Effectiveness and safety of using statin therapy for the primary prevention of cardiovascular diseases in older patients with chronic kidney disease who are hypercholesterolemic: a target trial emulation study

Abstract

Background

There remains a scarcity of evidence on initiating statin therapy for the primary prevention of cardiovascular diseases among older adults with chronic kidney disease due to the under-representation of this population in randomised controlled trials. This study aimed to evaluate the effectiveness and safety of using statin therapy for the primary prevention of cardiovascular diseases in older adults (aged 75–84 years) and very old adults (aged ≥85 years) with chronic kidney disease.

Methods

Using territory-wide public electronic health records in Hong Kong, patients older than 60 years with chronic kidney disease and with hyperlipidaemia (defined as elevated LDL cholesterol of ≥2·6 mmol/L) were identified for inclusion in the analyses and were included on a rolling basis in each calendar month from January, 2008, to December, 2015. Patients were categorised into different age groups (ie, 60–74 years, 75–84 years, and ≥85 years) for analysis, and the 60–74 years age group was used as a benchmark group to test the validity of our emulated trial since the effect of statin therapy is well established in this age group. The framework of target trial emulation was adopted to investigate the association between statin therapy and the risk of overall cardiovascular disease incidence, specific cardiovascular disease subtypes (ie, myocardial infarction, heart failure, and stroke), and all-cause mortality, as well as major adverse events (ie, myopathies and liver dysfunction). The primary outcome was overall cardiovascular disease incidence. The hazard ratios for the outcomes were estimated by pooled logistic models in the intention-to-treat analysis and the per-protocol analysis.

Findings

711 966 person-trials from 96 trials were eligible for inclusion in the study. 19 423 unique individuals with chronic kidney disease aged 60–74 years, 22 565 unique individuals with chronic kidney disease aged 75–84 years, and 8811 unique individuals with chronic kidney disease aged 85 years and older were identified for inclusion in the analyses. In patients aged 75–84 years, a significant risk reduction was observed for overall cardiovascular disease incidence in both the intention-to-treat analysis (hazard ratio [HR] 0·94 [95% CI 0·89–0·99]) and in the per-protocol analysis (0·86 [0·80–0·92]) and for all-cause mortality (0·87 [0·82–0·91] in the intention-to-treat analysis and 0·78 [0·72–0·84] in the per-protocol analysis). This risk reduction was also observed among patients aged 85 years and older for cardiovascular diseases (HR 0·88 [0·79–0·99] in the intention-to-treat analysis and 0·81 [0·71–0·92] in the per-protocol analysis), and for all-cause mortality (0·89 [0·81–0·98] in the intention-to-treat analysis and 0·80 [0·71–0·91] in the per-protocol analysis). Substantial risk reduction for myocardial infarction, heart failure, and stroke were also observed across all age groups. No significantly increased risk of myopathies or liver dysfunction was observed in any of the age groups.

Interpretation

Statin therapy is beneficial for hypercholesterolemic older patients with chronic kidney disease aged 75 years and older regarding the primary prevention against cardiovascular diseases and all-cause mortality, without posing an increased risk of major adverse events. The benefits and safety persist in those aged 85 years and older.

Funding

National Natural Science Foundation of China Excellent Young Scientists Fund (Hong Kong and Macau).