Pulmonary Pharmacology & Therapeutics 30 (2015) 11e15
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Indacaterol and tiotropium combination therapy in patients with chronic obstructive pulmonary disease Sayomi Matsushima a, Naoki Inui a, b, *, Hideki Yasui a, Masato Kono a, Yutaro Nakamura a, Mikio Toyoshima c, Toshihiro Shirai d, Takafumi Suda a a
Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan Department of Respiratory Medicine, Hamamatsu Rosai Hospital, 25 Shougen-cho, Hamamatsu 430-8525, Japan d Department of Respiratory Medicine, Shizuoka General Hospital, 4-27-1 Kita-ando, Shizuoka 420-0881, Japan b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 September 2014 Received in revised form 14 October 2014 Accepted 22 October 2014 Available online 30 October 2014
Background: Combination therapy with a long-acting antimuscarinic agent and a long-acting b2-agonist are recommended in chronic obstructive pulmonary disease (COPD) if control is not adequate with one long-acting bronchodilator alone. We evaluated the effects of indacaterol and tiotropium combination therapy, including the effects of adding indacaterol to tiotropium (indacaterol add-on group) and adding tiotropium to indacaterol (tiotropium add-on group). Methods: We recruited 79 patients with COPD already treated with tiotropium or indacaterol. We undertook pulmonary function tests, the COPD assessment test (CAT), and the multi-frequency forced oscillation technique (to measure respiratory resistance and reactance) before and after 8 weeks of indacaterol and tiotropium combination therapy. Results: The median age was 72.1 years and the mean forced expiratory volume in 1 s (FEV1) as a proportion of predicted was 57.2 ± 18.3%. After 8 weeks of combination therapy, FEV1 and %predicted FEV1 had increased significantly. There was no change in CAT score. For respiratory impedance, combination therapy improved resistance at 5 Hz (R5) and resistance at 20 Hz (R20) in the whole-breath, inspiratory and expiratory phases, and resonant frequency (Fres) in the inspiratory phase. The indacaterol add-on group (43 patients) and tiotropium add-on group (36 patients) showed improvements in FEV1 and % predicted FEV1 over monotherapy, although the CAT score fell significantly in the indacaterol add-on group (p ¼ 0.005). Conclusions: Indacaterol and tiotropium combination therapy improved airflow limitation and respiratory resistances. Adding indacaterol to tiotropium, or tiotropium to indacaterol, had similar effects on airflow limitation. © 2014 Elsevier Ltd. All rights reserved.
Keywords: Chronic obstructive pulmonary disease Combination therapy Forced oscillation technique Indacaterol Tiotropium
1. Introduction Chronic obstructive pulmonary disease (COPD) causes significant morbidity and mortality throughout the world. Airflow limitation in COPD is persistent and incompletely reversible, which leads to potentially distressing symptoms, decreased exercise tolerance, and poor quality of life [1,2]. Current medical treatment aims to manage symptoms, maintain physical activity and
* Corresponding author. Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 4313192, Japan. Tel.: þ81 53 435 2263; fax: þ81 53 435 2386. E-mail address: [email protected] (N. Inui). http://dx.doi.org/10.1016/j.pupt.2014.10.003 1094-5539/© 2014 Elsevier Ltd. All rights reserved.
pulmonary function, and prevent exacerbations. Long-acting inhaled bronchodilators are the mainstay of the pharmacotherapy of COPD [1,2], and may be achieved with a muscarinic antagonist, a b2-adrenergic agonist, or a combination of both. Tiotropium is a commonly used long-acting anti-muscarinic agent (LAMA) that antagonizes cholinergic bronchoconstriction. It has a persistent bronchodilator effect that lasts 24 h [3], and there is abundant evidence that it improves airflow limitation, symptoms and quality of life, and reduces the incidence of exacerbations and hospitalizations [4]. Long-acting b2-agonist bronchodilators (LABAs) act at b2-adrenergic receptors in bronchial smooth muscle to cause bronchodilation. Indacaterol is a novel LABA with a rapid and longacting bronchodilator effect [5]. The clinical benefits of indacaterol therapy on pulmonary function, symptoms, and health status are
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reportedly superior to the older LABAs, salmeterol and formoterol [6,7]. The choice of LAMA and LABA is influenced by therapeutic response and adverse effects; however, it is not known which class of bronchodilators is best for first-line treatment [1], especially in the case of indacaterol. If control is not adequate with long-acting bronchodilator monotherapy, combination therapy with a LAMA and a LABA is recommended [1,2]. Nonetheless, few studies have examined the combination of indacaterol and tiotropium [8], and the benefits and risks of this therapeutic strategy are not fully understood [9]. We undertook a study of combination treatment with tiotropium and indacaterol in Japanese patients with COPD who had already been treated with either tiotropium or indacaterol. We evaluated the effect of combination treatment on pulmonary function, symptoms, and respiratory impedance detected by the multi-frequency forced oscillation technique (FOT). The latter is a non-invasive method of measuring respiratory impedance at different frequencies in an effort-independent manner [10e12], and is a sensitive means of measuring day-to-day respiratory function and changes in response to therapy [10,13,14]. As patients had already received either tiotropium or indacaterol monotherapy, we also examined the impact of adding indacaterol to tiotropium, and tiotropium to indacaterol. 2. Methods 2.1. Patients Patients aged 40 years with a forced expiratory volume in 1 s (FEV1) 30e80% of predicted were eligible for inclusion. All were current or former smokers with a 10 pack-years history of smoking. All had a diagnosis of COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification [1]. We restricted eligible patients to those who were currently being treated with either tiotropium (Spiriva HandiHaler; Boehringer Ingelheim, Ingelheim, Germany) or indacaterol (Onbrez; Novartis Pharmaceuticals, Basel, Switzerland), and had been for at least the previous 8 weeks. Patients were excluded from the study if they met the following criteria: two or more courses of oral corticosteroid or antibiotics in the previous 6 months; admission to hospital because of exacerbation in the previous 6 months; presence of a large bulla or pneumothorax; severe chronic heart failure; symptomatic prostatic hypertrophy; narrow-angle glaucoma or use of long-term oxygen therapy. We also excluded patients who exhibited significantly reversible bronchoconstriction compatible with a diagnosis of bronchial asthma. 2.2. Study design This was a multicenter, open-label, single-arm trial conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board of each participating institution. All patients provided written informed consent. The trial was registered with the University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN ID 000011958). During the study, inhaled LAMAs other than tiotropium, LABAs other than indacaterol, methylxanthine, inhaled and systemic corticosteroids, and mucolytic agents were withdrawn. Eligible patients were treated with once-daily tiotropium 18 mg and indacaterol 150 mg using a HandiHaler device and a Breezhaler device, respectively, for 8 weeks. A short-acting rescue inhaled b2-agonist was used as needed to control symptoms throughout the study. Pulmonary function tests and FOT were performed before and after 8 weeks of treatment. The FEV1, forced vital capacity (FVC), maximum
mid-expiratory flow rate (MMF), and inspiratory capacity were measured according to the American Thoracic Society/European Respiratory Society recommendations. FVC and FEV1 were expressed as percentages of the predicted values according to the algorithms of the Japanese Respiratory Society [15]. All measurements were taken before use of the drugs in the morning and at least 1 h after drinking and eating. Short-acting b2-agonists had not been used for 12 h before these tests in all cases. Symptoms and health status were assessed using the COPD assessment test (CAT) [16]. 2.3. Measurement of respiratory impedance Respiratory impedance was measured using a commercially available multi-frequency FOT device (MostGraph-01; Chest M.I. Co. Ltd., Tokyo, Japan) as previously described [12,17,18] following a standard protocol [10]. Briefly, impulse oscillatory signals generated by a loud speaker at 0.25-s intervals were applied to the respiratory system through a mouthpiece during tidal breathing at rest. Mouth pressure and flow signals were measured and calculated, and the resistance and reactance properties obtained at different oscillatory frequencies. The FOT was performed before pulmonary function testing. During measurements, the subjects supported their cheeks firmly while sitting with their neck in a comfortable neutral posture. We measured the resistance at 5 Hz (R5), resistance at 20 Hz (R20), reactance at 5 Hz (X5), resonant frequency (Fres, where the reactance crosses zero and the elastic and inertial forces are equal but opposite in magnitude), and lowfrequency reactance area (ALX, the integral of X5 to Fres). Each oscillatory index was reported in the whole-breath, inspiratory, and expiratory phases. 2.4. Statistical analysis The therapeutic benefits of indacaterol and tiotropium combination treatment were assessed by the extent of changes in pulmonary function, FOT and CAT. The Wilcoxon test was used for continuous variables and the chi-square test for categorized groups. All p values were two-sided, and values of p < 0.05 were considered to be statistically significant. All data are described as means ± standard deviation (SD) unless otherwise indicated. All analyses were undertaken using SPSS Statistics (version 21.0; IBM, Armonk, NY, USA). 3. Results 3.1. Characteristics of patients with COPD We recruited 79 patients with COPD (Table 1). The mean age was 72.1 years (range: 52e89 years). All were former or current
Table 1 Characteristics of study participants. Number of patients Age, years (range) Sex Male Female Smoking status Former smoker Current smoker Pack-years (range) Body mass index (kg/m2) GOLD criteria (number) I/II/III/IV
79 72.1 ± 8.6 (52e89) 76 (96.2%) 3 (3.8%) 65 (82.3%) 14 (17.7%) 60.5 (20e150) 22.1 ± 3.6 18/30/27/4
Data are expressed as number (percentage) or mean ± standard deviation. GOLD, global initiative for chronic obstructive lung disease.
S. Matsushima et al. / Pulmonary Pharmacology & Therapeutics 30 (2015) 11e15
smokers with a mean smoking history of 60.5 pack-years. Eighteen (22.8%) were classified as GOLD stage I, 30 (38.0%) as stage II, 27 (34.2%) as stage III, and four (5.0%) as stage IV. The mean FVC, FEV1 and inspiratory capacity at enrollment were 3.01 L, 1.66 L, and 1.96 L, respectively. The mean CAT score was 8.89; 32 patients (40.5%) had a score of more than 10. Forty-three patients (54.4%) had received tiotropium at enrollment and therefore were given additional indacaterol for 8 weeks (indacaterol add-on group). Thirty-six (45.6%) had received indacaterol treatment at enrollment and were given additional tiotropium (tiotropium add-on group). The baseline characteristics of the indacaterol add-on and tiotropium add-on groups at enrollment were broadly comparable.
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indacaterol add-on group, R20 significantly improved in the wholebreath phase, and R5 and R20 improved in the inspiratory phase. 3.4. Safety Sixteen patients reported adverse events, the most common of which was cough (9.5%). However, this was tolerable and no patient elected to discontinue treatment. There were no episodes of irreversible toxicity that were judged to have been caused by treatment. Five patients (6.0%) experienced clinical deterioration that required treatment with systemic steroids and antibiotics. 4. Discussion
3.2. Lung function and COPD control After 8 weeks of combination therapy with indacaterol and tiotropium, FEV1, percentage of predicted FEV1, FEV1/FVC, and MMF were significantly increased. These improvements occurred irrespective of the initial severity of airflow limitation. There was no change in inspiratory capacity or CAT score (Table 2). According to the GOLD classification criteria, combination therapy improved inspiratory capacity (from 1.59 ± 0.43 L to 1.74 ± 0.40 L, p ¼ 0.041) and CAT score (from 12.59 ± 7.15 to 10.44 ± 7.34, p ¼ 0.008) in patients with stage III disease. Sub-group analysis of patients informed by their initial therapeutic regime revealed significant improvements in FEV1 (by 51 mL, 95% confidence interval [95% CI]: 10e92 mL in the tiotropium add-on group; and by 88 mL, 95% CI: 39e137 mL in the indacaterol add-on group) and percentage of predicted FEV1 over monotherapy. There was no significant difference in improvements in pulmonary function between the tiotropium and indacaterol add-on groups. There were significant improvements in FVC and CAT score in the indacaterol add-on group (Table 2). There were no significant differences in any of the outcome measures between the tiotropium and indacaterol add-on groups save for the CAT score: there was a significant reduction in the indacaterol add-on group compared with the tiotropium add-on group (1.54 ± 3.55 versus 1.42 ± 4.86, respectively; p ¼ 0.005). 3.3. Forced oscillation technique The respiratory resistance and respiratory reactance in the whole-breath, inspiratory, and expiratory phases are shown in Table 3: R5 and R20 were significantly decreased in all phases after 8 weeks of indacaterol and tiotropium combination therapy. In addition, Fres was significantly decreased in the inspiratory phase. When compared according to treatment group, the tiotropium addon group showed improvements in R5 and R20 in all phases. In the
We assessed the therapeutic benefit of combination therapy with indacaterol and tiotropium in 79 patients with COPD, and found that after 8 weeks of treatment FEV1, percentage of predicted FEV1, FEV1/FVC, and MMF significantly improved, and that CAT score fell in patients with GOLD stage III disease. As for respiratory impedance, combination therapy decreased R5, R20 and Fres. Although the extent of the improvement in respiratory function was comparable between patients already treated with tiotropium and those receiving indacaterol monotherapy, patients receiving indacaterol add-on therapy showed significant improvements in CAT score. Indacaterol was a newly licensed LABA. As a monotherapy, indacaterol can reportedly effect a 60e100 mL greater improvement in trough FEV1 than salmeterol or formoterol 12 h after dosing [6,7]. With respect to dyspnea and health status, indacaterol reportedly effects better outcomes than twice-daily salmeterol and formoterol [6,7]. The relative efficacy of indacaterol on pulmonary function, dyspnea and health status is reportedly at least noninferior to tiotropium [5,19e21]. These advantages suggest that combination therapy with tiotropium would be a promising strategy. Mahler et al. investigated the combination of indacaterol and tiotropium in COPD in two identical studies, INTRUST-1 and INTRUST-2 [22]. Combination therapy significantly increased FEV1 at week 12 by 70e80 mL and inspiratory capacity by 100e130 mL. Indacaterol plus tiotropium also improved symptom scores and reduced the need for rescue salbutamol. On sub-group analysis according to COPD severity, the improvement in FEV1 was 90 mL in those with moderate disease and 60e70 mL in severe disease. Cough (in about 10% of participants) and deterioration in COPD were common adverse events in both studies. Although cough is often reported as a side effect of indacaterol-containing therapy, most cases are mild and only one participant in over 1000 in INTRUST-1 and INTRUST-2 discontinued therapy because of it. We found that combination therapy increased trough FEV1 by 70 mL in
Table 2 Pulmonary function and COPD assessment scores before and after 8 weeks of indacaterol and tiotropium combination treatment. Indacaterol add-on group (n ¼ 43)
Tiotropium add-on group (n ¼ 36)
Baseline
After
Baseline
After
Baseline
After
3.01 1.66 63.2 54.7 1.96 0.86 8.89
3.08 1.73 66.1 55.7 2.00 0.88 8.70
3.04 1.64 61.6 53.8 1.93 0.90 9.95
3.14 1.73 65.4 54.4 2.02 0.86 8.41
2.99 1.67 65.1 55.7 1.99 0.83 7.61
3.00 1.72 66.9 57.1 1.98 0.90 9.02
All patients
FVC (L) FEV1 (L) FEV1, % predicted (%) FEV1/FVC (%) Inspiratory capacity (L) MMF (L/s) CAT
(0.72) (0.64) (20.1) (15.0) (0.55) (0.69) (6.55)
(0.72) (0.64)** (19.3)** (14.9)* (0.50) (0.64)* (6.30)
(0.78) (0.70) (20.7) (15.5) (0.58) (0.68) (7.13)
(0.72)* (0.68)* (18.6)* (14.9) (0.50) (0.59) (6.40)*,y
(0.66) (0.57) (19.4) (14.6) (0.53) (0.71) (5.54)
Values are expressed as mean (standard deviation). FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s; MMF, maximum mid-expiratory flow rate; CAT, COPD assessment test. * p < 0.05 versus baseline. ** p < 0.001 versus baseline. y p < 0.05 difference between indacaterol and tiotropium add-on groups.
(0.72) (0.59)* (20.4)* (15.0) (0.51) (0.71) (6.25)
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S. Matsushima et al. / Pulmonary Pharmacology & Therapeutics 30 (2015) 11e15
Table 3 Respiratory resistance and respiratory reactance in the whole-breath, inspiratory and expiratory phases before and after 8 weeks of indacaterol and tiotropium treatment. All patients Baseline Whole breath R5 3.11 (1.18) R20 2.44 (0.84) R5eR20 0.62 (0.48) X5 0.98 (1.09) Fres 12.01 (5.86) ALX 7.11 (10.60) Expiratory phase R5 3.44 (1.36) R20 2.65 (0.91) R5eR20 0.79 (0.63) X5 1.21 (1.52) Fres 12.76 (7.03) ALX 10.08 (15.93) Inspiratory phase R5 2.77 (1.10) R20 2.33 (0.82) R5eR20 0.43 (0.44) X5 0.65 (0.93) Fres 11.11 (4.86) ALX 4.06 (7.38)
After
Indacaterol add-on group (n ¼ 43)
Tiotropium add-on group (n ¼ 36)
Baseline
After
Baseline
After
2.87 2.25 0.61 0.94 11.50 6.58
(1.09)** (0.64)** (0.46) (1.00) (5.53) (9.55)
3.04 2.40 0.64 1.05 12.41 7.65
(1.23) (0.87) (0.50) (1.18) (5.79) (10.58)
2.83 2.20 0.63 0.96 11.78 6.63
(0.99) (0.62)* (0.44) (1.01) (5.25) (9.40)
3.19 2.59 0.60 0.90 11.53 6.46
(1.14) (0.81) (0.47) (0.99) (5.98) (10.74)
2.91 2.32 0.59 0.91 11.15 6.51
(1.21)* (0.84)* (0.48) (1.00) (5.90) (9.85)
3.25 2.44 0.81 1.18 12.56 9.28
(1.27)** (0.80)** (0.57) (1.46) (6.88) (14.63)
3.35 2.55 0.80 1.31 13.36 11.32
(1.41) (0.92) (0.69) (1.60) (7.07) (16.44)
3.25 2.39 0.85 1.23 13.10 9.52
(1.16) (0.71) (0.53) (1.47) (6.63) (14.39)
3.55 2.77 0.78 1.08 12.04 8.61
(1.31) (0.90) (0.57) (1.42) (7.02) (15.39)
3.25 (1.39)* 2.49 (0.90)* 0.77 (0.61) 1.12 (1.46) 11.92 (7.22) 9.00 (15.10)
2.49 2.07 0.41 0.67 10.48 3.88
(1.00)** (0.72)** (0.41) (0.59) (4.56)* (5.51)
2.72 2.25 0.47 0.60 11.47 3.87
(1.14) (0.86) (0.46) (1.14) (4.85) (8.06)
2.42 2.00 0.41 0.68 10.56 3.76
(0.90)* (0.59)* (0.43) (0.59) (4.27) (5.34)
2.83 2.42 0.40 0.71 10.69 4.29
(1.07) (0.77) (0.42) (0.61) (4.91) (6.57)
2.57 2.16 0.41 0.67 10.38 4.01
(1.12)* (0.85)* (0.40) (0.60) (4.94) (5.78)
*
p < 0.05 versus baseline. p < 0.001 versus baseline. p < 0.05 difference between indacaterol and tiotropium add-on groups.
** y
all patients and by 90 mL in patients with GOLD stages II and III disease. We found that 9.5% patients experienced cough, but no patient discontinued indacaterol or tiotropium during the 8-week study period. We recruited stable patients who had no history of exacerbation or hospitalization for COPD in the previous 6 months and had already received monotherapy with indacaterol or tiotropium, enabling us to compare the effects of adding indacaterol to tiotropium and tiotropium to indacaterol. The relative benefits of each agent as first-line therapy has not been established [23] and current guidelines do not recommend which should be used first [1]. Furthermore, it is not known whether the choice of first-line bronchodilator influences the response of an additional bronchodilator added in combination. In our cohort, the indacaterol add-on and tiotropium add-on groups experienced broadly similar additional improvement in pulmonary function. The addition of indacaterol to tiotropium increased FEV1 by a mean of 88 mL and adding tiotropium to indacaterol increased FEV1 by a mean of 51 mL, which was not a significant difference. We also used the CAT questionnaire to assess the global impact of COPD on health status [16]. The indacaterol add-on group had a significantly improved CAT score. The accepted minimum clinically important difference [24], a decrease 2 points, was observed in 18 patients (41.9%) in the indacaterol add-on group and seven patients (19.4%) in the tiotropium add-on group. Cazzola et al. assessed the additional effect of tiotropium on formoterol in patients receiving regular monotherapy [25]. Patients established on inhaled tiotropium once daily or formoterol twice daily were given the other as an additional bronchodilator. Those who received formoterol in addition to tiotropium demonstrated a mean maximal change in 3-h post-dose FEV1 of 81 mL (95% CI: 29e133 mL). Those in whom tiotropium was added to formoterol showed a mean 54-mL (95% CI: 16e92 mL) improvement in FEV1. In contrast, a previous study has reported that the sequence of introduction of anticholinergic and adrenergic agents may indeed influence the extent of additional bronchodilation [26]. When the adrenergic agent was given first, further bronchodilation was achieved with an additional anticholinergic agent; however, no additional bronchodilation was achieved in
those who received an adrenergic agent after the anticholinergic agent. In this study it was reportedly difficult to distinguish between the effects of each drug, and the effect of the additional bronchodilator may have been influenced by a carry-over effect from the first [25]. In our study, patients established on tiotropium experienced an additional improvement in FEV1 with indacaterol and vice versa, suggesting that order of initiating bronchodilator therapy with indacaterol and tiotropium does not influence the effects that can be achieved with combination therapy. The FOT measures respiratory impedance non-invasively at different frequencies, with the results reported as threedimensional color images on a time axis. Respiratory impedance comprises resistance and reactance. Resistance is an index of airway caliber and increased resistance contributes to airflow limitation in COPD [10,27]. Reactance reflects the elastic and inertial properties of the lung [10]. We found that the resistance components R5 and R20 were significantly altered by treatment with indacaterol and tiotropium. Bronchodilators increase central and small airway diameters and decrease airway resistance [13], the latter reflected in the improvement in indices of resistance. Although it remains controversial whether FOT can differentiate between the central and peripheral airways and demonstrate peripheral airway disease directly in practice, there is a body of opinion that R5 and R20 reflect total and central airway resistance. As R5 and R20 were significantly decreased after 8 weeks of indacaterol and tiotropium treatment, combination therapy might act mainly at the central airways. As well as indacaterol and tiotropium, other bronchodilator combinations have been studied using the FOT [28,29]. Interestingly, significant improvements in FOT variables occurred even in the absence of a significant change in spirometry or ventilation parameters. When used in patients with COPD, bronchodilators cause complex changes in pulmonary physiology, and the FOT is a sensitive means of detecting small changes in response to therapy [10,13,14]. In this study, correlations between FOT and different pulmonary function parameters and CAT scores were evaluated. There was a correlation between Fres and the percentage of predicted FEV1; however the correlation coefficient was low
S. Matsushima et al. / Pulmonary Pharmacology & Therapeutics 30 (2015) 11e15
(Spearman's rank correlation coefficient, r ¼ 0.36, p ¼ 0.001). Although FOT might represent a different property of the lung from preexisting parameters, the significance of FOT in the clinical setting needs further clarification. Our study had some limitations. First, it was a single-arm study, and a further crossover study with three arms (tiotropium, indacaterol, and tiotropium plus indacaterol) is needed to confirm our results. Second, the study period was 8 weeks. Although indacaterol and tiotropium combination therapy improved airflow limitation, a study with a longer follow-up period is necessary to assess the effects on exacerbation and mortality. Rodrigo et al. found that combination therapy with tiotropium and formoterol or salmeterol did not reduce the rate of COPD exacerbations compared with tiotropium monotherapy. Their systematic review reported that rate of exacerbations (per 100 patient-years) was 32.1 in the LABA/ tiotropium group and 33.1 in the tiotropium group [23]. In conclusion, combination therapy with indacaterol and tiotropium improved airflow limitation and respiratory resistance. Adding indacaterol to tiotropium or tiotropium to indacaterol has similar effects on airflow limitation. As the combination of these once-daily long-acting bronchodilators can simplify the treatment regimen for patients and improve adherence, combination therapy with tiotropium plus indacaterol seems likely to be a useful treatment strategy for COPD. Acknowledgments No financial support was provided for this study. References [1] Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease. Updated 2014. http://www.goldcopd.org/guidelines-global-strategy-fordiagnosis-management.html. [accessed 20.05.14] [2] Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007;176:532e55. [3] van Noord JA, Bantje TA, Eland ME, Korducki L, Cornelissen PJ. A randomised controlled comparison of tiotropium nd ipratropium in the treatment of chronic obstructive pulmonary disease. The Dutch Tiotropium Study Group. Thorax 2000;55:289e94. [4] Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359:1543e54. [5] Vogelmeier C, Ramos-Barbon D, Jack D, Piggott S, Owen R, Higgins M, et al. Indacaterol provides 24-hour bronchodilation in COPD: a placebo-controlled blinded comparison with tiotropium. Respir Res 2010;11:135. [6] Dahl R, Chung KF, Buhl R, Magnussen H, Nonikov V, Jack D, et al. Efficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twicedaily formoterol in COPD. Thorax 2010;65:473e9. [7] Kornmann O, Dahl R, Centanni S, Dogra A, Owen R, Lassen C, et al., investigators I-s. Once-daily indacaterol versus twice-daily salmeterol for COPD: a placebo-controlled comparison. Eur Respir J 2011;37:273e9. [8] Tashkin DP, Ferguson GT. Combination bronchodilator therapy in the management of chronic obstructive pulmonary disease. Respir Res 2013;14:49.
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[9] Karner C, Cates CJ. Long-acting beta(2)-agonist in addition to tiotropium versus either tiotropium or long-acting beta(2)-agonist alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2012;4: CD008989. [10] Oostveen E, MacLeod D, Lorino H, Farre R, Hantos Z, Desager K, et al. The forced oscillation technique in clinical practice: methodology, recommendations and future developments. Eur Respir J 2003;22:1026e41. [11] Paredi P, Goldman M, Alamen A, Ausin P, Usmani OS, Pride NB, et al. Comparison of inspiratory and expiratory resistance and reactance in patients with asthma and chronic obstructive pulmonary disease. Thorax 2010;65: 263e7. [12] Mori K, Shirai T, Mikamo M, Shishido Y, Akita T, Morita S, et al. Colored 3dimensional analyses of respiratory resistance and reactance in COPD and asthma. COPD 2011;8:456e63. [13] Borrill ZL, Houghton CM, Woodcock AA, Vestbo J, Singh D. Measuring bronchodilation in COPD clinical trials. Br J Clin Pharmacol 2005;59:379e84. [14] Borrill ZL, Houghton CM, Tal-Singer R, Vessey SR, Faiferman I, Langley SJ, et al. The use of plethysmography and oscillometry to compare long-acting bronchodilators in patients with COPD. Br J Clin Pharmacol 2008;65:244e52. [15] Japanese Respiratory Society. Guidelines of respiratory function tests: spirometry, flow-volume curve, and diffusion capacity of the lung (in Japanese). Tokyo: Japanese Respiratory Society; 2004. [16] Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation of the COPD Assessment Test. Eur Respir J 2009;34: 648e54. [17] Mori K, Shirai T, Mikamo M, Shishido Y, Akita T, Morita S, et al. Respiratory mechanics measured by forced oscillation technique in combined pulmonary fibrosis and emphysema. Respir Physiol Neurobiol 2013;185:235e40. [18] Shirai T, Mori K, Mikamo M, Shishido Y, Akita T, Morita S, et al. Respiratory mechanics and peripheral airway inflammation and dysfunction in asthma. Clin Exp Allergy 2013;43:521e6. Rodrigo GJ, Neffen H. Comparison of indacaterol with tiotropium or twice-daily long-acting beta -agonists for stable COPD: a systematic review. Chest 2012;142:1104e10. [19] Donohue JF, Fogarty C, Lotvall J, Mahler DA, Worth H, Yorgancioglu A, et al. Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Am J Respir Crit Care Med 2010;182:155e62. [20] Buhl R, Dunn LJ, Disdier C, Lassen C, Amos C, Henley M, et al. Blinded 12-week comparison of once-daily indacaterol and tiotropium in COPD. Eur Respir J 2011;38:797e803. [21] Cope S, Donohue JF, Jansen JP, Kraemer M, Capkun-Niggli G, Baldwin M, et al. Comparative efficacy of long-acting bronchodilators for COPD e a network meta-analysis. Respir Res 2013;14:100. [22] Mahler DA, D'Urzo A, Bateman ED, Ozkan SA, White T, Peckitt C, et al. Concurrent use of indacaterol plus tiotropium in patients with COPD provides superior bronchodilation compared with tiotropium alone: a randomised, double-blind comparison. Thorax 2012;67:781e8. [23] Rodrigo GJ, Plaza V, Castro-Rodriguez JA. Comparison of three combined pharmacological approaches with tiotropium monotherapy in stable moderate to severe COPD: a systematic review. Pulm Pharmacol Ther 2012;25:40e7. [24] Kon SS, Canavan JL, Jones SE, Nolan CM, Clark AL, Dickson MJ, et al. Minimum clinically important difference for the COPD assessment test: a prospective analysis. Lancet Respir Med 2014;2:195e203. [25] Cazzola M, Noschese P, Salzillo A, De Giglio C, D'Amato G, Matera MG. Bronchodilator response to formoterol after regular tiotropium or to tiotropium after regular formoterol in COPD patients. Respir Med 2005;99:524e8. [26] Gross NJ, Skorodin MS. Role of the parasympathetic system in airway obstruction due to emphysema. N Engl J Med 1984;311:421e5. [27] Williamson PA, Clearie K, Menzies D, Vaidyanathan S, Lipworth BJ. Assessment of small-airways disease using alveolar nitric oxide and impulse oscillometry in asthma and COPD. Lung 2011;189:121e9. [28] Abe T, Setoguchi Y, Kono Y, Togashi Y, Sugiyama S, Tanakadate M, et al. Effects of inhaled tiotropium plus transdermal tulobuterol versus tiotropium alone on impulse oscillation system (IOS)-assessed measures of peripheral airway resistance and reactance, lung function and quality of life in patients with COPD: a randomized crossover study. Pulm Pharmacol Ther 2011;24:617e24. [29] Timmins SC, Diba C, Schoeffel RE, Salome CM, King GG, Thamrin C. Changes in oscillatory impedance and nitrogen washout with combination fluticasone/ salmeterol therapy in COPD. Respir Med 2014;108:344e50.
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Pulmonary Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/ypupt
Indacaterol and tiotropium combination therapy in patients with chronic obstructive pulmonary disease Sayomi Matsushima a, Naoki Inui a, b, *, Hideki Yasui a, Masato Kono a, Yutaro Nakamura a, Mikio Toyoshima c, Toshihiro Shirai d, Takafumi Suda a a
Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan Department of Respiratory Medicine, Hamamatsu Rosai Hospital, 25 Shougen-cho, Hamamatsu 430-8525, Japan d Department of Respiratory Medicine, Shizuoka General Hospital, 4-27-1 Kita-ando, Shizuoka 420-0881, Japan b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 September 2014 Received in revised form 14 October 2014 Accepted 22 October 2014 Available online 30 October 2014
Background: Combination therapy with a long-acting antimuscarinic agent and a long-acting b2-agonist are recommended in chronic obstructive pulmonary disease (COPD) if control is not adequate with one long-acting bronchodilator alone. We evaluated the effects of indacaterol and tiotropium combination therapy, including the effects of adding indacaterol to tiotropium (indacaterol add-on group) and adding tiotropium to indacaterol (tiotropium add-on group). Methods: We recruited 79 patients with COPD already treated with tiotropium or indacaterol. We undertook pulmonary function tests, the COPD assessment test (CAT), and the multi-frequency forced oscillation technique (to measure respiratory resistance and reactance) before and after 8 weeks of indacaterol and tiotropium combination therapy. Results: The median age was 72.1 years and the mean forced expiratory volume in 1 s (FEV1) as a proportion of predicted was 57.2 ± 18.3%. After 8 weeks of combination therapy, FEV1 and %predicted FEV1 had increased significantly. There was no change in CAT score. For respiratory impedance, combination therapy improved resistance at 5 Hz (R5) and resistance at 20 Hz (R20) in the whole-breath, inspiratory and expiratory phases, and resonant frequency (Fres) in the inspiratory phase. The indacaterol add-on group (43 patients) and tiotropium add-on group (36 patients) showed improvements in FEV1 and % predicted FEV1 over monotherapy, although the CAT score fell significantly in the indacaterol add-on group (p ¼ 0.005). Conclusions: Indacaterol and tiotropium combination therapy improved airflow limitation and respiratory resistances. Adding indacaterol to tiotropium, or tiotropium to indacaterol, had similar effects on airflow limitation. © 2014 Elsevier Ltd. All rights reserved.
Keywords: Chronic obstructive pulmonary disease Combination therapy Forced oscillation technique Indacaterol Tiotropium
1. Introduction Chronic obstructive pulmonary disease (COPD) causes significant morbidity and mortality throughout the world. Airflow limitation in COPD is persistent and incompletely reversible, which leads to potentially distressing symptoms, decreased exercise tolerance, and poor quality of life [1,2]. Current medical treatment aims to manage symptoms, maintain physical activity and
* Corresponding author. Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 4313192, Japan. Tel.: þ81 53 435 2263; fax: þ81 53 435 2386. E-mail address: [email protected] (N. Inui). http://dx.doi.org/10.1016/j.pupt.2014.10.003 1094-5539/© 2014 Elsevier Ltd. All rights reserved.
pulmonary function, and prevent exacerbations. Long-acting inhaled bronchodilators are the mainstay of the pharmacotherapy of COPD [1,2], and may be achieved with a muscarinic antagonist, a b2-adrenergic agonist, or a combination of both. Tiotropium is a commonly used long-acting anti-muscarinic agent (LAMA) that antagonizes cholinergic bronchoconstriction. It has a persistent bronchodilator effect that lasts 24 h [3], and there is abundant evidence that it improves airflow limitation, symptoms and quality of life, and reduces the incidence of exacerbations and hospitalizations [4]. Long-acting b2-agonist bronchodilators (LABAs) act at b2-adrenergic receptors in bronchial smooth muscle to cause bronchodilation. Indacaterol is a novel LABA with a rapid and longacting bronchodilator effect [5]. The clinical benefits of indacaterol therapy on pulmonary function, symptoms, and health status are
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S. Matsushima et al. / Pulmonary Pharmacology & Therapeutics 30 (2015) 11e15
reportedly superior to the older LABAs, salmeterol and formoterol [6,7]. The choice of LAMA and LABA is influenced by therapeutic response and adverse effects; however, it is not known which class of bronchodilators is best for first-line treatment [1], especially in the case of indacaterol. If control is not adequate with long-acting bronchodilator monotherapy, combination therapy with a LAMA and a LABA is recommended [1,2]. Nonetheless, few studies have examined the combination of indacaterol and tiotropium [8], and the benefits and risks of this therapeutic strategy are not fully understood [9]. We undertook a study of combination treatment with tiotropium and indacaterol in Japanese patients with COPD who had already been treated with either tiotropium or indacaterol. We evaluated the effect of combination treatment on pulmonary function, symptoms, and respiratory impedance detected by the multi-frequency forced oscillation technique (FOT). The latter is a non-invasive method of measuring respiratory impedance at different frequencies in an effort-independent manner [10e12], and is a sensitive means of measuring day-to-day respiratory function and changes in response to therapy [10,13,14]. As patients had already received either tiotropium or indacaterol monotherapy, we also examined the impact of adding indacaterol to tiotropium, and tiotropium to indacaterol. 2. Methods 2.1. Patients Patients aged 40 years with a forced expiratory volume in 1 s (FEV1) 30e80% of predicted were eligible for inclusion. All were current or former smokers with a 10 pack-years history of smoking. All had a diagnosis of COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification [1]. We restricted eligible patients to those who were currently being treated with either tiotropium (Spiriva HandiHaler; Boehringer Ingelheim, Ingelheim, Germany) or indacaterol (Onbrez; Novartis Pharmaceuticals, Basel, Switzerland), and had been for at least the previous 8 weeks. Patients were excluded from the study if they met the following criteria: two or more courses of oral corticosteroid or antibiotics in the previous 6 months; admission to hospital because of exacerbation in the previous 6 months; presence of a large bulla or pneumothorax; severe chronic heart failure; symptomatic prostatic hypertrophy; narrow-angle glaucoma or use of long-term oxygen therapy. We also excluded patients who exhibited significantly reversible bronchoconstriction compatible with a diagnosis of bronchial asthma. 2.2. Study design This was a multicenter, open-label, single-arm trial conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board of each participating institution. All patients provided written informed consent. The trial was registered with the University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN ID 000011958). During the study, inhaled LAMAs other than tiotropium, LABAs other than indacaterol, methylxanthine, inhaled and systemic corticosteroids, and mucolytic agents were withdrawn. Eligible patients were treated with once-daily tiotropium 18 mg and indacaterol 150 mg using a HandiHaler device and a Breezhaler device, respectively, for 8 weeks. A short-acting rescue inhaled b2-agonist was used as needed to control symptoms throughout the study. Pulmonary function tests and FOT were performed before and after 8 weeks of treatment. The FEV1, forced vital capacity (FVC), maximum
mid-expiratory flow rate (MMF), and inspiratory capacity were measured according to the American Thoracic Society/European Respiratory Society recommendations. FVC and FEV1 were expressed as percentages of the predicted values according to the algorithms of the Japanese Respiratory Society [15]. All measurements were taken before use of the drugs in the morning and at least 1 h after drinking and eating. Short-acting b2-agonists had not been used for 12 h before these tests in all cases. Symptoms and health status were assessed using the COPD assessment test (CAT) [16]. 2.3. Measurement of respiratory impedance Respiratory impedance was measured using a commercially available multi-frequency FOT device (MostGraph-01; Chest M.I. Co. Ltd., Tokyo, Japan) as previously described [12,17,18] following a standard protocol [10]. Briefly, impulse oscillatory signals generated by a loud speaker at 0.25-s intervals were applied to the respiratory system through a mouthpiece during tidal breathing at rest. Mouth pressure and flow signals were measured and calculated, and the resistance and reactance properties obtained at different oscillatory frequencies. The FOT was performed before pulmonary function testing. During measurements, the subjects supported their cheeks firmly while sitting with their neck in a comfortable neutral posture. We measured the resistance at 5 Hz (R5), resistance at 20 Hz (R20), reactance at 5 Hz (X5), resonant frequency (Fres, where the reactance crosses zero and the elastic and inertial forces are equal but opposite in magnitude), and lowfrequency reactance area (ALX, the integral of X5 to Fres). Each oscillatory index was reported in the whole-breath, inspiratory, and expiratory phases. 2.4. Statistical analysis The therapeutic benefits of indacaterol and tiotropium combination treatment were assessed by the extent of changes in pulmonary function, FOT and CAT. The Wilcoxon test was used for continuous variables and the chi-square test for categorized groups. All p values were two-sided, and values of p < 0.05 were considered to be statistically significant. All data are described as means ± standard deviation (SD) unless otherwise indicated. All analyses were undertaken using SPSS Statistics (version 21.0; IBM, Armonk, NY, USA). 3. Results 3.1. Characteristics of patients with COPD We recruited 79 patients with COPD (Table 1). The mean age was 72.1 years (range: 52e89 years). All were former or current
Table 1 Characteristics of study participants. Number of patients Age, years (range) Sex Male Female Smoking status Former smoker Current smoker Pack-years (range) Body mass index (kg/m2) GOLD criteria (number) I/II/III/IV
79 72.1 ± 8.6 (52e89) 76 (96.2%) 3 (3.8%) 65 (82.3%) 14 (17.7%) 60.5 (20e150) 22.1 ± 3.6 18/30/27/4
Data are expressed as number (percentage) or mean ± standard deviation. GOLD, global initiative for chronic obstructive lung disease.
S. Matsushima et al. / Pulmonary Pharmacology & Therapeutics 30 (2015) 11e15
smokers with a mean smoking history of 60.5 pack-years. Eighteen (22.8%) were classified as GOLD stage I, 30 (38.0%) as stage II, 27 (34.2%) as stage III, and four (5.0%) as stage IV. The mean FVC, FEV1 and inspiratory capacity at enrollment were 3.01 L, 1.66 L, and 1.96 L, respectively. The mean CAT score was 8.89; 32 patients (40.5%) had a score of more than 10. Forty-three patients (54.4%) had received tiotropium at enrollment and therefore were given additional indacaterol for 8 weeks (indacaterol add-on group). Thirty-six (45.6%) had received indacaterol treatment at enrollment and were given additional tiotropium (tiotropium add-on group). The baseline characteristics of the indacaterol add-on and tiotropium add-on groups at enrollment were broadly comparable.
13
indacaterol add-on group, R20 significantly improved in the wholebreath phase, and R5 and R20 improved in the inspiratory phase. 3.4. Safety Sixteen patients reported adverse events, the most common of which was cough (9.5%). However, this was tolerable and no patient elected to discontinue treatment. There were no episodes of irreversible toxicity that were judged to have been caused by treatment. Five patients (6.0%) experienced clinical deterioration that required treatment with systemic steroids and antibiotics. 4. Discussion
3.2. Lung function and COPD control After 8 weeks of combination therapy with indacaterol and tiotropium, FEV1, percentage of predicted FEV1, FEV1/FVC, and MMF were significantly increased. These improvements occurred irrespective of the initial severity of airflow limitation. There was no change in inspiratory capacity or CAT score (Table 2). According to the GOLD classification criteria, combination therapy improved inspiratory capacity (from 1.59 ± 0.43 L to 1.74 ± 0.40 L, p ¼ 0.041) and CAT score (from 12.59 ± 7.15 to 10.44 ± 7.34, p ¼ 0.008) in patients with stage III disease. Sub-group analysis of patients informed by their initial therapeutic regime revealed significant improvements in FEV1 (by 51 mL, 95% confidence interval [95% CI]: 10e92 mL in the tiotropium add-on group; and by 88 mL, 95% CI: 39e137 mL in the indacaterol add-on group) and percentage of predicted FEV1 over monotherapy. There was no significant difference in improvements in pulmonary function between the tiotropium and indacaterol add-on groups. There were significant improvements in FVC and CAT score in the indacaterol add-on group (Table 2). There were no significant differences in any of the outcome measures between the tiotropium and indacaterol add-on groups save for the CAT score: there was a significant reduction in the indacaterol add-on group compared with the tiotropium add-on group (1.54 ± 3.55 versus 1.42 ± 4.86, respectively; p ¼ 0.005). 3.3. Forced oscillation technique The respiratory resistance and respiratory reactance in the whole-breath, inspiratory, and expiratory phases are shown in Table 3: R5 and R20 were significantly decreased in all phases after 8 weeks of indacaterol and tiotropium combination therapy. In addition, Fres was significantly decreased in the inspiratory phase. When compared according to treatment group, the tiotropium addon group showed improvements in R5 and R20 in all phases. In the
We assessed the therapeutic benefit of combination therapy with indacaterol and tiotropium in 79 patients with COPD, and found that after 8 weeks of treatment FEV1, percentage of predicted FEV1, FEV1/FVC, and MMF significantly improved, and that CAT score fell in patients with GOLD stage III disease. As for respiratory impedance, combination therapy decreased R5, R20 and Fres. Although the extent of the improvement in respiratory function was comparable between patients already treated with tiotropium and those receiving indacaterol monotherapy, patients receiving indacaterol add-on therapy showed significant improvements in CAT score. Indacaterol was a newly licensed LABA. As a monotherapy, indacaterol can reportedly effect a 60e100 mL greater improvement in trough FEV1 than salmeterol or formoterol 12 h after dosing [6,7]. With respect to dyspnea and health status, indacaterol reportedly effects better outcomes than twice-daily salmeterol and formoterol [6,7]. The relative efficacy of indacaterol on pulmonary function, dyspnea and health status is reportedly at least noninferior to tiotropium [5,19e21]. These advantages suggest that combination therapy with tiotropium would be a promising strategy. Mahler et al. investigated the combination of indacaterol and tiotropium in COPD in two identical studies, INTRUST-1 and INTRUST-2 [22]. Combination therapy significantly increased FEV1 at week 12 by 70e80 mL and inspiratory capacity by 100e130 mL. Indacaterol plus tiotropium also improved symptom scores and reduced the need for rescue salbutamol. On sub-group analysis according to COPD severity, the improvement in FEV1 was 90 mL in those with moderate disease and 60e70 mL in severe disease. Cough (in about 10% of participants) and deterioration in COPD were common adverse events in both studies. Although cough is often reported as a side effect of indacaterol-containing therapy, most cases are mild and only one participant in over 1000 in INTRUST-1 and INTRUST-2 discontinued therapy because of it. We found that combination therapy increased trough FEV1 by 70 mL in
Table 2 Pulmonary function and COPD assessment scores before and after 8 weeks of indacaterol and tiotropium combination treatment. Indacaterol add-on group (n ¼ 43)
Tiotropium add-on group (n ¼ 36)
Baseline
After
Baseline
After
Baseline
After
3.01 1.66 63.2 54.7 1.96 0.86 8.89
3.08 1.73 66.1 55.7 2.00 0.88 8.70
3.04 1.64 61.6 53.8 1.93 0.90 9.95
3.14 1.73 65.4 54.4 2.02 0.86 8.41
2.99 1.67 65.1 55.7 1.99 0.83 7.61
3.00 1.72 66.9 57.1 1.98 0.90 9.02
All patients
FVC (L) FEV1 (L) FEV1, % predicted (%) FEV1/FVC (%) Inspiratory capacity (L) MMF (L/s) CAT
(0.72) (0.64) (20.1) (15.0) (0.55) (0.69) (6.55)
(0.72) (0.64)** (19.3)** (14.9)* (0.50) (0.64)* (6.30)
(0.78) (0.70) (20.7) (15.5) (0.58) (0.68) (7.13)
(0.72)* (0.68)* (18.6)* (14.9) (0.50) (0.59) (6.40)*,y
(0.66) (0.57) (19.4) (14.6) (0.53) (0.71) (5.54)
Values are expressed as mean (standard deviation). FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s; MMF, maximum mid-expiratory flow rate; CAT, COPD assessment test. * p < 0.05 versus baseline. ** p < 0.001 versus baseline. y p < 0.05 difference between indacaterol and tiotropium add-on groups.
(0.72) (0.59)* (20.4)* (15.0) (0.51) (0.71) (6.25)
14
S. Matsushima et al. / Pulmonary Pharmacology & Therapeutics 30 (2015) 11e15
Table 3 Respiratory resistance and respiratory reactance in the whole-breath, inspiratory and expiratory phases before and after 8 weeks of indacaterol and tiotropium treatment. All patients Baseline Whole breath R5 3.11 (1.18) R20 2.44 (0.84) R5eR20 0.62 (0.48) X5 0.98 (1.09) Fres 12.01 (5.86) ALX 7.11 (10.60) Expiratory phase R5 3.44 (1.36) R20 2.65 (0.91) R5eR20 0.79 (0.63) X5 1.21 (1.52) Fres 12.76 (7.03) ALX 10.08 (15.93) Inspiratory phase R5 2.77 (1.10) R20 2.33 (0.82) R5eR20 0.43 (0.44) X5 0.65 (0.93) Fres 11.11 (4.86) ALX 4.06 (7.38)
After
Indacaterol add-on group (n ¼ 43)
Tiotropium add-on group (n ¼ 36)
Baseline
After
Baseline
After
2.87 2.25 0.61 0.94 11.50 6.58
(1.09)** (0.64)** (0.46) (1.00) (5.53) (9.55)
3.04 2.40 0.64 1.05 12.41 7.65
(1.23) (0.87) (0.50) (1.18) (5.79) (10.58)
2.83 2.20 0.63 0.96 11.78 6.63
(0.99) (0.62)* (0.44) (1.01) (5.25) (9.40)
3.19 2.59 0.60 0.90 11.53 6.46
(1.14) (0.81) (0.47) (0.99) (5.98) (10.74)
2.91 2.32 0.59 0.91 11.15 6.51
(1.21)* (0.84)* (0.48) (1.00) (5.90) (9.85)
3.25 2.44 0.81 1.18 12.56 9.28
(1.27)** (0.80)** (0.57) (1.46) (6.88) (14.63)
3.35 2.55 0.80 1.31 13.36 11.32
(1.41) (0.92) (0.69) (1.60) (7.07) (16.44)
3.25 2.39 0.85 1.23 13.10 9.52
(1.16) (0.71) (0.53) (1.47) (6.63) (14.39)
3.55 2.77 0.78 1.08 12.04 8.61
(1.31) (0.90) (0.57) (1.42) (7.02) (15.39)
3.25 (1.39)* 2.49 (0.90)* 0.77 (0.61) 1.12 (1.46) 11.92 (7.22) 9.00 (15.10)
2.49 2.07 0.41 0.67 10.48 3.88
(1.00)** (0.72)** (0.41) (0.59) (4.56)* (5.51)
2.72 2.25 0.47 0.60 11.47 3.87
(1.14) (0.86) (0.46) (1.14) (4.85) (8.06)
2.42 2.00 0.41 0.68 10.56 3.76
(0.90)* (0.59)* (0.43) (0.59) (4.27) (5.34)
2.83 2.42 0.40 0.71 10.69 4.29
(1.07) (0.77) (0.42) (0.61) (4.91) (6.57)
2.57 2.16 0.41 0.67 10.38 4.01
(1.12)* (0.85)* (0.40) (0.60) (4.94) (5.78)
*
p < 0.05 versus baseline. p < 0.001 versus baseline. p < 0.05 difference between indacaterol and tiotropium add-on groups.
** y
all patients and by 90 mL in patients with GOLD stages II and III disease. We found that 9.5% patients experienced cough, but no patient discontinued indacaterol or tiotropium during the 8-week study period. We recruited stable patients who had no history of exacerbation or hospitalization for COPD in the previous 6 months and had already received monotherapy with indacaterol or tiotropium, enabling us to compare the effects of adding indacaterol to tiotropium and tiotropium to indacaterol. The relative benefits of each agent as first-line therapy has not been established [23] and current guidelines do not recommend which should be used first [1]. Furthermore, it is not known whether the choice of first-line bronchodilator influences the response of an additional bronchodilator added in combination. In our cohort, the indacaterol add-on and tiotropium add-on groups experienced broadly similar additional improvement in pulmonary function. The addition of indacaterol to tiotropium increased FEV1 by a mean of 88 mL and adding tiotropium to indacaterol increased FEV1 by a mean of 51 mL, which was not a significant difference. We also used the CAT questionnaire to assess the global impact of COPD on health status [16]. The indacaterol add-on group had a significantly improved CAT score. The accepted minimum clinically important difference [24], a decrease 2 points, was observed in 18 patients (41.9%) in the indacaterol add-on group and seven patients (19.4%) in the tiotropium add-on group. Cazzola et al. assessed the additional effect of tiotropium on formoterol in patients receiving regular monotherapy [25]. Patients established on inhaled tiotropium once daily or formoterol twice daily were given the other as an additional bronchodilator. Those who received formoterol in addition to tiotropium demonstrated a mean maximal change in 3-h post-dose FEV1 of 81 mL (95% CI: 29e133 mL). Those in whom tiotropium was added to formoterol showed a mean 54-mL (95% CI: 16e92 mL) improvement in FEV1. In contrast, a previous study has reported that the sequence of introduction of anticholinergic and adrenergic agents may indeed influence the extent of additional bronchodilation [26]. When the adrenergic agent was given first, further bronchodilation was achieved with an additional anticholinergic agent; however, no additional bronchodilation was achieved in
those who received an adrenergic agent after the anticholinergic agent. In this study it was reportedly difficult to distinguish between the effects of each drug, and the effect of the additional bronchodilator may have been influenced by a carry-over effect from the first [25]. In our study, patients established on tiotropium experienced an additional improvement in FEV1 with indacaterol and vice versa, suggesting that order of initiating bronchodilator therapy with indacaterol and tiotropium does not influence the effects that can be achieved with combination therapy. The FOT measures respiratory impedance non-invasively at different frequencies, with the results reported as threedimensional color images on a time axis. Respiratory impedance comprises resistance and reactance. Resistance is an index of airway caliber and increased resistance contributes to airflow limitation in COPD [10,27]. Reactance reflects the elastic and inertial properties of the lung [10]. We found that the resistance components R5 and R20 were significantly altered by treatment with indacaterol and tiotropium. Bronchodilators increase central and small airway diameters and decrease airway resistance [13], the latter reflected in the improvement in indices of resistance. Although it remains controversial whether FOT can differentiate between the central and peripheral airways and demonstrate peripheral airway disease directly in practice, there is a body of opinion that R5 and R20 reflect total and central airway resistance. As R5 and R20 were significantly decreased after 8 weeks of indacaterol and tiotropium treatment, combination therapy might act mainly at the central airways. As well as indacaterol and tiotropium, other bronchodilator combinations have been studied using the FOT [28,29]. Interestingly, significant improvements in FOT variables occurred even in the absence of a significant change in spirometry or ventilation parameters. When used in patients with COPD, bronchodilators cause complex changes in pulmonary physiology, and the FOT is a sensitive means of detecting small changes in response to therapy [10,13,14]. In this study, correlations between FOT and different pulmonary function parameters and CAT scores were evaluated. There was a correlation between Fres and the percentage of predicted FEV1; however the correlation coefficient was low
S. Matsushima et al. / Pulmonary Pharmacology & Therapeutics 30 (2015) 11e15
(Spearman's rank correlation coefficient, r ¼ 0.36, p ¼ 0.001). Although FOT might represent a different property of the lung from preexisting parameters, the significance of FOT in the clinical setting needs further clarification. Our study had some limitations. First, it was a single-arm study, and a further crossover study with three arms (tiotropium, indacaterol, and tiotropium plus indacaterol) is needed to confirm our results. Second, the study period was 8 weeks. Although indacaterol and tiotropium combination therapy improved airflow limitation, a study with a longer follow-up period is necessary to assess the effects on exacerbation and mortality. Rodrigo et al. found that combination therapy with tiotropium and formoterol or salmeterol did not reduce the rate of COPD exacerbations compared with tiotropium monotherapy. Their systematic review reported that rate of exacerbations (per 100 patient-years) was 32.1 in the LABA/ tiotropium group and 33.1 in the tiotropium group [23]. In conclusion, combination therapy with indacaterol and tiotropium improved airflow limitation and respiratory resistance. Adding indacaterol to tiotropium or tiotropium to indacaterol has similar effects on airflow limitation. As the combination of these once-daily long-acting bronchodilators can simplify the treatment regimen for patients and improve adherence, combination therapy with tiotropium plus indacaterol seems likely to be a useful treatment strategy for COPD. Acknowledgments No financial support was provided for this study. References [1] Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease. Updated 2014. http://www.goldcopd.org/guidelines-global-strategy-fordiagnosis-management.html. [accessed 20.05.14] [2] Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007;176:532e55. [3] van Noord JA, Bantje TA, Eland ME, Korducki L, Cornelissen PJ. A randomised controlled comparison of tiotropium nd ipratropium in the treatment of chronic obstructive pulmonary disease. The Dutch Tiotropium Study Group. Thorax 2000;55:289e94. [4] Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359:1543e54. [5] Vogelmeier C, Ramos-Barbon D, Jack D, Piggott S, Owen R, Higgins M, et al. Indacaterol provides 24-hour bronchodilation in COPD: a placebo-controlled blinded comparison with tiotropium. Respir Res 2010;11:135. [6] Dahl R, Chung KF, Buhl R, Magnussen H, Nonikov V, Jack D, et al. Efficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twicedaily formoterol in COPD. Thorax 2010;65:473e9. [7] Kornmann O, Dahl R, Centanni S, Dogra A, Owen R, Lassen C, et al., investigators I-s. Once-daily indacaterol versus twice-daily salmeterol for COPD: a placebo-controlled comparison. Eur Respir J 2011;37:273e9. [8] Tashkin DP, Ferguson GT. Combination bronchodilator therapy in the management of chronic obstructive pulmonary disease. Respir Res 2013;14:49.
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