Sample size determination and statistical analysis
bleeding, dabigatran‐based, ACS, diabetes
BLEEDING, SECONDARY, EVENTS, APPENDIX, DIABETES
The OPTIMA‐4 trial aims to simultaneously test the following two hypotheses of dabigatran‐based DATT in eligible patients: (1) clopidogrel is superior to ticagrelor regarding major bleeding and CRNMB events and (2) clopidogrel is noninferior to ticagrelor regarding the composite efficacy endpoint. According to the RE‐DUAL PCI trial, the anticipated incidence of annual efficacy endpoint is 18.9% in the arm of ticagrelor.Descriptive statistics will be used to summarize and analyze the baseline demographic characteristics (mean, SD, median, minimum, first quartile, third quartile, and maximum for continuous measures; frequency counts and percentages for categorical measures) of each treatment group; the Student To control the type I error at one‐side 0.025 level, a hierarchical procedure for multiple testing will be used. The paradigm of the hierarchical procedure in OPTIMA‐4 trial is detailed below:
Superiority of dabigatran combined with clopidogrel to dabigatran combined with ticagrelor concerning major bleeding and CRNMB is met at the one‐sided 0.025 level of significance.Noninferiority of dabigatran combined with clopidogrel to dabigatran combined with ticagrelor for the efficacy endpoint is met at the one‐sided 0.025 level of significance.If step 1 fails to meet statistical significance, step 2 will not be performed.The primary endpoints will be treated as time‐to‐event endpoints, and the Kaplan–Meier method will be employed to estimate the cumulative incidences of endpoints by treatment group. The primary endpoints between the two groups will be compared using the Cox proportional hazards model with treatment as a fixed effect and adjusted for other covariates separately. The estimated hazard ratio (HR) and two‐sided 95% confidential interval (CI) or one‐sided 97.5% CI for the noninferiority test will be provided. For the noninferiority test in the composite efficacy endpoint, the noninferiority margin is 1.38 on the HR scale. The upper boundary of CI for the HR (one‐sided 97.5%) will be compared to this margin. All the above analyses will also be conducted in predefined subgroups. The secondary time‐to‐event endpoints will be analyzed using the methods mentioned above. All statistical analyses will be performed using SAS version 9.4 (SAS Institute Inc.).The analysis sets are as follows: (1) full analysis set (FAS): according to the intention‐to‐treat principle, the FAS is defined as all patients being randomized who receive at least one dose of the assigned treatment; (2) per‐protocol analysis set (PPS): the PPS is a subset of FAS, which includes all randomized patients meeting the study eligibility criteria, without major protocol deviation (see Supporting Information: Appendix Subgroup analyses are planned across major subgroups by age, sex, body mass index, diabetes, ACS diagnosis, the Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score, and CHA