Statistical Evaluation and Analysis of Regional Interactions: The PLATO Trial Case Study

Multiregional randomized clinical trials often are conducted to evaluate interventions proposed for treatment or prevention of diseases, especially in clinical settings such as cardiovascular diseases where it is important to enroll a large number of patients in a timely manner. As outlined in the International Conference on harmonization E5 Ethnic Factors in the Acceptability of Foreign Clinical Data, an obvious interest when evaluating the results of such trials is the consistency of effects across regions. The purpose of this article is to review a recent example, a large cardiovascular outcomes trial known as “PLATO,” where substantial evidence of regional heterogeneity emerged during the analysis. We present the statistical thinking and methodology that went into the evaluation of the results and the logic that led to the judgment that, while chance cannot be ruled out entirely, the appearance of the regional heterogeneity was likely a manifestation of an underlying interaction with concurrent aspirin dosage. This example may provide a useful reference point for the statistical evaluation of regional effects in future large outcomes trials. Supplementary materials for this article are available online.