In a systematic review and network meta-analysis, DOACs demonstrated comparable efficacy but distinct safety profiles in patients with active cancer and thrombosis. Apixaban appeared to offer antithrombotic benefits with no increased bleeding risk.

This summary is based on the publication of Fujisaki T,Sueta D, Yamamoto E, et al. - Comparing Anticoagulation Strategies for Venous Thromboembolism Associated With Active Cancer: A Systematic Review and Meta-Analysis. JACC: CardioOncol. 2024 Jan 9 [Online ahead of print]. doi: 10.1016/j.jaccao.2023.10.009

Introduction and methods

Background

In patients with active cancer, cancer-associated thrombosis is the second leading cause of death [1]. The most recent ESC guidelines on cardio-oncology recommend the use of apixaban, edoxaban, rivaroxaban, and parenteral anticoagulation to treat patients with cancer-associated thrombosis [2]. However, whether the efficacy and safety for the treatment of venous thromboembolism (VTE) in patients with active cancer varies between these DOACs needs further investigation [3,4].

Aim of the study

The authors investigated the efficacy and safety of various anticoagulation strategies, with a particular focus on comparing DOACs, in patients with active cancer and VTE.

Methods

For this systematic review and network meta-analysis, the authors conducted literature searches in PubMed, Embase, and Cochrane Central. They identified 17 RCTs investigating anticoagulation strategies (VKAs, parenteral anticoagulation (e.g., low-molecular weight heparin and fondaparinux), and DOACs (dabigatran, apixaban, edoxaban, and rivaroxaban)) for the treatment and recurrence prevention of cancer-associated VTE in patients with active cancer. The network meta-analysis comprised a total of 6623 patients, with a mean weighted follow-up duration of 7.8 months (SD: 2.9).

Outcomes

The primary efficacy endpoint was recurrent VTE, defined as a composite outcome of objectively confirmed fatal and nonfatal pulmonary embolism or deep venous thrombosis (DVT). Secondary efficacy endpoints were recurrent pulmonary embolism only and recurrent DVT only. The primary safety endpoint was major bleeding, defined as a composite outcome of fatal bleeding, decrease in hemoglobin ≥2 g/dL, transfusion of ≥2 U packed red blood cells, or bleeding occurring at a critical site. Secondary safety endpoints were trial-defined clinically relevant nonmajor bleeding (CRNMB) and a composite outcome of major bleeding or CRNMB.

Main results

Efficacy

• Among the DOACs (16 studies), there was no significant difference in the occurrence of the primary efficacy endpoint of recurrent VTE. No significant heterogeneity (I²=0%; P=0.73) or inconsistency (P=0.35) was observed across the studies.
• When all 4 DOACs were grouped together in a sensitivity analysis, the all-DOAC group was associated with a decreased risk of VTE compared with parenteral anticoagulation (HR: 0.70; 95%CI: 0.54–0.89) and VKAs (HR: 0.45; 95%CI: 0.33–0.61).
• Based on P scores, apixaban ranked first for this endpoint, followed by edoxaban, rivaroxaban, and dabigatran, whereas parenteral anticoagulation and VKAs received lower rankings.
• For recurrent pulmonary embolism (9 studies), no significant differences were found among the 6 anticoagulation strategies (I²=0%; P=0.98; inconsistency not assessed due limited number of included studies).
• For recurrent DVT (8 studies), there were no significant differences between the DOACs (I²=0%; P=0.61; inconsistency not assessed).

Safety

• Apixaban was associated with a reduced risk of the primary safety endpoint of major bleeding compared with edoxaban (HR: 0.38; 95%CI: 0.15–0.93), but there was no significant difference between apixaban and dabigatran or rivaroxaban (comparison of 16 studies: I²=10.9%; P=0.33; inconsistency: P=0.36).
• According to P scores, apixaban ranked first for this endpoint, followed by dabigatran and rivaroxaban. Parenteral anticoagulation, VKAs, and edoxaban were ranked lower.
• Rivaroxaban was associated with an increased risk of CRNMB compared with edoxaban (HR: 3.24; 95%CI: 1.10–9.58) and parenteral anticoagulation (HR: 3.76; 95%CI: 1.43–9.88) (comparison of 5 studies: I²=37.1%; P=0.19; inconsistency: P=0.15).
• For the composite outcome of major bleeding or CRNMB, there were no significant differences between the DOACs (comparison of 9 studies: I²=0%; P=0.62; inconsistency; P=0.81).

Conclusion

This systematic review and network meta-analysis among patients with active cancer and VTE showed that although DOACs demonstrated comparable efficacy in the treatment and recurrence prevention of VTE, they exhibited distinct safety profiles in terms of bleeding outcomes. Apixaban appeared to offer an antithrombotic benefit with no increased bleeding risk.

The authors claim their “novel findings provide evidence for the potential preferential use of apixaban over edoxaban or rivaroxaban in patients with active cancer and VTE [although] these 3 agents are equally recommended for cancer-associated VTE in the recent guidelines.”

References

1. Puurunen MK, Gona PN, LarsonMG, Murabito JM, Magnani JW, O’Donnell CJ. Epidemiology of venous thromboembolism in the Framingham Heart Study. Thromb Res. 2016;145:27–33.

2. Lyon AR, López-Fernández T, Couch LS, et al. 2022 ESC guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (ICOS). Eur Heart J. 2022;43:4229–4361.\

3. Gervaso L, Dave H, Khorana AA. Venous and arterial thromboembolism in patients with cancer: JACC: CardioOncology state-of-the-art review. J Am Coll Cardiol CardioOnc. 2021;3:173–190.

4. Sabatino J, De Rosa S, Polimeni A, Sorrentino S, Indolfi C. Direct oral anticoagulants in patients with active cancer: a systematic review and meta-analysis. J Am Coll Cardiol CardioOnc. 2020;2:428–440.

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