Switching to NOACs in frail AF patients associated with more bleeding compared to VKAs

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Switching vitamin K antagonist (VKA) treatment to a non-vitamin K antagonist oral anticoagulant (NOAC) in frail elderly patients with atrial fibrillation (AF) is associated with more bleeding complications compared to continuing VKA treatment.

This is according to the findings of the FRAIL-AF trial, late-breaking research presented in a Hot Line session at the European Society of Cardiology (ESC) congress (25–28 August, Amsterdam, The Netherlands) by Linda Joosten (Utrecht University, Utrecht, The Netherlands).

NOACs are preferred over VKAs for the prevention of stroke in patients with newly diagnosed. ESC guidelines state that in AF patients already using a VKA, it is recommended to consider switching to a NOAC, especially if the time in therapeutic range is not well-controlled despite good drug adherence. However, there are limited data on the comparison between VKAs and NOACs in frail elderly patients with AF and it is unclear whether those currently managed with VKAs should be switched to NOACs.

The FRAIL-AF trial investigated whether switching VKA treatment to NOAC treatment was superior in terms of major and/or clinically relevant non-major bleeding complications in frail elderly patients with AF. Patients were at least 75 years of age, had a Groningen Frailty Indicator score of 3 or higher, and were currently managed with VKAs at one of the seven participating thrombosis centres in The Netherlands. Patients with severe renal impairment (estimated glomerular filtration rate below 30mL/min/1.73m2) or with valvular AF were excluded from randomisation.

Participants were randomised in a 1:1 ratio to switch from a VKA to a NOAC or to continue a VKA. The choice of NOAC was left to the discretion of the treating physician. The follow-up duration was 12 months. The cause-specific hazard ratio (HR) was calculated for occurrence of the primary outcome which was major or clinically relevant non-major bleeding, whichever came first, accounting for death as a competing risk.

Analyses followed the intention-to-treat principle and were stratified for renal function. Secondary outcomes included thromboembolic events, defined as ischaemic stroke, transient ischaemic attack, and/or peripheral arterial thromboembolism.

Between January 2018 and April 2022, a total of 1,330 patients were randomised. The mean age was 83 years and 38.8% were women. After 163 primary outcome events (101 in the switch arm, 62 in the continue arm), the trial was stopped for futility on advice from the Data Safety and Monitoring Board following a prespecified futility analysis. The HR for the primary outcome of major or clinically relevant non-major bleeding was 1.69 (95% confidence interval [CI] 1.23 to 2.32) for switching to a NOAC relative to continuing a VKA. The HR for thromboembolic events was 1.26 (95% CI 0.60 to 2.61).

Regarding secondary outcomes, 16 thromboembolic events occurred in the NOAC arm versus 13 in the VKA arm, yielding incidence rates of 2.6 (95% CI 1.5 to 4.3) and 2.1 (95% CI 1.1 to 3.6) per 100 patient-years, respectively.

Joosten said: “Switching VKA treatment to a NOAC in frail elderly patients with atrial fibrillation was associated with more bleeding complications compared to continuing a VKA. This higher bleeding risk with NOACs was not offset by a lower risk of thromboembolic events.”


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