Background: The risk of venous thromboembolism (VTE) is increased in cancer patients, which can result in significant increases in mortality, morbidity and healthcare expenditures. The recent AVERT trial (N Engl J Med 2019 Feb 21;380(8):711-719), showed that prophylactic apixaban lowered the rate of VTE when compared to placebo in cancer patients starting chemotherapy. However, the risk-benefit ratio of primary thromboprophylaxis in patients initiating chemotherapy for recurrent disease compared to those with newly diagnosed patients who are chemotherapy naïve is unknown.
Methods: This is a post-hoc analysis of the AVERT trial. The AVERT trial assessed apixaban therapy vs. placebo for prophylaxis among patients with cancer who were intermediate-to-high risk for VTE (Khorana score ≥2; the Khorana score is ranged from 0 to 6 with higher scores reflecting an increased risk of VTE) and were initiating chemotherapy. It was a randomized, placebo-controlled, double-blind clinical trial. The primary efficacy outcome was VTE and the main safety outcomes were major bleeding episodes. Secondary outcome measures included clinically relevant non-major bleeding (CRNMB). The severity of major bleeding was stratified from category 1 to 4, with category 4 being the most severe type. We performed time-to-event analysis on the primary efficacy and main safety end-points in patients with recurrent and new diagnosed cancers. The hazard ratio (HR) for the outcomes were estimated using a Cox regression model controlling for age, gender, and center.
Results: A total of 574 patients were randomized in the AVERT trial. 563 were included in the modified intention-to-treat analysis. 237 and 232 patients with newly diagnosed cancer were allocated to the apixaban and placebo groups, respectively. Similarly, 51 and 43 patients with recurrent cancer were allocated to the apixaban and placebo groups, respectively. Baseline demographics and clinical characteristics are depicted in Table 1A and Table 1B. In patients with newly diagnosed cancers, the use of apixaban was associated with a significantly lower risk of VTE (HR: 0.45; 95% CI: 0.27-0.76; p = 0.002) and a higher rate of major bleeding complications (HR: 2.10; 95% CI: 1.09-4.08; p = 0.028) but not of CRNMB (HR: 1.06; 95% CI: 0.61-1.82) (Table 2A). A majority of the major bleeding complications were of category 2. In patients with recurrent cancer, apixaban was associated with a significant lower rate of VTE (HR: 0.26; 95% CI: 0.13-0.53; p < 0.001) without an associated significant increased risk of major bleeding complication (HR: 1.82; 95% CI: 0.36-9.15; p = 0.466) but with a significant increase rate of CRNMB (HR: 2.78; 95% CI: 0.58-1.34; p = 0.006) (Table 2B). Major bleeding episodes were split evenly between severity category 1 and 2.
Conclusion: The risk-benefit ratio of primary thromboprophylaxis with apixaban might differ between patients with recurrent or newly diagnosed cancers. Apixaban was associated with a lower rate of VTE compared to placebo in both groups. Patients with recurrent cancer initiating chemotherapy may potentially have a more favorable risk benefit profile, as shown through the HR and the prevalence of major bleeding episodes. However, more trials are required to confirm these findings to help tailor thromboprophylaxis in this patient population. (AVERT ClinicalTrials.gov number, NCT02048865.)
Wells:BMS/Pfizer: Honoraria, Research Funding; Bayer: Honoraria; Sanofi: Honoraria; Daiichi Sankyo: Honoraria. Carrier:Leo Pharma: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Servier: Honoraria; Bayer: Honoraria; Pfizer: Honoraria, Research Funding.
Apixaban can be used as postoperative prophylaxis of DVT/PE and for treatment of DVT/PE. This study will show whether the prophylactic effects of apixaban will be more effective when used with patients with recurrent cancer or patients with newly diagnosed cancer.
Asterisk with author names denotes non-ASH members.