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“The further you can look back, the longer you can look forward.”
Winston Churchill, Royal College of Physicians, 1944
Cardiovascular medicine has developed dramatically over the past 20–30 years, with major advances in the understanding and treatment of such diseases as coronary heart disease, cerebrovascular disease, hypertension, peripheral artery disease, and heart failure. Of major importance in this improved treatment are the many clinical trials and the advancement of evidence based medicine that these trials have documented. However, in this development not all trials have been successful and, in fact, the intervention in several trials has been associated with increased risk. Furthermore, the interpretation of trial outcomes has not always been correct and we know that history can bring about a different answer.
The intention with this article is to provide some examples of fallacies in cardiovascular trials that can improve our understanding in the design, conduct and interpretation of future trials.
Randomised, large intervention outcome trials are usually not designed to assess mechanisms. Interpretation of mechanisms based on trial results will most often be difficult and can easily result in wrong conclusions being drawn. The reason is that an outcome trial needs a large number of patients and usually many more than what are needed to analyse effects of an analogue variable. Often trials include sub-studies to address questions about mechanisms. However, the sub-study can be underpowered and therefore it has to be designed based on the overall trial that might not allow for a focused recruitment that a mechanistic study can allow. In the ILLUMINATE trial, patients were randomised to atorvastatin or atorvastatin combined with torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, in order to optimise blood lipid values.1 Because previous studies had shown beneficial effects when using such a surrogate, a positive effect on outcome …