Results of FRAIL-AF trial suggest increased bleeding risk with DOACs

According to the findings of the FRAIL-AF trial, switching frail patients with atrial fibrillation (AF) from a vitamin K antagonist (VKA) to a direct oral anticoagulant (DOAC) should not be considered without a clear indication. In contrast to the hypothesis of the research team, switching to a DOAC resulted in a significantly higher risk for bleeding among these patients.

Dr Linda Joosten (University Medical Center Utrecht, the Netherlands) argued that it is important to evaluate the use of anticoagulants for AF in frail patients since frail individuals comprise 12% of the population, the prevalence of AF in frail older people is high (18%), and the incidence of stroke in frail AF patients is remarkably higher than in non-frail AF patients (12.3% vs 3.9%) [1–3]. “The 2023 EHRA expert consensus statement on the management of arrhythmias in frailty syndrome states that the advantages of DOACs relative to VKAs are likely to be consistent in frail and non-frail AF patients,” said Dr Joosten [1]. “However, evidence for this statement is lacking.”

The FRAIL-AF trial investigated whether switching from a VKA to a DOAC reduced bleeding risk in frail older patients with AF, as compared with continuing treatment on a VKA [4]. Thus, the 1,330 enrolled participants were randomised 1:1 to either of these options. Dr Joosten pointed out that the population of the current trial was different from the standard populations tested in DOAC trials, with a mean age of 83 years, a median Groningen Frailty Indicator score of 4, and a median CHA₂DS₂-VASc score of 4. The primary endpoint of FRAIL-AF was major or clinically relevant non-major bleeding.

After 1 year of follow-up, the primary outcome data showed that participants who switched to a DOAC had an increased risk for bleeding compared with those who continued on a VKA (15.3% vs 9.4%; HR 1.69; 95% CI 1.23–2.32; P=0.0011). This effect appeared to be mainly driven by an increase in clinically relevant non-major bleedings in the DOAC arm (12.7% vs 7.4%; HR 1.77; 95% CI 1.24–2.52). Dr Joosten mentioned that there was no difference in the occurrence of thromboembolic events between VKA receivers and DOAC receivers (2.0% vs 2.4%; HR 1.26; 95% CI 0.60–2.61). All-cause mortality rates were also similar between both study groups (7.0% vs 6.7%).

Discussant Dr Isabelle van Gelder (University Medical Center Groningen, the Netherlands) mentioned that 50.2% of the participants in the DOAC group switched to rivaroxaban and that this DOAC has been associated with a higher risk for bleeding [5]. “However, I believe that the main explanation for the results is to be found in the constitution of the study population. These are frail patients, very different from the populations that were studied in the DOAC trials, and they take many medications. Polypharmacy has been associated with an increased risk for bleeding and DOACs are novel drugs that may come with unknown interaction effects with some of these medications [6].”

1. 
   
   1. Savelieva I, et al. Europace. 2023;25(4):1249–1276.
   2. Proietti M, et al. Ageing Res Rev. 2022;79:101652.
   3. Wilkinson C, et al. Age ageing. 2019;48(2):196–203.
   4. Joosten LPT, et al. Safety of switching from a VKA to a NOAC in frail older patients with atrial fibrillation: results of the FRAIL-AF randomised controlled trial. Hot Line Session 6, ESC Congress 2023, 25–28 August, Amsterdam, the Netherlands.
   5. Al-Khalili F, et al. Current Medical Research and Opinion. 2016;32(4):1–28.
   6. Piccini JP, et al. Circulation. 2016;133(4):352–360.

 

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Posted on 30 October 20238 February 2024