the placebo group).
During the treatment period, major bleeding occurred in six of 288 patients in the apixaban group (2.1%) and in three of 275 patients in the placebo group (1.1%; HR=1.89; 95% CI 0.39-9.24; p value not reported).
Sixty-two patients died during study follow-up: 35 in the apixaban group (12.2%) and 27 in the placebo group (9.8%). Most deaths (n=54; 87%) were related to cancer or cancer progression. “Our trial showed no significant between-group difference in overall survival,” the authors reported, likely reflecting the advanced stage of cancer in this patient population. “Although prevention of VTE would ideally reduce overall mortality, a different trial design and a much larger sample would be required to address this question.”
The authors noted several limitations of this analysis. “As with all trials of thromboprophylaxis involving patients with cancer, between-trial comparisons can be biased owing to differences in tumor types in patients enrolled in the trial,” they cautioned, noting that the inclusion of few patients with colorectal or prostate cancer might limit the generalizability of these results to certain cancer types. In addition, “only 5.9 percent of patients had renal dysfunction, … so our results may be less applicable to [these patients], who are known to have a higher risk of bleeding than patients with normal renal function.”
The authors report relationships with the Bristol-Myers Squibb–Pfizer Alliance, which supported the trial.
Carrier M, Abou-Nassar K, Mallick R, et al. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2018 December 4. [Epub ahead of print]