The efficacy and safety of intensive statin therapy: a meta-analysis of randomized trials

I read with interest the meta-analysis by Josan et al [1] on the safety of intensive statin therapy but was disappointed with their avoidance of commenting on the need to monitor hepatotoxicity. In their analysis, even with the intensive statin therapy only 1.5% showed elevations in serum aminotransferase (ALT) levels [1]. Unfortunately, most subjects starting statins get their ALT levels tested and retested unnecessarily.

Randomized controlled trials have shown no difference between placebo and statin groups in withdrawals due to raised ALT levels [2]. Tolman [3] has reviewed the literature for lovastatin, which has been in use since 1986 with 24 million patient-years of clinical experience. Elevated ALT was documented at the rate of 2.6% and 5% for lovastatin doses of 20 mg/day and 80 mg/day, respectively. In many, the elevation in liver enzymes were transient and improved even with continuing therapy. Acute liver failure occurred in 1 per 1.14 million patient-treatment years. This is equivalent to background rate of acute liver failure in the general population.

Minor elevations in ALT are poorly predictive of hepatotoxicity and hence ineffective in preventing serious liver disease [4]. Furthermore, in a review from primary care setting to determine the value of routine monitoring of enzyme levels (ALT and CK) in over 1000 patients taking statins [5] only 1% had significant elevation in ALT. None appeared to be related to statin use. Similar results were obtained for the analysis of CK levels. They questioned the usefulness of routine monitoring in all patients taking statins. ALT elevations due to statin therapy will almost always resolve within 6 weeks of discontinuation. The decision to reinstitute therapy should be based on an individualized risk versus benefit analysis [6]. Signs and symptoms of hepatic failure (especially jaundice) should prompt immediate discontinuation of therapy and referral to a specialist.

There is a need to review and change the old published guidelines recommending initial screening laboratory testing as well as ongoing monitoring of liver enzymes during therapy. Judicious use of laboratory testing will minimize needless evaluation and premature discontinuation of statin therapy.

References 1. Josan K, Majumdar SR, McAlister FA. The efficacy and safety of intensive statin therapy: a meta-analysis of randomized trials. CMAJ 2008; 178:576-84. 2. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7-22. 3. Tolman KG. The liver and lovastatin. Am J Cardiol 2002; 89: 1374-1380. 4. Bolego C, Baetta R, Bellosta S, Corsini A, Paoletti R. Safety considerations for statins. Curr Opin Lipidol 2002;13:637-644 5. Smith CC, Bernstein LI, Davis RB, Rind DM, Shmerling RH. Screening for statin-related toxicity: the yield of transaminase and creatine kinase measurements in a primary care setting. Arch Intern Med 2003;163:688-92. 6. Gotto AM Jr. Safety and statin therapy: reconsidering the risks and benefits. Arch Intern Med 2003; 163:657-659.

Conflict of Interest:

None declared