ArticlesSafety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis
Introduction
Investigations into the relation of statin treatment to the liver have predominantly dealt with liver-related adverse effects, which mainly manifest as raised concentrations of the serum transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST).1, 2 However, several small studies3, 4, 5, 6, 7, 8, 9, 10, 11 of patients with raised transaminase or γ-glutamyl transpeptidase (GGT) activity because of non-alcoholic fatty liver disease (NAFLD) showed that statins are safe and improve liver histology and liver tests. Although the true prevalence of such disease is unknown, some estimates suggest that it might affect up to 33% of American, European, and Japanese adults.3, 4, 12 NAFLD is the most common cause of abnormal liver tests in the developed world.3, 4 Its prevalence increases, and more advanced stages of the disease, such as non-alcoholic steatohepatitis or fibrosis are noted with increased age, body-mass index, and triglyceride concentrations, and in patients with diabetes mellitus, hypertension, or insulin resistance.12 Patients with NAFLD have 69% higher all-cause mortality than the general population.13 This increased risk is mainly caused by cardiovascular disease and, to a lesser extent, liver disease.13 Patients with non-alcoholic steatohepatitis have an even higher rise in all-cause mortality rates than do patients with NAFLD.13
Statin treatment is part of the therapeutic strategy for NAFLD.3, 4, 5, 6, 7, 8, 9, 10, 11 However, the risk-to-benefit ratio of statin treatment in patients with this disease has not been investigated in cardiovascular disease outcome studies. Our post-hoc analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study14 was done to address this issue. Because of the increased cardiovascular risk in patients with NAFLD13 and the established benefits of statin in prevention of cardiovascular disease,15 study of the effect of statins in this population is important.
Section snippets
Participants and study design
The design and results (mortality, morbidity, cost-effectiveness, and long-term safety) of the GREACE study have been described elsewhere.14, 16 Briefly, GREACE was a prospective, randomised, open label, intention-to-treat, unsponsored, survival study. 1600 patients (1248 [78%] men) with established coronary heart disease, aged younger than 75 years (mean 58·3, SD 13·0; figure 1) were enrolled. Serum concentrations of LDL cholesterol had to be more than 2·6 mmol/L and concentrations of serum
Results
Figure 1 shows the GREACE Study profile and table 1 lists baseline characteristics of all participants according to liver tests and statin treatment. As per protocol, patients with concentrations of liver enzymes of more than three times the upper limit of normal were not included in the study. Mild-to-moderate increases in serum concentrations of ALT or AST up to three times the upper limit of normal were noted in 437 of 1600 patients assessed at baseline (before statin treatment initiation).
Discussion
We show that frequency of liver-related adverse effects during chronic statin treatment is low (1·1%) in patients with coronary heart disease and dyslipidaemia and does not differ from rates reported in patients not treated with statins (0·4%, p=0·2). Additionally, all patients with abnormal rises in AST or ALT concentrations of up to three times the upper limit of normal who were given a statin had a substantial improvement in liver tests during 3-year follow-up. By contrast, patients with
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