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Correspondence
]
The Importance of Considering Safety Data From Large-scale Clinical Trials in Patients With Asthma To the Editor:
We read with interest the article by Drs Rodrigo and Castro-Rodríguez1 in CHEST (February 2015). Although the article is well written and informative for physicians, we would like to highlight an important omission from the literature review and suggest two revisions. We were interested to see that in the penultimate sentence of the Discussion, the authors state: “Although the results of this review showed no increase in AEs [adverse events] associated with the use of tiotropium Respimat, potential undesirable effects (cardiovascular and others) must be taken into consideration given several warnings made in the literature.”1 In drawing this conclusion, the authors fail to acknowledge that they are based on observations from studies in patients with COPD and that these undesirable effects have not been observed in patients with asthma. The authors also appear to have overlooked very relevant data from the Tiotropium Safety and Performance in Respimat (TIOSPIR) trial. This trial, involving 17,135 patients, compared the safety and efficacy of once-daily tiotropium Respimat 5 mg or 2.5 mg with once-daily tiotropium 18 mg delivered by the HandiHaler device2 and found that tiotropium Respimat did not increase the risk of death (5 mg: hazard ratio [HR], 0.96; 95% CI, 0.84-1.09; 2.5 mg: HR, 1.00; 95% CI, 0.87-1.14) or major adverse cardiac events (5 mg: HR, 1.10; 95% CI, 0.91-1.33; 2.5 mg: HR, 1.11; 95% CI, 0.91-1.34) in patients with COPD, compared with patients receiving tiotropium delivered by the HandiHaler device. The TIOSPIR authors note that caution is required when interpreting results to avoid unwarranted over-interpretation of cause-specific mortality.3 Further, a study by Hohlfeld et al4 comparing the pharmacokinetics and pharmacodynamics of tiotropium Respimat 5 mg and tiotropium 18 mg delivered by the HandiHaler device in patients with COPD demonstrated that the incidence of adverse events was balanced between the tiotropium treatment groups and comparable with placebo; both treatments were well tolerated, with no apparent relation to dose or device. We, therefore, recommend that these
journal.publications.chestnet.org
results are taken into consideration to provide a more balanced overview of the currently available literature for the safety of tiotropium, delivered by the Respimat device. We also note that in the section about tiotropium as an add-on to long-acting b2-agonist (LABA) plus inhaled corticosteroids (ICSs), it is stated: “Although the combination of tiotropium, LABA, and ICS resulted in significant increases in AQLQ [Asthma Quality of Life Questionnaire] and ACQ-7 [Asthma Control Questionnaire 7] total scores...”. An improvement in ACQ-7 score is actually shown by a decrease in total score,5 and so this sentence should be revised to read: “Although the combination of tiotropium, LABA, and ICS resulted in significant increases in AQLQ and decreases in ACQ-7 total scores...”. Similarly, the sentence “Even so, patients receiving tiotropium had a slightly higher probability of experiencing an increase of ⱖ 0.5 points in ACQ-7 score...” in the Discussion should read “Even so, patients receiving tiotropium had a slightly higher probability of experiencing a decrease of ⱖ 0.5 points...”. Ronald Dahl, MD Odense, Denmark AFFILIATIONS: From the University of Southern Denmark; and the University of Aarhus, Aarhus, Denmark. FINANCIAL/NONFINANCIAL DISCLOSURES: The author has reported to CHEST the following conflict of interest: Dr Dahl is a member of the steering and publication committee for the TIOSPIR trial sponsored by Boehringer-Ingelheim and received no honorarium for this. CORRESPONDENCE TO: Ronald Dahl, MD, Allergy Centre, Sdr. Blvd 29, Odense University Hospital, 5000 Odense C, Denmark; e-mail: [email protected] © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.15-0086
References 1. Rodrigo GJ, Castro-Rodríguez JA. What is the role of tiotropium in asthma? A systematic review with meta-analysis. Chest. 2015; 147(2):388-396. 2. Wise RA, Anzueto A, Cotton D, et al; TIOSPIR Investigators. Tiotropium Respimat inhaler and the risk of death in COPD. N Engl J Med. 2013;369(16):1491-1501. 3. Wise RA. Tiotropium and the risk of death in COPD. N Engl J Med. 2014;370(5):481-482. 4. Hohlfeld JM, Sharma A, van Noord JA, et al. Pharmacokinetics and pharmacodynamics of tiotropium solution and tiotropium powder in chronic obstructive pulmonary disease. J Clin Pharmacol. 2014; 54(4):405-414. 5. Juniper EF, Svensson K, Mörk AC, Ståhl E. Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Respir Med. 2005;99(5):553-558.
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Correspondence
]
The Importance of Considering Safety Data From Large-scale Clinical Trials in Patients With Asthma To the Editor:
We read with interest the article by Drs Rodrigo and Castro-Rodríguez1 in CHEST (February 2015). Although the article is well written and informative for physicians, we would like to highlight an important omission from the literature review and suggest two revisions. We were interested to see that in the penultimate sentence of the Discussion, the authors state: “Although the results of this review showed no increase in AEs [adverse events] associated with the use of tiotropium Respimat, potential undesirable effects (cardiovascular and others) must be taken into consideration given several warnings made in the literature.”1 In drawing this conclusion, the authors fail to acknowledge that they are based on observations from studies in patients with COPD and that these undesirable effects have not been observed in patients with asthma. The authors also appear to have overlooked very relevant data from the Tiotropium Safety and Performance in Respimat (TIOSPIR) trial. This trial, involving 17,135 patients, compared the safety and efficacy of once-daily tiotropium Respimat 5 mg or 2.5 mg with once-daily tiotropium 18 mg delivered by the HandiHaler device2 and found that tiotropium Respimat did not increase the risk of death (5 mg: hazard ratio [HR], 0.96; 95% CI, 0.84-1.09; 2.5 mg: HR, 1.00; 95% CI, 0.87-1.14) or major adverse cardiac events (5 mg: HR, 1.10; 95% CI, 0.91-1.33; 2.5 mg: HR, 1.11; 95% CI, 0.91-1.34) in patients with COPD, compared with patients receiving tiotropium delivered by the HandiHaler device. The TIOSPIR authors note that caution is required when interpreting results to avoid unwarranted over-interpretation of cause-specific mortality.3 Further, a study by Hohlfeld et al4 comparing the pharmacokinetics and pharmacodynamics of tiotropium Respimat 5 mg and tiotropium 18 mg delivered by the HandiHaler device in patients with COPD demonstrated that the incidence of adverse events was balanced between the tiotropium treatment groups and comparable with placebo; both treatments were well tolerated, with no apparent relation to dose or device. We, therefore, recommend that these
journal.publications.chestnet.org
results are taken into consideration to provide a more balanced overview of the currently available literature for the safety of tiotropium, delivered by the Respimat device. We also note that in the section about tiotropium as an add-on to long-acting b2-agonist (LABA) plus inhaled corticosteroids (ICSs), it is stated: “Although the combination of tiotropium, LABA, and ICS resulted in significant increases in AQLQ [Asthma Quality of Life Questionnaire] and ACQ-7 [Asthma Control Questionnaire 7] total scores...”. An improvement in ACQ-7 score is actually shown by a decrease in total score,5 and so this sentence should be revised to read: “Although the combination of tiotropium, LABA, and ICS resulted in significant increases in AQLQ and decreases in ACQ-7 total scores...”. Similarly, the sentence “Even so, patients receiving tiotropium had a slightly higher probability of experiencing an increase of ⱖ 0.5 points in ACQ-7 score...” in the Discussion should read “Even so, patients receiving tiotropium had a slightly higher probability of experiencing a decrease of ⱖ 0.5 points...”. Ronald Dahl, MD Odense, Denmark AFFILIATIONS: From the University of Southern Denmark; and the University of Aarhus, Aarhus, Denmark. FINANCIAL/NONFINANCIAL DISCLOSURES: The author has reported to CHEST the following conflict of interest: Dr Dahl is a member of the steering and publication committee for the TIOSPIR trial sponsored by Boehringer-Ingelheim and received no honorarium for this. CORRESPONDENCE TO: Ronald Dahl, MD, Allergy Centre, Sdr. Blvd 29, Odense University Hospital, 5000 Odense C, Denmark; e-mail: [email protected] © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.15-0086
References 1. Rodrigo GJ, Castro-Rodríguez JA. What is the role of tiotropium in asthma? A systematic review with meta-analysis. Chest. 2015; 147(2):388-396. 2. Wise RA, Anzueto A, Cotton D, et al; TIOSPIR Investigators. Tiotropium Respimat inhaler and the risk of death in COPD. N Engl J Med. 2013;369(16):1491-1501. 3. Wise RA. Tiotropium and the risk of death in COPD. N Engl J Med. 2014;370(5):481-482. 4. Hohlfeld JM, Sharma A, van Noord JA, et al. Pharmacokinetics and pharmacodynamics of tiotropium solution and tiotropium powder in chronic obstructive pulmonary disease. J Clin Pharmacol. 2014; 54(4):405-414. 5. Juniper EF, Svensson K, Mörk AC, Ståhl E. Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Respir Med. 2005;99(5):553-558.
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