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

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) 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 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.

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).

Keywords: Holter ECG; arrhythmia; heart rate; olodaterol; safety; tiotropium.

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, 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.

© 2020 Andreas et al.

Figures

Figure 1
Figure 1
(A) Shifts in SVPB: T/O vs monocomponents at Week 12 (TONADO 1 and 2), and (B) shifts in VPB: T/O vs monocomponents at Week 12 (TONADO 1 and 2). P-value based on Chi-squared test: no statistical difference in frequency of increase or decrease. Abbreviations: Olo, olodaterol; SVPB, supraventricular premature beat; T/O, tiotropium/olodaterol; Tio, tiotropium; VPB, ventricular premature beat. For definition of shifts in SVPB and VPB, see Methods section (Sub-analyses on Holter ECGs).
Figure 2
Figure 2
Adjusted mean Holter heart rate over 24 hours at Week 12: T/O vs monocomponents at baseline and Week 12 (TONADO 1 and 2). Treated set: adjusted data. Baseline data are unadjusted. P-values are for adjusted mean change from baseline data. Standard errors for baseline are 0.71, 0.84 and 0.93, respectively, and for week 12 were 0.53, 0.53 and 0.72, respectively. Abbreviations: bpm, beats per minute; Olo, olodaterol; T/O, tiotropium/olodaterol; Tio, tiotropium.

References

    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. Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report: GOLD executive summary. Am J Respir Crit Care Med. 2017;195(5):557–582. doi:10.1164/rccm.201701-0218PP
    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. Hawkins NM, Petrie MC, Macdonald MR, et al. Heart failure and chronic obstructive pulmonary disease the quandary of beta-blockers and beta-agonists. J Am Coll Cardiol. 2011;57(21):2127–2138. doi:10.1016/j.jacc.2011.02.020
    1. Boehringer Ingelheim International GmbH. Striverdi Respimat 2.5 microgram, solution for inhalation – Summary of Product Characteristics, Europe; 2019. Available from: . Accessed December4, 2019.
    1. Boehringer Ingelheim International GmbH. Spiriva® Respimat® 2.5 microgram, solution for inhalation – Summary of Product Characteristics, Europe; 2016. Available from: . Accessed November6, 2019.
    1. Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359(15):1543–1554. doi:10.1056/NEJMoa0805800
    1. O’Donnell DE, Fluge T, Gerken F, et al. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J. 2004;23(6):832–840. doi:10.1183/09031936.04.00116004
    1. Wise RA, Anzueto A, Cotton D, et al. Tiotropium Respimat inhaler and the risk of death in COPD. N Engl J Med. 2013;369(16):1491–1501. doi:10.1056/NEJMoa1303342
    1. Anzueto A, Wise R, Calverley P, et al. The tiotropium safety and performance in Respimat® (TIOSPIR®) trial: spirometry outcomes. Respir Res. 2015;16:107. doi:10.1186/s12931-015-0269-4
    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. 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. Koch A, Watz H, Maleki-Yazdi MR, et al. Comprehensive assessment of the safety of olodaterol 5 µg in the Respimat® device for maintenance treatment of COPD: comparison with the long-acting β2-agonist formoterol. NPJ Prim Care Respir Med. 2017;27(1):60. doi:10.1038/s41533-017-0059-1
    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. Singh D, Ferguson GT, Bolitschek J, et al. Tiotropium + olodaterol shows clinically meaningful improvements in quality of life. Respir Med. 2015;109(10):1312–1319. doi:10.1016/j.rmed.2015.08.002
    1. Singh D, Gaga M, Schmidt O, et al. Effects of tiotropium + olodaterol versus tiotropium or placebo by COPD disease severity and previous treatment history in the OTEMTO® studies. Respir Res. 2016;17(1):73. doi:10.1186/s12931-016-0387-7
    1. Beeh KM, Westerman J, Kirsten AM, et al. The 24-h lung-function profile of once-daily tiotropium and olodaterol fixed-dose combination in chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2015;32:53–59. doi:10.1016/j.pupt.2015.04.002
    1. Maltais F, Hamilton A, Voss F, Maleki-Yazdi MR. Dose determination for a fixed-dose drug combination: a Phase II randomized controlled trial for tiotropium/olodaterol versus tiotropium in patients with COPD. Adv Ther. 2019;36(4):962–968. doi:10.1007/s12325-019-00911-y
    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. Singh S, Loke YK, Enright PL, Furberg CD. Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials. BMJ. 2011;342:d3215. doi:10.1136/bmj.d3215
    1. Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA. 2008;300(12):1439–1450. doi:10.1001/jama.300.12.1439
    1. Andreas S, Bothner U, de la Hoz A, Kloer I, Trampisch M, Alter P. A post hoc Holter ECG analysis of olodaterol and formoterol in moderate-to-very-severe COPD Int J Chron Obstruct Pulmon Dis. In press 2020.
    1. Hohlfeld JM, Furtwaengler A, Konen-Bergmann M, Wallenstein G, Walter B, Bateman ED. Cardiac safety of tiotropium in patients with COPD: a combined analysis of Holter-ECG data from four randomised clinical trials. Int J Clin Pract. 2015;69(1):72––80..
    1. Halpin DM, Dahl R, Hallmann C, Mueller A, Tashkin D. Tiotropium HandiHaler(®) and Respimat(®) in COPD: a pooled safety analysis. Int J Chron Obstruct Pulmon Dis. 2015;10:239–259. doi:10.2147/COPD.S75146
    1. Buhl R, Magder S, Bothner U, et al. Long-term general and cardiovascular safety of tiotropium/olodaterol in patients with moderate to very severe chronic obstructive pulmonary disease. Respir Med. 2017;122:58–66. doi:10.1016/j.rmed.2016.11.011
    1. Karner C, Chong J, Poole P. Tiotropium versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;11(7):CD009285.
    1. Dong YH, Lin HH, Shau WY, Wu YC, Chang CH, Lai MS. Comparative safety of inhaled medications in patients with chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-analysis of randomised controlled trials. Thorax. 2013;68(1):48–56. doi:10.1136/thoraxjnl-2012-201926
    1. Suissa S, Dell’Aniello S, Ernst P. Concurrent use of long-acting bronchodilators in COPD and the risk of adverse cardiovascular events. Eur Respir J. 2017;49(5):1602245. doi:10.1183/13993003.02245-2016
    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. Haarmann H, Mohrlang C, Tschiesner U, et al. Inhaled β-agonist does not modify sympathetic activity in patients with COPD. BMC Pulm Med. 2015;15:46. doi:10.1186/s12890-015-0054-7
    1. Ferguson GT, Funck-Brentano C, Fischer T, Darken P, Reisner C. Cardiovascular safety of salmeterol in COPD. Chest. 2003;123(6):1817–1824. doi:10.1378/chest.123.6.1817
    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. Buhl R, Maltais F, Abrahams R, et al. Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2-4). Eur Respir J. 2015;45(4):969–979. doi:10.1183/09031936.00136014
    1. Global Initiative for Chronic Obstructive Lung Disease. Pocket guide to COPD diagnosis, management and prevention – A guide for health care professionals (2019report); 2019. Available from: . Accessed December19, 2019.
    1. Ferguson GT, Buhl R, Bothner U, et al. Safety of tiotropium/olodaterol in chronic obstructive pulmonary disease: pooled analysis of three large, 52-week, randomized clinical trials. Respir Med. 2018;143:67–73. doi:10.1016/j.rmed.2018.08.012
    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. Lötvall J, Palmqvist M, Ankerst J, et al. The effect of formoterol over 24h in patients with asthma: the role of enantiomers. Pulm Pharmacol Ther. 2005;18(2):109–113. doi:10.1016/j.pupt.2004.10.007
    1. Terasaki J, Nishi S, Ameredes B, Sharma G. Arformoterol: rationale for use in chronic obstructive pulmonary disease. Clin Investig (Lond). 2014;4:429–439.
    1. Andreas S, McGarvey L, Bothner U, et al. Absence of adverse effects of tiotropium/olodaterol compared with the monocomponents on long-term heart rate and blood pressure in patients with moderate-to-very-severe COPD. Int J Chron Obstruct Pulmon Dis. In press 2020.
    1. Andreas S, Anker SD, Scanlon PD, Somers VK. Neurohumoral activation as a link to systemic manifestations of chronic lung disease. Chest. 2005;128(5):3618–3624. doi:10.1378/chest.128.5.3618
    1. Andreas S, Haarmann H, Klarner S, Hasenfuss G, Raupach T. Increased sympathetic nerve activity in COPD is associated with morbidity and mortality. Lung. 2014;192(2):235–241. doi:10.1007/s00408-013-9544-7
    1. Byrd JB, Newby DE, Anderson JA, et al. Blood pressure, heart rate, and mortality in chronic obstructive pulmonary disease: the SUMMIT trial. Eur Heart J. 2018;39(33):3128–3134. doi:10.1093/eurheartj/ehy451
    1. Huiart L, Ernst P, Suissa S. Cardiovascular morbidity and mortality in COPD. Chest. 2005;128(4):2640–2646. doi:10.1378/chest.128.4.2640
    1. Fuhrman C, Jougla E, Nicolau J, Eilstein D, Delmas MC. Deaths from chronic obstructive pulmonary disease in France, 1979–2002: a multiple cause analysis. Thorax. 2006;61(11):930–934. doi:10.1136/thx.2006.061267
    1. Jensen MT, Suadicani P, Hein HO, Gyntelberg F. Elevated resting heart rate, physical fitness and all-cause mortality: a 16-year follow-up in the Copenhagen Male Study. Heart. 2013;99(12):882–887. doi:10.1136/heartjnl-2012-303375
    1. Schrier RW, Abraham WT. Hormones and hemodynamics in heart failure. N Engl J Med. 1999;341(8):577–585. doi:10.1056/NEJM199908193410806

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