Evidence at the Edge: Statins After Age 75 in an Era of Polypharmacy

The average adult over age 65 is on 4 or more medications daily and 5 or more when including dietary supplements.¹ As a result, polypharmacy is a common concern amongst older patients, and evidence supporting deprescribing remains limited or suggests potential harm. For instance, one study reported over 50% of adults 65 years or older were on a lipid-lowering therapy between March 2017 and March 2020.²

The current American College of Cardiology (ACC)/American Heart Association (AHA) guidelines state discontinuing statin therapy may be appropriate for patients with a life expectancy of less than 1 year to limit medication burden and risks, including drug-drug interactions and adverse effects.³ However, the benefit of statin therapy beyond age 75 years remains uncertain, and prospective clinical trials have not adequately established the risks versus benefits to support deprescribing. Despite these uncertainties, retrospective studies have offered evidence supporting continued use of statins among older patients.

Primary Prevention of ASCVD

These considerations highlight the importance of guideline-directed therapy in informing statin use for primary prevention in older populations. At the present time, guidelines recommend low-density lipoprotein (LDL)-lowering therapies for primary prevention in patients aged 40 to 75 years with diabetes, chronic kidney disease stage 3 or 4, or human immunodeficiency virus due to intermediate risk of an ASCVD event.³ LDL-lowering therapy for patients aged 75 years and older is recommended to consider along with lifestyle interventions.

Such guidance is particularly critical as ASCVD risk increases with age for patients with concomitant diabetes.³ In a cohort study in patients with type 2 diabetes (T2D) without established ASCVD, average incident rates of myocardial infarction (MI) were 25.6 per 1000 person-years (95% CI, 24.1-27.2) in patients older than 75 years.⁴ For patients without T2D, average incident rates of MI were 11.3 per 1000 person-years (95% CI, 10.9-11.8).⁴ Additionally, another cohort study involving patients with type 1 diabetes and aged 75 years and older reported a 10-year fatal CVD risk of 70% in men and 40% in women.⁵

Secondary Prevention With Established ASCVD

The clinical consequences of statin discontinuation may be even greater in the setting of established ASCVD. Deprescribing statins in patients with existing cardiovascular disease (CVD) has been associated with adverse outcomes. In an observational cohort study in Denmark between 2011 and 2016, statin discontinuation was associated with 1 additional major adverse cardiovascular event (MACE) for every 77 patients per year for secondary prevention and found 1 additional MACE for every 122 patients per year for primary prevention.⁶

Polypharmacy

Similar concerns have been observed in older adults with polypharmacy. A 2021 retrospective cohort study conducted in Italy evaluated the clinical impact of statin discontinuation while continuing other medications among 29,047 older adults with polypharmacy.⁷ The mean age of patients included was 76.5 (SD, 6.4) years. Results showed that discontinuation of statin therapy was significantly associated with increased risk of hospitalization for heart failure and any cardiovascular outcome, death from any cause, and emergency admission for any cause. These findings suggest potential benefit of continuing statin therapy despite polypharmacy concerns; however, conclusions are limited by the observational nature of the study and the lack of robust randomized clinical trial data.⁷

Clinical Trials

To date, randomized clinical trials have not provided sufficient evidence to support routine statin discontinuation for primary and secondary prevention among individuals aged 75 years or older without increasing risk of MACE. However, a meta-analysis may provide data to suggest continued cardiovascular benefit from statin therapy in older adults. Although few patients with T2D were included, a 2017 meta-analysis of the JUPITER (NCT00239681) and HOPE-3 (NCT00468923) trials demonstrated that ASCVD reduction among patients aged 71 years and older resembled that of patients aged less than 70 years.⁸ Similarly, another meta-analysis evaluating the safety and effectiveness of statin therapy in patients aged 55 years and older found a proportional reduction in MACE per 1.0 mmol/L reduction in LDL-C, with significant risk reductions in all age groups, including those aged older than 75 years at enrollment.⁹

Building on these findings, several ongoing randomized trials aim to address existing evidence gaps in older populations. Two notable studies currently underway include STAREE (NCT02099123) and PREVENTABLE (NCT04262206), both of which are evaluating potential benefits of statin therapy beyond traditional cardiovascular outcomes, including effects on cognitive decline and dementia.^10,11 STAREE is a double-blind randomized, placebo-controlled prevention trial with participants aged 70 years or older on statin therapy without history of ASCVD, diabetes, or cognitive impairment.¹¹ Participant recruitment was completed March 2023 with a planned 6-year follow-up. The primary outcome includes change in brain free water fraction—a composite marker of vascular leakage, neuroinflammation and neurodegeneration—and white matter hyperintensity volume, small vessel disease.¹¹

In contrast, the PREVENTABLE trial extends this investigation by specifically incorporating both cognitive and cardiovascular outcomes. PREVENTABLE is a double-blind, placebo-controlled randomized pragmatic clinical trial that is actively recruiting participants aged 75 years and older on statin therapy without history of ASCVD, dementia, or significant disability.¹⁰ Enrollment began in September 2020, and participants will be followed for up to 6 years. The primary outcome is survival free of new dementia or persisting disability. Co-secondary outcomes include a “composite of cardiovascular death, hospitalization for unstable angina or myocardial infarction, heart failure, stroke, or coronary revascularization; and a composite of mild cognitive impairment or dementia.”¹⁰

Clinical Implications

Although polypharmacy is common in older adults and may increase the risk of adverse events and drug-drug interactions, statin therapy may continue to provide benefit in patients older than 75 years. Current retrospective and observational evidence indicate a potential benefit to continuing statin therapy for patients with more than 1 year of life expectancy. Although additional randomized clinical trials are needed to better define safety and efficacy of statins for primary and secondary prevention of ASCVD, ongoing studies may soon provide important insight, particularly in cerebrovascular disease prevention.

REFERENCES

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8.Ridker PM, Lonn E, Paynter NP, Glynn R, Yusuf S. Primary prevention with statin therapy in the elderly. Circulation. 2017;135(20):1979-1981. doi:10.1161/CIRCULATIONAHA.117.028271

9.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. The Lancet. 2019;393(10170):407-415. doi:10.1016/S0140-6736(18)31942-1

10. Joseph J, Pajewski NM, Dolor RJ, et al. Pragmatic evaluation of events and benefits of lipid lowering in older adults (PREVENTABLE): Trial design and rationale. J Am Geriatr Soc. 2023;71(6):1701-1713. doi:10.1111/jgs.18312

11. Harding IH, Ryan J, Heritier S, et al. STAREE-Mind imaging study: a randomised placebo-controlled trial of atorvastatin for prevention of cerebrovascular decline and neurodegeneration in older individuals. BMJ Neurol Open. 2023;5(2). doi:10.1136/bmjno-2023-000541