PMID- 29949492 OWN - NLM STAT- MEDLINE DCOM- 20180705 LR - 20181015 IS - 1533-4406 (Electronic) IS - 0028-4793 (Linking) VI - 378 IP - 26 DP - 2018 Jun 28 TI - Combined Analysis of Asthma Safety Trials of Long-Acting beta(2)-Agonists. PG - 2497-2505 LID - 10.1056/NEJMoa1716868 [doi] AB - BACKGROUND: Safety concerns regarding long-acting beta(2)-agonists (LABAs) in asthma management were initially identified in a large postmarketing trial in which the risk of death was increased. In 2010, the Food and Drug Administration (FDA) mandated that the four companies marketing LABAs for asthma perform prospective, randomized, controlled trials comparing the safety of combination therapy with a LABA plus an inhaled glucocorticoid with that of an inhaled glucocorticoid alone in adolescents (12 to 17 years of age) and adults. In conjunction with the FDA, the manufacturers harmonized their trial methods to allow an independent joint oversight committee to provide a final combined analysis of the four trials. METHODS: As members of the joint oversight committee, we performed a combined analysis of the four trials comparing an inhaled glucocorticoid plus a LABA (combination therapy) with an inhaled glucocorticoid alone. The primary outcome was a composite of asthma-related intubation or death. Post hoc secondary outcomes included serious asthma-related events and asthma exacerbations. RESULTS: Among the 36,010 patients in the intention-to-treat study, there were three asthma-related intubations (two in the inhaled-glucocorticoid group and one in the combination-therapy group) and two asthma-related deaths (both in the combination-therapy group) in 4 patients. In the secondary analysis of serious asthma-related events (a composite of hospitalization, intubation, or death), 108 of 18,006 patients (0.60%) in the inhaled-glucocorticoid group and 119 of 18,004 patients (0.66%) in the combination-therapy group had at least one composite event (relative risk in the combination-therapy group, 1.09; 95% confidence interval [CI], 0.83 to 1.43; P=0.55); 2100 patients in the inhaled-glucocorticoid group (11.7%) and 1768 in the combination-therapy group (9.8%) had at least one asthma exacerbation (relative risk, 0.83; 95% CI, 0.78 to 0.89; P<0.001). CONCLUSIONS: Combination therapy with a LABA plus an inhaled glucocorticoid did not result in a significantly higher risk of serious asthma-related events than treatment with an inhaled glucocorticoid alone but resulted in significantly fewer asthma exacerbations. FAU - Busse, William W AU - Busse WW AD - From the Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, Madison (W.W.B.); the Pulmonary Division, Department of Medicine, University of Cape Town, Cape Town, South Africa (E.D.B.); the Division of Medical Ethics, Department of Population Health, New York University School of Medicine, New York (A.L.C.); the Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque (H.W.K.); the Department of Medicine, McMaster University, Hamilton, ON, Canada (P.M.O.); LungenClinic Grosshansdorf and Christian Albrechts University Kiel, Kiel, and Airway Research Center North, German Center for Lung Research, Grosshansdorf - both in Germany (K.F.R.); and the Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA (V.M.C.). FAU - Bateman, Eric D AU - Bateman ED AD - From the Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, Madison (W.W.B.); the Pulmonary Division, Department of Medicine, University of Cape Town, Cape Town, South Africa (E.D.B.); the Division of Medical Ethics, Department of Population Health, New York University School of Medicine, New York (A.L.C.); the Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque (H.W.K.); the Department of Medicine, McMaster University, Hamilton, ON, Canada (P.M.O.); LungenClinic Grosshansdorf and Christian Albrechts University Kiel, Kiel, and Airway Research Center North, German Center for Lung Research, Grosshansdorf - both in Germany (K.F.R.); and the Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA (V.M.C.). FAU - Caplan, Arthur L AU - Caplan AL AD - From the Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, Madison (W.W.B.); the Pulmonary Division, Department of Medicine, University of Cape Town, Cape Town, South Africa (E.D.B.); the Division of Medical Ethics, Department of Population Health, New York University School of Medicine, New York (A.L.C.); the Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque (H.W.K.); the Department of Medicine, McMaster University, Hamilton, ON, Canada (P.M.O.); LungenClinic Grosshansdorf and Christian Albrechts University Kiel, Kiel, and Airway Research Center North, German Center for Lung Research, Grosshansdorf - both in Germany (K.F.R.); and the Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA (V.M.C.). FAU - Kelly, H William AU - Kelly HW AD - From the Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, Madison (W.W.B.); the Pulmonary Division, Department of Medicine, University of Cape Town, Cape Town, South Africa (E.D.B.); the Division of Medical Ethics, Department of Population Health, New York University School of Medicine, New York (A.L.C.); the Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque (H.W.K.); the Department of Medicine, McMaster University, Hamilton, ON, Canada (P.M.O.); LungenClinic Grosshansdorf and Christian Albrechts University Kiel, Kiel, and Airway Research Center North, German Center for Lung Research, Grosshansdorf - both in Germany (K.F.R.); and the Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA (V.M.C.). FAU - O'Byrne, Paul M AU - O'Byrne PM AD - From the Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, Madison (W.W.B.); the Pulmonary Division, Department of Medicine, University of Cape Town, Cape Town, South Africa (E.D.B.); the Division of Medical Ethics, Department of Population Health, New York University School of Medicine, New York (A.L.C.); the Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque (H.W.K.); the Department of Medicine, McMaster University, Hamilton, ON, Canada (P.M.O.); LungenClinic Grosshansdorf and Christian Albrechts University Kiel, Kiel, and Airway Research Center North, German Center for Lung Research, Grosshansdorf - both in Germany (K.F.R.); and the Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA (V.M.C.). FAU - Rabe, Klaus F AU - Rabe KF AD - From the Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, Madison (W.W.B.); the Pulmonary Division, Department of Medicine, University of Cape Town, Cape Town, South Africa (E.D.B.); the Division of Medical Ethics, Department of Population Health, New York University School of Medicine, New York (A.L.C.); the Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque (H.W.K.); the Department of Medicine, McMaster University, Hamilton, ON, Canada (P.M.O.); LungenClinic Grosshansdorf and Christian Albrechts University Kiel, Kiel, and Airway Research Center North, German Center for Lung Research, Grosshansdorf - both in Germany (K.F.R.); and the Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA (V.M.C.). FAU - Chinchilli, Vernon M AU - Chinchilli VM AD - From the Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, Madison (W.W.B.); the Pulmonary Division, Department of Medicine, University of Cape Town, Cape Town, South Africa (E.D.B.); the Division of Medical Ethics, Department of Population Health, New York University School of Medicine, New York (A.L.C.); the Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque (H.W.K.); the Department of Medicine, McMaster University, Hamilton, ON, Canada (P.M.O.); LungenClinic Grosshansdorf and Christian Albrechts University Kiel, Kiel, and Airway Research Center North, German Center for Lung Research, Grosshansdorf - both in Germany (K.F.R.); and the Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA (V.M.C.). LA - eng PT - Comparative Study PT - Journal Article PL - United States TA - N Engl J Med JT - The New England journal of medicine JID - 0255562 RN - 0 (Adrenergic beta-Agonists) RN - 0 (Anti-Asthmatic Agents) RN - 0 (Delayed-Action Preparations) RN - 0 (Glucocorticoids) SB - IM CIN - N Engl J Med. 2018 Oct 11;379(15):1481-2. PMID: 30318886 CIN - J Pediatr. 2018 Nov;202:330-333. PMID: 30360876 CIN - Ann Intern Med. 2018 Nov 20;169(10):JC53. PMID: 30452560 MH - Administration, Inhalation MH - Adolescent MH - Adrenergic beta-Agonists/*administration & dosage/adverse effects MH - Adult MH - Aged MH - Aged, 80 and over MH - Anti-Asthmatic Agents/*administration & dosage/adverse effects MH - Asthma/*drug therapy MH - Child MH - Delayed-Action Preparations MH - Drug Therapy, Combination MH - Equivalence Trials as Topic MH - Female MH - Glucocorticoids/*administration & dosage/adverse effects MH - Humans MH - Intention to Treat Analysis MH - Male MH - Middle Aged MH - Multicenter Studies as Topic MH - Randomized Controlled Trials as Topic MH - Young Adult EDAT- 2018/06/28 06:00 MHDA- 2018/07/06 06:00 CRDT- 2018/06/28 06:00 PHST- 2018/06/28 06:00 [entrez] PHST- 2018/06/28 06:00 [pubmed] PHST- 2018/07/06 06:00 [medline] AID - 10.1056/NEJMoa1716868 [doi] PST - ppublish SO - N Engl J Med. 2018 Jun 28;378(26):2497-2505. doi: 10.1056/NEJMoa1716868.