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Effects of LAMA/LABA Alone and in Combination on Cardiac Safety

Authors Andreas S

Received 17 January 2020

Accepted for publication 24 January 2020

Published 10 August 2020 Volume 2020:15 Pages 1931—1933

DOI https://doi.org/10.2147/COPD.S246356

Checked for plagiarism Yes

Editor who approved publication: Dr Richard Russell


Stefan Andreas 1, 2

1Department of Cardiology and Pneumology, University Medical Centre Göttingen, Göttingen, Germany; 2LungClinic Immenhausen, Immenhausen, Germany, Member of the German Center for Lung Research (DZL)

Correspondence: Stefan Andreas
Department of Cardiology and Pneumology, Herzzentrum Gottingen, Robert-Koch-Str. 40, Göttingen, Germany
Tel +49 05673 501 1112
Fax +49 05673-501-1101
Email stefan.andreas@med.uni-goettingen.de

Chronic obstructive pulmonary disease (COPD) is a multidimensional, progressive condition characterized by airflow obstruction, worsening dyspnea and respiratory failure.1 The Global Initiative for Chronic Obstructive Lung Disease (GOLD) report suggests that long-acting β 2-agonists (LABAs) or long-acting muscarinic antagonists (LAMAs) are the preferred initial pharmacologic therapy option in the majority of patients with COPD, with escalation to dual therapy as required. 1
Extensive clinical data show that the LAMA tiotropium (SPIRIVA®; Boehringer Ingelheim Pharma GmbH, Ingelheim, Germany) delivered as a dry powder formulation by HandiHaler® (DPI; 18 μg nominal dose) or as an aqueous solution via the Respimat® Soft Mist™ inhaler (SMI; 5 μg nominal dose) can improve lung function, symptoms and outcomes, such as dyspnea and quality of life, and reduce exacerbations in patients with COPD. 2 Olodaterol (Striverdi®; Boehringer Ingelheim Pharma GmbH & Co K.G., Ingelheim, Germany) is a LABA that provides 24-hr bronchodilation, and has been shown to improve lung function and reduce symptoms in patients with COPD. 3 When given in a fixed-dose combination with tiotropium via the SMI (Spiolto®; Boehringer Ingelheim Pharma GmbH & Co K.G., Ingelheim, Germany), further improvements in lung function and health-related quality of life have been reported. 4
 

Patients with COPD often have comorbidities that can impact disease management, including choice of treatment. The most serious and prevalent comorbidities are cardiovascular (CV) diseases,58 which are known to be leading causes of hospitalization and death.6,9 In a study by Fuhrman et al in patients for whom COPD was an associated cause of death, 32.0% of patients had an underlying CV disease, and 13.6% of the total population had ischemic heart disease.6 As such, initial concerns were raised regarding the cardiac safety of LAMAs and LABAs, particularly among patients with CV comorbidities.10,11 For LABAs, for example, there are theoretical concerns over increases in heart rate and blood pressure resulting from their interaction with β2-adrenoceptors in the atria, ventricles and peripheral vasculature via the baroreflex mechanism.12 However, since these concerns were raised, there have been many reassuring analyses from safety databases of LABA and LAMA.1317 For tiotropium and olodaterol, in particular, there is a large volume of published safety data on the long-term general and specific CV adverse events (AEs) of these agents. These data show that tiotropium and olodaterol given as monotherapy have similar, or lower, AE rates than placebo,18,19 and in combination can be safely administered to patients with moderate-to-very-severe COPD, including patients with CV comorbidities.20

Since the early debate about the CV safety of LABAs and LAMAs, and the reassurance provided by extensive clinical and real-world experience with these agents, attention has focused on the wider implications of bronchodilation therapy on the CV system of individuals with COPD. In this context, real-time measurement of physiologic data such as heart rate, heart rhythm and blood pressure are of interest. Two papers investigating the cardiac safety of tiotropium and olodaterol treatment in COPD have previously been published.21,22 The first investigated the long-term effects of tiotropium maintenance therapy on cardiac parameters using a combined analysis of Holter-ECG data from four randomized clinical trials.21 This paper concluded that tiotropium maintenance therapy administered using the SMI (1.25–10 μg) or DPI (18 μg) once daily for up to 48 weeks was well tolerated, with no increased risk of supraventricular or ventricular arrhythmia in patients with COPD. The second paper investigated the effect of olodaterol (5 or 10 µg) and formoterol (12 µg) on heart rate and blood pressure in moderate-to-severe COPD, demonstrating that heart rate and blood pressure are not adversely affected following long-term administration.22

In the current series, we conducted detailed analyses of heart rate, 24-hr Holter electrocardiogram data and blood pressure from large clinical cohorts of patients with moderate-to-severe COPD receiving tiotropium and/or olodaterol as mono- or combination therapy.

In the first article, we report a post hoc analysis of the effects of dual bronchodilation with tiotropium/olodaterol 5/5 µg versus tiotropium 5 µg or olodaterol 5 µg on heart rate and blood pressure in patients included in the two large, 52-week TONADO® studies. This analysis included 3100 patients with moderate-to-very-severe COPD, and was the first study to comprehensively investigate heart rate and blood pressure in a large Phase III study of dual bronchodilation.23

In the second article, we report a sub-analysis of the extensive Holter ECG data from four 48-week, Phase III studies that assessed olodaterol 5 µg versus placebo to investigate whether olodaterol monotherapy increases the risk of cardiac arrhythmia in patients with COPD. Two of the studies also included formoterol (12 µg). Holter ECG records were evaluated for 24-hr mean heart rate as well as the number of supraventricular premature beats and ventricular premature beats.24

The final paper in this series reports the results of Holter ECG examinations from two large, long-term, controlled clinical COPD trials (TONADO® 1 and 2) to investigate whether tiotropium/olodaterol 5/5 µg increases the risk of cardiac arrhythmia compared with tiotropium 5 µg or olodaterol 5 µg. Holter ECG records from 506 patients were evaluated for 24-hr mean heart rate as well as the number of supraventricular premature beats and ventricular premature beats.25

Overall, this series of analyses showed that long-term administration of dual bronchodilation therapy was not associated with changes in heart rate or blood pressure and did not present any medically relevant effects on arrhythmias compared with monotherapies.23,25 Additionally, treatment with olodaterol or formoterol was not associated with arrhythmias or persistent increases in heart rate in patients with COPD.24 The conclusions from these extensive analyses of our clinical database support the findings of the previously published monotherapy evaluations.21,22 We now have an extensive body of published evidence supporting the CV safety of tiotropium and olodaterol administered either alone or as a fixed-dose combination in patients with moderate-to-very-severe COPD.

Acknowledgments

Medical writing assistance in the form of the preparation and revision of the draft editorial was supported financially by Boehringer Ingelheim and provided by Francesca Lomas of MediTech Media, under the author’s conceptual direction and based on feedback from the author. Boehringer Ingelheim was given the opportunity to review the manuscripts for factual accuracy only.

Disclosure

Professor Stefan Andreas reports personal fees from Boehringer Ingelheim and GlaxoSmithKline as part of advisory boards, and held presentations for AstraZeneca, Berlin Chemie, Chiesi, and Novartis, outside the submitted work. The author reports no other conflicts of interest in this work.

References

1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report); 2019. Available from: https://goldcopd.org/wp-content/uploads/2019/11/GOLD-2020-REPORT-ver1.0wms.pdf. Accessed December 6, 2019.

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. Karch A, Vogelmeier C, Welte T, et al. The German COPD cohort COSYCONET: aims, methods and descriptive analysis of the study population at baseline. Respir Med. 2016;114:27–37. doi:10.1016/j.rmed.2016.03.008

9. Sidney S, Sorel M, Quesenberry CP Jr, DeLuise C, Lanes S, Eisner MD. COPD and incident cardiovascular disease hospitalizations and mortality: Kaiser Permanente Medical Care Program. Chest. 2005;128(4):2068–2075. doi:10.1378/chest.128.4.2068

10. 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

11. 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

12. 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

13. 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:10.1183/13993003.13902245-13992016

14. Tricco AC, Strifler L, Veroniki AA, et al. Comparative safety and effectiveness of long-acting inhaled agents for treating chronic obstructive pulmonary disease: a systematic review and network meta-analysis. BMJ Open. 2015;5(10):e009183. doi:10.1136/bmjopen-2015-009183

15. Rossi A, Khirani S, Cazzola M. Long-acting beta2-agonists (LABA) in chronic obstructive pulmonary disease: efficacy and safety. Int J Chron Obstruct Pulmon Dis. 2008;3(4):521–529. doi:10.2147/COPD.S1353

16. Han MK, Ray R, Foo J, Morel C, Hahn B. Systematic literature review and meta-analysis of US-approved LAMA/LABA therapies versus tiotropium in moderate-to-severe COPD. NPJ Primary Care Respir Med. 2018;28(1):32. doi:10.1038/s41533-018-0099-1

17. Rodrigo GJ, Nannini LJ, Rodríguez-Roisin R. Safety of long-acting ß-agonists in stable COPD: a systematic review. Chest. 2008;133(5):1079–1087. doi:10.1378/chest.07-1167

18. 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

19. 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

20. 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

21. 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. doi:10.1111/ijcp.12596

22. 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

23. 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

24. 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

25. Andreas S, Bothner U, de la Hoz A, Kloer I, Trampisch M, Alter P. 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. Int J Chron Obstruct Pulmon Dis. In press 2020

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