Long-term safety of tiotropium/olodaterol Respimat^® in patients with moderate-to-very severe COPD and renal impairment in the TONADO^® studies

Abstract

Introduction

The safety, lung function efficacy, and symptomatic benefits of combined tiotropium and olodaterol in patients with COPD were established in the 1-year TONADO^® studies (NCT1431274; NCT1431287). As tiotropium is predominantly excreted by the kidneys, the long-term safety profile of tiotropium/olodaterol was investigated in patients with renal impairment in a prespecified safety analysis of the TONADO studies.

Methods

These were 2 replicate, randomized, double-blind, parallel-group, 52-week Phase III studies that assessed tiotropium/olodaterol compared with tiotropium or olodaterol alone (all via Respimat^®) in patients with moderate-to-very severe COPD. In this analysis, renal impairment was defined as mild (creatinine clearance [CLcr] 60–89 mL/min), moderate (CLcr 30–59 mL/min) or severe (CLcr 15–29 mL/min). Adverse events (AEs) were pooled from both studies.

Results

Of 3,041 patients included in this analysis, 1,333 (43.8%) had mild, 404 (13.3%) had moderate, and 5 (0.2%) had severe renal impairment; these were distributed equally between treatment groups. Almost one-quarter of all treated patients (23.4%) had a history of cardiac disorder, 45.6% had hypertension, and 13.3% had glucose metabolism disorders, including diabetes. AEs with olodaterol, tiotropium, and tiotropium/olodaterol occurred in 75.1%, 70.8%, and 72.0% of patients with no renal impairment, 75.7%, 74.0%, and 73.3% with mild renal impairment, and 84.3%, 79.5%, and 79.7% with moderate renal impairment, respectively. There was no notable effect of renal impairment on the proportion of patients with an AE, and no differences were observed between tiotropium/olodaterol versus the monocomponents. There was no difference in the incidence of major adverse cardiac events, renal and urinary tract AEs, or potential anticholinergic effects with increasing severity of renal impairment.

Conclusion

Over half the patients enrolled in the TONADO studies had renal impairment, and there was a high level of pre-existing cardiovascular comorbidity. The safety and tolerability of tiotropium/olodaterol is comparable to the monocomponents, irrespective of the level of renal impairment.

Video abstract

Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use:

http://youtu.be/fBn38LINnwE

Keywords:

• COPD
• renal impairment
• comorbidities
• tiotropium
• olodaterol
• safety

Supplementary material

Figure S1 Exposure-adjusted incidence rate ratios and 95% confidence intervals (forest plots) of clinically relevant adverse event groups associated with renal impairment comparing tio/olo with the monocomponents.

Notes: (A) Cardiovascular events. (B) Respiratory events. (C) Urinary tract events. (D) Potential anticholinergic events. ^aTreatment exposure time adjusted.

Abbreviations: MACE, major adverse cardiovascular event; Olo, olodaterol; Tio, tiotropium.

Acknowledgments

Medical writing assistance was provided by Lisa Jolly of MediTech Media, which was contracted and compensated by Boehringer Ingelheim International.

Disclosure

RB reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Roche, and Teva, as well as grants to Mainz University from Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Roche, outside the submitted work. ED’s clinical department has received financial support from Boehringer Ingelheim and Novartis to perform clinical studies; he has participated in advisory boards for Boehringer Ingelheim, Chiesi, Cipla, Novartis, and AstraZeneca, for which a fee was given (not related to this work); he has received travel grants from Boehringer Ingelheim, GlaxoSmithKline, and AstraZeneca to attend international congresses and has received speaker’s fees from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, and Novartis. UB, IMK, and MT are employees of Boehringer Ingelheim International. CLF has received financial support from Boehringer Ingelheim to perform clinical studies. The authors report no other conflicts of interest in this work.

Author contributions

The authors meet the criteria for authorship as recommended by the International Committee of Medical Journal Editors. All authors contributed toward data analysis and interpretation, drafting and revising the paper, and agree to be accountable for all aspects of the work. The authors received no compensation related to the development of the manuscript.