|Year : 2015 | Volume
| Issue : 2 | Page : 244-246
Late onset rhabdomyolysis developing secondary to atorvastatin therapy in a coronary artery disease patient
Somak Kumar Das1, Saikat Ghosh1, Anand Sharma2
1 Department of Medicine, College of Medicine, JNM Hospital, Kalyani, Nadia, India
2 Department of Medicine, Sagore Dutta Hospital, Kamarhati, West Bengal, India
|Date of Web Publication||13-Mar-2015|
Somak Kumar Das
A/14, Katjunagar, Jadavpur, 2nd Floor, Kolkata - 700 032, West Bengal
Source of Support: None, Conflict of Interest: None
Rhabdomyolysis, a clinical syndrome in which skeletal muscle damage and necrosis, is precipitated by multi-therapy is most frequently described during statin treatment. Rhabdomyolysis is a rare, but serious side-effect that may lead to renal failure and dangerous electrolyte abnormalities in patients. We report a case of rhabdomyolysis after 5 years of atorvastatin therapy in an elderly patient, in multi-treatment for coronary artery disease.
Keywords: Atorvastatin, creatine phosphokinase, rhabdomyolysis
|How to cite this article:|
Das SK, Ghosh S, Sharma A. Late onset rhabdomyolysis developing secondary to atorvastatin therapy in a coronary artery disease patient. Med J DY Patil Univ 2015;8:244-6
| Introduction|| |
Rhabdomyolysis, a clinical syndrome in which skeletal muscle damage and necrosis, leads to the release of intracellular contents of muscle. In extreme cases, this can lead to severe serum muscle enzyme elevations, electrolyte imbalances, renal failure, and death.  The most common adverse effects of statins are skeletal muscle complaints, including clinically myositis and rhabdomyolysis, mild serum creatine kinase elevations, myalgia, muscle weakness, muscle cramps, and persistent myalgia  The risk of rhabdomyolysis and other adverse effects of statin use can be exacerbated by several factors, including compromised hepatic and renal function, hypothyroidism, diabetes, and concomitant multiple medications and drug-drug interaction.  We report a case of rhabdomyolysis after 5 years of atorvastatin therapy in an elderly patient, in multi-treatment for coronary artery disease.
| Case report|| |
A 63-year-old male came to the emergency department with acute onset painful weakness in both lower limbs. He did not have any fever, sensory symptoms, back pain, rashes, bladder and bowel disturbances or weight loss. He had no family history of any muscle diseases. He was a nondiabetic and had no addictions. He was suffering from hypertension and ischemic heart disease, and had undergone coronary artery bypass graft surgery 5 years back. Since 5 years, he was on antiplatelets - aspirin-75 mg/day, omeprazole-20 mg/day, ramipril-5 mg/day and atorvastatin - 10 mg/day. For last 2 months, he was prescribed ranolazine 500 mg twice daily. Examination revealed predominantly proximal lower limb weakness with relative sparing of distal muscles. Power in upper limbs was near normal and deep tendon reflexes were preserved in all limbs. He also did not show any cranial nerve abnormality.
His blood and urine investigations are summarized in [Table 1]. Of special note, in his initial reports, there are markedly raised creatine phosphokinase (CPK) and slightly high creatinine levels, and also urine positive for myoglobin. His thyroid function tests were normal. His electrocardiogram did not show any features of any acute cardiac event. His nerve conduction velocity studies and magnetic resonance imaging of dorsal and lumbo-sacral spine were unremarkable. Immediately, atorvastatin were stopped in view of their myotoxicity. Ranolazine and omeprazole were also omitted suspecting pharmacologic drug interaction with atorvastatin. His renal derangement progressed in the initial few days. He was kept on alkaline diuresis under cardiac monitoring and maintained adequate urine output. His CPK also rose for next couple of days but then started decreasing. His weakness started improving on the 6 th day of his illness and significant improvements were seen by the 10 th day. Meanwhile the report of muscle biopsy from the quadriceps, which was done on the 4 th day of admission (after stopping the antiplatelets for 3 days), showed necrotic muscle fibers suggestive of rhabdomyolysis. He was discharged 18 days after his admission with ability to freely move around and a near normal renal function.
| Discussion|| |
Rhabdomyolysis is rapid destruction of striated muscle fibers leading to appearance of myoglobin and other muscle contents into the bloodstream. Various toxins can cause this including alcohol, statins, fibrates, cocaine, amphetamines, organophosphates and snake venom. The patients usually present with acute onset proximal muscle weakness, which is often painful. The deep tendon reflexes are preserved. The myoglobin that is released into circulation appears in the urine and may cause nephrotoxicity and acute renal failure. The creatine kinase is elevated markedly. Muscle biopsy shows necrosis and regeneration of muscle fibers. The treatment is usually directed towards ceasing exposure to the offending agents and preventing renal shutdown by alkaline diuresis to prevent myoglobin casts from forming. 
Statin induced muscle changes comprise of a spectrum, which include myalgia, myositis, rhabdomyolysis and an asymptomatic rise in serum creatine kinase.  The mechanism is not well understood, but may be due to inherent enzyme defects or reduced levels of ubiquinone and mevalonic acid. Sarcolemmal cholesterol decrease has also been proposed as a possible cause.  Rhabdomyolysis is a very rare occurrence among statin induced myopathies and is estimated to occur in a frequency of 1.6/100000 patient years according to a recent survey.  Graham et al. in their study reported the incidence of statin induced rhabdomyolysis to be 0.44 in 10000 patient years.  The risk for cerivastatin was comparatively much greater leading to the withdrawal of the drug from the market. The risk of rhabdomyolysis is considerably increased with the combined use of statins and fibrates. 
Atorvastatin is one of the most popular statins and is safely used and tolerated by the vast majority of patients without any major side-effects. Hepatitis, headaches, gastrointestinal discomfort and arthralgia are among the side-effects of atorvastatin.  Although it occurs rarely, rhabdomyolysis is the most serious adverse effect and has been reported with catastrophic events and even death in some patients. 
The reported case is unique due to the much delayed appearance of rhabdomyolysis in the patient. Most cases of statin induced rhabdomyolysis have been found to occur in the first 12 weeks of therapy as per analysis of the THIN database though it can occur rarely as late as 4 years  Schindler et al. have reported a case of statin induced rhabdomyolysis after more than 3 years of therapy.  Al-Sulaiman et al. reported a case of statin induced rhabdomyolysis after 2 years of therapy.  Eshraghian and Kamyab reported the case of a patient with liver cirrhosis receiving atorvastatin therapy for ischemic heart disease and hyperlipidemia who developed rhabdomyolysis and acute renal failure.  Our patient was on statin therapy for 5 years. The risk of rhabdomyolysis and other adverse effects of statin use can be exacerbated by several factors, including compromised hepatic and renal function, hypothyroidism, diabetes, and concomitant medications.  All other common causes and aggravating factor were excluded by respective investigations. Hence, pharmacologic drug interaction with omeprazole and recently added ranolazine must be considered as potential aggravating factors in this case. Proton pump (P-glycoprotein) inhibitors may increase serum hydroxymethylglutaryl coenzyme A reductase inhibitor concentrations.  Due to impairment of statin clearance by drugs sharing cytochrome P450 biotransformation pathway like ranolazine, rhabdomyolysis must be suspected during polypharmacy with statin. However, data are conflicting regarding the role of P-glycoprotein in the disposition of atorvastatin, and the ability of proton pump inhibitors such as omeprazole to inhibit P-glycoprotein at therapeutic concentrations. The resolution of the symptoms after the cessation of statin therapy in this case further indicated that the primary cause of rhabdomyelysis was atorvastatin.
| Conclusion|| |
Although very rare, rhabdomyolysis is the most dangerous side effect of statin therapy. Atorvastatin, one of the most popular and safe statin, does this complication, though rarely. Statin induced rhabdomyolysis may happen even after 4-5 years of uneventful regular use. Pharmacological drug interactions must be remembered when clinicians prescribe multiple other drugs with statin. Good knowledge of clinical pharmacology and early clinical suspicion of statin induced muscle disorders may prevent life-threatening rhabdomyolysis.
| References|| |
Tokinaga K, Oeda T, Suzuki Y, Matsushima Y. HMG-CoA reductase inhibitors (statins) might cause high elevations of creatine phosphokinase (CK) in patients with unnoticed hypothyroidism. Endocr J 2006;53:401-5.
Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA 2003;289:1681-90.
Sathasivam S, Lecky B. Statin induced myopathy. BMJ 2008;337:2286.
Efstratiadis G, Voulgaridou A, Nikiforou D, Kyventidis A, Kourkouni E, Vergoulas G. Rhabdomyolysis updated. Hippokratia 2007;11:129-37.
Harper CR, Jacobson TA. The broad spectrum of statin myopathy: From myalgia to rhabdomyolysis. Curr Opin Lipidol 2007;18:401-8.
Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L, et al.
Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004;292:2585-90.
Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP. Atorvastatin: Safety and tolerability. Expert Opin Drug Saf 2010;9:667-74.
Noordally SO, Sohawon S, Vanderhulst J, Duttmann R, Corazza F, Devriendt J. A fatal case of cutaneous adverse drug-induced toxic epidermal necrolysis associated with severe rhabdomyolysis. Ann Saudi Med 2012;32:309-11.
Kordas KC, Phillips PS, Golomb BA. Clinical characteristics of 1053 patients with statin associated muscle complaints. Arterioscler Thromb Vasc Biol 2004;24:E51-136.
Schindler C, Thorns M, Matschke K, Tugtekin SM, Kirch W. Asymptomatic statin-induced rhabdomyolysis after long-term therapy with the hydrophilic drug pravastatin. Clin Ther 2007;29:172-6.
Al-Sulaiman AA, Al-Muslim NI, Al-Quorain AA, Al-Sulaiman RM. The self-limiting nature of statin-induced rhabdomyolysis. J Family Community Med 2009;16:119-21.
Eshraghian A, Kamyab AA. Rhabdomyolysis developing secondary to atorvastatin therapy in a patient with liver cirrhosis. Intern Med 2013;52:823-5.
Elazzazy S, Eziada SS, Zaidan M. Rhabdomyolysis secondary to drug interaction between atorvastatin, omeprazole, and dexamethasone. Int Med Case Rep J 2012;5:59-61.
Sipe BE, Jones RJ, Bokhart GH. Rhabdomyolysis causing AV blockade due to possible atorvastatin, esomeprazole, and clarithromycin interaction. Ann Pharmacother 2003;37:808-11.