Abstract
Studies in vascular cells in culture and in laboratory animals revealed that statin discontinuation triggers a rebound deterioration of vascular function. Retrospective studies of patients admitted with an acute coronary syndrome revealed that stopping statins during the first days of admission was associated with worse outcomes. In a prospective, randomized controlled trial in patients with a hemispheric ischemic stroke, stopping statins for 3 days was associated with a 4.7-fold increase in the risk of death or dependency, greater neurological deterioration, and a larger infarct volume. Discontinuing statins during the post-operative period following major vascular surgery was associated with a higher incidence of myocardial ischemia, nonfatal myocardial infarction, and cardiovascular death. However, no increase in adverse outcomes was observed in patients with stable chronic coronary artery disease following statin treatment discontinuation. Despite some study limitations, the bulk of the evidence suggests that under conditions of severe acute vascular stress, removal of statins must be contraindicated.
References
Papers of particular interest, published recently, have been highlighted as: • Of importance
Levine GN, Keaney JF, Vita JA. Cholesterol reduction in cardiovascular disease. N Engl J Med 1995;332 (8):512–521.
Farmer JA and Gotto Am, Jr. Current and future therapeutic approaches to hyperlipidemia. Adv Pharmacol 1996;35:79–114.
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 2002; 285:2486-2497.
Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA-reductase inhibitors. Circulation. 1998 Mar 31;97(12):1129–1135.
Endres M, Laufs U. Effects of statins on endothelium and signaling mechanisms. Stroke. 2004; 35(11 Suppl 1):2708–2711.
Laufs U and Liao JK. Targeting Rho in cardiovascular disease. Circ Res 2000;87 (7): 526–528.
SSSS Investigators. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet.1994; 344:1383–1389.
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;333:1301–1307.
Amarenco P, Bogousslavsky J, Callahan A, et al. High-Dose Atorvastatin after Stroke or Transient Ischemic Attack, The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. N Engl J Med 2006; 355:549–559.
Bukkapatnam RN, Gabler NB, Lewis WR. Statins for primary prevention of cardiovascular mortality in women: a systematic review and meta-analysis. Prev Cardiol 2010;13(2):84–90.
• Feher A, Pusch G, Koltai K, et al. Statin therapy in the primary and the secondary prevention of ischaemic cerebrovascular diseases. Int J Cardiol 2010 Sep 14. [Epub ahead of print]. This article discusses the benefits of statin therapy in primary and secondary prevention of stroke.
Cubeddu LX, Seamon M. Statin withdrawal: Clinical implications and molecular mechanisms. Pharmacotherapy 2006;26(9):1288–1296.
Laufs U, Endres M, Custodis F, et al. Suppression of endothelial nitric oxide production after withdrawal of statin treatment is mediated by negative feedback regulation of rho GTPase gene transcription. Circulation 2000; 102 (25):3104–1310.
Westphal S, Abletshauser C, Luley C. Fluvastatin treatment and withdrawal: effects on endothelial function. Angiology 2008;59(5):613–618
Brandes RP, Beer S, Ha T, Busse R. Withdrawal of cerivastatin induces monocyte chemoattractant protein 1 and tissue factor expression in cultured vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2003;23(10):1794–1800.
Touyz RM and Schiffrin El. Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells. Pharmacol Rev 2000;52(4):639–672.
Castejon AM, Zollner E, Tristano AG, Cubeddu LX. Upregulation of angiotensin II-AT1 receptors during statin withdrawal in vascular smooth muscle cells. J Cardiovasc Pharmacol 2007;50(6):708–711.
Gertz K, Laufs U, Lindauer U, et al. Withdrawal of statin treatment abrogates stroke protection in mice. Stroke 2003; 34(2):551–557.
Vecchione C and Brandes RP. Withdrawal of 2-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors elicits oxidative stress and induces endothelial dysfunction in mice. Circ Res 2002; 91: 173–179.
Rosengarten B, Auch D, Kaps M. Effect of initiation and acute withdrawal of statins on the neurovascular coupling mechanism in healthy, normocholesterolemic humans. Stroke 2007; 38:3193–3197.
Heeschen C, Hamm CW, Laufs U, et al. Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation 2002;105:1446–1452.
Heeschen C, Hamm CW, Laufs U, et al. Withdrawal of statins in patients with acute coronary syndromes. Circulation. 2003 Jan 28;107(3):e27.
Spencer FA, Fonarow GC, Frederick PD, et al. Early withdrawal of statin therapy in patients with non-ST-segment elevation myocardial infarction. Arch Intern Med 2004;164:2162–2168.
Spencer FA, Allegrone J, Goldberg RJ, et al. Association of statin therapy with outcomes of acute coronary syndromes: The GRACE study. Ann Intern Med 2004;140:857–866.
Colvicchi F, Bassi A, Santini M, Caltagirone C. Discontinuation of statin therapy and clinical outcome after ischemic stroke. Stroke 2007;38:2652–2657.
Blanco M, Nombela F, Castellanos M, et al. Statin treatment withdrawal in ischemic stroke: a controlled randomized study. Neurology 2007;69:904–910.
Schouten O, Hoeks SE, Welten G, et al. Effect of statin withdrawal on frequency of cardiac events after vascular surgery. Am J Cardiol 2007;100:316–320.
Le Manach Y, Godet G, Coriat P, et al. The impact of postoperative discontinuation or continuation of chronic statin therapy on cardiac outcome after major vascular surgery. Anesth Analg 2007;104:1326–1333.
Le Manach Y, Godet G, Coriat P, et al. The impact of postoperative discontinuation or continuation of chronic statin therapy on cardiac outcome after major vascular surgery. Anesth Analg 2007;104:1326–1333.
O’Neil-Callahan K, Katsimaglis G, Tepper MR, et al. Statins decrease perioperative cardiac complications in patients undergoing noncardiac vascular surgery: the statins for risk reduction in surgery (StaRRS) study. Am J Cardiol 2005;45:336–342.
Durazzo AE, Machado FS, Ikeoka DT, et al. Reduction in cardiovascular events alter vascular surgery with atorvastatin: a randomized trial. J Vasc Surg 2004;39:967–976.
Lindenauer PK, Pekow P, Wang K, et al. Lipid-lowering therapy and in-hospital mortality following major noncardiac surgery. JAMA 2004;291:2092–2099.
• Risselada R, Straatman H, van Kooten F, et al. Withdrawal of statins and risk of subarachnoid hemorrhage. Stroke 2009; 40:2887–2892. This article shows that recent withdrawal of statin therapy (< 30days) is associated with increased risk of developing a subarachnoid hemorrhage.
McGowan MP. There is no evidence for an increase in acute coronary syndromes after short-term abrupt discontinuation of statins in stable cardiac patients. Circulation 2004; 110:2333–2335.
Wassmann S, Laufs U, Baumer AT, Muller K, Konkol C, Sauer H, Bohm M and Nickenig G. Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1 receptor expression and Rac1 GTPase. Mol Pharmacol 2001;59(3): 646–654.
Li JJ, Li YS, Chen J, Yang JQ. Rebound phenomenon of inflammatory response may be a major mechanism responsible for increased cardiovascular events after abrupt cessation of statin therapy. Med Hypotheses 2006;66(6):1199–1204.
Poldermans D, Bax JJ, Kertai MD, et al. Statins are associated with reduced incidence of perioperative mortality in patients undergoing major noncardiac vascular surgery. Circulation 2003;107:1848–1851.
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Andres Pineda reports no potential conflict of interest relevant to this article. Luigi Cubeddu reports no potential conflict of interest relevant to this article.
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Pineda, A., Cubeddu, L.X. Statin Rebound or Withdrawal Syndrome: Does It Exist?. Curr Atheroscler Rep 13, 23–30 (2011). https://doi.org/10.1007/s11883-010-0148-x
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DOI: https://doi.org/10.1007/s11883-010-0148-x