Extended Anticoagulation in Cancer-associated Thrombosis (CAT): Can We Lower the Dose Yet?

The management of cancer-associated thrombosis (CAT) has changed considerably in the past five years, with direct oral anticoagulants (DOACs) now commonplace in the management of acute CAT. The current ASH 2021 guidelines for management of venous thromboembolism (VTE): prevention and treatment in patients with cancer, recommend that patients with active cancer and CAT continue indefinite anticoagulation for secondary prophylaxis.¹  This conditional recommendation is supported by data that suggest long-term anticoagulation may decrease recurrent VTE, pulmonary embolism, and deep vein thrombosis. There is a lack of data in patients with malignancy, however, and this recommendation is made partially based on data derived from the general population. Thus, the duration of anticoagulation and the safety and efficacy of dose-reduction remain key controversies.

Patients with CAT are at higher risk of recurrent VTE and bleeding than patients without cancer,²  and both risks are highest in the first month of treatment.^2,3  A recent systematic review of CAT studies demonstrated ongoing rates of recurrent VTE to be up to 12 percent, and rates of major bleeding to be up to 4.8 percent annually in patients with cancer on anticoagulation.⁴  Recent data in patients with non–malignancy-associated VTE have demonstrated the efficacy and safety of dose reduction for secondary prophylaxis after six months of full dose treatment with a DOAC. Doses of apixaban⁵  and rivaroxaban⁶  can be reduced without a significant increase in the risk of recurrent VTE and with similar bleeding risks.

To date, data regarding dose reduction in the CAT population have not been available. In this study, Dr. Trine-Lise Larsen and colleagues address the question of whether patients with CAT can receive a lower dose DOAC for secondary prophylaxis. This single-arm clinical trial enrolled 298 patients with newly diagnosed CAT who were then treated with full dose apixaban (5 mg orally twice daily [PO BID]) for six months. At six months, the 196 remaining patients were switched to low-dose apixaban (2.5 mg PO BID) for the remainder of the trial. Patients with platelets lower than 50×10⁹/L and a creatinine clearance less than 30 mL/min were excluded. The primary end points were recurrent VTE, major bleeding, and clinically relevant nonmajor bleeding. During the full dose treatment period, the incidence rate of recurrent VTE was 1.4 percent (95% CI, 0.5-3.6) in the first month, and 0.8 percent (95% CI, 0.4-1.6) per month from months 2 to 6, with a total 4 percent incidence rate in months 1 to 6 (95% CI, 2.1-6.9). Following dose reduction, the incidence rate of recurrent VTE was 1.0 percent (95% CI, 0.5-1.9) per person per month from months 7 to 12, and 7.1 percent overall (95% CI, 4.0-11.7) between months 7 to 36. An overall decline in the rate of recurrence to well below 1 percent per month was observed beyond 12 months.

By contrast, the incidence rate of major bleeding in the first six months was 5.4 percent (95% CI, 3.1-8.6). The highest incidence was observed in the first month at 1.7 percent (95% CI, 0.7-4.1) and thereafter at 1.1 percent (95% CI, 0.62-2.0) in months 2 to 6. After dose reduction, the cumulative incidence was 3.1 percent (95% CI, 1.1-6.5) from months 7 to 36. The incidence rates of bleeding remained below 0.32 percent (95% CI, 0.10-1.0) per month in months 7 to 36. The most common site of major bleeding was gastrointestinal (GI) and in patients with GI malignancy, the risk of bleeding was greater in unresected (6.7%; 95% CI, 1.9-16) versus resected (3.0%; 95% CI, 0.37-11) cancer.

This study included patients with a variety of primary cancers including resected and unresected GI malignancies, reflecting a typical patient population in a thrombosis practice. Death and study completion were the most common reasons for discontinuation as is expected in the CAT population. While there was no comparator arm, the low overall rate of recurrent VTE after dose reduction and the low overall bleeding rates in the period of extended anticoagulation beyond six months are reassuring.