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Abnormal Liver Enzymes No Reason to Avoid Statins

— Statins are not only safe and effective for patients with liver enzyme abnormalities but also appear to improve their liver function, researchers found.

Ƶ MedicalToday

Statins are not only safe and effective for patients with liver enzyme abnormalities but also appear to improve their liver function, researchers found.

Liver test results in patients with moderately abnormal liver tests at baseline -- possibly associated with non-alcoholic fatty liver disease -- improved with statin treatment but continued to worsen on usual care without statin treatment (P<0.0001), Dimitri P. Mikhailidis, MD, of University College London, and colleagues reported online in The Lancet.

Action Points

  • Note that in current practice many patients are denied statins because of pre­existing changes in liver ­function tests, and statins are discontinued in other patients when alanine aminotransferase (ALT) increases.
  • Point out that the current study suggests that statin therapy will actually lead to improvement in moderately abnormal liver tests in patients with non-alcoholic fatty liver disease, in addition to providing a significant cardiovascular benefit.

Their retrospective analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) trial showed a greater statin effect on cardiovascular risk reduction in these high-risk patients than in those with normal liver tests (P=0.0074).

The findings add to evidence that should render liver tests irrelevant when prescribing statins, Ted Bader, MD, of the University of Oklahoma Health Sciences Center in Oklahoma City, argued in an accompanying commentary.

"Statin-induced hepatotoxicity is a myth," he wrote in Lancet.

About 10% of patients see liver enzymes rise after starting a statin, which can exceed the threshold of three times the upper limit of normal for 1%, but these eventually return to normal even when continuing the same statin, Bader noted.

His group reported a small pilot study in 2007 that actually suggested a liver function boost on statin treatment for patients with chronic hepatitis C infection.

Yet reluctance to start statins in patients with out-of-range alanine aminotransferase (ALT) levels, and discontinuation of statins for ALT increases, might keep statins from 10% to 30% of those who need them, he estimated.

The language of package inserts is likely to blame for the misperception that statins cause liver disease, according to Bader. He encouraged drug companies to request label modification for all the statins.

"Although most patients [in the trial] took atorvastatin, there is no reason to believe that other statins would behave differently," Bader wrote in the commentary.

The single-center, prospective GREACE trial originally compared statin treatment with usual care (which could include a statin) with regard to survival effects in 1,600 patients with coronary artery disease. Study participants were under age 75, had serum concentrations of LDL cholesterol over 2.6 mmol/L, and had triglycerides under 4.5 mmol/L.

The post-hoc analysis included the 437 patients in the study with moderately abnormal ALT, asparte aminotransferase (AST), and gamma-glutamyl transpeptidase (GGT) concentrations at baseline, all believed to be due to fatty liver or non-alcoholic steatohepatitis (NASH) since alcohol misuse and other liver diseases were excluded.

Of these participants, 227 received a statin, predominantly 24 mg daily of atorvastatin (Lipitor), in the trial.

The main analysis showed that statin treatment reduced the risk of first occurrence of any cardiovascular event -- defined as death from any cause or from coronary heart disease as well as nonfatal myocardial infarction, revascularization, unstable angina, congestive heart failure, and stroke.

Overall in the trial, statins were associated with a lower cardiovascular event rate (13% or 4.2 per 100 patient-years versus 25% or 8.3 per 100 patient-years) for a 49% relative risk reduction compared with the usual care group (P<0.0001).

The post-hoc analysis showed that the patients with abnormal liver tests gained proportionately more from statin treatment.

Among participants with abnormal liver tests, statins reduced the risk of a first cardiovascular event by a relative 68% compared with usual care (10% or 3.2 per 100 patient-years versus 30% or 10.0 per 100 patient-years, P<0.0001).

By comparison, statins produced a 39% relative risk reduction among patients with normal liver tests (14% or 4.6 per 100 patient-years versus 23% or 7.6 per 100 patient-years, P<0.0001).

The reason for the greater benefit might be the elevated cardiovascular risk of patients with nonalcoholic fatty liver disease, the researchers speculated.

In the overall study, liver enzyme concentration increases on statins led to dose reductions in three of 880 patients. Less than 1% (seven of 880) withdrew from the study because of liver-related adverse effects attributed to statin treatment.

No patients required liver biopsy because of elevated liver enzymes or developed an increase in bilirubin to more than 34.2 μmol/L or alkaline phosphatase concentrations to more than twice the upper limit of normal.

Estimated glomerular filtration rates (eGFRs) actually rose by the end of the study in statin-treated patients compared with the others (P<0.0001).

The researchers cautioned that their study was faced by the same limitations characteristic of post-hoc analyses generally, and the small number of patients with liver test abnormalities in the study.

Whether the results generalize to patients with more than moderately elevated liver test results still needs to be established, they added.

Disclosures

The researchers reported having no conflicts of interest to disclose but noted that some of the authors have attended conferences, given lectures, and participated in advisory boards or trials sponsored by various pharmaceutical companies.

Bader reported sharing a patent application with the University of Oklahoma for use of statins in viral hepatitis.

Primary Source

The Lancet

Source Reference: 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; DOI: 10.1016/S0140-6736(10)61272-X.

Secondary Source

The Lancet

Source Reference: Bader T "Liver tests are irrelevant when prescribing statins" Lancet 2010; DOI: 10.1016/S0140-6736(10)62142-3.