Impact of concurrent antiplatelet/NSAID use on the safety and efficacy of thromboprophylaxis with apixaban in patients with cancer: A post-hoc analysis of the AVERT trial

Abstract Background: The risk of venous thromboembolism (VTE) is significantly increased in patients with cancer compared to the general population. The AVERT trial demonstrated that thromboprophylaxis with apixaban significantly reduced the risk of VTE in intermediate-to-high-risk patients with cancer initiating chemotherapy but may be associated with a higher rate of major bleeding. There is a paucity of data on the risks of bleeding associated with the concurrent use of prophylactic doses of an anticoagulant and anti-platelet agents or nonsteroidal anti-inflammatory drugs (NSAID), particularly in patients with active cancer. Thus, we aim to evaluate the impact of concurrent antiplatelet/NSAID use on the safety and efficacy of apixaban thromboprophylaxis in patients with cancer. Methods: This is a post-hoc analysis of the AVERT trial, which was a randomized, placebo-controlled, double-blind clinical trial comparing apixaban (2.5 mg twice daily) to placebo for thromboprophylaxis in intermediate-to-high risk (Khorana score ≥2) ambulatory patients with cancer who were initiating chemotherapy. For the current analysis, the primary outcome was clinically relevant bleeding defined as a combination of major and clinically relevant non-major bleeding (CRNMB) as per the International Society on Thrombosis and Haemostasis. Secondary outcomes included major VTE, major bleeding, CRNMB and death. Hazard ratios (HR) for the different outcomes in patients with and without concurrent antiplatelet or NSAID use were calculated using a Cox-proportional hazards model, controlling for age and sex. Additional subgroup analyses were performed to calculate HRs separately among patients using antiplatelet agents and those using NSAIDs. Results: Out of the 574 patients randomized in the AVERT trial, a total of 557 patients were included in this study and stratified according to the presence or absence of concurrent antiplatelet/NSAID use throughout the study period. Of all patients, 182 had concurrent antiplatelet/NSAID use (apixaban n=98, placebo n=84) while 375 did not (apixaban n=186, placebo n=189). In the apixaban group, those using concurrent antiplatelets or NSAIDs had a significantly higher risk of clinically relevant bleeding (HR 1.78, 95% CI 1.13 to 2.78) and CRNMB (HR 1.98, 95% CI 1.19 to 3.30), without a significant reduction in VTE (HR 0.60, 95% CI 0.26 to 1.39), compared to those with no concurrent use. The risk of major bleeding did not differ between those two groups (HR 1.02, 95% CI 0.25 to 4.10). Among the subgroup of patients taking antiplatelet agents (n=61), the risks of clinically relevant bleeding (HR 2.0, 95% 1.27 to 3.15) and CRNMB (HR 2.59, 95% CI 1.57 to 4.28) were significantly higher compared to those with no concurrent antiplatelet use, with no increased risk of major bleeding (HR 0.73, 95% CI 0.16 to 3.4). Among the subgroup of patients taking NSAIDs (n=42), there were no significant differences in the risks of clinically relevant bleeding (HR 1.31, 95% CI 0.56 to 3.04), CRNMB (HR 0.86, 95% CI 0.65 to 1.14) or major bleeding (HR 3.59, 95% CI 0.52 to 24.75). In the placebo group, concurrent antiplatelet/NSAID use was not associated with a higher risk of clinically relevant bleeding (HR 1.38, 95% CI 0.78 to 2.46) or decreased risk of VTE (HR 1.03, 95% CI 0.61 to 1.73) but was associated with a higher risk of CRNMB (HR 1.91, 95% CI 1.0 to 3.64). In both groups, antiplatelet/NSAID use did not affect mortality outcomes. Conclusions: The use of antiplatelet agents or NSAIDs in cancer patients receiving apixaban thromboprophylaxis is associated with a significantly increased risk of clinically relevant bleeding and CRNMB, with no reduction in VTE risk. These findings highlight the need to re-evaluate the indication for antiplatelet agent and NSAID use, and to conduct an individualized bleeding risk assessment prior to the initiation of thromboprophylaxis in cancer patients.