JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY Volume 27, Number 0, 2014 ª Mary Ann Liebert, Inc. Pp. 1–6 DOI: 10.1089/jamp.2014.1125

Effect of Tiotropium on Heart Rate Variability in Stable Chronic Obstructive Pulmonary Disease Patients Yao-Kuang Wu, MD,1,2 Chun-Yao Huang, MD,1 Mei-Chen Yang, MD,1,2 Guo-Liang Huang, MD,1 Sin-Yi Chen, MD,1 and Chou-Chin Lan, MD1,2

Abstract

Background: The chronic use of the long-acting anticholinergic agent, tiotropium, in chronic obstructive pulmonary disease (COPD) has been linked in some reports to an increase in adverse cardiovascular effects. Decreased heart rate variability (HRV) is a condition seen in COPD patients that has also been linked to poor cardiovascular outcome. We aimed in this study to investigate changes in HRV caused by tiotropium administration to COPD patients in order to determine whether changes occurred that might contribute to an increase in adverse cardiovascular events. Methods: Seventy patients with moderate-to-severe stable COPD were treated with once-daily dosing of tiotropium (two puffs of Spiriva Respimat, 2.5 lg solution) for 3 months. HRV, pulmonary function, and quality of life were measured before and after 1 and 3 months of therapy. Results: Pulmonary function and quality of life improved significantly, after both 1 and 3 months of therapy. No significant change in HRV parameters occurred, except for a significant decrease in the high-frequency and increase in the low-frequency component of HRV at the 1-month assessment. Conclusion: Changes in HRV caused by tiotropium use are not sufficient to explain a possible increase in adverse cardiovascular events. Key words: adverse event, anticholinergic agent, autonomic function, chronic obstructive pulmonary disease, heart rate variability, sympathetic system, tiotropium

inhaled anticholinergics have been used in COPD since the 1970s. They have been shown to be a safe and effective therapy,(3,4) but the need for frequent dosing has been a limitation to their use. Tiotropium bromide (Spiriva) is a selective long-acting anticholinergic that provides 24-hr bronchodilation with once-daily inhaled dosing. Its long action is due to its very slow dissociation from the M3 muscarinic receptors that are located on airway smooth muscle and are responsible for maintenance of resting tone.(2,5,6) Inhaled anticholinergics have been reported in some,(7–9) although not all,(10–13) studies to be associated with a significantly increased risk of adverse cardiovascular events in COPD patients. COPD patients themselves are known to have autonomic dysfunction(14–16) and an alteration in sympathetic/parasympathetic balance.(17) It is possible that

Introduction

C

hronic obstructive pulmonary disease (COPD) is a progressive and disabling condition in which chronic airflow limitation causes dyspnea. It is accompanied by an underlying lung inflammation and is often associated with multiple comorbidities.(1) Inadequate treatment of moderateto-severe COPD will result in acute exacerbations, and frequent acute exacerbations are associated with a decline in lung function, increased dyspnea, reduced physical functioning, and an impaired quality of life.(1) Long-acting inhaled bronchodilators, including anticholinergics, are recommended as first-line maintenance treatment for patients with moderate-to-severe COPD.(1) Anticholinergics act by decreasing airway smooth muscle resting tone, which is elevated in COPD.(2) Short-acting

1 Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan. 2 School of Medicine, Tzu-Chi University, Hualien, Taiwan.

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inhaled anticholinergics increase cardiovascular risk by further alterations in this balance. Heart rate variability (HRV) can be used to assess autonomic nervous system control of the heart.(18) When beatto-beat electrocardiogram (ECG) depolarization intervals are recorded, they can be divided into high-frequency (HF) and low-frequency (LF) components. Changes in the HF component reflect changes in vagal input during the respiratory cycle. Changes in the LF component reflect sympathetic/parasympathetic adjustments in response to baroreceptor input.(18) Reduced HRV has been associated with increased sympathetic and decreased vagal modulation, as well as with poor cardiovascular outcome in a number of clinical conditions.(18) Inhaled tiotropium has been reported to decrease the sympathetic activation that occurs during exercise, perhaps through improving lung function.(19) It has been reported to improve left ventricular diastolic function after pulmonary resection(20) in COPD patients, also perhaps through improving pulmonary dynamics. But the effect of chronic inhaled tiotropium on HRV and sympathetic/parasympathetic balance has not yet been studied. The aim of this study was to investigate HRV, pulmonary function, and quality of life before and after chronic treatment with tiotropium, and to see whether tiotropium-induced changes in autonomic nervous system balance might contribute to the reported cardiovascular risk in vulnerable COPD patients seen in some studies.

Study design

Assessments were done before initiating chronic tiotropium use (Spiriva Respimat, tiotropium 2.5 lg solution, 2 puffs/day) and after 1 and 3 months of use. Tiotropium was administered once daily at home. All patients were trained by the physicians and nurses to make sure that they were able to administer tiotropium correctly and effectively at home. Study sessions were in the hospital after the patient’s routine office visit. Physiologic parameters were assessed by HRV and spirometry. The health-related quality of life and dyspnea symptoms were assessed using the St. George’s Respiratory Questionnaire (SGRQ). Measurements

Materials and Methods Subjects

Patients with COPD were recruited from the out-patient clinic of the Buddhist Tzu-Chi General Hospital. The diagnosis of COPD was based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging criteria.(1) This diagnosis is based on smoking history and pulmonary function tests documenting chronic bronchial obstruction [forced expiratory volume in 1 sec/forced vital capacity (FEV1/FVC) ratio < 0.70]. Only moderate-to-severe COPD patients (FEV1 < 80% of predicted) who had stable disease with no exacerbations or worsening of respiratory symptoms for at least the previous 3 months(21) and who were able to mobilize independently were eligible for enrollment. Subjects with diabetes mellitus, coronary artery disease, respiratory or neurological

Table 1. Demographic Characteristics of the Study Group of COPD Patients (N = 70) COPD (n = 70) Age (years) Gender (male) BMI (kg/m2) Smoking Current smoker Ex-smoker COPD stage Stage I Stage II Stage III

disease, use of systemic drugs, or any other systemic disorder that might influence autonomic function were excluded. The research protocol was approved by the ethics committee of the Buddhist Tzu-Chi General Hospital, and all patients provided informed consent. Patients did not use tiotropium or other anticholinergics before entry into the study, and they did not use other anticholinergics during the study period. Their physical examinations and resting 12-lead ECG were normal. Participants were asked to refrain from alcohol, caffeine-containing beverages, and strenuous exercise for 24 hr prior to each study session. All procedures necessary for data collection were explained to the individuals, and subjects were instructed to avoid talking during data collection.

69.0 – 11.5 58 (82.9%) 25.0 – 4.3 28 (40.0%) 42 (60.0%) 20 (28.6%) 39 (55.7%) 11 (15.7%)

BMI, body mass index; COPD, chronic obstructive pulmonary disease.

HRV recordings. Before recording, all subjects underwent a full physical examination, and no abnormal findings were observed. They had a light breakfast after an overnight period of fasting and were taken to a quiet, dimly lighted room with a temperature of 24–26C. Studies were carried out between 9:00 AM and 12:00 PM to avoid circadian variations in HRV parameters. All participants were taken to the test room and allowed to rest in sitting position for 20 min on a comfortable chair to stabilize heart rate. HRV measurement was then performed for 5 min. HRV measurement was performed as previously described.(22) Version 3.0 of the ‘‘CheckMyHeart (CMH)’’ HRV analysis software (CheckMyHeart, DailyCare BioMedical Inc., Zhongli City, Taiwan) was used for all transformations and analyses. CMH is a single-lead electrocardiography recorder (lead I or lead II is available). Beat-by-beat R-R interval values (resolution 4 msec) were obtained from the ECG signals. CMH software rejects irregular R-R intervals (non-NN interval) automatically. However, the software provides filtering of non-NN intervals. Detrended time series were cubically interpolated and resampled at 1 Hz. After detrending via leastsquare second-order polynomial fitting, the power spectral density of the R-R interval time series was estimated by discrete Fourier transform. The power in the very-low-frequency (VLF; 0.00–0.04 Hz), LF (0.04–0.15 Hz), and HF (0.15–0.40 Hz) bands was obtained by numerical integration. Spectral components were expressed as normalized units (nu), which were calculated as follows: (absolute power of the components)/ (total power – VLF power) · 100.(23) The LF/HF ratio was also determined. Spectral analysis was also performed using the autoregressive method (Burg algorithm) with spectral decomposition ( Johnsen and Andersen algorithm). Spectral powers of the VLF, LF, and HF bands were computed by summing the

TIOTROPIUM EFFECTS ON HRV IN COPD PATIENTS

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respective spectral components. Time-domain HRV parameters were also computed. The standard deviation of the normal R-R intervals (SDNN), that is, the square root of variance, and the square root of the mean sum of the squares of the difference between adjacent normal R-R intervals within a given time minus one (RMSSD) were analyzed. Pulmonary function test. Pulmonary function measurements, including FVC, FEV1, and forced mid-expiratory airflow 25–75% (FEF25–75%), were made by spirometry (Medical Graphics Corporation, St. Paul, MN), following the standards of the American Thoracic Society and European Respiratory Society.(24,25) Health-related quality-of-life assessment (HRQL). The HRQL was assessed using the validated Chinese version of the SGRQ,(26) a questionnaire designed to measure the influence of chest diseases on HRQL. Responses to its 50 items were aggregated into an overall score and three subscores for symptoms (8 items), activity (16 items), and impact (26 items). Responses were weighted and scores were calculated by dividing the summed weights by the maximum possible weight, with 0 as the best possible score and 100 the worst.

Results

Seventy patients were enrolled during the study period. Their demographic characteristics are shown in Table 1. COPD stage had a significant negative relationship with the baseline pulmonary function parameters (FVC: r = - 0.409; FEV1: r = - 0.588; FEV1/FVC: r = - 0.473; all p < 0.001). However, there was no statistically significant relationship between COPD stage and HRV parameters, or between HRV parameters and pulmonary function parameters. There was no significant difference in time domains (SDNN, RMSSD). Compared with baseline frequency domain parameters, the patients had significantly increased LF norm and decreased HF norm after 1 month of tiotropium treatment (both p £ 0.015), but not after 3 months of treatment. There were no significant differences in other frequency domain parameters at the three times (Table 2). Compared with baseline pulmonary function parameters, patients had significantly increased FVC, FEV1, and FEV1/ FVC after 1 and 3 months of tiotropium treatment (all p £ 0.002) (Table 3). Compared with baseline SGRQ parameters, all domains of the SGRQ showed significant improvement after 1 and 3 months of tiotropium treatment (all p < 0.001). As time increased, the SGRQ total score decreased ( p < 0.001) (Table 4).

Statistical analysis

Continuous variables are presented as means – SD, and categorical variables as count and percentage. We applied the mixed effect model to deal with the time effect for repeated outcome measurements. When a significant difference between times was apparent, multiple comparisons were performed using the Bonferroni procedure with type-I error adjustment. Linear relationships were examined by Pearson’s correlation. The statistical analyses were performed with SAS software version 9.2 (SAS Institute Inc., Cary, NC). A two-sided p value < 0.05 was considered as statistically significant.

Discussion

In the current study, chronic tiotropium use in COPD patients caused significant improvement in pulmonary function and quality of life, but no significant change in HRV parameters, except for a significant decrease in HF norm and increase in LF norm at 1 month, but not at 3 months. In other words, at 1 month, a relative decrease in parasympathetic and increase in sympathetic modulation of heart rate occurred that lessened with time. We did not find any change in HRV parameters that was of sufficient magnitude to explain the increased cardiovascular

Table 2. Heart Rate Variability (HRV) Parameters of COPD Patients Before and After Chronic Tiotropium Use Variables SDNN (msec) RMSSD (msec) sNN50 total pNN50 (%) VLF (msec2) LF (msec2) HF (msec2) Total (msec2) LF norm (nu) HF norm (nu) LF/HF

Baseline (n = 70)

After 1 month (n = 70)

After 3 months (n = 56)

p value

39.02 – 35.58 35.07 – 40.63 18.49 – 31.25 6.72 – 11.93 294.30 – 445.10 405.00 – 1,068.59 658.77 – 1,444.87 1,359.21 – 2,864.90 44.28 – 18.19 55.66 – 18.18 1.27 – 2.08

38.46 – 46.05 34.36 – 71.99 15.49 – 32.48 7.19 – 15.28 541.39 – 2,863.31 906.96 – 5,375.23 6,657.26 – 49,610.18 8,106.70 – 50,468.60 50.16 – 19.40a 49.81 – 19.40a 1.52 – 1.57

48.12 – 45.99 41.75 – 58.21 18.43 – 28.30 11.92 – 19.36 446.34 – 1,257.74 569.55 – 966.46 1,108.75 – 2,605.73 2,125.84 – 3,685.10 48.43 – 19.80 51.54 – 19.77 1.47 – 1.90

0.258 0.669 0.734 0.158 0.078 0.479 0.341 0.296 0.048b 0.049b 0.548

SDNN, standard deviation of all NN intervals; RMSSD, square root of the mean of the sum of the squares of differences between adjacent NN intervals; sNN50, total count of the total number of differences between adjacent RR intervals that were greater than 50 msec; pNN50, the number of pairs of adjacent NN intervals differing by more than 50 msec divided by the total number of all NN intervals; VLF, very low frequency; LF, low frequency; HF, high frequency; nu, normalized unit. HRV parameters are presented as means – SD, and compared between different times by mixed effect model. a p < 0.05 indicates a significant difference when compared with baseline. b p < 0.05 indicates a significant difference among the three times.

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Table 3. Pulmonary Function Parameters of COPD Patients Before and After Chronic Tiotropium Use Variables FVC (L) FEV1 (L) FEV1/FVC (%) SpO2 (%)

Baseline (n = 70)

After 1 month (n = 70)

After 3 months (n = 56)

p value

2.40 – 0.65 1.48 – 0.47 0.62 – 0.09 0.96 – 0.02

2.62 – 0.67a 1.67 – 0.49a 0.64 – 0.12a 0.97 – 0.02

2.61 – 0.67a 1.67 – 0.49a 0.64 – 0.12a 0.97 – 0.02

< 0.001b < 0.001b 0.005b 0.431

FVC, forced vital capacity; FEV1, forced expiratory volume 1 sec; SpO2, pulse oximetry oxygen saturation. Pulmonary function parameters are presented as means – SD, and compared between different times by mixed effect model. a p < 0.05 indicates a significant difference when compared with baseline. b p < 0.05 indicates a significant difference among the three times.

risk with tiotropium use that has been reported in some clinical trials. However, the possibility of increased cardiovascular risk with the use of tiotropium cannot be ignored. Most clinical trials of tiotropium have used the HandiHaler and, although cardiovascular disease is a common comorbidity in COPD patients,(27) these trials have excluded patients with pre-existing cardiovascular problems. Inhaled tiotropium can be administered in two ways, either as a dry powder (the HandiHaler) or as a solution (Respimat). When the spray button of the Respimat is pressed, a fine aerosol mist is ejected, independent of respiratory effort.(28) Compared with dry powder delivery, the aerosol contains at least twice as many fine ( < 5.8 mm) particles, a fifth of the dry powder’s delivery speed, and a 4–10 times longer delivery time.(29) Thus, the fine mist used in the Respimat inhaler allows the inhalation of smaller particles that are able to penetrate deeper into the lung than the particles in the HandiHaler. Tiotropium use with the Respimat inhaler has been reported in several recent publications to increase cardiovascular risk.(12,30) However, other studies have reported the two inhaler types to have a similar cardiovascular event profile.(13,31) A pharmacokinetic comparison of 5 lg Respimat and 18 lg HandiHaler has shown plasma concentrations of tiotropium to have a time course with both inhalers and the 5 lg Respimat dose to produce lower plasma concentrations.(32) COPD itself affects cardiac function in several ways. HRV is reduced, and a lack of response to parasympathetic and sympathetic stimuli is seen.(17,33) A decrease in HRV has been shown in animal studies to decrease the fibrillation threshold,(18) and the risk of arrhythmia is increased in COPD.(17) Pulmonary artery pressure is increased, which causes right heart overload and a risk of right heart failure.(17,20)

Tiotropium can affect cardiac function in two opposing ways: by decreasing parasympathetic input and by indirectly decreasing sympathetic input. By decreasing parasympathetic input to the heart, it can increase the incidence of tachyarrhythmias and ischemia.(30) By relaxing bronchiolar smooth muscle and increasing airflow, it increases oxygenation and decreases hyperinflation in the lung, thus decreasing pulmonary artery pressure, right ventricular overload, and the compensatory sympathetic stimulation of the heart, which could lessen the incidence of tachyarrhythmias and ischemia. Gershon et al. have reported that new use of a long-acting anticholinergic increases the risk of cardiovascular events, and that these events are most likely to occur in the first 2 or 3 weeks of therapy.(34) It takes 2 or 3 weeks for plasma concentrations of tiotropium to reach steady state when inhaled once daily.(5) One wonders if the direct and indirect cardiac actions of tiotropium are in a different balance in relationship to each other during the initial 2–3-week period than they are when steady-state plasma concentrations have been reached, and that is the reason that adverse cardiac events tend to cluster in this initial period. The results in this study are for resting conditions. Another question is how tiotropium affects HRV during exercise, and whether this effect has any relationship to increased cardiac risk. In COPD patients, exercise causes a significant increase in HF that is not seen in normal controls. This relative increase in the portion of HRV that is due to respiratory sinus arrhythmia might be due to the breathing difficulty experienced during exercise by COPD patients. One might expect, although no studies have been done, that tiotropium would inhibit this exercise-induced increase, either through a direct action on muscarinic receptors in the

Table 4. Comparison of SGRQ Parameters of Patients with COPD Before and After Chronic Tiotropium Use Variables Symptom Impact Activity Total

Baseline (n = 70) 56.48 – 24.48 15.52 – 18.22 46.79 – 20.29 31.51 – 16.78

After 1 month (n = 70) a

37.2 – 24.47 5.59 – 9.25a 31.74 – 20.07a 18.54 – 12.53a

After 3 months (n = 56) a

34.68 – 23.09 3.78 – 8.49a 29.49 – 19.05a 16.46 – 12.07a,c

The SGRQ parameters are presented as means – SD, and compared between different times by mixed effect model. a p < 0.05 indicates a significant difference when compared with baseline. b p < 0.05 indicates a significant difference among the three times. c p < 0.05 indicates a significant difference when compared with 1 month.

p value < 0.001b < 0.001b < 0.001b < 0.001b

TIOTROPIUM EFFECTS ON HRV IN COPD PATIENTS

heart, or by an improvement in pulmonary function and oxygenation. An increase in cardiovascular risk is seen with ipratropium compared with tiotropium.(35,36) This could be either the result of the substantial fluctuations in plasma concentration seen in dosing with the short-acting ipratropium, or because ipratropium, unlike tiotropium, is a nonselective blocker and blocks the M2 receptors that provide negative feedback on acetylcholine release, as well as the M3 receptors on airway smooth muscle that cause contraction. Two study limitations are that the present study included only a small number of COPD patients and that only shortterm records were obtained. In addition, the effect of tiotropium in exercise in COPD was not investigated and should be studied in the future. In summary, changes in HRV caused by tiotropium use are not sufficient to explain a possible increase in adverse cardiovascular events. Author Disclosure Statement

The authors declare that there are no conflicts of interest. References

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Received on January 17, 2014 in final form, April 17, 2014 Reviewed by: David Kaminsky Address correspondence to: Dr. Chou-Chin Lan Division of Pulmonary Medicine Department of Internal Medicine Taipei Tzu Chi Hospital Buddhist Tzu Chi Medical Foundation No. 289, Jianguo Rd. Xindian Dist. New Taipei City Taiwan, R.O.C. E-mail: [email protected]