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 (NCT01431274; NCT01431287). 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.

Keywords: COPD; comorbidities; olodaterol; renal impairment; safety; tiotropium.

Figure 1

Baseline comorbidity by renal impairment category.

Figure 2

Incidence of adverse events and serious adverse events by renal impairment category. Notes: (A) Patients with any AE. (B) Patients with SAEs. (C) Fatal SAEs. Abbreviations: AE, adverse event; Olo, olodaterol; SAE, serious AE; Tio, tiotropium.

Figure 3

Discontinuation of study medication by renal impairment category. Notes: (A) Prematurely discontinued from trial medication. (B) Discontinued due to adverse event. Abbreviations: Olo, olodaterol; Tio, tiotropium.

Figure 4

Exposure-adjusted incidence rate ratios and 95% CI (forest plots) of clinically relevant adverse event groups associated with renal impairment comparing tiotropium/olodaterol with the monocomponents. Note: ^aTreatment exposure time adjusted. Abbreviations: MACE, major adverse cardiovascular event; Olo, olodaterol; Tio, tiotropium.