Fig. 5

TSA; On the left, the inward-sloping red lines represent the boundaries of sequential trial monitoring. On the right, the outward-sloping red lines constitute the futility region. The continuous blue line is the cumulative Z-curve. Dark red line (Z = 1.98). In detail this TSA graph shows the cumulative Z-curve (blue line) as datasets are sequentially added, plotted against the accrued sample size. The red inclined lines represent the trial sequential monitoring boundaries, which adjust for the risk of type I and II errors in cumulative meta-analysis. The inward-sloping boundaries indicate the threshold for statistical significance, whereas the outward-sloping lines delineate the futility area. The graph demonstrates that the cumulative Z-curve crosses the significance boundary from the first dataset and reaches the required information size (RIS) of 36 from the second dataset onward, thereby confirming that the evidence is robust and sufficient to support the observed effect