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Table 1.  

Myopathy* -- Complaints of myalgia (muscle pain or soreness), weakness, and/or cramps, plus -- Elevation in serum CK > 10x ULN
Rhabdomyolysis -- CK > 10,000 IU/L, or -- CK > 10x ULN plus an elevation in serum creatinine or medical intervention with IV hydration therapy

New Definitions to Describe Muscle Findings in Patients Taking Statins[21]

CK = creatine kinase; IV = intravenous; ULN = upper limit of normal *A patient may describe intolerable muscle symptoms but not be found to have a CK level > 10x ULN. This patient may be considered to be experiencing myopathy for the purposes of further evaluation. The CK level may be < 10x ULN depending on the temporal relation between the event and the drawing of the laboratory sample.

Table 2.  

1. Whenever muscle symptoms or an increased CK level is encountered in a patient receiving statin therapy, health professionals should attempt to rule out other etiologies, because these are most likely to explain the findings. Other common etiologies include increased physical activity, trauma, falls, accidents, seizure, shaking chills, hypothyroidism, infections, carbon monoxide poisoning, polymyositis, dermatomyositis, alcohol abuse, and drug abuse (cocaine, amphetamines, heroin, or PCP).
2. Obtaining a pretreatment, baseline CK level may be considered in patients who are at high risk of experiencing a muscle toxicity (eg, older individuals or when combining a statin with an agent known to increase myotoxicity), but this is not routinely necessary in other patients.
3. It is not necessary to measure CK levels in asymptomatic patients during the course of statin therapy, because marked, clinically important CK elevations are rare and are usually related to physical exertion or other causes.
4. Patients receiving statin therapy should be counseled about the increased risk of muscle complaints, particularly if the initiation of vigorous, sustained endurance exercise or a surgical operation is being contemplated; they should be advised to report such muscle symptoms to a health professional.
5. CK measurements should be obtained in symptomatic patients to help gauge the severity of muscle damage and facilitate a decision of whether to continue therapy or alter doses.
6. In patients who develop intolerable muscle symptoms with or without a CK elevation and in whom other etiologies have been ruled out, the statin should be discontinued. Once asymptomatic, the same or different statin at the same or lower dose can be restarted to test the reproducibility of symptoms. Recurrence of symptoms with multiple statins and doses requires initiation of other lipid-altering therapy.
7. In patients who develop tolerable muscle complaints or are asymptomatic with a CK < 10x ULN, statin therapy may be continued at the same or reduced doses and symptoms may be used as the clinical guide to stop or continue therapy.
8. In patients who develop rhabdomyolysis (a CK > 10,000 IU/L or a CK >10x ULN with an elevation in serum creatinine or requiring IV hydration therapy), statin therapy should be stopped. IV hydration therapy in a hospital setting should be instituted if indicated for patients experiencing rhabdomyolysis. Once recovered, the risk vs benefit of statin therapy should be carefully reconsidered.

Recommendations to Health Professionals Regarding the Muscle and Statin Safety[21]

CK = creatine kinase; IV = intravenous; PCP = phencyclidine; ULN = upper limit of normal

Table 3.  

1. During the routine general evaluation of patients being considered for statin and other lipid-lowering therapy, it is advisable to obtain liver transaminase levels. If these tests are found to be abnormal, further investigation should be performed to determine the etiology of the abnormal test results.
2. Until there is a change in the FDA-approved prescribing information for statins, it is appropriate to continue to measure transaminase levels before starting therapy, 12 weeks after initiating therapy, after a dose increase, and periodically thereafter. However, routine monitoring of liver function tests is not supported by the available evidence, and the current recommendation for monitoring needs to be reconsidered by the FDA.
3. The clinician should be alert to patient reports of jaundice, malaise, fatigue, lethargy, and related symptoms in patients taking statin therapy as a signal of potential hepatotoxicity. Evidence for hepatotoxicity includes jaundice, hepatomegaly, increased indirect bilirubin level, and elevated prothrombin time (rather than simple elevations in liver transaminase levels).
4. The preferred biochemical test to ascertain significant liver injury is fractionated bilirubin, which, in the absence of biliary obstruction, is a more accurate prognosticator of liver injury than isolated aminotransferase levels.
5. Should the clinician identify objective evidence of significant liver injury in a patient receiving a statin, the statin should be discontinued. The etiology should be sought and, if indicated, the patient referred to a gastroenterologist or hepatologist.
6. If an isolated asymptomatic transaminase level is found to be elevated 1-3x ULN, there is no need to discontinue the statin.
7. If an isolated asymptomatic transaminase level is found to be > 3x ULN during a routine evaluation of a patient administering a statin, the test should be repeated and, if still elevated, other etiologies should be ruled out. Consideration should be given to continuing the statin, reducing its dose, or discontinuing it based on clinical judgment.
8. According to the Expert Liver Panel, patients with chronic liver disease, nonalcoholic fatty liver disease, or nonalcoholic steatohepatitis may safely receive statin therapy.[26]

Recommendations to Healthcare Professionals Regarding the Liver and Statin Safety[21]

FDA = US Food and Drug Administration; ULN = upper limit of normal

Table 4.  

1. During the management of patients with statin therapy, it is not necessary to carry out serum creatinine and proteinuria monitoring routinely for the purpose of identifying an adverse effect, although an assessment of renal function is advisable before initiating statin therapy.
2. If serum creatinine becomes elevated in a patient without rhabdomyolysis while receiving statin therapy, there is generally no need to withdraw the statin, but in some cases, according to prescribing information, an adjustment in the statin dose may be required.
3. If unexpected proteinuria develops in a patient receiving a statin, there is no need to withdraw statin therapy or to alter the dose of the statin. An investigation into the cause of the proteinuria is warranted, as is consideration of a change in the statin dose as guided by the prescribing information for each statin.
4. Chronic kidney disease does not preclude the use of a statin. However, the dose of some statins should be adjusted in cases of moderate or severe renal insufficiency.

Recommendations to Health Professionals Regarding the Kidney and Statin Safety[21]

Table 5.  

1. Routine neurologic monitoring of patients administering statin therapy for changes indicative of peripheral neuropathy or impaired cognition is not recommended.
2. Patients experiencing symptoms consistent with peripheral neuropathy while receiving a statin should be evaluated to rule out secondary causes (eg, diabetes mellitus, renal insufficiency, alcohol abuse, vitamin B12 deficiency, cancer, hypothyroidism, acquired immunodeficiency syndrome, Lyme disease, or heavy metal intoxication).
3. If another etiology of the neurologic symptoms is not identified, it is appropriate to withdraw statin therapy for a period of 3-6 months to establish whether an apparent association with statin therapy exists.
4. If the patient's neurologic symptoms improve while off statin therapy, a presumptive diagnosis of statin-induced peripheral neuropathy might be made. However, because of the proven benefit of statin therapy, reinitiation of statin therapy should be considered with a different statin and dose.
5. If the patient's neurologic symptoms do not improve after statin therapy has been withdrawn for the specified period, statin therapy should be restarted based on a risk-benefit analysis.
6. If the patient experiences impaired cognition while receiving statin therapy, it is appropriate to follow a similar course of evaluation as suggested above for peripheral neuropathy, ie, first rule out other etiologies, and if none are found, then withdraw the statin for 1-3 months. If improvement is not seen, statin therapy should be restarted based on a risk-benefit analysis.

Recommendations for Health Professionals Regarding Neurologic Disorders and Statin Therapy[21]

Overview: Recommendations of the Statin Safety Task Force and Benefit: Risk Considerations With Statin Therapy: Benefit:Risk Ratio of Statin Therapy


Benefit:Risk Ratio of Statin Therapy

To apply this substantial body of statin safety data meaningfully in benefit:risk assessments for both public policy decisions and individual patient decision making, it must be considered within the framework of statins as potentially life-saving medications.[11] To place the risk of adverse effects and cardioprotective benefits of statin treatment in context, they can be discussed in terms of events per person-year of statin treatment. Examining mortality effects first, fatal rhabdomyolysis is the only well-defined mortality risk associated with statin therapy. A systematic review of clinical trial and cohort data yielded an estimated mortality risk from rhabdomyolysis of 0.3 cases per 100,000 person-years of statin therapy.[15] The survival benefit of statins in patients with CHD, based on a meta-analysis of 17 placebo-controlled, secondary-prevention trials, is 360 lives saved per 100,000 person-years based on reductions in cardiovascular mortality.[6]

The morbidity risk vs benefit, specifically in terms of permanent organ damage either caused or prevented by statins, can be analyzed in similar fashion. On the basis of results of studies involving patients with CHD or CHD-risk equivalents, the morbidity benefits of statins can be expressed as the number of averted cases per 100,000 person-years: 380 cases of MI or coronary death, 410 cases of MI or coronary death in patients with diabetes mellitus, and 260 cases of stroke in patients with diabetes mellitus.[11,49-52]

The central morbidity risk of statin treatment, in terms of causing permanent organ damage, relates to rhabdomyolysis, myopathy, and peripheral neuropathy, although both myopathy and neuropathy are frequently reversible.[11] The spontaneous reporting rate of acute liver failure with statin use is approximately equivalent to the background rate in the general population, and available evidence does not support a link between statin treatment and kidney damage.[29,32] The risk of rhabdomyolysis is approximately 3 cases per 100,000 person-years, and the estimated incidence of statin-related peripheral neuropathy is 12 per 100,000 person-years.[15] The few reported cases of statin-associated myopathy with normal CK levels are insufficient to determine an occurrence rate.[11,53] In the context of the magnitude of the survival and morbidity benefit of statins in terms of averting MI and cerebral infarction, the benefit:risk ratio for statin therapy is very high and similar for all currently marketed statins.[11]

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