Efficacy and safety of lowering LDL cholesterol in older patients: a systematic review and meta-analysis of randomised controlled trials

Abstract

Background: The clinical benefit of LDL cholesterol lowering treatment in older patients remains debated. We aimed to summarise the evidence of LDL cholesterol lowering therapies in older patients.

Methods: In this systematic review and meta-analysis, we searched MEDLINE and Embase for articles published between March 1, 2015, and Aug 14, 2020, without any language restrictions. We included randomised controlled trials of cardiovascular outcomes of an LDL cholesterol-lowering drug recommended by the 2018 American College of Cardiology and American Heart Association guidelines, with a median follow-up of at least 2 years and data on older patients (aged ≥75 years). We excluded trials that exclusively enrolled participants with heart failure or on dialysis because guidelines do not recommend lipid-lowering therapy in such patients who do not have another indication. We extracted data for older patients using a standardised data form for aggregated study-level data. We meta-analysed the risk ratio (RR) for major vascular events (a composite of cardiovascular death, myocardial infarction or other acute coronary syndrome, stroke, or coronary revascularisation) per 1 mmol/L reduction in LDL cholesterol.

Findings: Data from six articles were included in the systematic review and meta-analysis, which included 24 trials from the Cholesterol Treatment Trialists' Collaboration meta-analysis plus five individual trials. Among 244 090 patients from 29 trials, 21 492 (8·8%) were aged at least 75 years, of whom 11 750 (54·7%) were from statin trials, 6209 (28·9%) from ezetimibe trials, and 3533 (16·4%) from PCSK9 inhibitor trials. Median follow-up ranged from 2·2 years to 6·0 years. LDL cholesterol lowering significantly reduced the risk of major vascular events (n=3519) in older patients by 26% per 1 mmol/L reduction in LDL cholesterol (RR 0·74 [95% CI 0·61-0·89]; p=0·0019), with no statistically significant difference with the risk reduction in patients younger than 75 years (0·85 [0·78-0·92]; p_interaction=0·37). Among older patients, RRs were not statistically different for statin (0·82 [0·73-0·91]) and non-statin treatment (0·67 [0·47-0·95]; p_interaction=0·64). The benefit of LDL cholesterol lowering in older patients was observed for each component of the composite, including cardiovascular death (0·85 [0·74-0·98]), myocardial infarction (0·80 [0·71-0·90]), stroke (0·73 [0·61-0·87]), and coronary revascularisation (0·80 [0·66-0·96]).

Interpretation: In patients aged 75 years and older, lipid lowering was as effective in reducing cardiovascular events as it was in patients younger than 75 years. These results should strengthen guideline recommendations for the use of lipid-lowering therapies, including non-statin treatment, in older patients.

Funding: None.

Figure 1:. Effect of LDL cholesterol lowering on the risk of major vascular events with statin and non-statin treatment in older patients

Older patients were aged 75 years or older. RRs per 1 mmol/L reduction in LDL cholesterol were generated from a random effects model. In the ODYSSEY OUTCOMES trial, the event numbers were provided at 4 years, whereas the RR is for the entire duration of trial. CTTC=Cholesterol Treatment Trialists’ Collaboration. EWTOPIA 75=Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerosclerotic Disease in 75 or Older. FOURIER=Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Patients with Elevated Risk. IMPROVE-IT=Improved Reduction of Outcomes: Vytorin Efficacy International Trial. ODYSSEY OUTCOMES=Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab. RR=risk ratio.

Figure 2:. Effect of LDL cholesterol lowering on the risk of major vascular events in older versus younger patients

Older patients were aged 75 years or older and younger patients were younger than 75 years. RRs per 1 mmol/L reduction in LDL cholesterol were generated from a random effects model. RR=risk ratio.

Figure 3:. Effect of LDL cholesterol lowering on the risk of individual efficacy endpoints in older patients

Older patients were aged 75 years or older. RRs per 1 mmol/L reduction in LDL cholesterol were generated from a random effects model. RR=risk ratio.

Figure 4:. Effect of LDL cholesterol lowering on the risk of safety endpoints in older patients

Older patients were aged 75 years or older. Data are n or n/N (%), unless otherwise indicated. RRs per 1 mmol/L reduction in LDL cholesterol were generated from a random effects model. The numbers of patients without cancer events per treatment group were not available in the Cholesterol Treatment Trialists’ Collaboration meta-analysis. The definitions of reported safety data in each trial are given in the appendix (p 18). RR=risk ratio.