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

Linda P T Joosten; Sander van Doorn; Peter M van de Ven; Bart T G Köhlen; Melchior C Nierman; Huiberdina L Koek; Martin E W Hemels; Menno V Huisman; Marieke Kruip; Laura M Faber; Nynke M Wiersma; Wim F Buding; Rob Fijnheer; Henk J Adriaansen; Kit C Roes; Arno W Hoes; Frans H Rutten; Geert-Jan Geersing

doi:10.1161/CIRCULATIONAHA.123.066485

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. 2024 Jan 23;149(4):279-289. doi: 10.1161/CIRCULATIONAHA.123.066485. Epub 2023 Aug 27.

Authors

Linda P T Joosten¹, Sander van Doorn¹, Peter M van de Ven², Bart T G Köhlen¹, Melchior C Nierman³, Huiberdina L Koek⁴, Martin E W Hemels^{5

6}, Menno V Huisman⁷, Marieke Kruip⁸, Laura M Faber⁹, Nynke M Wiersma¹⁰, Wim F Buding¹¹, Rob Fijnheer¹², Henk J Adriaansen¹³, Kit C Roes¹⁴, Arno W Hoes¹⁵, Frans H Rutten¹, Geert-Jan Geersing¹

Affiliations

¹ Department of Primary Care & Nursing Science (L.P.T.J., S.v.D., B.T.G.K., F.H.R., G.-J.G.), University Medical Center Utrecht, Julius Center for Health Sciences and Primary Care, Utrecht University, The Netherlands.
² Department of Data Science & Biostatistics (P.M.v.d.V.), University Medical Center Utrecht, Julius Center for Health Sciences and Primary Care, Utrecht University, The Netherlands.
³ Department of Thrombosis and Anticoagulation, Atalmedial Medical Diagnostic Centers, Amsterdam, The Netherlands (M.C.N.,).
⁴ Department of Geriatrics, University Medical Center Utrecht, Utrecht University, The Netherlands (H.L.K.).
⁵ Department of Cardiology, Rijnstate Hospital, Arnhem, The Netherlands (M.E.W.H.).
⁶ Department of Cardiology (M.E.W.H.), Radboud University Medical Center, Radboud University, Nijmegen, The Netherlands.
⁷ Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden University, Leiden, The Netherlands (M.V.H.).
⁸ Department of Hematology, Erasmus University Medical Center Rotterdam, Erasmus University, The Netherlands (M.K.).
⁹ Department of Thrombosis and Anticoagulation, Starlet Medical Diagnostic Center, Alkmaar, The Netherlands (L.M.F.).
¹⁰ Department of Thrombosis and Anticoagulation, Diagnostic Center Saltro, Utrecht, The Netherlands (N.M.W.).
¹¹ Patient representative from Dutch Organization for patients using anticoagulant medication, CTD, Leiden, The Netherlands (W.F.B.).
¹² Department of Internal Medicine, Meander Hospital, Amersfoort, The Netherlands (B.F.).
¹³ Department of Thrombosis and Anticoagulation, Tergooi Medical Center, Hilversum, The Netherlands (H.J.A.).
¹⁴ Department Health Evidence and Biostatistics (K.C.R.), Radboud University Medical Center, Radboud University, Nijmegen, The Netherlands.
¹⁵ University Medical Center Utrecht, Dean, Board of Directors, Utrecht University, The Netherlands (A.W.H.).

PMID: 37634130
DOI: 10.1161/CIRCULATIONAHA.123.066485

Abstract

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).

Keywords: anticoagulants; atrial fibrillation; frail elderly; vitamin K.

Publication types

Randomized Controlled Trial
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Aged
Aged, 80 and over
Anticoagulants / adverse effects
Atrial Fibrillation* / complications
Frail Elderly
Frailty* / diagnosis
Humans
Stroke* / etiology
Thromboembolism* / epidemiology
Thromboembolism* / etiology
Thromboembolism* / prevention & control
Vitamin K

Substances

Anticoagulants
Vitamin K

Associated data

ClinicalTrials.gov/2017-000393-11