Toward “Pain-Free” Statin Prescribing: Clinical Algorithm for Diagnosis and Management of Myalgia
2008; Elsevier BV; Volume: 83; Issue: 6 Linguagem: Inglês
10.4065/83.6.687
ISSN1942-5546
Autores Tópico(s)Lipoproteins and Cardiovascular Health
ResumoMyalgia, which often manifests as pain or soreness in skeletal muscles, is among the most salient adverse events associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Clinical issues related to statin-associated myotoxicity include (1) incidence in randomized controlled trials and occurrence in postmarketing surveillance databases; (2) potential differences between statins in their associations with such adverse events; and (3) diagnostic and treatment strategies to prevent, recognize, and manage these events. Data from systematic reviews, meta-analyses, clinical and observational trials, and postmarketing surveillance indicate that statin-associated myalgia typically affects approximately 5.0% of patients, as myopathy in 0.1% and as rhabdomyolysis in 0.01%. However, studies also suggest that myalgia is among the leading reasons patients discontinue statins (particularly high-dose statin monotherapy) and that treatment with certain statins (eg, fluvastatin) is unlikely to result in such adverse events. This review presents a clinical algorithm for monitoring and managing statin-associated myotoxicity. The algorithm highlights risk factors for muscle toxicity and provides recommendations for (1) creatine kinase measurements and monitoring; (2) statin dosage reduction, discontinuation, and rechallenge; and (3) treatment alternatives, such as extended-release fluvastatin with or without ezetimibe, low-dose or alternate-day rosuvastatin, or ezetimibe with or without colesevelam. The algorithm should help to inform and enhance patient care and reduce the risk of myalgia and other potentially treatment-limiting muscle effects that might undermine patient adherence and compromise the overall cardioprotective benefits of statins. Myalgia, which often manifests as pain or soreness in skeletal muscles, is among the most salient adverse events associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Clinical issues related to statin-associated myotoxicity include (1) incidence in randomized controlled trials and occurrence in postmarketing surveillance databases; (2) potential differences between statins in their associations with such adverse events; and (3) diagnostic and treatment strategies to prevent, recognize, and manage these events. Data from systematic reviews, meta-analyses, clinical and observational trials, and postmarketing surveillance indicate that statin-associated myalgia typically affects approximately 5.0% of patients, as myopathy in 0.1% and as rhabdomyolysis in 0.01%. However, studies also suggest that myalgia is among the leading reasons patients discontinue statins (particularly high-dose statin monotherapy) and that treatment with certain statins (eg, fluvastatin) is unlikely to result in such adverse events. This review presents a clinical algorithm for monitoring and managing statin-associated myotoxicity. The algorithm highlights risk factors for muscle toxicity and provides recommendations for (1) creatine kinase measurements and monitoring; (2) statin dosage reduction, discontinuation, and rechallenge; and (3) treatment alternatives, such as extended-release fluvastatin with or without ezetimibe, low-dose or alternate-day rosuvastatin, or ezetimibe with or without colesevelam. The algorithm should help to inform and enhance patient care and reduce the risk of myalgia and other potentially treatment-limiting muscle effects that might undermine patient adherence and compromise the overall cardioprotective benefits of statins. Despite reducing relative risks of coronary events and mortality from coronary events and all causes in several landmark clinical trials, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are underused.1Vaughan CJ Gotto Jr, AM Update on statins: 2003.Circulation. 2004; 110: 886-892Crossref PubMed Scopus (209) Google Scholar, 2Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).Lancet. 1994; 344: 1383-1389Abstract PubMed Scopus (11265) Google Scholar, 3The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.N Engl J Med. 1998; 339: 1349-1357Crossref PubMed Scopus (5567) Google Scholar, 4Friday KE Aggressive lipid management for cardiovascular prevention: evidence from clinical trials.Exp Biol Med (Maywood). 2003; 228: 769-778PubMed Google Scholar, 5Wilt TJ Bloomfield HE MacDonald R et al.Effectiveness of statin therapy in adults with coronary heart disease.Arch Intern Med. 2004; 164: 1427-1436Crossref PubMed Scopus (220) Google Scholar, 6Mantel-Teeuwisse AK Klungel OH Schalekamp T Verschuren WM Porsius AJ de Boer A Suboptimal choices and dosing of statins at start of therapy.Br J Clin Pharmacol. 2005; 60: 83-89Crossref PubMed Scopus (19) Google Scholar, 7Ford ES Mokdad AH Giles WH Mensah GA Serum total cholesterol concentrations and awareness, treatment, and control of hypercholesterolemia among US adults: findings from the National Health and Nutrition Examination Survey, 1999 to 2000.Circulation. 2003 May 6; 107 (Epub 2003 Apr 28.): 2185-2189Crossref PubMed Scopus (319) Google Scholar Many health care professionals have expressed concern about potential adverse events (AEs), particularly severe muscle toxicity, which has been recognized as an impediment to appropriate statin use.8Antons KA Williams CD Baker SK Phillips PS Clinical perspectives of statin-induced rhabdomyolysis.Am J Med. 2006; 119: 400-409Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar, 9Kashani A Phillips CO Foody JM et al.Risks associated with statin therapy: a systematic overview of randomized clinical trials.Circulation. 2006 Dec 19; 114 (Epub 2006 Dec 11.): 2788-2797Crossref PubMed Scopus (411) Google Scholar, 10Pasternak RC Smith Jr, SC Bairey-Merz CN Grundy SM Cleeman JI Lenfant C ACC/AHA/NHLBI clinical advisory on the use and safety of statins.Circulation. 2002; 106: 1024-1028Crossref PubMed Scopus (463) Google Scholar Milder muscle symptoms (eg, myalgia) associated with statins and their potential to reduce medication adherence are not as well defined.11Franc S Dejager S Bruckert E Chauvenet M Giral P Turpin G A comprehensive description of muscle symptoms associated with lipid-lowering drugs.Cardiovasc Drugs Ther. 2003; 17: 459-465Crossref PubMed Scopus (96) Google Scholar, 12Thompson PD Clarkson P Karas RH Statin-associated myopathy.JAMA. 2003; 289: 1681-1690Crossref PubMed Scopus (1228) Google Scholar Because hypercholesterolemia is largely asymptomatic, any unpleasant effects of pharmacologic agents used to manage it can undermine adherence.13Miller NH Compliance with treatment regimens in chronic asymptomatic diseases.Am J Med. 1997; 102: 43-49Abstract Full Text PDF PubMed Scopus (278) Google Scholar However, patients underestimate the degree to which elevated cholesterol increases their risk of coronary events.14Erhardt LR Barriers to effective implementation of guideline recommendations.Am J Med. 2005; 118: 36S-41SAbstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar Given these perceptions, an AE, such as myalgia, can assume an important role in a patient's decision to discontinue a much-needed lipid-modifying medication. Indeed, several studies document a significant decrease in adherence to lipid-lowering treatments over time among outpatients, and some indicate that patients' perception of AEs is a primary reason for discontinuation.15Hughes DA Walley T Predicting "real world" effectiveness by integrating adherence with pharmacodynamic modeling.Clin Pharmacol Ther. 2003; 74: 1-8Crossref PubMed Scopus (24) Google Scholar, 16Benner JS Glynn RJ Mogun H Neumann PJ Weinstein MC Avorn J Long-term persistence in use of statin therapy in elderly patients.JAMA. 2002; 288: 455-461Crossref PubMed Scopus (1042) Google Scholar, 17Jackevicius CA Mamdani M Tu JV Adherence with statin therapy in elderly patients with and without acute coronary syndromes.JAMA. 2002; 288: 462-467Crossref PubMed Scopus (932) Google Scholar, 18Avorn J Monette J Lacour A et al.Persistence of use of lipid-lowering medications: a cross-national study.JAMA. 1998; 279: 1458-1462Crossref PubMed Scopus (578) Google Scholar, 19Sung JC Nichol MB Venturini F Bailey KL McCombs JS Cody M Factors affecting patient compliance with antihyperlipidemic medications in an HMO population.Am J Manag Care. 1998; 4: 1421-1430PubMed Google Scholar, 20Simons LA Levis G Simons J Apparent discontinuation rates in patients prescribed lipid-lowering drugs.Med J Aust. 1996; 164: 208-211PubMed Google Scholar, 21Andrade SE Walker AM Gottlieb LK et al.Discontinuation of antihyperlipidemic drugs: do rates reported in clinical trials reflect rates in primary care settings?.N Engl J Med. 1995; 332: 1125-1131Crossref PubMed Scopus (358) Google Scholar, 22Bruckert E Simonetta C Giral P CREOLE Study Team Compliance with fluvastatin treatment characterization of the nonadherent population within a population of 3845 patients with hyperlipidemia.J Clin Epidemiol. 1999; 52: 589-594Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 23Kiortsis DN Giral P Bruckert E Turpin G Factors associated with low compliance with lipid-lowering drugs in hyperlipidemic patients.J Clin Pharm Ther. 2000; 25: 445-451Crossref PubMed Scopus (103) Google Scholar A more collaborative physician-patient relationship, which might include asking the patient about statin tolerance, has been recommended to foster adherence.24Osterberg L Blaschke T Adherence to medication.N Engl J Med. 2005; 353: 487-497Crossref PubMed Scopus (6115) Google Scholar In light of these considerations, several clinical issues arise. What is the magnitude of statin-associated myalgia? How does it affect patient acceptance of and adherence to statin therapy? Are there clinically meaningful differences among the statins that might affect the risks of myalgia, myopathy, and rhabdomyolysis? How can the risk and severity of statin-associated myopathy be minimized? How can statin-associated muscle symptoms be managed? This review delineates the scope of statin-related myalgia, myopathy, and rhabdomyolysis on the basis of findings from recent meta-analyses, cohort trials, and clinical trials and of analyses of Food and Drug Administration (FDA) data; explores the clinical effects of statin-associated muscle symptoms; and outlines diagnostic and management strategies for muscle symptoms. Consensus guidelines concerning statin safety issues were reviewed, and certain articles cited in their bibliographies were included. An English-language PubMed search spanning the past 30 years (January 1, 1977-December 31, 2007) was conducted. Search terms included adherence, compliance, creatine kinase, hydroxymethylglutaryl coenzyme A reductase inhibitors, human, hypercholesterolemia, muscle, myalgia, myopathy, myositis, pain, rhabdomyolysis, safety, tolerability, toxicity, treatment discontinuation, treatment outcome, and weakness. Only prospective studies were included. Although case series, case reports, and open-label studies were excluded, observational studies and retrospective analyses, including analyses of postmarketing surveillance databases, were eligible for inclusion. Muscle symptoms, signs (creatine kinase [CK] elevations), or a combination thereof (myositis or rhabdomyolysis) are the most prevalent and important AEs associated with statin therapy.25McKenney JM Davidson MH Jacobson TA Guyton JR Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force.Am J Cardiol. 2006 Apr 17; 97 (Epub 2006 Feb 28.): 89C-94CAbstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar The term myalgia has been defined as muscle aches or weakness in the absence of CK elevation.10Pasternak RC Smith Jr, SC Bairey-Merz CN Grundy SM Cleeman JI Lenfant C ACC/AHA/NHLBI clinical advisory on the use and safety of statins.Circulation. 2002; 106: 1024-1028Crossref PubMed Scopus (463) Google Scholar However, for the purposes of the current review, symptoms of myalgia include cramping, pain, aches, tenderness, soreness, stiffness, heaviness, and weakness, either at rest or during physical exertion (eg, loss of strength). In some patients, weakness is the only symptom and develops insidiously. Many patients experience myalgia, including a loss of strength, only during physical exertion. Myositis is defined as elevated CK in the presence of muscle symptoms. Rhabdomyolysis is defined as pronounced CK elevation, 10 times the upper limit of normal (ULN), with serum creatinine elevation, in the presence of muscle symptoms.10Pasternak RC Smith Jr, SC Bairey-Merz CN Grundy SM Cleeman JI Lenfant C ACC/AHA/NHLBI clinical advisory on the use and safety of statins.Circulation. 2002; 106: 1024-1028Crossref PubMed Scopus (463) Google Scholar Consensus guidelines from the American College of Cardiology, American Heart Association, and National Heart, Lung, and Blood Institute define myopathy generally as any disease of muscles—either congenital or acquired.10Pasternak RC Smith Jr, SC Bairey-Merz CN Grundy SM Cleeman JI Lenfant C ACC/AHA/NHLBI clinical advisory on the use and safety of statins.Circulation. 2002; 106: 1024-1028Crossref PubMed Scopus (463) Google Scholar However, in some studies myopathy has been defined as muscle symptoms in the presence of CK elevation. In their review, Thompson et al12Thompson PD Clarkson P Karas RH Statin-associated myopathy.JAMA. 2003; 289: 1681-1690Crossref PubMed Scopus (1228) Google Scholar commented on the limitations of these definitions, including their imprecision. It should also be noted that CK can be increased by factors other than lipid-modifying treatment, including immunoglobulin-bound CK (macro CK), which has been documented since 197926Stein W Bohner J Immunoglobulin-bound creatine kinase BB ("macro CK") in three patients with different diseases [letter].Clin Chem. 1979; 25: 1513-1514PubMed Google Scholar and could be responsible for (largely artifactual) CK elevations in approximately 3% of patients. The exact mechanism for statin-associated myopathy, including myalgia, has yet to be elucidated. The pharmacodynamic basis of this problem might involve depletion of mevalonate derivatives distal to the rate-limiting enzyme blocked by statins (HMG-CoA reductase). These derivatives mediate certain processes critical to the integrity of the skeletal myocyte. One such metabolite is ubiquinone (also termed coenzyme Q10 [CoQ10]), a constituent of the mitochondrial electron transport chain.27Rosenson RS Current overview of statin-induced myopathy.Am J Med. 2004; 116: 408-416Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar Blockade of the mevalonate pathway also leads to decreased formation of G proteins involved in cell maintenance.28Owczarek J Jasinska M Orszulak-Michalak D Drug-induced myopathies: an overview of the possible mechanisms.Pharmacol Rep. 2005; 57: 23-34PubMed Google Scholar Other proposed mechanisms of myopathy include depletion of cholesterol, leading to alterations in myocyte membrane cholesterol, or statin depletion of key isoprenoids that control myofiber-apoptosis.12Thompson PD Clarkson P Karas RH Statin-associated myopathy.JAMA. 2003; 289: 1681-1690Crossref PubMed Scopus (1228) Google Scholar, 27Rosenson RS Current overview of statin-induced myopathy.Am J Med. 2004; 116: 408-416Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar Isoprenoids, lipids that are a product of the HMG-CoA reductase pathway, are linked to proteins by either farnesylation or geranylgeranylation. A reduction in the farnesylation or geranylgeranylation of proteins is thought to increase levels of cytosolic calcium, which activates a cascade of events leading to the activation of caspase-3, a proteolytic enzyme that has a central role in cell death. Variation in definitions, the failure to carefully characterize AEs reported in the literature, and potential limitations of the FDA Adverse Event Reporting System (AERS) all hamper the determination of the absolute risks of muscle-related AEs with statins.29Jacobson TA Statin safety: lessons from new drug applications for marketed statins.Am J Cardiol. 2006 Apr 17; 97 (Epub 2006 Feb 2.): 44C-51CAbstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 30Davidson MH Clark JA Glass LM Kanumalla A Statin safety: an appraisal from the adverse event reporting system.Am J Cardiol. 2006 Apr 17; 97 (Epub 2006 Feb 3.): 32C-43CAbstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar These limitations not-withstanding, serious muscle toxicity with marketed statins is rare: myopathy occurs in 5 patients per 100,000 person-years and rhabdomyolysis in 1.6 patients per 100,000 person-years.31Law M Rudnicka AR Statin safety: a systematic review.Am J Cardiol. 2006 Apr 17; 97 (Epub 2006 Feb 3.): 52C-60CAbstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar The most common AE of statins that affects muscle is myalgia.31Law M Rudnicka AR Statin safety: a systematic review.Am J Cardiol. 2006 Apr 17; 97 (Epub 2006 Feb 3.): 52C-60CAbstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar, 32Bays H Statin safety: an overview and assessment of the data - 2005.Am J Cardiol. 2006 Apr 17; 97 (Epub 2006 Feb 8.): 6C-26CAbstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar, 33Thompson PD Clarkson P Rosenson RS An assessment of statin safety by muscle experts.Am J Cardiol. 2006 Apr 17; 97 (Epub 2006 Feb 9.): 69C-76CAbstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar The incidence of myalgia, which is not as well defined as that of more serious myotoxicities, is reported in randomized controlled trials (RCTs) as ranging from 1.5% to 3.0%.31Law M Rudnicka AR Statin safety: a systematic review.Am J Cardiol. 2006 Apr 17; 97 (Epub 2006 Feb 3.): 52C-60CAbstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar, 32Bays H Statin safety: an overview and assessment of the data - 2005.Am J Cardiol. 2006 Apr 17; 97 (Epub 2006 Feb 8.): 6C-26CAbstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar However, in clinical practice, up to 10% of outpatients receiving statins report muscle pain.22Bruckert E Simonetta C Giral P CREOLE Study Team Compliance with fluvastatin treatment characterization of the nonadherent population within a population of 3845 patients with hyperlipidemia.J Clin Epidemiol. 1999; 52: 589-594Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 34Bruckert E Hayem G Dejager S Yau C Begaud B Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study.Cardiovasc Drugs Ther. 2005; 19: 403-414Crossref PubMed Scopus (974) Google Scholar, 35Dart A Jerums G Nicholson G et al.A multicenter, double-blind, one-year study comparing safety and efficacy of atorvastatin versus simvastatin in patients with hypercholesterolemia.Am J Cardiol. 1997; 80: 39-44Abstract Full Text PDF PubMed Scopus (193) Google Scholar, 36Bertolini S Bon GB Campbell LM et al.Efficacy and safety of atorvastatin compared to pravastatin in patients with hypercholesterolemia.Atherosclerosis. 1997; 130: 191-197Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 37Lambrecht LJ Malini PL European Study Group Efficacy and tolerability of simvastatin 20 mg vs pravastatin 20 mg in patients with primary hypercholesterolemia.Acta Cardiol. 1993; 48: 541-554PubMed Google Scholar, 38Jokubaitis LA Updated clinical safety experience with fluvastatin.Am J Cardiol. 1994; 73: 18D-24DAbstract Full Text PDF PubMed Scopus (49) Google Scholar The higher rate in clinical practice reflects the tendency to exclude from RCTs potentially statin-intolerant patients and those with risk factors for muscle toxicity (eg, elderly patients, those receiving polypharmacy, individuals with renal or hepatic impairment).25McKenney JM Davidson MH Jacobson TA Guyton JR Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force.Am J Cardiol. 2006 Apr 17; 97 (Epub 2006 Feb 28.): 89C-94CAbstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar, 39Jacobson TA Overcoming 'ageism' bias in the treatment of hypercholesterolaemia: a review of safety issues with statins in the elderly.Drug Saf. 2006; 29: 421-448Crossref PubMed Scopus (42) Google Scholar The frequency of mild muscle-related symptoms in primary care could be underestimated because physicians might overlook, and patients might fail to report, such symptoms.40Sinzinger H Wolfram R Peskar BA Muscular side effects of statins.J Cardiovasc Pharmacol. 2002; 40: 163-171Crossref PubMed Scopus (104) Google Scholar For these reasons, observational studies that include an unselected patient population or use more liberal eligibility criteria can impart more meaningful information to clinicians administering statins than RCTs and are hence the focus of the following section on the clinical effect of statin-related myalgia. Examination of recent systematic reviews and meta-analyses, FDA postmarketing surveillance data analyses, clinical and observational trials, and claims database reviews sheds light on the scope of statin-associated myotoxicity and potential differences among statins. However, as already stated, muscle-related symptoms in clinical trials, which involve highly selected patient populations with high treatmentadherence and statin tolerance, do not reflect the true prevalence of myalgia in the clinic, as reflected by findings in observational studies. Statin-associated myalgia can compromise patients' quality of life, medication adherence, and, consequently, treatment outcome.11Franc S Dejager S Bruckert E Chauvenet M Giral P Turpin G A comprehensive description of muscle symptoms associated with lipid-lowering drugs.Cardiovasc Drugs Ther. 2003; 17: 459-465Crossref PubMed Scopus (96) Google Scholar, 12Thompson PD Clarkson P Karas RH Statin-associated myopathy.JAMA. 2003; 289: 1681-1690Crossref PubMed Scopus (1228) Google Scholar In 2 database analyses, myalgia contributed to 6% to 25% of all AEs reported from statin use.41Ucar M Mjorndal T Dahlqvist R HMG-CoA reductase inhibitors and myotoxicity.Drug Saf. 2000; 22: 441-457Crossref PubMed Scopus (257) Google Scholar, 42Hamilton-Craig I Statin-associated myopathy.Med J Aust. 2001; 175: 486-489PubMed Google Scholar Statin-associated myalgia was the most common reason for discontinuing rosuvastatin (13.6% of all reasons specified) in an observational cohort study of 11,680 patients.43Kasliwal R Wilton LV Cornelius V Aurich-Barrera B Shakir SA Safety profile of rosuvastatin.Drug Saf. 2007; 30: 157-170Crossref PubMed Scopus (34) Google Scholar In a systematic review of RCTs, the mean difference between active-treatment and placebo groups in the incidence of muscle pain, tenderness, or weakness sufficient to consult a physician or stop taking treatment was 5 per 100,000 person-years (confidence interval [CI], -17 to 27).31Law M Rudnicka AR Statin safety: a systematic review.Am J Cardiol. 2006 Apr 17; 97 (Epub 2006 Feb 3.): 52C-60CAbstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar Seven (16%; our computation) of 45 patients experiencing myalgia in a 2-year study of simvastatin (80 mg/d; N=508) discontinued treatment because of this AE.44de Sauvage Nolting PR Buirma RJ Hutten BA Kastelein JJ Dutch ExPRESS Investigator Group Two-year efficacy and safety of simvastatin 80 mg in familial hypercholesterolemia (the Examination of Probands and Relatives in Statin Studies With Familial Hypercholesterolemia [ExPRESS FH]).Am J Cardiol. 2002; 90: 181-184Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar Among 165 patients reporting muscle symptoms attributed to lipid-lowering therapy on a self-administered questionnaire, 48.1% experienced moderate discomfort and 9.8% experienced discomfort severe enough to confine them to bed or to cause them to stop working.11Franc S Dejager S Bruckert E Chauvenet M Giral P Turpin G A comprehensive description of muscle symptoms associated with lipid-lowering drugs.Cardiovasc Drugs Ther. 2003; 17: 459-465Crossref PubMed Scopus (96) Google Scholar Further information on the frequency of muscle symptoms was shown in the Prediction of Muscular Risk in Observational Conditions (PRIMO) study.34Bruckert E Hayem G Dejager S Yau C Begaud B Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study.Cardiovasc Drugs Ther. 2005; 19: 403-414Crossref PubMed Scopus (974) Google Scholar The PRIMO study enrolled an unselected population of 7924 French adult outpatients aged 18 to 75 years (mean ± SD, 58.4±10.8 years) who had hypercholesterolemia and received high-dose statins for 3 or more months before the study. These daily statin regimens included atorvastatin (40 or 80 mg), fluvastatin (80 mg) (chiefly fluvastatin extended-release [XL]), pravastatin (40 mg), or simvastatin (40 or 80 mg). Patients were eligible provided that they were not receiving statins under the auspices of a clinical trial and were not participating in any study during the 12-month observation period. Men outnumbered women by about 2:1 in groups with and without muscle-related symptoms. The 2 groups were similar across other demographic and baseline characteristics, with the exception of a significantly lower fat mass in those with muscle-related symptoms (29.7%) than in those without muscle-related symptoms (28.8%; P=.004). A total of 832 patients (10.5%) reported muscle-related symptoms. This proportion was at least 2 times higher than has been observed in clinical trials involving statins (1%-5%).12Thompson PD Clarkson P Karas RH Statin-associated myopathy.JAMA. 2003; 289: 1681-1690Crossref PubMed Scopus (1228) Google Scholar Among the high-dose statins examined, the proportion of patients reporting muscle-related symptoms was lowest in those receiving fluvastatin XL (5.1% vs 10.9% for high-dose pravastatin, 14.9% for atorvastatin, and 18.2% for simvastatin) (Table 1).34Bruckert E Hayem G Dejager S Yau C Begaud B Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study.Cardiovasc Drugs Ther. 2005; 19: 403-414Crossref PubMed Scopus (974) Google ScholarTABLE 1Rate of Occurrence of Muscular Symptoms Among Patients Receiving High-Dose Statin Therapy in the PRIMO StudyaAll data are reported as number (percentage) unless otherwise indicated. Table excludes 31 patients for whom data on individual statin were missing. AE = adverse event; PRIMO = Prediction of Muscular Risk in Observational Conditions; XL = extended release.StatinNo. of patientsPersonal history of muscular or tendonitis-associated AEs during lipid-lowering therapyMuscular pathologyMuscular symptomsbPercentage of patients with symptoms relative to total number of patients (with or without muscular symptoms).Patients with muscular symptoms receiving statin (%)Personal historyFamily historyYesNoPravastatin1901156 (8.2)86 (4.5)21 (1.1)208 (25.1)1693 (24.0)10.9Atorvastatin1844196 (10.7)cSignificant differences (P<.05) as determined by Pearson χ2 test. From Cardiovasc Drugs Ther,34 with permission of Springer Science and Business Media.83 (4.5)32 (1.8)274 (33.1)1570 (22.2)14.9Simvastatin1027100 (9.8)55 (5.4)13 (1.3)187 (22.6)840 (11.9)18.2Fluvastatin XL3121274 (8.8)115 (3.7)47 (1.6)159 (19.2)2962 (41.9)5.1a All data are reported as number (percentage) unless otherwise indicated. Table excludes 31 patients for whom data on individual statin were missing. AE = adverse event; PRIMO = Prediction of Muscular Risk in Observational Conditions; XL = extended release.b Percentage of patients with symptoms relative to total number of patients (with or without muscular symptoms).c Significant differences (P<.05) as determined by Pearson χ2Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).Lancet. 1994; 344: 1383-1389Abstract PubMed Scopus (11265) Google Scholar test. From Cardiovasc Drugs Ther,34Bruckert E Hayem G Dejager S Yau C Begaud B Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study.Cardiovasc Drugs Ther. 2005; 19: 403-414Crossref PubMed Scopus (974) Google Scholar with permission of Springer Science and Business Media. Open table in a new tab The clinical presentation of myalgia was heterogeneous, with diverse symptoms that, in the aggregate, tended to occur soon after initiation of high-dose statin regimens or intensification of statin doses (Figure 1). The median time to onset of muscle-related symptoms was 1 month after treatment initiation or intensification. The finding that the time to onset of muscle-related symptoms was unimodal (on logarithmic transformation of data) after either initiation or intensification of statin doses is consistent with an association between increased statin doses and the onset of muscle-related symptoms.34Bruckert E Hayem G Dejager S Yau C Begaud B Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study.Cardiovasc Drugs Ther. 2005; 19: 403-414Crossref PubMed Scopus (974) Google Scholar In addition, about 15% of patients reporting muscle-related symptoms had symptoms that appeared more than 6 months after treatment initiation. Most patients (58.7%) could not identify any particular trigger for their muscle-related sympt
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