Direct Oral Anticoagulant Versus Low Molecular Weight Heparin for the Treatment of Cancer-Associated Thromboembolism: 2021 Updated Meta-Analysis of Randomized Controlled Trials
Authors: Frere Corinne , Farge Dominique , Schrag Deborah , Prata Pedro H. , Connors Jean M. 
Published: November 2021

Abstract
Introduction: International clinical practice guidelines (ITAC, ASCO, NCCN and ASH) have progressively endorsed direct factor Xa inhibitors (edoxaban, rivaroxaban and apixaban) as an alternative to monotherapy with low-molecular-weight heparin (LMWH) for the treatment of venous thromboembolism (VTE) in cancer patients. The results from new randomized controlled trials (RCT) which assessed the efficacy and the safety of direct oral anticoagulants (DOAC) compared to LMWH for the treatment of cancer-associated thrombosis (CAT) were released during the past months. We therefore performed an updated meta-analysis of all publicly available data from RCT comparing DOAC with LMWH for the treatment of CAT.
Methods: Embase, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) and conference proceedings from all languages were searched up to August 2, 2021. Search strategy, study selection, data extraction and statistical analysis were performed in accordance with the Preferred Reporting Items for Meta-Analyses (PRISMA) guidelines. The primary efficacy outcome was recurrent VTE, and the primary safety outcome was major bleeding. Secondary outcomes included clinically relevant nonmajor bleeding (CRNMB), and all-cause mortality. Risk of bias was assessed by using the Cochrane risk-of-bias tool in randomized controlled trials version 2.0. Pooled relative risk (RR) and 95% confidence intervals (CIs) were estimated using the Mantel-Haenszel method of Der Simonian and Laird within a random-effect model. Heterogeneity of effect size across studies was assessed using the I 2 statistic. Publication bias was assessed by visual inspection of funnel plots. All the statistical analyses were performed with the RevMan 5.3 software.
Results: Six RCT comparing the efficacy and safety of DOAC versus LMWH, which enrolled a total of 3,690 cancer patients with acute VTE (1850 randomized to the DOAC arms and 1840 randomized to the LMWH arms), were included in the pooled analysis. Main study characteristics are summarized in Table 1. During a follow-up of 3 to 6 months under anticoagulant treatment, recurrent VTE occurred in 99 of 1,850 (5.3%) patients receiving DOACs versus 152 of 1,840 (8.3%) patients receiving LMWH. The risk of recurrent VTE was significantly lower with DOAC than with LMWH (RR 0.67, 95% CI 0.52-0.85, p = 0.001, I 2 = 0%, Figure 1A). Major bleeding occurred in 78 (4.2%) patients with CAT treated with DOAC versus 65 (3.5%) patients treated with LMWH. The risk of major bleeding was non significantly higher with DOAC (RR 1.20, 95% CI 0.85-1.70, p = 0.31, I 2= 7%, Figure 1B). CRNMB was more frequent in cancer patients receiving DOAC compared to those receiving LMWH (10.3% versus 6.3%, RR 1.63, 95% CI 1.25-2.11, p = 0.0003, I²= 6%, Figure 1C). The rates of all-cause mortality did not differ between the two groups (23.6% in the DOAC arms versus 23.3% in the LMWH arms, RR 1.02, 95% CI 0.89-1.16, p = 0.80, I² = 13%, Figure 1D).
Conclusions: In this August 2021 meta-analysis of 3,690 patients treated for CAT, DOAC significantly reduced the risk of recurrent VTE compared with LMWH, without increasing the risk of major bleeding. However, as previously highlighted, the use of DOAC was associated with an increased risk of CRNMB. Our results provide additional evidence for the use of DOAC as a safe and effective first-line option for the treatment of CAT in patients who are not at high risk of bleeding. These findings may increase the level of certainty for the evidence used in the national or international clinical practice guidelines supporting the use of DOAC in cancer patients with CAT.
Figure 1 Figure 1.

Disclosures
Connors: CSL Behring: Research Funding; Pfizer: Honoraria; Alnylam: Consultancy; takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Abbott: Consultancy.