The American Heart Association (AHA)/American College of Cardiology (ACC) guidelines for the management of blood cholesterol provide guidance for treating cholesterol in 1 The evidence however is limited and the recommendations are consequently weaker than those provided for younger patients. The guidelines say that it is reasonable to initiate or continue treatment with statins and other lipid-lowering medication in the very elderly who have confirmed atherosclerotic cardiovascular disease (ASCVD). It is also reasonable to consider statin therapy for very elderly patients who do not have ASCVD but do have diabetes or another condition that increases their risk of ASCVD. As with other age groups, lipid-lowering treatment in the very elderly should be considered (or continued) in the context of a discussion of potential risks and benefits which vary considerably with age.
Evidence for the benefit of statin therapy in people 75 or older is stronger for patients with confirmed ASCVD as secondary prevention for cardiovascular events.2–5 Shepherd et al. conducted a randomized controlled trial (RCT) of 5804 men and women who were 70 – 82 years of age with ASCVD or risk factors for vascular disease.3 Patients received either pravastatin 40 mg or placebo for an average of 3.2 years. Patients taking the statin had fewer cardiovascular events compared to placebo (hazard ratio [HR] 0.85, 95% confidence interval [CI] [0.74 – 0.97], p=0.14). The effect was strongest for coronary death and non-fatal myocardial infarction. Stroke risk was unaffected by statin use. Serious adverse events were reported with similar frequency in both treatment (56%) and placebo (55%) groups.
A 2010 meta-analysis conducted by the Cholesterol Treatment Trialists Collaboration (CTT) found a significant reduction in cardiovascular events in patients taking statins in all age groups, although only 7.7% were 75 years of age or older.5 The same group conducted another analysis of 28 RCTs in 2019 to evaluate effects of statin by age (n=186,854, 8% were over 75 years of age).2 The reduction in vascular mortality among statin users compared to placebo was significant in all age groups, but there was a trend toward smaller reduction in mortality with advancing age. Overall, there was a 21% reduction in the risk of the first major vascular event; the reduction in risk for those over 75 was 13%. In addition, the protective effects of statins were less pronounced in individuals without pre-existing cardiovascular disease.
The use of statins for individuals 75 and older who do not have ASCVD in order to prevent the development of ASCVD has been studied in several RCTs.6–9 Ridker et al. performed a meta-analysis of data from the JUPITER (Justification for Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) and HOPE-3 (Heart Outcomes Prevention Evaluation) trials to examine the efficacy of statins by age category.10
The JUPITER study included 17,802 healthy people with low-density lipoprotein cholesterol levels below 130 and elevated high-sensitivity C-reactive protein taking rosuvastatin 20 mg or placebo.7 Over all age groups, statin use resulted in a 47% reduction in the risk of ASCVD events. Of the 5695 JUPITER participants who were 70 or older, the risk reduction was 39% (HR 0.61, 95% CI [0.43 – 0.83], p=0.004). Rates of drug withdrawal among patients taking rosuvastatin increased with increasing age, which may be a reflection of an increased risk or lower tolerability of side effects10
The HOPE-3 trial randomized 12,705 patients without ASCVD at intermediate risk of future ASCVD events to take rosuvastatin 10 mg or placebo.6 The overall risk reduction for ASCVD events among those taking rosuvastatin was 24% (HR 0.76, 95% CI [0.64 – 0.91], p=0.002). The risk reduction among the 3086 participants 70 or older was a non-significant 17% (HR 0.76, 95% CI [0.64 – 1.07], p=0.16). Drug withdrawal rates in the HOPE-3 study also increased with increasing age.10
Savarese et al. conducted a meta-analysis of eight RCTs of statin use among elderly patients (age >65) without cardiovascular disease (n=24,674).9 In this analysis statins reduced the risk of myocardial infarction by 39.4% (relative risk [RR] 0.606, 95% CI [0.434 – 0.847], p=0.003), and the risk of stroke by 23.8% (RR 0.762, 95% CI [0.626 – 0.926], p=0.006). The risks of all-cause mortality and cardiovascular mortality, however, were not significantly reduced among elderly patients taking statins.
Risk versus Benefit Assessment
The risk/benefit calculus of lipid-lowering treatment for people 75 years of age or older is more difficult to assess for several reasons. An estimate of their future risk is not calculable in existing pooled cohort equations because of a lack of adequate aggregate data to assign a numerical estimate of risk.11 While age over 65 is itself considered a risk factor for cardiovascular disease events, older age also increases the risks of statin treatment. Older patients are more likely to have co-morbidity and to take a higher number of medications that might interfere with statin safety and efficacy.12
In addition, the aging body, in general, has a lowered ability to metabolize drugs, so older age people may have an increased risk of adverse events.13 However, there is inconsistent evidence that very elderly patients have an increased rate of adverse events on statins compared to younger patients. Link et al. reported a higher risk of statin-associated myopathy, including rhabdomyolysis, in people age 65 or older taking high-dose statins compared to younger patients.14 A meta-analysis (n= 91,140) determined that incident diabetes rate in statin users who were over 75 was higher than in younger patients, although the rate of new-onset diabetes overall among patients taking statins was not high (1 new case for every 255 people taking statins for 4 years).15
Iwere and Hewitt conducted a meta-analysis of published data for individuals taking statins who were age 65 or older at randomization.17 There was a small and statistically insignificant increase of non-severe muscle-related adverse effects when comparing statin- and placebo-treated individuals (odds ratio 1.03, [95% CI 090 – 1.17], p=0.66). To date large RCTs have not shown excess risk of adverse effects attributed to age. 18-21 However, the CTT continues to examine adverse event rates including whether age influences the risk of diabetes or dementia.22
Goals of Care: Longevity versus Quality of Life
Elderly patients, in some analyses, are more likely than younger patients to value quality of life and avoiding disability than they value extending life.23,24 This may influence patients’ decisions regarding statin use, as the available evidence is weighed.
References
- Grundy S, Stone N, Beam C, Birtcher KK, Harm PD. 2018 AHA/ACC/AACVPR/AAPA/ ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. J Am Coll Cardiol 2019; 73 (24): e285-e350.
- Armitage J, Baigent C, Barnes E et al. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet 2019; 393 (10170): 407-415.
- Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease ( PROSPER ): a randomised controlled trial. Lancet 2002; 360 (9346): 1623-1630.
- Mortensen M, Falk E. Primary prevention with statins in the elderly. J Am Coll Cardiol 2018; 71 (1): 85-94.
- 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 (9753): 1670-1681.
- Yusuf S, Bosch J, Dagenais G, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016; 374 (21): 2021-2031.
- Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. New Engl J Med 2008; 359 (21): 2195-2207.
- Glynn RJ, Koenig W, Nordestgaard BG, Ridker PM. Rosuvastatin for primary prevention in older individuals with high C-reactive protein and low LDL levels: exploratory analysis of a randomized trial. Ann Intern Med 2010; 152 (8): 488-496.
- Savarese G, Gotto A, Pailillo S, et al. Benefits of statins in elderly subjects without established cardiovascular disease. J Am Coll Cardiol 2013; 62 (22): 2090-2099.
- Ridker P, Lonn E, Paynter N, 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 (20): 1979-1981.
- Wilmot KA, Khan A, Krishnan S, Eapen DJ. Statins in the elderly: a patient-focused approach. Clin Cardiol 2015; 38 (1): 56-61.
- Rich MW, Maurer MS, Mcclurken JB, Resnick BM. Knowledge gaps in cardiovascular care of the older adult population. J Am Coll Cardiol 2016; 67 (20): 2419-2440.
- Wooten JM. Pharmacotherapy considerations in elderly adults. South Med J 2012; 105 (8): 437-445.
- Link E, Parish S, Armitage J et al. SLCO1B1 variants and statin-induced myopathy — a genomewide study. N Engl J Med 2008; 359 (8): 789-799.
- Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes : a collaborative meta-analysis of randomised statin trials. Lancet 2010; 375 (9716): 735-742.
- Budoff M, Young R, Lopez V, et al. Progression of coronary calcium and incident coronary heart disease events: MESA (Multi-Ethnic Study of Atherosclerosis ). J Am Coll Cardiol 2013; 61 (12): 1231-1239.
- Iwere RB, Hewitt J. Myopathy in older people receiving statin therapy: a systematic review and meta-analysis. Br J Clin Pharmacol. 2015;80(3):363–371.
- Heart Protection Study Collaborative Group, MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360 (9326): 7-22.
- Shepherd J, Blauw GJ, Murphy MB. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet.2002;360:1623–1630.
- Feldman HH, Doody RS, Kivipelto M. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology. 2015;74:956–964
- McGuinness B, Craig D, Bullock R, Passmore P. Statins for the prevention of dementia. Cochrane Database Syst Rev. 2016;1CD003160.
- Cholesterol Treatment Trialists' (CTT) Collaboration. Protocol for analyses of adverse event data from randomized controlled trials of statin therapy. Am Heart J. 2016;176:63–69.
- Stolker JM, Spertus JA, Cohen DJ, et al. Rethinking composite end points in clinical trials: insights from patients and trialists. Circulation 2014; 130 (15): 1254-1261.
- Armstrong PW, Westerhout CM. Composite end points in clinical research: a time for reappraisal. Circulation 2017; 135 (23): 2299-2307.
