Clinician Article

Clinical and safety outcomes associated with treatment of acute venous thromboembolism: a systematic review and meta-analysis.

  • Castellucci LA
  • Cameron C
  • Le Gal G
  • Rodger MA
  • Coyle D
  • Wells PS, et al.
JAMA. 2014 Sep 17;312(11):1122-35. doi: 10.1001/jama.2014.10538. (Review)
PMID: 25226478
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  • Internal Medicine
    Relevance - 7/7
    Newsworthiness - 7/7
  • FM/GP/Anesthesia
    Relevance - 6/7
    Newsworthiness - 7/7
  • Hematology
    Relevance - 5/7
    Newsworthiness - 6/7
  • Hemostasis and Thrombosis
    Relevance - 5/7
    Newsworthiness - 6/7
  • Family Medicine (FM)/General Practice (GP)
    Relevance - 5/7
    Newsworthiness - 3/7
  • General Internal Medicine-Primary Care(US)
    Relevance - 5/7
    Newsworthiness - 3/7


IMPORTANCE: Many anticoagulant strategies are available for the treatment of acute venous thromboembolism, yet little guidance exists regarding which drug is most effective and safe.

OBJECTIVE: To summarize and compare the efficacy and safety outcomes associated with 8 anticoagulation options (unfractionated heparin [UFH], low-molecular-weight heparin [LMWH], or fondaparinux in combination with vitamin K antagonists); LMWH with dabigatran or edoxaban; rivaroxaban; apixaban; and LMWH alone) for treatment of venous thromboembolism.

DATA SOURCES: A systematic literature search was conducted using MEDLINE, EMBASE, and the evidence-based medicine reviews from inception through February 28, 2014.

STUDY SELECTION: Eligible studies were randomized trials reporting rates of recurrent venous thromboembolism and major bleeding in patients with acute venous thromboembolism. Of the 1197 studies identified, 45 trials including 44,989 patients were included in the analyses.

DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted trial-level data including number of patients, duration of follow-up, and outcomes. The data were pooled using network meta-analysis.

MAIN OUTCOMES AND MEASURES: The primary clinical and safety outcomes were recurrent venous thromboembolism and major bleeding, respectively.

RESULTS: Compared with the LMWH-vitamin K antagonist combination, a treatment strategy using the UFH-vitamin K antagonist combination was associated with an increased risk of recurrent venous thromboembolism (hazard ratio [HR], 1.42; 95% credible interval [CrI], 1.15-1.79). The proportion of patients experiencing recurrent venous thromboembolism during 3 months of treatment were 1.84% (95% CrI, 1.33%-2.51%) for the UFH-vitamin K antagonist combination and 1.30% (95% CrI, 1.02%-1.62%) for the LMWH-vitamin K antagonist combination. Rivaroxaban (HR, 0.55; 95% CrI, 0.35-0.89) and apixaban (HR, 0.31; 95% CrI, 0.15-0.62) were associated with a lower risk of bleeding than was the LMWH-vitamin K antagonist combination, with a lower proportion of patients experiencing a major bleeding event during 3 months of anticoagulation: 0.49% (95% CrI, 0.29%-0.85%) for rivaroxaban, 0.28% (95% CrI, 0.14%-0.50%) for apixaban, and 0.89% (95% CrI, 0.66%-1.16%) for the LMWH-vitamin K antagonist combination.

CONCLUSIONS AND RELEVANCE: Using meta-analytic pooling, there were no statistically significant differences for efficacy and safety associated with most treatment strategies used to treat acute venous thromboembolism compared with the LMWH-vitamin K antagonist combination. However, findings suggest that the UFH-vitamin K antagonist combination is associated with the least effective strategy and that rivaroxaban and apixaban may be associated with the lowest risk for bleeding.

Clinical Comments


This article is very helpful especially for treatment following surgery for joint replacements; although, enough may not be made of prevention in those surgeries.


As Apixaban has been recently approved for use in treatment of VTE and PE in the USA by the FDA and will likely soon be approved for the same in Canada soon, its lower bleed rate seems to make it first choice when selecting anticoagulants for patients not suitable for VKA.


This is an excellent summary of available management options for venous thromboembolism. It shows that the widespread regiment of unfractionated heparin followed by vitamin K anatagonists is probably the least effective option. This is particularly reassuring because it obviates the need for hospital admission since all other regimens allow for ambulatory management of patients with venous thromboembolism in the absence of other indications for hospitalization.

Internal Medicine

Well written, easy-to-read and insightful commentary. The general medical community could benefit highly from having this article presented to them.

Internal Medicine

As a physician from a developing country, I find it important to know that UFH combination with Vit K antagonists is not as good as that with LMWH, the former one being commonly used due to cost constraints.

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