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Commentary on: Kahale LA, Hakoum MB, Tsolakian IG, et al. Anticoagulation for the long-term treatment of venous thromboembolism in people with cancer. Cochrane Database Syst Rev. 2018;6:CD006650.
Context
Venous thromboembolism (VTE) complicates the course of 5%–10% of patients with cancer and remains the second leading cause of death in patients with cancer after the malignancy itself.1 Until recently, the standard-of-care treatment for cancer-associated VTE has been low molecular weight heparin (LMWH) for extended periods based on the results of several randomised controlled trials (RCT) comparing LMWH with vitamin K antagonists (VKA). As an injectable, expensive agent, adherence may be poor by both patients and providers.1 The direct oral anticoagulants (DOAC) are a new oral treatment option that does not require regular anticoagulant monitoring, and therefore an attractive potential alternative to LMWH and VKAs. Published evidence for the efficacy and safety of DOACs in comparison with LMWH is currently limited to two RCTs. This systematic review examines the RCTs published comparing these three treatment modalities for cancer-associated VTE.2
Methods
This was a systematic review of RCTs comparing efficacy and safety of ‘long-term’ treatment options for cancer-associated VTE (beyond the first 5–10 days of treatment). The central outcomes analysed included all-cause mortality, recurrent VTE, major bleeding and minor bleeding. Studies were assessed for heterogeneity and risk of bias and clearly described data extraction (done in duplicate), search methodology and data analysis (results reported as relative risk (RR) with 95% CI). As a Cochrane review, the review adhered to standard protocol from the Cochrane Collaboration.
Findings
Sixteen RCTs met eligibility criteria, which included a total of 5167 patients with cancer with VTE. Eight studies compared LMWH with VKAs, finding a lower rate of recurrent VTE with LMWH compared with VKAs (RR=0.58, 95% CI 0.43 to 0.77) but comparable rates of mortality, major bleeding and minor bleeding. Five studies compared DOACs with VKAs, finding no significant difference in any outcome. Two studies compared DOACs with LMWH, though only one was included in the analysis; the included study demonstrated a likely reduction in recurrent VTE with DOAC treatment (RR=0.69, 95% CI 0.47 to 1.01) but with increased major bleeding (RR=1.71, 95% CI 1.01 to 2.88) and likely increased minor bleeding (RR 1.31, 95% CI 0.95 to 1.80).
Commentary
This ‘living systematic review’ (incorporating new evidence as it becomes available) was updated following the publication of the first RCT comparing a DOAC (edoxaban) with LMWH. While timely, it lacks the nuanced scrutiny of these trials necessary for proper analysis. For example, the analysed ‘cancer patient’ subsets from the pivotal trials comparing DOACs with VKAs that formed the basis for this part of the review were not representative of the patient population with cancer (some excluded patients with active cancer; others excluded patients with cancer in whom long-term treatment with LMWH was anticipated). Half of the analysed studies compared LMWH with VKAs, a settled comparison reflected by evidence-based guidelines recommending LMWH over VKAs. The most important component of the updated review was the comparison of DOACs with LMWH, but one of the two published RCTs (SELECT-D: Anticoagulation Therapy in SELECTeD Cancer Patients at Risk of Recurrence of Venous Thromboembolism) was excluded from the main analysis because it was only published in abstract form at the time of the review (it has since been published in full3). Therefore, the most noteworthy aspect of the updated analysis was limited to a single study. This review aside, each of the two studies comparing DOACs with LMWH demonstrate increased rates of major bleeding and suggest possible decreased rates of VTE recurrence in the DOAC arm. The increased bleeding appears to be predominantly gastrointestinal bleeding in patients with gastrointestinal malignancies (upper gastrointestinal malignancies in particular). These conclusions are clear from the two studies themselves and this review does not clarify or expand on them in any meaningful way.
Implications for practice
The optimal anticoagulant for each subset of the heterogeneous patient population with cancer remains unclear. Data show that DOACs have been used for cancer-associated VTE in clinical practice for several years now even prior to the published RCTs. The two available studies support this practice, with the caveat that DOACs may be inappropriate for patients with gastrointestinal malignancies. Several additional RCTs comparing DOACs with LMWH in patients with cancer are ongoing and will likely refine our understanding of their efficacy and safety, allowing for personalisation of anticoagulant therapy based on malignancy type, patient preference and economic considerations. An update of this systematic review at that time would be more impactful.
Footnotes
Contributors HAS wrote the manuscript and was solely responsible for concept and design, critical revision of the intellectual content and final approval.
Competing interests HAS: consultancy (Agios), outside of the topic of the submitted work.
Patient consent Not required.
Provenance and peer review Commissioned; internally peer reviewed.