Search

Background: Two large randomized trials of regular salmeterol monotherapy in adults with asthma found an increased risk of asthma-related mortality for salmeterol versus placebo or regular salbutamol. There are no similar large trials in children, and the safety of monotherapy with salmeterol or other long-acting beta2-agonists in children with asthma is unclear. Current guidelines recommend that regular long-acting beta2-agonist therapy should be given only in combination with regular inhaled corticosteroids. However, the safety of combination therapy in children with asthma is also unclear. Objectives: We used the paediatric trial results from Cochrane systematic reviews to assess the safety of regular long-acting beta2-agonist therapy, either as monotherapy or as combination therapy with inhaled corticosteroids, in children with asthma. Methods: We searched the Cochrane Database of Systematic Reviews in May 2012 for Cochrane reviews relating to the safety of regular formoterol and salmeterol, and ran updated searches for trials for each of the Cochrane reviews. We used odds ratios (ORs) to summarize the direct randomized evidence on safety from trials comparing regular formoterol or regular salmeterol as monotherapy versus placebo and then as combination therapy with inhaled corticosteroids versus the same dose of inhaled corticosteroids. We indirectly compared the safety of monotherapy and combination therapy by testing for differences between the pooled ORs for monotherapy and for combination therapy. We used ORs to summarize the direct randomized evidence on safety from trials comparing regular formoterol with regular salmeterol. We also compared the safety of regular formoterol and regular salmeterol indirectly by calculating an OR for the pooled results of trials assessing formoterol and the pooled results of trials assessing salmeterol, and then combined the direct and indirect evidence by calculating an overall OR for this comparison. Results: We identified four Cochrane reviews examining the safety of regular formoterol or salmeterol as either monotherapy or combination therapy. The reviews included 19 trials in children and we found two additional studies on salmeterol combination therapy, for a total of 21 trials in 7318 children. We identified two Cochrane reviews comparing the safety of formoterol with salmeterol, which included a single trial in 156 children. We found a statistically significant increase in the odds of suffering a nonfatal serious adverse event in children on formoterol monotherapy [OR = 2.48; 95% confidence interval (CI) = 1.27-4.83, I2 = 0%, five trials, N = 1335] and smaller nonsignificant increases in odds for salmeterol monotherapy (OR = 1.30; 95% CI = 0.82-2.05, I2 = 17%, five trials, N = 1333), formoterol combination therapy (OR = 1.60; 95% CI = 0.80-3.28, I2 = 32%, seven trials, N = 2788) and salmeterol combination therapy (OR = 1.20; 95% CI = 0.37-2.91, I2 = 0%, five trials, N = 1862). There was no significant difference between the pooled ORs of a serious adverse event on monotherapy (OR = 1.60; 95% CI = 1.10-2.33, 10 trials, N = 2668) and combination therapy (OR = 1.50; 95% CI = 0.82-2.75, 12 trials, N = 4650). However, there was an absolute increase of 21 children (95% CI = 4-45) suffering a severe adverse event of any cause for every thousand children treated over six months on monotherapy, compared with an absolute increase of three (95% CI = 1 fewer to 12 more) per 1000 children over three months on combination therapy. The evidence comparing the safety of regular salmeterol to regular formoterol was limited, and even when direct and indirect evidence were combined, the CI around the effect on serious adverse events was too wide to tell whether there was a difference in the comparative safety of formoterol and salmeterol (OR = 1.26; 95% CI = 0.37-4.32). Only one child died across all the trials, so the impact on mortality could not be assessed. Authors' conclusions: Although regular combination therapy is likely to be safer than monotherapy in children with asthma, the safety of regular combination therapy with formoterol or salmeterol in children remains uncertain, particularly in terms of mortality. The relative safety of formoterol and salmeterol is also unclear. There are currently large ongoing surveillance studies that may clarify the risks of combination therapy in children and adolescents with asthma. Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. The Cochrane Collaboration [ABSTRACT FROM AUTHOR]

A recently published ERS core outcome set recommends that all trials of COPD exacerbation management should assess the treatment success (or "cure" of the exacerbation), defined as a dichotomous measure of the overall outcome of an exacerbation. This methodological systematic review describes and compares the instruments that were used to assess treatment success or failure in 54 such RCTs, published between 2006–2020. Twenty-three RCTs used composite measures consisting of several undesirable outcomes of an exacerbation, together defining an overall unfavourable outcome, to define treatment failure. Thirty-four RCTs used descriptive instruments that used qualitative or semi-quantitative descriptions to define cure, marked improvement, improvement of the exacerbation, or treatment failure. Treatment success and failure rates among patients receiving guidelines-directed treatments at different settings and timepoints are described and could be used to inform power calculations in future trials. Descriptive instruments appeared more sensitive to treatment effects compared to composite instruments. Further methodological studies are needed to optimise the evaluation of treatment success/failure. In the meantime, based on the findings of this systematic review, the ERS core outcome set recommends that cure should be defined as sufficient improvement of the signs and symptoms of the exacerbation such that no additional systemic treatments are required. [ABSTRACT FROM AUTHOR]

Clinical trials evaluating the management of acute exacerbations of COPD assess heterogeneous outcomes, often omitting those that are clinically relevant or more important to patients. We have developed a core outcome set, a consensus-based minimum set of important outcomes that we recommend are evaluated in all future clinical trials on exacerbations management, to improve their quality and comparability. COPD exacerbations outcomes were identified through methodological systematic reviews and qualitative interviews with 86 patients from 11 countries globally. The most critical outcomes were prioritised for inclusion in the core outcome set through a two-round Delphi survey completed by 1063 participants (256 patients, 488 health professionals and 319 clinical academics) from 88 countries in five continents. Two global, multi-stakeholder, virtual consensus meetings were conducted to 1) finalise the core outcome set and 2) prioritise a single measurement instrument to be used for evaluating each of the prioritised outcomes. Consensus was informed by rigorous methodological systematic reviews. The views of patients with COPD were accounted for at all stages of the project. Survival, treatment success, breathlessness, quality of life, activities of daily living, the need for a higher level of care, arterial blood gases, disease progression, future exacerbations and hospital admissions, treatment safety and adherence were all included in the core outcome set. Focused methodological research was recommended to further validate and optimise some of the selected measurement instruments. The panel did not consider the prioritised set of outcomes and associated measurement instruments to be burdensome for patients and health professionals to use., Competing Interests: Conflict of interest: A.G. Mathioudakis reports grants from Boehringer Ingelheim, outside the submitted work. Conflict of interest: F. Abroug has nothing to disclose. Conflict of interest: A. Agusti reports grants and personal fees for advisory board work and lectures from GSK, Menarini, Chiesi and AZ, outside the submitted work. Conflict of interest: S. Ananth has nothing to disclose. Conflict of interest: P. Bakke reports personal fees for lectures from AstraZeneca, Novartis and GlaxoSmithKline, outside the submitted work. Conflict of interest: K. Bartziokas has nothing to disclose. Conflict of interest: B. Beghe has nothing to disclose. Conflict of interest: A. Bikov has nothing to disclose. Conflict of interest: T. Bradbury reports receiving an academic scholarship funded by GlaxoSmithKline outside the submitted work. Conflict of interest: G. Brusselle reports personal fees for advisory board work and lectures from Astra Zeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Sanofi and Teva, outside the submitted work. Conflict of interest: C. Cadus reports personal fees from Mundipharma and AstraZeneca outside the submitted work. Conflict of interest: C. Coleman is an employee of the European Lung Foundation. Conflict of interest: M. Contoli reports board membership, payment for lectures, grants for research and travel expenses reimbursement from Chiesi, AstraZeneca and GlaxoSmithKline, board membership, consultancy, payment for lectures, grants for research and travel expenses reimbursement from Boehringer Ingelheim, board membership, consultancy and travel expenses reimbursement from Alk-Abello, board membership, payment for lectures, travel expenses reimbursement from Novartis and Zambon, grants from University of Ferrara, Italy, outside the submitted work. Conflict of interest: A. Corlateanu has nothing to disclose. Conflict of interest: O. Corlateanu has nothing to disclose. Conflict of interest: G.J. Criner reports grants and personal fees from GlaxoSmithKline, Boehringer Ingelheim, Chiesi, Mereo, AstraZeneca, Pulmonx, Pneumrx, Olympus, Broncus, Lungpacer, Nuvaira, ResMed, Respironics and Patara, personal fees from Verona, BTG, EOLO and NGM, grants from Alung, Fisher Paykel and Galapagos, outside the submitted work. Conflict of interest: B. Csoma has nothing to disclose. Conflict of interest: A. Emelyanov has nothing to disclose. Conflict of interest: R. Faner reports grants and other (advisory board) from GSK, grants from Menarini and AstraZeneca, other (lecture fee) from Chiesi, outside the submitted work. Conflict of interest: G. Fernandez Romero has nothing to disclose. Conflict of interest: Z. Hammouda has nothing to disclose. Conflict of interest: P. Horváth has nothing to disclose. Conflict of interest: A. Huerta Garcia has nothing to disclose. Conflict of interest: M. Jacobs has nothing to disclose. Conflict of interest: C. Jenkins reports personal fees for advisory board work and educational content from AstraZeneca and Boehringer Ingelheim, grants and personal fees for advisory board work and educational content from GlaxoSmithKline, personal fees for consultancy, advisory board work and educational content from Novartis, outside the submitted work. Conflict of interest: G. Joos reports grants, personal fees for lectures and advisory board work, and non-financial support from AstraZeneca and GlaxoSmithKline, grants from Chiesi, personal fees for lectures from Novartis and Lapharcon, outside the submitted work; all fees were paid to his department. Conflict of interest: O. Kharevich has nothing to disclose. Conflict of interest: K. Kostikas was an employee and shareholder of Novartis Pharma AG until 2018; he has received honoraria for presentations and consultancy fees from AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, ELPEN, GSK, Menarini, Novartis, Sanofi Genzyme and WebMD; his department has received funding and grants from AstraZeneca, Boehringer Ingelheim, Chiesi, Innovis, ELPEN, GSK, Menarini, Novartis and NuvoAir; and he is a member of the GOLD Assembly. Conflict of interest: E. Lapteva has nothing to disclose. Conflict of interest: Z. Lazar has nothing to disclose. Conflict of interest: J.D. Leuppi is supported by grants from the Swiss National Science Foundation (SNF 160072 and 185592) as well as by Swiss Personalised Health Network (SPHN 2018DR108); and has also received unrestricted grants from AstraZeneca AG Switzerland, Boehringer Ingelheim GmbH Switzerland, GSK AG Switzerland, and Novartis AG Switzerland. Conflict of interest: C. Liddle has nothing to disclose. Conflict of interest: J. Linnell has nothing to disclose. Conflict of interest: A. López-Giraldo has nothing to disclose. Conflict of interest: V.M. McDonald reports grants and personal fees from GSK and AZ, personal fees from Novartis, outside the submitted work. Conflict of interest: R. Nielsen reports grants from GlaxoSmithKline Norway and Boehringer Ingelheim, grants and personal fees from AstraZeneca, outside the submitted work. Conflict of interest: A. Papi report grants, personal fees, non-financial support, and other interests at AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Mundipharma and Teva; personal fees and non-financial support from Menarini, Novartis and Zambon; and grants from Sanofi. Conflict of interest: I. Saraiva has nothing to disclose. Conflict of interest: G. Sergeeva has nothing to disclose. Conflict of interest: A. Sioutkou has nothing to disclose. Conflict of interest: P. Sivapalan reports personal fees for lectures from Boehringer Ingelheim, AstraZeneca and GSK, outside the submitted work. Conflict of interest: E. Stovold has nothing to disclose. Conflict of interest: H. Wang has nothing to disclose. Conflict of interest: F. Wen has nothing to disclose. Conflict of interest: J. Yorke has nothing to disclose. Conflict of interest: P.R. Williamson reports personal fees from European Respiratory Society, during the conduct of the study. Conflict of interest: J. Vestbo reports personal fees for consultancy and lectures from AstraZeneca, Chiesi and Novartis, grants and personal fees for consultancy and lectures from Boehringer Ingelheim, personal fees for consultancy from GSK, outside the submitted work; and the author's son works for Chiesi. Conflict of interest: J-U. Jensen has nothing to disclose., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)