Who Benefits From Taking a Statin, and When?

On Fundamentally Restructuring Our Thinking Regarding Primary Prevention of Cardiovascular Disease

Maarten J.G. Leening, MD, PhD

Circulation. 2020;142(9):838-840. 

Abstract and Introduction

Introduction

Some time ago, a 38-year-old woman consulted me to discuss how she could reduce her chances of myocardial infarction or stroke. Her low-density lipoprotein cholesterol level was ≈160 mg/dL and she had recently quit smoking after her sister had a heart attack. She was not so much interested in her absolute risk of atherosclerotic cardiovascular disease (ASCVD), but she wanted to know "if" she could benefit from taking a statin and "when" to start doing so. I was unable to provide her with unequivocal answers. This made me think about how we approach primary prevention of ASCVD.

The Current Paradigm

Atherosclerosis does not affect all of us, and does not affect all those struck by it to the same extent or at similar age. In part these differences remain elusive, but the most important determinants have been known for nearly 60 years: the first concept of "factors of risk" in medicine dates back to one of the early publications from the Framingham Heart Study describing the associations of serum cholesterol concentrations and systolic blood pressure with the incidence of coronary heart disease.[1] Currently, we have a clear understanding how cumulative exposure to atherogenic lipid fractions drives the process of atherosclerosis across the lifespan through a complex interplay of genetic and lifestyle determinants.[2–4]

Statins are generally well-tolerated and safe drugs to lower low-density lipoprotein cholesterol levels and consequently lower ASCVD risk.[5] Statins rank among the most studied drug classes: half of the middle-aged population without ASCVD would have been eligible for at least one of the many randomized trials demonstrating the effectiveness of statins in a primary prevention setting.[6] These trials each targeted a subgroup of the general population with specific atherogenic attributes, including dyslipidemia, diabetes mellitus, hypertension, and chronic inflammation. The evidence provided by these trials is implemented in clinical practice guidelines around the globe: statins are recommended for primary prevention in patients with extremely high low-density lipoprotein levels, patients with diabetes mellitus, and patients with the greatest short-term (ie, 10-year) predicted risk of ASCVD, because these groups are deemed to derive the greatest short-term benefit from treatment.

The seeming discordance between the statin trial entry criteria and statin eligibility in current prevention guidelines deviates from guideline recommendations in most other areas of cardiology.[6] This is the result of decades of evolution in the way we approach cardiovascular risk factor management.[7] In the 20th century, prevention simply entailed identifying and treating individuals with extremely high cholesterol or blood pressure levels. About 20 years ago, ASCVD prevention became a more holistic endeavor when treatment recommendations were based on risk factors placed into the context of an individual's age, sex, and interactions with other risk factors. This was done using coronary risk prediction models, with the most well-known based on data from the Framingham Heart Study. Although the risk prediction models have changed over time by including broader ASCVD outcomes instead of only coronary outcomes and combining data from contemporary population-based studies of various ethnicities, the basic principle has remained unchanged for many years.

Expected Benefits of Statin use

The next phase should be the transition from treatment decisions based on short-term risk to long-term expected benefit.[7,8] The expected benefit is dependent on multiple factors, including the underlying cardiovascular risk, the amount of low-density lipoprotein lowering that can be achieved, and the remaining life expectancy.[7,8]

In this issue of Circulation, Pencina and colleagues[9] present a thought-provoking modeling study on the expected benefits of long-term statin use in younger individuals. The results are based on data from 3148 National Health and Nutrition Examination Survey participants, age 30 to 59 years, without ASCVD, and not qualifying for statin treatment under current American College of Cardiology/American Heart Association guidelines. Two different conceptual biological assumptions were tested, assuming either short-term risk reduction as observed in statin trials or long-term risk reduction as derived from Mendelian randomization studies. Anticipated benefits, expressed as absolute and relative ASCVD risk reduction over a 30-year horizon, were calculated across several model parameters, including non–high-density lipoprotein levels, statin dosage, age at statin initiation, and duration of statin use. The study thereby not only provides tools to understand "if" taking a statin should be considered, but also "when" statin initiation should be considered.

Based on the long-term benefits calculations by Pencina and colleagues,[9] high-intensity statin use could prevent 51% to 71% of premature ASCVD events among patients age 30 to 39 years when treated for 30 years, which amounts to almost 1.4 million events in the United States.[9] This is an impressive statistic that requires careful consideration. First, the 30-year cardiovascular risk model underlying the calculations includes hemorrhagic stroke as an outcome.[10] It is unlikely that the incidence of hemorrhagic stroke would be lowered with statin use and a minor risk increase might even be associated with statin treatment.[5] Second, the models ignore the legacy effect of statins by halting plaque formation that results in lowering of ASCVD hospitalization rates and mortality decades after a statin is used.[11] Similarly, only first ASCVD events were taken into account, but long-term statin treatment may prevent additional subsequent events as well. This, on the other hand, has likely resulted in an underestimation of the expected benefits. Third, the authors presented expected benefits modeled for 30 years of statin use. Taking a statin is often a lifelong commitment, and hence it would have been fairer to compare expected benefits across age groups for a lifetime horizon instead.

Remaining Uncertainties

Whereas advancing age is consistently associated with increasing short-term cardiovascular risk, the inverse is true for its relation with expected benefit of statin use for primary prevention of ASCVD.[9] In other words, the older you are when you start a statin, the less likely you are to benefit from it during your lifetime, because initiating a statin at older age implies a greater cumulative exposure to atherogenic lipids before statin initiation. However, uncertainties exist on how to identify young individuals at increased lifetime risk, as irrespective of risk factor burden, short-term predicted ASCVD risk is universally low. Recent iterations of prevention guidelines have suggested the use of long-term (eg, 30-year) or lifetime risk estimation using traditional risk factors similar to what Pencina and colleagues[9] used in their modeling study.[10,12] Other options include expressing traditional risk factor burden relative to peers of the same age using novel metrics or measuring the amount of subclinical atherosclerosis with noninvasive imaging techniques.[8] The ongoing ROBINSCA trial (Risk or Benefit in Screening for Cardiovascular Diseases; URL: www.trialregister.nl/trial/6297) has randomized over 43 000 individuals without ASCVD to 1 of 3 screening approaches: contemporary guideline-directed usual care, active traditional risk factor assessment, or coronary calcium scoring using noncontrast computed tomography.[13] Results from this study will inform us whether quantifying subclinical atherosclerosis improves identification of individuals at increased cardiovascular risk and subsequently leads to a lower incidence of ASCVD events.

The effectiveness of statins has mostly been studied in middle-aged and older individuals during relatively short treatment periods. It remains unknown to what extent results from these trials can be extrapolated to younger individuals. So far, there is no clear reason to believe that statins are not effective in this setting, but the forthcoming ECAD trial (Eliminate Coronary Artery Disease; URL: https://www.clinicaltrials.gov; Unique identifier: NCT02245087) will provide insight into the effectiveness and safety of atorvastatin in younger individuals without ASCVD.[14] As also pointed out by Pencina and colleagues,[9] very long-term data on randomized and double-blinded follow-up from statin trials in primary prevention are unlikely to ever be accrued in any age group.

Economic implications of early cholesterol assessment, treatment, and follow-up remain uncertain. Back-of-an-envelope calculations show that, at the current price point of €1 per week, it costs less than €1600 ($1750) to take a generic high-dose high-intensity statin for 30 years. Based on the expected absolute risk reductions from the modeling study by Pencina and colleagues,[9] among select individuals, these costs are likely below accepted willingness-to-pay thresholds for gains in quality of life in most Western societies. Formal cost-effectiveness analyses should inform us at what age, ASCVD risk, and cholesterol levels early and prolonged treatment with statins could be recommended.

Possibly the largest challenge will be to get young, healthy individuals to have their cardiovascular risk factors assessed and get them motivated to take a statin long-term on a daily basis. To do so, we need better tools to communicate expected long-term benefits of taking preventive medications such as statins.[7,8] Traditional absolute and relative ASCVD risk reduction percentages are generally considered too abstract by patients, but the benefit model lends itself well to calculate more tangible metrics such as gains in (ASCVD-free) life expectancy.[15]

The Road Forward

Some uncertainties regarding statin use in primary prevention of ASCVD will be clarified in the years to come, and some will never be removed. The work by Pencina and colleagues[9] is an important step in restructuring our collective thinking regarding cholesterol management in primary prevention of ASCVD. The long-term benefit approach should be the basis of future guidance concerning in whom preventive treatment should be targeted, and when. This may increase statin use among young individuals with great expected long-term benefits, but may also decrease statin use among elderly patients with competing noncardiovascular risks. In any case, the long-term benefit approach should enhance our discussions with patients regarding "if" and "when" to start taking a statin.

References

  1. Kannel WB, Dawber TR, Kagan A, Revotskie N, Stokes J III. Factors of risk in the development of coronary heart disease: six year follow-up experience: the Framingham Study. Ann Intern Med. 1961;55:33–50. doi: 10.7326/0003-4819-55-1-33

  2. Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R, Barbalic M, Jensen MK, Hindy G, Hólm H, Ding EL, Johnson T, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet. 2012;380:572–580. doi: 10.1016/S0140-6736(12)60312-2

  3. Navar-Boggan AM, Peterson ED, D'Agostino RB Sr, Neely B, Sniderman AD, Pencina MJ. Hyperlipidemia in early adulthood increases long-term risk of coronary heart disease. Circulation. 2015;131:451–458. doi: 10.1161/CIRCULATIONAHA.114.012477

  4. Khera AV, Emdin CA, Drake I, Natarajan P, Bick AG, Cook NR, Chasman DI, Baber U, Mehran R, Rader DJ, et al. Genetic risk, adherence to a healthy lifestyle, and coronary disease. N Engl J Med. 2016;375:2349–2358. doi: 10.1056/NEJMoa1605086

  5. Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, Blumenthal R, Danesh J, Smith GD, DeMets D, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388:2532–2561. doi: 10.1016/S0140-6736(16)31357-5

  6. Pavlovic J, Greenland P, Deckers JW, Brugts JJ, Kavousi M, Dhana K, Ikram MA, Hofman A, Stricker BH, Franco OH, et al. Comparison of ACC/AHA and ESC guideline recommendations following trial evidence for statin use in primary prevention of cardiovascular disease: results from the population-based Rotterdam Study. JAMA Cardiol. 2016;1:708–713. doi:10.1001/jamacardio.2016.1577

  7. Leening MJG, Ikram MA. Primary prevention of cardiovascular disease: the past, present, and future of blood pressure- and cholesterol-lowering treatments. PLoS Med. 2018;15:e1002539. doi: 10.1371/journal.pmed.1002539

  8. Leening MJG, Cook NR, Ridker PM. Should we reconsider the role of age in treatment allocation for primary prevention of cardiovascular disease? Eur Heart J. 2017;38:1542–1547. doi: 10.1093/eurheartj/ehw287

  9. Pencina MJ, Pencina KM, Lloyd-Jones D, Catapano AL, Thanassoulis G, Sniderman AD. The expected 30-year benefits of early versus delayed primary prevention of cardiovascular disease by lipid lowering. Circulation. 2020;142:827–837. doi: 10.1161/CIRCULATIONAHA.120.045851

  10. Pencina MJ, D'Agostino RB Sr, Larson MG, Massaro JM, Vasan RS. Predicting the 30-year risk of cardiovascular disease: the Framingham Heart Study. Circulation. 2009;119:3078–3084. doi: 10.1161/CIRCULATIONAHA.108.816694

  11. Ford I, Murray H, McCowan C, Packard CJ. Long-term safety and efficacy of lowering low-density lipoprotein cholesterol with statin therapy: 20-year follow-up of West of Scotland Coronary Prevention Study. Circulation. 2016;133:1073–1080. doi: 10.1161/CIRCULATIONAHA.115.019014

  12. Leening MJ, Berry JD, Allen NB. Lifetime perspectives on primary prevention of atherosclerotic cardiovascular disease. JAMA. 2016;315:1449–1450. doi: 10.1001/jama.2016.1654

  13. Denissen SJ, van der Aalst CM, Vonder M, Oudkerk M, de Koning HJ. Impact of a cardiovascular disease risk screening result on preventive behaviour in asymptomatic participants of the ROBINSCA trial. Eur J Prev Cardiol. 2019;26:1313–1322. doi: 10.1177/2047487319843396

  14. Domanski MJ, Fuster V, Diaz-Mitoma F, Grundy S, Lloyd-Jones D, Mamdani M, Roberts R, Thorpe K, Hall J, Udell JA, et al. Next steps in primary prevention of coronary heart disease: rationale for and design of the ECAD trial. J Am Coll Cardiol. 2015;66:1828–1836. doi: 10.1016/j.jacc.2015.08.857

  15. Ferket BS, van Kempen BJ, Heeringa J, Spronk S, Fleischmann KE, Nijhuis RL, Hofman A, Steyerberg EW, Hunink MG. Personalized prediction of lifetime benefits with statin therapy for asymptomatic individuals: a modeling study. PLoS Med. 2012;9:e1001361. doi: 10.1371/journal.pmed.1001361