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Keynote webinar | Spotlight on medication adherence

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Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
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Lung
Published in: Lung 1/2014

01-02-2014

Cardiovascular Safety of Long Acting Beta Agonist-Inhaled Corticosteroid Combination Products in Adult Patients with Asthma: A Systematic Review

Authors: Imran H. Iftikhar, Muhammad Imtiaz, Allan S. Brett, David J. Amrol

Published in: Lung | Issue 1/2014

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Abstract

Introduction

Long-acting beta agonists and inhaled corticosteroids combination products (LABA-ICS) are widely used in the treatment of asthma. However, there appears to be little data on their cardiovascular safety. The purpose of this study was to conduct a systematic review of the available studies and trials on the cardiovascular safety of LABA-ICS in adults with asthma.

Methods

Two independent reviewers screened citations from PubMed and National Clinical Trials registry to identify studies and trials on the cardiovascular effects of LABA-ICS in patients with asthma.

Results

A total of 15 studies (with 17 cohorts on LABA-ICS to compare with a comparator or placebo) with 5,440 total study participants met the inclusion criteria. Two studies on budesonide–formoterol and one on fluticasone–salmeterol reported treatment emergent cardiovascular adverse events, all of which were dysrhythmias. For comparison, the pooled estimate of the Peto odds ratio (0.72; 95 % confidence interval [CI] 0.17–3; p = 0.65) and the summary risk ratio (0.77; 95 % CI 0.26–2.3; p = 0.64) indicated a nonsignificant difference between LABA-ICS and comparator/placebo groups.

Conclusions

Our systematic review found that few studies and trials reported treatment emergent cardiovascular adverse events with LABA-ICS. However, the Peto odds ratio and risk ratio for these outcomes was statistically nonsignificant. This suggests that LABA-ICS products may have a safe cardiovascular profile in asthma patients.
Literature
1.
Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald M et al (2008) Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J 31(1):143–178CrossRefPubMed
2.
Prenner BM (2008) Role of long-acting beta2-adrenergic agonists in asthma management based on updated asthma guidelines. Curr Opin Pulm Med 14(1):57–63PubMed
3.
Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM (2006) The salmeterol multicenter asthma research trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 129(1):15–26CrossRefPubMed
4.
Jaeschke R, O’Byrne PM, Nair P, Mejza F, Lesniak W, Brozek J et al (2008) The safety of formoterol among patients with asthma using inhaled corticosteroids. Systematic review and meta-analysis. Pol Arch Med Wewn 118(11):627–635PubMed
5.
Chowdhury BA, Dal Pan G (2010) The FDA and safe use of long-acting beta-agonists in the treatment of asthma. N Engl J Med 362(13):1169–1171CrossRefPubMed
6.
Nelson HS (2003) Beta-adrenergic agonists. In: Adkinson NF, Yunginger JW, Busse WW et al (eds) Middleton’s allergy: principles and practice, 6th edn. Mosby, St. Louis, p 803
7.
Seider N, Abinader EG, Oliven A (1993) Cardiac arrhythmias after inhaled bronchodilators in patients with COPD and ischemic heart disease. Chest 104(4):1070–1074CrossRefPubMed
8.
Au DH, Udris EM, Fan VS, Curtis JR, McDonell MB, Fihn SD (2003) Risk of mortality and heart failure exacerbations associated with inhaled beta-adrenoceptor agonists among patients with known left ventricular systolic dysfunction. Chest 123(6):1964–1969CrossRefPubMed
9.
Cazzola M, Imperatore F, Salzillo A, Di Perna F, Calderaro F, Imperatore A et al (1998) Cardiac effects of formoterol and salmeterol in patients suffering from COPD with preexisting cardiac arrhythmias and hypoxemia. Chest 114(2):411–415CrossRefPubMed
10.
Hampel FC, Martin P, Mezzanotte WS (2008) Early bronchodilatory effects of budesonide/formoterol pMDI compared with fluticasone/salmeterol DPI and albuterol pMDI: two randomized controlled trials in adults with persistent asthma previously treated with inhaled corticosteroids. J Asthma 45(4):265–272CrossRefPubMed
11.
Lotvall J, Langley S, Woodcock A (2006) Inhaled steroid/long-acting beta 2 agonist combination products provide 24 hours improvement in lung function in adult asthmatic patients. Respir Res 7:110PubMedCentralCrossRefPubMed
12.
Peters SP, Prenner BM, Mezzanotte WS, Martin P, O’Brien CD (2008) Long-term safety and asthma control with budesonide/formoterol versus budesonide pressurized metered-dose inhaler in asthma patients. Allergy Asthma Proc 29(5):499–516CrossRefPubMed
13.
AstraZeneca. An efficacy study comparing SYMBICORT® Pressurised Metered Dose Inhaler (pMDI) With Budesonide Hydrofluoroalkanes (HFA) pMDI, in Hispanic Subjects With ICS Dependent Asthma. [ClinicalTrials.gov identifier NCT00419757]. U.S. National Institutes of Health, ClinicalTrials.gov [online]. http://​www.​clinicaltrials.​gov. Accessed 21 Dec 2012
14.
AstraZeneca. Phase4/Symbicort® Versus Pulmicort Flexhaler® in African Americans (Titan). [ClinicalTrials.gov identifier NCT00702325]. U.S. National Institutes of Health, ClinicalTrials.gov [online]. http://​www.​clinicaltrials.​gov. Accessed 21 Dec 2012
15.
AstraZeneca. Study to investigate the safety and efficacy of high dose of Symbicort® SMART in Japanese patients. [ClinicalTrials.gov identifier NCT00837967]. US National Institutes of Health, ClinicalTrials.gov [online]. http://​www.​clinicaltrials.​gov. Accessed 21 Dec 2012
16.
AstraZeneca. Comparing Symbicort® as-needed or Bricanyl as-needed or Pulmicort® once daily + Bricanyl as-needed in asthma patients (MIA). [ClinicalTrials.gov identifier NCT00989833]. U.S. National Institutes of Health, ClinicalTrials.gov [online]. URL: http://​www.​clinicaltrials.​gov. Accessed 21 Dec 2012
17.
AstraZeneca. A Comparison of SYMBICORT® pMDI with Budesonide HFA pMDI in African American subjects with asthma. [ClinicalTrials.gov identifier NCT00419952]. US National Institutes of Health, ClinicalTrials.gov [online]. http://​www.​clinicaltrials.​gov. Accessed 21 Dec 2012
18.
GlaxoSmithKline. A 12-month study comparing fluticasone propionate/salmeterol (ADVAIR) DISKUS combination product 250/50 mcg twice daily to fluticasone propionate (FLOVENT) DISKUS 250 mcg twice daily in symptomatic patients with asthma. [ClinicalTrials.gov identifier NCT00452348]. U.S. National Institutes of Health, ClinicalTrials.gov [online]. http://​www.​clinicaltrials.​gov. Accessed 21 Jan 2012
19.
GlaxoSmithKline. A 12-month study comparing fluticasone propionate/salmeterol (ADVAIR) DISKUS combination product 250/50 mcg BID to fluticasone propionate (FLOVENT) DISKUS 250 mcg BID in symptomatic subjects with asthma. [ClinicalTrials.gov identifier NCT00452699]. US National Institutes of Health, ClinicalTrials.gov [online]. http://​www.​clinicaltrials.​gov. Accessed 21 Dec 2012
20.
GlaxoSmithKline. SERETIDE 100/50 bd (twice daily) versus FLIXOTIDE 100 bd as initial maintenance therapy in moderate asthma in adults. [ClinicalTrials.gov identifier NCT00461500]. US National Institutes of Health, ClinicalTrials.gov [online]. http://​www.​clinicaltrials.​gov. Accessed 21 Dec 2012
21.
Schering-Plough. Effects of mometasone furoate/formoterol combination versus mometasone furoate alone in persistent asthmatics (Study P04334AM1) (completed). [ClinicalTrials.gov identifier NCT00383240]. U.S. National Institutes of Health, ClinicalTrials.gov [online]. http://​www.​clinicaltrials.​gov. Accessed 20 Dec 2012
22.
Schering-Plough. Effects of mometasone furoate/formoterol combination versus mometasone furoate alone in persistent asthmatics (Study P04073AM1) (completed). [ClinicalTrials.gov identifier NCT00383552]. US National Institutes of Health, ClinicalTrials.gov [online]. http://​www.​clinicaltrials.​gov. Accessed 21 Dec 2012
23.
Schering-Plough. Asthma study comparing anti-inflammatory effects of 3 doses of mometasone furoate/formoterol fumarate and medium dose mometasone furoate (Study P05122 AM1) (completed). [ClinicalTrials.gov identifier NCT00635882]. US National Institutes of Health, ClinicalTrials.gov [online]. http://​www.​clinicaltrials.​gov. Accessed 21 Dec 2012
24.
Schering-Plough. Effects of mometasone furoate/formoterol combination versus mometasone furoate alone in persistent asthmatics (Study P04431AM2) (completed). [ClinicalTrials.gov identifier NCT00381485]. US National Institutes of Health, ClinicalTrials.gov [online]. http://​www.​clinicaltrials.​gov. Accessed 21 Dec 2012
25.
Tattersfield AE (2006) Current issues with beta2-adrenoceptor agonists: historical background. Clin Rev Allergy Immunol 31(2–3):107–118CrossRefPubMed
26.
Castle W, Fuller R, Hall J, Palmer J (1993) Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ 306(6884):1034–1037PubMedCentralCrossRefPubMed
27.
Mann M, Chowdhury B, Sullivan E, Nicklas R, Anthracite R, Meyer RJ (2003) Serious asthma exacerbations in asthmatics treated with high-dose formoterol. Chest 124(1):70–74CrossRefPubMed
28.
Cates CJ, Cates MJ, Lasserson TJ (2008) Regular treatment with formoterol for chronic asthma: serious adverse events. Cochrane Database Syst Rev (4): CD006923
29.
Rodrigo GJ, Moral VP, Marcos LG, Castro-Rodriguez JA (2009) Safety of regular use of long-acting beta agonists as monotherapy or added to inhaled corticosteroids in asthma. A systematic review. Pulm Pharmacol Ther 22(1):9–19CrossRefPubMed
30.
Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE (2006) Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths. Ann Intern Med 144(12):904–912CrossRefPubMed
31.
Weatherall M, Wijesinghe M, Perrin K, Harwood M, Beasley R (2010) Meta-analysis of the risk of mortality with salmeterol and the effect of concomitant inhaled corticosteroid therapy. Thorax 65(1):39–43CrossRefPubMed
32.
Ducharme FM, Ni Chroinin M, Greenstone I, Lasserson TJ (2010) Addition of long-acting beta2-agonists to inhaled corticosteroids versus same dose inhaled corticosteroids for chronic asthma in adults and children. Cochrane Database Syst Rev (5): CD005535
33.
Jaeschke R, O’Byrne PM, Mejza F, Nair P, Lesniak W, Brozek J et al (2008) The safety of long-acting beta-agonists among patients with asthma using inhaled corticosteroids: systematic review and metaanalysis. Am J Respir Crit Care Med 178(10):1009–1016CrossRefPubMed
34.
Ni Chroinin M, Lasserson TJ, Greenstone I, Ducharme FM (2009) Addition of long-acting beta-agonists to inhaled corticosteroids for chronic asthma in children. Cochrane Database Syst Rev (3): CD00794
35.
Man SF, Sin DD (2005) Effects of corticosteroids on systemic inflammation in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2(1):78–82CrossRefPubMed
36.
Sin DD, Man SF, Marciniuk DD, Ford G, FitzGerald M, Wong E et al (2008) The effects of fluticasone with or without salmeterol on systemic biomarkers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 177(11):1207–1214CrossRefPubMed
37.
Metadata
Title
Cardiovascular Safety of Long Acting Beta Agonist-Inhaled Corticosteroid Combination Products in Adult Patients with Asthma: A Systematic Review
Authors
Imran H. Iftikhar
Muhammad Imtiaz
Allan S. Brett
David J. Amrol
Publication date
01-02-2014
Publisher
Springer US
Published in
Lung / Issue 1/2014
Print ISSN: 0341-2040
Electronic ISSN: 1432-1750
DOI
https://doi.org/10.1007/s00408-013-9525-x

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Keynote webinar | Spotlight on medication adherence

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WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

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