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Background: There is ambiguity whether frail patients with atrial fibrillation managed with vitamin K antagonists (VKAs) should be switched to a non-vitamin K oral anticoagulant (NOAC)., Methods: We conducted a pragmatic, multicenter, open-label, randomized controlled superiority trial. Older patients with atrial fibrillation living with frailty (≥75 years of age plus a Groningen Frailty Indicator score ≥3) were randomly assigned to switch from international normalized ratio-guided VKA treatment to an NOAC or to continued VKA treatment. Patients with a glomerular filtration rate <30 mL·min -1 ·1.73 m -2 or with valvular atrial fibrillation were excluded. Follow-up was 12 months. The cause-specific hazard ratio was calculated for occurrence of the primary outcome that was a major or clinically relevant nonmajor bleeding complication, whichever came first, accounting for death as a competing risk. Analyses followed the intention-to-treat principle. Secondary outcomes included thromboembolic events., Results: Between January 2018 and June 2022, a total of 2621 patients were screened for eligibility and 1330 patients were randomly assigned (mean age 83 years, median Groningen Frailty Indicator score 4). After randomization, 6 patients in the switch-to-NOAC arm and 1 patient in the continue-with-VKA arm were excluded due to the presence of exclusion criteria, leaving 662 patients switched from a VKA to an NOAC and 661 patients continued VKAs in the intention-to-treat population. After 163 primary outcome events (101 in the switch arm, 62 in the continue arm), the trial was stopped for futility according to a prespecified futility analysis. The hazard ratio for our primary outcome was 1.69 (95% CI, 1.23-2.32). The hazard ratio for thromboembolic events was 1.26 (95% CI, 0.60-2.61)., Conclusions: Switching international normalized ratio-guided VKA treatment to an NOAC in frail older patients with atrial fibrillation was associated with more bleeding complications compared with continuing VKA treatment, without an associated reduction in thromboembolic complications., Registration: URL: https://eudract.ema.europa.eu; Unique identifier: 2017-000393-11. URL: https://eudract.ema.europa.eu; Unique identifier: 6721 (FRAIL-AF study)., Competing Interests: Disclosures Dr Hemels reports payment for educational lectures from Bayer, BMS/Pfizer, Boehringer Ingelheim, and Daiichi Sankyo. Dr Huisman reports payment to institution from Dutch Healthcare Fund, Dutch Heart Foundation, Bayer Health Care, Pfizer, and Leo Pharma. Dr Kruip reports payment to institution of unrestricted grants from Sobi, payment to institution of research grants from The Netherlands Organisation for Health Research and Development and The Netherlands Thrombosis Foundation, and payment to institution of speaker fees from Sobi, Roche, Dr Geersing reports payment to institution of unrestricted grants from Boehringer-Ingelheim, Bayer Healthcare, BMS Pfizer, and Daiichi Sankyo. Dr Rutten reports payment to institution of unrestricted grants from Boehringer-Ingelheim, Bayer Healthcare, BMS Pfizer, and Daiichi Sankyo.

Introduction: Clinical guidelines recommend non-vitamin K antagonist oral anticoagulants (NOACs) over vitamin K antagonists (VKAs) for stroke prevention in most patients with atrial fibrillation (AF). Frail elderly were under-represented in the landmark NOAC-trials, leaving a knowledge gap on the optimal anticoagulant management (VKA or NOAC) in this increasing population. The aim of the Frail-AF (FRAIL-AF) study is to assess 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 AF., Methods and Analysis: The FRAIL-AF study is a pragmatic, multicentre, open-label, randomised controlled clinical trial. Frail elderly (age ≥75 years plus a Groningen Frailty Indicator score ≥3) who receive VKA-treatment for AF in the absence of a mechanical heart valve or severe mitral valve stenosis will be randomised to switch to a NOAC-based treatment strategy or to continue INR-guided VKA-management. Patients with severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m 2 ) will be excluded from randomisation. Based on existing trial evidence in non-frail patients, we will aim to explore whether NOAC-treatment is superior to VKA-therapy in reducing major or clinically relevant non-major bleeding events. Secondary outcomes include minor bleeding, the composite of ischaemic and haemorrhagic stroke, health-related quality of life and cost-effectiveness. The follow-up period for all subjects is 12 months., Ethics and Dissemination: The protocol was approved by the Medical Research Ethics Committee of the University Medical Center Utrecht, the Netherlands and by the Central Committee on Research Involving Human Subjects, the Netherlands. All patients are asked written informed consent. Results are expected in 2022 and will be disseminated through peer-reviewed journals as well as presentations at national and international conferences., Trial Registration Number: EudraCT: 2017-000393-11; The Netherlands Trial Registry: 6721 (FRAIL-AF study)., Competing Interests: Competing interests: G-JG and FHR report unrestricted institutional grants for performing research in the field of atrial fibrillation from Boehringer-Ingelheim, Bayer Healthcare, BMS Pfizer and Daiichi Sankyo. MEWH reports personal fees from Boehringer-Ingelheim, Bayer Healthcare, BMS Pfizer and Daiichi Sankyo, and grants from The Netherlands Organisation for Health Research and Development (ZonMw), outside the submitted work. MVH reports grants from The Netherlands Organisation for Health Research and Development (ZonMw), Dutch Healthcare Fund and grants and personal fees from Boehringer-Ingelheim, Bayer Healthcare, BMS Pfizer, Daiichi Sankyo and Aspen, outside the submitted work. All other authors (LPTJ, SvD, AWH, MCN, NMW, HLK, KCR, RMvdB and WFB) report no competing interests., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)