13 GENERAL INTRODUCTION RCTs performed in a selective population including few or no frail elderly are incorrectly generalised to frail older people. The assumption that the results from RCTs in general cannot simply be generalised to the population of frail older people is entirely valid. Frail older people have a large volatility, for example in anticoagulation status. This large volatility is due to problems with treatment adherence which is often associated with polypharmacy and some degree of cognitive impairment. Furthermore, these fluctuations are due to different pharmacokinetics and pharmacodynamics, which respectively means that the human body of frail elderly, who often suffer from multimorbidity, processes medication differently compared to non-frail elderly (i.e. they have a different absorption, distribution, metabolism and excretion of medication), and that medication itself has different effects in frail elderly compared to non-frail elderly. Therefore, the balance, in this example between coagulation and bleeding, is more fragile in frail older people. Regarding AF management, this fragile balance may influence the effects of oral anticoagulation. Perhaps VKA treatment with monitoring through international normalised ratio testing instead of NOAC treatment is safer for frail older patients because it allows early intervention by titrating the VKA dose to the most optimal range. Given the differences between frail and non-frail elderly and current speculations rather than evidence, RCTs in frail elderly patients are urgently needed, especially towards comparing VKA treatment with NOAC treatment in frail older patients with AF. THESIS OUTLINE In the management of patients it may be useful to understand the underlying pathophysiological mechanisms of the disease involved or to have an explainable model of the particular disease. Therefore, in Chapter 2 the role of a hypercoagulable or prothrombotic state as pathophysiological mechanism for increased ischaemic stroke risk in patients with AF was explored. A hypercoagulable or prothrombotic state may also at least partly explain why patients with an respiratory tract infection, such as coronavirus disease 2019 (COVID-19), are more prone to developing AF and other (cardiovascular) morbidities. In Chapter 3, the sex- and age specific association of new-onset AF with in-hospital mortality was assessed in hospitalised COVID-19 patients mainly during the first COVID-19 wave. Chapters four to eight consist of studies on oral anticoagulant treatment of AF. Chapter 4 is a response letter to a published article about stroke rate variation and anticoagulation benefit in patients with AF. Notably, the balance between the risk of ischaemic stroke and bleeding in those with a low CHA2DS2-VASc score was discussed. Chapter 5 provides an overview of the trends in prevalence of AF and antithrombotic 1
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