- The FRAIL-AF trial is an open-label, randomized controlled trial that randomized frail adults (75 years or older) who were on VKA for atrial fibrillation to either continuing VKA or switching to a NOAC.
- The study found a relative 69% increased risk in bleeding events among patients who were switched from VKA to NOACs (p=0.001). This was driven primarily by a 77% increase in clinically relevant non-major bleeding, as there was no significant difference in major bleeding events.
Vitamin K antagonists (VKA) and non-VKA oral anticoagulant (NOAC) are widely used to prevent strokes in patients with atrial fibrillation. Over the last decade, a number of randomized controlled trials have compared VKAs and NOACs in the patients with atrial fibrillation, and have found lower bleeding rates in patients treated with NOACs compared to those treated with VKAs.1-4 In the 2016 European Society of Cardiology guidelines for management of atrial fibrillation, there is a class I recommendation for NOACs over VKA in the majority of patients, with exceptions made for those with mechanical valves or moderate-to-severe mitral stenosis. There is also a class IIb indication to switch patients with atrial fibrillation already on VKA to treatment with NOACs if they are eligible.5 Whether frail older patients can safely be switched from VKA to NOACs has not yet been studied.
The FRAIL-AF trial is an open-label, randomized controlled trial which randomized 1,323 frail adults who were on VKA for atrial fibrillation to either continuing VKA or switching to a NOAC. Patients included in the trial were diagnosed with atrial fibrillation, currently taking VKA, aged 75 years or more, and frail. Frailty was determined based on a score of 3 or higher on the Groningen Frailty Index questionnaire which assessed for reductions in mobility, cognition, nutrition, health, and functional status. Exclusion criteria for randomization included valvular atrial fibrillation, participation in another trial, inability to provide consent, and severe renal impairment. The primary outcome measured was any major or clinically relevant non-major bleeding during 1 year of follow-up. Secondary outcomes were thromboembolic events and all-cause mortality. The design of the study was pragmatic as the decision of which NOAC (dabigatran, rivaroxaban, apixaban and edoxaban) to switch to and what dose to give was made based on patient and prescribing physicians’ preferences.
The mean age of patients included in the trail was 83 years old, and 39% of the trial participants 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).
The FRAIL-AF trial found a relative 69% increased risk in bleeding events among patients who were switched from VKA to NOACs (p=0.001). This was driven primarily by a 77% increase in clinically relevant non-major bleeding, as there was no significant difference in major bleeding events. This result is unexpected in light of prior randomized controlled trials that compared NOACs with VKA in patients with atrial fibrillation (RE-LY1, ROCKET AF,2 ARISTOTLE3, and ENGAGE AF-TIMI 484) which all showed significantly lower rates of bleeding in patients treated with NOACs compared to those treated with VKA. These prior studies included older adults, though did not exclusively enroll frail older adults as was done in FRAIL-AF. Further studies are warranted to elucidate the mechanism driving the increased bleeding rates in frail older patients switching from VKA to NOACs and to inform future clinical practice for this patient population.
- Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. New England Journal of Medicine. 2009;361(12):1139-1151.
- Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. New England Journal of Medicine. 2011;365(10):883-891.
- Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. New England Journal of Medicine. 2011;365(11):981-992.
- Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus Warfarin in Patients with Atrial Fibrillation. New England Journal of Medicine. 2013;369(22):2093-2104.
- Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. European Journal of Cardio-Thoracic Surgery. 2016;50(5):e1-e88.