DOACs versus LMWH for the treatment of cancer-associated thrombosis

Direct Oral Anticoagulants Compared With Dalteparin for Treatment of Cancer-Associated Thrombosis: A Living, Interactive Systematic Review and Network Meta-analysis

Literature - Riaz I, Fuentes HE, Arsalan Ahmed Naqviet S et al. - Mayo Clin Proc. 2022 Feb;97(2):308-324. doi: 10.1016/j.mayocp.2020.10.041.

Introduction and methods

Background and aim of the study

The authors developed a novel, living, interactive systematic review and network meta-analysis which includes randomized controlled trials (RCTs) evaluating the efficacy and safety of direct oral anticoagulants (DOACs) compared with low-molecular-weight heparin (LMWH) in patients with cancer-associated thrombosis (CAT). The current article includes four RCTs, but results will be constantly be updated as results from new RCTs become available.


The current analysis included data from four RCTs (n=2894): Hokusai VTE (edoxaban vs. dalteparin) [1], SELECT-D (rivaroxaban vs. dalteparin) [2], ADAM VTE (apixaban vs. dalteparin) [3] and Caravaggio (apixaban vs. dalteparin) [4]. Caravaggio and Hokusai VTE included both patients with active cancer and a history of cancer, while SELECT-D and ADAM VTE only included patients with active cancer. The treatment duration in the Hokusai VTE trial was 6 to 12 months. In the other trials, the treatment duration was 6 months.

The efficacy and safety of DOACs compared with dalteparin were analyzed in a pairwise meta-analysis. A network meta-analysis was used to evaluate the comparative effectiveness and safety of different DOACs.


The primary efficacy outcome was recurrent VTE. Major safety outcomes included major bleeding and clinically relevant nonmajor bleeding. Other outcomes included net clinical benefit (composite of VTE and major bleeding), fatal bleeding and all-cause mortality.

Main results

DOACs versus dalteparin

  • DOACs significantly decreased recurrent VTE events compared with dalteparin (OR 0.59, 95% CI 0.41-0.86, I² 25%).
  • There was no significant difference between DOACs and dalteparin for major bleeding (OR 1.34, 95% CI 0.83-2.18, I² 28%). However, DOACs significantly increased clinically relevant nonmajor bleeding events compared with dalteparin (OR 1.69, 95% CI 1.13-2.24, I² 41%).

Mixed treatment comparisons

  • Apixaban and rivaroxaban significantly decreased recurrent VTE events compared with dalteparin (OR 0.58, 95% CrI 0.37-0.90, and OR 0.41, 95% CrI 0.16-0.95, respectively). No statistically significant differences were observed between different DOACs with regard to reducing recurrent VTE events.
  • Compared with dalteparin, edoxaban significantly increased major bleeding (OR 1.73, 95% CrI 1.04-3.16). However, there was no significant difference between edoxaban, apixaban and rivaroxaban with regard to major bleeding.
  • Rivaroxaban significantly increased clinically relevant nonmajor bleeding compared with dalteparin, apixaban and edoxaban (OR 4.09, 95% CrI 1.79-10.59; OR 2.73, 95% CrI 1.08-7.71; and OR 2.99, 95% CrI 1.21-8.26, respectively).
  • Apixaban significantly decreased the composite outcome of recurrent VTE events and major bleeding events compared with dalteparin (OR 0.66, 95% CrI 0.46-0.95). There was no significant difference between apixaban, edoxaban and rivaroxaban for this outcome.
  • There were no significant differences between DOACs and dalteparin or between DOACs with regard to mortality.


DOACs decreased recurrent VTE events compared with dalteparin in patients with CAT. There was no difference between DOACs and dalteparin with regard to major bleedings. DOACs were associated with increased rates of clinically relevant nonmajor bleeding compared to dalteparin.

The authors wrote “The choice of DOACs is not an easy decision in the absence of direct clinical trial evidence. Both apixaban and rivaroxaban significantly reduce the risk of VTE recurrence compared with dalteparin. Both rivaroxaban and edoxaban appear to increase bleeding outcomes, which was not seen with apixaban.”


1. Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018;378(7):615-624.

2. Young AM, Marshall A, Thirlwall J, et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018;36(20):2017-2023.

3. McBane RD II, Wysokinski WE, Le-Rademacher JG, et al. Apixaban and dalteparin in active malignancy-associated venous thromboembolism: the ADAM VTE trial. J Thromb Haemost. 2020;18(2):411-421.

4. Agnelli G, Becattini C, Meyer G, et al. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med. 2020;382(17):1599-1607.

Find this article online at Mayo Clin Proc. The living interactive results can be found here

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