November 24, 2010The Lancet
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
Key result
Statins reduce recurrent cardiovascular events ~68% in CHD patients with abnormal liver tests.
- 68% relative risk reduction
- P<0.0001
- n=1,600
Why the study?
The safety and efficacy of long-term statin treatment in patients with coronary heart disease and abnormal liver tests was unclear.
Does statin therapy reduce first recurrent cardiovascular events in patients with coronary heart disease and moderately abnormal liver tests?
Key Points
- To assess the safety and cardiovascular efficacy of long-term statin therapy in patients with coronary heart disease and moderately abnormal baseline liver tests.
- Post-hoc analysis of the prospective GREACE study, in which 1600 patients with coronary heart disease (aged <75 years) were randomly assigned via a computer-generated list to statin therapy or usual care at Hippokration University Hospital in Greece.
- Evaluated 437 patients with moderately abnormal baseline liver tests (<3 times the upper limit of normal for alanine aminotransferase or aspartate aminotransferase), comparing 227 statin-treated patients with 210 untreated patients.
- Cardiovascular events occurred in 22 of 227 (10%; 3.2 per 100 patient-years) statin-treated patients versus 63 of 210 (30%; 10.0 per 100 patient-years) untreated patients with abnormal liver tests (68% relative risk reduction, p<0.0001).
- Statin therapy led to significant improvement in liver enzyme tests (p<0.0001), whereas untreated patients experienced further increases in liver enzyme concentrations.
- Treatment discontinuation due to liver-related adverse effects (transaminases >3 times the upper limit of normal) occurred in 7 of 880 (<1%) statin-treated participants.
Study Design
Type
RCT (n=1,600)
Randomization
computer-generated randomisation list
Multicenter
No
Structured PICO
Does statin therapy reduce first recurrent cardiovascular events in patients with coronary heart disease and moderately abnormal liver tests?
P
Population
1,600 patients aged <75 years with coronary heart disease and dyslipidemia, analyzed post-hoc for outcomes among 437 patients with moderately abnormal liver tests.
I
Intervention
Statin therapy (mainly atorvastatin 24 mg per day)
C
Comparator
Usual care (which could include statins)
O
Outcome
First recurrent cardiovascular eventhard clinical
Main Result
Effect estimate: 68% relative risk reduction
Absolute Event Rate: 10% vs 30%
p-value: p=<0.0001
Limitations
- Post-hoc analysis
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“The data in the last few years have shown that these patients with elevated liver-function tests are at a greater risk of vascular events, and we wanted to see if that were true. Indeed, there was an increased risk among these patients, and we found that they also had a bigger benefit and that they improved their liver function with a statin. Also, we found the opposite in patients not treated with a statin, that their liver-function tests tended to become more abnormal over time, although this probably reflects them getting fatter over three years in the study.”
AJAndrew J. BoyleInterventional cardiologist, University of California, San Francisco
“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 large group represents a substantial source of cardiovascular disease, which is not being prevented. Further harm ensues from the cost of monitoring with liver-function tests. One estimate conservatively placed the cost of monitoring statins with liver-function tests at US $10 billion per year.”
Implication
Statin therapy should not be withheld in coronary heart disease with moderately abnormal liver tests; extends randomized evidence to this subgroup.
Abstract
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.
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Cite This Study
Athyros et al. (2010) conducted an RCT in Coronary heart disease with abnormal liver tests (n=1,600). Statin therapy (mainly atorvastatin) vs. Usual care (no statin treatment) was evaluated on First recurrent cardiovascular event (68% relative risk reduction, p=<0.0001). Statin treatment significantly reduced the risk of first recurrent cardiovascular events in patients with coronary heart disease and moderately abnormal liver tests (10% vs 30%; P<0.0001).