Assessing gaps in cholesterol treatment guidelines for primary prevention of cardiovascular disease based on available randomised clinical trial evidence: The Rotterdam Study

Background: The purpose of this study was to determine how American College of Cardiology/American Heart Association (ACC/AHA) 2013 and European Society of Cardiology 2016 guidelines for the primary prevention of atherosclerotic cardiovascular disease (CVD) compare in reflecting the totality of accrued randomised clinical trial evidence for statin treatment at population level. Methods: From 1997–2008, 7279 participants aged 45–75 years, free of atherosclerotic cardiovascular disease, from the population-based Rotterdam Study were included. For each participant, we compared eligibility for each one of 11 randomised clinical trials on statin use in primary prevention of CVD, with recommendations on lipid-lowering therapy from the ACC/AHA and European Society of Cardiology (ESC) guidelines. Atherosclerotic cardiovascular disease incidence and cardiovascular disease mortality rates were calculated. Results: The proportion of participants eligible for each trial ranged from 0.4% for ALLHAT-LLT to 30.8% for MEGA. The likelihood of being recommended for lipid-lowering treatment was lowest for those eligible for low-to-intermediate risk RCTs (HOPE-3, MEGA, and JUPITER), and highest for high-risk individuals with diabetes (MRC/BHF HPS, CARDS, and ASPEN) or elderly PROSPER. Eligibility for an increasing number of randomised clinical trials correlated with a greater likelihood of being recommended lipid-lowering treatment by either guideline (p < 0.001 for both guidelines). Conclusion: Compared to RCTs done in high risk populations, randomised clinical trials targeting low-to-intermediate risk populations are less well-reflected in the ACC/AHA, and even less so in the ESC guideline recommendations. Importantly, the low-to-intermediate risk population targeted by HOPE-3, the most recent randomised clinical trial in this field, is not well-captured by the current European prevention guidelines and should be specifically considered in future iterations of the guidelines.