title: Long-term general and cardiovascular safety of tiotropium/olodaterol in patients with moderate to very severe chronic obstructive pulmonary disease.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  ClinicalTrials.gov, Nos.: NCT01431274, NCT01431287.
authors.affiliation: Pulmonary Department, Mainz University Hospital, Mainz, Germany. Electronic address: r.buhl@3-med.klinik.uni-mainz.de.
authors.forename: Roland
authors.initials: R
authors.lastname: Buhl
authors.affiliation: Royal Victoria Hospital, Montreal, Quebec, Canada.
authors.forename: Sheldon
authors.initials: S
authors.lastname: Magder
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bothner
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; Department of Sports Medicine, Medical Clinic V, University of Tübingen, Tübingen, Germany.
authors.forename: Kay
authors.initials: K
authors.lastname: Tetzlaff
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Voß
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
authors.forename: Lazaro
authors.initials: L
authors.lastname: Loaiza
authors.affiliation: 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.
authors.forename: Claus F
authors.initials: CF
authors.lastname: Vogelmeier
authors.affiliation: Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
authors.forename: Lorcan
authors.initials: L
authors.lastname: McGarvey
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D000368:Aged; D048588:Benzoxazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000150:complications* / Q000453:epidemiology; D015897:Comorbidity; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D005500:Follow-Up Studies; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000188:drug therapy* / Q000453:epidemiology; D000069447:Tiotropium Bromide / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D048588:Benzoxazines; D001993:Bronchodilator Agents; D004338:Drug Combinations; D018727:Muscarinic Antagonists; C549647:olodaterol; D000069447:Tiotropium Bromide
keywords: COPD; Long-acting muscarinic antagonist; Long-acting β-agonist; Maintenance bronchodilator; Safety