Ms. K is an 83-year-old female who presents to clinic for a second opinion regarding management of cardiac risk factors. She first presented to clinic two years ago with chest pain and shortness of breath, both at rest and with exertion. Her medical history included hypertension and hyperlipidemia but no prior cardiovascular disease (CVD) and no smoking history nor diabetes. Her medications included daily aspirin 81mg, lisinopril 10mg, and metoprolol tartrate 25mg twice daily (BID). Blood pressure was 146/72 mmHg with a pulse of 60 bpm. The physical exam was remarkable for a 1/6 systolic murmur best heard at the left sternal border; otherwise, it was normal. Her weight was 199 pounds with a body mass index (BMI) of 39 kg/ m². A recent echocardiogram showed a normal ejection fraction with moderate left ventricular hypertrophy. Her lipid panel showed total cholesterol of 220 mg/dl, triglycerides of 155 mg/dl, highdensity lipoprotein (HDL) 36 md/dl, and low-density lipoprotein (LDL) of 153 mg/dl. Given her age and cardiac risk factors, a dobutamine stress echo was done and was negative for ischemia. The patient was informed of the benefits of maintaining a systolic blood pressure of less than 140 mmHg and was counseled about weight loss to improve her lipids. She was concerned because her mother died from a stroke at age 78 and her father died suddenly at the age of 84. She twice raised the question of taking a statin medication. However, she was concerned about side effects. Several of her friends stopped the medication due to muscle aches and she already had trouble with joint pain.

Many physicians are faced with a growing elderly population in their practice and the resulting therapeutic dilemmas. A 10- year CVD risk calculation cannot be done using the American Heart Association/ American College of Cardiology (AHA/ ACC) risk calculator when the patient’s age exceeds 79. If 79 is used as the age in such a calculation, this women’s 10- year CVD risk is estimated at 36 percent. After discussing the risks and benefits with the patient, the decision was made to start her on 20mg of atorvastatin daily. After three months, her LDL-cholesterol (LDL-C) was reduced to 98 mg/dl. The patient was happy with the result and her joint pain, which she mentioned before she started a statin, did not increase. She also pays more attention to her nutrition. We decided to continue with the same therapeutic regimen.

Cardiovascular disease is an important cause of morbidity and mortality in the older population. Among those ≥80 years of age, 84.7 percent and 85.9 percent of men and women, respectively, have CVD (coronary heart disease, heart failure, stroke, or hypertension).1 Although CVD is common in this population, preventive therapies remain an important consideration. Unfortunately, in the case of statins, there is less data to inform the appropriate therapy.

The benefit of high-intensity statins for secondary prevention of CVD is well established in individuals younger than 75 years. For people over 75, it is likely there still is a mortality and morbidity benefit2 and the 2013 AHA/ACC Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults provide a Class IIa recommendation for continuing statins if already prescribed in this age group. They also state it is reasonable to consider initiation of moderate-intensity statins in those ≥75 years based on clinical judgement and patient preferences.3

Recommendations for primary prevention are less clear and vary by institution. The AHA/ACC recommend consideration of comorbidities, safety, and patient preference when offering statins to those older than 75. The 2016 European Society of Cardiology (ESC) guidelines uses the SCORE CVD risk criteria to guide statin use, which considers people ages 40 to 65. They advise caution for statin use outside that age range.4 National guidelines are unable to give strong recommendations for statin use in the elderly population because of a lack of randomized control trial (RCT) data involving participants over the age of 75. The National Lipid Association (NLA) has addressed the value and safety of statin therapy in older patients in the Recommendations for Patient-Centered Management of Dyslipidemia – Part 2.5

Several statin trials include subgroups of elderly participants. The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) enrolled adults ages 70 to 82 with either preexisting vascular disease or a high risk for CVD. Participants were randomized to 40mg of pravastatin or placebo. There was a 15 percent reduction in the primary outcome of fatal or nonfatal myocardial infarction (MI) or stroke for those taking pravastatin. However, subgroup analyses did not find a significant reduction in the primary outcome in the primary prevention group. A more recent study, Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), randomized participants without CVD history to 20mg of rosuvastatin or placebo. The rosuvastatin group had a 44 percent reduction in risk for the composite primary outcome of CVD death, nonfatal MI, stroke, hospitalization for unstable angina, or a revascularization procedure.7 A secondary analysis of this data assessing the efficacy of rosuvastatin in 5,695 individuals ages 70 or older demonstrated a 39 percent reduction in the primary outcome.8 A meta-analysis of eight RCTs was published in 2013, studying the effectiveness of statin use for primary prevention of CVD in participants over the age of 65. The authors described a reduced risk for MI and stroke of 39 and 24 percent, respectively.9 Even though relative risk (RR) reduction may be lower in the older population, absolute risk reduction can be higher because of the high prevalence of CVD in this age group.10 The CTT Collaboration metaanalysis of data from 26 randomized controlled primary and secondary prevention trials of statin therapy in 170,000 subjects examined the RR of fatal or non-fatal MI, percutaneous coronary intervention or bypass grafting, stroke, and new cancer diagnosis, and included subgroup analyses of those ≤65, >65 to ≤75, and >75 years of age.11 The latter two groups included 4,032 and 885 subjects, respectively, comparing either statin therapy or more intensive statin therapy vs. a control or less intensive statin therapy. The RR for those >65 to ≤75 years of age was 0.78 (95 percent CI 0.74–0.83); for those >75 years of age, it was 0.84 (95% CI 0.73–0.97). There was no increased cancer incidence or cancer death.

These findings suggest the beneficial effect of statins on CVD persists late into life. However, the elderly population may be more impacted by the adverse effects attributed to statin use. Comorbidities become more common as people age and often require additional medications for treatment. Each new medication adds risk for a drug interaction, so adding a statin medication in a highly medicated population may increase the risk of adverse effects such as myopathy. A recent meta- analysis comparing muscle adverse effects in participants over the age of 65 taking a statin versus placebo showed no difference in risk.

New-onset diabetes is an adverse effect related to statin use first described by a large clinical trial in JUPITER.7 This contradicted the previously published results of the West of Scotland Coronary Prevention Study (WOSCOPS), which reported a reduction in the risk of diabetes for the statin treatment arm.13 A meta- analysis in Lancet in 2010 analyzed 13 studies with data for nondiabetic participants and found a 9 percent increased risk for diabetes with statin use.14 Aside from JUPITER, the only other trial in this analysis with a significant association between statins and diabetes was PROSPER. The risk was 32 percent (vs. 26 percent in JUPITER), suggesting increased risk among older participants. However, the overall increased absolute risk of diabetes was small — approximately one case in 1,000 person years higher in the statin group than in the placebo group.

Statin use could, theoretically, improve cognition, especially vascular dementia. On the contrary, anecdotal reports of cognitive impairment led the U.S. Food and Drug Administration (FDA) in 2012 to release a statement warning about potential adverse effects on cognition. The Cardiovascular Health Study, a prospective epidemiologic study of risk factors for CVD in older adults, observed a small reduction in cognitive decline in statin users.15 A 2013 systemic review did not find evidence of any cognitive impairment or dementia associated with statin use, although the review included few high-quality studies.16 The Cochrane Database recently updated their analysis regarding this issue but only included two studies in their review. Their conclusion was there was no difference in cognitive test results or dementia in the statin and placebo groups.17

Another consideration when prescribing statins is renal function. A retrospective analysis of observational data, including patients with a mean age of 68 years, showed a 34 percent increased risk of acute renal injury in individuals prescribed high- vs. low-dose statins in the first four months.18 The risk was attenuated but persistent (15 percent) over longer follow-up. Shortly after this study was published, an analysis of renalrelated serious adverse events in placebocontrolled RCTs found no increased risk in the statin arm.

Evidence supports the effectiveness of statins for reducing CVD late in life. The adverse effects of statins make it challenging to initiate in the older adult population and include polypharmacy and drug interactions, myopathy, and a diagnosis of diabetes.

A cost-effectiveness analysis of primaryprevention statin use in people over the age of 75 reported cost savings or highvalue outcomes with each treatment strategy tested.19 The authors do warn that the model is very sensitive to small increases in the rate of adverse events, primarily functional limitations and mild cognitive impairment. More data are needed to better inform a recommendation for continuation or initiation of primary-prevention statin use in this age range. A group in Australia is recruiting patients for a placebo-controlled trial of primaryprevention atorvastatin in adults 70 years or older.20 In the meantime, we must continue to follow the multiguideline recommendation of shared decisionmaking between the provider and patient, accounting for the magnitude of risk reduction, life expectancy, frailty and function status, risk of diabetes, and potential drug interactions.

In conclusion, limited data are available regarding the benefits and risks of cholesterol reduction in those ages >80 years without cardiovascular disease or diabetes. Given the demographics of the population and life expectancy after the age of 80, a clinical trial is urgently needed to evaluate cardiovascular risk factor interventions in older persons.

Disclosure statement: Dr. Van’t Hof has no disclosures to report. Dr. Duprez has received research grants from Sanofi, Regeneron, Pfizer, consultancy fee from Amgen, speakers’ fee from Amgen.

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