Safety and Potential Side Effects of ß2-Agonists: A Still Debated Question
DOI:
https://doi.org/10.12974/2311-8687.2013.01.01.2Keywords:
Safety profile, ß2-agonists, therapyAbstract
In the last years, the safety profile of ß2-agonists has been largely discussed as there are concerns about the adverse effects of their regular use. In this review, we analyze the main questions relating both morbidity and mortality of currently available ß2-agonists. Although questions still remain regarding the issue of safety, evidence from epidemiological studies is strongly suggestive that the use of ß2-agonists is not dangerous.
References
Beasley R, Pearce N, Crane J, Burgess C. B-agonists: What is the evidence that their use increases the risk of asthma morbidity and mortality? J Allergy Clin Immunol 1999; 103: S18-30. http://dx.doi.org/10.1016/S0091-6749(99)70270-8 DOI: https://doi.org/10.1016/S0091-6749(99)70270-8
Benson RL, Perlman F. Clinical effects of epinephrine by inhalation. J Allergy 1948; 19: 129-40. http://dx.doi.org/10.1016/0021-8707(48)90101-4 DOI: https://doi.org/10.1016/0021-8707(48)90101-4
Fox N. Chronic effect of epinephrine and ephedrine on nasal mucosa. Arch Otolaryngol 1931; 13: 73-6. http://dx.doi.org/10.1001/archotol.1931.03660010083008 DOI: https://doi.org/10.1001/archotol.1931.03660010083008
Galgiani JV, Proescher F, Dock W, Tainter ML. Local and systemic effects from inhalation of strong solutions of epinephrine. JAMA 1939; 112: 1929-33. http://dx.doi.org/10.1001/jama.1939.02800190043011 DOI: https://doi.org/10.1001/jama.1939.02800190043011
Hunnicutt LF. The effects of drugs on the nasal mucous membrane. Transactions of the Pacific Coast Otolaryngology Society 1941; 26: 53-67.
Rodrigo GJ, Plaza Moral V, Garcia Marcos L, Castro- Rodriguez JA. Safety of regular use of long-acting beta agonists as monotherapy or added to inhaled corticosteroids in asthma. A systematic review. Pulmonary Pharmacology & Therapeutics 2009; 22: 9-19. http://dx.doi.org/10.1016/j.pupt.2008.10.008 DOI: https://doi.org/10.1016/j.pupt.2008.10.008
Lowell FC, Curry JJ, Schiller IW. A clinical and experimental study of isoprel in spontaneous and induced asthma. N Engl J Med 1949; 240: 45-51. http://dx.doi.org/10.1056/NEJM194901132400201 DOI: https://doi.org/10.1056/NEJM194901132400201
Greenberg MJ, Pines A. Pressurised aerosols in asthma. Br Med J 1967; 1: 563. http://dx.doi.org/10.1136/bmj.1.5539.563 DOI: https://doi.org/10.1136/bmj.1.5539.563
Van Metre TE. Adverse effects of inhalation of excessive amounts of nebulized isoproterenol in status asthmatics. J Allergy 1969; 43: 101-13. http://dx.doi.org/10.1016/0021-8707(69)90130-0 DOI: https://doi.org/10.1016/0021-8707(69)90130-0
Sovani MP, Whale CI, Tattersfield AE. A Benefit-Risk Assessment of Inhaled Long-Acting b2-Agonists in the Management of Obstructive Pulmonary Disease. Drug Safety 2004; 27 (10): 689-715. http://dx.doi.org/10.2165/00002018-200427100-00001 DOI: https://doi.org/10.2165/00002018-200427100-00001
Newhouse M, Chapman K, McCallum A, Abboud RT, Bowie DM, Hodder RV, et al. Cardiovascular safety of high doses of inhaled fenoterol and albuterol in acute severe asthma. Chest 1996; 110: 595-603. http://dx.doi.org/10.1378/chest.110.3.595 DOI: https://doi.org/10.1378/chest.110.3.595
Oppenheimer J, Nelson HS. Safety of long-acting betaagonists in asthma: a review. Curr Opin Pulm Med 2008; 14(1): 64-9. http://dx.doi.org/10.1097/MCP.0b013e3282f1980b DOI: https://doi.org/10.1097/MCP.0b013e3282f1980b
Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Metaanalysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths. Ann Inter Med 2006; 144: 904-12. http://dx.doi.org/10.7326/0003-4819-144-12-200606200- 00126 DOI: https://doi.org/10.7326/0003-4819-144-12-200606200-00126
Martinez FD. Serious adverse events and death associated with treatment using long-acting beta-agonists. Clin Rev Allergy Immunol 2006; 31(2-3): 269-78. http://dx.doi.org/10.1385/CRIAI:31:2:269 DOI: https://doi.org/10.1385/CRIAI:31:2:269
Williams C, Crossland L, Finnerty J, Crane J, Holgate ST, Pearce N, et al. A case-control study of salmeterol and near fatal attacks of asthma. Thorax 1998; 53: 7-13. http://dx.doi.org/10.1136/thx.53.1.7 DOI: https://doi.org/10.1136/thx.53.1.7
Van Ganse E, van der Linden PD, Leufkens HG, Herings RM, Vincken W, Ernst P. Asthma medications and disease exacerbations: an epidemiological study as a method for asthma surveillaince. Eur Respir J 1995; 8 (11): 1856-60. http://dx.doi.org/10.1183/09031936.95.08111856 DOI: https://doi.org/10.1183/09031936.95.08111856
Mann M, Chowdhury B, Sullivan E, Nicklas R, Anthracite R, Meyer RJ. Serious asthma antichoexacerbations in asthmatics treated with high-dose formoterol. Chest 2003; 124: 70-4. http://dx.doi.org/10.1378/chest.124.1.70 DOI: https://doi.org/10.1378/chest.124.1.70
Garrett JE, Lanes SF, Kolbe J, Rea HH. Risk of severe life threatening asthma and beta agonist type: an example of confounding by severity. Thorax 1996; 51: 1093-9. http://dx.doi.org/10.1136/thx.51.11.1093 DOI: https://doi.org/10.1136/thx.51.11.1093
Van der Merwe L, Plaatjes M, Van Schalwyk E. Risk factors for near-fatal and fatal asthma in a third world population. Respirology 2002; 7 Suppl: A26.
Taylor DR, Town GI, Herbison GP, Boothman-Burrell D, Flannery EM, Hancox B et al. Asthma control during long term treatment with regular inhaled salbutamol and salmeterol. Thorax 1998; 53: 744-52. http://dx.doi.org/10.1136/thx.53.9.744 DOI: https://doi.org/10.1136/thx.53.9.744
Nelson HS. Is there a problem with inhaled long-acting betaadrenergic agonists? J Allergy Clin Immunol 2006 Jan; 117(1): 3-16. http://dx.doi.org/10.1016/j.jaci.2005.10.013 DOI: https://doi.org/10.1016/j.jaci.2005.10.013
Donohue JF, Menjoge S, Kesten S. Tolerance to bronchodilating effects of salmeterol in COPD. Respir Med 2003; 97: 1014-20. http://dx.doi.org/10.1016/S0954-6111(03)00131-8 DOI: https://doi.org/10.1016/S0954-6111(03)00131-8
Nelson HS, Raine D Jr, Doner HC, Posey WC. Subsensitivity to the bronchodilator action of albuterol produced by chronic administration. Am Rev Respire Dis 1977; 116: 871-8.
Israel E, Drazen JM, Liggett SB, Boushey HA, Cherniack RM, Chinchilli VM, et al. The effect of polymorphisms of the b2 adrerngic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med 2000; 162: 75-80. http://dx.doi.org/10.1164/ajrccm.162.1.9907092 DOI: https://doi.org/10.1164/ajrccm.162.1.9907092
Taylor DR, Drazen JM, Herbison GP, Yandava CN, Hancox RJ, Town GI. Asthma exacerbations during long term b agonist use: influence of b2 adrenoceptor polymorphism. Thorax 2000; 55: 762-7. http://dx.doi.org/10.1136/thorax.55.9.762 DOI: https://doi.org/10.1136/thorax.55.9.762
Martinez FD, Graves PE, Baldini M, Solomon S, Erickson R. Association between genetic polymorphisms of the b2- adrenoceptor and response to albuterol in children with and without a history of wheezing. J Clin Invest 1997; 100: 3184- 88. http://dx.doi.org/10.1172/JCI119874 DOI: https://doi.org/10.1172/JCI119874
Lima J, Thomason D, Mohamed M, Eberle L, Self T, Johnson J. Impact of genetic polymorphisms of the b2-adrenegic receptor on albuterol bronchodilator pharmacodynamics. Clin Pharmacol Ther 1999; 65: 519-25. http://dx.doi.org/10.1016/S0009-9236(99)70071-8 DOI: https://doi.org/10.1016/S0009-9236(99)70071-8
Israel E, Drazen JM, Liggett SB, Boushey HA, Cherniack RM, Chinchilli VM, et al. National Heart, Lung, and Blood Institute's Asthma Clinical Research Network Effect of polymorphism of the beta(2)-adrenergic receptor on response to regular use of albuterol in asthma. Int Arch Allergy Immunol 2001; 124(1-3): 183-6. http://dx.doi.org/10.1159/000053705 DOI: https://doi.org/10.1159/000053705
Rossi A, Kristufek P, Levine BE, Thomson MH, Till D, Kottakis J, Della Cioppa G; Formoterol in Chronic Obstructive Pulmonary Disease (FICOPD) II Study Group. Comparison of the efficacy, tolerability, and safety of formoterol dry powder and oral, slow-release theophylline in the treatment of COPD. Chest 2002; 121: 1058-69. http://dx.doi.org/10.1378/chest.121.4.1058 DOI: https://doi.org/10.1378/chest.121.4.1058
Wilkinson JRW, Roberts JA, Brackling P, Holgate ST, Howarth PH. Paradoxical bronchoconstriction in asthmatic patients after salmeterol by MDI. BMJ 1992; 305: 931-2. http://dx.doi.org/10.1136/bmj.305.6859.931 DOI: https://doi.org/10.1136/bmj.305.6859.931
Salpeter SR, Ormiston TM, Salpeter EE. Cardiovascular effects of b-agonists in patients with asthma and COPD Chest 2004; 125: 2309-21. http://dx.doi.org/10.1378/chest.125.6.2309 DOI: https://doi.org/10.1378/chest.125.6.2309
Rossi A, Khirani S, Cazzola M. Long-acting b2-agonists (LABA) in chronic obstructive pulmonary disease: efficacy and safety. International Journal of COPD 2008: 3(4) 521-9. DOI: https://doi.org/10.2147/COPD.S1353
Cazzola M, Matera MG, Donner CF. Inhaled b2-adrenoceptor agonists, cardiovascular safety in patients with obstructive lung disease. Drugs 2005; 65: 1595-610. http://dx.doi.org/10.2165/00003495-200565120-00001 DOI: https://doi.org/10.2165/00003495-200565120-00001
The TORCH Study Group. The TORCH (Towards a Revolution in COPD Health) survival study protocol. Eur Respir J 2004. 24: 206-10. http://dx.doi.org/10.1183/09031936.04.00120603 DOI: https://doi.org/10.1183/09031936.04.00120603
Au DH, Udris EM, Curtis JR, McDonell MD, Fihn SD, the ACQUIP investigators. Association between chronic heart failure and inhaled B2-adrenoceptor agonists. Am Heart J 2004; 148: 915-20. http://dx.doi.org/10.1016/j.ahj.2004.03.048 DOI: https://doi.org/10.1016/j.ahj.2004.03.048
Jackson CM, Lipworth B. Benefit-risk assessment of longacting b2-agonists in asthma. Drug Saf 2004; 27(4): 243-70. http://dx.doi.org/10.2165/00002018-200427040-00003 DOI: https://doi.org/10.2165/00002018-200427040-00003
Wraight WJ, Smith AD, Cowan JO, Flannery M, Herbison GP, Taylor DR. Adverse effects of short-acting beta-agonists: Potential impact when anti-inflammatory therapy is inadequate. Respirology 2004; 9: 215-21. http://dx.doi.org/10.1111/j.1440-1843.2004.00557.x DOI: https://doi.org/10.1111/j.1440-1843.2004.00557.x
Murray DR, Prabhu SD, Chandrasekar B. Chronic b- adrenergic stimulation induces myocardial proinflammatory cytokine expression. Circulation 2000; 101: 2338-41. http://dx.doi.org/10.1161/01.CIR.101.20.2338 DOI: https://doi.org/10.1161/01.CIR.101.20.2338
Suissa S, Assimes T, Ernst P. Inhaled short acting betaagonist use in COPD and the risk of acute myocardial infarction. Thorax 2003; 58: 43-6. http://dx.doi.org/10.1136/thorax.58.1.43 DOI: https://doi.org/10.1136/thorax.58.1.43
Sengstock DM, Obeidat O, Pasnoori V, Mehra P, Sandberg KR, McCullough PA. Asthma, B-agonists and development of Congestive heart failure: results of the ABCHF study. J Card Fail 2002; 8: 232-8. http://dx.doi.org/10.1054/jcaf.2002.127771 DOI: https://doi.org/10.1054/jcaf.2002.127771
Cazzola M, Matera MG. Tremor and b2-adrenergic agents: Is it a real clinical problem? Pulmonary Pharmacology & Therapeutics 2012; 25: 4-10. http://dx.doi.org/10.1016/j.pupt.2011.12.004 DOI: https://doi.org/10.1016/j.pupt.2011.12.004
Shrewsbury S, Hallett C. Salmeterol 100 mg: an analysis of its tolerability in single and chronic-dose studies. Ann Allergy Asthma Immunol 2001; 87: 465-73. http://dx.doi.org/10.1016/S1081-1206(10)62259-4 DOI: https://doi.org/10.1016/S1081-1206(10)62259-4
Smucny J, Flynn C, Becker L, Glazier R. B2-agonists for acute bronchitis. Cochrane Database Syst Rev 2001; 1: CD001726. DOI: https://doi.org/10.1002/14651858.CD001726
Freedman BJ. Trial of new bronchodilator, terbutaline, in asthma. Br Med J 1971; 1: 633-6. http://dx.doi.org/10.1136/bmj.1.5750.633 DOI: https://doi.org/10.1136/bmj.1.5750.633
Foley TH, Marsden CD, Owen DA. Evidence for a direct peripheral effect of adrenaline on physiological tremor in man. J Physiol 1967; 189: 65P-6P.
Lakie M, Hayes NR, Combes N, Langford N. Is postural tremor size controlled by interstitial potassium concentration in muscle? J Neurol Neurosurg Psychiatry 2004; 75: 1013-8. http://dx.doi.org/10.1136/jnnp.2003.022749 DOI: https://doi.org/10.1136/jnnp.2003.022749
Legge JS, Gaddie J, Palmer KN. Comparison of two oral selective b2-adrenergic stimulant drugs in bronchial asthma. Br Med J 1971; 1: 637-9. http://dx.doi.org/10.1136/bmj.1.5750.637 DOI: https://doi.org/10.1136/bmj.1.5750.637
Whale CI, Sovani MP, Mortimer KJ, Harrison TW, Tattersfield AE. Systemic and bronchodilator effects of inhaled racformoterol in subjects with chronic obstructive pulmonary disease: a dose response study. Br J Clin Pharmacol 2008; 65: 841-7. http://dx.doi.org/10.1111/j.1365-2125.2007.03081.x DOI: https://doi.org/10.1111/j.1365-2125.2007.03081.x
Lötvall J, Ankerst J. Long duration of airway but not systemic effects of inhaled formoterol in asthmatic patients. Respir Med 2008; 102: 449-56. http://dx.doi.org/10.1016/j.rmed.2007.10.003 DOI: https://doi.org/10.1016/j.rmed.2007.10.003
Prati HF. Abuse of salbutamol inhalers in young people. Clinical Allergy 1982; 12: 203-6. http://dx.doi.org/10.1111/j.1365-2222.1982.tb01640.x DOI: https://doi.org/10.1111/j.1365-2222.1982.tb01640.x
Widlocher D, Lecrubier Y, Jouvent R, Puech AJ, Simon P. Antidepressant effect of salbutamol. Lancet 1977; 2: 767-8. http://dx.doi.org/10.1016/S0140-6736(77)90279-3 DOI: https://doi.org/10.1016/S0140-6736(77)90279-3
Miller WC, Rice DL. A comparison of oral terbutaline and fenoterol in asthma. Annals of Allergy 1980; 44: 15-18.
Raghunathan K, Nagajothi N. Paradoxical bronchospasm: a potentially life threatening adverse effect of albuterol. South Med J 2006; 99 (3): 288-9. http://dx.doi.org/10.1097/01.smj.0000202699.93002.e8 DOI: https://doi.org/10.1097/01.smj.0000202699.93002.e8
Finnerty JP, Howarth PH. Paradoxical bronchoconstriction with nebulized albuterol but not with terbutaline. Am Rev Respir Dis 1993; 148: 512-3. http://dx.doi.org/10.1164/ajrccm/148.2.512 DOI: https://doi.org/10.1164/ajrccm/148.2.512
O’Callaghan C, Milner AD, Swarbrick A. Paradoxical deterioration in lung function after nebulised salbutamol in wheezy infants. Lancet 1986; 2: 1424-5. http://dx.doi.org/10.1016/S0140-6736(86)92735-2 DOI: https://doi.org/10.1016/S0140-6736(86)92735-2
Spooner L, Olin JL. Paradoxical bronchoconstriction with albuterol administered by metered-dose inhaler and nebulizer solution. Ann Pharmacother 2005; 39 (11): 1924-7. http://dx.doi.org/10.1345/aph.1G248 DOI: https://doi.org/10.1345/aph.1G248
Lulich KM, Goldie RG, Ryan G, Paterson JW. Adverse reactions to b2-agonist bronchodilators. Med Toxicol 1986; 1(4): 286-99. DOI: https://doi.org/10.1007/BF03259844
Andrade Capuchinho-Júnior G, Marques Dias R, Regina da Silva de Carvalho S. One hour effects of salbutamol and formoterol on blood pressure, heart rate and oxygen saturation in asthmatics. Rev Port Pneumol 2008; 14(3): 353- 61. DOI: https://doi.org/10.1016/S2173-5115(08)70266-5
Edwards JG, Holgate ST. Dependency upon salbutamol inhalers. Br J Psychiatry 1979; 134: 624-6. http://dx.doi.org/10.1192/bjp.134.6.624 DOI: https://doi.org/10.1192/bjp.134.6.624
Thompson PJ, Dhillon P, Cole P. Addiction to aerosol treatment the asthmatic alternative to glue sniffing. Br Med J 1983; 287: 1515-6. http://dx.doi.org/10.1136/bmj.287.6404.1515-a DOI: https://doi.org/10.1136/bmj.287.6404.1515-a
Drexel H, Regele M, Langle V. Successful treatment of terbataline-induced bronchospasm with orciprenalinesulphate. Lancet 1982; 2: 446. http://dx.doi.org/10.1016/S0140-6736(82)90478-0 DOI: https://doi.org/10.1016/S0140-6736(82)90478-0
Rolf Smith S, Ryder C, Kendall MH, Holder R. Cardiovascular and biochemical responses to nebulized salbutamol in normal subjects. British Journal of Clinical Pharmacology 1984; 18: 641-4. http://dx.doi.org/10.1111/j.1365-2125.1984.tb02520.x DOI: https://doi.org/10.1111/j.1365-2125.1984.tb02520.x
Paterson JW, Lulich KM, Goldie RG. A comment on betsagonists and their use in asthma. Trends in Pharmacol Sciences 1983; 4: 67-9. http://dx.doi.org/10.1016/0165-6147(83)90290-0 DOI: https://doi.org/10.1016/0165-6147(83)90290-0
Gundogdu AS, Brown PM, Jirial S, Sach I, Sunksen PH. Comparison of hormonal and metabolic effects of salbutamol infusion in normal subjects and insulin-requiring diabetes. Lancet 1985; 1: 1125-7.
Habashy D, Lam LT, Browne GJ. The administration of b2- agonists for paediatric asthma and its adverse reaction in Australian and New Zealand emergency departments: a cross-sectional survey. Eur J Emerg Med 2003; 10(3): 219- 24. http://dx.doi.org/10.1097/00063110-200309000-00012
Rakhmanina NY, Kearns GL, Farrar HC 3rd. Hypokalemia in an asthmatic child from abuse of albuterol metered dose inhaler. Pediatr Emerg Care 1998; 14(2): 145-7. http://dx.doi.org/10.1097/00006565-199804000-00015 DOI: https://doi.org/10.1097/00006565-199804000-00015
Daubert GP, Mabasa VH, Leung VW, Aaron C. Acute clenbuterol overdose resulting in supraventricular tachycardia and atrial fibrillation. J Med Toxicol 2007; 3(2): 56-60. http://dx.doi.org/10.1007/BF03160909 DOI: https://doi.org/10.1007/BF03160909
Hanrahan JP, Grogan DR, Baumgartner RA, Wilson A, Cheng H, Zimetbaum PJ, Morganroth J. Arrhythmias in patients with chronic obstructive pulmonary disease (COPD): occurrence frequency and the effect of treatment with the inhaled long-acting b2-agonists arformoterol and salmeterol. Medicine (Baltimore) 2008; 87(6): 319-28. http://dx.doi.org/10.1097/MD.0b013e31818fcc02 DOI: https://doi.org/10.1097/MD.0b013e31818fcc02
Habashy D, Lam LT, Browne GJ. The administration of b2- agonists for paediatric asthma and its adverse reaction in Australian and New Zealand emergency departments: a cross-sectional survey. Eur J Emerg Med 2003; 10(3): 219- 24. http://dx.doi.org/10.1097/00063110-200309000-00012 DOI: https://doi.org/10.1097/00063110-200309000-00012
Portnoy J, Nadel G, Amado M, Willsie-Ediger S. Continuous nebulization for status asthmaticus. Ann Allergy 1992; 69(1): 71-9.
Inman MHW, Adelstein AM. Rise and fall of asthma mortality in England and Wales in relation to use of pressurised aerosols. Lancet 1969; 2: 279-85. http://dx.doi.org/10.1016/S0140-6736(69)90051-8 DOI: https://doi.org/10.1016/S0140-6736(69)90051-8
Stolley PD. Why the United States was spared an epidemic of deaths due to asthma. Am Rev Respir Dis 1972; 105: 883- 90.
Jackson RT, Beaglehole R, Rea HH, Sutherland DC. Mortality from asthma: a new epidemic in New Zealand. Br Med J 1982; 285: 771-4. http://dx.doi.org/10.1136/bmj.285.6344.771 DOI: https://doi.org/10.1136/bmj.285.6344.771
Pearce N, Beasley R, Crane J, Burgess C, Jackson R. End of the New Zealand asthma mortality epidemic. Lancet 1995; 345: 41-4. http://dx.doi.org/10.1016/S0140-6736(95)91159-6 DOI: https://doi.org/10.1016/S0140-6736(95)91159-6
Speizer FE, Doll R, Heaf P. Observations on recent increases in mortality from asthma. Br Med J 1968; i: 3359. DOI: https://doi.org/10.1136/bmj.1.5588.335
Stolley PD, Schinnar R. Association between asthma mortality and isoproterenol aerosols: a review. Prev Med 1978; 7: 319-38. http://dx.doi.org/10.1016/0091-7435(78)90265-7 DOI: https://doi.org/10.1016/0091-7435(78)90265-7
Crane J, Pearce N, Flatt A, Burgess C, Jackson R, Kwong T, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-83: case control study. Lancet 1989; 1: 917- 22. http://dx.doi.org/10.1016/S0140-6736(89)92505-1 DOI: https://doi.org/10.1016/S0140-6736(89)92505-1
Pearce N, Grainger J, Atkinson M, Crane J, Burgess C, Culling C, et al. Case-control study of prescribed fenoterol and death from asthma in New Zealand, 1977-1981. Thorax 1990; 45: 170-5. http://dx.doi.org/10.1136/thx.45.3.170 DOI: https://doi.org/10.1136/thx.45.3.170
Grainger J, Woodman K, Pearce N, Crane J, Burgess C, Keane A, Beasley R. Prescribed fenoterol and death from asthma in New Zealand, 1981-1987: a further case-control study. Thorax 1991; 46: 105-11. http://dx.doi.org/10.1136/thx.46.2.105 DOI: https://doi.org/10.1136/thx.46.2.105
Sackett DL, Shannon HS, Browman GW. Fenoterol and fatal asthma. Lancet 1990; 1: 46. DOI: https://doi.org/10.1016/0140-6736(90)90168-5
Spitzer WD, Suissa S, Ernst P, Horwitz RI, Habbick B, Cockcroft D, et al. The use of beta agonists and the risk of death and near death from asthma. N Engl J Med 1992; 326: 501-6. http://dx.doi.org/10.1056/NEJM199202203260801 DOI: https://doi.org/10.1056/NEJM199202203260801
Suissa S, Ernst P, Boivin J-F, Horwitz RI, Cockcroft D, Blais L, et al. A cohort analysis of excess mortality in asthma and the use of inhaled beta agonists. Am J Respir Crit Care Med 1994; 149: 604-10. http://dx.doi.org/10.1164/ajrccm.149.3.8118625 DOI: https://doi.org/10.1164/ajrccm.149.3.8118625
Hasford J, Virchow JC. Excess mortality in patients with asthma on long-acting b2-agonists. Eur Respir J 2006; 28: 900-2. http://dx.doi.org/10.1183/09031936.00085606 DOI: https://doi.org/10.1183/09031936.00085606
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: 15-26. http://dx.doi.org/10.1378/chest.129.1.15 DOI: https://doi.org/10.1378/chest.129.1.15
Mann RD, Kubota K, Pearce G, Wilton L. Salmeterol: a study by prescription event monitoring in a UK cohort of 15,407 patients. J Clin Epidemiol 1996; 49: 247-50. http://dx.doi.org/10.1016/0895-4356(95)00555-2 DOI: https://doi.org/10.1016/0895-4356(95)00555-2
Blais L, Ernst P, Suissa S. Confounding by indication and channeling over time: the risks of b2-agonists. Am J Epidemiol 1996; 144: 1161-9. http://dx.doi.org/10.1093/oxfordjournals.aje.a008895 DOI: https://doi.org/10.1093/oxfordjournals.aje.a008895
Hanania NA. Evaluating the Safety of COPD Medications: An Evidence-Based Review. Chest 2013; 144(4): 1357-1367. http://dx.doi.org/10.1378/chest.12-2438 DOI: https://doi.org/10.1378/chest.12-2438
Kelly HW. Risk versus benefit considerations for the n(2)- agonists. Pharmacotherapy 2006; 26(9 pt 2): 164S-174S. http://dx.doi.org/10.1592/phco.26.9part2.164S DOI: https://doi.org/10.1592/phco.26.9part2.164S
Hanania NA, Sharafkhaneh A, Barber R, Dickey BF. b- agonist intrinsic efficacy: measurement and clinical significance. Am J Respir Crit Care Med 2002; 165(10): 1353-1358. http://dx.doi.org/10.1164/rccm.2109060 DOI: https://doi.org/10.1164/rccm.2109060
Ridolo E, Montagni M, Olivieri E, Riario-Sforza GG, Incorvaia C. Role of indacaterol and the newer very long-acting b2- agonists in patients with stable COPD: a review. Int J Chron Obstruct Pulmon Dis 2013; 8: 425-432. http://dx.doi.org/10.2147/COPD.S49179 DOI: https://doi.org/10.2147/COPD.S49179
