medwireNews: Reduced doses of direct oral anticoagulants (DOACs) did not meet noninferiority criteria compared with full doses in patients at high risk for recurrent venous thromboembolism (VTE) in the RENOVE trial.
However, low VTE rates overall and improved safety with reduced doses means they could still be considered as a treatment option, say the researchers in The Lancet.
The 5-year cumulative incidence of symptomatic recurrent VTE, defined as fatal or nonfatal pulmonary embolism or proximal deep vein thrombosis, was 2.2% among participants given reduced-dose apixaban 2.5 mg twice daily or rivaroxaban 10 mg/day for a median of 36 months.
This compared with an incidence of 1.8% among patients given full doses of the DOACs, namely apixaban 5 mg twice daily and rivaroxaban 20 mg/day, for the same duration.
The hazard ratio (HR) for the primary outcome in the reduced versus the full-dose group, after taking into account confounding factors, such as age, BMI, and sex, was 1.32, with an upper confidence interval of 2.60, which exceeded the predefined noninferiority margin of 1.70.
However, the VTE rates over the median 37.1 months of follow-up were low in both groups, note the study authors, occurring in 19 of 1383 patients given reduced-dose DOACs and 15 of 1385 of those given full-dose DOACs. Moreover, the 5-year cumulative incidences of major or clinically relevant nonmajor bleeding – a secondary endpoint – were lower for patients given reduced-dose apixaban or rivaroxaban than those given full doses of the DOACS, at 9.9% versus 15.2% and an HR of 0.61. Two fatal bleeding events occurred in the reduced-dose group and three in the full-dose group.
“Our findings show an unexpectedly low risk of recurrent venous thromboembolism in both groups and a 39% reduction in risk of major and clinically relevant non-major bleeding in the reduced-dose group, resulting in a 33% reduction in net adverse clinical events,” say investigators Francis Couturaud, from Centre Hospitalier Universitaire Brest in France, and colleagues.
The study participants had a strong indication for extended anticoagulation, primarily due to having a first unprovoked or recurrent VTE, and had received 6–24 months of full-dose anticoagulant drugs. They had a mean age of around 62 years and 65% were men.
Given the findings, the team recommends further research “to clarify whether the substantial reduction of clinically relevant bleeding events obtained with the reduced dose could support this regimen as an option in patients who need extended coagulation.”
They add that it will also be necessary “to identify subgroups for whom the anticoagulation dose should not be reduced.”
In a linked comment on the study, Saskia Middeldorp and Jenneke Leentjens, both from Radboud University Medical Center in Nijmegen, the Netherlands, highlight the “reassuringly low” recurrent VTE rates, adding that the “potential inferiority of the reduced dose lacks clinical relevance in the context of these low absolute risks.”
They continue: “[W]e are interested in the benefits in terms of safety and net clinical benefit.”
The commentators say this was shown in the RENOVE trial by a decreased risk for bleeding among patients taking reduced-dose DOACs, making them possibly the “safest option in the long term” for patients with VTE needing extended anticoagulation.
They add, however, that more research is needed on their use for certain subgroups of patients, such as those with obesity or cancer.
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