Prophylactic use of a direct oral anticoagulant in cancer patients

Agnelli G. Direct oral anticoagulants for thromboprophylaxis in ambulatory patients with cancer. N Engl J Med 2019;380(8):781-3

These two large randomized controlled trials on the prophylactic use of a direct oral anticoagulant (rivaroxaban in CASSINI and apixaban in AVERT) over a period of 180 days in ambulatory cancer patients were recently published in the same edition of the New England Journal of Medicine.

In the CASSINI trial, 841 adult ambulatory patients with a solid tumor or lymphoma (no brain cancer and no brain metastases) with an increased risk of venous thromboembolism (VTE), defined by a Khorana score ≥ 2, who were receiving a systemic cancer treatment were randomly assigned to receive either rivaroxaban 10 mg or placebo for up to 180 days. The primary efficacy endpoint, the composite of proximal lower limb deep vein thrombosis (DVT), pulmonary embolism (PE), symptomatic upper limb DVT or distal lower limb DVT and death from VTE, occurred less frequently in the rivaroxaban group. However, this difference only reached statistical significance in the prespecified intervention-period analysis.

In the AVERT trial, 574 adult ambulatory patients with a newly diagnosed cancer or progressive disease, who were scheduled for a systemic cancer treatment, and – similar to CASSINI – a Khorana score ≥ 2, were randomized to receive either apixaban 2.5 mg twice daily or placebo. In this study, the incidence of VTE was lower in the apixaban treatment group than in the placebo group. In the modified intention-to-treat analysis, which only included patients who received at least one dose of the study drug, the rate of major bleeding was higher in the apixaban group than in the placebo group, mainly due to gastrointenstinal, gynecologic bleeding and hematuria, which goes in line with previous studies on the use of direct oral anticoagulants in cancer patients. In contrast, no differences in rates of major bleedings were observed in the CASSINI study.

The differences between CASSINI and AVERT might be attributable to differences in trial design: in CASSINI, a baseline ultrasound screening was mandatory, excluding patients with preexisting thrombosis. Further, the modified intention-to-treat analysis in AVERT might explain the inconsistencies in the findings of both studies.

In addition, the use of the Khorana score, which might not apply for all types of cancer in the same way, as well as the underrepresentation of some cancer entities can be brought up as potential limitations, as it was recently discussed by Agnelli [1].

In conclusion, both trials conjointly encourage the evaluating the use of direct oral anticoagulants in the prophylaxis of venous thromboembolism in ambulatory patients with cancer initiating chemotherapy. However, the high rate of discontinuation of the medical trial regimen as well as the mentioned limitations reflect the complexity of this issue and illustrate the need for further studies.