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Vasanthamohan L, Boonyawat K, Chai-Adisaksopha C, et al. Reduced-dose direct oral anticoagulants in the extended treatment of venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost. 2018 Jul;16(7):1288-1295. doi: 10.1111/jth.14156. Epub 2018 Jun 17.
Area Score
Hemostasis and Thrombosis
Family Medicine (FM)/General Practice (GP)
General Internal Medicine-Primary Care(US)
Internal Medicine

Essentials In venous thromboembolism (VTE), benefits of extended treatment are balanced by bleeding risks. This is a meta-analysis of reduced-dose direct oral anticoagulants (DOACs) in extended treatment. Reduced-dose DOACs are as effective as full anticoagulation with bleeding risks similar to placebo. Reduced-dose DOACs are an attractive option for patients in the extended phase of VTE treatment.

SUMMARY: Background Extended-duration anticoagulation is beneficial for preventing recurrent venous thromboembolism (VTE). Reduced-dose direct oral anticoagulants (DOACs) may be preferable if they preserve efficacy and cause less bleeding. We conducted a systematic review and meta-analysis of trials comparing reduced-dose DOACs with full-dose DOACs and aspirin or placebo in the extended phase of VTE treatment. Methods A literature search was conducted by use of the MEDLINE, EMBASE and CINAHL databases, supplemented by hand-searching. One thousand three hundred and ninety-nine titles were screened, with data from accepted studies being extracted by two independent reviewers. Major outcomes analyzed included recurrent VTE and major and clinically relevant non-major bleeding events, presented as risk ratios (RRs) and 95% confidence intervals (CI). Results Two trials met the prespecified inclusion criteria. Data from 5847 patients were analyzed for efficacy outcomes, and from 5842 patients for safety outcomes. Reduced-dose DOACs were as effective as full-dose treatment in preventing recurrent VTE at 1 year (RR 1.12 [95% CI 0.67-1.87]), and more effective than aspirin or placebo (RR 0.26 [95% CI 0.14-0.46]). Rates of major or clinically relevant non-major bleeding events were similar between patients receiving reduced-dose DOACs and and those receiving aspirin or placebo (RR 1.19 [95% CI 0.81-1.77]). There was a trend towards less bleeding when reduced-dose and full-dose DOACs were compared (RR 0.74 [95% CI 0.52-1.05]). Conclusions Extended-duration treatment of VTE with reduced-dose DOACs may be as efficacious as full-dose treatment, with rates of major bleeding being similar to those in patients receiving treatment with aspirin or placebo, but further long-term studies are needed.

Comments from MORE raters

General Internal Medicine-Primary Care(US) rater

DOACs are rapidly supplanting VKAs for secondary prevention of VTE in clinical practice. DOACs provide superior protection against recurrent VTE with less bleeding, both during the initial 3-6 months but also when prophylaxis is extended because of increased risk (eg, unprovoked VTE, cancer, documented thrombophilia [Gomez-Outes, J Cardiovasc Pharmacol Ther 2015; Marik, PLoS One 2015]). This meta-analysis suggests that for extended prophylaxis against recurrent VTE, DOACs given in reduced doses can provide comparable protection against recurrent VTE with reduced risk for bleeding. Unfortunately, it is limited by analysis of only two RCTs of different DOACs. The sum total of studies to date clearly support the extended use of DOACs for secondary prevention of VTE, but additional large RCTs that include elderly and other high-risk patients and all DOACs are needed before we can conclude reduced doses of DOACs provide comparable protection with greater safety regarding bleeding.

Hemostasis and Thrombosis rater

Not an elaborate meta-analysis given that only 2 relevant trials have been completed. Important information, consistent across the 2 trials, and nicely summarized. Having the data compiled in a concise manner may help change practice.

Hemostasis and Thrombosis rater

This superbly done meta-analysis (granted, only 2 studies) strongly assists clinicians trying to decide what to do with their patients with unprovoked VTE who have completed 6 to 12 months of full anticoagulation. For those with low bleeding risk and equipoise for continuation vs cessation of therapy, there is an alternative: 1/2 dose apixaban or 1/2 dose rivaroxaban (for at least one more year). Either affords greater VTE protection than aspirin or placebo. Low-dose warfarin is known not to work.

Internal Medicine rater

Results not terribly different from the individual studies.