Large simple trials: really, it can't be that simple!

In this issue of the European Heart Journal, Calvo et al. present another plea for simplified approaches to clinical trials evaluating cardiovascular therapies. In the interest of disclosure, I note that I work closely with many of the authors of this article. Dr Christopher Granger, in particular, is a long-time collaborator and senior investigator in my own institution. The thesis advanced by Calvo et al. could be called the ‘large simple trial (LST) mantra’. Although I agreewith most of the concepts expressed in their paper—and indeed, I co-chair the Clinical Trials Transformation Initiative (http://www.ctti-clinicaltrials.org/), a public-private partnership with the US Food and Drug Administration (FDA), and more than 60 other organizations that champion similar ideas—this mantra nonetheless omits important aspects that should be considered if LSTs are to be understood within a larger context. To clarify the role that LSTs can play in informing the cardiovascular evidence base, I believe that the following issues deserve consideration.