Extended anticoagulation for the secondary prevention of venous thromboembolic events: An updated network meta-analysis

Abstract

Background: Extended treatment is preconized in a significant proportion of patients with unprovoked venous thromboembolism (VTE). However, limited direct/indirect comparisons are available to appropriately weight the benefit/risk ratio of the diverse treatments available. We aimed to compare the rate of symptomatic recurrent VTE and major bleeding (MB), the net clinical benefit (VTE+MB) and death on vitamin-K antagonist (VKA), direct oral anticoagulants (DOAC) and antiplatelet drugs for extended anticoagulation.

Methods: A systematic literature search through September 2018 identified randomized trials studying these pharmacologic therapies for extended anticoagulation following VTE. Treatment effects were calculated using network meta-analysis with frequentist fixed-effects model.

Results: 18 trials (18,221 patients) were included in the analysis. All treatments reduced the risk of recurrence compared to placebo/observation. Nonetheless, VKA (RR 0.22; 95%CI 0.13-0.39) and DOAC (RRs ranging from 0.25-0.32; 95%CI ranging from 0.13-0.52) were more effective than aspirin, whereas low-dose VKA was less effective than standard-dose VKA (RR 2.47; 95%CI 1.34-4.55). The efficacy of DOAC was globally comparable to standard-adjusted dose VKA. Low- (RR 3.13; 95%CI 1.37-7.16) and standard-dose (RR 3.23; 95%CI 1.16-8.99) VKA also increased the risk of MB, which was not the case for any DOAC. Low-dose VKA and low-dose DOAC had similar effects on MB compared to standard-doses. Although there was a trend for reduced MB and enhanced net clinical benefit for DOAC compared to VKA, this was not statistically significant. The specific anticoagulant therapies had no significant effects on deaths.

Conclusion: Standard-dose VKA and low/standard-dose DOAC share similar effects on VTE recurrence and MB, whereas aspirin and low-dose VKA were associated with lower benefit/risk ratio.

Fig 1. Study flow chart.

Fig 2. Evidence network of included studies.

The width of lines for each connection in the evidence network are proportional to the number of randomized controlled trials (RCTs) comparing each pair of treatments. Multiarm trials are represented in dotted lines. The size of each treatment node is proportional to the number of randomized participants (sample size). Direct oral anticoagulants for the main analysis included apixaban, dabigatran and rivaroxaban, whereas unmarketed drugs (shaded in gray) (idraparinux, sulodexide and ximelagatran) were used for sensitivity analyses only (see online supplement). ASA: aspirin; RCT: randomized controlled trial; VKA: vitamin K antagonist.

Fig 3

Relative risks (95% confidence interval) for (A) recurrent venous thromboembolic events and (B) major bleeding in network meta-analysis versus observation or placebo. ASA: aspirin; INR: international normalized ratio; VKA: vitamin k antagonist.

Fig 4

Relative risks (95% confidence interval) for net clinical benefit (A) and death related to fatal recurrent venous thromboembolism and major bleeding (B) in network meta-analysis versus observation or placebo. ASA: aspirin; INR: international normalized ratio; VKA: vitamin k antagonist.