197 SUMMARY The findings of the FRAIL-AF trial are described in Chapter 7.20 1,330 frail older AF patients were randomised.20 The mean age of the analysed population was 83 years, 74% had a GFI of ≥4, and the median CHA2DS2-VASc score was 4. 20 Most patients in the intervention arm switched to rivaroxaban (50%), followed by apixaban (17%), edoxaban (16%) and dabigatran (9%) and dosing followed the summary of product characteristics in most patients (except for 6.6% of patients in the intervention arm who received an off-label dose reduction).20 A prespecified interim analysis was planned after at least 160 primary outcome events had occurred.20 The results of this interim analysis appeared to be completely different from what was expected: the composite primary outcome (i.e. the first major or clinically relevant non-major bleeding complication) occurred in 101 patients in the intervention arm (incidence rate 17.8 events per 100 person-years) and in 62 patients in the control arm (incidence rate 10.5 events per 100 person-years).20 Thus, switching from a VKA to a NOAC compared to continuing VKA treatment increased the risk of a major or clinically relevant non-major bleeding complication (hazard ratio (HR) for the primary outcome of 1.69 with a 95% confidence interval (CI) of 1.23-2.32).20 Subsequently, the independent Data Safety Monitoring Board recommended to stop inclusion according to prespecified rules for halting the trial due to futility.20 In the analysis where the two components of the primary outcome were assessed separately, the observed difference between both treatment arms seemed mainly driven by an increase in clinically relevant non-major bleeding.20 Regarding secondary outcomes, the occurrence of thromboembolic events and allcause mortality were similar in the intervention arm (16 thromboembolic events and 44 deaths) and the control arm (13 thromboembolic events and 46 deaths) a HR of 1.26 (95% CI 0.60-2.61) and 0.96 (95% CI 0.64-1.45), respectively.20 In conclusion, the FRAIL-AF RCT showed that switching from a VKA to a NOAC should not be considered without a clear indication in frail older patients with AF, as switching to a NOAC leads to 69% more bleeding.20 CLINICAL CONSEQUENCES OF OFF-LABEL REDUCED DOSING OF NONVITAMIN K ANTAGONIST ORAL ANTICOAGULANTS IN PATIENTS WITH ATRIAL FIBRILLATION According to postmarketing observational studies, 20-30% of AF patients receive a reduced NOAC dose without a clear indication, probably aiming to reduce an assumed high risk of bleeding.21–25 Chapter 8 is a systematic review and meta-analysis on the clinical consequences (i.e. bleeding, stroke/thromboembolism and all-cause mortality) of this so-called off-label reduced dosing (OLRD) of NOACs compared to on-label non-reduced dosing (OLNRD) of NOACs in patients with AF.26 The initial search in PubMed and Embase resulted in 10,780 publications and ultimately in the inclusion of 19 articles after applying the predefined inclusion criteria.26 These 19 observational studies included in total 170,394 patients with AF and reported percentages of OLRD A
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