179 GENERAL DISCUSSION symptom-based rhythm control was applied.5 This thesis focuses on the A and C of the ABC pathway for the management of AF. The most important findings of this thesis and their practical implications are as follows: • The FRAIL-AF randomised trial showed that switching from a vitamin K antagonist (VKA) to a NOAC compared to continuing with a VKA in frail older patients with AF should not be considered without a clear indication, as switching leads to 69% more major or clinically relevant non-major bleeding.6,7 Therefore, the decision of the general practitioner (GP) of Mrs. de Jong not to change the oral anticoagulation from a VKA to a NOAC, seems reasonable. As already mentioned, the FRAIL-AF randomised trial is unique as it is the first randomised NOAC trial that exclusively included frail older AF patients. Thereby, this RCT provides important information beyond available evidence; evidence that cannot be obtained from underpowered subgroup analyses of the pivotal NOAC trials that incorporated no or very low numbers of frail older patients, nor from observational data because of the inherent problem of bias due to residual confounding.8–11 The fact that the results of the FRAIL-AF trial showed an effect that turned out to be completely different from what was expected, underlines the importance of proper research using RCTs in frail older patients prior to uncritically generalising the findings of studies conducted in non-frail populations. • The prevalence of AF is increasing as a result of ageing of the population and increased awareness, detection and registration.12 Routine care data from the Julius General Practitioners’ Network in The Netherlands showed that the prevalence of AF already more than tripled from 0.4% in 2008 to 1.4% in 2017. In that period frail older patients with new-onset AF, such as Mrs. de Jong, were more likely to be prescribed a VKA instead of a NOAC.12 Given the important increase in AF prevalence, AF care needs to be reorganised. A holistic approach following the aforementioned ABC pathway and coordinated by GPs seems to be an adequate answer in healthcare settings with a strong primary care system.4 A good example is the ALL-IN trial where integrated AF care, orchestrated by primary care, compared with care as usual led to a 45% reduction in all-cause mortality.13 • Postmarketing observational studies reported that 20-30% of AF patients receive a reduced NOAC dose without a clear medical indication, maybe to minimise an assumed high bleeding risk.14–19 After a comprehensive systematic review and metaanalysis of AF patients using a NOAC, it can be concluded that this so-called offlabel reduced dosing (OLRD) of NOACs compared to on-label non-reduced dosing of NOACs did not reduce bleeding risk with a hazard ratio (HR) of 1.10 (95% confidence interval (CI) 0.95-1.29), nor all-cause mortality with a HR of 1.22 (95% CI 0.81-1.84) and had no clear effect on thromboembolism with a HR of 1.04 (95% CI 0.83-1.29)).20 9
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