180 CHAPTER 9 Because this meta-analysis shows no compelling evidence that OLRD can be helpful,20 physicians should adhere to prescription guidelines that are based on drug dosing studies. • A recent meta-analysis showed that respiratory tract infections, such as coronavirus disease 2019 (COVID-19), increase the risk of cardiovascular diseases, including AF, about 1.5-5 fold within one month after the infection.21 Moreover, the development of AF in COVID-19 patients has been associated with increased mortality.22–24 However, these studies did not assess sex-specific influences, nor the effect of age (on a continuous scale). After conducting a multicentre cohort study of patients hospitalised with COVID-19, mainly during the first COVID-19 wave in spring 2020, it can be concluded that 7.3% of them developed new-onset AF or atrial flutter (AFL) during hospitalisation.25 In a multivariable model with sex, age, and new-onset AF and/or AFL, new-onset AF and/or AFL in hospitalised COVID-19 patients was associated with a two- to three-fold increased risk of in-hospital mortality in men aged 60-72 years, but not in women (like Mrs. de Jong) or younger men.25 This is an interesting finding knowing that women with AF and/or AFL generally have a worse prognosis than men with AF and/or AFL.26 The results of this study were an important building block in creating more knowledge about COVID-19 during the pandemic, and might also be generalised to patients with other viral respiratory tract infections (e.g. influenza) as a recent study shows a similar increase in mortality in hospitalised influenza patients with AF and/or AFL.27 UNANSWERED QUESTIONS IN RELATION TO THE FRAIL-AF TRIAL Like any study, the FRAIL-AF RCT also leads to new, unanswered questions. For example, it may be that the results of the FRAIL-AF trial are disadvantageous to NOACs because the current on-label NOAC dose (also used in the FRAIL-AF trial) was in fact too high for frail older AF patients. Frail older people have different pharmacokinetics and pharmacodynamics. For example, the distribution of medication is different because of an altered body composition (i.e. less muscle tissue and more fatty tissue) and lower elimination capacity of both liver and kidneys. This generally results in a longer availability of medication and thus in higher serum NOAC levels in (frail) older people. For example, a study in older AF patients receiving apixaban showed that apixaban concentrations were higher than expected based on clinical trial data,28 and another study in frail older patients receiving a NOAC showed that higher levels of frailty were associated with higher apixaban exposure.29 Therefore, an RCT on the optimal (perhaps lower) dosing of NOACs in frail older AF patients would be recommendable.
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