Elsevier

The Lancet

Volume 376, Issue 9756, 4–10 December 2010, Pages 1916-1922
The Lancet

Articles
Safety 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

https://doi.org/10.1016/S0140-6736(10)61272-XGet rights and content

Summary

Background

Long-term statin treatment reduces the frequency of cardiovascular events, but safety and efficacy in patients with abnormal liver tests is unclear. We assessed whether statin therapy is safe and effective for these patients through post-hoc analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study population.

Methods

GREACE was a prospective, intention-to-treat study that randomly assigned by a computer-generated randomisation list 1600 patients with coronary heart disease (aged <75 years, with serum concentrations of LDL cholesterol >2·6 mmol/L and triglycerides <4·5 mmol/L) at the Hippokration University Hospital, Thessaloniki, Greece to receive statin or usual care, which could include statins. The primary outcome of our post-hoc analysis was risk reduction for first recurrent cardiovascular event in patients treated with a statin who had moderately abnormal liver tests (defined as serum alanine aminotransferase or aspartate aminotransferase concentrations of less than three times the upper limit of normal) compared with patients with abnormal liver tests who did not receive a statin. This risk reduction was compared with that for patients treated (or not) with statin and normal liver tests.

Findings

Of 437 patients with moderately abnormal liver tests at baseline, which were possibly associated with non-alcoholic fatty liver disease, 227 who were treated with a statin (mainly atorvastatin 24 mg per day) had substantial improvement in liver tests (p<0·0001) whereas 210 not treated with a statin had further increases of liver enzyme concentrations. Cardiovascular events occurred in 22 (10%) of 227 patients with abnormal liver tests who received statin (3·2 events per 100 patient-years) and 63 (30%) of 210 patients with abnormal liver tests who did not receive statin (10·0 events per 100 patient-years; 68% relative risk reduction, p<0·0001). This cardiovascular disease benefit was greater (p=0·0074) than it was in patients with normal liver tests (90 [14%] events in 653 patients receiving a statin [4·6 per 100 patient-years] vs 117 [23%] in 510 patients not receiving a statin [7·6 per 100 patient-years]; 39% relative risk reduction, p<0·0001). Seven (<1%) of 880 participants who received a statin discontinued statin treatment because of liver-related adverse effects (transaminase concentrations more than three-times the upper limit of normal).

Interpretation

Statin treatment is safe and can improve liver tests and reduce cardiovascular morbidity in patients with mild-to-moderately abnormal liver tests that are potentially attributable to non-alcoholic fatty liver disease.

Funding

None.

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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