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Importance: For primary prevention of atherosclerotic cardiovascular disease (ASCVD), the 2021 European Society of Cardiology (ESC) guidelines on statin use (hereafter European-ESC) recommend a new risk model (Systematic Coronary Risk Evaluation 2 [European-SCORE2]) as well as new age-specific treatment thresholds (≥7.5% 10-year ASCVD risk if aged 40-49 years and ≥10% if aged 50-69 years).Objective: To compare the clinical performance of the 2021 European-ESC, American College of Cardiology/American Heart Association (hereafter US-ACC/AHA), UK National Institute for Health and Care Excellence (UK-NICE), and 2019 ESC/European Atherosclerosis Society (EAS) guidelines in apparently healthy individuals.Design, Setting, and Participants: This population-based contemporary cohort study included 66 909 individuals from the Copenhagen General Population Study. Participants were aged 40 to 69 years and were free of ASCVD, diabetes, chronic kidney disease, and statin use at baseline in 2003 to 2015. Mean follow-up time was 9.2 years. Data were analyzed from November 2021 to April 2022.Exposures: Statin treatment according to guideline criteria.Main Outcomes and Measures: Calibration of risk calculators, statin eligibility, sensitivity, and specificity for ASCVD events according to guideline criteria.Results: During follow-up, a range of 2962 to 4277 nonfatal and fatal ASCVD events was observed, as defined by the 2021 European-SCORE2, US pooled cohort equations (PCE), and UK-QRISK3 models, and 180 fatal ASCVD events were noted as defined by the 2019 European-SCORE1 model. European-SCORE2 was slightly better calibrated with a predicted/observed ASCVD event ratio of 0.8 vs 1.3 for US-PCE, 1.3 for UK-QRISK3, and 5.8 for European-SCORE1. For primary prevention class I recommendations in individuals aged 40 to 69 years, 2862 of 66 909 (4%) qualified for statins according to the 2021 European-ESC guidelines compared with 23 029 (34%) with US-ACC/AHA, 17 659 (26%) with UK-NICE, and 13 496 (20%) with 2019 European-ESC/EAS guidelines, with associated sensitivities for detecting future European-SCORE2-defined ASCVD events of 12%, 60%, 51%, and 36%, respectively. The sensitivity of the European-ESC guidelines was improved considerably by lowering the treatment thresholds, resulting in smaller losses in specificity. To obtain similar clinical performance with the 2021 European-ESC guidelines as in the other guidelines, the threshold with European-SCORE2 should be reduced to 5% overall to match US-ACC/AHA, to 6% to match UK-NICE, and to 7% to match 2019 European-ESC/EAS guidelines.Conclusions and Relevance: Despite an improved European-SCORE2 prediction model, the new treatment thresholds in the 2021 European-ESC guidelines dramatically reduce eligibility for primary prevention with statins in low-risk European countries. Using lower treatment thresholds can improve overall guideline performance.

Importance: Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk.Objective: To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD.Design, Setting, and Participants: A mendelian randomization analysis was conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018.Exposures: Genetic LPA score and plasma Lp(a) mass concentration.Main Outcomes and Measures: Coronary heart disease.Results: Of the included study participants, 53% were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95% CI, 0.933-0.951; P = 3 × 10-37), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (OR, 0.855; 95% CI, 0.818-0.893; P = 2 × 10-12). Thus, a 101.5-mg/dL change (95% CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk.Conclusions and Relevance: The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (ie, 1 mmol/L).