Evidence for Primary Prevention
The PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) was published in 2002 to assess the efficacy of pravastatin in patients between the ages of 70 and 82 (mean age 75 years) with pre-existing vascular disease (coronary, cerebral, or peripheral) or at an elevated risk (smoking, hypertension, or diabetes). Patients were randomized to receive either placebo or pravastatin 40 mg (a moderate-intensity statin). They found that pravastatin therapy reduced the risk of the composite outcome of CHD-related death, nonfatal MI, and fatal or nonfatal stroke in this elderly population. A post-hoc analysis comparing primary versus secondary prevention groups found no significant differences between these subgroups [7].
Han et al recently conducted a post hoc secondary analysis of older participants (65 years and older) in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial–Lipid-Lowering Trial (ALLHAT-LLT). The intervention for ALLHAT-LLT was 40 mg pravastatin. They found no significant differences in all-cause mortality or cardiovascular outcomes between the pravastatin and usual care groups [27]
JUPITER (Justification for Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin), published in 2008, examined the efficacy of rosuvastatin vs. placebo in low- to moderate-risk men 50 years and older and women 60 years and older using a composite outcome of MI, unstable angina, stroke, arterial revascularization, or CVD death. Rosuvastatin did significantly decrease the primary endpoint, however it did not reduce the risk of overall death [28]. A subgroup analysis was performed on the elderly (65–75 years) study participants in JUPITER demonstrating a significant risk reduction for the combined CV endpoint and a nonsignificant reduction of all-cause mortality [29].
CARDS (Collaborative Atorvastatin Diabetes Study), published in 2004, looked at statin use for primary prevention in high-risk patients with type 2 diabetes without high LDL-C, but they had to have at least 1 additional risk factor for CVD. The primary outcome was first acute CHD event (myocardial infarction including silent infarction, unstable angina, acute coronary heart disease death, resuscitated cardiac arrest), coronary revascularization procedures, or stroke. Atorvastatin 10 mg, a moderate-intensity statin, significantly decreased occurrence of the primary outcome [30]. A subgroup analysis was performed to evaluate patients specifically between the ages of 65 and 75 and found a similar outcome in the elderly with a significant reduction in first major CV event and stroke [31].
A recent study evaluating primary prevention in patients with an intermediate risk for CVD was the HOPE-3 (Heart Outcomes Prevention Evaluation), published in 2016. Two co-primary outcomes were evaluated: the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, while the second primary outcome also included revascularization, heart failure, and resuscitated cardiac arrest. Rosuvastatin significantly decreased occurrence of both co-primary endpoints. About half of the study populations was over the age of 65 with a median age of 71 [32].
In addition to these trials of primary prevention, summarized in Table 3, a meta-analysis was published in 2013 to assess whether statins reduce all-cause mortality and CV events in elderly people without established CV disease.
As demonstrated by the above studies, it is evident that statins do help reduce the risk of CV events, regardless of statin intensity, but they do not consistently prevent death. However, the trials that did not demonstrate a significant outcome related to death utilized a moderate-intensity statin; if a high-intensity statin was used in those trials, there may have been a benefit [7,27]. More study is needed to evaluate the use of high-intensity statins in the elderly for the prevention of all-cause mortality and CV-related death.
Fortunately, the ongoing STAREE (STAtin Therapy for Reducing Events in the Elderly) study is looking specifically at the impact of statin therapy in adults 70 and older. Patients with a history of CVD or dementia are excluded. Results are set to be released in 2020 [34].
Risks of Using Statins in Older Adults
Statin use has been linked to a number of unwanted adverse effects.
Myalgia
Myalgia is variable but may occur in up to 25% of patients using statin therapy, and elderly patients typically experience more statin-associated myalgia than younger patients [35,36]. Elderly patients are more prone to decreased muscle mass and therefore may be at a higher risk of developing myalgia pain. Elderly patients are also utilizing more medications, leading to the potential for increased drug-drug interactions that could lead to myalgia. Elderly patients may also lose the function of drug metabolizing enzymes responsible for breaking down statin therapy, which may also increase the risk for statin-associated myalgia. One study demonstrated that elderly patients were more likely to discontinue statin therapy due to muscle pain and elderly patients reported more muscle side effects than their younger cohorts [37]. It is important to monitor for muscle pain and weakness in every patient. If they experience any myalgia, it is recommended to either lower the dose or discontinue the statin once it is determined to be statin-related. After myalgia resolves, therapy can be reinitiated at a lower dose or with a different statin if the patient is deemed high-risk. If creatine phosphokinase levels are greater than 10 times above the upper limit of normal, then discontinue the statin and wait for levels to return to normal. Re-initiation may be appropriate, but the the risks and benefits must be weighed. Simvastatin and atorvastatin are associated with higher rates of myalgia while pravastatin and rosuvastatin have the least myalgia pain associated with use [38,39].