FRAIL-AF is a pragmatic, multicenter, open-label, randomized controlled superiority trial that investigated whether switching from international normalised ratio (INR)-guided VKA-management to a NOAC-based treatment strategy compared with continuing VKA-management is safe in frail elderly patients with atrial fibrillation (AF).

While NOACs are preferred for non-frail AF patients, a lack of trial evidence and confounding bias in observational studies make it unclear whether frail AF patients should use NOACs instead of VKAs, and if they should switch from VKAs to NOACs.
In the FRAIL-AF trial a total of 1,330 patients were randomized (mean age 83 years, median GFI 4). Half of the patients continued their usual VKA treatment with specific INR targets, while the other half switched to NOAC treatments after randomization.

The trial focused on older atrial fibrillation patients with frailty, excluding those with severe kidney impairment or valvular AF. The follow-up period lasted for 12 months. The cause-specific hazard ratio (HR) was calculated for the occurrence of the primary outcome, which was a major or clinically relevant non-major bleeding complication, whichever occurred first, while accounting for death as a competing risk. Analyses adhered to the intention-to-treat principle. Secondary outcomes included thromboembolic events.

Dr Linda Joosten, investigator of FRAIL-AF, described the results as “very surprising and also unexpected”:  The trial was designed as a superiority trial with the hypothesis that switching from VKA to NOAC would reduce bleeding events.However, at the 12-month mark, the NOAC group experienced 101 major or clinically significant non-major bleeding events, a notable contrast to the 62 events observed in the VKA continued medication group, resulting in a Hazard Ratio of 1.69.The trial was halted for futility based on guidance from the Data Safety and Monitoring Board after a pre-planned futility analysis. Additionally, investigators recorded 16 thromboembolic events in the NOAC group, while the VKA group experienced 13 such events.

This unique trial, the first randomized study of non-vitamin K antagonist oral anticoagulants in frail older patients, concludes that transitioning from vitamin K antagonist therapy to NOAC treatment in this group results in a 69% increased risk of bleeding.

FRAIL-AF also highlights the knowledge gaps, raising questions about the appropriate NOAC dosages for frail AF patients and the potential benefits of factor eleven inhibitors, highlighting the need for further research in these areas.

Sources:

Joosten LPT: ESC 23: FRAIL-AF: Non-Vitamin K Antagonist Anticoagulation in Frail Elderly Patients With AF. Radcliffe Cardiology 2023. https://www.aerjournal.com/video-index/esc-23-frail-af-non-vitamin-k-antagonist-anticoagulation-frail-elderly-patients-af

Joosten LPT, et al. 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. Circulation 2023. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.123.066485