ESC/EAS guidelines for the detection, prevention, and treatment of individuals at risk of a first myocardial infarction: effect of 5 years of updates and the new SCORE2

Abstract

Aims

The European Society of Cardiology (ESC) has released three consecutive guidelines within 5 years addressing cardiovascular prevention, risk scores, and cholesterol treatment. This study aims to evaluate whether the 2021 ESC guidelines improved the eligibility of individuals for primary prevention statin therapy before their first ST-segment elevation myocardial infarction (STEMI), and for intensive lipid-lowering treatments in secondary prevention.

Methods and results

The cardiovascular risk category of 2757 consecutive individuals admitted for a first STEMI was evaluated to assess whether they would have been eligible for primary prevention statins according to 2021 vs. 2019 and 2016 ESC guidelines. Eligibility for intensive lipid-lowering therapy in secondary prevention was assessed according to the real-life follow-up low-density lipoprotein cholesterol (LDL-C) and the expected follow-up LDL-C. More individuals would have been eligible for primary prevention statins according to 2021 and 2019 vs. 2016 guidelines (61.8% vs. 38.7% vs. 23.6%, P < 0.01), a finding observed in both men (62.3% vs. 35.0% vs. 24.9%, P < 0.01) and women (60.2% vs. 50.7% vs. 19.3%, P = 0.18). Only 27% of individuals reached the LDL-C objective of 55 mg/L in secondary prevention: using the ESC stepwise approach, 61.7% were eligible for higher doses of statins, 26.2% for ezetimibe, and 12.1% for a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (PCSK9i). Based on expected LDL-C reductions, eligibility for a PCSK9i in secondary prevention was greater with 2021 vs. 2016 guidelines (44.5% vs. 22.5%, P < 0.01).

Conclusion

The 2021 ESC guidelines improved the detection and treatment of individuals at risk for a first myocardial infarction. In secondary prevention, 70% of patients kept LDL-C levels above 55 mg/dL: increasing the statin dose and adding ezetimibe were the most frequently recommended therapeutic actions.

Graphical Abstract

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Introduction

Despite the major advancements in the detection and treatment of cardiovascular risk, cardiovascular disease (CVD) is still the main cause of mortality in Europe with 4 million deaths per year, including 2.2 million deaths of women.^1,2 From 2016 to 2021, the European Society of Cardiology (ESC) provided three consecutive guidelines aiming to prevent cardiovascular disease.^3–5 In 2019, the ESC/EAS Guidelines for the Management of Dyslipidaemias: Lipid Modification to Reduce Cardiovascular Risk updated the recommendations on the detection and treatment of individuals at risk in primary and secondary prevention with the following major changes: first, the task force implemented risk modifiers to target specific populations at risk, especially sex-related risk factors, in the algorithms; secondly, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9is) are recommended with a class I for very high risk patients before any symptomatic cardiovascular disease; thirdly, in secondary prevention, PCSK9is are recommended on top of statins and ezetimibe in case of a persistently elevated low-density lipoprotein cholesterol (LDL-C) above 55 mg/dL (1.4 mmol/L). In 2021, the ESC Guidelines on Cardiovascular Disease (CVD) Prevention in Clinical Practice (2021 ESC guidelines) implemented the use of Systematic Coronary Risk Estimation 2 (SCORE2) and Systematic Coronary Risk Estimation 2—Older Persons (SCORE2-OP) in place of the Systematic Coronary Risk Estimation (SCORE), which was reported to underestimate the CVD burden because of including only fatal events.^6–8 Population-based studies have demonstrated the limitations of previous ESC guidelines to detect and recommend primary prevention statins in patients at risk of cardiovascular disease. Furthermore, while theoretical estimations of ezetimibe and PCSK9i eligibility in secondary prevention have been based on LDL-C expected reductions, the real-life effect of the stepwise approach in patients after a first ST-segment elevation myocardial infarction (STEMI) is unknown.

Thus, using baseline characteristics of patients admitted for a first STEMI, our primary objective was to assess whether they would have been eligible for primary prevention statins based on 2021, 2019, and 2016 ESC guidelines if they had been seen before this first event. Our second objective was to evaluate the guideline-recommended response for intensive lipid-lowering therapies in secondary prevention overall and according to sex.

Methods

Study design and population

The e-PARIS registry is a prospective registry of all consecutive individuals admitted for an STEMI at the University Hospital of Pitié-Salpêtrière, Paris, France. The design of the e-PARIS registry has been well described before.^9,10 In brief, it includes a pre-specified data set of clinical and biological characteristics, cardiovascular risk factors, angiographic characteristics, and follow-up for major non-fatal cardiovascular events and vital status. For the present study, we included individuals of the e-PARIS registry admitted for a first STEMI between January 2000 and October 2018, free of prior cardiovascular disease, with available cholesterol samples at admission. STEMI was defined as the presence of clinical myocardial ischaemia, associated with new or presumed new ST-segment elevation of 1 mm or more in two or more contiguous leads, bundle-branch block, or true posterior myocardial infarction (MI). The final diagnosis of STEMI was confirmed by the presence of an acute coronary artery occlusion during the coronary angiography. The registry was approved by the local ethical committee of the University Hospital Pitié-Salpêtrière of Paris.

Cardiovascular risk assessment prior to first ST-segment elevation myocardial infarction

Cardiovascular risk prior to first STEMI was estimated using the data collected at admission. The ESC/ European Atherosclerosis Society (EAS) guidelines classify individuals as ‘very high risk’, ‘high risk’, ‘moderate risk’, and ‘low risk’, with each category related to goals of LDL-C levels to determine eligibility for primary prevention statins. Following 2019 and 2021 ESC/EAS algorithms (Supplementary material online, Tables S1 and S2), individuals were classified based on (1) prior high-risk comorbidities such as diabetes with or without target organ damage, severe or moderate chronic kidney disease, familial hypercholesterolaemia, and severe arterial hypertension; (2) the SCORE (2016 and 2019 ESC guidelines) and SCORE2 (2021 ESC guidelines) charts for low-risk countries for ‘apparently healthy individuals’ (without previous high-risk comorbidities); and (3) their baseline LDL-C at admission. This risk estimation allowed assessing the number of individuals who would have been recommended for preventive statin treatment before their first STEMI.

Interpretation of 2019 and 2021 ESC guidelines for primary prevention

The updates that occurred from the 2016 to 2019/2021 ESC guidelines are reported in the Supplementary material online, Table S3. In brief, the 2019 ESC/EAS guidelines provided several updates compared with the 2016 ESC/EAS guidelines: first, the SCORE model included patients up to 70 years of age, compared with 65 years in prior guidelines; secondly, individuals aged 70 or more were considered eligible for statins (class IIb), while there was no prior recommendation for this age category before; more importantly, low-risk and moderate-risk individuals became eligible for direct intervention with statins in case of LDL-C above the level of 190 mg/dL. The recommendation for primary prevention using statins was updated from class IIa to I for all the high-risk individuals with a baseline LDL-C above 100 mg/dL. PCSK9i therapy was recommended for individuals at very high risk and uncontrolled LDL-C under maximal tolerated dose of statins and ezetimibe, either in a primary prevention setting (class IIb) or in secondary prevention (class I).

In the 2021 ESC guidelines, SCORE was replaced by SCORE2/2OP to stratify the risk of individuals without diabetes and without prior cardiovascular disease. The newness of SCORE2/2OP is that it included individuals from 40 to 89 years old, provides a different risk stratification giving more importance for risk factors other than for age or sex, and evaluates the risk of both non-fatal and fatal events at 10 years. The age extension allows a better risk screening, especially in female individuals who present their coronary events later than male ones.¹¹ The model was validated using a global population of 12.5 million individuals. Patients already treated with statins at admission were considered as eligible for both guidelines.

Eligibility for intensive lipid-lowering therapy after a first ST-segment elevation myocardial infarction

In secondary prevention, real-life follow-up LDL-C and guideline-based response were also evaluated among a subset of patients with intrahospital follow-up by using consultation reports and hospitalizations records. Medical data were checked for LDL-C levels until a censoring point of death occurrence or the date of 1 January 2021. Persistent active smoking, hypertension (>140/90 mmHg), diabetes control (Hb1ac > 6.5%), and lipid-lowering therapies prescribed were also obtained. Eligibility was assessed using the collected data and each patient's specific follow-up.

In a secondary analysis, the individual LDL-C level expected during follow-up was calculated based on baseline LDL-C, following the ESC guidelines: 50% of baseline LDL-C reduction in individuals discharged with high-intensity statins, 65% of baseline LDL-C reduction in individuals discharged with high-intensity statins plus ezetimibe, and 85% reduction of baseline LDL-C with high-intensity statins with ezetimibe plus PCSK9i. Thus, using the expected LDL-C follow-up and considering a maximal dosage of statin at discharge with full adherence, we also tried to assess the theoretical eligibility for either ezetimibe or PCSK9i.

Similarly, major adverse cardiovascular events (MACEs) defined by death, recurrence of acute coronary syndrome (ACS), or stroke were collected.

Endpoints

The first objective was to compare the 2016, 2019, and 2021 ESC/EAS guidelines’ efficiency to detect and treat patients who will develop a first STEMI, and then in men vs. women. Thus, eligibility for statins prior to a first STEMI was defined as a class I, IIa, or IIb recommendation. Secondly, we compared the proportion of men and women with hospital follow-up eligible for an intensive lipid-lowering therapy with PCSK9i and ezetimibe, based on real-life LDL-C. A similar analysis was performed according to expected reductions of LDL-C as described in ESC/EAS guidelines.

Statistical analysis

Continuous variables are presented as median and interquartile ranges and compared across sex categories using P-values for trends: Cochrane–Armitage Trend test for binary variables, Cochran–Mantel–Haenszel test for categorical variables, and Spearman correlation test for continuous variables. Descriptive summaries of the cohort and risk factors are based on available data with missing values excluded from calculations. The performance of the 2016 and 2021/2019 ESC/EAS guidelines were compared using a Welch/Student's t-test or the Mann–Whitney U test, as appropriate. No adjustment was made for multiple comparisons. A two-sided P-value <0.05 was considered significant. Statistical analysis was performed using GraphPad Prism version 6.04 for Windows, GraphPad Software, La Jolla, CA, USA.

Results

Baseline characteristics

Between February 2000 and October 2018, 2757 patients were admitted for a first STEMI, including 648 women (23.5%). Baseline characteristics are displayed in Table 1. Risk modifiers were more frequent in women than men, especially chronic inflammatory diseases. The median LDL-C level at admission for acute MI was 115 mg/dL (2.9 mmol/L) in women [interquartile range (IQR) 92–151] and 121 mg/dL (3.1 mmol/L) in men (IQR 92–151) (P = 0.52).

According to 2019 ESC guidelines, 17.2% of individuals with a first STEMI would have been considered at very high risk for a MACE (Table 2). Following the updates provided by the 2021 ESC/EAS guidelines, using SCORE2, 40.9% of individuals were considered at very high risk for a first major cardiovascular (Table 2). The SCORE and SCORE2 of individuals aged at least 40 years old without diabetes or chronic kidney disease are displayed in the Supplementary material online, Table S4.

At discharge, the maximal dosage of statin was administered to 72.4% of patients, with women being less likely to be discharged on the maximal dose of statin (69.8% vs. 73.1%, P < 0.001). Atorvastatine was the most prescribed drug.

Eligibility for primary prevention intervention in men and women

Based on the 2021 ESC guidelines, 61.8% of individuals would have met a class I, IIa, or IIb recommendation for primary prevention statins prior to STEMI, 38.6% according to the 2019 ESC/EAS guidelines, and 24% with the 2016 guidelines (P < 0.01) (Figure 1A). The increase in detection of individuals at risk from 2016 to 2021 occurred in both women (60.2% vs. 50.7% vs. 19.3%, P < 0.001) and men (62.3% vs. 35.0% vs. 24.9%, P < 0.001) (Figure 1B). Of note, based on the 2016 ESC guidelines, 24% of patients were not given any recommendation—either because of too low CV risk or because of their age being too advanced. The proportion of patients left out of any recommendation dropped to 5% with the 2019 guidelines, and 0% in 2021.

According to the 2019 ESC/EAS guidelines, 368 (17.4%) men and 106 (16.4%) women were considered at very high risk and thus would be potentially eligible for primary prevention PCSK9is in case of uncontrolled LDL-C with statins and ezetimibe. According to the 2021 ESC guidelines, intensive lipid-lowering therapy before a first cardiovascular event in very high risk patients would involve 879 (41.6%) men and 251 (38.8%) women.

Guideline-based intensive lipid-lowering therapy after a first ST-segment elevation myocardial infarction according to real-life low-density lipoprotein cholesterol (n = 975 patients)

Using health records linked to the ePARIS registry, the LDL-C levels of 975 patients were collected. After a median follow-up of 33 months [interquartile range: 7–71] after the MI, only 27% of patients reached the LDL-C objective below 55 mg/dL (1.4 mmol/L), and 39% below 70 mg/dL (1.8 mmol/L) (Figure 2).

Following the stepwise approach recommended by ESC guidelines, among 711 patients out of the LDL-C objective during follow-up, 439 (61.7%) were eligible for an increase of their statin dosage, 186 (26.2%) were eligible to add ezetimibe, and 86 (12.1%) were eligible to add a PCSK9i because they were already on the maximally tolerated dose of statins and ezetimibe without significant gender differences (Figure 3A and B). Following its introduction in the 2021 ESC guidelines with a class IIB recommendation, 189 (19.4%) patients were also eligible to add icosapent ethyl due to a triglyceride level >135 mg/dL.

Guideline-based intensive lipid-lowering therapy after a first ST-segment elevation myocardial infarction according to expected low-density lipoprotein cholesterol (n = 2757)

Using the ESC estimation of LDL-C reductions at discharge after a first STEMI, 38.7% of the cohort would reach LDL-C ≤55 mg/dL (≤1.4 mmol/L) even under a full dose of statins and total adherence, 16.8% of patients would require ezetimibe, and 44.5% would still have LDL-C above 55 mg/dL (1.4 mmol/L) under statins and ezetimibe and thus be eligible for a PCSK9i without statistical difference between men and women (Figure 4). Using the 2016 guidelines, 14.3% of patients would be eligible for ezetimibe and 22.5% for a PCSK9i for LDL-C levels below 70 mg/dL (1.8 mmol/L).

Control of other cardiovascular risk factors and outcomes

The follow-up of cardiovascular risk factors is displayed in Table 3. Persistent active smoking was frequent and concerned 35% of men and 14% of women. Among diabetic patients, Hb1aC was above 6.5% in 81 (47%) men and 21 (68%) women. The vast majority of patients had a well-controlled blood pressure (72%). During total follow-up, the composite of ACS, stroke, or death occurred at a rate of 5.1 per 1000 patient-years.

Discussion

Within 5 years, the ESC and EAS have implemented a substantial number of updates in the guidelines: the 2019 ESC/EAS guidelines lowered the LDL-C thresholds to start primary prevention therapy, modified the criteria to be considered at very high risk, and implemented novel intensive lipid-lowering therapy such as PCSK9is on top of statins and ezetimibe, with an objective of LDL-C at 55 mg/dL (1.4 mmol/L) or below. The 2021 ESC guidelines on CVD prevention for clinical practice implemented a new SCORE2 to improve risk stratification and provide an estimation of both non-fatal and fatal events at 10 years. Based on a cohort of consecutive individuals admitted for a first STEMI, we observed a significant improvement in the detection of high-risk individuals, with a three-fold increase in the eligibility for primary prevention statins. This improvement was especially observed for women, for whom cardiovascular risk was previously underestimated.^12,13 When analysing the follow-up of risk factors in secondary prevention and a guideline-based stepwise approach, most of the patients were eligible for an increase in statin dosage or for adding ezetimibe, but rarely a PCSK9i despite a vast majority of the patients having persistently high LDL-C levels.

In 2019, the ESC/EAS Guidelines for the Management of Dyslipidemia improved the identification of individuals at risk of MI compared with prior guidelines but still failed to assign direct statin therapy to 60% of these individuals. This improvement in the identification and treatment of adults who developed MI involved both men and women but was mostly seen in the population of women. Similarly to our findings, MB Mortensen et al. also showed an increase in eligibility for primary prevention statins from 15% to 32% in the Copenhagen General Population Study with new European guidelines.¹⁴ Of note, this improvement was particularly driven by the increase in age from 65 to 70 years in the recommendation for statins, which particularly involved women. Despite the improvements to identifying and treating individuals at risk, the 2019 ESC guidelines failed to identify 60% of the patients before their first MI. The first explanation involved the SCORE system itself: pivotal in the management of primary prevention, this algorithm has several well-documented limitations, the first being the estimation of the ‘last fatal event’ rather than the first non-fatal ischaemic event. The second reason is the use of old epidemiological data from 1986 not reflecting the actual CVD burden and underestimating global or individual risk. Eventually, the restricted age range of the previous SCORE (40–70 years old), prevented an efficient detection of women at risk of cardiovascular disease, for whom the average age of MI in Western Europe is 75 years. Thus, using an updated SCORE2 apprehending both non-fatal and fatal events, the new 2021 ESC guidelines greatly improve the identification and treatment of individuals before they have a first MI, with more than one-third of individuals considered at very high risk and two-thirds directly eligible for statin therapy. Such improvement was made possible via the risk model recalibration, which particularly changed the eligibility for statins for women at risk.

Still, the latest ESC guidelines failed to identify and treat more than one-third of individuals before their first MI. A better implementation of risk modifiers in the decisional algorithms is paramount to better detect and treat high-risk subgroups such as women and young individuals despite their many high-risk features.^15,16 While the task force listed important, meaningful, and frequent risk modifiers in the women and young individuals of our cohort, such as social deprivation and chronic immune-mediated inflammatory disorder, none of these criteria were efficiently implemented to guide the decision to prescribe statins. In parallel, improvements in the detection of high-risk patients should be weighted with the necessity to avoid unnecessary exposure to statins, with their potential side effects and health costs. As described by Mortensen et al., the improved sensitivity of the 2019 ESC guidelines compared with 2016 was associated with a reduction in specificity, and thus statin treatment for patients who would have not developed atherosclerotic cardiovascular disease.¹⁴

Within 3 years after their first STEMI, more than 70% of the patients did not meet the LDL-C target of 55 mg/dL (1.4 mmol/L): these patients were mostly treated with low- to moderate-intensity statins and without ezetimibe. Thus, when following the gradual response recommended by ESC guidelines, 26% of individuals would be eligible for ezetimibe and 12% for a PCSK9i after a first event—because more than 60% would be first eligible for an increase in statins before considering such therapies. A low rate of patients eligible for PCSK9is after a first MI based on the guidelines was also found by a previous study in a UK real-world study.¹⁷ In contrast, when using the ESC algorithm to predict the expected follow-up LDL-C, around 17% of patients could be eligible for ezetimibe and 40% for a PCSK9i.

Questions remain regarding the proportion of patients requiring a PCSK9i on top of statins and ezetimibe directly after an ACS to reduce LDL-C levels below 55 mg/dL as recommended by the ESC/EAS. In the EVACS (Evolocumab in Acute Coronary Syndrome) trial, only 23.8% of the patients treated with statins reached the objective of LDL-C ≤ 55 mg/dL (≤1.4 mmol/L) at 30 days, demonstrating that nearly 80% would be eligible for a PCSK9i; in contrast, LDL-C ≤ 55 mg/dL was reached for 65.4% and 90% of patients with a PCSK9i at discharge and 30 days, respectively.¹⁸ In the EVOPACS (Evolocumab for Early Reduction of LDL-cholesterol Levels in Patients with Acute Coronary Syndromes) trial, only 37% of the patients on statins reached LDL-C < 70 mg/dL at 1 year, highlighting that at least 70% of the patients would need a PCSK9i to reach the recommended goal of 55 mg/dL.¹⁹

Thus, the immediate implementation of PCSK9 after a first STEMI could be the next important step to reduce cardiovascular death or events and enable an effective and rapid reduction in LDL-C levels, especially as evolocumab and alirocumab were associated with a reduction of 15–20% of cardiovascular events, including death.^20,21 The ongoing AMUNDSEN (Acute Myocardial Infarction Upbound to PCI Immediately or in the Next Three Days and Randomized to Subcutaneous Evolocumab or Normal Strategies to Reach Guidelines LDL Objectives in the Real-world) trial (NCT04951856) is the largest study to evaluate the direct introduction of evolocumab vs. standard of care in individuals admitted for an ACS. Better strategies are needed to improve the control of cardiovascular risk factors after a first STEMI. Persistent smoking was present in one out of three individuals, and new-onset diabetes in 10% of the population. These results are consistent with the observations of Sverre et al.: in a nationwide Norwegian registry of post-MI patients, half of the individuals continued smoking, and 46% with persistent high blood pressure.²² Beyond pharmacological interventions, education about cardiovascular risk and change of lifestyle remain a cornerstone to improve the outcomes of patients admitted with a first STEMI. We demonstrated that lifestyle intervention alone, or before therapeutic intervention, was recommended in most patients before their first STEMI.

Study limitations

The present study contains limitations. First, risk modifiers such as coronary artery calcium score (CACS), carotid plaques, and CT coronary angiography (CTCA) were not collected or used in the algorithms to determine eligibility for statins. As a result, we could have underestimated the proportions of patients eligible for primary prevention statins, but this also reflects the simple clinical decision tools used in daily practice. Secondly, patients with non-st-elevation myocardial infarction (NSTEMI) were not analysed in this study, as our cohort only includes STEMI patients. Thirdly, our simulated analysis did not take into consideration individual variations in response to treatments and compliance, which may have led to an overestimation of eligibility. LDL-C levels were measured on samples taken within the hour of admission for STEMI and used as baseline LDL-C, based on studies showing very minimal variations between LDL-C before and after ACS.^23,24 Tolerance of statins in secondary prevention was not collected to decide whether an increase in the dosage was permitted, leading to a potential underestimation of patients eligible for ezetimibe and a PCSK9i during follow-up. Eventually, our real-life follow-up LDL-C was incomplete, but our findings were consistent with prior descriptions.

Conclusions

The 2021 ESC Guidelines on Cardiovascular Disease Prevention in Clinical Practice improve the identification of subjects at risk for a first STEMI compared with the 2019 and 2016 guidelines, in both men and women. However, one-third of individuals admitted for a first STEMI would not have met the criteria provided by the 2021 ESC/EAS guidelines for primary prevention statin therapy. In secondary prevention, a vast majority of patients kept LDL-C levels above the goal of 55 mg/dL, for whom increasing the statin dose and adding ezetimibe were the most frequently recommended therapeutic actions. Ongoing trials are currently challenging this stepwise approach vs. the direct introduction of PCSK9is after a first STEMI.

Funding

Action Study Group.

Conflict of interest: G.M. reports research grants, funding, or consulting fees from Abbott, Amgen, AstraZeneca, Axis, Bayer, BMS, Boehringer Ingelheim, Boston Scientific, Cell Prothera, CSL Behring, Idorsia, Leo Pharma, Lilly, Medtronic, Novartis, Pfizer, Quantum Genomics, Sanofi, and Terumo. M.Z. reports research grants, funding, or consulting fees from Fédération Française de Cardiologie, Institut Servier, BMS/Pfizer, and AstraZeneca. J.S. reports research grants, funding, or consulting fees from AstraZeneca, Bayer HealthCare SAS, Abbott Medical France SAS, Biotronik, Boehringer Ingelheim France, CSL Behring SA, Gilead Science, and Sanofi-Aventis France, and is a stock holder of Pharmaseeds, Terumo France SAS, and Zoll. M.K. reports research grants, funding, or consulting fees from Fédération Française de Cardiologie, du Programme PHRC N, de l'Institut Servier et des honoraires de Bayer, Sanofi, and Servier. P.S. reports research grants, funding, or consulting fees from Amgen, AstraZeneca, Bayer, BMS, Boehringer, Bouchara Recordati, Eli Lilly, MSD, Novartis, Pfizer, Sanofi, Servier, and Vifor. B.L. reports research grants, funding, or consulting fees from Biotronik, Boston Scientific, Daiichi Sankyo, and the Fédération Française de Cardiologie et Institute of CardioMetabolism and Nutrition; and honoraria from Daiichi Sankyo, Eli Lilly, AstraZeneca, Medtronic, and Novartis. J.P.C. reports research grants, funding, or consulting fees from AstraZeneca, Boston Scientific, Bristol Myers Squibb, COR2ED, Lead-Up, Medtronic, and WebMD. D.S., P.G., O.B., D.B., E.M., J.P., N.P., and T.S. report no conflicts of interest.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.

References

Author notes