PMID- 27993292
OWN - NLM
STAT- MEDLINE
DCOM- 20171024
LR  - 20220408
IS  - 1532-3064 (Electronic)
IS  - 0954-6111 (Linking)
VI  - 122
DP  - 2017 Jan
TI  - Long-term general and cardiovascular safety of tiotropium/olodaterol in patients 
      with moderate to very severe chronic obstructive pulmonary disease.
PG  - 58-66
LID - S0954-6111(16)30299-2 [pii]
LID - 10.1016/j.rmed.2016.11.011 [doi]
AB  - BACKGROUND: Long-term safety, particularly cardiovascular safety, is of special 
      interest in maintenance treatment of chronic obstructive pulmonary disease (COPD) 
      with long-acting beta(2)-agonists and long-acting muscarinic antagonists, given 
      potential cardiovascular effects. METHODS: Two 52-week Phase III trials 
      (TONADO((R))) investigated tiotropium/olodaterol (5/5 and 2.5/5 mug) versus 
      tiotropium 2.5, 5 mug and olodaterol 5 mug. 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 mug can be safely administered 
      once-daily to patients with moderate to very severe COPD long-term, including 
      those with significant cardiovascular co-morbidity. TRIAL REGISTRY: 
      ClinicalTrials.gov, Nos.: NCT01431274, NCT01431287.
CI  - Copyright (c) 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.
FAU - Buhl, Roland
AU  - Buhl R
AD  - Pulmonary Department, Mainz University Hospital, Mainz, Germany. Electronic 
      address: r.buhl@3-med.klinik.uni-mainz.de.
FAU - Magder, Sheldon
AU  - Magder S
AD  - Royal Victoria Hospital, Montreal, Quebec, Canada.
FAU - Bothner, Ulrich
AU  - Bothner U
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
FAU - Tetzlaff, Kay
AU  - Tetzlaff K
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; Department of 
      Sports Medicine, Medical Clinic V, University of Tubingen, Tubingen, Germany.
FAU - Voss, Florian
AU  - Voss F
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
FAU - Loaiza, Lazaro
AU  - Loaiza L
AD  - Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
FAU - Vogelmeier, Claus F
AU  - Vogelmeier CF
AD  - Department of Medicine, Pulmonary and Critical Care Medicine, University Medical 
      Center Giessen and Marburg, Philipps-University Marburg, Member of the German 
      Center for Lung Research (DZL), Marburg, Germany.
FAU - McGarvey, Lorcan
AU  - McGarvey L
AD  - Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical 
      Sciences, Queen's University Belfast, Belfast, UK.
LA  - eng
SI  - ClinicalTrials.gov/NCT01431274
SI  - ClinicalTrials.gov/NCT01431287
PT  - Clinical Trial, Phase III
PT  - Comparative Study
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20161114
PL  - England
TA  - Respir Med
JT  - Respiratory medicine
JID - 8908438
RN  - 0 (Adrenergic beta-2 Receptor Agonists)
RN  - 0 (Benzoxazines)
RN  - 0 (Bronchodilator Agents)
RN  - 0 (Drug Combinations)
RN  - 0 (Muscarinic Antagonists)
RN  - VD2YSN1AFD (olodaterol)
RN  - XX112XZP0J (Tiotropium Bromide)
SB  - IM
MH  - Administration, Inhalation
MH  - Adrenergic beta-2 Receptor Agonists/administration & dosage/*adverse 
      effects/therapeutic use
MH  - Aged
MH  - Benzoxazines/administration & dosage/*adverse effects/therapeutic use
MH  - Bronchodilator Agents/administration & dosage/*adverse effects/therapeutic use
MH  - Cardiovascular Diseases/*complications/epidemiology
MH  - Comorbidity
MH  - Double-Blind Method
MH  - Drug Combinations
MH  - Female
MH  - Follow-Up Studies
MH  - Forced Expiratory Volume/drug effects
MH  - Humans
MH  - Incidence
MH  - Male
MH  - Middle Aged
MH  - Muscarinic Antagonists/administration & dosage/*adverse effects/therapeutic use
MH  - Pulmonary Disease, Chronic Obstructive/complications/*drug therapy/epidemiology
MH  - Tiotropium Bromide/administration & dosage/*adverse effects/therapeutic use
OTO - NOTNLM
OT  - COPD
OT  - Long-acting muscarinic antagonist
OT  - Long-acting beta-agonist
OT  - Maintenance bronchodilator
OT  - Safety
EDAT- 2016/12/21 06:00
MHDA- 2017/10/25 06:00
CRDT- 2016/12/21 06:00
PHST- 2016/07/21 00:00 [received]
PHST- 2016/10/31 00:00 [revised]
PHST- 2016/11/13 00:00 [accepted]
PHST- 2016/12/21 06:00 [entrez]
PHST- 2016/12/21 06:00 [pubmed]
PHST- 2017/10/25 06:00 [medline]
AID - S0954-6111(16)30299-2 [pii]
AID - 10.1016/j.rmed.2016.11.011 [doi]
PST - ppublish
SO  - Respir Med. 2017 Jan;122:58-66. doi: 10.1016/j.rmed.2016.11.011. Epub 2016 Nov 
      14.