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Yaa-Hui Dong, PhD; Chia-Hsuin Chang, MD, ScD; Donald A. Mahler, MD, FCCP
Author and Funding Information

From the Division of Pharmacoepidemiology and Pharmacoeconomics (Dr Dong), Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School; Department of Internal Medicine (Dr Chang), National Taiwan University Hospital and Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University; and Section of Pulmomary and Critical Care Medicine (Dr Mahler), Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock.

CORRESPONDENCE TO: Chia-Hsuin Chang, MD, ScD, Department of Internal Medicine, National Taiwan University Hospital, 7, Chung-Shan South Road, Taipei 10002, Taiwan; e-mail: chiahsuin123@yahoo.com.tw


FINANCIAL/NONFINANCIAL DISCLOSURES: Dr Mahler has consulted for Boehringer Ingelheim GmbH, Forest Laboratories, Inc, GlaxoSmithKline plc, Novartis AG, and Sunovion Pharmaceuticals Inc; has participated in advisory boards for Forest Laboratories, Inc, GlaxoSmithKline plc, Merck Sharp & Dohme Corp, Novartis AG, Pearl Therapeutics Inc, and Sunovion Pharmaceuticals Inc; and has received royalties from Mapi Research Institute (Mapi Développement) and Taylor & Francis Group (Informa UK Limited). The clinical trials office at Dartmouth-Hitchcock has received grant support from Boehringer Ingelheim GmbH, GlaxoSmithKline plc, Novartis AG, and Sunovion Pharmaceuticals Inc for which Dr Mahler was principal investigator. Drs Dong and Chang have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(6):e212-e213. doi:10.1378/chest.14-1837
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To the Editor:

We thank Drs Khera and Ramakrishnan for their attention and comments regarding our recent article.1 The aim of this study was to conduct a systematic review and meta-analysis of randomized controlled trials to examine the risk of TB and influenza associated with use of inhaled corticosteroids (ICSs) in patients with COPD. As noted in the viewpoints of Drs Khera and Ramakrishnan, trials recruited in our study were primarily designed for efficacy evaluation, and none of them included TB or influenza as a predefined outcome. This may raise the concerns of underdetection or misclassification of TB or influenza cases and reflect inherent challenges of assessing drug safety in clinical trials.2 However, as per the discussion in our article, given that trial participants were under regular follow-up and close monitoring, trial reports of serious adverse events still potentially provided valuable and complete information on TB case ascertainment. Furthermore, because all of the recruited trials were double-blind, misclassification of TB or influenza cases would be likely to be nondifferential, and the direction of bias may be toward the null.

In our study, we mainly estimated the risk estimates with the Peto OR given that it does not require a continuity correction and has the advantage of providing the best CI coverage when events are rare.3 To account for the potential imbalance of sample size between treatment groups within trials and inherent limitations that relative statistics are not easily defined for trials with zero events,3,4 we also applied the Mantel-Haenszel (M-H) and the Bayesian approaches. Each meta-analytic approach yields similar results.

With different meta-analytic methods, weights assigned to individual trials were various in our study, which could prove the robustness of our results and clarify the impacts of influential trials, such as the study by Calverley et al.5 Based on the pooled M-H risk difference, ICS treatment was still associated with a nonsignificantly increased risk of TB vs non-ICS treatment (M-H risk difference, 0.09%; 95% CI, −0.03%-0.21%), in which the weight of the study by Calverley et al5 was 27.57%.

Our meta-analysis quantitatively summarized available scientific evidence, which facilitated to provide pooled-risk estimates with better precision as compared with individual recruited trials. We recognize that drug safety assessment using trial data should be performed carefully. A detailed prespecified protocol for study inclusion, evaluation of the risk of bias across studies, and appropriate statistical methods are necessary to offer valid and complementary safety information.

References

Dong Y-H, Chang C-H, Wu F-LL, et al. Use of inhaled corticosteroids in patients with COPD and the risk of TB and influenza: a systematic review and meta-analysis of randomized controlled trials. Chest. 2014;145(6):1286-1297. [CrossRef] [PubMed]
 
Singh S, Loke YK. Drug safety assessment in clinical trials: methodological challenges and opportunities. Trials. 2012;13:138. [CrossRef] [PubMed]
 
Bradburn MJ, Deeks JJ, Berlin JA, Russell Localio A. Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med. 2007;26(1):53-77. [CrossRef] [PubMed]
 
Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med. 2004;23(9):1351-1375. [CrossRef] [PubMed]
 
Calverley PM, Anderson JA, Celli B, et al; TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775-789. [CrossRef] [PubMed]
 

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References

Dong Y-H, Chang C-H, Wu F-LL, et al. Use of inhaled corticosteroids in patients with COPD and the risk of TB and influenza: a systematic review and meta-analysis of randomized controlled trials. Chest. 2014;145(6):1286-1297. [CrossRef] [PubMed]
 
Singh S, Loke YK. Drug safety assessment in clinical trials: methodological challenges and opportunities. Trials. 2012;13:138. [CrossRef] [PubMed]
 
Bradburn MJ, Deeks JJ, Berlin JA, Russell Localio A. Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med. 2007;26(1):53-77. [CrossRef] [PubMed]
 
Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med. 2004;23(9):1351-1375. [CrossRef] [PubMed]
 
Calverley PM, Anderson JA, Celli B, et al; TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775-789. [CrossRef] [PubMed]
 
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