Statins Reduce CV
Events in People With Abnormal Liver Function Tests CME/CE
News Author: Michael O’Riordan
CME Author: Laurie Barclay, MD
CME/CE Released: 12/01/2010; Valid
for credit through 12/01/2011
December 1, 2010 — A
post hoc analysis of the Greek Atorvastatin and
Coronary Heart Disease Evaluation (GREACE) study suggests that physicians
should not let mildly to moderately abnormal liver test results stop them from
using a statin in patients with coronary heart
disease [1]. Statin
therapy is not only safe in these patients, report investigators, but it
significantly reduces the risk of cardiovascular events and improves
liver-function tests.
"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,"
senior investigator Dr Dimitri Mikhailidis
(University College London Medical School, UK) told heartwire
. "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."
In an editorial accompanying the
study [2], Dr Ted Bader (University of
Oklahoma Health Sciences Center, Oklahoma City) called the analysis
"groundbreaking." He said it is unknown how many patients are denied statins because of preexisting changes in liver-function
tests or how many have the lipid-lowering drugs stopped after elevations in
liver-enzyme concentrations, but he suspects that 10% to 30% of patients who
need statins might fall into this category.
"This large group represents a
substantial source of cardiovascular disease, which is not being
prevented," writes Bader. "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."
The results of the study and
editorial are published online November 24, 2010 in the Lancet.
The GREACE Trial
To heartwire
, Mikhailidis said that nonalcoholic fatty liver
disease (NAFLD) is the most common cause of abnormal liver-function tests and
that the severity of NAFLD increases in patients with higher body-mass index
and triglyceride concentrations, as well as in patients with diabetes,
hypertension, and insulin resistance. These patients also have a higher risk of
all-cause mortality, mainly caused by an increased risk of cardiovascular
events. Previously published data, however, as well as their own experience,
suggested that statins were safe in patients with
NAFLD.
Despite this, physicians can practice
medicine defensively, said Mikhailidis, and might be
reluctant to prescribe statins to patients with
elevated liver enzymes at baseline. The purpose of the post hoc analysis was to
assess the risk/benefit ratio in GREACE patients treated with a statin who had moderately abnormal liver tests, defined as
serum alanine aminotransferase
(ALT) or aspartate aminotransferase
(AST) less than three times the upper limit of normal (<3x ULN).
In total, 227 patients were treated
with statins, typically atorvastatin
(Lipitor, Pfizer), over the three-year study. Statin
therapy reduced baseline low-density lipoprotein cholesterol levels from 170
mg/dL to 95 mg/dL, as well
as significantly reduced total cholesterol and triglyceride levels. Measures of
liver function were also significantly improved, with ALT and AST
concentrations reduced 35% and 47%, respectively. In a control cohort of 210
patients not treated with statins, lipid levels were
unchanged, while liver-function tests showed increased ALT and AST
concentrations.
In terms of cardiovascular morbidity,
fewer patients with impaired liver-function tests treated with a statin had a cardiovascular event--nonfatal MI,
revascularization, unstable angina, and congestive heart failure, as well as
stroke and all-cause mortality--when compared with impaired liver-function-test
patients who did not receive a statin. After three
years, the event rate was 9.7%, or 3.2 events per 100-patient years, among the statin-treated patients, compared with 30.0%, or 10.0
cardiovascular events per 100-patient years, among those not treated with a statin.
Speaking with heartwire ,
Mikhailidis said the relative benefit among patients
with mildly to moderately elevated liver-function tests was greater than that
observed among patients with normal liver-function tests at baseline. For
example, in those with normal ALT and AST concentrations at baseline, the
relative reduction in cardiovascular events was 39%, compared with a 68%
relative reduction in cardiovascular risk among those with mild to moderate
elevations in liver enzymes.
Despite the results, Mikhailidis said there are important limitations to the
study. "You have to remember, the numbers are small, with just 200
patients or so in each arm, and the duration is short, at three years," he
said. "Most important of all, it's a post hoc analysis. You have to be
very, very careful in post hoc analyses that you don't go about finding things
and then proclaiming something huge. All of these factors are a considerable disadvantage,
or weakness, in our conclusions."
Still, Mikhailidis
told heartwire the data confirm
the elevated risk of cardiovascular events among patients with NAFLD and hopes
the work triggers similar post hoc analyses of the larger statin
trials.
Statin-Induced Hepatotoxicity
a Myth
In his editorial, Bader said that statin-induced liver toxicity is a myth, one that is fueled
by the language in the package insert of the drugs. Large studies have shown no
difference in the frequency or degree of ALT increases between treatment and
placebo groups, and there are no reports of chronic carriers of drug-induced
liver damage from statins.
Bader stressed that an elevation in
ALT does not represent a disease state, yet many US physicians are reluctant to
prescribe a statin to patients with ALT increases
even 1.5x ULN. The finding of improved liver function among the statin-treated patients confirms studies performed in
hepatitis-C patients treated with statins, another
group in whom doctors are reluctant to prescribe the lipid-lowering drugs,
writes Bader.
|
The
authors report no conflicts of interest. Bader reports a patent application
with the |
References
1.
Athyros VG, Tziomalos K, Gossios TD, 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; DOI:10.1016/S0140-6736(10)61272-X.
Available at: http://www.thelancet.com.
2.
Bader
T. Liver tests are irrelevant when prescribing statins.
Lancet 2010; DOI:10.1016/S0140-6736(10)61272-X.
Available at: http://www.thelancet.com.
Additional Resource
The National Cholesterol Education Program provides ATP III
Guidelines At-A-Glance Quick Desk Reference as a downloadable document.
By inhibiting hepatic production of
cholesterol, statin treatment helps reduce the risk
for cardiovascular events including myocardial infarction and stroke. Rarely, statin use may cause the adverse effect of increased levels
of liver enzymes or serum transaminases such as ALT.
Although statins have not been linked to liver injury,
a survey showed that half of US academic physicians would be reluctant to give
a statin to a patient with an ALT level of more than
1.5 times ULN and that 10% to 30% of patients who could benefit from statins would be denied this treatment.
NAFLD, which affects up to one third
of adults in the