PMID- 32848380 OWN - NLM STAT- MEDLINE DCOM- 20210625 LR - 20240329 IS - 1178-2005 (Electronic) IS - 1176-9106 (Print) IS - 1176-9106 (Linking) VI - 15 DP - 2020 TI - 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. PG - 1945-1953 LID - 10.2147/COPD.S246350 [doi] AB - BACKGROUND: 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 microg therapy versus tiotropium 5 microg or olodaterol 5 microg monotherapy, inhaled once daily (two single inhalations) using the Respimat((R)) 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 microg combination therapy and its monocomponents. Compared with baseline, a small but statistically significant increase in adjusted mean heart rate was observed for tiotropium 5 microg (+1.6 beats per minute [bpm]; P=0.0010), but no difference was observed for olodaterol 5 microg (+0.3 bpm; P=0.2778) or tiotropium/olodaterol 5/5 microg (-0.1 bpm; P=0.4607). MACE and fatal MACE were limited to 1 to 3 patients across treatment groups. CONCLUSION: 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 (ClinicalTrials.gov: NCT01431274); TONADO 2 (ClinicalTrials.gov: NCT01431287). CI - (c) 2020 Andreas et al. FAU - Andreas, Stefan AU - Andreas S AUID- ORCID: 0000-0003-3918-6909 AD - Department of Cardiology and Pneumology, University Medical Centre Gottingen, Gottingen, Germany. AD - LungClinic Immenhausen, Immenhausen, Germany, Member of the German Center for Lung Research (DZL). FAU - Bothner, Ulrich AU - Bothner U AD - Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany. FAU - de la Hoz, Alberto AU - de la Hoz A AD - Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany. FAU - Kloer, Isabel AU - Kloer I AD - Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany. FAU - Trampisch, Matthias AU - Trampisch M AD - Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany. FAU - Alter, Peter AU - Alter P AUID- ORCID: 0000-0002-2115-1743 AD - Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Marburg, Germany, Member of the German Center for Lung Research (DZL). LA - eng SI - ClinicalTrials.gov/NCT01431287 SI - ClinicalTrials.gov/NCT01431274 PT - Journal Article DEP - 20200810 PL - New Zealand TA - Int J Chron Obstruct Pulmon Dis JT - International journal of chronic obstructive pulmonary disease JID - 101273481 RN - 0 (Benzoxazines) RN - 0 (Bronchodilator Agents) RN - VD2YSN1AFD (olodaterol) RN - XX112XZP0J (Tiotropium Bromide) SB - IM MH - Administration, Inhalation MH - Arrhythmias, Cardiac MH - Benzoxazines/adverse effects MH - Bronchodilator Agents/adverse effects MH - Double-Blind Method MH - *Electrocardiography, Ambulatory MH - Forced Expiratory Volume MH - Heart Rate MH - Humans MH - *Pulmonary Disease, Chronic Obstructive/diagnosis/drug therapy MH - Tiotropium Bromide/adverse effects MH - Treatment Outcome PMC - PMC7429402 OTO - NOTNLM OT - Holter ECG OT - arrhythmia OT - heart rate OT - olodaterol OT - safety OT - tiotropium COIS- SA reports personal fees from Boehringer Ingelheim and GlaxoSmithKline, and payments for presenting from Boehringer Ingelheim, AstraZeneca, Berlin Chemie, Chiesi and Novartis, outside the submitted work. UB, AdlH, IK and MT are employees of Boehringer Ingelheim. PA reports grants from the German Federal Ministry of Education and Research (BMBF) Competence Network Asthma and COPD (ASCONET), AstraZeneca, GlaxoSmithKline, Grifols Deutschland, MSD Sharp & Dohme, Pfizer, Takeda, Boehringer Ingelheim and Novartis Deutschland, grants and non-financial support from Bayer Schering Pharma AG and Chiesi, and grants, personal fees and non-financial support from Novartis Deutschland, outside the submitted work. The authors report no other conflicts of interest in this work. EDAT- 2020/08/28 06:00 MHDA- 2021/06/29 06:00 PMCR- 2020/08/10 CRDT- 2020/08/28 06:00 PHST- 2020/01/17 00:00 [received] PHST- 2020/04/20 00:00 [accepted] PHST- 2020/08/28 06:00 [entrez] PHST- 2020/08/28 06:00 [pubmed] PHST- 2021/06/29 06:00 [medline] PHST- 2020/08/10 00:00 [pmc-release] AID - 246350 [pii] AID - 10.2147/COPD.S246350 [doi] PST - epublish SO - Int J Chron Obstruct Pulmon Dis. 2020 Aug 10;15:1945-1953. doi: 10.2147/COPD.S246350. eCollection 2020.