Clinical Context

American College of Cardiology (ACC)/American Heart Association (AHA), UK-National Institute for Health and Care Excellence (NICE) guidelines define statin thresholds for atherosclerotic cardiovascular disease primary prevention based on randomized clinical trials evidence and risk-benefit considerations. These guidelines improved clinical performance compared with SCORE1-based European-European Society of Cardiology (ESC) guidelines.

The 2021 ESC prevention guidelines incorporated the European-SCORE2 model, predicting fatal and nonfatal atherosclerotic cardiovascular disease events, and new age-specific treatment thresholds for statins.

Study Synopsis and Perspective

New risk thresholds used to guide statin therapy for primary prevention of atherosclerotic cardiovascular disease in the latest European guidelines dramatically reduce eligibility for statin use in low-risk countries, a new study has found.

The authors report that new risk thresholds that were chosen for statin treatment in the 2021 ESC guidelines reduce statin eligibility to only 4% of the target population and essentially eliminate a statin indication in women.

"We have guidelines in place to try to prevent cardiovascular disease, but the risk threshold in this new guideline means that almost nobody qualifies for treatment in many countries, which will lead to almost no prevention of future cardiovascular disease in those countries," lead author Martin Bødtker Mortensen, MD, PhD, Aarhus University Hospital, Denmark, commented to theheart.org | Medscape Cardiology.

"We argue that the risk thresholds need to be lowered to get the statin eligibility in European countries to be in line with thresholds in the UK and US, which are based on randomized controlled trials," he added.

The study was published online in JAMA Cardiology on July 6.^[1]

An accompanying editorial describes the results of the study as "alarming," and, if confirmed, says the guidelines should be revisited to "prevent a step backwards in the use of statins in primary prevention."^[2]

For the study, Dr Mortensen and colleagues set out to compare the clinical performance of the new European prevention guidelines with ACC/AHA, UK-NICE, and the 2019 European guidelines in a contemporary European cohort of 66,909 apparently healthy individuals from the Copenhagen General Population Study.

During the 9-year follow-up, a range of 2962 to 4277 nonfatal and fatal cardiovascular events was observed, as defined by the models in the various guidelines.

Results showed that although the new 2021 European guidelines introduced a new and improved risk model, known as SCORE2, the updated age-specific recommendations dramatically reduced eligibility for a class I recommendation for statin therapy to only 4% of individuals, aged 40 to 69 years, and less than 1% of women.

This is in sharp contrast to the previous 2019 European guidelines, as well as current UK-NICE and US-ACC/AHA guidelines that provide class I/strong recommendations to 20%, 26%, and 34% of individuals, respectively, with better clinical performance in both men and women, the authors report.

The researchers also report other analyses in which the sensitivity of the new European guidelines was improved considerably by lowering the treatment thresholds.

Dr Mortensen explained to theheart.org | Medscape Cardiology that the original SCORE risk model used in ESC guidelines was problematic, as it only predicts the 10-year risk for fatal atherosclerotic cardiovascular events, whereas those from the US and UK used both fatal and nonfatal cardiovascular events.

"Now the ESC has updated its model, and the new model is much better, in that it predicts both fatal and nonfatal events, and the predicted risk correlates well with the actual risk. So that's a big step forward. However, the new thresholds for statin treatment are far too high for low-risk European countries because very few individuals will now qualify for statin therapy," he said.

"The problem is that if we use these guidelines, the vast majority of those individuals who will develop cardiovascular disease within 10 years will not be assigned statin therapy that can reduce this risk. There will be lots of individuals who are at high risk of cardiovascular disease, but these guidelines will not identify them as needing to take a statin," Dr Mortensen commented.

"If we use the UK or US guidelines, far more people in these low-risk European countries would be eligible for statin therapy and we would prevent far more events than if we use the new ESC guidelines," he added.

Dr Mortensen explained that the problem arises from having 4 different risk score models in Europe for areas at different risk, but they all use the same risk thresholds for statin treatment.

"In general, Eastern European countries have higher risk than Western European countries, so these guidelines may work quite well in Eastern European countries but in low-risk Western European countries, where the low-risk score model is used, very few people will qualify for statin therapy," he said.

Although Dr Mortensen is not against the idea of different risk models in areas that have different risks, he says that this needs to be accompanied by different risk thresholds in the different risk areas.

Asked whether there is an argument that most individuals in low-risk countries may not need to take a statin, Dr Mortensen countered: "One of the reasons the risk is low in many of these European countries is the high use of preventative medication. So, if a threshold that is too high is used most people will not take a statin anymore and the risk in these countries will increase again."

Authors of the accompanying editorial, Ann Marie Navar, MD, PhD, from the University of Texas Southwestern Medical Center, Dallas; Gregg C. Fonarow, MD, from the University of California, Los Angeles; and Michael J. Pencina, PhD, from the Duke University Medical Center, Durham, North Carolina, agree with Dr Mortensen that the problems appear to arise from use of a risk score that is highly influenced by regional cardiovascular burden.

They point out that under the current guidelines, a 55-year-old woman (smoker; systolic blood pressure 130 mm Hg; non-high-density lipoprotein cholesterol 4.0 mmol/L) would have a 10-year predicted risk of having a cardiovascular event of 5% in Denmark but a predicted risk of 18% in Romania.

"While there may be regional differences in environmental risk factors, location alone should not cause a fourfold difference in an individual's predicted cardiovascular risk," they write.

The editorialists also elaborate on Dr Mortensen's point that the new guideline creates a system that eventually becomes a victim of its own success.

"As countries are successful in implementing statin therapy to lower [cardiovascular disease, cardiovascular disease] rates drop, and progressively fewer individuals are then eligible for the very therapy that contributed to the decline in [cardiovascular disease] in the first place," they note.

The editorialists call for the analysis to be replicated in other low-risk countries and extended to higher-risk regions, with a focus on potential overtreatment of men and older adults.

"If confirmed, the present findings should be a catalyst for the ESC to revisit or augment their current guidelines to prevent a step backward in the use of statins in primary prevention," they conclude.

Medscape Medical News asked the ESC whether they would like to respond to the findings, but no comment was available at this time.

This work was supported by the Lundbeck Foundation, Herlev and Gentofte Hospital, Copenhagen University Hospital, the Copenhagen County Foundation, and Aarhus University, Denmark. Dr Mortensen has disclosed no relevant financial relationships.

JAMA Card. Published online July 7, 2022.

Clinical Implications

• 2021 ESC guidelines dramatically reduce statin eligibility to only 4% in the target population and essentially eliminate statin indication in women.
• Future European guidelines should consider lower treatment thresholds to increase statin use for primary cardiovascular disease prevention.
• Implications for the Health Care Team: To optimize primary cardiovascular disease prevention, members of the healthcare team should balance regional differences in environmental risk with patient-specific risk factors and sex-specific thresholds.

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