Relative safety profiles of high dose statin regimens

Carlos Escobar, Rocio Echarri, Vivencio Barrios, Carlos Escobar, Rocio Echarri, Vivencio Barrios

Abstract

Recent clinical trials recommend achieving a low-density lipoprotein cholesterol level of <100 mg/dl in high-risk and <70 mg/dl in very high risk patients. To attain these goals, however, many patients will need statins at high doses. The most frequent side effects related to the use of statins, myopathy, rhabdomyolysis, and increased levels of transaminases, are unusual. Although low and moderate doses show a favourable profile, there is concern about the tolerability of higher doses. During recent years, numerous trials to analyze the efficacy and tolerability of high doses of statins have been published. This paper updates the published data on the safety of statins at high doses.

Keywords: high doses; liver; muscle; statins; tolerability.

Figures

Figure 1
Figure 1
Risk of coronary risk or any cardiovascular event (myocardial infarction, stroke, hospitalization for unstable angina or revascularization) (Cannon et al 2006). Abbreviations: CVD, cardiovascular diseases; CHD, coronary heart disease; prav, pravastatin; ator, atorvastatin; sim, simvastatin; std, standard.

References

    1. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT) JAMA. 2002;288:2998–3007.
    1. Alsheikh-Ali AA, Maddukuri PV, Han H, et al. Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials. J Am Coll Cardiol. 2007;50:409–18.
    1. Armitage J. The safety of statins in clinical practice. Lancet. 2007;370(9601):1781–90.
    1. Ashton E, Liew D, Krum H. Should patients with chronic heart faliure be treated with “statins”? Heart Fail Monit. 2003;3:82–86.
    1. Ballantyne CM, Corsini A, Davidson MH, et al. Risk for myopathy with statin therapy in high-risk patients. Arch Intern Med. 2003;163:553–64.
    1. Bays H. Statin safety: an overview and assessment of the data-2005. Am J Cardiol. 2006;97:6C–26C.
    1. Barrios V, Amabile N, Paganelli F, et al. Lipid-altering efficacy of switching from atorvastatin 10 mg/day to ezetimibe/simvastatin in hypercholesterolaemic patients with atherosclerosis or coronary artery disease. Int J Clin Pract. 2005;59:1377–86.
    1. Barrios V, Escobar C, Calderon A, et al. Cardiovascular risk profile and risk stratification of the hypertensive population attended by general practitioners and specialists in Spain. The CONTROLRISK study. J Hum Hypertens. 2007;21:479–85.
    1. Brass LM, Alberts MJ, Sparks L. An assessment of statin safety by neurologists. Am J Cardiol. 2006;97(suppl 8A):86C–88C.
    1. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495–504.
    1. Cannon CP, Steinberg BA, Murphy SA, et al. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol. 2006;48:438–45.
    1. Celik T, Iyisoy A, Yuksel UC, et al. The panacea for cardiovascular diseases: The role of statins in the management of heart failure. Int J Cardiol. 2007 Aug 8; Epub ahead of print.
    1. Chan PS, Nallamothu BK, Gurm HS, et al. Incremental benefit and cost-effectiveness of high-dose statin therapy in high-risk patients with coronary artery disease. Circulation. 2007;115:2398–409.
    1. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267–78.
    1. Christopher-Stine L. Statin myopathy: an update. Curr Opin Rheumatol. 2006;18:647–53.
    1. Cohen DE, Anania FA, Chalasani N. An assessment of statin safety by hepatologists. Am J Cardiol. 2006;97(suppl 8A):77C–81C.

    1. Crestor (rosuvastatin calcium) [prescribing information]. August 2005. Accessed April 2006. URL:

    1. Davidson MH. Controversy surrounding the safety of cerivastatin. Expert Opin Drug Saf. 2002;1:207–12.
    1. Dale KM, White CM, Henyan NN, et al. Impact of statin dosing intensity on transaminase and creatine kinase. Am J Med. 2007;120:706–12.
    1. Davidson MH, Clark JA, Glass LM, et al. Statin safety: an appraisal from the Adverse Event Reporting System (AERS) Am J Cardiol. 2006;97(suppl 8A):32C–43C.
    1. Davidson MH, Robinson JG. Safety of aggressive lipid management. J Am Coll Cardiol. 2007;49:1753–62.
    1. 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;292:1307–16.
    1. Dirks AJ, Jones KM. Statin induced apoptosis and skeletal myopathy. Am J Physiol Cell Physiol. 2006;291:1208–12.
    1. Downs JR, Clearfield DO, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. JAMA. 1998;279:1615–22.
    1. Ergin A, Muntner P, Sherwin R, et al. Secular trends in cardiovascular disease mortality, incidence, and case fatality rates in adults in the United States. Am J Med. 2004;117:219–27.
    1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III) JAMA. 2001;285:2486–97.
    1. Gaist D, Garcia Rodriguez LA, Huerta C, et al. Are users of lipid-lowering drugs at increased risk of peripheral neuropathy? Eur J Clin Pharmacol. 2001;56:931–33.
    1. Gerson RJ, MacDonald JS, Alberts AW, et al. On the etiology of subcapsular lenticular opacities produced in dogs receiving HMG-CoA reductase inhibitors. Exp Eye Res. 1990;50:65–78.
    1. 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;110:227–39.
    1. Harper CR, Jacobson TA. The broad spectrum of statin myopathy: from myalgia to rhabdomyolysis. Curr Opin Lipidol. 2007;18:401–8.
    1. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7–22.
    1. Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20,536 people with cerebrovascular disease or other high-risk conditions. Lancet. 2004;363:757–67.
    1. Hermann M, Bogsrud MP, Molden E, et al. Exposure of atorvastatin is unchanged but lactone and acid metabolites are increased several-fold in patients with atorvastatin-induced myopathy. Clin Pharmacol Ther. 2006;79:532–39.
    1. Horvath R, Schneiderat P, Schoser BG, et al. Coenzyme Q10 deficiency and isolated myopathy. Neurology. 2006;66:253–5.
    1. Horwich TB, Hamilton MA, Maclellan WR, et al. Low serum total cholesterol is associated with marked increase in mortality in advanced heart faliure. J Card Fail. 2002;8:216–24.
    1. Hulten E, Jackson JL, Douglas K, et al. The effect of early, intensive statin therapy on acute coronary syndrome: a meta-analysis of randomized controlled trials. Arch Intern Med. 2006;166:1814–21.
    1. Jacobson TA. Statin safety: lessons from new drug applications for marketed statins. Am J Cardio. 2006;97(suppl):44C–51C.
    1. Kasiske BL, Wanner C, O’Neill WC. An assessment of statin safety by nephrologists. Am J Cardiol. 2006;97(suppl 8A):82C–85C.
    1. Khush KK, Waters DD, Bittner V, et al. Effect of high-dose atorvastatin on hospitalizations for heart failure: subgroup analysis of the Treating to New Targets (TNT) study. Circulation. 2007;115:576–83.
    1. Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007;357:2248–61.
    1. Krum H, McMurray JJ. Statins and chronic heart failure: do we need a large-scale outcome trial? J Am Coll Cardiol. 2002;8:216–24.
    1. Kuulasmaa K, Tunstall-Pedoe H, Dobson A, et al. Estimation of contribution of changes in classic risk factors to trends in coronary-event rates across the WHO MONICA Project populations. Lancet. 2000;355:675–87.
    1. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425–35.

    1. Lipitor (atorvastatin calcium) [prescribing information]. September 2005. Accessed April 2006. URL:

    1. McKenney JM, Davidson MH, Jacobson TA, et al. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol. 2006;97:89C–94C.
    1. Menotti A, Kromhout D, Blackburn H, et al. Forty-year mortality from cardiovascular diseases and all causes of death in the US Railroad cohort of the Seven Countries Study. Eur J Epidemiol. 2004;19:417–24.
    1. Morgan RE, Palinkas LA, Barrett-Connor EL, et al. Plasma cholesterol and depressive symptoms in older men. Lancet. 1993;341:75–9.
    1. Nicholls SJ, Tuzcu EM, Sipahi I, et al. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA. 2007;297:499–508.
    1. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071–80.
    1. Okrainec K, Banerjee DK, Eisenberg MJ. Coronary artery disease in the developing world. Am Heart J. 2004;148:7–15.
    1. Olsson AG, Schwartz GG, Szarek M, et al. Effects of high-dose atorvastatin in patients > or =65 years of age with acute coronary syndrome (from the myocardial ischemia reduction with aggressive cholesterol lowering [MIRACL] study) Am J Cardiol. 2007;99:632–35.
    1. Paiva H, Thelen KM, Van CR, et al. High dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial. Clin Pharm Ther. 2005;78:60–68.
    1. Pasternac RC, Smith SC, Bairey-merz CN, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Col Cardiol. 2002;40:567–72.
    1. Pedersen TR, Faergeman O, Kastelein JJ, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005;294:2437–45.
    1. Raina A, Pickering T, Shimbo D. Statin use in heart failure: a cause for concern? Am Heart J. 2006;152:39–49.
    1. Rauchhaus M, Clark AL, Doehner W, et al. The relationship between cholesterol and survival in patients with chronic heart faliure. J Am Coll Cardiol. 2003;42:1993–40.
    1. Rosser WW. Application of evidence from randomised controlled trials to general practice. Lancet. 1999;353:661–64.
    1. Scirica BM, Morrow DA, Cannon CP, et al. Intensive statin therapy and the risk of hospitalization for heart failure after an acute coronary syndrome in the PROVE IT-TIMI 22 study. J Am Coll Cardiol. 2006;47:2326–31.
    1. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149–58.
    1. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. PROspective Study of Pravastatin in the Elderly at Risk. Lancet. 2002;360:1623–30.
    1. Staffa JA, Chang J, Green I. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med. 2002;346:539–40.
    1. Steg PG, Lopez-Sendon J, Lopez de Sa E, et al. External validity of clinical trials in acute myocardial infarction. Arch Intern Med. 2007;167:68–73.

    1. US Food and Drug Administration. Baycol Supplementary NDA (0.8 mg dose). FDA Medical Review. Cited July 19, 2000. [US Food and Drug Administration Web site.] Accessed August 30, 2005. URL:

    1. Wagstaff LR, Mitton MW, Arvik BM, et al. Statin-associated memory loss: analysis of 60 case reports and review of the literature. Pharmacotherapy. 2003;23:871–80.
    1. Wardle J, Armitage J, Collins R, et al. Randomised placebo controlled trial of effect on mood of lowering cholesterol concentration. Oxford Cholesterol Study Group. BMJ. 1996;313:75–8.
    1. Wenger NK, Lewis SJ, Herrington DM, et al. Outcomes of using high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary heart disease. Ann Intern Med. 2007;147:1–9.
    1. Westwood FR, Bigley A, Randall K, et al. Statin induced muscle necrosis in the rat: distribution, development, and fibre selectivity. Toxicol Pathol. 2005;33:246–57.

    1. Zocor (simvastatin) [prescribing information]. August 2005. Accessed December 2005 URL:

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren