A Post Hoc Holter ECG Analysis of Olodaterol and Formoterol in Moderate-to-Very-Severe COPD

Stefan Andreas, Ulrich Bothner, Alberto de la Hoz, Isabel Kloer, Matthias Trampisch, Peter Alter, Stefan Andreas, Ulrich Bothner, Alberto de la Hoz, Isabel Kloer, Matthias Trampisch, Peter Alter

Abstract

Background: 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 differences were observed in the adjusted mean heart rate from baseline during treatment in all groups. There was a numerically small but statistically significant increase for formoterol at Week 24, olodaterol 5 μg at Weeks 12 and 40, and olodaterol 10 μg at Week 40 (all less than 3.0 beats per minute). Mean heart rates returned to a statistically non-significant change at Week 48 for all treatment groups. No increase in major adverse cardiovascular events was observed.

Conclusion: Treatment with olodaterol or formoterol is not associated with arrhythmias or a persistent increase in heart rate as assessed by Holter ECG in patients with COPD.

Trial registration: ClinicalTrials.gov identifiers: NCT00782210 (1222.11); NCT00782509 (1222.12); NCT00793624 (1222.13); NCT00796653 (1222.14).

Keywords: Holter ECG; arrhythmia; formoterol; heart rate; olodaterol.

Conflict of interest statement

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, grants, personal fees and non-financial support from Novartis Deutschland, and grants and personal fees from Novartis Deutschland, outside the submitted work. The authors report no other conflicts of interest in this work.

© 2020 Andreas et al.

Figures

Figure 1
Figure 1
Shifts in SVPB: olodaterol and formoterol vs placebo at (A) Week 12, (B) Week 24, (C) Week 40 and (D) Week 48. P-values for overall differences between category of change and category of treatment calculated by Chi-squared frequency tests; Numbers above the bars are % of patients whereas numbers within the bars are number of patients. Abbreviations: Form, formoterol; Olo, olodaterol; SVPB, supraventricular premature beats.
Figure 2
Figure 2
Shifts in VPB: olodaterol and formoterol vs placebo at (A) Week 12, (B) Week 24, (C) Week 40 and (D) Week 48. P-values for overall differences between category of change and category of treatment calculated by Chi-squared frequency tests; Numbers above the bars are % of patients whereas numbers within the bars are number of patients. Abbreviations: Form, formoterol; Olo, olodaterol; VPB, ventricular premature beats.
Figure 3
Figure 3
Unadjusted baseline heart rate (A) and adjusted mean change in heart rate from baseline (B): olodaterol and formoterol vs placebo during treatment. *P<0.05. P-values are for adjusted mean change from baseline. Abbreviations: bpm, beats per minute; Form, formoterol; Olo, olodaterol; SD, standard deviation; SE, standard error.

References

    1. Alter P, Mayerhofer B, Kahnert K, et al. Prevalence of cardiac comorbidities, and their underdetection and contribution to exertional symptoms in COPD: results from the COSYCONET cohort. Int J Chron Obstruct Pulmon Dis. 2019;14:2163–2172. doi:10.2147/COPD.S209343
    1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report). Published 2019. Available from: . Accessed February14, 2020.
    1. Feary JR, Rodrigues LC, Smith CJ, Hubbard RB, Gibson JE. Prevalence of major comorbidities in subjects with COPD and incidence of myocardial infarction and stroke: a comprehensive analysis using data from primary care. Thorax. 2010;65(11):956–962. doi:10.1136/thx.2009.128082
    1. Cazzola M, Calzetta L, Bettoncelli G, et al. Cardiovascular disease in asthma and COPD: a population-based retrospective cross-sectional study. Respir Med. 2012;106(2):249–256. doi:10.1016/j.rmed.2011.07.021
    1. Cazzola M, Rogliani P, Matera MG. Cardiovascular disease in patients with COPD. Lancet Respir Med. 2015;3(8):593–595. doi:10.1016/S2213-2600(15)00279-9
    1. Janssen O, Schaumann F, Holz O, et al. Low-dose endotoxin inhalation in healthy volunteers-a challenge model for early clinical drug development. BMC Pulm Med. 2013;13(1):19. doi:10.1186/1471-2466-13-19
    1. Hawkins NM, Huang Z, Pieper KS, et al. Chronic obstructive pulmonary disease is an independent predictor of death but not atherosclerotic events in patients with myocardial infarction: analysis of the Valsartan in Acute Myocardial Infarction Trial (VALIANT). Eur J Heart Fail. 2009;11(3):292–298. doi:10.1093/eurjhf/hfp001
    1. Sin DD, Anthonisen NR, Soriano JB, Agusti AG. Mortality in COPD: role of comorbidities. Eur Respir J. 2006;28(6):1245–1257. doi:10.1183/09031936.00133805
    1. Cazzola M, Imperatore F, Salzillo A, et al. Cardiac effects of formoterol and salmeterol in patients suffering from COPD with preexisting cardiac arrhythmias and hypoxemia. Chest. 1998;114(2):411–415. doi:10.1378/chest.114.2.411
    1. Boehringer Ingelheim International GmbH. Striverdi Respimat 2.5 microgram, solution for inhalation – summary of product characteristics, Europe. Published 2019. Available from: . Accessed December4, 2019.
    1. Chen Y-F, Cheng Y-C, Chou C-H, Chen C-Y, Yu C-J. Major comorbidities lead to the risk of adverse cardiovascular events in chronic obstructive pulmonary disease patients using inhaled long-acting bronchodilators: a case-control study. BMC Pulm Med. 2019;19(1):233. doi:10.1186/s12890-019-0999-z
    1. Salpeter SR, Ormiston TM, Salpeter EE. Cardiovascular effects of β-agonists in patients with asthma and COPD. Chest. 2004;125(6):2309–2321. doi:10.1378/chest.125.6.2309
    1. Andreas S, Bothner U, Trampisch M, Haensel M, Buhl R, Alter P. Effect of long-acting β2-agonists olodaterol and formoterol on heart rate and blood pressure in chronic obstructive pulmonary disease patients. Pulm Pharmacol Ther. 2018;52:1–6. doi:10.1016/j.pupt.2018.08.002
    1. Rabe KF, Hurst JR, Suissa S. Cardiovascular disease and COPD: dangerous liaisons? Eur Respir Rev. 2018;27(149):pii:180057. doi:10.1183/16000617.0057-2018
    1. Matera MG, Ora J, Cazzola M. Differential pharmacology and clinical utility of long-acting bronchodilators in COPD - focus on olodaterol. Ther Clin Risk Manag. 2015;11:1805–1811. doi:10.2147/TCRM.S73581
    1. Handley DA, Morley J. The pursuit of precision pharmaceuticals: divergent effects of β2 agonist isomers. Expert Opin Investig Drugs. 1998;7(10):1601–1616. doi:10.1517/13543784.7.10.1601
    1. Ramsay CM, Cowan J, Flannery E, McLachlan C, Taylor DR. Bronchoprotective and bronchodilator effects of single doses of (S)-salbutamol, (R)-salbutamol and racemic salbutamol in patients with bronchial asthma. Eur J Clin Pharmacol. 1999;55(5):353–359. doi:10.1007/s002280050640
    1. Ferguson GT, Feldman GJ, Hofbauer P, et al. Efficacy and safety of olodaterol once daily delivered via Respimat® in patients with GOLD 2–4 COPD: results from two replicate 48-week studies. Int J Chron Obstruct Pulmon Dis. 2014;9:629–645. doi:10.2147/COPD.S61717
    1. Koch A, Pizzichini E, Hamilton A, et al. Lung function efficacy and symptomatic benefit of olodaterol once daily delivered via Respimat® versus placebo and formoterol twice daily in patients with GOLD 2–4 COPD: results from two replicate 48-week studies. Int J Chron Obstruct Pulmon Dis. 2014;9:697–714. doi:10.2147/COPD.S62502
    1. McGarvey L, Niewoehner D, Magder S, et al. One-year safety of olodaterol once daily via Respimat® in patients with GOLD 2–4 chronic obstructive pulmonary disease: results of a pre-specified pooled analysis. COPD. 2015;12(5):484–493. doi:10.3109/15412555.2014.991864
    1. Alter P, Watz H, Kahnert K, et al. Airway obstruction and lung hyperinflation in COPD are linked to an impaired left ventricular diastolic filling. Respir Med. 2018;137:14–22. doi:10.1016/j.rmed.2018.02.011
    1. Watz H, Waschki B, Meyer T, et al. Decreasing cardiac chamber sizes and associated heart dysfunction in COPD: role of hyperinflation. Chest. 2010;138(1):32–38. doi:10.1378/chest.09-2810
    1. Hohlfeld JM, Vogel-Claussen J, Biller H, et al. Effect of lung deflation with indacaterol plus glycopyrronium on ventricular filling in patients with hyperinflation and COPD (CLAIM): a double-blind, randomised, crossover, placebo-controlled, single-centre trial. Lancet Respir Med. 2018;6(5):368–378. doi:10.1016/S2213-2600(18)30054-7
    1. Raupach T, Bahr F, Herrmann P, et al. Slow breathing reduces sympathoexcitation in COPD. Eur Respir J. 2008;32(2):387–392. doi:10.1183/09031936.00109607
    1. Maltais F, O’Donnell D, Galdiz Iturri JB, et al. Effect of 12 weeks of once-daily tiotropium/olodaterol on exercise endurance during constant work-rate cycling and endurance shuttle walking in chronic obstructive pulmonary disease. Ther Adv Respir Dis. 2018;12:1–13. doi:10.1177/1753465818755091
    1. Berton DC, Barbosa PB, Takara LS, et al. Bronchodilators accelerate the dynamics of muscle O2 delivery and utilisation during exercise in COPD. Thorax. 2010;65(7):588–593. doi:10.1136/thx.2009.120857
    1. Lahousse L, Verhamme KM, Stricker BH, Brusselle GG. Cardiac effects of current treatments of chronic obstructive pulmonary disease. Lancet Respir Med. 2016;4(2):149–164. doi:10.1016/S2213-2600(15)00518-4
    1. Galli A, Ambrosini F, Lombardi F. Holter monitoring and loop recorders: from research to clinical practice. Arrhythm Electrophysiol Rev. 2016;5(2):136–143. doi:10.15420/AER.2016.17.2
    1. Priori SG, Blomström-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: the task force for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death of the European Society of Cardiology (ESC) Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). EP Europace. 2015;17(11):1601–1687. doi:10.1093/europace/euv319
    1. Incorvaia C, Montagni M, Makri E, Riario-Sforza GG, Ridolo E. Striving for optimal bronchodilation: focus on olodaterol. Int J Chron Obstruct Pulmon Dis. 2016;11:439–444. doi:10.2147/COPD.S96070
    1. Watz H, Troosters T, Beeh KM, et al. ACTIVATE: the effect of aclidinium/formoterol on hyperinflation, exercise capacity, and physical activity in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2017;12:2545–2558. doi:10.2147/COPD.S143488
    1. Nelson HS, Gross NJ, Levine B, et al. Cardiac safety profile of nebulized formoterol in adults with COPD: a 12-week, multicenter, randomized, double- blind, double-dummy, placebo- and active-controlled trial. Clin Ther. 2007;29(10):2167–2178. doi:10.1016/j.clinthera.2007.10.007
    1. Borghardt JM, Kloft C, Sharma A. Inhaled therapy in respiratory disease: the complex interplay of pulmonary kinetic processes. Can Respir J. 2018;2018:2732017. doi:10.1155/2018/2732017
    1. Bouyssou T, Hoenke C, Rudolf K, et al. Discovery of olodaterol, a novel inhaled β2-adrenoceptor agonist with a 24h bronchodilatory efficacy. Bioorg Med Chem Lett. 2010;20(4):1410–1414. doi:10.1016/j.bmcl.2009.12.087
    1. Maleki-Yazdi MR, Beck E, Hamilton AL, Korducki L, Koker P, Fogarty C. A randomised, placebo-controlled, phase II, dose-ranging trial of once-daily treatment with olodaterol, a novel long-acting β2-agonist, for 4 weeks in patients with chronic obstructive pulmonary disease. Respir Med. 2015;109(5):596–605. doi:10.1016/j.rmed.2015.02.012
    1. Wang M-T, Liou J-T, Lin CW, et al. Association of cardiovascular risk with inhaled long-acting bronchodilators in patients with chronic obstructive pulmonary disease: a nested case-control study. JAMA Intern Med. 2018;178(2):229–238. doi:10.1001/jamainternmed.2017.7720

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅