Journal of the American College of Cardiology 2002 by the American College of Cardiology Foundation and the American Heart Association ACC/AHA/NHLBI CLINICAL ADVISORY ON STATINS ACC/AHA/NHLBI Clinical Advisoryon the Use and Safety of Statins WRITING COMMITTEE MEMBERS
and Blood Institute (ACC/AHA/NHLBI) Clinical Advi-sory is intended to summarize for professionals the current understanding of statin use, focused on myopathy, and to provide updated recommendations for the appropriate use of statins, including cautions, contraindications, and safetymonitoring for statin therapy. Its purpose is not to discour- age the appropriate use of statins, which have life-saving potential in properly selected patients, particularly thosewith established coronary heart disease (CHD) and others at high risk for developing CHD. Included are recent 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) Increased Risk States for Statin-Induced Myopathy .570 In the literature, the general terminology used to describe muscle toxicity is inconsistent. Therefore, for the purpose ofthis document, the following terms are used as defined here: Myopathy—a general term referring to any disease of mus-cles; myopathies can be acquired or inherited and can occur at birth or later in life (Source: NINDS Myopathy Page- 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- 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 have demonstrated a decrease in CHD and total mortality, and Coordinating Committee in May 2002, and by the National Heart, Lung andBlood 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 These Association, and National Heart, Lung and Blood Institute would appreciate the trials documented a benefit in both men and women, following citation format: Pasternak RC, Smith SC, Jr., Bairey-Merz CN, GrundySM, 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 the AHA than 50,000 individuals have been randomized to either a placebo or statin in these trials, and no serious morbidity or ACC/AHA/NHLBI Clinical Advisory on Statins increase in mortality was observed in the drug treatment 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 Whether transami- very few drug to drug interactions. Although the experiencewith the safety of statin therapy outside of clinical trials has nase elevation with statin therapy constitutes true hepato- 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 Reversal of transaminase elevation is frequently noted 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 Cholestasis and active liver disease are listed as report) 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 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- 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 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 characterized by muscle aches, soreness or weak- for use in the U.S. in 1997. In August 2001, the manufac- ness and associated with elevated creatine kinase levels, turer, Bayer AG, announced the withdrawal of all dosages generally greater than 10 times the ULN. In this setting, of its cholesterol-lowering drug with the brand names failure to discontinue drug therapy can lead to rhabdomy- Baycol/Lipobay (cerivastatin) because of increasingly fre- olysis, myoglobinuria, and acute renal necrosis Myo- quent reports of serious myopathy, including severe and sitis is most likely to occur in persons who have complex life-threatening rhabdomyolysis. Rhabdomyolysis was re- medical problems and/or who are taking multiple medica- ported most frequently when cerivastatin was used at higher tions. It may rarely occur with statin monotherapy, but it doses and, particularly, in combination with another lipid- occurs more frequently when statins are used in combina- lowering drug, gemfibrozil (LOPID and generics). At the tion with a variety of medications, including cyclosporine, time of withdrawal, the FDA had received reports of 31 fibrates, macrolide antibiotics, certain antifungal drugs, and U.S. deaths due to severe rhabdomyolysis associated with niacin Some of the drug to drug interactions the use of cerivastatin, 12 of which involved concomitant involve specific interactions with the cytochrome P-450 drug-metabolizing system, especially those involving the Subsequently, the Wall Street Journal (1/21/02, 3A4 isozyme The combination of statins with a pg. A10) reported that Bayer AG had indicated that as fibrate is attractive for persons who have both high serum many as 100 deaths have been linked to Baycol. The FDA cholesterol and high triglycerides or for those who continue reports that the rate of fatal rhabdomyolysis is 16 to 80 to have elevated triglycerides after reaching their LDL- times more frequent for cerivastatin as compared to any cholesterol target on statin therapy. However, there may be a concern about an increased danger of developing myop- ACC/AHA/NHLBI Clinical Advisory on Statins athy with this combination. In the past, this combination with lovastatin and gemfibrozil, but it is reasonable to was thought to be “contraindicated” because of the potential believe that the experiences with other statin-fibrate danger of myopathy. More recently, it has been used increasingly with apparent safety in the majority of persons.
This combination is now presented by the ATP III report as an option, with careful monitoring, for some forms of Because it occurs so rarely, little is known about the fundamental mechanisms of statin-associated myopathy. It The FDA report comparing the rate of fatal rhabdomy- has been suggested that statins lead to inhibited synthesis of olsis among different statins is of considerable importance compounds arising from the synthetic pathway of choles- The FDA performed a detailed review of all reports of terol. In theory, this could lead to ubiquinone (an essential fatal rhabdomyolysis in their Adverse Event Reporting intracellular energy component) deficiency in muscle cell System and obtained the number of prescriptions dispensed mitochondria, disturbing normal cellular respiration and since marketing of each statin began in the U.S. Fatal causing adverse effects including rhabdomyolysis. Despite rhabdomyolysis was extremely rare (less than 1 death/ in-vitro support for this concept a human study of million prescriptions). As previously noted, the rate of fatal six months of simvastatin treatment (20 mg per day) on rhabdomyolsis for cerivastatin was far greater than that for skeletal muscle concentrations of high-energy phosphates other statins (16 to 80 times higher). Even after excluding and ubiquinone demonstrated that the muscle high-energy cases in which cerivastatin was administered with gemfibro- phosphate and ubiquinone concentrations assayed after zil, the reporting rate for fatal rhabdomyolysis with ceriv- simvastatin treatment were similar to those observed at astatin monotherapy (1.9 deaths per million prescriptions) baseline and did not differ from values in control subjects was 10 to 50 times higher than for other statins. The FDA No clinical study has yet provided support for the report also noted that more than 60% of the fatal cases hypothesis of diminished isoprenoid synthesis or energy with cerivastain were associated with use of the highest generation in muscle cells during statin therapy. Some dose (0.8 mg daily). The FDA notes that the data are have proposed that statin interaction with the cyto- reporting rates, not incidence rates. Thus, statistically chrome P-450 hepatic enzyme system might be related to “rigorous comparisons between drugs . . . are not recom- myopathy Support for this concept comes, in part, mended” Nevertheless, review of these data strongly from the known enhanced toxicity when statins are suggests that there were no clinically important differ- administered with agents sharing metabolism by the same ences in the rate of fatal complications among the five cytochrome isoforms. Finally, it has been shown that statins now available in the U.S. (atorvastatin, fluvastatin, exercise in combination with lovastatin produces greater lovastatin, pravastatin, and simvastatin). Clinicians creatine kinase elevations than those produced by exercise should consider the rates of severe myopathy as equiva- alone, suggesting that statins can exacerbate exercise- lent among all of these approved statins.
The following are summary comments reflecting current Routine laboratory monitoring of CK is of little value in the Statin therapy appears to carry a small but definite risk of absence of clinical signs or symptoms. Therefore, all persons myopathy when used alone. According to several large beginning to receive statins should be instructed to report clinical trial databases, the incidence of severe myopathy muscle discomfort or weakness or brown urine immediately, is reported to be 0.08% with lovastatin and simvastatin which should then prompt a CK measurement.
Elevations of CK greater than 10 times the ULNhave been reported in 0.09% of persons treated with pravastatin. All currently marketed statins appear to havea similar potential for causing this adverse effect.
Baseline Measurements
● Fibrate treatment alone appears to be associated with Before initiating statin therapy, baseline measurements, some (probably similar) risk of myopathy.
including a lipid and lipoprotein profile, that will be used to ● Of the nearly 600 persons who have participated in follow the drug’s efficacy and safety should be documented.
controlled clinical trials of a statin and fibrate combina- Current labeling for all statins requires baseline measure- tion, 1% have experienced a CK greater than 3 times the ments of liver function, including alanine transferase and ULN without muscle symptoms, and 1% have been aspartate transferase, although this is not agreed on by many withdrawn from therapy because of muscle discomfort liver experts and will likely undergo review in the future.
None of these findings were considered serious Modest transaminase elevations (less than 3 times the by the trial investigators. No cases of rhabdomyolysis or ULN) are not thought to represent a contraindication to myoglobinuria have been encountered in these clinical initiating, continuing, or advancing statin therapy, as long as trials. The experience in these trials is predominantly patients are carefully monitored. Many experts also favor, ACC/AHA/NHLBI Clinical Advisory on Statins and the ATP III report recommends, baseline CK measure- ment, reasoning that asymptomatic CK elevations are com- Increased Risk States for Statin-Associated Myopathy
mon and pre-treatment knowledge of this condition can aidin later clinical decision making.
Prevention of statin-associated myopathy can best be ac-complished by attention to those factors that might increase Monitoring for Adverse Reactions and Adjusting Therapy
Once therapy has been initiated, symptoms may appear at ● Advanced age (especially more than 80 years) in patients any time. If myositis is present or strongly suspected, the statin should be discontinued immediately. Several key ● Multisystem disease (e.g., chronic renal insufficiency, Obtain a CK measurement if the patient reports sugges- tive muscle symptoms, and compare to CK blood level prior to beginning therapy. Because hypothyroidism predisposes ● Specific concomitant medications or consumption as to myopathy, a thyroid-stimulating hormone level should listed below (check specific statin package insert for also be obtained in any patient with muscle symptoms.
If the patient experiences muscle soreness, tenderness, or ⅐ Fibrates (especially gemfibrozil, but other fibrates too) pain, with or without CK elevations, rule out common causes such as exercise or strenuous work. Advise modera- tion in activity for persons who experience these symptoms Discontinue statin therapy (or statin and niacin or fibrate if the patient is on combination therapy) if a CK greater than 10 times the ULN is encountered in a patient with muscle soreness, tenderness, or pain.
If the patient experiences muscle soreness, tenderness, or pain with either no CK elevation or a moderate elevation (3 to 10 times the ULN), follow the patient’s symptoms and ⅐ Large quantities of grapefruit juice (usually more than 1 CK levels weekly until there is no longer medical concern or symptoms worsen to the situation described previously (at ⅐ Alcohol abuse (independently predisposes to myop- which point therapy should be discontinued). For patients who develop muscle discomfort and/or weakness and whoalso have progressive elevations of CK on serial measure- Clinical Precautions
ments, either a reduction of statin dose or a temporary Most myopathy associated with statins appears to occur in discontinuation may be prudent. A decision can then be patients who are at risk for the condition. For this reason, made whether or when to reinstitute statin therapy.
physicians should be aware of several caveats when prescrib-ing statin therapy. Myopathy is more likely to occur at Asymptomatic Patients With CK Elevation
higher statin doses than at lower doses. For this reason, Prior to the withdrawal of cerivastatin, the ATP III report doses should not exceed those required to attain theATP III goal of therapy. As a rule, statin therapy should did not recommend routine ongoing monitoring of CK in be employed more cautiously in older persons, particularly asymptomatic patients. If a physician chooses to obtain CK older thin or frail women, but it is not contraindicated in values in asymptomatic patients, particularly those on com- these or other high-risk patients. Among older persons, bination therapy, and CKs are elevated to more than 10 those with multisystem disease apparently are at higher risk.
times the ULN, strong consideration should be given to Patients with diabetes combined with chronic renal failure stopping therapy. Following discontinuation, wait for symp- also appear to be at higher risk for myopathy—such patients toms to resolve and CK levels to return to normal before should be monitored carefully. In several instances, myop- reinitiating therapy with either drug and use a lower dose of athy has developed when patients were continued on statin therapy during hospitalization for major surgery. Therefore, Some asymptomatic patients will have moderate (i.e., it probably is prudent to withhold statins during such between 3 and 10 times the ULN) CK elevations at baseline, during treatment, or after a drug holiday. Such Particular attention should be given to drug interactions patients can usually be treated with a statin without harm.
when employing statin therapy. Although the combination However, particularly careful monitoring of symptoms and of statin plus fibrate is accompanied by an increased danger more frequent CK measurements are indicated.
of myopathy, the use of moderate statin doses combined ACC/AHA/NHLBI Clinical Advisory on Statins Table 1. Summary of HMG CoA Reductase Inhibitors patient may receive prescriptions from many different care-givers.
HDL cholesterol 1 5–15 percentTriglycerides 2 7–30 percent Statin therapy holds great promise for reducing the inci- dence of major coronary events, coronary procedures, and stroke in high-risk patients. At present, this potential has not been fully realized, because many patients at heightened risk are not being treated with these drugs. There is a well documented under-use of statins in clinical practice. Statins have proven to be extremely safe in the vast majority of patients receiving them. Few significant side effects were observed in clinical trials, and post-marketing reports of adverse events have been very limited when considered in comparison to the very large number of persons safely receiving these drugs. Even so, these drugs are not entirely free of side effects, and as for all drugs, they should be used appropriately and judiciously. This advisory encourages the appropriate use of statins while pointing out the possibility of side effects in certain patients. If statins are used with appropriate caution in these selected patients, the likelihood of developing clinically important myopathy should be Simvastatin - 5, 10, 20, 40, 80 mg tablets Fluvastatin - 20, 40, 80 (xl) mg tabletsAtorvastatin - 10, 20, 40, 80 mg tablets with fibrate appears to have a relatively low incidence of 1. Executive Summary of The Third Report of The National Cholesterol myopathy, especially when used in persons without multi- Education Program (NCEP) Expert Panel on Detection, Evaluation, system disease or multiple medications. The combination of And Treatment of High Blood Cholesterol In Adults (Adult Treat- statin plus nicotinic acid seemingly carries a lower risk for ment Panel III). JAMA 2001;285:2486 –97.
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