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Meta-Analysis
. 2021 Apr 14;4(4):CD007694.
doi: 10.1002/14651858.CD007694.pub3.

Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events

Orlagh O'Shea  1 , Elizabeth Stovold  2 , Christopher J Cates  2
Affiliations
Meta-Analysis

Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events

Orlagh O'Shea et al. Cochrane Database Syst Rev. .

Abstract

Background: Asthma is characterised by chronic inflammation of the airways and recurrent exacerbations with wheezing, chest tightness, and cough. Treatment with inhaled steroids and bronchodilators can result in good control of symptoms, prevention of further morbidity, and improved quality of life. However, an increase in serious adverse events with the use of both regular formoterol and regular salmeterol (long-acting beta₂-agonists) compared with placebo for chronic asthma has been demonstrated in previous Cochrane Reviews. This increase was statistically significant in trials that did not randomise participants to an inhaled corticosteroid, but not when formoterol or salmeterol was combined with an inhaled corticosteroid. The confidence intervals were found to be too wide to ensure that the addition of an inhaled corticosteroid renders regular long-acting beta₂-agonists completely safe; few participants and insufficient serious adverse events in these trials precluded a definitive decision about the safety of combination treatments.

Objectives: To assess risks of mortality and non-fatal serious adverse events in trials that have randomised patients with chronic asthma to regular formoterol and an inhaled corticosteroid versus regular salmeterol and an inhaled corticosteroid.

Search methods: We searched the Cochrane Airways Register of Trials, CENTRAL, MEDLINE, Embase, and two trial registries to identify reports of randomised trials for inclusion. We checked manufacturers' websites and clinical trial registers for unpublished trial data, as well as Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol. The date of the most recent search was 24 February 2021.

Selection criteria: We included controlled clinical trials with a parallel design, recruiting patients of any age and severity of asthma, if they randomised patients to treatment with regular formoterol versus regular salmeterol (each with a randomised inhaled corticosteroid) and were of at least 12 weeks' duration.

Data collection and analysis: Two review authors independently selected trials for inclusion in the review, extracted outcome data from published papers and trial registries, and applied GRADE rating for the results. We sought unpublished data on mortality and serious adverse events from study sponsors and authors. The primary outcomes were all cause mortality and non-fatal serious adverse events. We chose not to calculate an average result from all the formulations of formoterol and inhaled steroid, as the doses and delivery devices are too diverse to assume a single class effect.

Main results: Twenty-one studies in 11,572 adults and adolescents and two studies in 723 children met the eligibility criteria of the review. No data were available for two studies; therefore these were not included in the analysis. Among adult and adolescent studies, seven compared formoterol and budesonide to salmeterol and fluticasone (N = 7764), six compared formoterol and beclomethasone to salmeterol and fluticasone (N = 1923), two compared formoterol and mometasone to salmeterol and fluticasone (N = 1126), two compared formoterol and fluticasone to salmeterol and fluticasone (N = 790), and one compared formoterol and budesonide to salmeterol and budesonide (N = 229). In total, five deaths were reported among adults, none of which was thought to be related to asthma. The certainty of evidence for all-cause mortality was low, as there were not enough deaths to permit any precise conclusions regarding the risk of mortality on combination formoterol versus combination salmeterol. In all, 201 adults reported non-fatal serious adverse events. In studies comparing formoterol and budesonide to salmeterol and fluticasone, there were 77 in the formoterol arm and 68 in the salmeterol arm (Peto odds ratio (OR) 1.14, 95% confidence interval (CI) 0.82 to 1.59; 5935 participants, 7 studies; moderate-certainty evidence). In the formoterol and beclomethasone studies, there were 12 adults in the formoterol arm and 13 in the salmeterol arm with events (Peto OR 0.94, 95% CI 0.43 to 2.08; 1941 participants, 6 studies; moderate-certainty evidence). In the formoterol and mometasone studies, there were 18 in the formoterol arm and 11 in the salmeterol arm (Peto OR 1.02, 95% CI 0.47 to 2.20; 1126 participants, 2 studies; moderate-certainty evidence). One adult in the formoterol and fluticasone studies in the salmeterol arm experienced an event (Peto OR 0.05, 95% CI 0.00 to 3.10; 293 participants, 2 studies; low-certainty evidence). Another adult in the formoterol and budesonide compared to salmeterol and budesonide study in the formoterol arm had an event (Peto OR 7.45, 95% CI 0.15 to 375.68; 229 participants, 1 study; low-certainty evidence). Only 46 adults were reported to have experienced asthma-related serious adverse events. The certainty of the evidence was low to very low due to the small number of events and the absence of independent assessment of causation. The two studies in children compared formoterol and fluticasone to salmeterol and fluticasone. No deaths and no asthma-related serious adverse events were reported in these studies. Four all-cause serious adverse events were reported: three in the formoterol arm, and one in the salmeterol arm (Peto OR 2.72, 95% CI 0.38 to 19.46; 548 participants, 2 studies; low-certainty evidence).

Authors' conclusions: Overall, for both adults and children, evidence is insufficient to show whether regular formoterol in combination with budesonide, beclomethasone, fluticasone, or mometasone has a different safety profile from salmeterol in combination with fluticasone or budesonide. Five deaths of any cause were reported across all studies and no deaths from asthma; this information is insufficient to permit any firm conclusions about the relative risks of mortality on combination formoterol in comparison to combination salmeterol inhalers. Evidence on all-cause non-fatal serious adverse events indicates that there is probably little to no difference between formoterol/budesonide and salmeterol/fluticasone inhalers. However events for the other formoterol combination inhalers were too few to allow conclusions. Only 46 non-fatal serious adverse events were thought to be asthma related; this small number in addition to the absence of independent outcome assessment means that we have very low confidence for this outcome. We found no evidence of safety issues that would affect the choice between salmeterol and formoterol combination inhalers used for regular maintenance therapy by adults and children with asthma.

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Conflict of interest statement

OOS: none known.

ES: none known.

CJC: none known.

Figures

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1
Screen4Me assessments, March 2020.
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Study flow diagram.
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Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
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Forest plot of comparison: 1 Fixed‐dose formoterol/ICS versus salmeterol/fluticasone, outcome: 1.1 All‐cause mortality.
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Forest plot of comparison: 1 Fixed‐dose formoterol/ICS versus salmeterol/fluticasone, outcome: 1.2 All‐cause non‐fatal serious adverse events.
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Forest plot of comparison: 3 Sensitivity analysis, outcome: 3.1 Busse SAE sensitivity analysis.
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Forest plot of comparison: 1 Fixed‐dose formoterol/ICS versus salmeterol/fluticasone, outcome: 1.3 Asthma‐related non‐fatal serious adverse events.
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Forest plot of comparison: 3 Sensitivity analysis, outcome: 3.2 Bernstein SAE sensitivity analysis.
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Forest plot of comparison: 2 Children formoterol/fluticasone versus salmeterol/fluticasone, outcome: 2.2 All‐cause non‐fatal serious adverse events.
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Forest plot of comparison: 3 Sensitivity analysis, outcome: 3.3 All‐cause non‐fatal SAE blinding.
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Forest plot of comparison: 3 Sensitivity analysis, outcome: 3.4 Asthma‐related non‐fatal SAE blinding.
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Funnel plot of comparison: 1 Adults formoterol/ICS versus salmeterol/ICS, outcome: 1.2 All‐cause non‐fatal serious adverse events.
1.1
1.1. Analysis
Comparison 1: Adults formoterol/ICS versus salmeterol/ICS, Outcome 1: All‐cause mortality
1.2
1.2. Analysis
Comparison 1: Adults formoterol/ICS versus salmeterol/ICS, Outcome 2: All‐cause non‐fatal serious adverse events
1.3
1.3. Analysis
Comparison 1: Adults formoterol/ICS versus salmeterol/ICS, Outcome 3: Asthma related non‐fatal serious adverse events
2.1
2.1. Analysis
Comparison 2: Children formoterol/fluticasone versus salmeterol/fluticasone, Outcome 1: All‐cause mortality
2.2
2.2. Analysis
Comparison 2: Children formoterol/fluticasone versus salmeterol/fluticasone, Outcome 2: All‐cause non‐fatal serious adverse events
2.3
2.3. Analysis
Comparison 2: Children formoterol/fluticasone versus salmeterol/fluticasone, Outcome 3: Asthma related non‐fatal serious adverse events
2.4
2.4. Analysis
Comparison 2: Children formoterol/fluticasone versus salmeterol/fluticasone, Outcome 4: All‐cause non‐fatal serious adverse events
3.1
3.1. Analysis
Comparison 3: Sensitivity analysis, Outcome 1: Busse SAE sensitivity analysis
3.2
3.2. Analysis
Comparison 3: Sensitivity analysis, Outcome 2: Bernstein SAE sensitivity analysis
3.3
3.3. Analysis
Comparison 3: Sensitivity analysis, Outcome 3: All‐cause non‐fatal SAE blinding
3.4
3.4. Analysis
Comparison 3: Sensitivity analysis, Outcome 4: Asthma‐related non‐fatal SAE blinding
3.5
3.5. Analysis
Comparison 3: Sensitivity analysis, Outcome 5: Single‐inhaler SAE sensitivity analysis
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    1. NCT00394368. Efficacy and tolerability of beclomethasone dipropionate 100 µg + formoterol 6 µg pMDI VIA HFA-134a vs. fluticasone 125 µg + salmeterol 25 µg pMDI [DOUBLE BLIND, MULTINATIONAL, MULTICENTRE, PARALLEL-GROUP DESIGN CLINICAL TRIAL OF THE EFFICACY AND TOLERABILITY OF CHF 1535 (BECLOMETHASONE DIPROPIONATE 100 µg + FORMOTEROL 6 µg) pMDI VIA HFA-134a vs. FLUTICASONE 125 µg + SALMETEROL 25 µg pMDI (SERETIDE®) IN THE 12-WEEK TREATMENT OF ADULT PATIENTS WITH MODERATE TO SEVERE PERSISTENT ASTHMA]. clinicaltrials.gov/show/NCT00394368 (first received 1 November 2006).
    1. Paggiaro P, Papi A, Feschenko YI, Nicolini G, Fabbri LM. Efficacy and safety of the new beclomethasone dipropionate/formoterol combination vs fluticasone propionate/salmeterol pMDIs in moderate to severe persistent asthma. European Respiratory Journal 2006;28(Suppl 50):205s [P1227].
    1. Papi A, Paggiaro P, Nicolini G, Vignola AM, Fabbri LM. Beclomethasone/formoterol vs fluticasone/salmeterol inhaled combination in moderate to severe asthma. European Journal of Allergy and Clinical Immunology 2007;62(10):1182-8. - PubMed
Papi 2012 {published data only}
    1. NCT00497237. Clinical trial of the efficacy and safety of beclomethasone dipropionate plus formoterol vs fluticasone propionate plus salmeterol in the 6 months step down treatment of asthma [Prospective, randomised, open-label, multicentre, active drug controlled, parallel group design clinical trial of the efficacy and safety of beclomethasone dipropionate 400 mcg + formoterol 24 mcg pMDI Via HFA-134a (Foster™) vs. fluticasone propionate 500 mcg + salmeterol xinafoate 100 mcg DPI (Seretide Diskus®) in the 6 months stepdown treatment of adult patients with controlled asthma]. clinicaltrials.gov/show/NCT00497237 (first received 6 July 2007).
    1. Paggiaro P, Nicolini G, Crimi N, Fabbri LM, Olivieri D, Rossi A, et al. Asthma control and lung function after step down from high dose ICS/LABA combination therapy. European Respiratory Journal 2011;38(55):722s [P3967].
    1. Papi A, Nicolini G, Crimi N, Fabbri L, Olivieri D, Rossi A, et al. Step-down from high dose fixed combination therapy in asthma patients: a randomized controlled trial. Respiratory Research 2012;13:54. - PMC - PubMed
Ploszczuk 2014 {published data only}
    1. CTRI//05/002704. Comparison of Flutiform, fluticasone and Seretide in treatment of moderate to severe asthma in paediatric patients aged 5 to less than 12 years. www.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2012/05/002704 (first received 28 May 2012).
    1. Ploszczuk A, Bosheva M, Spooner K, McIver T, Dissanayake S. Efficacy and safety of fluticasone propionate/formoterol fumarate in pediatric asthma patients: a randomized controlled trial. Therapeutic Advances in Respiratory Disease 2018;12:1753466618777924. - PMC - PubMed
    1. Ploszczuk A, Bosheva M, Spooner K, McIver T, Dissanayake S. Efficacy and safety of fluticasone propionate/formoterol in paediatric patients with asthma. European Respiratory Journal 2014;44:P1167. - PMC - PubMed
Ringdal 2002 {published data only}
    1. Jenkins C, Wilson J, Rutherford C, Perry AS, Whitehead PJ. Asthma management costs are lower with combination fluticasone/salmeterol (25/50 mcg BD) in a single inhaler than with budesonide (800 mcg BD) plus eformoterol (12 mcg BD) via separate inhalers. Respirology 2002;7(Suppl):A20 Abstract number (P23).
    1. Martin AA, Whitehead PJ, McCarthy TP. Asthma costs with salmeterol/fluticasone combination 50/250mcg bd compared to budesonide 800mcg bd plus formoterol 12mcg bd [abstract]. In: American Thoracic Society 99th International Conference; 2003 May 16-21; Seattle. 2003:D034 Poster C43.
    1. Ringdal N, Chovan L, Chuchalin AG, Whitehead PJ. Advair™/Seretide™ (250µg/50µg bid) shows exacerbation benefit over budesonide 800µg + formoterol 12µg in moderate-severe asthma [abstract]. American Journal of Respiratory and Critical Care Medicine 2001;163(Suppl 5):A866.
    1. Ringdal N, Chuchalin A, Chovan L, Tudoric N, Maggi E, Whitehead PJ, et al. Evaluation of different inhaled combination therapies (EDICT): a randomised, double-blind comparison of Seretide (50/250 mug bd Diskus vs. formoterol (12 mug bd) and budesonide (800 mug bd) given concurrently (both via Turbuhaler) in patients with moderate-to-severe asthma. Respiratory Medicine 2002;96(11):851-61. - PubMed
    1. Ringdal N, Chuchalin AG, Chovan L, Whitehead PJ. A comparison of Advair™/Seretide™ (salmeterol 50 µg/fluticasone propionate 250 µg bid) with formoterol 12 µg + budesonide 800 µg bid in moderate-severe asthma. American Journal of Respiratory and Critical Care Medicine 2000;161(Suppl 3):A196.
SAM 40010 {published data only}
    1. SAM40010. A randomised, double blind, double-dummy, parallel-group, twelve week comparison of salmeterol/fluticasone propionate (FP) DISKUS/ACCUHALER 50/100mcg bd. with budesonide 200mcg bd. plus formoterol 4.5mcg bd. (both by breath-activated dry powder inhaler [BADPI]) in adult and adolescent asthmatics. www.gsk-studyregister.com/en/trial-details/?id=SAM40010 (first received 26 January 2000).
SAM 40048 {published data only}
    1. SAM40048. Randomised, double-blind, parallel group study on the efficacy and tolerability of the salmeterol 50 mcg/fluticasone 250 mcg combination Diskus compared to the formoterol 6mcg / budesonide 200mcg combination Turbohaler administered twice daily in patients with moderate bronchial asthma. GlaxoSmithKline Clinical Trial Register (first received 16 August 2001).
Scichilone 2010 {published data only}
    1. EUCTR-000512-25-IT. Double blind, double dummy, randomised, parallel group, monocentric clinical trial on the effects of chf 1535 mdi or seretide dpi on biological and functional markers of small airways in patients with asthma: a pilot study - nd. www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2006-000512-25-IT (first received 20 April 2006).
    1. Scichilone N, Battaglia S, Sorino C, Paglino G, Martino L, Paterno A, et al. Effects of extra-fine inhaled beclomethasone/formoterol on both large and small airways in asthma. Allergy 2010;65(7):897-902. - PubMed
Usmani 2017 {published data only}
    1. Kemppinen A, Gardener E, Thomas V, Raju P, Callan C, McLoughlin A, et al. Pragmatic trial stepping down Flutiform in patients maintained on high dose ICS. Journal of Thoracic Disease 2016;8(Suppl 5):AB039.
    1. Usmani OS, Kemppinen A, Gardener E, Thomas V, Konduru PR, Callan C, et al. A randomized pragmatic trial of changing to and stepping down fluticasone/formoterol in asthma. Journal of Allergy and Clinical Immunology 2017;5(5):1378-87.e5. - PubMed
Woo 2020 {published data only}
    1. Woo SD, Ye YM, Lee Y, Lee SH, Shin YS, Park JH, et al. Efficacy and safety of a pressurized metered-dose inhaler in older asthmatics: comparison to a dry powder inhaler in a 12-week randomized trial. Allergy, Asthma and Immunology Research 2020;12(3):454-66. - PMC - PubMed

References to studies excluded from this review

Bleecker 2008 {published data only}
    1. Bleecker ER, Postma DS, Lawrance RM, Meyers DA, Ambrose HJ, Goldman M. Effect of ADRB2 polymorphisms on response to long acting beta2-agonist therapy: a pharmacogenetic analysis of two randomised studies. Lancet 2008;370(9605):2118-25. - PubMed
Dhillon 2006 {published data only}
    1. Dhillon S, Keating GM. Beclometasone dipropionate/formoterol in an HFA-propelled pressurised metered-dose inhaler. Drugs 2006;66(11):1475-83. - PubMed
Hampel 2008 {published data only}
    1. Hampel FC, Martin P, Mezzanotte WS. Early bronchodilatory effects of budesonide/formoterol pMDI compared with fluticasone/salmeterol DPI and albuterol pMDI: 2 randomized controlled trials in adults with persistent asthma previously treated with inhaled corticosteroids. Journal of Asthma 2008;45(4):265-72. - PubMed
Jung 2008 {published data only}
    1. Jung KS, Uh ST, Lee YC, Shim JJ, Park SK, Williams AE, et al. Comparison of the clinical efficacy and safety of salmeterol/fluticasone propionate versus current care in the management of persistent asthma in Korea. Current Medical Research and Opinion 2008;24(12):3571-82. - PubMed
Lee 2003 {published data only}
    1. Lee DKC, Currie GP, Cockburtn WJ, Lipworth BJ. Comparison of budesonide/formoterol versus fluticasone/salmeterol combination inhalers in moderate persistent asthma. In: American Thoracic Society 99th International Conference; 2003 May 16-21; Seattle. 2003:D094 Poster 613.
Lyseng‐Williamson 2003 {published data only}
    1. Lyseng-Williamson KA, Plosker GL. Inhaled salmeterol/fluticasone propionate combination: a pharmacoeconomic review of its use in the management of asthma. Pharmacoeconomics 2003;21(13):951-89. - PubMed
NCT02491970 {published data only}
    1. NCT02491970. Small airway function of fluticasone/formoterol (Flutiform®) and fluticasone/salmeterol (RECONFFIRM) [A single-blind, randomized, active-controlled, multi-center and phase IV study to evaluate the small airway parameters of fluticasone/formoterol (Flutiform®) compared to fluticasone/salmeterol in asthma patients]. clinicaltrials.gov/show/NCT02491970 (first received 8 July 2015).
Rani 2016 {published data only}
    1. Rani S, Rawal M, Kumar S, Lamba S. To compare efficacy and safety of fixed drug combination of salmeterol / fluticasone and budesonide / formoterol on the lung functions in childhood patients with moderate persistent asthma. Indian Journal of Public Health Research and Development 2016;7(4):203-7.
UMIN000006572 {published data only}
    1. JPRN-UMIN000006572. Study on the effects of the budesonide/formoterol combination formulation in improving airway inflammation and airway resistance in patients with bronchial asthma. www.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-UMIN000006572 (first received 18 October 2011).

References to ongoing studies

NCT03387241 {published data only}
    1. NCT03387241. Efficacy of FLUTIFORM ® vs Seretide® in moderate to severe persistent asthma in subjects aged ≥12 years [A double blind, double dummy, randomised, multicentre, two arm parallel group study to assess the efficacy and safety of FLUTIFORM® pMDI (2 puffs bid) vs Seretide® pMDI (2 puffs bid) in subjects aged ≥12 years with moderate to severe persistent, reversible asthma]. ClinicalTrials.gov/show/NCT03387241 (first received 2 January 2018).

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References to other published versions of this review

Cates 2009
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