Statin Withdrawal: Clinical Implications and Molecular Mechanisms

Luigi X. Cubeddu, M.D., Ph.D.; Matthew J. Seamon, Pharm.D.

Disclosures

Pharmacotherapy. 2006;26(9):1288-1296. 

In This Article

Abstract and Introduction

Abstract

Retrospective analyses of data from the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM), the National Registry of Myocardial Infarction 4, and the Global Registry of Acute Coronary Events (GRACE) trials revealed that the benefits of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) on acute coronary outcomes are rapidly lost and outcomes worsened if statins are discontinued during a patient’s hospitalization for an acute coronary syndrome. Withdrawal of statin therapy in the first 24 hours of hospitalization for non–ST-elevation myocardial infarction increased the hospital morbidity and mortality rate versus continued therapy (11.9% vs 5.7%, p<0.01). Data from the Treating New Targets (TNT) study, however, suggested that short-term discontinuation of statin therapy in patients with stable cardiac conditions may not substantially increase the risk of acute coronary syndromes. In patients with acute coronary syndromes who discontinue statins, the rapid increase in risk of an event may result not only from the lost benefits from the therapy, but also from rebound inhibition of vascular protective substances and activation of vascular deleterious substances. Statins inhibit cholesterol synthesis in vascular cells. By reducing levels of isoprenoid intermediates, statins increase the production of nitric oxide and downregulate angiotensin II AT1 receptors, endothelin-1, vascular inflammatory adhesion molecules, and inflammatory cytokines. These benefits are rapidly lost and often transiently reversed when statins are acutely discontinued. Acute removal of pleiotropic effects and rebound vascular dysfunction may be more important in an acute coronary event, where inflammation promotes rupture of atherosclerotic plaques and inflammatory and prothrombosis markers are present in high concentration, than in stable chronic vascular disease. In the absence of data from randomized controlled trials, current information suggests that statin therapy should be continued, and possibly boosted, during hospitalization for an acute coronary syndrome. Because statins are discontinued during the early hospitalization of many patients, practitioners must ensure that statins are not omitted, unless contraindicated, from the treatment of patients with acute coronary syndromes.

Introduction

Coronary heart disease, the result of coronary atherosclerosis, is the largest cause of death among Americans, and it is the leading cause of morbidity and mortality worldwide.[1] Central to the pathogenesis of atherosclerosis are the deposition and retention of cholesterol in arterial walls, which make lipid modification the key to preventing coronary heart disease. Lowering cholesterol unequivocally reduces the frequency of cardiovascular events and atherosclerosis.[2–9] Nearly 105 million American adults have total blood cholesterol levels of 200 mg/dl or higher. About 42 million of these individuals have levels of 240 mg/dl or higher and are considered to be at high risk.[10] Individuals with preexisting coronary heart disease or risk equivalents are also at high risk and require aggressive lipid lowering.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, collectively referred to as statins, have assumed the central role in the treatment of hypercholesterolemia because of their superior ability to reduce levels of low-density lipoprotein cholesterol (LDL).[3,4,7–11] Statins reduce the frequency of coronary heart disease by as much as 21–43%. They are effective in the primary and secondary prevention of coronary heart disease.[12]

In the United States, yearly sales of lipid-lowering drugs were estimated to be $16.5 billion in 2005, up from $7.0 billion in 2000. This massive growth in the use of statins in clinical practice has resulted from increased awareness about and the frequency of dyslipidemia and atherosclerotic vascular disease. In the United States, statin use has also increased because of stringent LDL guidelines established in the third report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III).[13,14] The panel even recom-mended lowering the goal for LDL to less than 70 mg/dl for those at very high risk of coronary heart disease. Furthermore, statin treatment is considered lifelong for many patients.

Although statins are generally well tolerated, nearly 1.5% of subjects receiving statin treatment develop complications and require either dosage reduction and/or discontinuation of therapy.[15] Drug-induced muscle weakness, myalgia, myositis, and rhabdomyolysis with or without acute renal failure were observed with statin use.[16,17] The MedWatch reporting system of the U.S. Food and Drug Administration lists 3339 cases of statin-associated rhabdomyolysis reported between January 1, 1990, and March 31, 2002. The withdrawal of cerivastatin from the U.S. market in August 2001, after the drug was associated with approximately 100 rhabdomyolysis-related deaths, underscores this risk.[18] Less serious adverse effects, such as muscle pain and weakness, affect approximately 1–5% of patients.[16] Liver toxicity is another important cause of statin discontinuation.[12,19]

In addition to adverse drug reactions, the high cost of statins and their long-term use may negatively affect patient compliance. At 6–7 months after the drug was initially supplied, discontinuation rates for statins averaged 30% and were similar for all statins.[20] To our knowledge, no guidelines for discontinuing statin therapy are available, and discontinuation of statin treatment may not be without risk. Acute statin discontinuation may induce endothelial dysfunction and increase the risk of cardiovascular events.[21–26]

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