89 FRAIL-AF RANDOMISED CONTROLLED TRIAL: RATIONALE AND DESIGN METHODS Study design FRAIL-AF is a pragmatic, multicentre, open-label, randomised controlled clinical trial with a superiority design. Because studies showed non-inferior efficacy of NOACs compared with VKAs,7–10 we powered primarily on the composite safety outcome of major or CRNM bleeding complications, where a clinically relevant reduction in bleeding complications in favour of NOACs may be expected if results of existing trial evidence in non-frail patients could be generalised to this patient category. During the planning, conduction and reporting of this protocol, we closely followed the Standard Protocol Items: Recommendations for Interventional Trials statement.17 Setting In the Netherlands, VKA therapy is monitored by thrombosis services. We will use existing registries of several of these thrombosis services spread over the Netherlands to select and invite eligible patients with AF on VKA treatment, typically acenocoumarol or phenprocoumon. Randomisation and follow-up will be coordinated at the study coordinating site (University Medical Center (UMC) Utrecht, the Netherlands). All four available NOACs (dabigatran, rivaroxaban, apixaban and edoxaban) are registered for stroke prevention in the Netherlands and can be prescribed in this study. Enrolment started in January 2018. Patient population Eligible subjects are 1) frail persons, 2) aged ≥75 years, 3) diagnosed with AF, 4) receiving VKA treatment and monitoring by one of the participating thrombosis services, and 5) willing to consider switching from a VKA to a NOAC. Frailty will be assessed with the Groningen Frailty Indicator (GFI) questionnaire (see Supplementary file S1).18 We set the threshold for frailty at ≥3 instead of the traditional cut-off ≥4 on a scale from 0 to 15, because the GFI is a generic questionnaire that insufficiently takes into account that patients with AF are more vulnerable than other elderly without AF because of the need for antithrombotic medication known for their rather small therapeutic range and risk of bleeding. Lowering the threshold in the GFI for patients with specific vulnerable diseases is a strategy that is also often applied in, for example, cancer research.19 Exclusion criteria are 1) valvular AF, that is, AF in the presence of a mechanical heart valve or severe mitral valve stenosis, 2) participation in other medical scientific drug research, and 3) unwilling or unable to provide written informed consent. In addition, patients with severe renal impairment (i.e. estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2) will not be randomised, but will be followed observationally in parallel to the trial in order to obtain additional information about risk factors for bleeding. 6
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