FRAIL-AF: Switching to NOACs in Older, Frail Patients Linked to Increased Bleeding Risk

Linda Joosten, MD
Credit: University Medical Center Utrecht

For frail elderly patients with atrial fibrillation, switching from a vitamin K antagonist (VKA) treatment to a non-vitamin K antagonist oral anticoagulant (NOAC) could increase risk of bleeding complications.

Results of the FRAIL-AF study, which was billed as the first randomized NOAC trial exclusively including frail older patients, suggest the rate of bleeding events was 69% greater among those who switched to a NOAC without significant benefit for thromboembolic events.¹

“Switching VKA treatment to a NOAC in frail elderly patients with atrial fibrillation was associated with more bleeding complications compared to continuing a VKA,” said Linda Joosten, MD, of the Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht.² “This higher bleeding risk with NOACs was not offset by a lower risk of thromboembolic events.”

Presented at the European Society of Cardiology (ESC) Congress 2023, the FRAIL-AD trial was launched with the intent of providing clarity on whether frail patients with atrial fibrillation should be managed with VKAs or switched to NOACs. For inclusion in the trial, patients needed to be at least 75 years of age, have a Groningen Frailty Indicator score of 3 or greater, and currently managed with VKAs at a participating thrombosis center in the Netherlands.¹

A cohort of 1330 patients were randomized. A total of 661 and 662 patients were included in the intention-to-treat populations for the VKA-only and the NOAC arms, respectively.¹

Of note, the trial was stopped for futility on advice from the Data Safety and Monitoring Board following a prespecified futility analysis. At the time the trial was stopped, a total of 163 primary outcome events were identified among the overall study cohort, with 101 in the switch arm and 62 in the continue arm.¹

Upon analysis, results suggested the risk of any major or clinically relevant nonmajor bleeding was 69% greater among those sitting to NOACs relative to those continuing on VKA (Hazard ratio, 1.69; 95% Confidence interval [CI], 1.23-2.32; P = .00112). When assessing bleeding types separately, risk increases of 52% and 77% were observed for major bleeding (HR, 1.52; 95% CI, 0.81-2.87) and clinically relevant nonmajor bleeding (HR, 1.77; 95% CI, 1.24-2.52) events, respectively, among those switching relative to those continuing on VKA.¹

Analysis of secondary outcomes indicated the rate of thromboembolic events was 2.0% and 2.4% among the VKA-only arm and those who switched to NOACs, respectively (HR, 1.26; 95% CI, 0.60-2.61). For all-cause mortality, the rates were 7.0% and 6.7% for the VKA-only arm and those who switched to NOACs, respectively (HR, 0.96; 95% CI, 0.64-1.45). Investigators also pointed out an assesment of risk for a composite of the primary outcome and thromboembolic events suggested the NOAC group had a 65% greater risk than those in the VKA-only group (HR, 1.65; 95% CI, 1.23-2.21).¹

“Our trial strengthens the evidence by studying at the complete domain of frailty (surpassing individual domains) in a large pragmatic trial in older [atrial fibrillation] patients, accounting for the downfalls of observational studies such as confounding bias,” wrote investigators.¹ “Even more so, we aimed to extend (i.e., ‘stretch the tails’ of) the trial evidence to the most vulnerable (and increasing) [atrial fibrillation] population, a population that previously was largely excluded in clinical trials”

References:

1. ^{Joosten LPT, van Doorn S, van de Ven PM, 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 [published online ahead of print, 2023 Aug 27]. Circulation. 2023;10.1161/CIRCULATIONAHA.123.066485. doi:10.1161/CIRCULATIONAHA.123.066485}
2. ^{European Society of Cardiology. Study reports on switch to newer anticoagulants in frail elderly with atrial fibrillation. ESC Congress Home 2023. August 27, 2023. Accessed August 28, 2023. https://www.escardio.org/The-ESC/Press-Office/Press-releases/Study-reports-on-switch-to-newer-anticoagulants-in-frail-elderly-with-atrial-fibrillation.}