Mild to Moderate Muscular Symptoms with High-Dosage Statin Therapy in Hyperlipidemic Patients —The PRIMO Study
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
Objectives: To characterize the risk factors, rate of occurrence, onset, nature and impact of mild to moderate muscular symptoms with high-dosage HMG-CoA reductase inhibitor (statin) therapy in general practice.
Methods: The Prédiction du Risque Musculaire en Observationnel (Prediction of Muscular Risk in Observational conditions, PRIMO) survey was an observational study of muscular symptoms in an unselected population of 7924 hyperlipidemic patients receiving high-dosage statin therapy in a usual care, outpatient setting in France. Information on patient demographics, treatment history and muscular symptoms was obtained by question-naires.
Results: Multivariate analysis revealed the strongest predictors for muscular symptoms to be a personal history of muscle pain during lipid-lowering therapy (odds ratio, OR, 10.12, 95% CI 8.23–12.45; P < 0.0001), unexplained cramps (OR 4.14; 95% CI 3.46–4.95; P < 0.0001) and a history of creatine kinase (CK) elevation (OR 2.04; 95% CI 1.55–2.68; P < 0.0001). Overall, muscular symptoms were reported by 832 patients (10.5%), with a median time of onset of 1 month following initiation of statin therapy. Muscular pain prevented even moderate exertion during everyday activities in 315 patients (38%), while 31 (4%) were confined to bed or unable to work. Fluvastatin XL was associated with the lowest rate of muscular symptoms (5.1%) among individual statins.
Conclusion: PRIMO demonstrated that mild to moderate muscular symptoms with high-dosage statin therapy may be more common and exert a greater impact on everyday lives than previously thought. Knowledge of the risk factors for muscular symptoms will allow identification and improved management of high-risk patients. The risk of muscular symptoms with fluvastatin XL treatment may be lower than with high dosages of other statins.
- Scandinavian Simvastatin Survival Study Investigators. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344(8934):1383–1389.
- The Long-Term Intervention with Pravastatin in Ischaemic 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(19):1349–1357.
- Bradford RH, Shear CL, Chremos AN, et al. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results: two-year efficacy and safety follow-up. Am J Cardiol 1994;74(7):667–673. CrossRef
- Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279(20):1615–1622. CrossRef
- Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996;335(14):1001–1009. CrossRef
- Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995;333(20):1301–1307. CrossRef
- The Pravastatin Multinational Study Group for Cardiac Risk Patients. Effects of pravastatin in patients with serum total cholesterol levels from 5.2 to 7.8 mmol/liter (200 to 300 mg/dl) plus two additional atherosclerotic risk factors. Am J Cardiol 1993;72(14):1031–1037.
- Bakker-Arkema RG, Nawrocki JW, Black DM. Safety profile of atorvastatin-treated patients with low LDL-cholesterol levels. Atherosclerosis 2000;149(1):123–129. CrossRef
- Bertolini S, Bon GB, Campbell LM, et al. Efficacy and safety of atorvastatin compared to pravastatin in patients with hypercholesterolemia. Atherosclerosis 1997;130(1–2):191–197.
- Nawrocki JW, Weiss SR, Davidson MH, et al. Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor. Arterioscler Thromb Vasc Biol 1995;15(5):678–682.
- Steinhagen-Thiessen E. Comparative efficacy and tolerability of 5 and 10 mg simvastatin and 10 mg pravastatin in moderate primary hypercholesterolemia. Simvastatin Pravastatin European Study Group. Cardiology 1994;85(3–4):244–254.
- Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med 2002;346(7):539–540.
- Lambrecht LJ, Malini PL. Efficacy and tolerability of simvastatin 20 mg vs pravastatin 20 mg in patients with primary hypercholesterolemia. European Study Group. Acta Cardiol 1993;48(6):541–554.
- Bruckert E, Simonetta C, Giral P. Compliance with fluvastatin treatment characterization of the noncompliant population within a population of 3845 patients with hyperlipidemia. CREOLE Study Team. J Clin Epidemiol 1999;52(6):589–594. CrossRef
- Dart 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(1):39–44. CrossRef
- Jokubaitis LA. Updated clinical safety experience with fluvastatin. Am J Cardiol 1994;73(14):18D–24D. CrossRef
- Grundy SM. Can statins cause chronic low-grade myopathy? Ann Intern Med 2002;137(7):617–618.
- Sinzinger H, Wolfram R, Peskar BA. Muscular side effects of statins. J Cardiovasc Pharmacol 2002;40(2):163–171. CrossRef
- Ballantyne CM, Corsini A, Davidson MH, et al. Risk for myopathy with statin therapy in high-risk patients. Arch Intern Med 2003;163(5):553–564. CrossRef
- De Lemos JA, Blazing MA, Wiviott SD, et al. Early Intensive vs a Delayed Conservative Simvastatin Strategy in Patients With Acute Coronary Syndromes: Phase Z of the A to Z Trial. JAMA 2004;292:1307–1316. CrossRef
- Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110(2):227–239. CrossRef
- Franc 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(5–6):459–465.
- Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol 2002;40(3):567–572. CrossRef
- Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA 2003;289(13):1681–1690. CrossRef
- Adverse Drug Reactions Advisory Committee (ADRAC). Risk factors for myopathy and rhabdomyolysis with the statins. Aust Adv Drug Reactions Bull 2004;23(1):1–2.
- Thompson PD, Zmuda JM, Domalik LJ, Zimet RJ, Staggers J, Guyton JR. Lovastatin increases exercise-induced skeletal muscle injury. Metabolism 1997;46(10):1206–1210. CrossRef
- Sauret JM, Marinides G, Wang GK. Rhabdomyolysis. Am Fam Physician 2002;65(5):907–912.
- Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003;326(7404):1423.
- Benghozi R, Bortolini M, Jia Y, Isaacsohn JL, Troendle AJ, Gonasun L. Frequency of creatine kinase elevation during treatment with fluvastatin. Am J Cardiol 2002;89(2):231–233. CrossRef
- Omar MA, Wilson JP, Cox TS. Rhabdomyolysis and HMG-CoA reductase inhibitors. Ann Pharmacother 2001;35(9):1096–1107.
- Fischer V, Johanson L, Heitz F, et al. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin: effect on human cytochrome P-450 and implications for metabolic drug interactions. Drug Metab Dispos 1999;27(3):410–416.
- MRC/BHF Heart Protection Study Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360(9326):7–22.
- Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA 2002;288(4):462–467. CrossRef
- Koppel C. Clinical features, pathogenesis and management of drug-induced rhabdomyolysis. Med Toxicol Adverse Drug Exp 1989;4(2):108–126.
- Mild to Moderate Muscular Symptoms with High-Dosage Statin Therapy in Hyperlipidemic Patients —The PRIMO Study
Cardiovascular Drugs and Therapy
Volume 19, Issue 6 , pp 403-414
- Cover Date
- Print ISSN
- Online ISSN
- Kluwer Academic Publishers
- Additional Links
- HMG-CoA reductase inhibitors
- Industry Sectors
- Author Affiliations
- 1. Department of Endocrinology, Hôpital de la Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris 83 Bd de L'Hôpital, 75 013, Paris, France
- 5. Department of Endocrinology, Hôpital de la Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris, 83 Bd de L'Hôpital, 75 013, Paris, France
- 2. Department of Rheumatology, Hôpital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, 75 018, Paris, France
- 3. Clinical Research and Development, Novartis Pharma SAS, Rueil-Malmaison, France
- 4. Université Victor Segalen Bordeaux 2, Bordeaux, France