93 FRAIL-AF RANDOMISED CONTROLLED TRIAL: RATIONALE AND DESIGN Randomisation Subjects are randomised to the intervention or control arm, following a computerised block randomisation with a 1:1 allocation ratio, and stratified by thrombosis service and renal function at baseline. For renal function, two strata are defined: patients with an eGFR of 30-50 mL/min/1.73 m2 and patients with an eGFR ≥50 mL/min/1.73 m2. Allocation using the randomisation results will be executed by the researchers at the study coordinating site. As this is a pragmatic randomised trial, neither patients nor treating physicians will be blinded to the allocated therapy. Intervention under study Patients randomised to the intervention switch from VKA therapy to a NOAC based treatment strategy. Because of the pragmatic design of the study and the lack of direct comparative research between NOACs that have evaluated which NOAC is the best, we feel it is not appropriate to prescribe only one type of NOAC. Therefore, treating physicians (usually general practitioners or cardiologists) of patients randomised to the intervention arm are asked which of the four available NOACs (dabigatran, rivaroxaban, apixaban, edoxaban) they want to continue after the initial month. If preferred by the physician, this allocation will be accomplished in collaboration with local cardiologists, the thrombosis service or in shared decision making between the treating physician and one of the senior researchers, and based on the summary of product characteristics (SPCs) and current guidelines.22–25 In case the treating physician’s chosen NOAC dosage for an individual patient does not correspond to the recommendation in the SPC, consultation takes place between the researchers and the treating physician. However, we explicitly follow any deliberately chosen prescription regimen of the treating physician, also if the treating physician willingly chooses a higher or (more likely) lower NOAC dose, again to mimic general clinical practice conditions as much as possible. In summary, the decision which NOAC is prescribed is tailored to the specific patients’ and physicians’ preferences; as such this study does not aim to compare different NOACs with each other. After all, this comparison would by highly affected by confounding by indication. The switching itself is carried out by the thrombosis services. Initially, the study protocol allowed patients to start the NOAC after the VKA was stopped for 48 hours if the previous INR measurement was within the therapeutic range for patients using acenocoumarol, or if a scheduled INR measurement was below 2.0 for patients on phenprocoumon. Following patient accrual into the study, the protocol of switching VKA treatment to NOAC treatment was adapted to best fit the frail population. With this adjustment a NOAC is only initiated the subsequent day after an INR measurement (performed 72 hours after stopping VKA treatment) is below 1.3. If the INR is still above 1.3, a subsequent INR will be performed the next day to check if INR levels have fallen below 1.3. 6
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