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ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins

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ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins Journal of the American College of Cardiology Vol. 40, No. 3, 2002 © 2002 by the American College of Cardiology Foundation and the American Heart Association ISSN 0735-1097/02/$22.00 Published by Elsevier Science Inc. PII S0735-1097(02)02030-2 ACC/AHA/NHLBI CLINICAL ADVISORY ON STATINS ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins WRITING COMMITTEE MEMBERS RICHARD C. PASTERNAK, MD, FACC, FAHA SCOTT M. GRUNDY, MD, PHD, FAHA SIDNEY C. SMITH, JR, MD, FACC, FAHA JAMES I. CLEEMAN, MD C. NOEL BAIREY-MERZ, MD, FACC CLAUDE LENFANT, MD, FACC (HON), FAHA TABLE OF CONTENTS and Blood Institute (ACC/AHA/NHLBI) Clinical Advi- sory is intended to summarize for professionals the current Preamble................................................................................................567 understanding of statin use, focused on myopathy, and to Introduction..........................................................................................567 provide updated recommendations for the appropriate use Incidence of Adverse Events............................................................568 of statins, including cautions, contraindications, and safety monitoring for statin therapy. Its purpose is not to discour- Mechanism of Myopathy..................................................................569 age the appropriate use of statins, which have life-saving Diagnosis...............................................................................................569 potential in properly selected patients, particularly those with established coronary heart disease (CHD) and others Management ........................................................................................569 at high risk for developing CHD. Included are recent Baseline Measurements.................................................................569 myopathy information compiled by the FDA, information Monitoring for Adverse Reactions and Adjusting Therapy ....570 from clinical trials, and summaries from the recently re- leased report of the Adult Treatment Panel III (ATP III) of Asymptomatic Patients With CK Elevation ...........................570 the National Cholesterol Education Program (NCEP) (1). Prevention.............................................................................................570 Increased Risk States for Statin-Induced Myopathy .............570 INTRODUCTION Clinical Precautions .......................................................................570 In the literature, the general terminology used to describe Summary ...............................................................................................571 muscle toxicity is inconsistent. Therefore, for the purpose of this document, the following terms are used as defined here: References.............................................................................................571 Myopathy—a general term referring to any disease of mus- cles; myopathies can be acquired or inherited and can occur PREAMBLE at birth or later in life (Source: NINDS Myopathy Page- http://accessible.ninds.nih.gov/health_and_medical/ The voluntary withdrawal of cerivastatin (Baycol) from the disorders/myopathy.htm). Myalgia—muscle ache or weak- U.S. market on August 8, 2001, by the manufacturer, in ness without creatine kinase (CK) elevation. Myositis—muscle agreement with the Food and Drug Administration (FDA), symptoms with increased CK levels. Rhabdomyolysis— has prompted concern on the part of physicians and patients muscle symptoms with marked CK elevation (typically regarding the safety of the cholesterol-lowering class of substantially greater than 10 times the upper limit of normal drugs called HMG CoA reductase inhibitors, more com- [ULN]) and with creatinine elevation (usually with brown monly known as “statins.” This American College of Car- urine and urinary myoglobin). diology/American Heart Association/National Heart, Lung Statins are powerful low-density lipoprotein (LDL)- lowering drugs that are widely used in clinical practice. This document was approved by the American College of Cardiology Foundation Results from clinical trials with a mean duration of 5.4 years Board of Trustees in May 2002, by the American Heart Association Science Advisory and Coordinating Committee in May 2002, and by the National Heart, Lung and have demonstrated a decrease in CHD and total mortality, Blood Institute in May 2002. reductions in myocardial infarctions, revascularization pro- When citing this document, the American College of Cardiology, American Heart cedures, stroke, and peripheral vascular disease (2–8). These Association, and National Heart, Lung and Blood Institute would appreciate the following citation format: Pasternak RC, Smith SC, Jr., Bairey-Merz CN, Grundy trials documented a benefit in both men and women, SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI Advisory on the Use and Safety of primarily in middle-aged and older persons treated in the Statins. J Am Coll Cardiol 2002;40:567–72. setting of either primary or secondary prevention. More This document is available on the Web sites of the ACC (www.acc.org), the AHA (www.americanheart.org), and the NHLBI (www.nhlbi.nih.gov/guidelines/ than 50,000 individuals have been randomized to either a cholesterol). placebo or statin in these trials, and no serious morbidity or 568 Pasternak et al. JACC Vol. 40, No. 3, 2002 ACC/AHA/NHLBI Clinical Advisory on Statins August 7, 2002:567–72 increase in mortality was observed in the drug treatment INCIDENCE OF ADVERSE EVENTS groups. These agents reduce the risk of essentially every The statins are well tolerated by most persons. Elevated clinical manifestation of the atherosclerotic process; they are hepatic transaminases generally occur in 0.5% to 2.0% of easy to administer, with good patient acceptance. There are cases and are dose-dependent (11,12). Whether transami- very few drug to drug interactions. Although the experience nase elevation with statin therapy constitutes true hepato- with the safety of statin therapy outside of clinical trials has not been fully reported, it is reasonable to suspect that the toxicity has not been determined. Progression to liver failure incidence of side effects may be higher in clinical situations specifically due to statins is exceedingly rare if it ever occurs where patients are not monitored as closely as they are in (13). Reversal of transaminase elevation is frequently noted clinical trials (9). with a reduction in dose, and elevations do not often recur The NCEP has published updated guidelines for treat- with either re-challenge or selection of another statin ment of high blood cholesterol (Adult Treatment Panel III (14,15). Cholestasis and active liver disease are listed as report) (1). These guidelines are endorsed by the ACC and contraindications to statin use; however, no specific evi- AHA. They identify elevated LDL cholesterol as the dence exists showing exacerbation of liver disease by statins. primary target of therapy and establish goals for LDL Furthermore, statins have not been shown to worsen the cholesterol that depend on a patient’s risk status. The Adult outcome in persons with chronic transaminase elevations Treatment Panel III report was able to apply rigorous due to hepatitis B or C, and treatment of hyperlipidemia clinical trial evidence to identify additional high-risk indi- may actually improve transaminase elevations in individuals viduals for treatment, greatly expanding the number of with fatty liver (16). An observational study (16a) has patients who are candidates for these drugs. These include suggested a rare association of statin use with polyneurop- patients with established CHD, other forms of atheroscle- athy. This has not been found in the large blinded random- rotic disease, diabetes mellitus, multiple risk factors impart- ized controlled trials. ing high risk, and severe hypercholesterolemia. In many The ability of statins to produce myopathy under some patients, relatively high doses of statins will be required to circumstances is well established. A common complaint is achieve LDL cholesterol goals of therapy. In addition, for non-specific muscle aches or joint pains that are generally patients with high triglycerides, non–high-density lipopro- not associated with significant increases in creatine kinase. tein (HDL) cholesterol (LDL ϩ VLDL [very low density In placebo-controlled trials, the incidence of these com- lipoprotein] cholesterol) has been identified as a secondary plaints (generally reported as about 5%) is similar between target of therapy. To achieve the non–HDL cholesterol placebo and active drug therapy, suggesting they may not be goal, many patients will require statin therapy as well. This drug-related (12–17). Nonetheless, in some patients, the broad expansion of statin use will require that increased temporal association with statin therapy is strong enough to attention be given to every aspect of statin therapy (i.e., implicate these drugs as a cause of these complaints. Other efficacy, safety, and cost-effectiveness). patients can have mild-to-moderate elevations of creatine In view of the demonstrated safety of these agents, both kinase without muscle complaints. Again, elevations may be medical professionals and the public were surprised by the non-specific, but a statin effect often cannot be ruled out. recent withdrawal of a relatively new statin, cerivastatin It is rare that patients treated with a statin exhibit severe (Baycol), from the market. Cerivastatin was first approved myositis
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