Eligibility for lipid-lowering randomised clinical trials and long-term outcomes in real-world contemporary patients with atherosclerotic cardiovascular disease

Background/Introduction Lipid-lowering randomised clinical trials (RCTs) inform guideline recommendations on lipid-lowering therapy for the prevention of atherosclerotic cardiovascular disease (ASCVD). However, these trials were often conducted several decades ago and employed stringent eligibility criteria to ensure internal validity, which may not reflect the diversity of contemporary real-world patients. Whether ineligible patients with coronary artery disease (CAD), cerebrovascular disease (CeVD), and peripheral artery disease (PAD) have a different prognosis than eligible patients remains unknown. Purpose To evaluate the proportion of contemporary real-world patients meeting eligibility criteria for pivotal lipid-lowering trials and to compare clinical characteristics and long-term outcomes between trial-eligible and ineligible patients. Methods Lipid-lowering RCTs informing European and American guidelines for secondary ASCVD prevention were identified. Eligibility criteria from eight selected RCTs were applied to patients with CAD, CeVD, and PAD. These patients were enrolled in an ongoing prospective cohort of individuals aged 18–90 years with high cardiovascular risk, referred to a tertiary hospital between 2000 and 2023. Eligibility proportions were calculated for each trial, and differences in clinical characteristics and risks of recurrent cardiovascular events and all-cause mortality were analysed, accounting for competing risks. A sensitivity analysis was conducted in patients included from 2010 onwards. Results The study included 8,537 patients with established ASCVD, of whom 5,673 had CAD, 2,493 had CeVD, and 1,302 had PAD. The median follow-up was 8.8 years (interquartile range [IQR]: 4.2–13.9 years). Eligibility proportions for lipid-lowering RCTs ranged from 9–85% for CAD (Figure 1), 7–42% for CeVD, and 8–78% for PAD. Trial-eligible and ineligible patients exhibited differences in clinical characteristics in most trials, but they had largely comparable risks of recurrent cardiovascular events and all-cause mortality. Rate ratios for recurrent cardiovascular events ranged from 0.70 (95% confidence interval [CI]: 0.62–0.79) to 1.55 (95% CI: 1.37–1.75) for CAD (Figure 2), 0.68 (95% CI: 0.56–0.83) to 2.12 (95% CI: 1.60–2.81) for CeVD, and 0.83 (95% CI: 0.64–1.08) to 1.94 (95% CI: 1.40–2.70) for PAD. Conclusions Eligibility of contemporary real-world patients for lipid-lowering trials varied substantially between trials and ASCVD disease locations. Patients with CeVD were the least likely to be eligible compared with those with CAD and PAD. Despite differences in clinical characteristics, trial-eligible and ineligible patients had similar risks of recurrent cardiovascular events and all-cause mortality in most trials.