The risk for anticoagulant-related major bleeding is considerable in patients receiving extended oral anticoagulant treatment for a first, unprovoked venous thromboembolism (VTE), and is significantly higher in those treated with vitamin K antagonists (VKAs) compared with direct oral anticoagulants (DOACs), according to results from a systematic review and meta-analysis published in the Annals of Internal Medicine. Major bleeding risks are also higher in older patients, those receiving antiplatelet therapy, as well as in those with kidney disease, a history of bleeding, or anemia.
Researchers hope that these results will guide clinicians in considering the estimated bleeding risks to inform their decisions about extended anticoagulation in these patients.
“Venous thromboembolism should be treated with anticoagulant therapy for at least 3 to 6 months; during this period, the risk for a potentially fatal recurrent VTE if treatment is discontinued clearly exceeds the risk for a potentially fatal major bleeding event associated with anticoagulation. Deciding whether to continue anticoagulant therapy beyond the initial 3 to 6 months (termed extended anticoagulation) requires estimating the net balance between absolute treatment benefits and harms through careful consideration of the long-term risks and case-fatality rates of both recurrent VTE if anticoagulation is discontinued and major bleeding if anticoagulation is continued,” wrote Marc A. Rodger, MD, of McGill University, Montreal, Quebec, Canada, and his MAJESTIC co-authors.
“This framework for decision making about treatment duration is most relevant to patients with a first unprovoked or weakly provoked VTE, for whom indefinite anticoagulation is often suggested, but the net clinical benefit of extended anticoagulation is uncertain,” they added.
For this review, Rodger and fellow researchers from the major bleeding risk during extended anticoagulation (MAJESTIC) collaboration, searched MEDLINE, Embase, and the Cochrane Register for randomized controlled trials and prospective studies that assessed major bleeding in patients during their initial, unprovoked VTE who were treated with oral anticoagulation for a minimum of 6 additional months after the first 3 months of initial therapy.
They identified 14 randomized controlled trials and 13 cohort studies, including a total of 9,982 patients who were treated with a VKA and 7,220 who were given DOAC. A first major bleeding event was the primary outcome, and intracranial and fatal bleeding were the secondary outcomes.
The 5-year cumulative incidence of major bleeding with VKA treatment was 1.74 events per 100 person-years (95% CI: 1:34-2.20 events), and with DOACs, 1.12 events per 100 person-years (95% CI: 0.72-1.62 events). The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (95% CI: 3.6%-10.0%). Researchers had insufficient data to estimate the incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs.
In patients treated with VKAs, the pooled case-fatality rate of major bleeding was 8.3% (95% CI: 5.1%-12.2%), and 9.7% in those treated with DOACs (95% CI: 3.2%-19.2%).
Upon subgroup analysis, Rodger et al found that among VKA recipients, the incidence of major bleeding was statistically significantly higher in women compared with men (incidence rate ratio [IRR]: 1.55; 95% CI: 1.17-2.06). Five-year cumulative incidences of major bleeding in patients treated with VKAs was 8.5% in women, compared with 6.5% in men. Among DOAC recipients, researchers found no differences according to sex (IRR: 1.00; 95% CI: 0.51-1.95).
The incidence of major bleeding was significantly higher in patients who were >65 years old, those with creatinine clearance ˂50 mL/min, a history of bleeding, concomitant antiplatelet therapy, and hemoglobin levels ˂100 g/L in both VKA and DOAC recipients.
Researchers found no significant differences in the incidence of major bleeding when comparing patient with initial isolated proximal DVT and those with isolated pulmonary embolism (PE), patients with initial isolated proximal DVT with concomitant PE and DVT, and patients with isolated PE with concomitant PE and DVT.
“Taken together, our results provide clinicians, patients, and policymakers with a management framework in which to consider the long-term risks for and consequences of major bleeding if anticoagulation is continued beyond the initial 3 to 6 months. When weighed against the long-term risks for and consequences of recurrent VTE if anticoagulation is discontinued, our results could be used to balance the benefits and harms of extended anticoagulation for unprovoked VTE,” wrote Khan and colleagues.
As an example, they cited the example of a patient with a first unprovoked VTE, who may not be a candidate for extended VKA anticoagulation. The patient completed at least 3 months of initial anticoagulative therapy and is either receiving concomitant antiplatelet therapy or has a history of bleeding. In this patient, anticoagulation discontinuation brings a 5-year risk for death from recurrent VTE of 1.0%, which increases to over 1.2% if anticoagulation is continued.
In this patient, “Over a 10-year horizon, the risk for death from recurrent VTE if anticoagulation is discontinued would be about 1.4% (36% risk for recurrent VTE at 10 years multiplied by 4% case-fatality rate of recurrent VTE) and the risk for death from major bleeding if anticoagulation is continued would be greater than 2.4% (>30% risk at 10 years multiplied by 8% case-fatality rate of major bleeding),” they calculated.
A summary for patients was also published alongside the meta-analysis.
“Given the need for precise estimates of the absolute long-term risk and case-fatality rate of major bleeding during extended anticoagulant therapy to guide decisions about treatment duration in unprovoked VTE, our findings are likely to affect clinical practice,” concluded Rodger et al.
Limitations of the study include limited data to compare bleeding risks in reduced- and therapeutic-dose DOACs and limited data beyond 1 year of DOAC extended anticoagulation., that most DOAC cohorts underwent anticoagulation with rivaroxaban, which limits the generalizability of results to all DOACs, underestimation of between-study variances due to the random-effects model used, and lack of an individual-patient data meta-analysis.
Major bleeding risk is higher with vitamin K antagonists (VKAs) compared with direct oral anticoagulants (DOACs) in patients receiving extended oral anticoagulant treatment for a first, unprovoked venous thromboembolism (VTE).
Major bleeding risks are also higher in older patients, those receiving antiplatelet therapy; and in those with kidney disease, a history of bleeding, or anemia.
Liz Meszaros, Deputy Managing Editor, BreakingMED™
This study was funded by the Canadian Institute of Health Research.
Rodger is a member of the CanVECTOR Network, which receives grant funding from the Canadian Institutes of Health Research, is the McGill University Harry Webster Thorp Professor of Medicine, and reported no other disclosures.
Cat ID: 309
Topic ID: 74,309,730,309,745,914,118,192,925