Intermediate end point cardiovascular clinical trials: an excellent idea based on an obsolete paradigm

Intermediate end points are widely used in cardiovascular clinical trials mainly to forecast/foreshadow actual clinical cardiovascular outcomes. This approach is based on the historical atherosclerosis paradigm which states in part that the effects of traditional cardiovascular risk factors on clinical cardiovascular disease (CVD) events are solely mediated through subclinical cardiovascular disease/atherosclerosis. The utility of intermediate end point CVD clinical trials using either historical subclinical CVD markers such as quantitative angiography or current sophisticated markers such as coronary artery calcium, carotid intima-media thickness or brachial flow mediated dilation has been variable. Discoveries of other pathways pertinent to the pathogenesis of atherosclerosis calls for a new conceptual model or paradigm and helps explain the discordance in results from prior and ongoing intermediate end point-clinical CVD event trial pairs.