Statins Use Proves Safe in Patients with Abnormal Liver-function Tests
Abstract & Commentary
By Andrew J. Boyle, MBBS, PhD, Assistant Professor of Medicine, Interventional Cardiology, University of California, San Francisco. Dr. Boyle reports no financial relationships relevant to this field of study.This article originally appeared in the January 2011 issue of Clinical Cardiology Alert. It was edited by Michael H. Crawford, MD, and peer reviewed by Ethan Weiss, MD. Dr. Crawford is Professor of Medicine, Chief of Cardiology, University of California, San Francisco, and Dr. Weiss is Assistant Professor of Medicine, Division of Cardiology and CVRI, University of California, San Francisco. Dr. Crawford is on the speaker for Astra-Zeneca, and Dr. Weiss reports no financial relationships relevant to this field of study.
Source: Athyros VG, et al. 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. Lancet. 2010;376:1916–1922.
The efficacy of statins in preventing cardiovascular events is well known, but approximately 10% of patients will develop elevations in liver function tests (LFTs). This has led to caution in prescribing statins to patients with baseline elevations of LFTs. The most common cause of abnormal LFTs in the western world is NAFLD (non-alcoholic fatty liver disease), a condition associated with obesity and insulin-resistance syndromes. The treatment of NAFLD includes statins, yet these are precisely the patients being denied statin therapy because of abnormal LFTs. Athyros and colleagues addressed the question of whether statin therapy is safe and effective in patients with mild-to-moderately elevated liver enzymes. They performed a post-hoc analysis of the GREACE study, which was a prospective, randomized trial of statins vs. usual care (which may or may not include statin use per physician discretion) in 1,600 patients with established coronary artery disease (CAD) and LDL cholesterol > 100 mg/dL. Follow-up was 3 years; LFTs were measured at baseline, after 6 weeks, and then every 6 months thereafter. They identified 437 patients with elevations in liver enzymes ≤ 3 times the upper limit or normal. No cause for the liver enzyme abnormalities was noted, but they presume most were due to NAFLD because alcohol misuse and other liver diseases were exclusion criteria for the original GREACE cohort. Of these, 227 patients were treated with a statin and 210 were not. Baseline characteristics and lipid levels were well-matched between those taking statins and those who were not. Less than 1% of patients withdrew from each group. The primary endpoint was the rate of cardiovascular events, defined as death, myocardial infarction, revascularization, acute coronary syndrome, or heart failure. The average daily statin doses were atorvastatin 24 mg, simvastatin 22 mg, pravastatin 31 mg, or fluvastatin 40 mg.
Results: Not surprisingly, those taking statins had greater reductions in LDL (-44% vs. -5%) and triglycerides (-32% vs. -7%) and a greater increase in HDL (+8% vs. +3%) over the 3-year follow-up period. All patients taking statins experienced a reduction in liver enzyme concentrations, whereas in those not taking statins, LFTs continued to increase. Patients taking statins had a cardiovascular event rate of 9.7%, compared to 30% in those not taking statins (p < 0.0001). The reduction in cardiovascular events with statins was more pronounced in the group with abnormal LFTs at baseline than in the entire GREACE cohort. The authors conclude that 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.
NAFLD has been associated with an increased risk for cardiovascular disease, although it remains unclear if this is due to the company it keeps (obesity, hypertension, insulin resistance) or to the liver dysfunction itself. Traditionally, statins have been withheld from patients with abnormal LFTs, but because NAFLD is a common condition in the western world, and often accompanies vascular disease, withholding statins from these patients may deprive a large number of people of the life-saving benefit of statin therapy. The data presented by Athyros and colleagues challenge this dogma and show that stain therapy is safe and beneficial in these patients. In fact, because the reduction in cardiovascular events with statins was more pronounced in the group with abnormal LFTs at baseline than in the entire GREACE cohort, abnormal LFTs may actually identify a subgroup in which statins achieve a better therapeutic response. It is important to mention that alcohol abuse and other liver diseases were exclusion criteria in this study, so the data cannot necessarily be extrapolated to patients with other liver diseases. Also, patients with liver enzyme elevations > 3 times the upper limit of normal were not included and, thus, the results may not apply to them. This study strengthens the safety data for statins, and once other serious liver diseases have been excluded, statin therapy appears safe in patients with mild-to-moderate elevations in LFTs. This does not mean we can stop checking LFTs, as there was still a small (< 1%) rate of discontinuation due to elevations in LFTs more than 3 times the upper limit of normal. Future prospective studies are warranted to confirm these findings and to expand the number of patients eligible for statin therapy.