Side-effects of statin use and focus on rhabdomyolysis

Background 

Major clinical trials (4S, WOSCOPS, CARE, LIPID) have shown that statins are important in reducing mortality from all causes, and especially cardiovascular mortality. Statin use for treatment and prevention of primary and secondary cardiovascular diseases has increased and lipid-lowering therapies have become more intense in complying with more aggressive targets after trials confirming safety and efficacy in high-risk patients (AVERT, HPS). For example, in those aged 45 years and older, statin use increased from 2% between 1988 and 1994 to 25% between 2005 and 2008 according to a 2010 center for disease control survey (1). In the last guidelines the treatment goal is an LDL-cholesterol concentration of <1.8mmol/L (<70mg/dl) for the patients with elevated risk (2-5).
However, the problem of potential adverse events due to side-effects from toxicity and drug interactions is heightened from more wide-spread use at increased dosages. This review aims to enable the clinician to adopt early measures in order to reduce related morbidity and mortality. 

1 - Mechanisms and guidelines

Cardiovascular disease reduction is mainly due to the reduction of LDL-cholesterol and therefore lower deposition of atherogenic lipoproteins on the wall of blood vessels - especially in coronary arteries. This occurs for plaque stabilisation, reversal of endothelial dysfunction and decreased thrombogenicity and other mechanisms (6).
In patients with acute coronary syndrome, the main guidelines are to use statins at high doses at the time of hospital admission - atorvastatin at a dose of 80mg daily or equivalent - independently of basal levels of cholesterol (7-10). Clinical trials have shown greater benefits with the onset of early and intensive treatment, on speculation of their pleiotropic effect (11,12).
However, the side effects of statins should always be taken into account: muscle pain, tenderness, stiffness, cramping, weakness, signs or symptoms of hepatotoxicity (unusual fatigue or weakness, loss of appetite, abdominal pain, dark-colored urine or yellowing of the skin or sclera). Rhabdomyolysis is a potentially severe clinical condition, associated with mortality in a considerable number of cases (13,14).

2 - Rhabdomyolysis

Case-report

A 76-year-old white man, a retired metallurgist, previously hypertensive and diabetic in irregular treatment and active smoker (smoking burden 40 years/pack), was admitted to the emergency room of our hospital with acute myocardial infarction without ST segment elevation, in stable hemodynamic condition. Initial drug management was dual antiplatelet therapy with aspirin 100 mg and clopidogrel 75 mg with loading dose of 300mg, anticoagulation with low molecular weight heparin (enoxaparin); beta blockade with metoprolol tartarate and high dose statin (Atorvastatin 80 mg/day).
The initial electrocardiogram showed atrial fibrillation, right bundle branch block and left ventricular hemiblock, left ventricular enlargement suggesting inferior infarction and altered repolarisation with ischemic and secondary changes. Coronary artery angiography showed moderate anterior descending artery lesion, with a long thin artery and the decision was to follow with conservative medical treatment. Serum laboratory tests at admission were: Creatinine 1,50mg/dl, Urea nitrogen 69mg/dL, Total cholesterol 134mg/dl, HDL cholesterol 32mg/dl, LDL cholesterol 90 mg/dl, Triglycerides 108mg/dl, AST 21U/l (n < 37), ALT 34U/l (n< 41), CK-MB Mass 5.52ng/ml (n<5) and Troponin T 0.18 (n< 0.01).
The patient was doing well on the medication, with cardiovascular stability.
On the sixth day of hospitalisation, he began complaining of discreet muscle pains, reduced urine output and change in color of urine (reddish-brown).
Lab tests were done, showing worsening of renal function and muscle enzymes elevation: Creatinine 3,27mg/dl, urea 118 mg/dl, potassium 7,0mEq/l, Troponin: > 10 ng/ml, CK-MB Mass 283 U (normal:<5) and CK 991U/l (normal: 35 to 232 U/l).
We immediately stopped atorvastatin and ruled out use of other potentially nephrotoxic drugs. We began vigorous hydration. The patient evolved satisfactorily, with gradual return to basal laboratory levels as shown in Table 1.
The patient was discharged on the fourteenth day of hospitalisation with total recovery of renal function, and asymptomatic. We opted to keep him without statin use until the next outpatient evaluation.

Table 1: Laboratory Tests

Prevention

Here are some aspects to consider in prevention of rhabdomyolysis - the association of muscle and renal damage and acute renal failure resulting from  in out-patient care:

1. Take a history of prior or current muscle symptoms (pain, weakness and stiffness) to establish a baseline before initiating statin therapy.
2. The emergence of myalgia, although of small magnitude, with loss of kidney function and high muscle enzyme and liver damage markers should always suggest rhabdomyolysis (15).
3. If mild to moderate muscle symptoms develop during statin therapy, discontinue the statin, evaluate the patient for other conditions that might increase the risk for muscle symptoms (e.g., hypothyroidism, reduced renal or hepatic function, rheumatologic disorders such as polymyalgia rheumatica, steroid myopathy, vitamin D deficiency, or primary muscle diseases). 
4. If unexplained severe muscle symptoms or fatigue develop during statin therapy, discontinue the statin and address the possibility of rhabdomyolysis by evaluating creatinine kinase activity (CK), creatinine, and a urinalysis for myoglobinuria. 
5. If muscle symptoms resolve, and if no contraindication exists, give the patient the original or a lower dose of the same statin to establish a causal relationship between the muscle symptoms and statin therapy. 
6. If a causal relationship exists, 1) discontinue the original statin 2) Once muscle symptoms resolve, use a low dose of a different statin 3) Once a low dose of a statin is tolerated, gradually increase the dose as tolerated
7. If, after 2 months without statin treatment, muscle symptoms or elevated CK levels do not resolve completely, consider other causes of muscle symptoms (16).

3 - Myopathies 

The myopathies - diseases of the muscles usually characterised by weakness - associated with the use of statin drugs range from discreet muscle pains to rhabdomyolysis. Here are general indications: 

1. An elevation of CK is the best indicator of statin-induced myopathy (myositis). Creatine phosphokinase elevation has become the primary marker for ongoing muscle cell death and destruction. However, myalgia (without CK elevation) occurs in 5-10% of patients in clinical practice. 
2. The definition of a tolerable elevation has been a rise of five times the upper normal limit of of this enzyme measured on two occasions - to levels about 2,000 IU/L.
3. Symptoms can start a week before treatment onset and can occur at any time during treatment. After the withdrawal of the drug, clinical and laboratory improvements can occur between 3 and 30 days.

4 - Prevalence

In the United States, deaths from rhabdomyolysis induced by statins occur in about 0.15 per million prescriptions (17).
The greatest risk was with the use of cerivastatin, which was withdrawn from the market in 2001, after 31 rhabdomyolysis deaths reported in elderly patients who used it in association with the gemfibrozil. The leading cause of death in rhabdomyolysis is acute renal failure (18).
A recent meta-analysis made the following considerations: only cases of myopathy that had progressed to rhabdomyolysis were sought from the individual trials.
Overall, the observed excess of rhabdomyolysis was 4 per 10,000 in the five trials of more versus less intensive statin therapy (14 vs six cases) compared with 1 per 10,000 in the 21 trials of standard statin regimens versus control (14 vs nine cases). All of the excess (ten vs no cases) with more intensive therapy occurred in the two trials of 80 mg versus 20 mg simvastatin daily; these two trials have also reported definite excesses in the incidence of myopathy with 80 mg simvastatin daily. There was no significant evidence in the meta-analysis of trials of more versus less intensive therapy that further lowering of LDL cholesterol (weighted mean of 2.5 mmol/L reduced to 2.0 mmol/L) produced any adverse effects, even in participants with baseline LDL cholesterol lower than 2.0 mmol/L. In summary, special more intensive statin therapy increases the risk of adverse side effects.
Myalgia, with or without changes of creatine phosphokinase (CK), elevation of liver enzymes (AST and ALT) and, in a very small number of cases - around 1:10,000 - rhabdomyolysis can occur. 

5 - Interactions

Interactions with lipid lowering agent may occur in pre-existing neuromuscular disorders, hypothyroidism, acute and chronic renal failure, obstructive liver disease and with some drugs (Table 2). 
When drug combinations are necessary, the risk of side effects can be minimised by identifying vulnerable patients and by avoiding statin interactions with specific drugs. Because statins are prescribed on a long-term basis, possible interactions with other drugs deserve  continuous attention, as many patients will receive pharmacological therapy for other diseases at the same time.
The risk of muscle injury is  substantially increased when taking both statins extensively metabolized by cytochrome P450 3A4 (lovastatin, simvastatin, atorvastatin)  and drugs that interfere with CYP3A4. Pravastatin, fluvastatin, rosuvastatin, and pitavastatin are preferred when concurrent therapy with a strong inhibitor of CYP3A4 cannot be avoided.
 
Table 2. Selected drugs that may increase risk of myopathy and rhabdomyolysis when used concomitantly with statin (CYP3A4 inhibitors/ substrates or other mechanisms) (5).

• Cyclosporin, Taclorimus
• Macrolides (Azithromycin, Clarithromycin, Erithromycin)
• Azole Antifunguls (itraconazole, ketoconazole, fluconazole)
• Calcium antagonists (mibefradil, diltiazem, verapamil)
• Nefazodone
• HIV protease inhibitors (ampremavir, indinavir, nelfinavir, ritonavir, saquinavir)
• Sildenafil
• Fibrates, especially Gemfibrozil
• Others

6 - Treatment

The treatment of this clinical condition is effective when started early and aims mainly to reduce kidney damage. It is based on drug interruption and vigorous hydration with correction of electrolytic disorders. Alkalinisation of the urine have controversial results (19).
In this case, the elevation of CK did not hit 10 times the value of reference. The association with acute renal failure and elevation of liver injury markers were sufficient to establish the diagnosis of rhabdomyolysis. Treatment was based mainly on vigorous hydration, which allowed increased urine output (diuresis) and gradual normalization of kidney function. 
While statin-myotoxicity is a function of dose, the patient received lipid-lowering management consistent with the guidelines for acute myocardial infarction, which recommended atorvastatin a a dose of 80mg/day. Although the LDL cholesterol was 90mg/dL his high risk condition constitutes a recommendation for intensive statin therapy. 

Conclusions

Side effects caused by the use of statins are infrequent, but should always be considered in all patients using this therapy.
When prescribing statins, take a history of muscle symptoms and watch for any signs of it - weakness, tenderness or pain -developing. Also address any potential drug interactions.  
If symptoms develop, early detection of clinical and laboratory findings - use as well as the early institution of treatment - may be crucial factor in the outcome of patients with rhabdomyolysis.