91 FRAIL-AF RANDOMISED CONTROLLED TRIAL: RATIONALE AND DESIGN of bleeding events in the experimental and control arm equal 10.5% and 15%, respectively (as explained above). If we assume the survival curves are exponential, the hazard in the control arm equals 0.0135 and the hazard in the experimental arm equals 0.0092. The assumed HR, therefore, equals 0.683. Using a one-sided alpha of 0.025 and a maximum sample size of 2,500 subjects (each being followed for twelve months), a power of 0.9209 is obtained for the design in which an interim analysis is performed after having observed 160 events. If, at that stage, the estimated HR exceeds 0.9925, the trial may be halted for futility, in collaboration with advice from the independent data safety monitoring board. Only if the HR then is estimated to be lower than 0.3592 (i.e. an extremely large difference in favour of the experimental treatment), the trial is halted for efficacy. If the trial continues, then the final analysis is performed after having observed 319 events. If the estimated HR at that point exceeds 0.8028, futility is concluded. If not, efficacy is considered demonstrated. Study procedures The flowchart of the FRAIL-AF study is shown in Figure 1. Recruitment and enrolment will be done by the participating thrombosis services using their own patient registries. Patients will only be contacted if the patient’s treating physician (usually general practitioner or cardiologist) has no objection to the patient’s participation in the study, notably because for ethical reasons this study does not allow the inclusion of patients who do not understand an informed consent conversation due to, for example, severe cognitive impairment. After obtaining informed consent and before the start of the study, patients and treating physicians will be asked to provide baseline data and renal function will be measured. Subjects with severe renal impairment (i.e. eGFR <30 mL/ min/1.73 m2) will not be randomised, but will be followed observationally to retrieve additional information about risk factors for bleeding. Subjects with an eGFR ≥30 mL/ min/1.73 m2 either receive care as usual (i.e. continuation of VKA treatment) (control arm) or switch to a NOAC based treatment strategy (intervention arm), based on the random allocation of patients. Those randomised to NOAC treatment receive their first prescription for one month by the research team. After one month, the treating physician will take over the NOAC prescription. This strategy exemplifies the pragmatic real-life setting of this trial. 6
RkJQdWJsaXNoZXIy MTk4NDMw