Effects of short-term treatment with atorvastatin in smokers with asthma--a randomized controlled trial

Georgina Braganza, Rekha Chaudhuri, Charles McSharry, Christopher J Weir, Iona Donnelly, Lisa Jolly, Jane Lafferty, Suzanne M Lloyd, Mark Spears, Frances Mair, Neil C Thomson, Georgina Braganza, Rekha Chaudhuri, Charles McSharry, Christopher J Weir, Iona Donnelly, Lisa Jolly, Jane Lafferty, Suzanne M Lloyd, Mark Spears, Frances Mair, Neil C Thomson

Abstract

Background: The immune modulating properties of statins may benefit smokers with asthma. We tested the hypothesis that short-term treatment with atorvastatin improves lung function or indices of asthma control in smokers with asthma.

Methods: Seventy one smokers with mild to moderate asthma were recruited to a randomized double-blind parallel group trial comparing treatment with atorvastatin (40 mg per day) versus placebo for 4 weeks. After 4 weeks treatment inhaled beclometasone (400 μg per day) was added to both treatment arms for a further 4 weeks. The primary outcome was morning peak expiratory flow after 4 weeks treatment. Secondary outcome measures included indices of asthma control and airway inflammation.

Results: At 4 weeks, there was no improvement in the atorvastatin group compared to the placebo group in morning peak expiratory flow [-10.67 L/min, 95% CI -38.70 to 17.37, p = 0.449], but there was an improvement with atorvastatin in asthma quality of life score [0.52, 95% CI 0.17 to 0.87 p = 0.005]. There was no significant improvement with atorvastatin and inhaled beclometasone compared to inhaled beclometasone alone in outcome measures at 8 weeks.

Conclusions: Short-term treatment with atorvastatin does not alter lung function but may improve asthma quality of life in smokers with mild to moderate asthma.

Trial registration: Clinicaltrials.gov identifier: NCT00463827.

Figures

Figure 1
Figure 1
Flow of patients through study.
Figure 2
Figure 2
Change from baseline for both treatment groups in (a) morning PEF [L/min], (b) ACQ score, (c) AQLQ total score at 4 weeks. P values are for comparisons of the mean change from baseline between the two treatments.

References

    1. Chaudhuri R, Livingston E, McMahon AD, Thomson L, Borland W, Thomson NC. Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma. Am J Respir Crit Care Med. 2003;168(11):1308–1311. doi: 10.1164/rccm.200304-503OC.
    1. Chalmers GW, Macleod KJ, Little SA, Thomson LJ, McSharry CP, Thomson NC. Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma. Thorax. 2002;57(3):226–230. doi: 10.1136/thorax.57.3.226.
    1. Tomlinson JEM, McMahon AD, Chaudhuri R, Thompson JM, Wood SF, Thomson NC. Efficacy of low and high dose inhaled corticosteroid in smokers versus non-smokers with mild asthma. Thorax. 2005;60(4):282–287. doi: 10.1136/thx.2004.033688.
    1. Thomson N, Chaudhuri R. Asthma in smokers: challenges and opportunities. Curr Opin Pulm Med. 2009;15:39–45. doi: 10.1097/MCP.0b013e32831da894.
    1. Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol. 2006;6(5):358–370. doi: 10.1038/nri1839.
    1. Hothersall E, McSharry C, Thomson NC. Potential therapeutic role for statins in respiratory disease. Thorax. 2006;61(8):729–734. doi: 10.1136/thx.2005.057976.
    1. McKay A, Leung BP, McInnes IB, Thomson NC, Liew FY. A Novel Anti-Inflammatory Role of Simvastatin in a Murine Model of Allergic Asthma. J Immunol. 2004;172(5):2903–2908.
    1. Zeki AA, Franzi L, Last J, Kenyon NJ. Simvastatin Inhibits Airway Hyperreactivity: Implications for the Mevalonate Pathway and Beyond. Am J Respir Crit Care Med. 2009;180(8):731–740. doi: 10.1164/rccm.200901-0018OC.
    1. Menzies D, Nair A, Meldrum KT, Fleming D, Barnes M, Lipworth BJ. Simvastatin does not exhibit therapeutic anti-inflammatory effects in asthma. J Allergy Clin Immunol. 2007;119(2):328–335. doi: 10.1016/j.jaci.2006.10.014.
    1. Hothersall EJ, Chaudhuri R, McSharry C, Donnelly I, Lafferty J, McMahon AD, Weir CJ, Meiklejohn J, Sattar N, McInnes I. et al.Effects of atorvastatin added to inhaled corticosteroids on lung function and sputum cell counts in atopic asthma. Thorax. 2008;63(12):1070–1075. doi: 10.1136/thx.2008.100198.
    1. Cowan DC, Cowan JO, Palmay R, Williamson A, Taylor DR. Simvastatin in the treatment of asthma: lack of steroid-sparing effect. Thorax. 2010;65(10):891–896. doi: 10.1136/thx.2010.138990.
    1. Lee J-H, Lee D-S, Kim E-K, Choe K-H, Oh Y-M, Shim T-S, Kim S-E, Lee Y-S, Lee S-D. Simvastatin Inhibits Cigarette Smoking-induced Emphysema and Pulmonary Hypertension in Rat Lungs. Am J Respir Crit Care Med. 2005;172(8):987–993. doi: 10.1164/rccm.200501-041OC.
    1. Takahashi S, Nakamura H, Seki M, Shiraishi Y, Yamamoto M, Furuuchi M, Nakajima T, Tsujimura S, Shirahata T, Nakamura M. et al.Reversal of elastase-induced pulmonary emphysema and promotion of alveolar epithelial cell proliferation by simvastatin in mice. Am J Physiol. 2008;294(5):L882–890.
    1. Samson K, Minoguchi K, Tanaka A, Oda N, Yokoe T, Yamamoto Y, Yamamoto M, Ohta S, Adachi M. Inhibitory effects of fluvastatin on cytokine and chemokine production by peripheral blood mononuclear cells in patients with allergic asthma. Clin Exp Allergy. 2006;36(4):475–482. doi: 10.1111/j.1365-2222.2006.02470.x.
    1. Maneechotesuwan K, Ekjiratrakul W, Kasetsinsombat K, Wongkajornsilp A, Barnes PJ. Statins enhance the anti-inflammatory effects of inhaled corticosteroids in asthmatic patients through increased induction of indoleamine 2, 3-dioxygenase. J Allergy Clin Immunol. 2010;126(4):754–762. doi: 10.1016/j.jaci.2010.08.005.
    1. N'Guessan PD, Riediger F, Vardarova K, Scharf S, Eitel J, Opitz B, Slevogt H, Weichert W, Hocke AC, Schmeck B. et al.Statins Control Oxidized LDL-Mediated Histone Modifications and Gene Expression in Cultured Human Endothelial Cells. Arterioscler Thromb Vasc Biol. 2009;29(3):380–386.
    1. Ito K, Lim S, Caramori G, Chung K, Barnes P, Adcock I. Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages. FASEB J. 2001;15(6):1110–1112.
    1. Alexeeff SE, Litonjua AA, Sparrow D, Vokonas PS, Schwartz J. Statin Use Reduces Decline in Lung Function: VA Normative Aging Study. Am J Respir Crit Care Med. 2007;176(8):742–747. doi: 10.1164/rccm.200705-656OC.
    1. Janda S, Park K, FitzGerald JM, Etminan M, Swiston J. Statins in COPD. Chest. 2009;136(3):734–743. doi: 10.1378/chest.09-0194.
    1. Joukhadar C, Klein N, Prinz M, Schrolnberger C, Vukovich T, Wolzt M, Schemetterer L, Dorner GT. Similar effects of atorvastatin, simvastatin and pravastatin on thrombogenic and inflammatory parameters in patients with hypercholesterolaemia. Thombosis and Haemostasis. 2001;85:47–51.
    1. McCarey DW, McInnes IB, Madhok R, Hampson R, Scherbakova O, Ford I, Capell HA, Sattar N. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet. 2004;363:2015–2021. doi: 10.1016/S0140-6736(04)16449-0.
    1. Chan KY, Boucher ES, Gandhi PJ, Silva MA. HMG-CoA reductase inhibitors for lowering elevated levels of C-reactive protein. American Journal of Health-System Pharmacy. 2004;61(16):1676–1681.
    1. GINA Report, Global Strategy for Asthma Management and Prevention.
    1. Santanello N, Barber B, Reiss T, Friedman B, Juniper E, Zhang J. Measurement characteristics of two asthma symptom diary scales for use in clinical trials. Eur Respir J. 1997;10:646–651.
    1. Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J. 1999;14(4):902–907. doi: 10.1034/j.1399-3003.1999.14d29.x.
    1. Juniper EF, Guyatt GH, Cox FM, Ferrie PJ, King DR. Development and validation of the Mini Asthma Quality of Life Questionnaire. Eur Respir J. 1999;14(1):32–38. doi: 10.1034/j.1399-3003.1999.14a08.x.
    1. ATS/ERS Recommendations for Standardized Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide. Am J Respir Crit Care Med. 2005;171(8):912–930. doi: 10.1164/rccm.200406-710ST.
    1. Cockcroft D, Killian D, Mellon J, Hargreave F. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy. 1977;7:235–243. doi: 10.1111/j.1365-2222.1977.tb01448.x.
    1. Pavord I, Pizzichini M, Pizzichini E, Hargreave F. The use of induced sputum to investigate airway inflammation. Thorax. 1997;52(6):498–501. doi: 10.1136/thx.52.6.498.
    1. Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. The Lancet. 1994;344(8917):219–224. doi: 10.1016/S0140-6736(94)92996-3.
    1. Eisner MD, Iribarren C. The influence of cigarette smoking on adult asthma outcomes. Nicotine Tob Res. 2007;9(1):53–56. doi: 10.1080/14622200601078293.
    1. Siroux V, Boudier A, Anto JM, Cazzoletti L, Accordini S, Alonso J, Cerveri I, Corsico A, Gulsvik A, Jarvis D. et al.Quality-of-life and asthma-severity in general population asthmatics: results of the ECRHS II study. Allergy. 2008;63(5):547–554. doi: 10.1111/j.1398-9995.2008.01638.x.
    1. Juniper EF, Guyatt GH, Willan A, Griffith LE. Determining a minimal important change in a disease-specific quality of life questionnaire. J Clin Epidemiol. 1994;47(1):81–87. doi: 10.1016/0895-4356(94)90036-1.
    1. Juniper E, Johnston P, Borkhoff C, Guyatt G, Boulet L, Haukioja A. Quality of life in asthma clinical trials: comparison of salmeterol and salbutamol. Am J Respir Crit Care Med. 1995;151(1):66–70.
    1. Dahlen S-E, Malmstrom K, Nizankowska EWA, Dahlen B, Kuna P, Kowalski M, Lumry WR, Picado C, Stevenson DD, Bousquet J. et al.Improvement of Aspirin-Intolerant Asthma by Montelukast, a Leukotriene Antagonist. A Randomized, Double-Blind, Placebo-Controlled Trial. Am J Repir Crit Care Med. 2002;165(1):9–14.
    1. Juniper E, Svensson K, Mork A, Stahl E. Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Resp Med. 2005;99:553–558. doi: 10.1016/j.rmed.2004.10.008.
    1. Juniper E, Price D, Stampone P, Creemers J, Mol S, Fireman P. Clinically Important Improvements in Asthma-Specific Quality of Life, But No Difference in Conventional Clinical Indexes in Patients Changed From Conventional Beclomethasone Dipropionate to Approximately Half the Dose of Extrafine Beclomethasone Dipropionate*. Chest. 2002;121(6):1824–1832. doi: 10.1378/chest.121.6.1824.
    1. Castro M, Rubin AS, Laviolette M, Fiterman J, De Andrade Lima M, Shah PL, Fiss E, Olivenstein R, Thomson NC, Niven RM. et al.Effectiveness and Safety of Bronchial Thermoplasty in the Treatment of Severe Asthma: A Multicenter, Randomized, Double-Blind, Sham-Controlled Clinical Trial. Am J Respir Crit Care Med. 2010;181(2):116–124. doi: 10.1164/rccm.200903-0354OC.
    1. Zhang X, Jin J, Peng X, Ramgolam VS, Markovic-Plese S. Simvastatin Inhibits IL-17 Secretion by Targeting Multiple IL-17-Regulatory Cytokines and by Inhibiting the Expression of IL-17 Transcription Factor RORC in CD4+ Lymphocytes. J Immunol. 2008;180(10):6988–6996.
    1. McKinley L, Alcorn JF, Peterson A, DuPont RB, Kapadia S, Logar A, Henry A, Irvin CG, Piganelli JD, Ray A. et al.TH17 Cells Mediate Steroid-Resistant Airway Inflammation and Airway Hyperresponsiveness in Mice. J Immunol. 2008;181(6):4089–4097.
    1. Spears M, Donnelly I, Jolly L, Brannigan M, Ito K, McSharry C, Lafferty J, Chaudhuri R, Braganza G, Adcock IM. et al.Effect of low-dose theophylline plus beclometasone on lung function in smokers with asthma: a pilot study. Eur Respir J. 2009;33(5):1010–1017. doi: 10.1183/09031936.00158208.
    1. Takeda N, Kondo M, Ito S, Ito Y, Shimokata K, Kume H. Role of RhoA Inactivation in Reduced Cell Proliferation of Human Airway Smooth Muscle by Simvastatin. Am J Respir Cell Mol Biol. 2006;35(6):722–729. doi: 10.1165/rcmb.2006-0034OC.
    1. Wright JL, Zhou S, Preobrazhenska O, Marshall C, Sin DD, Laher I, Golbidi S, Churg AM. Statin Reverses Smoke-induced Pulmonary Hypertension and Prevents Emphysema but Not Airway Remodeling. Am J Respir Crit Care Med. 2011;183(1):50–58. doi: 10.1164/rccm.201003-0399OC.
    1. Zeki AA, Bratt JM, Rabowsky M, Last JA, Kenyon NJ. Simvastatin inhibits goblet cell hyperplasia and lung arginase in a mouse model of allergic asthma: a novel treatment for airway remodeling? Translational Research. 2010;156(6):335–349. doi: 10.1016/j.trsl.2010.09.003.
    1. Ou X, Wen F, Uhal B, Feng Y, Huang X, Wang T, Wang K, Liu D, Wang X, Chen L. Simvastatin attenuates experimental small airway remodelling in rats. Respirology. 2009;14(5):734–745. doi: 10.1111/j.1440-1843.2009.01549.x.

Source: PubMed

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