Risk for fatal statin-induced rhabdomyolysis as a consequence of misinterpretation of ‘evidence-based medicine’

Mats Eriksson, Centre for Metabolism and Endocrinology, Department of Medicine, Karolinska University Hospital, 141 86 Huddinge, Sweden.
(fax: +8 585 82407; e-mail: mats.eriksson@medhs.ki.se).

Dear Sir,

Statin treatment is an enormous progress in the treatment of atherosclerosis. The careful institution of such therapy in large numbers of patients at increased risk for coronary death represents a great challenge both to practising physicians and to the funding bodies of health care. In order to ensure appropriate treatment at low cost there is presently a trend to recommend statin treatment at a fixed dose regardless of initial lipid values and without evaluating therapeutic effects such as cholesterol levels. Evidence of such measures is mainly based on the data published from the MRC/BHF Heart Protection Study (HPS) where 40 mg simvastatin was used as a fixed dose [1]. Further, from July 2004, simvastatin is available without prescription in the UK [2].

We recently observed two cases of severe rhabdomyolysis caused by simvastatin treatment initiated based on regional recommendations. One of them was an 80-year-old female with a history of myocardial infarctions, kidney insufficiency, myocardial infarctions and heart insufficiency. She was given 40 mg of simvastatin promptly after a myocardial infarction, and was readmitted 6 months later because of weakness and severe muscle pain. Myoglobin level was above 3000 μL−1 and she died of multiple organ insufficiency after a month. Our opinion is that 40 mg simvastatin was the causative agent for this severe rhabdomyolysis and death.

In the HPS [1] study, a very low frequency of side-effects was seen and there was no statistical difference between the treatment group (40 mg simvastatin) and the placebo group regarding myopathy or creatinine kinase (CK) elevations. At the end of the study compliance was 85% in the simvastatin group (n = 8590). However, in the placebo group 17% took a non-study statin (n = 1715). There is no mention of whether those who developed myopathy in the placebo group were those taking a non-study statin. If so, there were a maximum of 14 cases of myopathy among patients (n = 10107) taking statins (0.14%). Rhabdomyolysis was seen in altogether eight cases, five in the treatment group and three in the placebo group.

A major drawback with the HPS study is that only 32% of all screened patients became randomized. In addition, the pre-run in phase where all patients were given 40 mg of simvastatin seems effectively to have sorted out cases with side-effects on statin treatment. The frequency of side-effects and especially myopathy presented has to be interpreted taking these facts into careful consideration.

Taking into account the above facts, there are several reasons to believe that the HPS trial underestimates the risk for dose-dependent myopathia by statin treatment. We do not at this moment find it relevant to start treatment with 40 mg of simvastatin without titration from a lower dosage, and without measuring cholesterol in order to reach predefined goals. The Swedish national [3] or the European expert [4] panels are of the same opinion in contrast to WHO Medicines and Policy Department [5]. The problems with interaction with other concomitant medications as well as the mechanisms behind statin-induced muscle problems have to be further studied.

Conflict of interest statement

No conflict of interest was declared.

M. Eriksson, B. Angelin, S. SjöbergFrom the Department of Medicine, Centre for Metabolism and Endocrinology, Karolinska University Hospital, Huddinge, Sweden