Introduction

Management of modifiable cardiovascular risk factors is a cornerstone of cardiovascular disease (CVD) prevention and emphasized in prevention guidelines.^1,2The European Society of Cardiology (ESC), together with other partner societies, has released guidelines on CVD prevention since 1994. In the 2016 ESC CVD prevention guidelines,²the systemic coronary risk estimation (SCORE) algorithm was recommended to estimate the 10-year risk of CVD death in apparently healthy individuals without established atherosclerotic cardiovascular disease (ASCVD), type 2 diabetes mellitus, or other severe comorbidities. In the most recent 2021 ESC guidelines,³a new SCORE2 algorithm was recommended to estimate the 10-year risk of fatal and non-fatal CVD in apparently healthy individuals aged 40–69 years without diabetes mellitus, chronic kidney disease, or familial hypercholesterolaemia. Using the SCORE2 algorithm in these individuals, CVD risk can be categorized as low-to-moderate, high, and very high risk. Together with consideration of other factors (e.g. risk modifiers, lifetime CVD risk, comorbidities, frailty, treatment benefit, and patient preferences), the risk categories are linked to recommended treatment strategies. These strategies include when lipid-lowering therapy (LLT) should be applied and the treatment goals of low-density lipoprotein cholesterol (LDL-C) that should be achieved.

To better understand the impact of implementing SCORE2 and the ESC guideline recommendations, we need contemporary data on the distribution of risk groups and LDL-C levels in an apparently healthy general population. We also need data on the prevalence of subclinical atherosclerosis in those who are and those who are not recommended LLT. The SCORE2 10-year CVD risk can be obtained from the SCORE2 equation⁴using a calculator or from a SCORE2 multicell chart where the average risks in relation to sex, smoking status, age, blood pressure, and non-HDL cholesterol intervals are given.^3,4How these two different ways of determining CVD risk group influence the SCORE2-derived indications for LLT has not been described.

The aims were to describe (i) the eligibility for LLT according to ESC guidelines, (ii) the proportion with coronary atherosclerosis on coronary computed tomography angiography (CCTA) and coronary artery calcium (CAC) scoring in those eligible or non-eligible for LLT, and (iii) potential differences in risk categorization when using the SCORE2 equation vs. the SCORE2 chart, in an apparently healthy middle-aged general population.

Discussion

This descriptive report from the largest cohort so far of apparently healthy middle-aged men and women undergoing extensive imaging, including CCTA, includes several important observations. If the SCORE2 equation is applied according to the 2021 ESC guidelines on a population-based sample of apparently heathy middle-aged individuals in Sweden, 35% of all individuals should be considered for LLT (class IIa recommendation). Among these, 38% had no signs of coronary atherosclerosis (SIS = 0 and CAC score = 0), 33% had no carotid atherosclerosis, and 16% had neither coronary nor carotid atherosclerosis. If the SCORE2 chart is used an additional 47%, i.e. more than half of the cohort, should be recommended LLT of which 44% had no signs of coronary atherosclerosis on CCTA. However, only 7% of those recommended LLT in this cohort were on treatment, and of those not on treatment, only 11% were prescribed LLT within 6 months from examination.

SCAPIS is the largest prospective study, to date, that includes extensive imaging examinations on a general middle-aged population. A total of 50% of the invited population participated in the study, which may have contributed to socioeconomic selection bias.¹²However, the distribution of risk factors and coronary atherosclerosis in the SCAPIS cohort and target population have been similar when standardizing for age, sex, and socioeconomical factors, indicating a limited selection bias.^8,12Furthermore, the distribution of the 10-year CVD risk categories in our study, according to SCORE2, is in line with that of the derivation and validation cohorts of SCORE2.⁴

To our knowledge, this is the first large study that assesses the potential eligibility for primary preventive LLT in a country with moderate baseline CVD risk, as a result of applying SCORE2 and the 2021 ESC CVD prevention guidelines, in an apparently healthy middle-aged population. With consideration to lifestyle modifications, patient preferences, lifetime CVD risk, treatment benefits, frailty, comorbidity, and risk modifiers, SCORE2 can help guide the CVD prevention treatment strategies and intensity. According to the current ESC guidelines, when using the stepwise approach (with the first step being lifestyle modifications and LDL-C < 2.6 mmol/L), the ultimate LDL-C treatment goal is <1.8 mmol/L and ≥50% reduction in high-risk individuals and <1.4 mmol/L and ≥50% reduction for those with very high risk.^3,10In our study, most individuals with high and very high risk had LDL-C levels above the ultimate treatment goals. Thus, in 35% (59% of men, 14% of women) of the individuals LLT should be considered according to the guidelines. This is similar to a smaller Swiss study on 4092 individuals, older than 40 years, where 41% were eligible or recommended LLT according to the 2021 ESC guidelines.¹³However, when SCORE2 was applied to a Danish middle-aged population, 19% were classified as high or very high risk and thus potentially eligible for LLT.¹⁴Neither of these previously mentioned studies, however, included the individuals’ LDL-C levels when estimating LLT eligibility. Furthermore, the difference with our results could be explained by the use of SCORE2 for countries with low baseline CVD risk in Denmark compared with the moderate baseline risk in Sweden. When we analysed LLT eligibility using the SCORE2 algorithm for countries with low baseline CVD risk, 22% of the study cohort were eligible. Since Sweden had a moderate baseline CVD risk at the time of inclusion of study participants and is classified as such in the 2021 ESC guidelines, we used the SCORE2 algorithm for moderate-risk countries in our primary analyses.

One of the strengths of our study is the extensive use of imaging with CAC score, CCTA, and carotid ultrasound. According to the 2021 ESC CVD prevention guidelines, results from CAC scoring and carotid ultrasound may be considered as CVD risk modifiers; however, no specific recommendations are given on how to implement them.³In this paper, we report that implementing SCORE2 on this apparently healthy middle-aged cohort would result in a significant proportion of individuals without signs of coronary atherosclerosis being classified as high or very high risk and eligible for LLT. About 5% of those classified as low–moderate risk had SIS ≥4 or CAC score ≥100, indicating eligibility for LLT. Previous studies have reported that CAC scoring can help distinguish individuals that would benefit the most from LLT.^15,16This is in line with US guideline recommendations that CAC = 0 may be used to lower some patients’ risk category and consequently potentially postpone or withhold statin therapy.¹⁷Furthermore, when risk modifiers such as CAC were used in addition to SCORE2, the predictive risk accuracy was improved.¹⁸Together with our results, this could indicate a need for more precise risk scores that incorporate data from imaging studies, when available.

In the 2021 ESC prevention guidelines, two ways of using the SCORE2 are presented: the SCORE2 algorithm (equation) and the SCORE2 multicell risk chart. Our analyses show that the SCORE2 chart categorizes 52% as eligible for LLT when compared with 35% when using the equation. As the easier to use chart might be preferred over calculators in clinical practice, this may impact treatment decisions for individual patients.

In our cohort, only 5% of the study population reported use of LLT at study inclusion. This is in line with a Dutch study where ∼8% of the middle-aged study population, without previous CVD, had LLT at baseline.¹⁹In addition, ∼10% of the total Norwegian population <80 years (including those with CVD) received a LLT prescription in 2019.²⁰Moreover, only 11% of individuals with high and very high CVD risk were prescribed de novoLLT within 6 months after study inclusion. This could highlight the ineffectiveness of giving the individuals the results of their lipid panels and lifestyle advice when it comes to subsequent LLT prescriptions.²¹This could also indicate a need for more structured recommendations for individuals participating in these types of cohort studies, despite the risk of affecting the observational nature of similar studies. It should, however, be noted that studies on general health checks and risk scoring have so far shown mixed results on CVD mortality.^22,23Future studies on the SCAPIS cohort might help bring into light whether or not study participants, with information from the examinations and imaging results, have a better CVD outcome compared with a non-participating control group.