Long-Term Risk for Major Bleeding During Extended Oral Anticoagulant Therapy for First Unprovoked Venous Thromboembolism: A Systematic Review and Meta-Analysis

Research output: Contribution to journalArticle (Academic Journal)peer-review

91 Citations (Scopus)

Abstract

Background:

The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain.

Purpose:

To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups.

Data Sources:

MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021.

Study Selection:

Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment.

Data Extraction:

Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies.

Data Synthesis:

Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs.

Limitation:

Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs.

Conclusion:

In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE.

Primary Funding Source:

Canadian Institutes of Health Research. (PROSPERO: CRD42019128597)

Original languageEnglish
Pages (from-to)1420-1429
Number of pages10
JournalAnnals of Internal Medicine
Volume174
Issue number10
Early online date14 Sept 2021
DOIs
Publication statusPublished - Oct 2021

Bibliographical note

Funding Information:
Financial Support: Mr. Khan and Drs. Tritschler, Kimpton, Wells, Kearon, Weitz, Parpia, Thavorn, Le Gal, Fergusson, and Rodger are members of the CanVECTOR Network; the Network receives grant funding from the Canadian Institutes of Health Research (CDT-142654). Mr. Khan holds the Frederick Banting and Charles Best doctoral research scholarship from the Canadian Institutes of Health Research. Dr. Weitz holds the Canada Research Chair (Tier I) in Thrombosis and the Heart and Stroke Foundation of Canada J.F. Mustard Chair in Cardiovascular Research. Dr. Tritschler held an Early Postdoc.Mobility Award from the Swiss National Science Foundation (SNSF P2ZHP3_177999) and a Fellowship Award from the CanVECTOR Network. Dr. Le Gal holds the Chair on Diagnosis of Venous Thromboembolism at the Department of Medicine, University of Ottawa, and a Clinician-Scientist Award from the Heart and Stroke Foundation of Canada. Dr. Rodger is the McGill University Harry Webster Thorp Professor of Medicine.

Publisher Copyright:
© 2021 American College of Physicians. All rights reserved.

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