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

Abstract

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.

Keywords::

• atherosclerosis
• clinical CVD event trials
• intermediate end point CVD clinical trials
• paradigm

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Intermediate end point cardiovascular disease (CVD) clinical trials are very popular because they are less costly and are thought to forecast/foreshadow actual clinical CVD events.

• Intermediate end point CVD clinical trial is an excellent idea based on an obsolete paradigm with variable utility.

• Recent discovery of other pathways involved in atherosclerosis, data on current subclinical CVD markers and the inherent measurement errors in CV risk factors and current subclinical CVD markers or both does not support the historical paradigm and hence does not support the use of current subclinical CVD markers as intermediate end points in CVD clinical trials.

• Continued use of current subclinical CVD markers as intermediate end points in CVD clinical trials are bound to produce discordant results, such as the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis–Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes/Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events and St Francis Heart randomized clinical trial–Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm trials.

• In the absence of better subclinical CVD markers that mediate significant effects of CV risk factors on clinical CVD events, a new tool consisting of current subclinical CVD markers and markers from all the other newly discovered pathways that play a central role in the pathogenesis of atherosclerosis should be built and used as the outcome variable for intermediate end point CVD clinical trials.

Notes