Linda Joosten

121 FRAIL-AF RANDOMISED CONTROLLED TRIAL: RESULTS the research question addressed in this trial, which was to study whether these patients (provided they were old and frail) should switch from a VKA to a NOAC. Also, inherent to the switching design, slightly more crossover in our trial was observed in ‘the switch to a NOAC arm’ (n=73) than in ‘the continue with a VKA arm’ (n=51). Nevertheless, adherence to the protocol in our trial was still relatively high, certainly for this frail older population: 89% adherence in the intervention arm versus 92% adherence in the control arm. Second, one could postulate that the infrastructure of INR guided VKA management is adequate in the Netherlands, which may positively affect the time in therapeutic range (TTR) in the VKA arm of our trial. Levels of the TTR were not an inclusion criterion in our trial nor were the individual participants’ TTR levels registered. Monitoring of the INR levels at the eight study sites of this pragmatic FRAIL-AF trial was done according to current Dutch clinical practice. The range of the TTR levels in Dutch clinical practice for the participating thrombosis services in this trial, specifically for the older individuals that are visited at home for their INR measurements (thus the frailest individuals), during the study years of our FRAIL-AF trial, was between 65.3% and 74.0% (measured as part of yearly quality reports, see https://www.fnt.nl/algemeen/ jaarverslagen). As a comparison, the effect of the TTR on efficacy and safety of apixaban versus warfarin was studied in the ARISTOTLE trial population and resulted in a TTR from patients recruited from the Netherlands around the median study average of 66.4%, which is similar to countries like the United States, the United Kingdom, Italy, Germany, and Canada.27 At that TTR level, apixaban compared with warfarin was still associated with a lower rate of major bleeding in a non-frail population with a median age of 70 years. Hence, we believe that levels of TTR did not influence our findings significantly or hamper generalisability to the substantial population of older patients living with frailty in many countries, and we consider our findings to be generalisable to patients currently receiving adequate INR guided VKA management. Our findings should lead to a careful consideration whether or not to switch a patient, who is stable on INR guided VKA management (TTR ±70%) to a NOAC, given our finding of a higher risk of major or CRNM bleeding. Our trial does not allow us to draw conclusions for patients with a low TTR for whom switching to a NOAC may certainly be considered appropriate. Third, the choice of the NOAC was at the discretion of treating physicians. Albeit this would mimic (future) clinical practice, it could have affected our results. In observational studies, rivaroxaban (the most prescribed NOAC in our trial) is associated with more bleeding complications than other NOAC types, notably gastrointestinal bleeding, with apixaban having the best safety profile in older individuals.26,28–30 In our trial, a post-hoc analysis per NOAC type showed that rivaroxaban and apixaban had a similar HR for our primary outcome. Nevertheless, because the type of NOAC prescribed was 7

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