Rhabdomyolysis and Acute Renal Failure Due to Simvastatin and Amiodarone

Haroon Siddique; Maria Mushkbar; Adrian Walker; John Scarpello

Disclosures

Br J Cardiol. 2007;14(4):242-244. 

In This Article

Discussion

In summary, we report a case of rhabdomyolysis secondary to concomitant use of high-dose simvastatin and amiodarone. Although myopathy/rhabdomyolysis is a well-documented adverse effect of statin therapy, a literature search had revealed only a few case reports[1,2,3,4] ( table 2 ) regarding the drug interaction between statin and amiodarone, resulting in rhabdomyolysis.

Rhabdomyolysis is defined by creatinine kinase levels of more than 10 times the upper limit of normal and elevated plasma creatinine, usually associated with myoglobinuria.[5] Statins reduce the risk of myocardial infarction, coronary heart disease and/or death, both in primary and secondary prevention. Myopathy occurs in 0.1-0.2% of people receiving statin therapy,[6] which if left untreated will progress to rhabdomyolysis in 0.04-0.2%.[7] Concurrent use of drugs that are metabolised by the enzyme cytochrome P450 3A4 increases the risk of statin-induced myopathy; one report suggests that approximately 58% of cases of statin-induced rhabdomyolysis are due to drug interactions.[6] About 10-50% of patients with rhabdomyolysis develop acute renal failure.[8] Advancing age, diabetes mellitus, liver disease, renal impairment, alcoholism, hypothyroidism and concurrent use of fibrates are additional risk factors associated with myopathy.[6] In one study the number needed to treat (NNT) to observe one case of rhabdomyolysis was 22,727 for statin monotherapy and 484 for older patients with diabetes mellitus taking both a statin and a fibrate.[9] Cerivastatin was withdrawn following a cluster of cases of rhabdomyolysis where, when combined with a fibrate, the risk was as high as one in 10.[9]

The classic triad of symptoms includes muscle pain, weakness and dark urine.[8] The suggested mechanisms of myotoxicity with statins include depletion of metabolic intermediates, apoptotic cell death, alterations of chloride-channel conductance within the myocytes, and selenoprotein deficiency.[5] The muscle pathology is characterised by loss of striations and nuclei, with regeneration in part, and no infiltration of inflammatory cells.[5] The pathophysiology of myoglobinuric acute renal failure has been studied extensively in the animal model of glycerol-induced acute renal failure. The main pathophysiological mechanisms include renal vasoconstriction, intraluminal cast formation and direct haem protein cytotoxicity.[10] The treatment of rhabdomyolysis includes aggressive fluid replacement and preservation of renal function. Mannitol and bicarbonate, although commonly recommended, are of unproven benefit.[8]

Individual statins may differ in their risk of inducing rhabdomyolysis, with some patients developing myopathy when switched from one statin to another, while others develop rhabdomyolysis when exposed to any statin.[8] One recent study showed that patients with statin-associated myopathy experienced full resolution of muscle pain on cessation of statin therapy and recurrent muscle pain was noticed on statin rechallenge.[11] The American College of Cardiology/American Heart Association/National Heart, Lung, and Blood Institute have summarised the current understanding of the appropriate use and safety of statins ( table 3 ).[12]

Amiodarone is a class III antiarrhythmic with a half-life of 40-50 days. The terminal elimination half-life of amiodarone after long-term oral treatment is approximately 40 days or longer. It is metabolised by the enzyme cytochrome P450 3A4.[13] Statins such as atorvastatin, lovastatin and simvastatin are metabolised via a cytochrome P450 3A-dependent pathway while fluvastatin, pravastatin and rosuvastatin are metabolised via cytochrome P450 3A-independent pathways.[5] As simvastatin and amiodarone are metabolised by the same isoenzyme, in the present case, the concomitant use of these drugs may have resulted in competition, resulting in excess of free plasma statin and thereby causing myotoxicity. However, there are limited publications on this interaction and the exact mechanism has not been established.

In the ongoing Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial, myopathy was observed in 6% of patients receiving simvastatin 80 mg/day in combination with amiodarone. There is a formal contraindication to the use of simvastatin 80 mg/day with amiodarone in the summary of product characteristics following early safety results from the above study. It was therefore recommended that the dose of simvastatin should not exceed 20 mg/day in patients concomitantly treated with amiodarone. Our patient was taking four times the dose recommended by the manufacturer.[14] Alisheikh-Ali and Karas[15] studied the percentage of statin-associated adverse event reports with concurrent use of amiodarone. The authors analysed muscle, liver, pancreas and bone marrow systems and found that simvastatin-related adverse reports with concomitant amiodarone use were 1%. The adverse event reports with atorvastatin and pravastatin use were 0.7% and 0.4%, respectively, when combined with amiodarone. About 77% of these adverse event reports were due to muscle toxicity.[15] Amiodarone can also cause hypothyroidism, which may be associated with myopathy. In this case the patient's marginal rise in thyroid stimulating hormone may not explain his symptoms.

Physicians should be aware of the risk of myopathy when using statins especially when co-prescribed with other drugs that are metabolised by the same isoenzyme, cytochrome P450 3A4. The prescribing physician should consider the co-morbid risk factors, including polypharmacy, and initiate statin at a lower dose in the elderly. Patients should be given adequate information concerning symptoms of myopathy and be advised to seek help promptly if they develop such symptoms.

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