- Email: [email protected]
Bronchodilator response to formoterol after regular tiotropium or to tiotropium after regular formoterol in COPD patients
ARTICLE IN PRESS Respiratory Medicine (2005) 99, 524–528
Bronchodilator response to formoterol after regular tiotropium or to tiotropium after regular formoterol in COPD patients Mario Cazzolaa,, Paolo Noschesea, Antonello Salzilloa, Carlo De Giglioa, Gennaro D’Amatoa, Maria Gabriella Materab a
Antonio Cardarelli Hospital, Department of Respiratory Medicine, Unit of Pneumology and Allergology, Naples, Italy b Second University of Naples, Department of Experimental Medicine, Unit of Pharmacology, Naples, Italy Received 29 September 2004
KEYWORDS COPD; Tiotropium; Formoterol; Sequential therapy
Summary We conducted a randomized, crossover trial with tiotropium 18 mg once daily (group A), and formoterol 12 mg twice daily (group B) over a 5-day period for each drug, with a 10-day washout, in 20 COPD patients. At the end of each period, patients inhaled both drugs separated by 180 min in alternate sequence (group A: tiotropium 18 mg+formoterol 12 mg; group B: formoterol 12 mg+tiotropium 18 mg). FEV1 and FVC were measured at baseline and after 30, 60, 120, 180, 210, 240, 300 and 360 min. FEV1 and FVC further improved after crossover with both sequences. The mean maximal change in FEV1 over baseline was 0.226 L (0.154–0.298) after tiotropium+formoterol and 0.228 L (0.165–0.291) after formoterol+tiotropium; the mean maximal change in FEV1 over pre-inhalation the second drug value was 0.081 L (0.029–0.133) after tiotropium+formoterol and 0.054 L (0.016–0.092) after formoterol+tiotropium. The mean maximal change in FVC over baseline was 0.519 L (0.361–0.676) after tiotropium+formoterol and 0.495 L (0.307–0.683) after formoterol+tiotropium; the mean maximal change in FVC over pre-inhalation of the second drug value was 0.159 L (0.048–0.270) after tiotropium+formoterol and 0.175 L (0.083–0.266) after formoterol+tiotropium. The FEV1 AUCs0–360 min were 62.70 (45.67–79.74) after tiotropium+formoterol and 69.20 (50.84–87.57) after formoterol+tiotropium, the FEV1 AUCs0–180 min were 24.70 (18.19–31.21) after tiotropium+formoterol and 29.74 (21.02–38.46) after formoterol+tiotropium, whereas the FEV1 AUCs180–360 min were 15.70 (10.88–20.52) after tiotropium+formoterol and 11.71
Corresponding author. Via del Parco Margherita 24, 80121 Napoli, Italy. Tel.: +39 081 7473334; fax: +39 081 404188.
E-mail address: [email protected] (M. Cazzola). 0954-6111/$ - see front matter & 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmed.2004.10.004
ARTICLE IN PRESS Bronchodilator response to formoterol after regular tiotropium
525
(7.21–16.21) after formoterol+tiotropium. Differences between the two treatments were not statistically significant (P40.05). The addition of second different longacting bronchodilator to a regularly administered long-acting bronchodilator seems to be to patient’s advantage. & 2004 Elsevier Ltd. All rights reserved.
Introduction b2-agonists and anticholinergics are distinct classes of drugs with differing mechanisms of action. Therefore, it seems reasonable to expect that they might have additive, complementary effects when combined.1–5 For this reason, some studies have examined various strategies for adding b2-agonists and anticholinergics in COPD. Unfortunately, they have provided conflicting results.6 In this study, we have examined the potential of an additive effect of a recommended dose of second long-acting bronchodilator (tiotropium, which is an anticholinergic agent, or formoterol, a b2-agonist) in COPD patients under regular treatment with a longacting bronchodilator of a different class (formoterol or tiotropium, respectively).
Patients and methods We conducted a randomized, crossover trial in 20 outpatients of either sex with moderate to severe COPD, but in a stable phase of disease and partially reversible airway obstruction, who gave their informed consent. Inclusion criteria were: 450 years with a 20 year smoking history, DFEV1/ predicted FEV1 p12% following 200 mg salbutamol, post-bronchodilator FEV1o80% in combination with an FEV1/FVCo70%. Patients were excluded if they had any current clinical evidence of asthma as primary diagnosis, allergic rhinitis, atopy, skin-test positively or with a total blood eosinophil count over 400 mm3, unstable respiratory disease requiring oral/parenteral corticosteroids within 4 weeks prior to commencing study, upper or lower respiratory tract infection within 4 weeks of screening visit, and coexisting cardiovascular or lung disorder. The patients continued to take the permitted medication for their COPD in stable doses, which included inhaled steroids, and mucolytics. Nor oral bronchodilator neither inhaled long-acting bronchodilator agent were permitted for one week before and during the study, whereas inhaled short-acting bronchodilator were not permitted for at least 24 h prior to each test, respectively. Patients also avoided consumption of cola drinks, coffee, tea,
and smoking in the hours before and during the investigation. The study, which was conducted according to the rules of the declaration of Helsinki, was performed using a randomised, crossover design. All patients gave written informed consent before any study procedure was undertaken. They were randomised into one of two treatment groups on test-day 1 after a baseline pulmonary function testing, and were treated initially with tiotropium 18 mg once daily (group A), or inhaled formoterol 12 mg twice daily (group B) over a 5-day period for each drug, with a 10-day washout. At the end of each period (test-day 6), patients inhaled both drugs separated by 180 min in alternate sequence (group A: tiotropium 18 mg+formoterol 12 mg; group B: formoterol 12 mg+tiotropium 18 mg), and serial pulmonary function testing was performed. Tiotropium was delivered via a breath-actuated powder inhaler (Handihaler), whereas, formoterol was administered via the hydrofluoroalkane Modulite inhaler. Pulmonary function testing always started between 08:00 and 09:00 h. Spirometric testing was performed according to the procedures described in the American Thoracic Society’s 1994 update.7 Three acceptable forced expiratory manoeuvres were performed in order to obtain two reproducible results for FVC and FEV1. The highest FEV1, obtained from one or the other of the reproducible curves, was kept for analysis. On test-day 6, measurements were performed immediately before inhalation of current treatment and after 30, 60, 120, 180, 210, 240, 300, and 360 min. Responses to the inhaled bronchodilators were evaluated in a blinded fashion. The functional indices’ increases from baseline after tiotropium and formoterol were assessed. As an expression of the total effect of each treatment, the areas under the FEV1 time–response curves (AUC) were calculated for each patient by means of the trapezoidal rule. Mean responses were compared by multifactorial analysis of variance (ANOVA) to establish any significant overall effect between treatments on each day. In the presence of a significant overall ANOVA, Duncan’s multiple range testing with 95% confidence limits was used to identify where differences were significant. A probability level of Po0.05 was considered as being of significance for all tests.
ARTICLE IN PRESS 526
M. Cazzola et al.
All patients completed the trial. There was no significant difference between the baseline spirometric values of the two treatment groups both at test-day 1 (P ¼ 0:946) and at test-day 6 (P ¼ 0:526). The mean baseline FEV1 at the start of treatment period was 1.137 L (95% CI: 0.958–1.315) for the tiotropium group and 1.134 L (95% CI: 0.942–1.326) for the formoterol group. On test-day 6, the mean FEV1 trough response was 1.194 L (95% CI: 1.008–1.380) for tiotropium and 1.170 L (95% CI: 0.975–1.364) for formoterol. Both tiotropium and formoterol produced a significant maximal improvement (Po0.0001) in pulmonary function over baseline (Figs. 1 and 2). FEV1 and FVC further improved after crossover with both sequences. Thirty minutes after inhalation of the last dose of tiotropium, there was a statistically significant increase of 0.099 L (95 CI: 0.062–0.138) in FEV1 over baseline (Po0.0001). The same was observed after inhalation of the last dose of formoterol (0.166 L; CI 95: 0.064–0.168; Po0.0002). The mean maximal change in FEV1 over baseline was 0.226 L (0.154–0.298) in group A and 0.228 L (0.165–0.291) in group B (Fig. 1). The mean maximal change in FEV1 over pre-inhalation the second drug value was 0.081 L (95% CI: 0.029–0.133; P ¼ 0:0043) after tiotropium-formoterol and 0.054 L (95% CI: 0.016–0.092; P ¼ 0:0161) after formoterol-tiotropium. The mean maximal change in FVC over baseline was 0.519 L (95% CI: 0.361–0.676) in group A and 0.495 L (95% CI: 0.307–0.683) in group B (Fig. 2). The mean maximal change in FVC over pre-
inhalation of the second drug value was 0.159 L (95% CI: 0.048–0.270; P=0.0074) after tiotropiumformoterol and 0.175 L (95% CI: 0.083–0.266; P=0.0008) after formoterol-tiotropium. The FEV1 AUCs0360 min were 66.38 (95% CI: 49.73–83.04) after tiotropium-formoterol and 70.18 (95% CI: 52.15–88.21) after formoteroltiotropium, the FEV1 AUCs0180 min were 24.70 (18.19–31.21) in Group A and 29.74 (21.02–38.46) in Group B, whereas the FEV1 AUCs180360 min were 15.70 (10.88–20.52) after tiotropium-formoterol and 11.71 (7.21–16.21) after formoterol-tiotropium (Fig. 3). All differences between the two treatments were not statistically significant (P40.05).
3.25
* ** §§§
3.00
§§
* §§§
§
L
Results
2.75 Tio-For For-Tio
2.50 0
60
120
180 min
240
300
360
Figure 2 Mean response curves following the sequential inhalation of tiotropium (Tio) and formoterol (For) for FVC. Arrow indicates the administration of the second drug. * Po0.05, ** Po0.01 in the sequence tiotropiumformoterol. y Po0.05, yy Po0.01, yyy Po0.001 in the sequence formoterol-tiotropium.
1.5
*
1.4
§
**
**
§
§§
**
75 Tio-For
L
For-Tio 1.3 50 1.2 Tio-For For-Tio
1.1
25 0
60
120
180 min
240
300
360
Figure 1 Mean response curves following the sequential inhalation of tiotropium (Tio) and formoterol (For) for FEV1. Arrow indicates the administration of the second drug. *Po0.05, **Po0.01, ***Po0.001 in the sequence tiotropium-formoterol. y Po0.05, yy Po0.01 in the sequence formoteroltiotropium.
0 0-360
0-180
180-360
FEV1 AUC
Figure 3 Mean FEV1 AUCs following the sequential inhalation of tiotropium and formoterol.
ARTICLE IN PRESS Bronchodilator response to formoterol after regular tiotropium
Discussion Significant improvement in pulmonary function has been achieved by adding tiotropium or formoterol at the recommended dosages in patients already in regular treatment with formoterol or tiotropium, respectively, with no statistically significant difference between the different sequences. The gain in FEV1 was similar in the two studied series and, although relatively small, it was likely useful for subjects suffering from a chronic airway obstruction that is only partially irreversible. Therefore, our results suggest that supplementing a second different long-acting bronchodilator to a regularly administered long-acting bronchodilator seems to be to patient’s advantage in terms of bronchodilation. In a previous our trial, we documented that the sequential administration of formoterol and oxitropium bromide induced an improvement in pulmonary function in a population of COPD patient similar to that examined in the present trial.8 However, prior administration of the long-acting b2-agonist allowed a response to the anticholinergic drug, which was higher that that observed when inhalation of oxitropium was preceding that of formoterol. We do not know if the diverse pharmacological characteristics of tiotropium and oxitropium could justify the different response that we have observed in the two studies. In effect, a comparison between these two anticholinergic agents is still lacking in literature. In any case, it is also possible that the regular treatment administered for several days in this study, but not in the first study in which oxitropium was only given in an acute manner, could explain why we have been unable to record a statistically significant difference between the two sequences. The present results seem to refute Karpel’s documentation9 that the addition of a second bronchodilator of a different class did not result in further spirometric improvement in most of patients with stable COPD. These findings were independent of the class of short-acting agents used, b2-agonist or antimuscarinic. On the contrary, they confirm and enlarge the opinion of Newnham et al.10 that inhaling an effective dose of b2-agonist as initial therapy gives rise to an adequate response, although the predominant vagal tone would appear to prevent optimum achievable dilatation being achieved. In fact, the subsequent addition of an anticholinergic still elicits a further small degree of bronchodilation. In any case, it must be highlighted that also Heimer et al.11 demonstrated some additional bronchodilatory response when an anticholinergic
527
agent (ipratropium bromide) 250 mg was given after a b-agonist (terbutaline 2.5 mg), but not when terbutaline was given after ipratropium bromide. Gross and Skorodin12 observed that when salbutamol was given first, subsequent administration of atropine methonitrate resulted in a further significant increase in FEV1. Salbutamol did not bring about any further improvement in FEV1 than had been achieved with atropine. When both agents were given at high doses, the improvement in FEV1 was similar to that found with atropine alone. Also in the study of Douglas et al.,13 when salbutamol was given until no further bronchodilation could be achieved, subsequent inhalation of 80 mg ipratropium resulted in a further increase in FEV1 and FVC. On the other hand, when salbutamol was administered 3 h after ipratropium, the FEV1 rose to higher levels than after either agent alone. We cannot exclude that the larger bronchodilatory response that we observed when a second bronchodilator was given after the first one should be justified by a carry over effect, considering that both formoterol and tiotropium are long-lasting bronchodilators. This consideration could justify the discrepancies that we have observed between the results of this study and those produced with short-acting bronchodilators. Nonetheless, it is well know that the mean peak bronchodilation with both formoterol and tiotropium in COPD patients is reached after 2–3 h,4 and we have documented that the addition of a second bronchodilator added 3 h after the inhalation of the first agent could amplify the maximum bronchodilation of the first agent. This finding seems to be important because it indicates the possibility that a patient who is unable to perceive bronchodilation or must perform an exercise could use a second long-acting bronchodilator that will assure a long-lasting effect.
References 1. Cazzola M, Spina D, Matera MG. The use of bronchodilators in stable chronic obstructive pulmonary disease. Pulm Pharmacol Ther 1997;10:129–44. 2. Dorinsky PM, Reisner C, Ferguson GT, Menjoge SS, Serby CW, Witek Jr TJ. The combination of ipratropium and albuterol optimizes pulmonary function reversibility testing in patients with COPD. Chest 1999;115:966–71. 3. Cazzola M, Matera MG, Di Perna E, Califano C, D’Amato M, Mazzarella G. Influence of higher than conventional doses of oxitropium bromide on formoterol-induced bronchodilation in COPD. Respir Med 1999;93:909–11. 4. Cazzola M, Di Marco F, Santus P, Boveri B, Verga M, Matera MG, Centanni S. The pharmacodynamic effects of single inhaled doses of formoterol, tiotropium and their combina-
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5.
6. 7. 8.
9.
tion in patients with COPD. Pulm Pharmacol Ther 2004; 17:35–9. Cazzola M, Centenni S, Santus P, Verga M, Mondoni M, Di Marco F, Matera MG. The functional impact of adding salmeterol and tiotropium in patients with stable COPD. Respir Med 2004 in press. Rennard SI. Combination bronchodilator therapy in COPD. Chest 1995;107(Suppl):171S–175. American Thoracic Society. Standardization of spirometry, 1994 Update. Am J Respir Crit Care Med 1995;152:1107–36. Cazzola M, Di Perna F, Califano C, Vinciguerra A, D’Amato M. Incremental benefit of adding oxitropium bromide to formoterol in patients with stable COPD. Pulm Pharmacol Ther 1999;12:267–71. Karpel JP. Bronchodilator responses to anticholinergic and badrenergic agents in acute and stable COPD. Chest 1991; 99:871–6.
M. Cazzola et al. 10. Newnham DM, Dhillon DP, Winter JH, Jackson CM, Clark RA, Lipworth BJ. Bronchodilator reversibility to low and high doses of terbutaline and ipratropium bromide in patients with chronic obstructive pulmonary disease. Thorax 1993;48:1151–5. 11. Heimer D, Brami JL, Liberman D, Bark H. Comparison of a b2 adrenergic agonist and an anticholinergic agent given by sequential inhalation in patients with severe chronic obstructive pulmonary disease. Isr J Med Sci 1991;27: 307–10. 12. Gross NJ, Skorodin MS. Role of the parasympathetic system in airway obstruction due to emphysema. N Engl J Med 1984;311:421–5. 13. Douglas NJ, Davidson I, Sudlow MF, Flenley DC. Bronchodilatation and the site of airway resistance in severe chronic bronchitis. Thorax 1979;34:51–6.
Bronchodilator response to formoterol after regular tiotropium or to tiotropium after regular formoterol in COPD patients Mario Cazzolaa,, Paolo Noschesea, Antonello Salzilloa, Carlo De Giglioa, Gennaro D’Amatoa, Maria Gabriella Materab a
Antonio Cardarelli Hospital, Department of Respiratory Medicine, Unit of Pneumology and Allergology, Naples, Italy b Second University of Naples, Department of Experimental Medicine, Unit of Pharmacology, Naples, Italy Received 29 September 2004
KEYWORDS COPD; Tiotropium; Formoterol; Sequential therapy
Summary We conducted a randomized, crossover trial with tiotropium 18 mg once daily (group A), and formoterol 12 mg twice daily (group B) over a 5-day period for each drug, with a 10-day washout, in 20 COPD patients. At the end of each period, patients inhaled both drugs separated by 180 min in alternate sequence (group A: tiotropium 18 mg+formoterol 12 mg; group B: formoterol 12 mg+tiotropium 18 mg). FEV1 and FVC were measured at baseline and after 30, 60, 120, 180, 210, 240, 300 and 360 min. FEV1 and FVC further improved after crossover with both sequences. The mean maximal change in FEV1 over baseline was 0.226 L (0.154–0.298) after tiotropium+formoterol and 0.228 L (0.165–0.291) after formoterol+tiotropium; the mean maximal change in FEV1 over pre-inhalation the second drug value was 0.081 L (0.029–0.133) after tiotropium+formoterol and 0.054 L (0.016–0.092) after formoterol+tiotropium. The mean maximal change in FVC over baseline was 0.519 L (0.361–0.676) after tiotropium+formoterol and 0.495 L (0.307–0.683) after formoterol+tiotropium; the mean maximal change in FVC over pre-inhalation of the second drug value was 0.159 L (0.048–0.270) after tiotropium+formoterol and 0.175 L (0.083–0.266) after formoterol+tiotropium. The FEV1 AUCs0–360 min were 62.70 (45.67–79.74) after tiotropium+formoterol and 69.20 (50.84–87.57) after formoterol+tiotropium, the FEV1 AUCs0–180 min were 24.70 (18.19–31.21) after tiotropium+formoterol and 29.74 (21.02–38.46) after formoterol+tiotropium, whereas the FEV1 AUCs180–360 min were 15.70 (10.88–20.52) after tiotropium+formoterol and 11.71
Corresponding author. Via del Parco Margherita 24, 80121 Napoli, Italy. Tel.: +39 081 7473334; fax: +39 081 404188.
E-mail address: [email protected] (M. Cazzola). 0954-6111/$ - see front matter & 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmed.2004.10.004
ARTICLE IN PRESS Bronchodilator response to formoterol after regular tiotropium
525
(7.21–16.21) after formoterol+tiotropium. Differences between the two treatments were not statistically significant (P40.05). The addition of second different longacting bronchodilator to a regularly administered long-acting bronchodilator seems to be to patient’s advantage. & 2004 Elsevier Ltd. All rights reserved.
Introduction b2-agonists and anticholinergics are distinct classes of drugs with differing mechanisms of action. Therefore, it seems reasonable to expect that they might have additive, complementary effects when combined.1–5 For this reason, some studies have examined various strategies for adding b2-agonists and anticholinergics in COPD. Unfortunately, they have provided conflicting results.6 In this study, we have examined the potential of an additive effect of a recommended dose of second long-acting bronchodilator (tiotropium, which is an anticholinergic agent, or formoterol, a b2-agonist) in COPD patients under regular treatment with a longacting bronchodilator of a different class (formoterol or tiotropium, respectively).
Patients and methods We conducted a randomized, crossover trial in 20 outpatients of either sex with moderate to severe COPD, but in a stable phase of disease and partially reversible airway obstruction, who gave their informed consent. Inclusion criteria were: 450 years with a 20 year smoking history, DFEV1/ predicted FEV1 p12% following 200 mg salbutamol, post-bronchodilator FEV1o80% in combination with an FEV1/FVCo70%. Patients were excluded if they had any current clinical evidence of asthma as primary diagnosis, allergic rhinitis, atopy, skin-test positively or with a total blood eosinophil count over 400 mm3, unstable respiratory disease requiring oral/parenteral corticosteroids within 4 weeks prior to commencing study, upper or lower respiratory tract infection within 4 weeks of screening visit, and coexisting cardiovascular or lung disorder. The patients continued to take the permitted medication for their COPD in stable doses, which included inhaled steroids, and mucolytics. Nor oral bronchodilator neither inhaled long-acting bronchodilator agent were permitted for one week before and during the study, whereas inhaled short-acting bronchodilator were not permitted for at least 24 h prior to each test, respectively. Patients also avoided consumption of cola drinks, coffee, tea,
and smoking in the hours before and during the investigation. The study, which was conducted according to the rules of the declaration of Helsinki, was performed using a randomised, crossover design. All patients gave written informed consent before any study procedure was undertaken. They were randomised into one of two treatment groups on test-day 1 after a baseline pulmonary function testing, and were treated initially with tiotropium 18 mg once daily (group A), or inhaled formoterol 12 mg twice daily (group B) over a 5-day period for each drug, with a 10-day washout. At the end of each period (test-day 6), patients inhaled both drugs separated by 180 min in alternate sequence (group A: tiotropium 18 mg+formoterol 12 mg; group B: formoterol 12 mg+tiotropium 18 mg), and serial pulmonary function testing was performed. Tiotropium was delivered via a breath-actuated powder inhaler (Handihaler), whereas, formoterol was administered via the hydrofluoroalkane Modulite inhaler. Pulmonary function testing always started between 08:00 and 09:00 h. Spirometric testing was performed according to the procedures described in the American Thoracic Society’s 1994 update.7 Three acceptable forced expiratory manoeuvres were performed in order to obtain two reproducible results for FVC and FEV1. The highest FEV1, obtained from one or the other of the reproducible curves, was kept for analysis. On test-day 6, measurements were performed immediately before inhalation of current treatment and after 30, 60, 120, 180, 210, 240, 300, and 360 min. Responses to the inhaled bronchodilators were evaluated in a blinded fashion. The functional indices’ increases from baseline after tiotropium and formoterol were assessed. As an expression of the total effect of each treatment, the areas under the FEV1 time–response curves (AUC) were calculated for each patient by means of the trapezoidal rule. Mean responses were compared by multifactorial analysis of variance (ANOVA) to establish any significant overall effect between treatments on each day. In the presence of a significant overall ANOVA, Duncan’s multiple range testing with 95% confidence limits was used to identify where differences were significant. A probability level of Po0.05 was considered as being of significance for all tests.
ARTICLE IN PRESS 526
M. Cazzola et al.
All patients completed the trial. There was no significant difference between the baseline spirometric values of the two treatment groups both at test-day 1 (P ¼ 0:946) and at test-day 6 (P ¼ 0:526). The mean baseline FEV1 at the start of treatment period was 1.137 L (95% CI: 0.958–1.315) for the tiotropium group and 1.134 L (95% CI: 0.942–1.326) for the formoterol group. On test-day 6, the mean FEV1 trough response was 1.194 L (95% CI: 1.008–1.380) for tiotropium and 1.170 L (95% CI: 0.975–1.364) for formoterol. Both tiotropium and formoterol produced a significant maximal improvement (Po0.0001) in pulmonary function over baseline (Figs. 1 and 2). FEV1 and FVC further improved after crossover with both sequences. Thirty minutes after inhalation of the last dose of tiotropium, there was a statistically significant increase of 0.099 L (95 CI: 0.062–0.138) in FEV1 over baseline (Po0.0001). The same was observed after inhalation of the last dose of formoterol (0.166 L; CI 95: 0.064–0.168; Po0.0002). The mean maximal change in FEV1 over baseline was 0.226 L (0.154–0.298) in group A and 0.228 L (0.165–0.291) in group B (Fig. 1). The mean maximal change in FEV1 over pre-inhalation the second drug value was 0.081 L (95% CI: 0.029–0.133; P ¼ 0:0043) after tiotropium-formoterol and 0.054 L (95% CI: 0.016–0.092; P ¼ 0:0161) after formoterol-tiotropium. The mean maximal change in FVC over baseline was 0.519 L (95% CI: 0.361–0.676) in group A and 0.495 L (95% CI: 0.307–0.683) in group B (Fig. 2). The mean maximal change in FVC over pre-
inhalation of the second drug value was 0.159 L (95% CI: 0.048–0.270; P=0.0074) after tiotropiumformoterol and 0.175 L (95% CI: 0.083–0.266; P=0.0008) after formoterol-tiotropium. The FEV1 AUCs0360 min were 66.38 (95% CI: 49.73–83.04) after tiotropium-formoterol and 70.18 (95% CI: 52.15–88.21) after formoteroltiotropium, the FEV1 AUCs0180 min were 24.70 (18.19–31.21) in Group A and 29.74 (21.02–38.46) in Group B, whereas the FEV1 AUCs180360 min were 15.70 (10.88–20.52) after tiotropium-formoterol and 11.71 (7.21–16.21) after formoterol-tiotropium (Fig. 3). All differences between the two treatments were not statistically significant (P40.05).
3.25
* ** §§§
3.00
§§
* §§§
§
L
Results
2.75 Tio-For For-Tio
2.50 0
60
120
180 min
240
300
360
Figure 2 Mean response curves following the sequential inhalation of tiotropium (Tio) and formoterol (For) for FVC. Arrow indicates the administration of the second drug. * Po0.05, ** Po0.01 in the sequence tiotropiumformoterol. y Po0.05, yy Po0.01, yyy Po0.001 in the sequence formoterol-tiotropium.
1.5
*
1.4
§
**
**
§
§§
**
75 Tio-For
L
For-Tio 1.3 50 1.2 Tio-For For-Tio
1.1
25 0
60
120
180 min
240
300
360
Figure 1 Mean response curves following the sequential inhalation of tiotropium (Tio) and formoterol (For) for FEV1. Arrow indicates the administration of the second drug. *Po0.05, **Po0.01, ***Po0.001 in the sequence tiotropium-formoterol. y Po0.05, yy Po0.01 in the sequence formoteroltiotropium.
0 0-360
0-180
180-360
FEV1 AUC
Figure 3 Mean FEV1 AUCs following the sequential inhalation of tiotropium and formoterol.
ARTICLE IN PRESS Bronchodilator response to formoterol after regular tiotropium
Discussion Significant improvement in pulmonary function has been achieved by adding tiotropium or formoterol at the recommended dosages in patients already in regular treatment with formoterol or tiotropium, respectively, with no statistically significant difference between the different sequences. The gain in FEV1 was similar in the two studied series and, although relatively small, it was likely useful for subjects suffering from a chronic airway obstruction that is only partially irreversible. Therefore, our results suggest that supplementing a second different long-acting bronchodilator to a regularly administered long-acting bronchodilator seems to be to patient’s advantage in terms of bronchodilation. In a previous our trial, we documented that the sequential administration of formoterol and oxitropium bromide induced an improvement in pulmonary function in a population of COPD patient similar to that examined in the present trial.8 However, prior administration of the long-acting b2-agonist allowed a response to the anticholinergic drug, which was higher that that observed when inhalation of oxitropium was preceding that of formoterol. We do not know if the diverse pharmacological characteristics of tiotropium and oxitropium could justify the different response that we have observed in the two studies. In effect, a comparison between these two anticholinergic agents is still lacking in literature. In any case, it is also possible that the regular treatment administered for several days in this study, but not in the first study in which oxitropium was only given in an acute manner, could explain why we have been unable to record a statistically significant difference between the two sequences. The present results seem to refute Karpel’s documentation9 that the addition of a second bronchodilator of a different class did not result in further spirometric improvement in most of patients with stable COPD. These findings were independent of the class of short-acting agents used, b2-agonist or antimuscarinic. On the contrary, they confirm and enlarge the opinion of Newnham et al.10 that inhaling an effective dose of b2-agonist as initial therapy gives rise to an adequate response, although the predominant vagal tone would appear to prevent optimum achievable dilatation being achieved. In fact, the subsequent addition of an anticholinergic still elicits a further small degree of bronchodilation. In any case, it must be highlighted that also Heimer et al.11 demonstrated some additional bronchodilatory response when an anticholinergic
527
agent (ipratropium bromide) 250 mg was given after a b-agonist (terbutaline 2.5 mg), but not when terbutaline was given after ipratropium bromide. Gross and Skorodin12 observed that when salbutamol was given first, subsequent administration of atropine methonitrate resulted in a further significant increase in FEV1. Salbutamol did not bring about any further improvement in FEV1 than had been achieved with atropine. When both agents were given at high doses, the improvement in FEV1 was similar to that found with atropine alone. Also in the study of Douglas et al.,13 when salbutamol was given until no further bronchodilation could be achieved, subsequent inhalation of 80 mg ipratropium resulted in a further increase in FEV1 and FVC. On the other hand, when salbutamol was administered 3 h after ipratropium, the FEV1 rose to higher levels than after either agent alone. We cannot exclude that the larger bronchodilatory response that we observed when a second bronchodilator was given after the first one should be justified by a carry over effect, considering that both formoterol and tiotropium are long-lasting bronchodilators. This consideration could justify the discrepancies that we have observed between the results of this study and those produced with short-acting bronchodilators. Nonetheless, it is well know that the mean peak bronchodilation with both formoterol and tiotropium in COPD patients is reached after 2–3 h,4 and we have documented that the addition of a second bronchodilator added 3 h after the inhalation of the first agent could amplify the maximum bronchodilation of the first agent. This finding seems to be important because it indicates the possibility that a patient who is unable to perceive bronchodilation or must perform an exercise could use a second long-acting bronchodilator that will assure a long-lasting effect.
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