Use of Direct Oral Anticoagulant Agents in Active Cancer: Meta-Analysis

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In a systematic review and meta-analysis reported in JACC: CardioOncology, Fujisaki et al found no significant differences among direct oral anticoagulant agents (DOACs) in the prevention of recurrent venous thromboembolism (VTE) associated with active cancer, whereas significant differences in bleeding risk were observed. 

Study Details

The study involved 17 randomized trials reported through November 2022 that included 6,623 patients with active cancer. Outcomes included recurrent VTE, recurrent pulmonary embolism, recurrent deep venous thrombosis, major bleeding, clinically relevant nonmajor bleeding, and a composite outcome of major bleeding or clinically relevant nonmajor bleeding.

Key Findings

No significant differences were found among the DOACs for the efficacy outcomes of recurrent VTE, pulmonary embolism, or deep venous thrombosis. However, differences among DOACs in bleeding risk were observed.

Apixaban was associated with a similar risk of major bleeding compared with dabigatran and rivaroxaban, but a decreased risk compared with edoxaban (hazard ratio [HR] = 0.38, 95% confidence interval [CI] = 0.15–0.93). Edoxaban was associated with a similar risk of clinically relevant nonmajor bleeding compared with apixaban, but a decreased risk compared with rivaroxaban (HR = 0.31, 95% CI = 0.10–0.91).

Differences between parenteral anticoagulation and DOACs included:

  • Reduced risk of recurrent VTE (HR = 0.60, 95% CI = 0.38–0.93), with no increase in bleeding with apixaban
  • Increased risk of major bleeding or clinically relevant nonmajor bleeding with edoxaban (HR = 1.35, 95% CI = 1.02–1.79)
  • Increased risk of clinically relevant nonmajor bleeding with rivaroxaban (HR = 3.76, 95% CI = 1.43–9.88).

The investigators concluded, “DOACs demonstrate comparable efficacy but exhibit different safety profiles. Apixaban may confer an antithrombotic benefit without an increased risk for bleeding, distinguishing it from other contemporary anticoagulation strategies in patients with active cancer and VTE.”

Editorial Comment

In an editorial comment accompanying the study by Fujisaki et al, Wang and Connors note: “Clinicians have long desired the ‘best’ anticoagulant that is effective in preventing VTE with low risk of bleeding, especially in vulnerable populations such as those with cancer who are known to have high risks of both recurrent VTE and bleeding events…. Therefore, the investigators’ efforts to address this question are appreciated. However, the results should be interpreted with caution as they are not direct head-to-head comparisons among different DOACs in the same cohort, and hence the evidence remains indirect.”

“[S]tudies such as the one by Fujisaki et al … could provide insights to guide clinicians in the anticoagulant management of cancer-associated thrombosis…. [T]he ‘one size fits all’ approach may not be appropriate, as the best anticoagulant for each individual patient may differ based on his or her unique medical and social considerations. Shared decision-making with patients for individualized treatment plans is needed. The road in search of the optimal anticoagulant for cancer-associated thrombosis continues—we have much to learn from current trials in progress in the near future.”

Eiichiro Yamamoto, MD, PhD, of the Department of Cardiovascular Medicine, Kumamoto University, Kumamoto, Japan, is the corresponding author for the JACC: CardioOncology article. Jean M. Connors, MD, of Brigham and Women’s Hospital, is the corresponding author for the JACC: CardioOncology editorial comment.

Disclosure: The study was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. For full disclosures of the study authors, visit

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