Return to strength - statin-induced myopathy

From: www.pharmacynews.com


12 March 2009 | by Debbie Rigby

Statins are well tolerated in most patients taking them, however a small percentage will experience statin-induced myopathy.

Home medicines reviews present an ideal opportunity to establish whether muscle pain or weakness may be related to any interacting medicines being taken.

One of the criteria for home medicines reviews (HMRs) is “symptoms suggestive of an adverse drug reaction”. While many GPs simply use five or more regular medicines as a risk factor trigger, it is useful to discuss the reason for referral with the GP and/or patient.

Using open-ended questions at the beginning of the HMR can identify patient concerns and guide the specific focus of discussion. Such questions might include, “What concerns do you have with your medications?” or “Do you have any questions or issues with your medicines?”

Case study

Mrs LP is an 83-year-old lady referred for a HMR. Her current medications include:

• Simvastatin 40mg daily.

• Pantoprazole 40mg 1 daily.

• Aspirin 100mg 1 daily.• Amiodarone 200mg 1 daily.• Isosorbide mononitrate 60mg 1 daily.• Irbesartan/hydrochlorothiazide (Avapro HCT) 300/12.5mg 1 mane.• Temazepam 10mg 1 nocte prn.• Paracetamol 500mg 1-2 q4h prn.• Meloxicam 15mg 1-2 daily prn.

Her past medical history includes tachyarrhythmias, angina, hypertension, hyperlipidaemia, reflux disease and osteoarthritis. No laboratory results are provided with the referral but Mrs LP says she has regular blood tests and her GP is happy with the results.

Mrs LP is concerned about persistent leg pain and weakness, mainly in the upper thigh, over the past few months. It is preventing her doing many common activities. She has not mentioned it to her GP as she thought it was just age-related muscle aches and pains. Further questioning reveals the muscle pain and weakness started after a recent admission to hospital and commencement of amiodarone. Her other medications have been prescribed in these doses for the past one to two years.

Drug interactions

The temporal relationship between commencement of amiodarone and the patient’s symptoms leads to a reasonable suspicion that the interaction between amiodarone and simvastatin is contributing to the patient’s myopathy.

Amiodarone increases risk of myopathy or rhabdomyolysis with simvastatin. Amiodarone interacts with grapefruit juice and many other drugs, as it inhibits CYP1A2, 2C9, 2D6 and 3A4. The Australian Medicines Handbook recommends use of an alternative statin (pravastatin) if possible; if a combination cannot be avoided, the lowest effective dose of simvastatin (no more than 20 mg daily) should be prescribed.

Drug interactions are an important consideration with some statins, greatly increasing the risk of statin-induced myopathy. Drugs affecting statin metabolism include:

• Fibrates.

• Nicotinic acid.

• Cyclosporine.

• Azole antifungals.

• Macrolide antibiotics.

• Protease inhibitors.

• Verapamil.

• Diltiazem.

• Amiodarone.

• Fluvoxamine.

• Warfarin.

• Grapefruit juice.

Simvastatin and atorvastatin are metabolised by CYP3A4, whereas pravastatin undergoes sulfation (phase 2 metabolism), and rosuvastatin and fluvastatin are metabolised mainly by CYP2C9.

Myopathy

Muscle damage, or myopathy, is an uncommon but important adverse reaction to statins. Myopathy typically occurs in fewer than one in 10,000 patients on standard statin doses. Clinically significant rhabdomyolysis is rare (three per 100,000 patient years) but potentially lethal. The incident rate is similar for monotherapy with atorvastatin, simvastatin and fluvastatin.

The terms myalgia, myositis, rhabdomyolysis and myopathy are often used interchangeably (incorrectly) to describe the muscle pain or weakness associated with use of statins. The term myopathy is often used to include the entire spectrum of muscle-related adverse effects.

Other cholesterol-lowering medications such as fibrates, nicotinic acid and ezetimibe (Ezetrol), can also lead to muscle toxicity.

Signs and symptoms

Symptoms of statin-induced myopathy include:

• Fatigue.

• Muscle pain.

• Muscle tenderness.

• Muscle weakness.

• Nocturnal cramping.

• Tendon pain.

The symptoms tend to be proximal, bilateral, generalised and worse with exercise. Patients will complain of decreased muscle strength and difficulty performing daily activities. The key symptoms of rhabdomyolysis include dark, red, or cola-coloured urine and severe muscle tenderness, stiffness, aching (myalgia) or weakness. Fever and malaise are also present.

Studies have shown the median time for onset of symptoms was one month following initiation of statin therapy, but could occur at any time. Muscle symptoms that develop in patients who have been taking statins for many years are unlikely to have been caused by the medication.

Myopathy most closely correlates with the dose of statins and is independent of reductions in LDL cholesterol.

Risk factors

Risk factors include advanced age, female sex, low BMI, reduced renal and hepatic function, multiple comorbidities, drug interactions, excess alcohol and dietary effects. Use of illicit drugs such as crack cocaine increases the risk of rhabdomyolysis.

The SEARCH study found that 60 per cent of people with statin-induced myopathy have genetic variants. This finding can potentially identify patients with an underlying susceptibility and therefore use a modified dose of statins to prevent myopathies. The prevalence of the genetic variant in the population is 15 per cent. A strong association was also shown in this study among patients concomitantly treated with amiodarone.

Evidence suggests that lipophilic statins (simvastatin, atorvastatin) are more likely to produce muscle side effects than are the relatively hydrophilic statins (pravastatin, rosuvastatin, fluvastatin). Lipophilic medications are more likely to penetrate muscle tissue.

Any factor that has the potential to increase the serum concentration of a statin has the potential to increase the risk of myopathy. Therefore, drug interactions with statins especially with medications that are inhibitors or substrates of the cytochrome P450 pathway may predispose patients to myopathy.

In patients with moderate to severe kidney disease, fluvastatin or atorvastatin may be better choices, as they are minimally excreted in the urine.
Laboratory tests

Statin-induced myopathy correlates with creatine kinase (CK) levels. Creatine kinase is an enzyme found primarily in skeletal muscle. However, slightly raised concentrations of creatine kinase are common in the general population and in black people.

The Heart Foundation guidelines on lipid management recommend the creatine kinase is measured at commencement of therapy; however pre-treatment evaluation is controversial and not been proven to be cost-effective. If suggestive muscle symptoms are reported, it is measured again with blood levels compared to earlier results. Routine monitoring of CK is not recommended in asymptomatic patients, although particular caution and monitoring is appropriate for patients taking particular concomitant medications and those with advanced age or with kidney dysfunction.

Patients with symptoms of muscle pain or weakness should also have thyroid-stimulating hormone (TSH) measured. This is because hypothyroidism, common in older people is a cause of hypercholesterolaemia and raised CK. It also predisposes people to statin-induced myopathy. Patients complaining of dark urine and with markedly raised CK levels should also have their renal function and urinary myoglobulin tested.

Management

If a patient’s history indicates muscle symptoms and markedly raised CK levels, first line management is to stop the suspected medication and monitor creatine kinase. Symptoms usually resolve rapidly, within a few days to weeks.

Patients with CK levels less than 10 times the upper limit of normal may require a statin holiday or dose decrease.

Patients complaining of muscle pain or weakness with normal CK levels should also consider withdrawal of the statin.

A repeat challenge after symptoms resolve is often indicated at a lower dose together with dietary therapy, considering the significant risk/benefit ration of reducing cholesterol levels, especially in high cardiovascular risk patients. If the lower dose is tolerated, the dose can be up-titrated slowly (at one to two-month intervals), with regular monitoring at three to six-month intervals, until target lipids are achieved.

If the re-challenge at a lower dose produces even mild symptoms, withdraw the medication and re-challenge with a low dose of a different statin.

Coenzyme Q10

Serum levels of coenzyme Q10 or ubiquinone have been shown to decrease with chronic use of statins. However evidence for use in prevention or treatment is lacking. Small studies and case reports have shown some limited benefit.

A systematic review of the role of coenzyme Q10 in statin-induced myopathy could not recommend routine use. The authors did suggest however that as the risks of the supplement is limited and that there is some anecdotal evidence, coenzyme Q10 may be an option for patients requiring statin treatment that develop muscle pain or weakness.

A small pilot study using coenzyme Q10 100mg/day or vitamin E 400 IU/day (as a placebo) showed a 40 per cent decrease in pain intensity after a month of coenzyme Q10 treatment. Interference of pain in daily activities was also improved by 38 per cent. Patients treated with vitamin E experienced no significant change in pain intensity. Pain scores did not correlate with CK concentrations before or after the intervention.

The best available evidence to date does not support routine use of CoQ10 to prevent myopathy, although there is limited evidence to treat statin-induced myopathy.

Recommendations

Given the temporal relationship between commencement of the amiodarone and commencement of the patient’s myopathy symptoms, it is reasonable to suspect this is the cause of the patient’s symptoms. It is suggested that simvastatin is withheld and creatine kinase, renal and thyroid function tests are ordered. If her symptoms resolve over a few weeks, a rechallenge of simvastatin at a lower dose of 20mg daily or alternatively a non-interacting statin such as pravastatin could be trialled.

Coenzyme Q10 could be suggested to the patient, with the counselling that there is limited quality evidence of benefit.

Summary

For most people, statins are safe and well tolerated. The incidence of statin-associated myopathy is small but significant. Interacting medications may inhibit the metabolism of certain statins, increasing the risk of myopathy. Mild, intermittent muscle aches and pains in older people are often believed to be due to statins. Measurement of creatine kinase in such patients can exclude myopathy and allow safe continuation of treatment. Any risks of myopathy and rhabdomyolysis can be kept to a minimum by knowledge of potential drug interactions.

As in all treatment decisions, the potential benefits of therapy must outweigh the risks. Patients should be informed the benefit/risk ratio of statin therapy is overwhelmingly positive in preventing and treating cardiovascular disease. Home medicines reviews provide an opportunity to discuss the risks and benefits of medications leading to optimal use and outcomes.