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Guidelines versus trial-evidence for statin use in primary prevention: The Copenhagen General Population Study

What was known?

All major guidelines on the primary prevention of atherosclerotic cardiovascular disease (ASCVD) with statin therapy are based on a risk calculator that estimates the 10-year risk of ASCVD. However, these risk calculators have never been evaluated in a randomised controlled trial (RCT).


The aim of this study was to evaluate the extent to which statin recommendations from the American College of Cardiology/American Heart Association (ACC/AHA), Canadian Cardiovascular Society (CCS), UK National Institute for Health and Care Excellence (NICE), and European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) are supported by evidence from RCTs.

What this study adds:

This analysis of a contemporary population cohort gives an insight into the evidence-base behind guideline recommended statin prescription. Among individuals eligible for statin therapy according to the ACC/AHA, CCS, NICE and ESC/EAS guidelines, the vast majority had direct RCT evidence of statin efficacy. In addition, the number needed to treat (NNT) to prevent one event is much smaller among individuals with RCT-based evidence who also fulfil guideline criteria.

Clinical implications:

These results support the use of guideline recommendations as a starting point for discussions about the initiation of primary prevention with statin therapy, as they can identify individuals who are most likely to benefit from statin therapy. However, selected individuals who do not meet guideline-based criteria for statin therapy but have RCT evidence may also benefit from statin therapy.

Study design:

This is an analysis of 79,171 individuals from the Copenhagen General Population Study (CGPS,, a prospective cohort study of the Danish population. The RCT evidence for statin efficacy in primary prevention of ASCVD was provided by seven high-quality RCTs. Patients underwent statin treatment according to the eligibility criteria of the different guidelines and RCTs. For each participant, the 10-year risk of ASCVD was calculated using guideline recommended prediction models. The rate of ASCVD (defined as non-fatal myocardial infarction [MI], fatal coronary heart disease [CHD], and stroke) was assessed in different groups according to whether they met guideline and/or RCT eligibility criteria. The NNT to prevent one ASCVD event in 10 years by prescribing statins was also assessed.

Study endpoint:

Clinical performance of guideline-versus RCT-based approaches

Inclusion criteria:

  • Aged 40–75
  • White and of Danish descent
  • Free of ASCVD and statin use at baseline
  • Meets statin eligibility criteria of guideline recommendations or key clinical trials

Notable exclusion criteria:

  • Pre-existing ASCVD
  • Statin use
  • Missing covariates at the baseline examination


  • During 8.2 years of follow-up, 4031 ASCVD events occurred
  • There was a strong correlation between the 10-year risk for ASCVD/CVD and the existence of RCT data supporting statin therapy using the 4 guideline-recommended risk calculators (spearman = 0.98–1.00, p < 0.0001)
  • Among participants eligible for statin therapy with class 1A or similar recommendation according to the ACC/AHA, CCS, NICE and ESC/EAS guidelines, the majority (86%, 88%, 88% and 84%, respectively) had direct RCT evidence of statin efficacy
  • Participants eligible for statin therapy according to both guidelines and RCT evidence (guideline-positive & RCT-positive) accounted for 26–37% of the total, with guideline-positive & RCT-negative 5–7%, guideline-negative & RCT-positive 28–39%, and guideline-negative & RCT-negative 30–31%
  • The ASCVD events per 1000 person-years were 11.4–12.7 (guideline-positive & RCT-positive), 6.3–8.0 (guideline-positive &R CT-negative) , 4.2–5.2 (guideline-negative & RCT-positive), and 2.3–2.5 (guideline-negative & RCT-negative). Those in the guideline-positive & RCT-positive group had an approximately 5-fold higher risk compared with the guideline-negative & RCT-negative group (hazard ratios, 4.6 to 5.4).
  • The NNT to prevent one ASCVD event with statins in the 4 groups were 19–21, 30–32, 48–60, and 105–125, respectively


These findings support the use of guideline recommendations and risk calculators for clinical decision making regarding the prescription of statin therapy, and also highlight the strong evidence base for the benefits of statin use in the primary prevention setting. The findings also raise questions that warrant further investigation, including whether individuals with RCT-based evidence of statin efficacy but without a guideline recommendation should be considered for statin therapy.


  • The study only included white individuals from a low risk population and may not be applicable to other ethnicities or high-risk populations
  • It was not possible to adjust for the uptake of preventive medications, including statins, during follow-up
  • Estimates of NNT to prevent one event are based on modelling and extrapolation from RCTs.
  • Only RCTs that evaluated hard ASCVD endpoints were included