Few Adults Eligible for Primary Prevention With Statins in Latest ESC Guidelines

The latest European guidelines for the primary prevention of cardiovascular disease appear to reduce the number of patients eligible for statin therapy compared with other international recommendations, a new study shows.

In a contemporary cohort of patients without cardiovascular disease, just 4% of adults would qualify for statin therapy according to the 2021 European Society of Cardiology (ESC) guidelines. Additionally, just 1% of women met the ESC criteria for a class I recommendation to start statins.

These numbers contrast starkly with what’s seen for other international guidelines, including recommendations from the UK’s National Institute for Health and Care Excellence (NICE) and American College of Cardiology/American Heart Association (ACC/AHA). More than one-third of these same patients qualify for statins (class I recommendation) using the pooled cohort equation forming the backbone of the ACC/AHA guidelines, for example.

Given this, researchers believe that the threshold for treatment should be lowered in the ESC guidelines to be more closely aligned with other international recommendations.  

“One of the reasons that cardiovascular risk is now so low is because preventive therapy with statins are widely used,” lead researcher Martin Bødtker Mortensen, MD, PhD (Aarhus University Hospital, Denmark), told TCTMD. “By having such a high threshold for treatment, it has major implications because we may start to take patients off preventive statin therapy. The American and NICE guidelines are based on randomized trials, so we have evidence [statins] are beneficial in these low-risk patients. In my opinion, at least, the European guidelines should come closer to the American and UK guidelines.”  

The 2021 ESC prevention guidelines recommend statin treatment based on the 10-year risk of atherosclerotic cardiovascular disease (ASCVD) using the updated Systematic Coronary Risk Evaluation (SCORE) model. As opposed to SCORE, which has been used since 2003, SCORE2 is age-specific, with different thresholds for treatment based on the patient’s age, and predicts both fatal and nonfatal ASCVD events.

“The vast majority of cardiovascular events are nonfatal, so you’d underestimate the number of events if you have a model that only uses fatal events,” he said, referring to the original SCORE risk-prediction model. “The European SCORE2 model is actually very good. It has nice calibration and is better than the previous model, but the major problem is the risk thresholds for assigning statin therapy.” 

Very Few Women Eligible

For the study, published July 6, 2022, in JAMA Cardiology, the researchers wanted to assess the clinical performance of the 2021 ESC prevention guidelines, particularly how well it stacks up against others, such as the 2019 ESC/European Atherosclerosis Society (ESC/EAS) dyslipidemia guidelines and the ACC/AHA and NICE guidelines. To do so, they turned to the Copenhagen General Population Study (CGPS), which is a prospective cohort study of Danish adults. In total, 66,909 healthy people were included in the analysis and investigators used the low-risk version of SCORE2, which is intended for western European countries (those considered low risk based on age- and sex-standardized mortality rates from the World Health Organization).

From the 2021 ESC guidelines, adults 40 to 49 years are eligible for statins if their 10-risk ASCVD risk is 7.5% or greater (class I recommendation). For those aged 50 to 69 years, statins are a class I recommendation if they have a 10-year risk of 10.0% or greater. Statins are a class II recommendation for those aged 40-49 and 50-69 years if the 10-year ASCVD risk is ≥ 2.5% or ≥ 5.0%, respectively, and other risk modifiers are present.

The ACC/AHA also uses the risk threshold of 7.5% or greater for statin therapy for all patients (class I recommendation), while the 2014 NICE guidelines say statins are strongly recommended if the 10-year risk is 10% or greater based on QRISK3. The ESC/EAS dyslipidemia guidelines recommend statins if the 10-year risk of fatal ASCVD is 5% or greater based on the original SCORE and then provide class I/II recommendations based on LDL-cholesterol levels.    

Of those in CGPS, just 2,862 qualified for a statin (4%) according to the ESC guidelines. In contrast, 34% of adults would be eligible for a statin based on the ACC/AHA guidelines and 26% based on the NICE recommendations. Similarly, 20% would be eligible for statins using the 2019 ESC/EAS dyslipidemia guidelines.

The sensitivity of the ESC, ACC/AHA, NICE, and ESC/EAS recommendations for detecting future SCORE2-defined ASCVD events was 12%, 60%, 51%, and 36%, respectively. Statin eligibility increased with age across the guidelines, but this was least pronounced in the 2021 ESC guidelines. Overall, almost no women aged 40 to 49 years had a 10-year risk of ASCVD 7.5% or greater and just 1% aged 50 to 69 years met the threshold for statins. In men aged 40-49 and 50-69 years old, 2% and 13% met the 10-year ASCVD risk threshold for statin therapy.

One of the reasons why fewer people are captured for preventive therapy with statins using the ESC guidelines may be that the 10-year risk of ASCVD is now much lower in adults, at least in those aged 40 to 69 years, said Mortensen.  

To offset this, he suggests lowering the age-specific threshold for treatment, which they tested out in their analysis. If the risk threshold was reduced—down from 7.5% to 4% in men and 2% in women aged 40 to 49 years old, respectively—they saw a marked improvement in the sensitivity of SCORE2 with just modest reductions in specificity. To perform as well as the ACC/AHA model, the SCORE2 threshold for starting therapy in adults aged 40 to 69 years should be reduced to 5%. To match the performance of NICE and ESC/EAS, the threshold should be reduced to 6% and 7%, respectively.

Mortensen noted that there are four SCORE2 risk models specific to different European regions based on their age- and sex CVD mortality risk, yet each uses the same threshold for starting preventive therapy.

Lower Threshold or Focus on Lifetime Risk

Ann Marie Navar, MD, PhD (University of Texas Southwestern Medical Center, Dallas), Gregg Fonarow, MD (University of California Los Angeles), and Michael Pencina, PhD (Duke University Medical Center, Durham, NC), all of whom have serve as editors for JAMA Cardiology, state that lowering the thresholds might be a short-term solution to ensure adults receive “safe, low-cost, effective therapy,” but would require continuous updating as population risk evolves over time. This would be difficult for the guideline writing committees to sustain long-term.

Instead, they recommend considering longer-term risk estimation, particularly for younger adults, because age plays such an outsized role in the current risk equations.

Another solution would be to stop using 10-year predicted risk as the jumping off point for statins and instead focus on a risk-benefit approach that factors in lifetime risk and the benefits of LDL-lowering. While the ESC guidelines do “briefly mention” this approach, Navar et al say it’s not clear how clinicians could apply this strategy in clinic. There is also a need for clearer guidance on how to incorporate risk modifiers into treatment decisions, they add.

Overall, they state that if this new analysis is confirmed, the ESC may need to “revisit or augment their current guidelines to prevent a step backward in the use of statins in primary prevention.”