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Case: A healthy 83-year-old woman with a history of hypertension comes to your office for a routine visit. Her only medication is lisinopril 5 mg daily, and her blood pressure is 130/75. Her total cholesterol is 180, high-density lipoprotein (HDL) is 35, and low-density lipoprotein (LDL) is 120 on a routine lipid panel. She has never smoked cigarettes. You wonder if she should be taking a statin. You try entering her information into a cardiovascular risk calculator but are unable to do so because her age is greater than the allowed limit. You calculate her risk as if she were 79 years old and find that her 10-year risk of a cardiovascular event would be 30%.¹ Should you prescribe her a statin?

Current American College of Cardiology (ACC)/American Heart Association (AHA) guidelines recommend the use of a moderate- or high-intensity statin in patients over 75 years of age with clinical atherosclerotic cardiovascular disease (ASCVD). In patients over 75 years of age without clinical ASCVD, with or without risk factors, a "clinician-patient discussion" is suggested.² Given the lack of more specific recommendations, what clinical considerations should be part of this discussion? What evidence exists for the efficacy and risks of statins in older adults, and what patient factors should be considered?

In patients under the age of 75, the efficacy of statins for primary prevention is well-established on the basis of multiple randomized trials, which have found that they reduce the relative risk of major vascular events by 20-30%.^3,4 The relative benefits of statins are consistent across multiple subgroups and similar for patients at both high and low risk for cardiovascular events; therefore, the absolute benefits of statins are greatest for high-risk patients. This forms the basis of the ACC/AHA recommendations on statins for primary prevention—namely, that statins are indicated for patients between 40 and 75 years of age with diabetes, LDL greater than 190, or a 10-year ASCVD risk of greater than 7.5%. While it has been estimated that 97% of individuals between 65 and 75 years of age meet criteria for a statin by these guidelines,⁵ there is no specific recommendation for adults over the age of 75 due to their under-inclusion in pivotal clinical trials.

There are reasons to believe that statins could have significant benefits in this age group. Advanced age is an important risk factor for cardiovascular events—80% of deaths from coronary heart disease occur in people over the age of 65.⁶ If statins had similar relative efficacy in older patients as in younger patients, the absolute population benefits would be considerable. The patient described above with an estimated 30% 10-year ASCVD risk (i.e., risk of a fatal or non-fatal myocardial infarction [MI] or stroke) could have that risk cut to 24% based on a 20% relative risk reduction, which could be achieved with a mild-to-moderate-intensity statin. Simultaneously, there are several reasons to question the efficacy of statins in older adults. For example, in patients over the age of 75, low total cholesterol levels have been paradoxically associated with increased mortality,⁷ although this may be due to confounders such as chronic illness, malnutrition, and frailty.⁸ Another question is whether statins have sufficient time to exert beneficial effects (i.e., regression of atherosclerosis) in older individuals who have limited life expectancies and may already have a large atherosclerotic disease burden. Pleotropic effects may confer short-term benefits (e.g., plaque stabilization, reduced inflammation, reversal of endothelial dysfunction, decreased thrombogenicity),⁹ although clinical trials have generally demonstrated that tangible clinical benefits (e.g., reduced event rates) do not occur until between six months and two years.¹⁰

Unfortunately, clinical trial evidence for the efficacy of statins for primary prevention in older adults is limited, as the majority of statin trials included few patients over 70 years of age. One notable exception is the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER),¹¹ which randomized patients aged 70 to 82 years of age with either pre-existing vascular disease (secondary prevention) or at least one risk factor of hypertension, diabetes, or smoking (primary prevention) to pravastatin 40 mg daily or placebo. The study found a significant reduction in the primary outcome of major vascular events (fatal or non-fatal MI or stroke) in the pravastatin group (RR: 0.85, 95% CI 0.74-0.97). While there was a finding of increased cancer risk with pravastatin (RR: 1.25, 95% CI: 1.04-1.51), a meta-analysis within the original manuscript that included this study among others found no significant increase in cancer risk, nor did a longer-term follow-up study of the original cohort.¹² As with many randomized clinical trials, the external validity of the PROSPER findings in "typical" older adults is unclear; for example, the trial excluded patients with cognitive impairment (Mini Mental State Examination score <24).

For patients ≥80 years of age, evidence for statins in primary prevention is limited to observational studies. A population-based study conducted in Iceland including men and women aged 66 to 96 years of age (mean age 77 years of age) found a decreased risk of all-cause mortality among diabetic statin users (HR 0.47, 95% CI 0.32-0.71) as compared to non-users,¹³ and in a cohort of patients born in Jerusalem, statin use at age 85 was associated with decreased mortality risk (HR 0.61, 95% CI 0.42 to 0.89) over the next five years compared with those not taking statins.¹⁴ In contrast, in an Australian cohort of community-dwelling older men (mean age 80 years), statin use was not significantly associated with mortality (HR 0.88, 95% CI 0.66 to 1.18).¹⁵ While each of these studies used multivariable models to control for several potential confounders, the potential for unmeasured confounding remains.

Shared decision-making with older adults is a key component of patient-centered care, and is especially important in an area where the evidence is not entirely clear. For medications such as statins, the potential harms as well as the benefits of therapies must be considered. Advanced age is associated with decreased metabolism of drugs through multiple mechanisms including lower hepatic and renal clearance, decreased serum albumin, increased fatty tissue volume, and altered chemoreceptor sensitivity.¹⁶ There is an increased risk of both medication-related adverse effects as well as drug interactions in a population where polypharmacy is the norm.

Data from statins in randomized trials in patients up to 80 years of age have shown that statins are generally safe and well-tolerated.^17,18 Severe liver injury is very rare, although mild elevations of liver function tests may occur. Muscle damage is another concern, although clinically significant myonecrosis (defined as a serum creatine kinase elevation of greater than ten times normal with symptoms) occurred in less than 0.5% of patients and has mainly been seen in patients on high doses of simvastatin,¹⁹ and in the context of drug interactions, particularly those that inhibit the CYP3A4 system (e.g., cyclosporine, macrolides, azole antifungals) or independently cause myopathy (e.g., fibrates).²⁰ Statins that are not metabolized through the CYP3A4 system (pravastatin, fluvastatin, and rosuvastatin) may have a lower risk of interactions with commonly prescribed medications.

More subtle effects of statins may be a concern in frail older adults who were excluded from the vast majority of randomized trials. For example, it is evident that while myonecrosis is rare, less severe muscle complaints including myalgias and weakness (without creatine kinase elevations) are relatively common (10-25%) in clinical practice.²¹ In theory, these adverse effects could have special relevance to older patients by predisposing them to mobility disability or falls, although to our knowledge this has not been borne out in any large studies. Another potential concern is the risk of diabetes with statin use,²² although the relevance to older patients remains unclear. Finally, there are concerns of cognitive effects and memory loss, particularly with lipophilic statins, but evidence is generally weak in this area,¹⁷ and some retrospective studies have found statin use to be associated with a lower risk of dementia.²³ Prior to initiating statins in older patients, a thorough understanding of these potential risks, as well as the strength of evidence (or lack of strength), is key to shared decision-making. After initiating therapy, close clinical follow-up for potential adverse effects is also warranted.

In summary, statins are probably both under- and over-utilized in older adults. For example, it is estimated that only 40-60% of patients over 65 are prescribed a statin after an acute MI;²⁴ conversely, a recent study found that 30% of patients with a cancer diagnosis were dispensed a statin within 30 days of dying.²⁵ For primary prevention, treatment recommendations should be individualized and take into account multiple factors including cardiovascular risk, life expectancy, frailty, comorbid conditions, and potential drug interactions. Involving patients in shared decision-making is key. In our patient, assuming she is otherwise in good health, she could very well experience a cardiovascular benefit given her functionality and relatively low burden of medications and comorbidities. If we initiate a low-to-moderate-intensity statin, close monitoring for adverse effects, medication changes, and development of comorbid illnesses is key as the risk/benefit profile may change over time.

References

1. ACC/AHA ASCVD Risk Estimator (ACC website). 2013. Available at: http://tools.cardiosource.org/ASCVD-Risk-Estimator/. Accessed 2/16/2015.
2. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014:2889-934.
3. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995:333:1301-7.
4. Cholesterol Treatment Trialists' Collaborators, Mihaylova B, Emberson J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: a meta-analysis of individual data from 27 randomized trials. Lancet 2012;380:581-90.
5. Miedema, Lopez FL, Blaha MJ, et al. Eligibility for statin therapy according to new cholesterol guidelines and prevalent use of medication to lower lipid levels in an older US cohort. JAMA Internal Medicine 2015;175:138-40.
6. American Heart Association. Older Americans and Cardiovascular Diseases: Statistical Fact Sheet 2013 Update (AHA website). 2013. Available at: http://www.heart.org/idc/groups/heart-public/@wcm/@sop/@smd/documents/downloadable/ucm_319574.pdf. Accessed 2/16/2015.
7. Tilvis RS, Valvanne JN, Strandberg TE, Miettinen TA. Prognostic significance of serum cholesterol, lathosterol, and sitosterol in old age; a 17-year population study. Ann Med 2011;43:292-301.
8. Corti MC, Guralnik JM, Salive ME, et al. Clarifying the direct relation between total cholesterol levels and death from coronary heart disease in older persons. Ann Intern Med 1997;126:753-60.
9. Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation 2004;109:III39-43.
10. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344:1383-9.
11. Shepherd, J et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial. Lancet 2002;360:1623-30.
12. Lloyd SM, Stott DJ, de Craen AJ, et al. Long-term effects of statin treatment in elderly people: extended follow-up of the prospective study of pravastatin in the elderly at risk (PROSPER). PLoS ONE 2013;8:e72642.
13. Olafsdottir E, Aspelund T, Sigurdsson G, et al. Effects of statin medication on mortality risk associated with type 2 diabetes in older persons: the population-based AGES-Reykjavik Study. BMJ Open 2011;1:e000132.
14. Jacobs JM, Cohen A, Ein-Mor E, Stessman J. Cholesterol, statins, and longevity from age 70 to 90 years. J Am Med Dir Assoc 2013;14:883-8.
15. Gnjidic D, Le Couteur DG, Blyth FM, et al. Statin use and clinical outcomes in older men: a prospective population-based study. BMJ Open 2013;3:e002333.
16. Szadkowska I, Stanczyk A, Aronow WS, et al. Statin therapy in the elderly: A review. Arch Gerontol Geriatr 2010;50:114-8.
17. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670-81.
18. Kashani A, Phillips CO, Foody JM, et al. Risks associated with statin therapy: a systematic overview of randomized clinical trials. Circulation 2006;114:2788-97.
19. Ganga HV, Slim HB, Thompson PD. A systematic review of statin-induced muscle problems in clinical trials. Am Heart J 2014;168:6-15.
20. Mendes P, Robles PG, Mathur S. Statin-induced rhabdomyolysis: a comprehensive review of case reports. Physiother Can 2014;66:124-32.
21. Parker BA, Thompson PD. Effect of statins on skeletal muscle: exercise, myopathy, and muscle outcomes. Exerc Sport Sci Rev 2012;40:188-94.
22. Macedo AF, Taylor FC, Casas JP, Adler A, Prieto-Merino D, Ebrahim S. Unintended effects of statins from observational studies in the general population: systematic review and meta-analysis. BMC Med 2014;12:51.
23. Haag MD, Hofman A, Koudstaal PJ, et al. Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study. J Neurol Neurosurg Psychiatry 2009;80:13-7.
24. Afialalo J, Duque G, Steele R, Jukema JW, de Craen AJ, Eisenberg MJ. Statins for secondary prevention in elderly patients, a hierarchical bayesian meta-analysis. J Am Coll Cardiol 2008:51:37-45.
25. Stavrou EP, Buckley N, Olivier J, Pearson SA. Discontinuation of statin therapy in older people: does a cancer diagnosis make a difference? An observational cohort study using data linkage. BMJ Open 2012;2:e000880.

Keywords: Dyslipidemias, Secondary Prevention, Adipose Tissue, Aged, American Heart Association, Atherosclerosis, Azoles, Blood Pressure, Cardiovascular Diseases, Cholesterol, Chronic Disease, Cognition, Comorbidity, Coronary Disease, Cost of Illness, Creatine Kinase, Cyclosporine, Cytochrome P-450 CYP3A, Dementia, Diabetes Mellitus, Drug Interactions, Fatty Acids, Monounsaturated, Fibric Acids, Fluorobenzenes, Frail Elderly, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertension, Indoles, Inflammation, Life Expectancy, Lipoproteins, HDL, Lipoproteins, LDL, Lisinopril, Liver, Liver Function Tests, Macrolides, Malnutrition, Memory Disorders, Myalgia, Myocardial Infarction, Neoplasms, Polypharmacy, Pravastatin, Primary Prevention, Prospective Studies, Pyrimidines, Retrospective Studies, Risk, Risk Factors, Serum Albumin, Simvastatin, Smoking, Stroke, Sulfonamides, Vascular Diseases

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