97 FRAIL-AF RANDOMISED CONTROLLED TRIAL: RATIONALE AND DESIGN VKA therapy. If - what might be expected from existing trial results and postmarketing observational studies in non-frail patients with AF - switching from INR guided VKA management to a NOAC based treatment strategy compared with continuing INR guided VKA management is superior in terms of less bleeding in frail elderly, this would be a breakthrough in managing stroke risk in these vulnerable patients with AF. Clinicians caring for these patients know that despite frequent INR monitoring in this patient group, it is often challenging to achieve a sufficient time in therapeutic range when treated with VKAs. The clinical consequence might be the occurrence of thromboembolic or bleeding complications.32 Older patients on a VKA showed that they are willing to switch to an alternative anticoagulant drug, provided it is safe and effective,33,34 which exactly is what we aim to evaluate in this trial. If the opposite is true and switching to NOACs is unsafe in frail elderly, we should reconsider switching from a VKA to a NOAC in frail elderly patients with AF. For full appreciation of this ongoing trial, several topics deserve attention. First, this trial will provide evidence on the question whether switching from a VKA to a NOAC reduces the risk of bleeding complications compared with continuing VKA treatment. Thus, findings should be considered in that light and are not directly applicable to anticoagulant naive frail elderly patients. Second, only patients willing to switch to a NOAC participate in our study. This is related to giving informed consent and could, to a certain extent, lead to patient selection. As with any randomised study, this may affect generalisability. However, this does not lead to selection bias, because selection in this study is the same for both groups due to randomisation after giving informed consent. Third, in our pragmatic study, patients are not blinded for randomisation allocation, as is common in studies evaluating VKAs in a non-explanatory trial. If patients would be blinded, mock INR blood samples from patients in the NOAC arm would have been needed, thereby increasing patient burden and influencing the estimation of two of our secondary outcomes (health related quality of life and cost-effectiveness). In addition, our primary outcome is major or CRNM bleeding complications, which we consider to be an objective measurement. The adjudication of all fatal outcomes will, however, be carried out blindly by an independent adjudication committee, which minimises the risk of information bias (e.g. misclassification). Fourth, this study relies on patient reported outcome measures, collected at regular intervals at one, three, six, nine, and twelve months. This might lead to reporting bias (reporting difference between the intervention and the control arm). Though, given the nature of the events collected (notably for our primary outcome major or CRNM bleeding complications) we believe missing events and reporting bias is unlikely. Additionally, when events are suspected based on our patient contacts, all routinely collected data will be scrutinised to enable accurate classification of outcome events. 6
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