Dear Editor,
We are writing in response to the letter to the Editor regarding our clinical trial published in Current Medical Research and Opinion, entitled “Bronchodilator efficacy of tiotropium/formoterol (18/12 µg once daily via a Discair inhaler; TIO/FORMfixed), tiotropium alone (18 µg by Handihaler; TIOmono) or combined with formoterol (12 µg twice daily by Aerolizer; TIO/FORMbid) in adults with moderate-to-severe stable COPD”Citation1.
We deeply appreciate the concerns raised by the authors. The primary endpoint of the study was to confirm the non-inferiority of TIO/FORMfixed vs TIO/FORMbid for the changes in forced expiratory volume in 1 s (FEV1) over a 24-h period. While our findings successfully met the primary endpoint, we also showed that 24-h bronchodilator efficacy of TIO/FORMfixed once daily by Discair was superior to tiotropium 18 µg monotherapy by HandihalerCitation1.
The authors who raise concerns regarding our findings mainly underline that 12 patients in the TIOmono group, 7 patients in the TIO/FORMbid group, and 9 patients in the TIO/FORMfixed group had at least one exacerbation in the last year. In addition to these, the mean CAT (COPD Assessment Test) score was 18.3 in the TIOmono group, 17.1 in the TIO/FORMbid group and 17.1 in the TIO/FORMfixed group. Due to these basal characteristics of the study arms, they claim that the patients in the TIOmono group had more exacerbations and were more symptomatic in the last year, thus leading to the worse lung function results over 24-h period compared to the both TIO/FORM groups.
Although we understand these concerns, we must remind them that the group comparisons for the previous exacerbation rates and basal CAT scores were not statistically significant (p = .3614 for the exacerbation rates, and p = .3861 for the CAT scores as shown in Table 1 in the published article). The situation was even more evident for the exacerbation rates when the study arms were subdivided according to the combined clinical evaluation and management system recommended by the GOLD (Global Initiative for Chronic Obstructive Lung Disease) 2020 using the total number of moderate and severe exacerbation in the last yearCitation2. In this classification, COPD patients are clinically classified as low-risk for future exacerbations if there are 0-1 exacerbations and high-risk for future exacerbations if there are 2 or more exacerbations. When we consider our data, we can see that 23 patients in the TIOmono group (82.1%) and 24 patients in the TIO/FORMfixed and TIO/FORMbid groups (85.7%) had 0–1 exacerbations in the previous 12 months (p = .913). So, we can say that the clinical distribution of the COPD patients included in our trial was also quite similar between the groups.
The authors also have some concerns about the differences between the mean CAT scores in the study arms (18.3 units in the TIOmono arm and 17.1 units in the both TIO/FORM arms), which might influence our findings in favour of the TIO/FORM arms. However, as mentioned above, the differences between the groups are not statistically significant (p = .3861, as shown in the Table 1 in the published article). Moreover, the differences less than 2 units between the mean CAT scores are not considered to be of any significance on the clinical grounds.
Several factors may have significant influence over the response to the bronchodilators as well as treatment success in COPD patients. Nevertheless, since the patient groups included in our study had strongly similar background clinical features including the exacerbation rates and the CAT scores, we do not think that any initial characteristics of our patient groups had positive or negative effect on our results.
Transparency
Declaration of funding
No funding to disclose.
Declaration of financial/other relationships
The authors received research support from Neutec Ar-Ge San. & Tic. A.S. (Turkey). None of the authors have received personal funding (salary) from Neutec.
Acknowledgements
None reported.
References
- Yildiz BP, Bayraktaroglu M, Gunen H. Bronchodilator efficacy of tiotropium/formoterol (18/12 µg once daily via a Discair® inhaler), tiotropium alone (18 µg by Handihaler®) or combined with formoterol (12 µg twice daily by Aerolizer®) in adults with moderate-to-severe stable COPD. Curr Med Res Opin. 2019;35(12):2187–2196.
- Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease, 2020. Report. Available from: https://goldcopd.org/wp-content/uploads/2019/12/GOLD-2020-FINAL-ver1.2-03Dec19_WMV.pdf.