Surrogate end points in secondary analyses of cardiovascular trials.

A surrogate end point is one that is used as a substitute for a clinical end point of more direct interest, usually for reasons of practicality, and that is expected to predict clinical benefit. Surrogate end points play a critical role in the advancement of all medical research, and cardiovascular (CV) research in particular. However, the relationship between a surrogate end point and its clinical end point is usually complex, and there are many examples where results based on surrogates have proved to be misleading. Secondary analyses of existing clinical trial data are likely to involve surrogate end points, if only because clinical end points will have been extensively studied as part of the primary analysis of a trial large enough to collect useful clinical end point data. Validation of a surrogate end point is a laudable goal for a secondary analysis of a large clinical end point trial (or meta-analysis of multiple smaller trials), and the result may be an important new tool for further study of a class of compounds in a particular disease context. Secondary analyses using surrogate end points may also provide new insight into disease or treatment mechanism, but as with any surrogate end point analysis, the results can mislead, and the existing literature is heavy on application and light on methodology. Surrogate end points often substitute efficiency for clarity, and while many interesting and potentially informative secondary analyses of CV trials will involve surrogates, results are likely to be ambiguous and should be interpreted with care.