Journal List > J Lipid Atheroscler > v.9(1) > 1141423

J Lipid Atheroscler. 2020 Jan;9(1):1-7. English.
Published online Jan 08, 2020.  https://doi.org/10.12997/jla.2020.9.1.1
Copyright © 2020 The Korean Society of Lipid and Atherosclerosis.
Effects of Statins for Primary Prevention in the Elderly: Recent Evidence
Kyu Kim and Sang-Hak Lee
Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

Correspondence to Sang-Hak Lee. Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea. Email: shl1106@yuhs.ac
Received Aug 15, 2019; Revised Oct 31, 2019; Accepted Dec 29, 2019.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


Abstract

The number of the elderly individuals is steeply increasing, and their absolute cardiovascular risk is higher than that of younger age groups. However, very few statin trials have included elderly patients alone. Recently, we published the SCOPE-75 study, which analyzed the effect of statins for primary prevention in elderly Koreans (>75 years). In this study, statin users showed significantly fewer cardiovascular events and a lower all-cause mortality rate, supporting more active use of statins in this population. In the current review, we further compare and discuss similar studies reported in the past decades and in recent years.

Keywords: Cardiovascular diseases; Statins; Elderly

INTRODUCTION

The prevalence of atherosclerotic cardiovascular disease (ASCVD) increases progressively with age.1 Individuals more than 75 years of age are more than 3 times as susceptible to cardiovascular mortality than younger age groups. Thus, primary prevention in this group is critical.2, 3 However, most randomized trials have excluded older patients, resulting in insufficient clinical evidence for primary cardiovascular prevention in this population.4, 5

We recently analyzed the effect of statins on clinical outcomes for primary prevention in patients aged >75 years. Here, we present the major results of that study and review other recent studies on the same topic, with a focus on the effects of statins for primary prevention in the elderly.

CURRENT STATIN GUIDELINES AND KNOWLEDGE GAPS REGARDING THE ELDERLY POPULATION

The 2018 American College of Cardiology/American Heart Association (ACC/AHA) and the 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines were recently released.6, 7 In Korea, the latest guideline for the management of dyslipidemia was released in 2019.8 However, these guidelines contain gaps regarding statin use in the elderly population; these gaps derive from concerns regarding frailty, multimorbidity, polypharmacy, and functional limitations in the elderly.9 Furthermore, each of these guidelines uses a different age threshold (Table 1). The recently published ESC/EAS guideline extended the age of the risk assessment system from 65 to 70, and recommended statin use for primary prevention according to individuals' level of risk until age 75.7 With this in mind, we have defined “elderly” as referring to individuals aged over 75 herein. We reviewed previous randomized controlled trials (RCTs), meta-analyses, and studies on statin therapy for primary statin prevention published since 2018.


Table 1
Comments on elderly patients in the latest guidelines
Click for larger imageClick for full tableDownload as Excel file

STATINS AND CLINICAL OUTCOMES OF PRIMARY PREVENTION IN INDIVIDUALS AGED >75 YEARS: THE SCOPE-75 STUDY

We recently conducted the SCOPE-75 study, which included patients aged >75 years who had at least 1 cardiovascular risk factor.10 In this retrospective, propensity score-matched study, we analyzed 639 statin users and 639 statin non-users. At a median follow-up of 5.2 years, statin users showed lower rates of major adverse cardiovascular and cerebrovascular events (1.25 vs 2.15 events/100 person-years; hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.40–0.85; p=0.005) and all-cause mortality (0.65 vs. 1.19 events/100 person-years; HR, 0.56; 95% CI, 0.34–0.93; p=0.02). The HRs were the same for each outcome variable in Kaplan-Meier curves (Fig. 1). In this study, statin use was associated with a minimal increase of new-onset diabetes, but showed no association with new-onset cancers. This study shed light on the controversial issue of statin use for primary prevention in the elderly by providing evidence of an association between statin use and cardiovascular risk reduction in people aged >75 years.


Fig. 1
Incidence of MACCE and all-cause mortality in the SCOPE-75 study (from Kim et al.10 with permission).
MACCE, major adverse cardiac and cerebrovascular events; HR, hazard ratio.
Click for larger imageDownload as PowerPoint slide

PRIOR STUDIES PERFORMED IN MIXED POPULATIONS

Several clinical trials have provided evidence that statin use is beneficial for primary prevention in patients aged >75 years11 Patients in this age range were included in trials such as Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA)12 and Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) (Table 2).13, 14 The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial-Lipid Lowering Trial (ALLHAT-LLT)15, 16 and PROspective Study of Pravastatin in the Elderly at Risk (PROSPER)17 trials enrolled patients aged 65–82. However, these studies contained mixed populations for primary and secondary prevention. These RCTs showed significant cardiovascular risk reduction in statin users, and the results were consistent in patients aged 66–75 years. Furthermore, 2 meta-analyses by Savarese et al.18 and Ridker et al.19 showed benefits of statin use for primary prevention in patients aged >65 years. Savarese et al.18 analyzed patients aged ≥65 years in 8 clinical trials and showed a relative risk reduction of 39.4% for myocardial infarction and 23.8% for stroke. Although the risk of all-cause and cardiovascular death was also reduced, that reduction was not statistically significant. The study by Ridker et al. 19 included the JUPITER and Heart Outcomes Prevention Evaluation-3 (HOPE-3) trials and analyzed 3 age groups: <65 years, 65 to <70 years, and ≥70 years. In all groups, statin therapy reduced cardiovascular risk (Table 2). A meta-analysis by the Cholesterol Treatment Trialists' Collaboration20 analyzed 186,864 patients from 28 clinical trials, of whom 14,483 (8%) were older than 75 years. In that study, statin therapy reduced major vascular events by 21% per 1.0 mmol/L decrease in low-density lipoprotein cholesterol. In the subgroup of elderly individuals (>75 years of age), statins were also associated with fewer vascular events (relative ratio [RR], 0.79; 95% CI, 0.77–0.81). However, for primary prevention in patients aged >75 years, the risk reduction was not significant (RR, 0.92; 95% CI, 0.73–1.16).20


Table 2
Prior studies on statin use for primary prevention that included mixed populations
Click for larger imageClick for full tableDownload as Excel file

STUDIES IN 2018 AND 2019 FOCUSING ONLY ON THE ELDERLY

Four retrospective studies—including ours—that analyzed the effects of statins for primary prevention in the elderly were published in 2018 and 2019 (Table 3).21 Ramos et al.22 analyzed 46,864 patients older than 74 with or without diabetes. In their study, statin users with diabetes showed significantly reduced risks of ASCVD (HR, 0.76; 95% CI, 0.65–0.89) and all-cause death (HR, 0.84; 95% CI, 0.75–0.94). However, statin treatment was not associated with a reduced risk of ASCVD (HR, 0.94; 95% CI, 0.86–1.04) or all-cause mortality (HR, 0.98; 95% CI, 0.91–1.05) in participants without diabetes. Their study also included 8,307 patients aged >85 years, but statins did not show a significant benefit in this subgroup. Bezin et al.23 reported that cumulative statin use for primary prevention was associated with a lower risk of acute coronary syndrome (adjusted HR, 0.93; 95% CI, 0.89–0.96) in patients aged 75 years or older who had modifiable risk factors. However, the benefits of statins were diminished in patients without risk factors (adjusted HR, 1.01; 95% CI, 0.86–1.18). Jun et al.24 conducted a nested case-control study using a Korean nationwide cohort, focusing on the elderly aged ≥75 years. That study showed that concurrent statin treatment reduced cardiovascular composite outcomes (adjusted odds ratio, 0.77; 95% CI, 0.71–0.84). However, former use of statins had no effect on cardiovascular outcomes or all-cause death. Their study also showed that a longer duration of statin exposure was associated with fewer cardiovascular events.24 As mentioned above, the SCOPE-75 study by us showed significantly lower cardiovascular risk and all-cause mortality in statin users.10 Collectively, these studies provide stronger evidence than was available before for the effects of statins on clinical outcomes. However, the lack of RCTs poses some limitations. The STAtins for Reducing Events in the Elderly (STAREE) trial, which is in progress, aims to determine the efficacy and safety of statins in elderly people aged ≥70 years.25 If properly finished, this trial might be able to provide more comprehensive information regarding the benefits and risks of statin use in the elderly population.


Table 3
Studies published in 2018–2019 analyzing the effects of statin use for primary prevention in the elderly
Click for larger imageClick for full tableDownload as Excel file

STATIN USE IN PATIENTS AGED OVER 85 YEARS

To date, data on statin use in patients aged over 85 years remain extremely limited. No risk scoring systems in current guidelines include this population. In the ESC/EAS and ACC/AHA guidelines, statin use for primary prevention in patients aged ≥85 is recommended, but at a weaker level.9, 10 The National Institute for Health and Care Excellence (NICE)-UK guideline suggests that atorvastatin (20 mg) might be beneficial in this age group.26 Only the study by Ramos et al.25 separately analyzed individuals 85 years of age or older separately, and statins showed no benefits in this subgroup.

CONCLUSIONS

Studies performed in the past decade regarding the effects of statin use for primary prevention in individuals aged >75 years have shown possible clinical benefits. The SCOPE-75 study by us and other very recent studies similarly revealed favorable clinical outcomes of statin use in this population. However, a further net-benefit analysis or a study of prospective data would strengthen the evidence base regarding this issue.

Notes

Funding:This work was supported by the National Research Foundation of Korea grant funded by the Korean government (No. 2019R1F1A1057952).

Conflict of Interest:The authors have no conflicts of interest to declare.

Author Contributions:

  • Conceptualization: Kim K.

  • Writing - original draft: Lee SH.

  • Writing - review & editing: Kim K.

References
1. Writing Group Members. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, et al. Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation 2016;133:e38–e360.
2. Marrugat J, Sala J, Manresa JM, Gil M, Elosua R, Pérez G, et al. Acute myocardial infarction population incidence and in-hospital management factors associated to 28-day case-fatality in the 65 year and older. Eur J Epidemiol 2004;19:231–237.
3. Rapsomaniki E, Thuresson M, Yang E, Blin P, Hunt P, Chung SC, et al. Using big data from health records from four countries to evaluate chronic disease outcomes: a study in 114 364 survivors of myocardial infarction. Eur Heart J Qual Care Clin Outcomes 2016;2:172–183.
4. Herrera AP, Snipes SA, King DW, Torres-Vigil I, Goldberg DS, Weinberg AD. Disparate inclusion of older adults in clinical trials: priorities and opportunities for policy and practice change. Am J Public Health 2010;100 Suppl 1:S105–S112.
5. Heiat A, Gross CP, Krumholz HM. Representation of the elderly, women, and minorities in heart failure clinical trials. Arch Intern Med 2002;162:1682–1688.
6. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Circulation 2019;139:e1082–e1143.
7. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111–188.
8. Rhee EJ, Kim HC, Kim JH, Lee EY, Kim BJ, Kim EM, et al. 2018 Guidelines for the management of dyslipidemia. Korean J Intern Med 2019;34:723–771.
9. Rich MW, Chyun DA, Skolnick AH, Alexander KP, Forman DE, Kitzman DW, et al. Knowledge gaps in cardiovascular care of the older adult population: a scientific statement from the American Heart Association, American College of Cardiology, and American Geriatrics Society. J Am Coll Cardiol 2016;67:2419–2440.
10. Kim K, Lee CJ, Shim CY, Kim JS, Kim BK, Park S, et al. Statin and clinical outcomes of primary prevention in individuals aged >75 years: The SCOPE-75 study. Atherosclerosis 2019;284:31–36.
11. Taylor FC, Huffman M, Ebrahim S. Statin therapy for primary prevention of cardiovascular disease. JAMA 2013;310:2451–2452.
12. Nakamura H, Arakawa K, Itakura H, Kitabatake A, Goto Y, Toyota T, et al. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet 2006;368:1155–1163.
13. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195–2207.
14. Glynn RJ, Koenig W, Nordestgaard BG, Shepherd J, Ridker PM. Rosuvastatin for primary prevention in older persons with elevated C-reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial. Ann Intern Med 2010;152:488–496. W174.
15. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002;288:2998–3007.
16. Han BH, Sutin D, Williamson JD, Davis BR, Piller LB, Pervin H, et al. Effect of statin treatment vs usual care on primary cardiovascular prevention among older adults: the ALLHAT-LLT randomized clinical trial. JAMA Intern Med 2017;177:955–965.
17. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623–1630.
18. Savarese G, Gotto AM Jr, Paolillo S, D'Amore C, Losco T, Musella F, et al. Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis. J Am Coll Cardiol 2013;62:2090–2099.
19. Ridker PM, Lonn E, Paynter NP, Glynn R, Yusuf S. Primary prevention with statin therapy in the elderly: new meta-analyses from the contemporary JUPITER and HOPE-3 randomized trials. Circulation 2017;135:1979–1981.
20. Cholesterol Treatment Trialists' Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet 2019;393:407–415.
21. Strandberg TE. Role of statin therapy in primary prevention of cardiovascular disease in elderly patients. Curr Atheroscler Rep 2019;21:28.
22. Ramos R, Comas-Cufí M, Martí-Lluch R, Balló E, Ponjoan A, Alves-Cabratosa L, et al. Statins for primary prevention of cardiovascular events and mortality in old and very old adults with and without type 2 diabetes: retrospective cohort study. BMJ 2018;362:k3359.
23. Bezin J, Moore N, Mansiaux Y, Steg PG, Pariente A. Real-life benefits of statins for cardiovascular prevention in elderly subjects: a population-based cohort study. Am J Med 2019;132:740–748.e7.
24. Jun JE, Cho IJ, Han K, Jeong IK, Ahn KJ, Chung HY, et al. Statins for primary prevention in adults aged 75 years and older: a nationwide population-based case-control study. Atherosclerosis 2019;283:28–34.
25. Zoungas S, Curtis A, Tonkin A, McNeil J. Statins in the elderly: an answered question? Curr Opin Cardiol 2014;29:372–380.
26. Rabar S, Harker M, O'Flynn N, Wierzbicki AS. Guideline Development Group. Lipid modification and cardiovascular risk assessment for the primary and secondary prevention of cardiovascular disease: summary of updated NICE guidance. BMJ 2014;349:g4356.