In the cardiovascular area, the rate of occurrence of relevant clinical events decreased over the last decades due to the large adoption of evidence-based treatments. This implies that large numbers of patients are needed to provide reliable answers to research open questions. Therefore, the conduction of multinational large-scale studies became necessary. In this setting, it is not infrequent to find relevant differences in the trial results across countries. The interpretation of these differences should be extremely cautious to avoid the well known mistakes related to subgroup analyses. To believe in differences, it is necessary to adopt appropriate methodologies in the analysis of data but, even more important, to find a biological plausibility that can explain the observed difference. A further confirmation from other studies can also help in the interpretation. In the literature there are some examples of such differences that, in some cases, produced erroneous interpretations of the results of a trial, and also induced regulatory authorities to take decisions based on these differences.