Efficacy and Safety of Statin Therapy in Older People: Meta-Analysis

Cholesterol Treatment Trialists’ Collaboration.
Efficacy and Safety of Statin Therapy in Older People: A Meta-Analysis of Individual Participant Data From 28 Randomised Controlled Trials. Lancet 2019;Feb 2:[Epub ahead of print].

The following are key points to remember from this meta-analysis of data from 28 trials on the efficacy and safety of statin therapy in older people:

  1. The study was conducted by the Cholesterol Treatment Trialists’ Collaboration, a group that includes the principle authors of nearly all of the major statin trials, which allowed the study group access to individual data in each study.
  2. Each of the randomized placebo-controlled statin trials designed to determine the value of statins in primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) over the past 20 years have established the drug class as safe and effective. While most included subjects up to 75 years and some have targeted the elderly, two well designed trials showed no value in primary prevention. There remains uncertainty about statin efficacy and safety among older people. The authors performed a meta-analysis to compare the effects of statin therapy at different ages.
  3. The authors used participant data from 22 trials (n = 134,537), detailed summary data from one trial (n = 12,705) of statin therapy versus control, plus individual participant data from five trials of more versus less intensive statin therapy (n = 39,612). Participants were subdivided into six age groups (≤55 years, 56–60 years, 61–65 years, 66–70 years, 71–75 years, and >75 years).
  4. Outcome endpoints were the estimated effects on major cardiovascular events (CVEs) (major coronary events, strokes, and coronary revascularizations), cause-specific mortality, and cancer incidence as the rate ratio per 1.0 mmol/L reduction (about 40 mg/dl) in low-density lipoprotein cholesterol (LDL-C). In the 28 trials of 186,854 participants, 8% (14,483) were >75 years at baseline and median follow-up was 4.9 years. There was a 21% proportional reduction in major CVEs per 1.0 mmol/L reduction in LDL-C, which decreased insignificantly with age and significantly in all age groups. Overall, statin or more intensive statin therapy yielded a 24% reduction in major CVEs per 1.0 mmol/L reduction, which trended to smaller proportional risk reducing in CVEs (p for trend = 0.009).
  5. Statins and more intensive statins were associated with a 25% reduction in proportional risk of coronary revascularization and a 16% reduction in risk of stroke, which did not differ across age groups. The reduction in major vascular events was similar across age groups with pre-existing vascular disease, but smaller in older than younger persons without vascular disease (p for trend = 0.05). For each 1.0 mmol/L reduction in LDL-C, there was a 12% reduction in vascular mortality with a trend toward smaller reductions with older age (p for trend = 0.004), a trend that did not persist after exclusion of heart failure or dialysis trials.
  6. In summary, statin therapy produces significant reductions in major vascular events irrespective of age, but there is less direct evidence of benefit among patients >75 years without established ASCVD. This is being addressed by further trials. Statin therapy is safe in the elderly and has no effect at any age on nonvascular mortality, cancer death, or cancer incidence.
  7. In persons >75 years, the absolute reduction in vascular events was about 0.5% per year per mmol/L decrease in LDL-C, which may or may not be greater in high-risk subjects. The value of statins in the elderly who are at higher risk for events and mortality may be limited by impact of poorly controlled hypertension, hypotension, chronic renal disease, atrial fibrillation, and nonadherence.
  8. Over the past several years, cost has not limited the use of statins in the elderly. The potential for better tolerance and benefit of low-dose statins plus ezetimibe or ezetimibe alone needs to be evaluated. The EWTOPIA 75 trial is a recent open-label blinded endpoint study of ezetimibe plus diet versus diet control alone in elderly moderate- and high-risk patients. All subjects were Japanese men and women with mean age 81 years, an LDL-C >140 mg/dl and one or more major risk factors, and a history of stroke or peripheral vascular disease. At 5-year follow-up, the CVE outcome (sudden cardiac death, myocardial infarction, percutaneous coronary intervention or coronary artery bypass grafting, and stroke) was 44% lower (p = 0.002) with ezetimibe.
  9. Amongst the questions that need to be addressed include the value in primary and secondary prevention with cholesterol-lowering drugs in the very elderly who have a reasonable life expectancy.

Keywords: Aged, 80 and over, Atherosclerosis, Atrial Fibrillation, Cholesterol, LDL, Diet, Geriatrics, Hypertension, Hypotension, Myocardial Infarction, Myocardial Revascularization, Neoplasms, Peripheral Vascular Diseases, Primary Prevention, Renal Insufficiency, Chronic, Risk Factors, Secondary Prevention, Stroke, Vascular Diseases

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