119 FRAIL-AF RANDOMISED CONTROLLED TRIAL: RESULTS DISCUSSION In our pragmatic randomised controlled trial among frail older patients with AF, switching INR guided VKA management to a NOAC based treatment strategy compared to continue INR guided VKA management was associated with a 69% increase in major and CRNM bleeding complications. Event rates for thromboembolic events, major bleeding in isolation, haemorrhagic stroke, and the composite of haemorrhagic and ischaemic stroke were low in both treatment arms, preventing us from drawing firm conclusions on these clinically relevant outcomes. There was no clear signal for either a reduced or an improved efficacy for these outcomes in patients switching from a VKA to a NOAC compared to continuing with a VKA. Our trial strengthens the evidence by studying the complete domain of frailty (surpassing individual domains) in a large pragmatic trial in older patients with AF, accounting for the downfalls of observational studies, such as confounding bias. Even more so, we aimed to extend (i.e. ‘stretch the tails’ of) the trial evidence to the most vulnerable (and increasing) AF population, a population that has previously been largely excluded from clinical trials. To elaborate on this, before our trial, trial evidence on the effect of ageing and frailty on clinical outcomes in NOAC or VKA treated individuals with AF was limited to subgroup analyses from either individual or aggregated data from the pivotal four NOAC trials.17– 20 However, it is difficult to compare these studies with our trial, given that frail older patients were underrepresented in the four NOAC trials, because these patients were either not eligible (e.g. due to a high anticipated bleeding risk) or physicians were hesitant to include these vulnerable older patients in clinical trials. Moreover, in these subgroup analyses, apart from the effect of ageing, frailty was predominantly quantified as a cumulative deficit of an increasing number of comorbidities and increasing polypharmacy. Albeit ageing, multimorbidity, and polypharmacy are important drivers of the concept of frailty, frailty is a clinical syndrome which is broader, including for instance weight loss, communication difficulties, loneliness, dependency on others, cognition, mental condition, and overall physical fitness, all items that are likely related to drug availability in the human body, and thus bleeding and thromboembolic risk. Nevertheless, some interesting comparisons with our findings can be drawn to put our trial into perspective. First, data from the COMBINE-AF consortium, that pooled individual patient data from all four pivotal NOAC trials (n=71,683 patients), revealed that, NOAC treatment compared with warfarin was associated with a lower risk of major or CRNM bleeding in patients regardless of age: the overall HR was 0.87 (95% CI 0.75–1.02) for standard dose NOAC treatment and 0.70 (95% CI 0.59–0.82) for reduced dose NOAC treatment.21,22 Although overall effects remained similar, the authors showed that the better efficacy 7
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