Safety of tiotropium/olodaterol in chronic obstructive pulmonary disease: pooled analysis of three large, 52-week, randomized clinical trials

Gary T. Ferguson, Roland Buhl, Ulrich Bothner, Alberto de la Hoz, Florian Voß, Antonio R Anzueto, Peter M.A. Calverley

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background: An extensive clinical trial program supports the efficacy and safety of tiotropium/olodaterol in chronic obstructive pulmonary disease (COPD). We examined the safety of tiotropium/olodaterol compared with tiotropium in a large population of patients, focusing on cardiovascular and respiratory events. Methods: Patients (n = 9942) who received once-daily tiotropium/olodaterol 5/5 μg or tiotropium 5 μg (via Respimat®) in TONADO 1 & 2 and DYNAGITO were included. The number of patients and exposure-adjusted rate of events are presented for adverse events (AEs), serious AEs (SAEs), AEs leading to discontinuation, and cardiovascular and respiratory events. Findings: Fewer patients discontinued due to AEs with tiotropium/olodaterol (5.9%) versus tiotropium (7.9%; rate ratio [RR] 0.72; 95% confidence interval [CI] 0.62–0.84). There was no significant difference in the incidence of AEs, SAEs, cardiovascular AEs or central nervous system vascular AEs between treatments. Incidences of major adverse cardiovascular events (MACE) were 2.11 per 100 patient-years with tiotropium/olodaterol and 2.22 with tiotropium (RR 0.95; 95% CI 0.72–1.25), and incidences of fatal MACE (including death with undetermined cause) were 0.91 and 1.00 per 100 patient-years with tiotropium/olodaterol and tiotropium, respectively (RR 0.91; 95% CI 0.60–1.37). Respiratory AEs were generally balanced between treatment groups. Conclusions: These results provide robust evidence that the benefits of tiotropium/olodaterol versus tiotropium are not at the expense of an increased risk of safety events. The combination is a suitable option for patients with COPD, even in the presence of cardiovascular risk factors. Clinical trials registration: clinicaltrials. gov (TONADO 1 and 2: NCT01431274, NCT01431287; DYNAGITO: NCT02296138).

Original languageEnglish (US)
Pages (from-to)67-73
Number of pages7
JournalRespiratory Medicine
Volume143
DOIs
StatePublished - Oct 1 2018

Fingerprint

Chronic Obstructive Pulmonary Disease
Randomized Controlled Trials
Safety
Confidence Intervals
Incidence
Clinical Trials
tiotropium-olodaterol
Blood Vessels
Tiotropium Bromide
Central Nervous System
Therapeutics
Population

Keywords

  • Cardiovascular
  • COPD
  • Long-acting muscarinic antagonist
  • Long-acting β-agonist
  • Safety

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Safety of tiotropium/olodaterol in chronic obstructive pulmonary disease : pooled analysis of three large, 52-week, randomized clinical trials. / Ferguson, Gary T.; Buhl, Roland; Bothner, Ulrich; Hoz, Alberto de la; Voß, Florian; Anzueto, Antonio R; Calverley, Peter M.A.

In: Respiratory Medicine, Vol. 143, 01.10.2018, p. 67-73.

Research output: Contribution to journalArticle

Ferguson, Gary T. ; Buhl, Roland ; Bothner, Ulrich ; Hoz, Alberto de la ; Voß, Florian ; Anzueto, Antonio R ; Calverley, Peter M.A. / Safety of tiotropium/olodaterol in chronic obstructive pulmonary disease : pooled analysis of three large, 52-week, randomized clinical trials. In: Respiratory Medicine. 2018 ; Vol. 143. pp. 67-73.
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abstract = "Background: An extensive clinical trial program supports the efficacy and safety of tiotropium/olodaterol in chronic obstructive pulmonary disease (COPD). We examined the safety of tiotropium/olodaterol compared with tiotropium in a large population of patients, focusing on cardiovascular and respiratory events. Methods: Patients (n = 9942) who received once-daily tiotropium/olodaterol 5/5 μg or tiotropium 5 μg (via Respimat{\circledR}) in TONADO 1 & 2 and DYNAGITO were included. The number of patients and exposure-adjusted rate of events are presented for adverse events (AEs), serious AEs (SAEs), AEs leading to discontinuation, and cardiovascular and respiratory events. Findings: Fewer patients discontinued due to AEs with tiotropium/olodaterol (5.9{\%}) versus tiotropium (7.9{\%}; rate ratio [RR] 0.72; 95{\%} confidence interval [CI] 0.62–0.84). There was no significant difference in the incidence of AEs, SAEs, cardiovascular AEs or central nervous system vascular AEs between treatments. Incidences of major adverse cardiovascular events (MACE) were 2.11 per 100 patient-years with tiotropium/olodaterol and 2.22 with tiotropium (RR 0.95; 95{\%} CI 0.72–1.25), and incidences of fatal MACE (including death with undetermined cause) were 0.91 and 1.00 per 100 patient-years with tiotropium/olodaterol and tiotropium, respectively (RR 0.91; 95{\%} CI 0.60–1.37). Respiratory AEs were generally balanced between treatment groups. Conclusions: These results provide robust evidence that the benefits of tiotropium/olodaterol versus tiotropium are not at the expense of an increased risk of safety events. The combination is a suitable option for patients with COPD, even in the presence of cardiovascular risk factors. Clinical trials registration: clinicaltrials. gov (TONADO 1 and 2: NCT01431274, NCT01431287; DYNAGITO: NCT02296138).",
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T1 - Safety of tiotropium/olodaterol in chronic obstructive pulmonary disease

T2 - pooled analysis of three large, 52-week, randomized clinical trials

AU - Ferguson, Gary T.

AU - Buhl, Roland

AU - Bothner, Ulrich

AU - Hoz, Alberto de la

AU - Voß, Florian

AU - Anzueto, Antonio R

AU - Calverley, Peter M.A.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Background: An extensive clinical trial program supports the efficacy and safety of tiotropium/olodaterol in chronic obstructive pulmonary disease (COPD). We examined the safety of tiotropium/olodaterol compared with tiotropium in a large population of patients, focusing on cardiovascular and respiratory events. Methods: Patients (n = 9942) who received once-daily tiotropium/olodaterol 5/5 μg or tiotropium 5 μg (via Respimat®) in TONADO 1 & 2 and DYNAGITO were included. The number of patients and exposure-adjusted rate of events are presented for adverse events (AEs), serious AEs (SAEs), AEs leading to discontinuation, and cardiovascular and respiratory events. Findings: Fewer patients discontinued due to AEs with tiotropium/olodaterol (5.9%) versus tiotropium (7.9%; rate ratio [RR] 0.72; 95% confidence interval [CI] 0.62–0.84). There was no significant difference in the incidence of AEs, SAEs, cardiovascular AEs or central nervous system vascular AEs between treatments. Incidences of major adverse cardiovascular events (MACE) were 2.11 per 100 patient-years with tiotropium/olodaterol and 2.22 with tiotropium (RR 0.95; 95% CI 0.72–1.25), and incidences of fatal MACE (including death with undetermined cause) were 0.91 and 1.00 per 100 patient-years with tiotropium/olodaterol and tiotropium, respectively (RR 0.91; 95% CI 0.60–1.37). Respiratory AEs were generally balanced between treatment groups. Conclusions: These results provide robust evidence that the benefits of tiotropium/olodaterol versus tiotropium are not at the expense of an increased risk of safety events. The combination is a suitable option for patients with COPD, even in the presence of cardiovascular risk factors. Clinical trials registration: clinicaltrials. gov (TONADO 1 and 2: NCT01431274, NCT01431287; DYNAGITO: NCT02296138).

AB - Background: An extensive clinical trial program supports the efficacy and safety of tiotropium/olodaterol in chronic obstructive pulmonary disease (COPD). We examined the safety of tiotropium/olodaterol compared with tiotropium in a large population of patients, focusing on cardiovascular and respiratory events. Methods: Patients (n = 9942) who received once-daily tiotropium/olodaterol 5/5 μg or tiotropium 5 μg (via Respimat®) in TONADO 1 & 2 and DYNAGITO were included. The number of patients and exposure-adjusted rate of events are presented for adverse events (AEs), serious AEs (SAEs), AEs leading to discontinuation, and cardiovascular and respiratory events. Findings: Fewer patients discontinued due to AEs with tiotropium/olodaterol (5.9%) versus tiotropium (7.9%; rate ratio [RR] 0.72; 95% confidence interval [CI] 0.62–0.84). There was no significant difference in the incidence of AEs, SAEs, cardiovascular AEs or central nervous system vascular AEs between treatments. Incidences of major adverse cardiovascular events (MACE) were 2.11 per 100 patient-years with tiotropium/olodaterol and 2.22 with tiotropium (RR 0.95; 95% CI 0.72–1.25), and incidences of fatal MACE (including death with undetermined cause) were 0.91 and 1.00 per 100 patient-years with tiotropium/olodaterol and tiotropium, respectively (RR 0.91; 95% CI 0.60–1.37). Respiratory AEs were generally balanced between treatment groups. Conclusions: These results provide robust evidence that the benefits of tiotropium/olodaterol versus tiotropium are not at the expense of an increased risk of safety events. The combination is a suitable option for patients with COPD, even in the presence of cardiovascular risk factors. Clinical trials registration: clinicaltrials. gov (TONADO 1 and 2: NCT01431274, NCT01431287; DYNAGITO: NCT02296138).

KW - Cardiovascular

KW - COPD

KW - Long-acting muscarinic antagonist

KW - Long-acting β-agonist

KW - Safety

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