Long-term general and cardiovascular safety of tiotropium/olodaterol in patients with moderate to very severe chronic obstructive pulmonary disease

Roland Buhl; Sheldon Magder; Ulrich Bothner; Kay Tetzlaff; Florian Voß; Lazaro Loaiza; Claus F Vogelmeier; Lorcan McGarvey

doi:10.1016/j.rmed.2016.11.011

Long-term general and cardiovascular safety of tiotropium/olodaterol in patients with moderate to very severe chronic obstructive pulmonary disease

Roland Buhl, Sheldon Magder, Ulrich Bothner, Kay Tetzlaff, Florian Voß, Lazaro Loaiza, Claus F Vogelmeier, Lorcan McGarvey

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Abstract

BACKGROUND: Long-term safety, particularly cardiovascular safety, is of special interest in maintenance treatment of chronic obstructive pulmonary disease (COPD) with long-acting β2-agonists and long-acting muscarinic antagonists, given potential cardiovascular effects.

METHODS: Two 52-week Phase III trials (TONADO(®)) investigated tiotropium/olodaterol (5/5 and 2.5/5 μg) versus tiotropium 2.5, 5 μg and olodaterol 5 μg. In a pre-specified safety analysis, investigator-reported treatment-emergent adverse events (AEs), electrocardiogram and laboratory data were pooled. All serious AE (SAE) reports were reviewed by an independent Adjudication Committee, which assessed whether deaths, hospitalisations or intubations were respiratory, cardiovascular, cerebrovascular or other disease related. Subgroup analyses investigated cardiovascular safety including major cardiac events in patients with cardiovascular co-morbidities.

RESULTS: This analysis comprised 3100 patients with moderate to very severe COPD, treated for ≤1 year, including 784 patients with cardiovascular co-morbidities. AEs were balanced across treatments in the total population as well as in patient subgroups with pre-existing cardiovascular co-morbidities. The incidence and nature of events were consistent with the disease under study and a 1-year trial duration. 494/3100 patients contributed to an adjudicated analysis of SAEs: 260 had respiratory-related, 53 had cardiovascular-related and 16 had cerebrovascular-related SAEs. Incidences of these SAEs were comparable between treatments. There was no evidence of any increased risk for the combination compared to the monotherapy groups.

CONCLUSIONS: These data provide confidence for clinicians that tiotropium/olodaterol 5/5 μg can be safely administered once-daily to patients with moderate to very severe COPD long-term, including those with significant cardiovascular co-morbidity.

Original language	English
Pages (from-to)	58-66
Number of pages	9
Journal	Respiratory Medicine
Volume	122
Early online date	14 Nov 2016
DOIs	https://doi.org/10.1016/j.rmed.2016.11.011
Publication status	Published - Jan 2017

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10.1016/j.rmed.2016.11.011Licence: CC BY-NC-ND

Long-term general and cardiovascular safety of tiotropium/olodaterol in patients with moderate to very severe chronic obstructive pulmonary disease
Copyright 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/),which permits distribution and reproduction for non-commercial purposes, provided the author and source are cited.
Final published version, 447 KBLicence: CC BY-NC-ND

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@article{f3f89a5183e94574a79f2c5d41fd3590,

title = "Long-term general and cardiovascular safety of tiotropium/olodaterol in patients with moderate to very severe chronic obstructive pulmonary disease",

abstract = "BACKGROUND: Long-term safety, particularly cardiovascular safety, is of special interest in maintenance treatment of chronic obstructive pulmonary disease (COPD) with long-acting β2-agonists and long-acting muscarinic antagonists, given potential cardiovascular effects.METHODS: Two 52-week Phase III trials (TONADO({\textregistered})) investigated tiotropium/olodaterol (5/5 and 2.5/5 μg) versus tiotropium 2.5, 5 μg and olodaterol 5 μg. In a pre-specified safety analysis, investigator-reported treatment-emergent adverse events (AEs), electrocardiogram and laboratory data were pooled. All serious AE (SAE) reports were reviewed by an independent Adjudication Committee, which assessed whether deaths, hospitalisations or intubations were respiratory, cardiovascular, cerebrovascular or other disease related. Subgroup analyses investigated cardiovascular safety including major cardiac events in patients with cardiovascular co-morbidities.RESULTS: This analysis comprised 3100 patients with moderate to very severe COPD, treated for ≤1 year, including 784 patients with cardiovascular co-morbidities. AEs were balanced across treatments in the total population as well as in patient subgroups with pre-existing cardiovascular co-morbidities. The incidence and nature of events were consistent with the disease under study and a 1-year trial duration. 494/3100 patients contributed to an adjudicated analysis of SAEs: 260 had respiratory-related, 53 had cardiovascular-related and 16 had cerebrovascular-related SAEs. Incidences of these SAEs were comparable between treatments. There was no evidence of any increased risk for the combination compared to the monotherapy groups.CONCLUSIONS: These data provide confidence for clinicians that tiotropium/olodaterol 5/5 μg can be safely administered once-daily to patients with moderate to very severe COPD long-term, including those with significant cardiovascular co-morbidity.",

author = "Roland Buhl and Sheldon Magder and Ulrich Bothner and Kay Tetzlaff and Florian Vo{\ss} and Lazaro Loaiza and Vogelmeier, {Claus F} and Lorcan McGarvey",

year = "2017",

month = jan,

doi = "10.1016/j.rmed.2016.11.011",

language = "English",

volume = "122",

pages = "58--66",

journal = "Respiratory Medicine",

issn = "0954-6111",

publisher = "W.B. Saunders Ltd",

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T1 - Long-term general and cardiovascular safety of tiotropium/olodaterol in patients with moderate to very severe chronic obstructive pulmonary disease

AU - Buhl, Roland

AU - Magder, Sheldon

AU - Bothner, Ulrich

AU - Tetzlaff, Kay

AU - Voß, Florian

AU - Loaiza, Lazaro

AU - Vogelmeier, Claus F

AU - McGarvey, Lorcan

PY - 2017/1

Y1 - 2017/1

N2 - BACKGROUND: Long-term safety, particularly cardiovascular safety, is of special interest in maintenance treatment of chronic obstructive pulmonary disease (COPD) with long-acting β2-agonists and long-acting muscarinic antagonists, given potential cardiovascular effects.METHODS: Two 52-week Phase III trials (TONADO(®)) investigated tiotropium/olodaterol (5/5 and 2.5/5 μg) versus tiotropium 2.5, 5 μg and olodaterol 5 μg. In a pre-specified safety analysis, investigator-reported treatment-emergent adverse events (AEs), electrocardiogram and laboratory data were pooled. All serious AE (SAE) reports were reviewed by an independent Adjudication Committee, which assessed whether deaths, hospitalisations or intubations were respiratory, cardiovascular, cerebrovascular or other disease related. Subgroup analyses investigated cardiovascular safety including major cardiac events in patients with cardiovascular co-morbidities.RESULTS: This analysis comprised 3100 patients with moderate to very severe COPD, treated for ≤1 year, including 784 patients with cardiovascular co-morbidities. AEs were balanced across treatments in the total population as well as in patient subgroups with pre-existing cardiovascular co-morbidities. The incidence and nature of events were consistent with the disease under study and a 1-year trial duration. 494/3100 patients contributed to an adjudicated analysis of SAEs: 260 had respiratory-related, 53 had cardiovascular-related and 16 had cerebrovascular-related SAEs. Incidences of these SAEs were comparable between treatments. There was no evidence of any increased risk for the combination compared to the monotherapy groups.CONCLUSIONS: These data provide confidence for clinicians that tiotropium/olodaterol 5/5 μg can be safely administered once-daily to patients with moderate to very severe COPD long-term, including those with significant cardiovascular co-morbidity.

AB - BACKGROUND: Long-term safety, particularly cardiovascular safety, is of special interest in maintenance treatment of chronic obstructive pulmonary disease (COPD) with long-acting β2-agonists and long-acting muscarinic antagonists, given potential cardiovascular effects.METHODS: Two 52-week Phase III trials (TONADO(®)) investigated tiotropium/olodaterol (5/5 and 2.5/5 μg) versus tiotropium 2.5, 5 μg and olodaterol 5 μg. In a pre-specified safety analysis, investigator-reported treatment-emergent adverse events (AEs), electrocardiogram and laboratory data were pooled. All serious AE (SAE) reports were reviewed by an independent Adjudication Committee, which assessed whether deaths, hospitalisations or intubations were respiratory, cardiovascular, cerebrovascular or other disease related. Subgroup analyses investigated cardiovascular safety including major cardiac events in patients with cardiovascular co-morbidities.RESULTS: This analysis comprised 3100 patients with moderate to very severe COPD, treated for ≤1 year, including 784 patients with cardiovascular co-morbidities. AEs were balanced across treatments in the total population as well as in patient subgroups with pre-existing cardiovascular co-morbidities. The incidence and nature of events were consistent with the disease under study and a 1-year trial duration. 494/3100 patients contributed to an adjudicated analysis of SAEs: 260 had respiratory-related, 53 had cardiovascular-related and 16 had cerebrovascular-related SAEs. Incidences of these SAEs were comparable between treatments. There was no evidence of any increased risk for the combination compared to the monotherapy groups.CONCLUSIONS: These data provide confidence for clinicians that tiotropium/olodaterol 5/5 μg can be safely administered once-daily to patients with moderate to very severe COPD long-term, including those with significant cardiovascular co-morbidity.

U2 - 10.1016/j.rmed.2016.11.011

DO - 10.1016/j.rmed.2016.11.011

M3 - Article

C2 - 27993292

SN - 0954-6111

VL - 122

SP - 58

EP - 66

JO - Respiratory Medicine

JF - Respiratory Medicine

ER -

Long-term general and cardiovascular safety of tiotropium/olodaterol in patients with moderate to very severe chronic obstructive pulmonary disease

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