Safety of switching from a Vitamin K antagonist to a non–Vitamin K antagonist oral anticoagulant in frail older patients with atrial fibrillation

FRAIL-AF trial investigators set out to study the question of whether frail, elderly patients with atrial fibrillation who were doing well with vitamin K antagonists (VKA) should be switched to direct-acting oral anticoagulants (DOAC).

Large DOAC vs warfarin trials included few elderly patients with frailty. Second, first author Linda Joosten, MD, in her presentation stressed that frailty is a lot more than aging. It is a clinical syndrome, which entails a “high burden of comorbidities, dependency on others, and a reduced ability to resist stressors.”

In the FRAIL-AF trial investigators (Senior author Geert-Jan Geersing, MD, PhD, from the University Medical Center Utrecht, Utrecht, the Netherlands) recruited elderly, frail patients with fibrillation who were treated with vitamin K antagonists and had stable international normalized ratios from outpatient clinics throughout the Netherlands. They screened about 2600 patients and enrolled nearly 1400. Most were excluded due to not being frail.

Half the group was randomized to switching to a DOAC — drug choice was left to the treating clinician (mostly apixaban and rivaroxaban) — and the other half was left on VKA. Patients were 83 years of age on average with a mean CHA2DS2-VASc score of 4. All four classes of DOAC were used in the switching arm. The primary endpoint was major or clinically relevant nonmajor bleeding, whichever came first, accounting for death as a competing risk. Follow-up was 1 year.

Results : “The results turned out to be different than we expected.” The authors designed the trial with the idea that switching to DOACs would be superior in safety to remaining on VKAs. But the trial was halted after an interim analysis found a rate of major bleeding in the switching arm of 15.3% vs 9.4% in the arm staying on VKA. The hazard ratio was 1.69 (95% CI, 1.23-2.32; P = .0012) The Kaplan-Meier event curves reveal that the excess risk of bleeding occurred after 100 days and increased with time. This argued against an early effect from transitioning the drugs. An analysis looking at specific DOAC drugs revealed similar hazards for the two most common ones used — apixaban and rivaroxaban.

See- “Safety of Switching From a Vitamin K Antagonist to a Non–Vitamin K Antagonist Oral Anticoagulant in Frail Older Patients With Atrial Fibrillation: Results of the FRAIL-AF Randomized Controlled Trial.”- Linda P.T. Joosten, Sander van Doorn, Peter M. van de Ven, et al., Originally published 27 Aug 2023 https://doi.org/10.1161/CIRCULATIONAHA.123.066485Circulation. 2024;149:279–289.