Treatment of venous thromboembolism in patients with cancer: A network meta-analysis comparing efficacy and safety of anticoagulants

Abstract

Introduction: Low-molecular-weight heparin (LMWH) and vitamin K antagonists (VKA) are current treatment options for cancer patients suffering from acute venous thromboembolism (VTE). The role of direct-acting oral anticoagulants (DOACs) for the treatment of VTE in cancer patients, particular in comparison with the current standard of care which is LMWH, remains unclear. In this network meta-analysis, we compared the relative efficacy and safety of LMWH, VKA, and DOAC for the treatment of cancer-associated VTE.

Methods: A pre-specified search protocol identified 10 randomized controlled trials including 3242 cancer patients. Relative risks (RR) of recurrent VTE (efficacy) and major bleeding (safety) were analyzed using a random-effects meta-regression model.

Results: LMWH emerged as significantly superior to VKA with respect to risk reduction of recurrent VTE (RR=0.60, 95%CI:0.45-0.79, p<0.001), and its safety was comparable to VKA (RR=1.08, 95%CI:0.70-1.66, p=0.74). For the DOAC vs. VKA efficacy and safety comparison, the relative risk estimates were in favor of DOAC, but had confidence intervals that still included equivalence (RR for recurrent VTE=0.65, 95%CI:0.38-1.09, p=0.10; RR for major bleeding=0.72, 95%CI:0.39-1.37, p=0.32). In the indirect network comparison between DOAC and LMWH, the results indicated comparable efficacy (RR=1.08, 95%CI:0.59-1.95, p=0.81), and a non-significant relative risk towards improved safety with DOAC (RR=0.67, 95%CI:0.31-1.46, p=0.31). The results prevailed after adjusting for different risk of recurrent VTE and major bleeding between LMWH vs. VKA and DOAC vs. VKA studies.

Conclusion: The efficacy and safety of LMWH and DOACs for the treatment of VTE in cancer patients may be comparable.

Funding: Austrian Science Fund (FWF-SFB-54).

Keywords: Cancer; Low-molecular-weight-heparin; Network meta analysis; Oral anticoagulants; Treatment; Venous thromboembolism.

Figure 1. Network plots of included studies on the treatment of cancer-associated VTE.

Nodes (blue dots) and edges (black connecting lines between nodes) are scaled according to the number of patients in the respective studies. Consequently, the larger the size of the respective trial(s), the larger the nodes and edges. (1A) Pooled network as analyzed in the network meta-analysis. As indicated by the size of the nodes and edges, most evidence exists for vitamin-K-antagonists (VKA), followed by low-molecular-weight heparin (LMWH) and non-vitamin-K-antagonist oral anticoagulants (DOAC). (1B) Full trial network showing individual LMWH and DOAC drugs. Again, the size of the nodes and edges is proportional to the size of the respective studies, and thus the amount of evidence for the drug within the trial network. Note: The length of the edges does not convey information, and differences in edge length is simply for better graphical presentation.

Figure 2. Forest plot of the relative risks (RR) for recurrent VTE – Pairwise random-effects meta-analysis.

(2A) RCTs comparing LMWH with VKA. (2B) RCTs comparing DOAC with VKA. Grey boxes surrounding relative risk estimates are proportional to the weight of the respective study. P-value of I² is from Q test.

Figure 3. Forest plot of the relative risks (RR) for major bleeding – Pairwise random-effects meta-analysis.

(3A) RCTs comparing LMWH with VKA. (3B) RCTs comparing DOAC with VKA. Grey boxes surrounding relative risk estimates are proportional to the weight of the respective study. P-value of I² is from Q test.

Figure 4. Forest plot of the relative risks (RR) with 95% Predictive Intervals – Network meta-analysis (NMA).

95% Confidence Intervals (95% CI) are black, 95% Predictive Intervals (95% PrI) are red. (4A) Estimates for recurrent VTE. (4B) Estimates for major bleeding.