Cardiovascular safety of new inhaled medications for asthma and chronic obstructive pulmonary disease: a critical review from pharmacist perspective
DOI:
https://doi.org/10.18203/2320-6012.ijrms20161728Keywords:
Cardiovascular complications, Laboratory monitoring, Respiratory medicineAbstract
Individuals with chronic respiratory disorder often have cardiovascular comorbidities and are more vulnerable to adverse effects from medication. Inhaler medications are effective in managing many respiratory diseases, but some have concern about its potential cardiovascular effect from long-term therapy and inappropriate use of these drugs. In the past few years, new members of inhaled long-acting beta-2 agonists and anticholinergics have become available. Based on the published data we reviewed, the adverse cardiovascular effects of these drugs are relatively low, and largely comparable to existing agents. However, most of the studies have very strict selection criteria for subjects, with limited study periods. Therefore, some level of concern remains with the clinical use of these agents, often in patients with substantial cardiovascular or other comorbidities, and are likely to use these drug for very long periods. Perhaps the monitoring of therapeutic efficacy and toxicity by laboratory methods needs to be further explored.
Metrics
References
US. Food and Drug Administration. Available from: http://www.accessdata.fda.gov/ scripts/ cder/ drugsatfda/ index.cfm?fuseaction=Search. Search_Drug_Name.
Therapeutic Good Administration (TGA), Australian Register of Therapeutic Goods (ARTG) Search. 2015. Available from: http://search-au.funnelback.com/ s/ search.html?collection=tga-artg.
Crompton G. A brief history of inhaled asthma therapy over the last fifty years. Primary Care Respiratory Journal. 2006;15(6):326-31.
Nelson HS. Long-Acting Beta-Agonists in Adult Asthma: Evidence that these Drugs are Safe. Primary Care Respiratory Journal. 2006;15(5):271-7.
Ducharme FM, Chroinin MN, Greenstone I, Lasserson TJ. Addition of long‐acting beta2‐agonists to inhaled corticosteroids versus same dose inhaled corticosteroids for chronic asthma in adults and children. The Cochrane Library. 2010;12;(5):CD005535.
Salpeter SR, Ormiston TM, Salpeter EE. Cardiovascular effects of beta-agonists in patients with asthma and COPD: a meta-analysis. Chest, 2004.125(6):2309.
Cazzola M, Matera MG, Donner CF. Inhaled beta2-Adrenoceptor Agonists: Cardiovascular Safety in Patients with Obstructive Lung Disease. Drugs. 2005;65(12):1595-610.
Polat TB, Saz EU, Nursoy MA. Effects of salbutamol given by metered-dose inhaler on dispersion of ventricular repolarization. Anadolu kardiyoloji dergisi : AKD = the Anatolian journal of cardiology. 2011;11(3):232.
Bateman ED, Pedersen SE, Pizzichini E, Bousquet J, Drazen JM, FitzGerald M, et al. Global strategy for asthma management and prevention: GINA executive summary. European Respiratory Journal. 2008;31(1):143-78.
National Asthma Council Australia. Australian Asthma Handbook. 2015. Available from: http://www.asthmahandbook.org.au.
Hanrahan JP, Grogan DR, Baumgartner RA, Wilson A, Cheng H, Zimetbaum PJ, et al. Arrhythmias in patients with chronic obstructive pulmonary disease (COPD): occurrence frequency and the effect of treatment with the inhaled long-acting beta2-agonists arformoterol and salmeterol. Medicine. 2008;87(6):319-28.
RuDusky BM. Acute Myocardial Infarction and Status Asthmaticus: A Case Report. Angiology. 2006;57(5):655-8.
Warnier MJ, Rutten FH, Kors JA, Lammers JW, de Boer A, Hoes AW, et al. Cardiac Arrhythmias in Adult Patients with Asthma. Journal of Asthma. 2012;49(9):942-6.
Appleton SL. Asthma is associated with cardiovascular disease in a representative population sample. Obesity Research and Clinical Practice, 2008;2(2):91-9.
Therapeutic Good Administration (TGA), Australian Public Assessment Report (AusPAR), Australian Public Assessment Report for Indacaterol (October 2010), D.o.H.a. Ageing, Editor. 2010, Therapeutic Goods Administration.
Jacobson GA, Yee KC, Premilovac D, Rattigan S, Enantioselective disposition of (R/S)-albuterol in skeletal and cardiac muscle. Drug Testing and Analysis. 2014;6(6):563-7.
Au DH, Udris EM, Curtis JR, McDonell MB, Fihn SD. Association between chronic heart failure and inhaled β-2-adrenoceptor agonists. American Heart Journal. 148(5):915-20.
Cates CJ, Lasserson TJ. Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events. Sao Paulo Medical Journal. 2010;128(5).
Liggett SB. The pharmacogenetics of beta (2)-adrenergic receptors: Relevance to asthma. Journal of Allergy and Clinical Immunology. 2000;105(2):S487-92.
Israel E. Genetics and the variability of treatment response in asthma. Journal of Allergy and Clinical Immunology. 2005;115(4):S532-8.
Cazzola M, Matera MG, Donner CF, Inhaled beta2-adrenoceptor agonists: cardiovascular safety in patients with obstructive lung disease. Drugs. 2005;65(12):1595-610.
Muthumala A, Drenos F, Elliott PM, Humphries SE. Role of beta adrenergic receptor polymorphisms in heart failure: systematic review and meta-analysis. Eur J Heart Fail. 2008;10(1):3-13.
Kallergis EM, Kanoupakis EM, Klapsinos NK, Schiza SE, Mavrakis HE, Klapsinos NK et al. Acute electrophysiologic effects of inhaled salbutamol in humans *. Chest. 2005;127(6):2057-63.
Khorfan FM, Smith P, Watt S, Barber KR. Effects of nebulized bronchodilator therapy on heart rate and arrhythmias in critically ill adult patients. Chest. 2011;140(6):1466-72.
Wilchesky M, Ernst P, Brophy JM, Platt RW, Suissa S. Bronchodilator use and the risk of arrhythmia in copd: Part 2: reassessment in the larger quebec cohort. Chest. 2012;142(2):305-11.
Appleton, SL, Ruffin RE, D.H.D. Wilson, Taylor AW, Adams RJCardiovascular disease risk associated with asthma and respiratory morbidity might be mediated by short-acting beta(2)-agonists. 2009;123(1):124-130.e1.
Nizet TAC, Broeders MEAC, Folgering HTM. Tremor side effects of salbutamol, quantified by a laser pointer technique. Respiratory Medicine. 2004;98(9):844-50.
Taylor DR, Ramsay CM, Richards G, Boothman-Burrell D, Flannery E, Hancox B, et al. Asthma control during long-term treatment with regular inhaled salbutamol and salmeterol. Thorax. 1998;53(9):744-52.
Hancox RJ. Concluding remarks: can we explain the association of beta-agonists with asthma mortality? A hypothesis. Clinical Reviews in Allergy and Immunology. 2006;31(2-3):279-88.
Pharmaceutical Society of Australia, Australian Medicines Handbook. 2014, Adelaide: Australian Medicines Handbook Pty Ltd.
Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest. 2006;129(1):15-26.
Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest. 2006;129(1):15-26.
Donohue JF. Safety and efficacy of beta agonists. Respir Care. 2008;53(5):618-22; discussion 623-4.
US Food and Drug Administration. Advair Diskus, Advair HFA, Brovana, Foradil, Perforomist, Serevent Diskus, and Symbicort Information (Long Acting Beta Agonists). 2008 05 March 2008 28 April 2015]; Available from: http://www.fda.gov/ Drugs/ DrugSafety/ Postmarket Drug Safety Information for Patients and Providers/ ucm108111.htm.
US Food and Drug Administration. FDA Drug Safety Communication: FDA requires post-market safety trials for Long-Acting Beta-Agonists (LABAs). Available from: http://www.fda.gov/ Drugs/ DrugSafety/ ucm251512.htm.
Nathan RA, D'Urzo A, Blazhko V, Kaiser K. Safety and efficacy of fluticasone/formoterol combination therapy in adolescent and adult patients with mild-to-moderate asthma: a randomised controlled trial. BMC pulmonary medicine. 2012;12(1):67.
Jenkins C, Kolarikova R, Kuna P, Caillaud D, Sanchis J, Popp W, et al. Efficacy and safety of high‐dose budesonide/formoterol (Symbicort®) compared with budesonide administered either concomitantly with formoterol or alone in patients with persistent symptomatic asthma. Respirology, 2006;11(3):276-86.
Vogelmeier C, Kardos P, Harari S, Gans SJ, Stenglein S, Thirlwell J. Formoterol mono- and combination therapy with tiotropium in patients with COPD: A 6-month study. Respiratory Medicine. 2008;102(11):1511-20.
Donohue JF, Niewoehner D, Brooks J, O'Dell D, Church A. Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg and umeclidinium 125 mcg in patients with chronic obstructive pulmonary disease: results from a 52-week, randomized, double-blind, placebo-controlled study. Respiratory research. 2014;15(1):78.
Korn S, Kerwin E, Atis S, Amos C, Owen R, Lassen C. Indacaterol once-daily provides superior efficacy to salmeterol twice-daily in COPD: A 12-week study. Respiratory Medicine. 2011;105(5):719-26.
Kinoshita M, Lee SH, Hang LW, Ichinose M, Hosoe M, Okino N et al. Efficacy and safety of indacaterol 150 and 300 µg in chronic obstructive pulmonary disease patients from six Asian areas including Japan: A 12‐week, placebo‐controlled study. Respirology. 2012;17(2):379-89.
TGA Australian Public Assessment Report (AusPAR), Extract from the Clinical Evaluation Report for Fluticasone furoate/Vilanterol trifenate, T.G. Administration, Editor. 2013, Therapeutic Goods Administration: Woden, ACT.
Scott LJ, Hair P. Umeclidinium/Vilanterol: First Global Approval. Drugs. 2014;74(3):389-95.
Therapeutic Good Administration (TGA), Australian Publuc Assessment Report (AusPAR). Australian Public Assessment Report: Breo Ellipta: Product Information. 2014. Available from: https://www.tga.gov.au/ auspar/ auspar-fluticasone-furoate-vilanterol-trifenatate.
Johnson M. Interactions between Corticosteroids and β2-Agonists in Asthma and Chronic Obstructive Pulmonary Disease. Proceedings of the American Thoracic Society. 2004;1(3):200-6.
Bisgaard H. Effect of long‐acting β2 agonists on exacerbation rates of asthma in children. Pediatric Pulmonology. 2003;36(5):391-8.
Campbell SC, Criner GJ, Levine BE. Cardiac safety of formoterol 12 μg twice daily in patients with chronic obstructive pulmonary disease. Pulmonary Pharmacology & Therapeutics. 2007;20(5):571-9.
Vogelmeier C, Hederer B, Glaab T, Schmidt H, Maureen PMH. Mölken R, et al., Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011;364(12):1093-103.
Ridolo E, Montagni M, Olivieri E, Riario-Sforza GG, Incorvaia C. Role of indacaterol and the newer very long-acting β2-agonists in patients with stable COPD: a review. International journal of chronic obstructive pulmonary disease. 2013;8:425.
Therapeutic Good Administration (TGA), Anoro Ellipta: Product Information. 2015. Available from: https://www.ebs.tga.gov.au/ ebs/ picmi/ picmirepository.nsf/ pdf?OpenAgent&id=CP-2014-PI-02195-1&d=2015040316114622412.
Dahl R, Kramer B, Chung KF, Magnussen H, Nonikov V, Jack D, et al. Efficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twice-daily formoterol in COPD. Thorax. 2010;65(6):473-9.
Therapeutic Good Administration (TGA), Australian Public Assessment Report for indacaterol maleate / glycopyrronium bromide, Department of Health, Editor. 2014.
Kornmann O, Dahl R, Centanni S, Dogra A, Owen R, Lassen C et al. Once-daily indacaterol versus twice-daily salmeterol for COPD: a placebo-controlled comparison. The European respiratory journal. 2011;37(2):273-9.
Kerwin EM, Gotfried MH, Lawrence D, Lassen C, Kramer B. Efficacy and tolerability of indacaterol 75 μg once daily in patients aged ≥40 years with chronic obstructive pulmonary disease: results from 2 double-blind, placebo-controlled 12-week studies. Clinical therapeutics. 2011;33(12):1974-84.
Feldman G, Siler T, Prasad N, Jack D, Piggott S, Owen R, et al. Efficacy and safety of indacaterol 150 microg once-daily in COPD: a double-blind, randomised, 12-week study. BMC pulmonary medicine, 2010;10:11.
Albertson TE, Harper R, Murin S, Sandrock C. Patient considerations in the treatment of COPD: focus on the new combination inhaler umeclidinium/vilanterol. Patient preference and adherence. 2015;9:235.
Therapeutic Good Administration (TGA),Australian Public Assessment Report (AusPAR). Anoro Ellipta: Highlights of prescribing information. 2014; Available from: https://www.gsksource.com/ gskprm/ htdocs/ documents/ ANORO-ELLIPTA-PI-MG.PDF.
Donohue JF, Maleki-Yazdi MR, Kilbride S, Mehta R, Kalberg C, Church A. Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Respiratory medicine. 2013;107(10):1538-46.
Hanania NA, Feldman G, Zachgo W, Shim JJ, Crim C, Sanford L et al. The efficacy and safety of the novel long-acting β2 agonist vilanterol in patients with COPD: a randomized placebo-controlled trial. CHEST Journal. 2012;142(1):119-27.
Donohue JF, Maleki-Yazdi MR, Kilbride S, Mehta R, Kalberg C, Church A. Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Respir Med. 2013;107(10):1538-46.
Myint PK, Fox C, Kwok CS, Luben RN, Wareham NJ, Khaw KT.Total anticholinergic burden and risk of mortality and cardiovascular disease over 10 years in 21,636 middle-aged and older men and women of EPIC-Norfolk prospective population study. Age Ageing. 2015;44(2):219-25.
Singh S, Loke YK, Enright P, Furberg CD. Pro-arrhythmic and pro-ischaemic effects of inhaled anticholinergic medications. Thorax. 2013;68(1):114-6.
Alzayer R, Hughes J, Parsons R, Lee YP.Comparison of risk of neurovascular and cardiovascular side effects between tiotropium and other anticholinergic agents. Qual Prim Care. 2010;18(3):189-99.
Loke Yk, Singh s. Risk of acute urinary retention associated with inhaled anticholinergics in patients with chronic obstructive lung disease: systematic review. Ther Adv Drug Saf. 2013;4(1):19-26.
U.S. Food and Drug Administration. Follow-Up to the October 2008 Updated Early Communication about an Ongoing Safety Review of Tiotropium (marketed as Spiriva HandiHaler). 2010 15th August 2013 [cited 2015 8th April]; Available from: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm197429.htm.
Laratta CR, Eeden S. Acute Exacerbation of Chronic Obstructive Pulmonary Disease: Cardiovascular Links. Biomed Research International. 2014.
Cazzola M, Calzetta L, Matera MG. The cardiovascular risk of tiotropium: is it real? Expert Opin Drug Saf. 2010;9(5):783-92.
Hilleman DE, Malesker MA, Morrow LE, Schuller D. A systematic review of the cardiovascular risk of inhaled anticholinergics in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2009;4:253-63.
Cheyne L, Irvin-Sellers MJ, White J. Tiotropium versus ipratropium bromide for chronic obstructive pulmonary disease. The Cochrane database of systematic reviews. 2013;9:CD009552.
Wang MT, Tsai CL, Lo YW, Liou JT, Lee WJ, Lai IC. Risk of stroke associated with inhaled ipratropium bromide in chronic obstructive pulmonary disease: a population-based nested case-control study. Int J Cardiol. 2012;158(2):279-84.
Ogale SS, Lee TA, Au DH, Boudreau DM, Sullivan SD. Cardiovascular Events Associated With Ipratropium Bromide in COPD. Chest. 2010;137(1):13-9.
Anthonisen NR, Connett JE, Enright PL, Connett, Paul L. Hospitalizations and mortality in the Lung Health Study. American Journal of Respiratory and Critical Care Medicine. 2002;166(3):333-9.
Bouvy ML, Heerdink ER, De Bruin ML. Use of sympathomimetic drugs leads to increased risk of hospitalization for arrhythmias in patients with congestive heart failure. Archives of Internal Medicine. 2000;160(16):2477-80.
Celli B, Decramer M, Kesten S. Mortality in the 4-Year Trial of Tiotropium (UPLIFT) in Patients with Chronic Obstructive Pulmonary Disease. American Journal of Respiratory and Critical Care Medicine, 2009;180(10):948-55.
Jara M, Wentworth C, Lane S. A new user cohort study comparing the safety of long-acting inhaled bronchodilators in COPD. BMJ. Open. 2012;2(3).
Dong YH, Lin HH, Shau WY, Wu YC, Chang CH, Lai MS. Comparative safety of inhaled medications in patients with chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-analysis of randomised controlled trials. Thorax. 2013;68(1):48-56.
van Noord JA, Cornelissen PJG, Aumann JL. The efficacy of tiotropium administered via Respimat (R) Soft MistT (TM) Inhaler or HandiHaler (R) in COPD patients. Respiratory Medicine. 2009;103(1):22-9.
Yohannes AM, Connolly MJ, Hanania NA. Ten years of tiotropium: clinical impact and patient perspectives. Int J Chron Obstruct Pulmon Dis. 2013;8:117-25.
Mathioudakis AG, Chatzimavridou-Grigoriadou V, Evangelopoulou E, Mathioudakis GA, Siafakas NM. Comparative mortality risk of tiotropium administered via handihaler or respimat in COPD patients: Are they equivalent? Pulmonary Pharmacology & Therapeutics. 2014;28(2):91-7.
Singh S, Loke YK, Enright PL. Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials. British Medical Journal. 2011;342.
Wu YK, Huang CY, Yang MC, Huang GL, Chen SY, Lan CC. Effect of Tiotropium on Heart Rate Variability in Stable Chronic Obstructive Pulmonary Disease Patients. J Aerosol Med Pulm Drug Deliv, 2015;28(2):100-5.
Halpin DMG, Dahl R, Hallmann C, Mueller A, Tashkin D. Tiotropium HandiHaler (R) and Respimat (R) in COPD: a pooled safety analysis. International Journal of Chronic Obstructive Pulmonary Disease. 2015;10:239-59.
Bartels C, Looby M, Sechaud R, Kaiser G. Determination of the pharmacokinetics of glycopyrronium in the lung using a population pharmacokinetic modelling approach. British Journal of Clinical Pharmacology. 2013;76(6):868-79.
Van de Maele B, Fabbri LM, Martin C, Horton R, Dolker M, Overend T. Cardiovascular safety of QVA149, a combination of Indacaterol and NVA237, in COPD patients. COPD. 2010;7(6):418-27.
Wedzicha JA, Dahl R, Buhl R, Schubert-Tennigkeit A, Chen H, D'Andrea P et al. Pooled safety analysis of the fixed-dose combination of indacaterol and glycopyrronium (QVA149), its monocomponents, and tiotropium versus placebo in COPD patients. Respir Med. 2014;108(10):1498-507.
Glycopyrronium for inhalation. COPD: another antimuscarinic with cardiac adverse effects that require monitoring. Prescrire Int. 2014;23(146):36-9.
Beeh KM, Singh D, Scala DL. Once-daily NVA237 improves exercise tolerance from the first dose in patients with COPD: the GLOW3 trial. Int J Chron Obstruct Pulmon Dis, 2012. 7: p. 503-13.
Buhl R, Gessner C, Schuermann W, Foerster K, Sieder C, Hiltl S, et al. Efficacy and safety of once-daily QVA149 compared with the free combination of once-daily tiotropium plus twice-daily formoterol in patients with moderate-to-severe COPD (QUANTIFY): a randomised, non-inferiority study. Thorax. 2015;70(4):311-9.
D'Urzo A, Ferguson GT, van Noord JA, Hirata K, Martin C, Horton R, et al., Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trial. Respir Res. 2011;12:156.
Kerwin E, Hébert J, Gallagher N, Martin C, Overend T, Alagappan VK, et al. Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 study. Eur Respir J, 2012. 40(5):1106-14.
Wang C, Sun T, Huang Y, Humphries M, Bai L, Li L, et al., Efficacy and safety of once-daily glycopyrronium in predominantly Chinese patients with moderate-to-severe chronic obstructive pulmonary disease: the GLOW7 study. Int J Chron Obstruct Pulmon Dis. 2015;10:57-68.
Dahl R, Chapman KR, Rudolf M, Mehta R, Kho P, Alagappan VK, et al. Safety and efficacy of dual bronchodilation with QVA149 in COPD patients: the enlighten study. Respir Med. 2013;107(10):1558-67.
Lasseter K, Dilzer S, Jansat JM, Garcia Gil E, Caracta CF, Ortiz S. Safety and pharmacokinetics of multiple doses of aclidinium bromide administered twice daily in healthy volunteers. Pulm Pharmacol Ther, 2012;25(2):193-9.
de la Motte S, Beier J, Schmid K, Pascual S, Jansat JM, Gil EG. Pharmacokinetics and safety of aclidinium bromide in younger and elderly patients with chronic obstructive pulmonary disease. International Journal of Clinical Pharmacology and Therapeutics. 2012;50(6):403-412.
Singh D, Magnussen H, Kirsten A, Mindt S, Caracta C, Seoane B, et al. A randomised, placebo- and active-controlled dose-finding study of aclidinium bromide administered twice a day in COPD patients. Pulm Pharmacol Ther. 2012;25(3):248-53.
Kerwin EM, D'Urzo AD, Gelb AF, Lakkis H, Garcia Gil EEfficacy and safety of a 12-week treatment with twice-daily aclidinium bromide in COPD patients (ACCORD COPD I). COPD. 2012;9(2):90-101.
Rennard SI, Scanlon PD, Ferguson GT, Rekeda L, Maurer BT, Garcia Gil E et al. ACCORD COPD II: a randomized clinical trial to evaluate the 12-week efficacy and safety of twice-daily aclidinium bromide in chronic obstructive pulmonary disease patients. Clin Drug Investig. 2013;33(12): 893-904.
Beier J, Kirsten AM, Mroz R. Efficacy and safety of aclidinium bromide compared with placebo and tiotropium in patients with moderate-to-severe chronic obstructive pulmonary disease: results from a 6-week, randomized, controlled Phase IIIb study. COPD. 2013;10(4):511-22.
Fuhr R, Magnussen H, Sarem K, Llovera AR, Kirsten AM, Falqués M, et al. Efficacy of aclidinium bromide 400 mug twice daily compared with placebo and tiotropium in patients with moderate to severe COPD. Chest. 2012;141(3):745-52.
Beeh KM, Watz H, Puente-Maestu L, de Teresa L, Jarreta D, Caracta C, et al. Aclidinium improves exercise endurance, dyspnea, lung hyperinflation, and physical activity in patients with COPD: a randomized, placebo-controlled, crossover trial. BMC Pulm Med. 2014;14:209.
D'Urzo A, Kerwin E, Rennard S, He T, Gil EG, Caracta C. One-year extension study of ACCORD COPD I: safety and efficacy of two doses of twice-daily aclidinium bromide in patients with COPD. COPD, 2013;10(4):500-10.
Jones PW, Singh D, Bateman ED, Agusti A, Lamarca R, de Miquel G, et al., Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study. Eur Respir J. 2012;40(4):830-6.
Gelb AF, Tashkin DP, Make BJ, Zhong X, Garcia Gil E, Caracta CLong-term safety and efficacy of twice-daily aclidinium bromide in patients with COPD. Respir Med. 2013;107(12):1957-65.
Singh D, Jones PW, Bateman ED. Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study. Bmc Pulmonary Medicine. 2014;14.
Mehta R, Kelleher D, Preece A, Hughes S, Crater G.Effect of verapamil on systemic exposure and safety of umeclidinium and vilanterol: a randomized and open-label study. Int J Chron Obstruct Pulmon Dis. 2013;8:159-67.
Trivedi R, Richard N, Mehta R, Church A. Umeclidinium in patients with COPD: a randomised, placebo-controlled study. Eur Respir J. 2014;43(1):72-81.
Donohue JF, Anzueto A, Brooks J, Mehta R, Kalberg C, Crater G. A randomized, double-blind dose-ranging study of the novel LAMA GSK573719 in patients with COPD. Respir Med. 2012;106(7):970-9.
Decramer M, Anzueto A, Kerwin E, Kaelin T, Richard N, Crater G, et al. Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials. Lancet Respir Med. 2014;2(6):472-86.
Kelleher D, Tombs L, Preece A, Brealey N, Mehta R. A randomized, placebo- and moxifloxacin-controlled thorough QT study of umeclidinium monotherapy and umeclidinium/vilanterol combination in healthy subjects. Pulmonary Pharmacology and Therapeutics. 2014;29(1):49-57.
Kelleher DL, Mehta RS, Jean-Francois BM, Preece AF, Blowers J, Crater GD, et al. Safety, tolerability, pharmacodynamics and pharmacokinetics of umeclidinium and vilanterol alone and in combination: a randomized crossover trial. PLoS One. 2012;7(12):e50716.
Harvey KL, Hussain A, Maddock HL. Ipratropium bromide-mediated myocardial injury in in vitro models of myocardial ischaemia/reperfusion. Toxicol Sci. 2014;138(2):457-67.
Yee KC, Jacobson GA, Wood-Baker R. Albuterol enantiomer levels, lung function and QTc interval in patients with acute severe asthma and COPD in the emergency department. International journal of emergency medicine. 2011;4(1):30.
Cahn A, Mehta R, Preece A, Blowers J, Donald A. Safety, Tolerability and Pharmacokinetics and Pharmacodynamics of Inhaled Once-Daily Umeclidinium in Healthy Adults Deficient in CYP2D6 Activity: A Double-Blind, Randomized Clinical Trial. Clinical Drug Investigation. 2013;33(9):653-64.
Downloads
Published
How to Cite
Issue
Section
