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      No Influence on Cardiac Arrhythmia or Heart Rate from Long-Term Treatment with Tiotropium/Olodaterol versus Monocomponents by Holter ECG Analysis in Patients with Moderate-to-Very-Severe COPD

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          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.


          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.


          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 baseline, a small but statistically significant increase in adjusted mean heart rate was observed for tiotropium 5 µg (+1.6 beats per minute [bpm]; P=0.0010), but no difference was observed for olodaterol 5 µg (+0.3 bpm; P=0.2778) or tiotropium/olodaterol 5/5 µg (–0.1 bpm; P=0.4607). MACE and fatal MACE were limited to 1 to 3 patients across treatment groups.


          Compared with the compounds given as monotherapy, treatment with tiotropium/olodaterol fixed-dose combination therapy is not associated with medically relevant or statistically significant effects on arrhythmia as assessed by Holter ECG. Based on these findings, there is no evidence to assume a clinically relevant impact on cardiac function from dual tiotropium/olodaterol treatment.

          Trial Registration

          TONADO 1 ( NCT01431274); TONADO 2 ( NCT01431287).

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          Most cited references 35

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            Tiotropium Respimat inhaler and the risk of death in COPD.

            Tiotropium delivered at a dose of 5 μg with the Respimat inhaler showed efficacy similar to that of 18 μg of tiotropium delivered with the HandiHaler inhalation device in placebo-controlled trials involving patients with chronic obstructive pulmonary disease (COPD). Although tiotropium HandiHaler was associated with reduced mortality, as compared with placebo, more deaths were reported with tiotropium Respimat than with placebo.
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              Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis.

              Inhaled anticholinergics (ipratropium bromide or tiotropium bromide) are widely used in patients with chronic obstructive pulmonary disease (COPD) but their effect on the risk of cardiovascular outcomes is unknown. To ascertain the cardiovascular risks of inhaled anticholinergics, including cardiovascular death, myocardial infarction (MI), and stroke. Systematic searches were conducted on March 19, 2008, of relevant articles in MEDLINE, the Cochrane Database of systematic reviews, regulatory authority Web sites in the United States and the United Kingdom, and manufacturers' trial registries with no date restrictions. Randomized controlled trials of any inhaled anticholinergic for treatment of COPD that had at least 30 days of treatment and reported on cardiovascular events. The primary outcome was a composite of cardiovascular death, MI, or stroke. The secondary outcome was all-cause mortality. Relative risks (RRs) were estimated using fixed-effects models and statistical heterogeneity was estimated with the I(2) statistic. After a detailed screening of 103 articles, 17 trials enrolling 13,645 [corrected] patients were analyzed. Follow-up duration ranged from 6 weeks to 5 years. Cardiovascular death, MI, or stroke occurred in 134 of 6984 [corrected] patients (1.9%) [corrected] receiving inhaled anticholinergics and 83 of 6661 [corrected] patients (1.2%) receiving control therapy (RR, 1.60 [corrected] [95% confidence interval {CI}, 1.22-2.10]; [corrected] P 6 months) confirmed the significantly increased risk of cardiovascular death, MI, or stroke (2.9% of patients treated with anticholinergics vs 1.8% of the control patients; RR, 1.73 [95% CI, 1.27-2.35]; [corrected] P < .001, I(2) = 0%). Inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD.

                Author and article information

                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of Chronic Obstructive Pulmonary Disease
                10 August 2020
                : 15
                : 1945-1953
                [1 ]Department of Cardiology and Pneumology, University Medical Centre Göttingen , Göttingen, Germany
                [2 ]LungClinic Immenhausen, Immenhausen, Germany , Member of the German Center for Lung Research (DZL)
                [3 ]Boehringer Ingelheim International GmbH , Ingelheim am Rhein, Germany
                [4 ]Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Marburg, Germany , Member of the German Center for Lung Research (DZL)
                Author notes
                Correspondence: Stefan Andreas Department of Cardiology and Pneumology , Robert-Koch-Str. 40., Göttingen, GermanyTel +49 05673 501 1112Fax +49 05673 501 1101 Email
                © 2020 Andreas et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (

                Page count
                Figures: 2, Tables: 2, References: 48, Pages: 9
                This work was supported by Boehringer Ingelheim International GmbH. Medical writing assistance, in the form of the preparation and revision of the manuscript, was supported financially by Boehringer Ingelheim, and provided by Ishmam Nawar of MediTech Media (London, UK) under the authors’ conceptual direction and based on feedback from the authors.
                Original Research

                Respiratory medicine

                safety, tiotropium, arrhythmia, heart rate, holter ecg, olodaterol


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