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

Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece.
The Lancet (Impact Factor: 45.22). 12/2010; 376(9756):1916-22. DOI: 10.1016/S0140-6736(10)61272-X
Source: PubMed


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.
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.
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).
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.

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Available from: Vasilios Gabriel Athyros, Mar 29, 2014
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    • "Statins have been tested in NAFLD treatment only in either underpowered, or not controlled, or in studies lacking histological assessment of liver damage, which still is the gold standard to assess the prognosis of the disease [23]. In these studies, statins were well tolerated and reduced cardiovascular risk [20] [24], but results on liver-related outcomes were not conclusive [25] [26] [27] [28] [29] [30]. Furthermore, randomized trials testing the effect of statins in individuals with NASH would be difficult to design because these patients often require statin treatment to reduce cardiovascular risk [31] [32]. "

    Journal of Hepatology 10/2015; DOI:10.1016/j.jhep.2015.09.023 · 11.34 Impact Factor
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    • "This study shows that statin users had lower ALT levels compared with their counterpart, even if no differences were observed in terms of histological liver damage. Our data might suggest a protective effect of statins in NAFLD, as reported in other studies on patients taking statins for cardiometabolic disorders [36] [37]. "
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    ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) has been associated with increased cardiovascular risk, including coronary artery disease and cardiac dysfunction. In addition, recent evidence highlighted the possible role of epicardial fat as a new cardiometabolic risk factor. We tested the correlation between epicardial fat, alterations in cardiac geometry and function and the severity of liver damage in patients with biopsy-proven NAFLD. The anthropometric, biochemical and metabolic features were recorded in 147 consecutive biopsy-proven NAFLD cases (Kleiner score). Epicardial fat thickness was measured by echocardiography. Epicardial fat was higher in patients with severe vs. milder fibrosis (8.5±3.0 vs. 7.2±2.3 mm; p=0.006); this association was maintained at multivariate logistic regression analysis (OR 1.22, 95%C.I. 1.01-1.47; p=0.04) after correction for gender, age>50 years, visceral obesity, IFG/diabetes, non-alcoholic steatohepatitis and severe steatosis. Of note 37.1% of patients with epicardial fat >7mm (median value) had severe liver fibrosis, compared to 18.3% of cases with lower epicardial fat (p=0.01). As for echocardiographic indices, after adjusting for cardiometabolic confounders, diastolic posterior-wall thickness (p=0.01), left ventricular mass (p=0.03), relative wall thickness (p=0.02), and left atrial volume (0.04), as well as ejection fraction (p=0.004), lower lateral TDI e' (p=0.009), E/A ratio (0.04) (cardiac geometry alterations and diastolic dysfunction) were linked to severe liver fibrosis. In patients with NAFLD, a higher epicardial fat thickness is associated with the severity of liver fibrosis, in keeping with a possible pathogenic role of ectopic fat depots in whole body organ damage. In addition, morphological and functional cardiac alterations are more pronounced according to the severity of fibrosis. Further studies are needed to validate our results. Copyright © 2014. Published by Elsevier B.V.
    Journal of Hepatology 11/2014; 62(4). DOI:10.1016/j.jhep.2014.11.030 · 11.34 Impact Factor
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    • "Raised transaminases are frequently seen in patients receiving statins (usually due to coexistent NAFLD) but they are safe in patients with liver disease, and serious liver injury is rarely seen in clinical practice.46 In a large cardiovascular outcomes study, statins were shown to improve liver enzymes and cardiovascular outcomes in patients with raised liver function tests (LFTs) due to NAFLD.68 "
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    ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) affects up to a third of the population in many developed countries. Between 10% and 30% of patients with NAFLD have non-alcoholic steatohepatitis (NASH) that can progress to cirrhosis. There are metabolic risk factors common to both NAFLD and cardiovascular disease, so patients with NASH have an increased risk of liver-related and cardiovascular death. Management of patients with NAFLD depends largely on the stage of disease, emphasising the importance of careful risk stratification. There are four main areas to focus on when thinking about management strategies in NAFLD: lifestyle modification, targeting the components of the metabolic syndrome, liver-directed pharmacotherapy for high risk patients and managing the complications of cirrhosis.
    10/2014; 5(4):277-286. DOI:10.1136/flgastro-2013-100404
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