Full Length ArticleTreatment of venous thromboembolism in patients with cancer: A network meta-analysis comparing efficacy and safety of anticoagulants
Graphical Abstract
Introduction
Venous thromboembolism (VTE) is a frequent complication and leading cause of death in patients with cancer [1]. The clinical course of cancer-associated VTE differs from VTE in non-cancer patients, most importantly because the risk of VTE recurrence and bleeding during anticoagulant therapy is substantially higher than in non-cancer patients [2]. Malignancy-associated morbidity and concurrent antineoplastic therapy further complicate the clinical management of VTE in patients with cancer [3].
The question on the optimal anticoagulation therapy for cancer patients with VTE is an ongoing area of research and debate [4], [5]. Current guidelines of the major societies in the field agree in recommending a 3–6 months course of daily therapeutic doses of low molecular weight heparin (LMWH) as the first-line treatment for cancer-associated VTE [3], [6], [7], [8], [9]. For patients, the administration of LMWH therapy via daily subcutaneous injections over a course of several months is associated with considerable burden. Guidelines further recommend vitamin K antagonists (VKA) in a target International normalized ratio (INR) range of 2.0 to 3.0 as an alternative therapy given LMWH is unavailable or not possible [3]. Here, the necessity for frequent INR monitoring and the potential interactions of VKA with patient diet and anti-cancer drugs are important limitations [8], [10].
Recently, direct-acting oral anticoagulants (DOACs) that directly inhibit either factor Xa (apixaban, edoxaban, and rivaroxaban) or thrombin (dabigatran) have been introduced as novel agents for treatment of VTE [11], [12], [13], [14]. Importantly, these drugs can be administered orally in a fixed dose without the need for laboratory monitoring, and appear to have less potential drug and dietary interactions than VKA [15]. In randomized controlled trials comparing standard VTE therapy (initial LMWH followed by long-term VKA) to DOACs, all DOACs were non-inferior with respect to efficacy (i.e. prevention of VTE recurrence), and tended to be associated with a smaller risk of bleeding [4]. While these studies included only a small proportion of cancer patients, several subgroup analyses and four recent meta-analyses in the cancer subpopulation suggest that the efficacy and safety patterns of DOACs in cancer patients may be comparable to the patterns observed in non-cancer patients [4], [16], [17], [18]. However, as head-to-head studies comparing DOACs with the currently recommended standard therapy for cancer-associated VTE, LMWH, have not been performed, the role of DOACs for the treatment of VTE in patients with cancer remains incompletely understood [3], [4], [19].
In the absence of real-world head-to-head studies, network meta-analyses (NMA) can provide indirect estimates of comparative effectiveness, and thus identify important trends in the data relevant for guideline makers, clinical practice, and the design of future trials [20]. In this study, we report a network meta-analysis on the efficacy and safety of DOACs, LMWH, and VKA for the treatment of VTE in patients with cancer. By performing an indirect comparison between DOACs and LMWH, we aim to explore DOACs in relation to the current standard therapy for cancer-associated VTE in terms of recurrent VTE and major bleeding.
Section snippets
Definition of Study Question
To compare the relative efficacy and safety of VKA, DOAC, and LMWH for the long-term treatment of VTE in patients with cancer.
Definition of Study Population, Interventions, and Study Designs
Adult cancer patients with any type of solid or hematologic malignancy suffering from an objectively-confirmed acute episode of VTE (i.e. deep vein thrombosis [DVT] and/or pulmonary embolism [PE]) represent the study population of this analysis. Eligible interventions were pharmacological agents from the groups of VKAs, DOACs, and LMWHs. These interventions had to be
The Evidence Base
Three-thousand-two-hundred-forty-two cancer patients from 10 two-arm RCTs were included in this analysis (Table 1). Six studies compared VKA with LMWH (n = 2078 patients), and five studies compared VKA with DOAC (n = 1164 patients). Two network plots graphically represent the evidence base (Fig. 1A+B). Most evidence existed for VKA, followed by LMWH and DOAC.
Assessment of Bias and Design Differences in Selected Studies
The risk of bias in the selected studies was assessed using Cochrane criteria (Supplemental Table 2). While all 10 studies only included
Discussion
In this network meta-analysis we provided estimates of the relative efficacy and safety of DOACs, LMWH and VKA for the treatment of VTE in patients with cancer. Further, we updated a previous pair-wise meta-analysis comparing DOAC/LMWH and LMWH/VKA [4], and identified issues relevant for the design of future real-world comparisons between DOAC and LMWH.
In terms of efficacy, LMWH emerged as significantly superior to VKA in both the pairwise and network meta-analysis, and its safety was
Conclusion
In this network meta-analysis on the optimal treatment of VTE in cancer patients, LMWH and DOAC appeared to be comparable with respect to prevention of recurrent VTE and the risk of major bleeding. This finding prevailed after adjusting for potential heterogeneity between DOAC and LMWH trials. A future head-to-head comparison between LMWH and DOAC for the treatment of cancer-associated VTE is warranted, and may be best performed using a non-inferiority design.
Author Contributions
Conceived and designed the study: FP CA. Performed statistical analyses: FP. Conducted literature search and study selection: FP OK IP CA. Interpreted the results: FP OK CZ IP CA. Wrote the first draft of the manuscript: FP CA. Contributed to the writing of the manuscript: FP OK CZ IP CA. Agree with the manuscript’s results and conclusions: FP OK CZ IP CA. ICMJE criteria for authorship read and met: FP OK CZ IP CA.
Acknowledgements, Funding, and Conflicts of Interest
This work was partly supported by an MD PhD studentship of the Austrian Science Fund (FWF-SFB-54 „Cellular Mediators linking Inflammation and Thrombosis – InThro“). Dr. Pabinger received honoraria for advisory board meetings and lectures from Bayer, Pfizer and Boehringer-Ingelheim. Dr. Ay received honoraria for lectures from Sanofi, Pfizer, Boehringer-Ingelheim, Bayer and Daiichi-Sankyo. The other authors have no conflicting interests to declare. The entities listed above had no role in the
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