Combined Statin-Fibrate Therapy-Induced Rhabdomyolysis : Case Report

Introduction Rhabdomyolysis is a rare, but serious and potentially fatal adverse reaction of the statin application that may be developed in any time of therapy. It is characterized by massive destruction of muscles associated with the large increase of creatine kinase (CK) leading to myoglobinuria and potential acute renal failure. Combined statin-fibrate therapy increases the risk of rhabdomyolysis, especially in elderly and diabetic patients.


INTRODUCTION
Rhabdomyolysis is a clinical syndrome characterized by necrosis of skeletal muscles with resulting release of toxic cell components into systemic circulation.The causes of rhabdomyolysis are multiple: metabolic myopathies, trauma, electrocution, excessive physical activity, infections, intoxication, hyperthermia, as well as use of specific drugs and their adverse interaction.Statins belong to the group of most studied medicines, and their benefit in treatment and prevention of cardiovascular and cerebrovascular diseases is definitely verified.In the last several decades, they were prescribed to millions of patients and besides efficacy, they confirmed good safety profile.Statin monotherapy is safe and well tolerated, with low frequency of adverse events.However, the conditions increasing the plasma statin concentration, such as higher doses or combined therapy may increase the risk of adverse events; it is estimated that approximately 50% of severe side effects of statin therapy is the consequence of interaction with other drugs.Most frequent side effect is myopathy characterized by muscle pain and/or weakness, but it may rarely cause muscular necrosis and rhabdomyolysis.Combined statin and fibrate treatment may increase the risk of rhabdomyolysis, especially in elderly people and diabetics.
The case report on combined statin-fibrate therapy-induced rhabdomyolysis is here presented to evaluate the significance of early diagnosis and adequate intensive therapy.

CASE REPORT
An 81-year-old male was admitted to Coronary Care Unit of the Emergency Center, Clinical Center of Serbia (CCS) with the clinical picture and electrocardiogram of the acute anterior wall myocardial infarction complicated with pulmonary edema.His personal medical history reported stable angina 2-3 months before presentation, cholelithiasis and surgery for the left kidney calculosis 21 years ago.He did not receive any therapy.
On physical examination, the patient was conscious, oriented, orthodispnoic, afebrile, and obese.On lung auscultation, prolonged expirium with diffuse rales to the scapulas corresponding to pulmonary edema was heard.The heart rate was regular at 130 beats/min, gal-lop rhythm, without murmurs; blood pressure was 210/140 mmHg bilaterally.The abdomen was soft, painless on palpation, without hepatosplenomegaly.He had no peripheral edema, and peripheral arterial pulsations were symmetrically palpable.On admission, ECG showed sinus rhythm and ST-segment elevations in leads V1-V6.In further course, an evolution of the anterior wall myocardial infarction was ECG recorded.
On admission, laboratory tests were as follows: glycemia 10.7…5.5 mmol/L; urea 9,2 mmol/L; creatinine (Cr) 179 μmol/L; eGFR 32 mL/min/1.73m 2 ; sodium 140 mmol/L; potassium 4. Upon admission, the patient was treated with diuretics (i.v.furosemide), nitroglycerin (NTG) infusion, dual antiplatelet therapy (aspirin and clopidogrel), and proton pump inhibitors as a protection; after normalization of blood pressure, thrombolytic therapy (i.v.alteplase 100 mg) and heparin infusion were administered.This resulted in significant clinical improvement of cardiac status in terms of regression of symptoms and signs of the heart failure, but an early hospital course was complicated by fever (since day 3) and verified right-sided pneumonia and urinary infection.The chest X-ray demonstrated the left pleural exudation, the right mediobasal pulmonary parenchyma consolidation and cardiomegaly with hilar stasis.Echocardiography showed normal size of the left ventricle with concentrically hypertrophic walls, akinesia of medial septum, anterior and lateral wall and apex, and reduced systolic function (EF 40%).
Besides anticoagulant and dual antiplatelet therapy, diuretics (furosemide and spironolactone), nitrates and proton pump inhibitors, angiotensin-converting enzyme (ACE) inhibitor (fosinopril) and antibiotics were introduced in therapy, as follows: initially ceftriaxone, later on replaced by ertapenem and ciprofloxacin for urinary infection and isolated Enterobacter spp. in the urine culture.Blood cultures were sterile.Due to mixed hyperlipidemia, the patient was initially administered rosuvastatin, but because of its shortage in our hospital, pravastatin 20 mg and fenofibrate 160 mg were included on day 3 of hospitalization.Since day 3 of his stay, he complained exclusively on pains in joints, at first in the knees and then ankles, and the following days were featured by progressive pain in leg muscles and inability to move them.
Neurological status: the impression of bilateral paratonia; upon upper extremities examination -sinking with pronation of both hands, more to the right; MR were more intensive bilaterally; lower extremities -no ability of moving his legs, MR bilaterally extinguished, bilateral "silent" soles of the feet.Laboratory analyses revealed markedly elevated CK to maximum 7080 U/L (Graph 1), elevated BUN and serum creatinine from the baseline level (Graph 2), hyperkaliemia with max.5.6 mmol/l along with hyponatremia (124 mmol/l) and hypochloremia (86 mmol/l), as well as positive inflammatory syndrome.The urine analysis was negative for myoglobin.
Given the clinical picture and laboratory parameters indicating the statin-induced rhabdomyolysis, pravastatin and fenofibrate treatment (applied 7 days) was discontinued, which, together with symptomatic measures, first of all intensive rehydration of patient, led to clinical improvement in view of complete resolution of muscular symptoms and restoration of CK and BUN and serum creatinine to baseline levels.
The patient was discharged in a stable condition with, among others, diagnosis of medicamentous myopathy.

DISCUSSION
The most common complication of statin use is different skeletal muscle side effects that may be generally designated as statin-induced myopathy (Table 1).
According to data of randomized clinical studies and registries, the incidence of myopathy is estimated as 5 patients/100,000 individuals/year, and rhabdomyolysis as 1.6 patients/100,000 individuals/year [2].Data of FDA AERS (Adverse Event Reporting System database) are 0.3-2.2cases of myopathy and 0.3-13.5 rhabdomyolysis cases in 1,000,000 prescribed statins [3].
Rhabdomyolysis is rare adverse effect of statin therapy occurring in less than 0.1% of patients [2], and mortality rate is approximately 0.15 deaths/1 million prescribed statins [4].Prediction of patients with tendency to develop complications is difficult, since the association of plasma concentrations and side effects is not linear [5].Higher doses are associated with higher risk of adverse effects.The factors increasing the plasma statin concentration increase the risk of rhabdomyolysis.These include renal diseases, hepatic insufficiency, age over 80 years, diabetes, hypothyreosis, genetic factors and interactions with other drugs.The most frequent drugs affecting the statin metabolism are presented in Table 2.
Cytochrome P450 (CYP) enzyme system in the liver is responsible for metabolism of multiple drugs, including the statins, with the exception of pravastatin [6].Pravastatin metabolizes via several pathways, including the isomerization, sulfation, glutathione conjugation and oxidation, and via CYP enzyme system in a very low percentage (1%).It is the only statin with excretion via kidneys (approximately 60%), according to its hydrophilic properties [7].These pharmacokinetic characteristics of pravastatin theoretically render it safer in interactions with other medication [8].Based on data obtained from epidemiological and clinical studies, the combination of any statin and fibrate increases the risk of myopathy usually in the first 12 weeks from the onset of therapy.The incidence of myotoxicity in combined statin-fibrate use is 0.12% [9].Although the majority of reports on rhabdomyolysis includes gemfibrozil, some other fibrates (bezafibrate, clofibrate, fenofibrate) are also responsible for rhabdomyolysis cases when combined with statins [10].
In our case, the most probable cause of rhabdomyolysis is an adverse interaction of pravastatin and fenofibrate, along with other existing factors that increase plasma statin concentration, such as age over 80 years, coexisting renal failure and bacterial infection [11,12].Medical management of rhabdomyolysis is focused on aggressive fluid hydration for diuresis stimulation, because myoglobin dilution in tubules prevents generation of toxic myoglobin cylinders and supports their excretion.Our patient responded well to intensive hydration, in addition to other therapy, what all resulted in resolution of skeletomuscular symptoms and clinical recovery.

Graph 1 .Graph 2 .
CK values during hospitalization Values of nitrogen substances (urea and creatinine) during hospitalization