90 CHAPTER 6 Sample size calculation There is uncertainty regarding the estimates of the yearly incidences of our composite outcome major or CRNM bleeding complications in frail elderly patients with AF treated with a VKA as well as the effect size of reducing the occurrence of this composite outcome when switching to a NOAC.7–10,20 Based on a Dutch study with an aged population we anticipate that the yearly incidence of major and CRNM bleeding complications is 10% to 15% in our frail elderly using a VKA.21 A relative reduction of 20% to 30% on the occurrence of these bleeding complications when switching to a NOAC can be expected on the basis of large-scale NOAC trials and postmarketing observational studies, although studies specifically in frail elderly patients are lacking.7–10 Assuming a two-sided alpha level of 0.05, a 1:1 allocation ratio, and 1,250 patients in each treatment arm, power will be at least 0.80 if the incidence of major or CRNM bleeding complications on VKA treatment is between 11% (with an incidence of our composite outcome on NOAC treatment of 7%) and 15% (with an incidence of our composite outcome on NOAC treatment of 11.2%). Given that power will drop below 0.50, only if the incidence of our composite outcome on VKA treatment is on the lower margin of our expected estimation (namely at 10%) and if at least 7.7% of patients on NOAC treatment experience major or CRNM bleeding complications (see Table 1), we consider 1,250 patients per arm to be sufficient. TABLE 1: SAMPLE SIZE CONSIDERATIONS. VKA: yearly incidence of bleeding complications (%) Assumed relative reduction (%) NOAC: yearly incidence of bleeding complications (%) Power* 15 30 10.5 0.92 15 25 11.25 0.79 15 20 12 0.59 10 30 7 0.77 10 25 7.5 0.60 10 20 8 0.42 * The power is calculated assuming a two-sided alpha level of 0.05, a 1:1 allocation ratio, and n=1,250 per arm. NOAC: non-vitamin K antagonist oral anticoagulant; VKA: vitamin K antagonist. Interim analysis plan Given the uncertainty on the ability to demonstrate a reduction in bleeding events in this frail population, a pre-planned interim analysis will be performed to compare the hazard ratio (HR) on major or CRNM bleeding complications between both treatment arms, in order to anticipate futile or negative trends at a relatively early stage. The bounds for this analysis are determined based on a two-sided, asymmetric, betaspending group sequential design with a non-binding lower bound, with an O’BrienFleming-type boundary (Hwang-Shih-DeCani spending function with gamma=−4) for futility and a highly conservative boundary (Hwang-Shih-DeCani spending function with gamma=−40) for efficacy. It is assumed that, after twelve months, the proportion
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