Trial sequential analysis for incidence of bradycardia, using required information size. (A) Scenario 1 in all studies, (B) scenario 2 in all studies, (C) scenario 3 in all studies, (D) scenario 1 in cesarean delivery studies, (E) scenario 2 in cesarean delivery studies, and (F) scenario 3 in cesarean delivery studies. The red inward sloping lines to the left of the graph make up the trial sequential monitoring (O’Brien-Fleming) boundaries. The red outward sloping lines to the right of the graph represent the futility region. The z-statistic (summary estimate over its SE) is computed when a trial enters the analysis. The blue line is the cumulative Z-curve, and each black square in the line represents one study. The number (in black) that is parallel to the end of the Z-curve represents the total number of patients in the corresponding meta-analysis. The intersection of the red lines at Z-score +1.96 and −1.96 represent the “conventional” significant P value (0.05). CEP = control event proportion; RIS = required information size; RRR = relative risk reduction.