Ottawa, Ontario—Long-term risks and consequences of anticoagulant-related major bleeding in patients with a first unprovoked venous thromboembolism (VTE) appear to be greater than often assumed, according to a recent study.

The report in Annals of Internal Medicine points out that for every 1,000 patients who use vitamin K antagonists, such as warfarin, for a year, 17 are expected to have a major bleeding event; the statistic for patients using direct oral anticoagulants, such as rivaroxaban, is 11 events.

However, University of Ottawa and Ottawa Hospital Research Institute–led researchers emphasize that the risk is much higher for some patients, including those who are older than age 65 years, have kidney disease, have a history of bleeding, are using antiplatelet therapy, or have anemia. “The risk for death from major bleeding with continued anticoagulation after 10 years would be more than 2.4%,” they note.

The risk for recurrent VTE after discontinuing anticoagulation is 10% at 1 year and 36% at 10 years, according to the report, with 4% of those cases being recurrent VTE resulting in death, and a 1.4% overall risk for death at 10 years due to recurrent thromboembolism.

“Many studies, particularly for direct oral anticoagulants, followed patients for only one year, so estimates for longer-term use are assumed to be similar to those in the first year,” the authors write. “The overall number of studies was small for some of the estimates, which may be subject to change with more research.”

In response, the Canadian study team sought 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.

To do that, the researchers searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to July 23, 2021. Included were randomized, controlled trials (RCTs) and prospective cohort studies discussing major bleeding among patients with a first unprovoked VTE who were prescribed oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial treatment.

In the 14 RCTs and 13 cohort studies included in the analysis, 9,982 patients received a vitamin K antagonist (VKA) and 7,220 received a direct oral anticoagulant (DOAC), according to the report.

Results indicate that the incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34-2.20 events) with VKAs and 1.12 events (CI, 0.72-1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6%-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 authors note. “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.”

The authors say that data were insufficient to estimate the incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs.

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

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