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Marc Miravitlles,1 Katia Verhamme,2 Peter MA Calverley,3 Michael Dreher,4 Valentina Bayer,5 Asparuh Gardev,6 Alberto de la Hoz,6 Jadwiga Wedzicha,7 David Price8,9 1Pneumology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Barcelona Hospital Campus, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain; 2Department of Medical Informatics, Erasmus MC, Rotterdam, the Netherlands; 3Clinical Science Centre, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK; 4Department of Pneumology and Intensive Care Medicine, University Hospital Aachen, Aachen, Germany; 5Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 6Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; 7Head Respiratory Division, National Heart and Lung Institute, Imperial College London, London, UK; 8Observational and Pragmatic Research Institute, Singapore; 9Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UKCorrespondence: Marc Miravitlles, Pneumology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Barcelona Hospital Campus, CIBER de Enfermedades Respiratorias (CIBERES), P° Vall d’Hebron 119-129, Barcelona, 08035, Spain, Email marcm@separ.esBackground: Recent studies report a lower mortality rate during treatment with long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA)/inhaled corticosteroid (ICS) versus LAMA/LABA in patients with symptomatic chronic obstructive pulmonary disease (COPD) and a history of exacerbations.Objective: We compared time to all-cause mortality with LAMA/LABA versus LAMA/LABA/ICS in patients with mild-to-very-severe COPD and a predominantly low exacerbation risk.Methods: Data were pooled from six randomized controlled trials (TONADO 1/2, DYNAGITO, WI

Donald A Mahler,1,2 Andrea Ludwig-Sengpiel,3 Gary T Ferguson,4 Alberto de la Hoz,5 John Ritz,6 Asif Shaikh,7 Henrik Watz8 1Geisel School of Medicine at Dartmouth, Hanover, NH, USA; 2Section of Pulmonary Medicine, Valley Regional Hospital, Claremont, NH, USA; 3KLB Gesundheitsforschung Lübeck GmbH, Lübeck, Germany; 4Department of Medicine, Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 5Cardio-Metabolism and Respiratory, Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; 6Biostatistics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 7Clinical Development & Medical Affairs, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 8Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, GermanyCorrespondence: Donald A MahlerMedicine, Geisel School of Medicine at Dartmouth, Hanover, NH, USATel +1 603 542-6777Fax +1 603 543-5613Email mahlerdonald@gmail.comBackground: Inhaled bronchodilator therapy is currently the mainstay of treatment for patients with chronic obstructive pulmonary disease (COPD). Some inhalers require patients to achieve certain inhalation efforts either to activate the device or to deliver medication to the site of action. For dry powder inhalers, low peak inspiratory flow (PIF) can result in poor medication delivery but the clinical significance of this is not well understood.Methods: TRONARTO was a 4-week, randomized, double-blind, placebo-controlled, multicenter, parallel-group study which stratified patients with moderate-to-severe COPD according to their PIF against medium-low resistance at screening. Patients were randomized to receive tiotropium/olodaterol (5 μg/5 μg) or matched placebo delivered via the Respimat® Soft Mist™ inhaler (SMI). After 4 weeks of treatment, we assessed change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve

Stefan Andreas,1,2 Ulrich Bothner,3 Alberto de la Hoz,3 Isabel Kloer,3 Matthias Trampisch,3 Peter Alter4 1Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; 2LungClinic Immenhausen, Immenhausen, Germany, Member of the German Center for Lung Research (DZL); 3Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; 4Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Marburg, GermanyCorrespondence: Stefan Andreas Department of Cardiology and PneumologyUniversity Medical Center Göttingen, Robert-Koch-Str. 40, Göttingen, GermanyTel +49 05673 501 1112Fax +49 05673-501-1101Email stefan.andreas@med.uni-goettingen.deBackground: Patients with chronic obstructive pulmonary disease (COPD) are at risk of developing cardiac arrhythmias and elevated heart rate. A theoretical mechanistic association based on the interaction of long-acting β2-agonists (LABAs) with adrenoreceptors in the heart and vasculature is assumed as a potential class-related risk. Therefore, we performed a pooled analysis of Holter electrocardiogram (ECG) data from four 48-week, randomized, double-blind, placebo-controlled, parallel-group, Phase III clinical trials evaluating olodaterol (5 μg or 10 μg) or formoterol (12 μg) versus placebo.Methods: We analyzed Holter ECG data from a representative subset of 775 patients with Global Initiative for Chronic Obstructive Lung Disease stage 2– 4 COPD from four studies (1222.11– 14) assessing olodaterol (5 μg and 10 μg) and formoterol (12 μg) versus placebo.Results: No statistically significant (P> 0.3) or clinically relevant differences in the shift from baseline of premature supraventricular or ventricular beats were observed among the active treatment and the placebo groups. Minor and transient

Stefan Andreas,1,2 Ulrich Bothner,3 Alberto de la Hoz,3 Isabel Kloer,3 Matthias Trampisch,3 Peter Alter4 1Department of Cardiology and Pneumology, University Medical Centre Göttingen, Göttingen, Germany; 2LungClinic Immenhausen, Immenhausen, Germany, Member of the German Center for Lung Research (DZL); 3Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; 4Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Marburg, Germany, Member of the German Center for Lung Research (DZL)Correspondence: Stefan AndreasDepartment of Cardiology and Pneumology, Robert-Koch-Str. 40., Göttingen, GermanyTel +49 05673 501 1112Fax +49 05673 501 1101Email stefan.andreas@med.uni-goettingen.deBackground: Patients with chronic obstructive pulmonary disease (COPD) and cardiovascular comorbidities may have an increased risk of medication-related cardiac arrhythmias. We therefore performed an analysis of Holter electrocardiogram (ECG) data from two large, long-term, controlled clinical COPD trials to investigate whether tiotropium/olodaterol increased the risk of cardiac arrhythmia and mean heart rate.Methods: We analyzed Holter ECG data from a representative subset of patients (N=506) from the two pooled replicate studies (TONADO 1 and 2) assessing tiotropium/olodaterol 5/5 μg therapy versus tiotropium 5 μg or olodaterol 5 μg monotherapy, inhaled once daily (two single inhalations) using the Respimat® Soft Mist™ inhaler device. Additionally, major adverse cardiac events (MACE) with tiotropium/olodaterol were assessed versus the respective monotherapies.Results: After 12 weeks of treatment, there was no difference in the number of patients who had an increase or decrease from baseline in 24-hour supraventricular premature beats or ventricular premature beats between tiotropium/olodaterol 5/5 μg combination therapy and its monocomponents. Compared with baselin

Stefan Andreas,1,2 Lorcan McGarvey,3 Ulrich Bothner,4 Matthias Trampisch,4 Alberto de la Hoz,4 Matjaz Fležar,5 Roland Buhl,6 Peter Alter7 1Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; 2LungClinic Immenhausen, Immenhausen, Germany, Member of the German Center for Lung Research (DZL); 3Queen’s University Belfast, Belfast, UK; 4Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; 5Klinika Golnik, Golnik, Slovenia; 6Pulmonary Department, Johannes Gutenberg University Mainz, Mainz, Germany; 7Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR); Member of the German Center for Lung Research (DZL), Marburg, GermanyCorrespondence: Stefan AndreasDepartment of Cardiology and Pneumology, University Medical Center Göttingen, Robert-Koch-Str. 40, Göttingen, GermanyTel +49 05673 501 1112Fax +49 05673-501-1101Email stefan.andreas@med.uni-goettingen.deIntroduction: Long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are established maintenance bronchodilator treatments for chronic obstructive pulmonary disease (COPD) with the potential to increase heart rate (HR) and impact blood pressure (BP). While previous studies indicate that HR and BP are not negatively influenced by tiotropium or olodaterol monotherapy, the effect of tiotropium/olodaterol has not been evaluated. We report a post hoc analysis of the effect of dual bronchodilation with tiotropium/olodaterol versus monocomponents on HR and BP in patients with moderate-to-very-severe COPD included in the large TONADO® study.Methods: The TONADO® trials (1237.5 [NCT01431274] and 1237.6 [NCT01431287]) were two replicate, randomized, double-blind, parallel-group, 52-week, Phase III trials that compared tiotropium/olodaterol (5/5 μg and 2.5/5 μg) with tiotropium (5 μg and 2.5 μg) and olodaterol

Ichinose M, Nishimura M, Akimoto M, et al. Int J Chron Obstruct Pulmon Dis. 2018;13:2147–2156.On page 2152, Figure 3 has been corrected. Read the original article&nbsp

Masakazu Ichinose,1 Masaharu Nishimura,2 Manabu Akimoto,3 Yasuhiro Kurotori,3 Yihua Zhao,4 Alberto de la Hoz,5 Michiaki Mishima6 1Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 2Department of Pulmonary Medicine, Faculty School of Medicine, Hokkaido University, Sapporo, Japan; 3Nippon Boehringer Ingelheim Co. Ltd, Tokyo, Japan; 4Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 5Boehringer Ingelheim International GmbH, Ingelheim, Germany; 6Osaka Saiseikai Noe Hospital, Osaka, Japan Background: The DYNAGITO study was a Phase IIIb, randomized, double-blind, multicenter, active-controlled, parallel-group, 52-week study designed to determine the efficacy and safety of tiotropium and olodaterol combination therapy (TIO+OLO 5/5 μg) versus tiotropium monotherapy (TIO 5 μg) for reducing moderate-to-severe exacerbations of COPD. This is a prespecified analysis of the DYNAGITO data in Japanese patients. Patients and methods: Enrolled patients had a diagnosis of COPD with at least one moderate-to-severe exacerbation in the previous 12 months. Of the total 7,880 treated patients in the DYNAGITO study, 461 (TIO+OLO 5/5 μg: n=226, TIO 5 μg: n=235) were Japanese. The primary endpoint was the annualized rate of moderate-to-severe COPD exacerbations. The key secondary endpoint was the time to first moderate-to-severe COPD exacerbation, and other secondary endpoints included the annualized rate of exacerbations leading to hospitalization, time to first COPD exacerbation leading to hospitalization, and all-cause mortality. Safety data were analyzed descriptively. Results: Combination therapy with TIO+OLO resulted in a 29% lower rate of moderate-to-severe COPD exacerbations relative to TIO monotherapy (rate ratio 0.71; 99% CI: 0.46, 1.10; p=0.0434). The risk of a first moderate-to-severe COPD exacerbation was 19% lower with TIO+OLO combination therapy than with TIO monotherapy (HR 0.81; 99% CI