198 SUMMARY ranging between 9% and 53%.26 A meta-analysis of 7 of these 19 studies (with in total 80,725 patients) that met the predefined criteria for the meta-analysis resulted in a pooled HR of OLRD of NOACs compared to OLNRD of NOACs of 1.10 (95% CI 0.951.29) for bleeding, 1.04 (95% CI 0.83-1.29) for stroke/thromboembolism, and 1.22 (95% CI 0.81-1.84) for all-cause mortality.26 Thus, this meta-analysis did not show a reduction in bleeding risk, nor an increased risk of stroke/thromboembolism, nor a significant difference in all-cause mortality in AF patients with OLRD compared to AF patients with OLNRD.26 GENERAL DISCUSSION In Chapter 9, the general discussion, the main findings of this thesis and their practical implications are summarised by returning to the case of Mrs. de Jong. In addition, suggestions for future research on NOACs in frail older patients with AF are provided. In the second part of this chapter the ‘inverse research law’, derived from the ‘inverse care law’, is explained and discussed in detail. It highlights the paucity of evidence in one of the largest and most difficult to manage populations. The FRAIL-AF trial, which is the centrepiece publication in this thesis, is one of the very few RCTs ever performed in frail older patients.20 As the FRAIL-AF trial showed that results in frail older patients are different compared to the non-frail populations from the four pivotal NOAC trials,27–30 the findings of the FRAIL-AF trial emphasises the need for more dedicated RCTs in frail older patients. Thus, besides the important finding of an increased risk of major or clinically relevant non-major bleeding complications in frail older AF patients switching from a VKA to a NOAC compared to those continuing with VKA treatment, another clear message stems from the unexpected results of the FRAIL-AF trial, namely that we need to reverse the ‘inverse research law’. Suggestions on how this could be achieved are provided in the last paragraphs of the general discussion.
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