Risk of major bleeding during extended oral anticoagulation in patients with first unprovoked venous thromboembolism: a systematic review and meta-analysis protocol

Background: The optimal duration of anticoagulation after a first unprovoked venous thromboembolism (VTE) remains controversial. Deciding to stop or continue anticoagulant therapy indefinitely after completing 3 to 6 months of initial treatment requires balancing the long-term risk of recurrent VTE if anticoagulation is stopped against the long-term risk of major bleeding if anticoagulation is continued. However, knowledge of the long-term risk for major bleeding events during extended anticoagulation in this patient population is limited. We plan to conduct a systematic review and meta-analysis to quantify the risk for major bleeding events during extended oral anticoagulation in patients with first unprovoked VTE. Methods: Electronic databases including MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials will be systematically searched with the assistance of an information specialist (from inception to March 1, 2019) to identify randomized controlled trials and prospective cohort studies reporting major bleeding during extended oral anticoagulation in patients with first unprovoked VTE, who have completed at least 3 months of initial anticoagulant therapy. Study selection, risk of bias assessment, and data extraction will be performed independently by at least two investigators. The number of major bleeding events and person-years of follow-up will be used to calculate the rate (events per 100 person-years) with its 95% confidence interval for each study cohort, during clinically relevant time periods of extended anticoagulant therapy. Results will be pooled using random effect meta-analysis. Discussion: The planned systematic review and meta-analysis will provide reliable estimates of the risk for major bleeding events during extended anticoagulation. This information will help inform patient prognosis and assist clinicians with balancing the risks and benefits of treatment to guide management of unprovoked VTE.