Acute Evect of Pretreatment with Single Conventional Dose Of

Thorax 1999;54:1083–1086 1083 Acute eVect of pretreatment with single

conventional dose of salmeterol on dose-response Thorax: first published as 10.1136/thx.54.12.1083 on 1 December 1999. Downloaded from curve to oxitropium bromide in chronic obstructive pulmonary disease

Mario Cazzola, Felice Di Perna, Stefano Centanni, Clara Califano, Claudio Ferdinando Donner, Maria D’Amato, Gennaro D’Amato

Abstract Keywords: salmeterol; oxitropium bromide; combina- Background—An earlier study docu- tion therapy; chronic obstructive pulmonary disease mented that, in patients with chronic obstructive pulmonary disease (COPD), addition of ipratropium bromide at the Recent British Thoracic Society guidelines for clinically recommended dose (40 µg) does the management of stable chronic obstructive not produce any further bronchodilation pulmonary disease (COPD) state that bron- than that achieved with salmeterol 50 µg chodilators are the cornerstone of symptomatic treatment for the reversible component of alone. However, the dose of ipratropium airways obstruction.1 Short acting â agonists bromide needed to produce near maximal 2 used as required should be tried ﬁrst in view of bronchodilation is several times higher their more rapid relief of symptoms. If these do than the customary dosage. The full not control symptoms adequately or if regular therapeutic potential of combined sal- maintenance therapy is desired, an anticholin- meterol plus an anticholinergic drug can ergic agent can be added. This recommen- therefore only be established using doses dation is based on the fact that anticholinergic higher than those currently recommended and â adrenergic agents, which are distinct in the marketing of these agents. A study classes of drugs with diVerent mechanisms of was undertaken to examine the possible 23 action, are additive when used together. acute eVects of higher than conventional Long acting â agonist bronchodilators such doses of an anticholinergic agent on the as formoterol and salmeterol are a new single dose salmeterol induced bronchodi- 4–6 interesting therapeutic option for COPD. lation in patients with stable and partially A. Cardarelli Hospital, However, their impact on combinations is still http://thorax.bmj.com/ reversible COPD. Division of unclear. Methods—Thirty two outpatients received Pneumology and A combination of ipratropium with 50 µg salmeterol or placebo. Two hours 7 8 Allergology, Naples, salmeterol or formoterol in their normal dos- Italy after inhalation a dose-response curve to ages does not appear to improve pulmonary M Cazzola inhaled oxitropium bromide (100 µg/puV) function, but this lack of improvement with the FDiPerna or placebo was constructed using one puV, C Califano combination should not in itself prevent imple- one puV,twopuVs, and two puVs—that is, a M D’Amato mentation of further therapeutic steps in G D’Amato total cumulative dose of 600 µg oxitropium

patients responsive to ipratropium and/or on September 23, 2021 by guest. Protected copyright. bromide. Dose increments were given at 20 salmeterol or formoterol administered singly. University of Milan, minute intervals with measurements being In the present study we have investigated the Medical School, San made 15 minutes after each dose. On four possible acute eVects of higher than normal Paolo Hospital, separate days all patients received one of Respiratory Diseases doses of an anticholinergic agent on the single the following: (1) 50 µg salmeterol + 600 µg Unit, Milan, Italy dose salmeterol induced bronchodilation in oxitropium bromide; (2) 50 µg salmeterol S Centanni patients with stable and partially reversible + placebo; (3) placebo + 600 µg oxitropium COPD. S Maugeri Foundation, bromide; (4) placebo + placebo. Institute of Care and Results—Salmeterol induced a good bron- Research, Medical chodilation (mean increase 0.272 l; 95% CI Methods Centre of Thirty two outpatients with moderate to severe Rehabilitation, 0.207 to 0.337) two hours after its inhala- Division of tion. Oxitropium bromide elicited an evi- COPD but in a stable phase of the disease and Pneumology, Veruno, dent dose-dependent increase in forced with partially reversible airway obstruction

Italy expiratory volume in one second (FEV1) were assessed. They gave their informed C F Donner and this occurred also after pretreatment consent to participate in the study. All fulﬁlled with salmeterol with a further mean the criteria proposed by the American Tho- Correspondence to: 9 Dr M Cazzola, Via del Parco maximum increase of 0.152 l (95% CI of racic Society —that is, they were >50 years of Margherita 24, 80121 diVerences 0.124 to 0.180). age, current or former smokers (>10 pack Napoli, Italy Conclusions—This study shows that acute years) without a history of asthmatic attacks, reporting chronic cough with or without Received 16 April 1999 pretreatment with 50 µg salmeterol does Returned to authors not block the possibility of inducing more sputum production and/or dyspnoea when 14 July 1999 bronchodilation with an anticholinergic walking quietly on level ground, or both; they Revised manuscript received agent when a higher than normal dosage had had no change in symptom severity or 29 July 1999 Accepted for publication of the muscarinic antagonist is used. treatment in the preceding four weeks, had 17 August 1999 (Thorax 1999;54:1083–1086) shown no signs of a respiratory tract infection 1084 Cazzola, Di Perna, Centanni, et al

Table 1 Anthropometric data and pulmonary function of patients The study, which was conducted according to the rules of the declaration of Helsinki, was Reversibility 15 min after 200 µg salbutamol performed using a randomised, double blind, Thorax: first published as 10.1136/thx.54.12.1083 on 1 December 1999. Downloaded from FEV1 FVC (% increase in FEV1 crossover design. Patients received two puVsof Patient Sex Age (years) (% predicted) (% predicted) from baseline) salmeterol (25 µg/puV) or placebo inhaled 1 F 62 48 51 15 from matched metered dose inhalers (MDI) 2 M 66 30 45 18 and a holding chamber (AeroChamber) with a 3 M 73 36 39 17 4 M 55 48 55 18 mouthpiece. Although oxitropium bromide 5 M 61 29 34 31 and placebo could have been given by neb- 6 M 58 36 48 21 7 M 71 19 24 18 uliser, we chose MDI dosing for this study 8 F 70 55 69 17 because salmeterol is not available as a solution 9 M 65 42 60 25 and a double blind study would otherwise have 10M57374421 11M68586515 not been possible. 12F62202724 Spirometric testing was performed accord- 13M68333615 ing to the procedures described in the Ameri- 14M69445423 10 15M58293619 can Thoracic Society’s 1987 update. Three 16M61476116 acceptable forced expiratory manoeuvres were 17F73434417 18M67405815 performed in order to obtain two reproducible 19M64385327 results for FVC and FEV1. The higher of the 20M65253228 two FEV results was kept for analysis. 21F71506126 1 22M55333924 Measurements were performed immediately 23M63476019 before inhalation of treatment and after two 24M68555616 hours. 25F74455118 26M72434920 Two hours after the inhalation of salmeterol 27M68182918 or placebo spirometric tests were performed in 28M64222515 each patient, after which a dose-response curve 29F62333519 30F58495517 to inhaled oxitropium (100 µg/puV) or placebo 31M65212819 was constructed using one puV, one puV,two 32M64415728 puVs, and two puVs—that is, a total cumulative

FEV1 = forced expiratory volume in one second; FVC = forced vital capacity. dose of 600 µg oxitropium. Oxitropium or placebo were administered from an MDI and in the month preceding or during the trial, had holding chamber (AeroChamber) with a not been taking oral or inhaled corticosteroids mouthpiece. Dose increments were given at 20 for at least three months, and had a forced minute intervals with measurements being expiratory volume in one second (FEV1)of made 15 minutes after each dose. On four <65% of predicted normal and a forced vital non-consecutive days all patients received one capacity (FVC) of <70% after bronchodilators

of the following: (1) 50 µg salmeterol + 600 µg http://thorax.bmj.com/ had been withheld for 24 hours and a best oxitropium bromide, (2) 50 µg salmeterol + post-bronchodilator FEV1/FVC of less than placebo, (3) placebo + 600 µg oxitropium bro- 0.7. Patients with allergic rhinitis, atopy, mide, or (4) placebo + placebo. positive skin test, or with a total blood eosino- The increases in the functional indices from –3 phil count over 400 mm were excluded. baseline after salmeterol or placebo were Patients were also excluded if they had any assessed. The FEV1 value induced by 600 µg co-existing cardiovascular or lung disorder. At oxitropium bromide or placebo (six puVs) was an initial screening visit patients were required chosen as the primary outcome variable. With on September 23, 2021 by guest. Protected copyright. to demonstrate an increase in FEV1 of at least an estimation of the within subject variability 15% from baseline to inhaled 200 µg salbuta- (residual standard deviation) of 0.10 l, this mol. Table 1 outlines the baseline characteris- crossover study with 32 patients had 80% tics of the population studied. power to detect a diVerence of at least 0.08 l No oral bronchodilators were permitted for between treatments. one week before and during the study while Analysis of spirometric data for each treat- inhaled short acting bronchodilator drugs and ment was performed using the Student’s t test inhaled long acting bronchodilator agents were for paired variables. Mean responses were also not permitted for at least 12 hours and 24 compared by multifactorial analysis of variance hours, respectively, before each test. Patients (ANOVA) to establish any significant overall were also asked to refrain from consumption of eVect between all four treatments. In the pres- cola drinks, coVee, tea, and smoking in the 12 ence of a significant overall ANOVA, Duncan’s hours before and during the investigation. multiple range testing with 95% confidence

Table 2 Mean (95% CI) baseline values and changes in FEV1 and FVC two hours after placebo (P) or 50 µg salmeterol (S), and changes from values at 2 hours after 6 puVs of oxitropium bromide (OB) or placebo (P). Values are mean (95% CI)

P+P P+OB S+P S+OB

FEV1 (l) Baseline 1.16 (1.02 to 1.30) 1.17 (1.02 to 1.32) 1.15 (1.01 to 1.29) 1.14 (1.00 to 1.28) Mean change from baseline after 2 hours 0.00 (−0.04 to 0.03) 0.00 (−0.08 to 0.07) 0.25 (0.19 to 0.31) 0.27 (0.21 to 0.34) Mean change from value at 2 hours after 6 puVs of OB or P 0.01 (−0.03 to 0.04) 0.27 (0.21 to 0.33) 0.03 (0.00 to 0.06) 0.15 (0.12 to 0.18) FVC (l) Baseline 2.05 (1.84 to 2.27) 2.02 (1.78 to 2.26) 1.97 (1.75 to 2.19) 1.98 (1.78 to 2.28) Mean change from baseline after 2 hours −0.03 (−0.15 to 0.09) 0.01 (−0.06 to 0.08) 0.23 (0.14 to 0.30) 0.18 (0.08 to 0.28) Mean change from values at 2 hours after 6 puVs of OB or P 0.02 (−0.05 to 0.09) 0.19 (0.05 to 0.33) 0.02 (−0.09 to 0.13) 0.06 (−0.09 to 0.20) Salmeterol and airway responses to oxitropium in COPD 1085

200 µg oxitropium after placebo (0.124 l; 95% P+P V 1.6 P+OB CI of di erences 0.075 to 0.173). S+P No patient complained of adverse symptoms Thorax: first published as 10.1136/thx.54.12.1083 on 1 December 1999. Downloaded from S+OB (palpitations or signiﬁcant increased heart rate) or reported any diVerence in the taste of the 1.5 inhalers.

Discussion 1.4 A number of clinical studies have shown the benefit of adding a â agonist to an anticholinergic agent such as ipratropium in COPD.11 Litres Combination therapy with an inhaled anti- 1.3 cholinergic and â agonist may be more effective in bronchodilation than either of the two agents alone.12 In particular, several studies have 1.2 â reported that standard doses of short acting 2 agonists do not give optimal results in patients with COPD and that an anticholinergic agent 13–15 1.1 gives additional bronchodilation. 0123456The introduction of long acting â agonist Cumulative puffs bronchodilators gives physicians additional Figure 1 Mean dose-response curves to inhaled oxitropium bromide (OB) or placebo (P) therapeutic options for COPD, but their place in its treatment is currently not known. In any constructed two hours after inhaling placebo or 50 µg salmeterol (S) for FEV1. case, both salmeterol and formoterol appear to limits was used to identify where diVerences be more eVective than short acting â agonists16 were significant. A probability level of p<0.05 and in patients with stable COPD salmeterol is was considered significant for all tests. more eVective than anticholinergic agents.17 18 Unfortunately, use of combination therapy â of a long acting inhaled 2 agonist and an anti- Results cholinergic agent in COPD has not been suY- All patients completed the four day study. ciently studied with respect to its eVect on pul- There were no significant diVerences between monary function. In particular, a trial of an the baseline spirometric values of the four anticholinergic agent in patients with inad- â treatment groups (FEV1, p = 0.411) equate responsiveness to long acting 2 ago- Salmeterol induced a significant bronchodi- nists, especially in those with severe airflow lation two hours after its inhalation (mean obstruction, is lacking. To our knowledge there increase 0.272 l; 95% CI of diVerences 0.207 are only two published studies on small to 0.337) whereas placebo did not modify the numbers of patients which found no substan- http://thorax.bmj.com/ V â baseline values (table 2). tial additive e ect when a long acting 2 agonist In the dose-response curve (fig 1) oxitro- was combined with ipratropium at the clini- pium but not placebo elicited an evident cally recommended dose (40 µg) in patients 7 increase in FEV1. Specifically, the further mean with COPD. Matera et al found that the peak maximum increase induced by 600 µg oxitro- response for 50 µg salmeterol was greater than pium after pretreatment with 50 µg salmeterol for 40 µg ipratropium, but equivalent peak was 0.152 l (95% CI of diVerences 0.124 to bronchodilation occurred with salmeterol and

0.180). Maximum values of bronchodilation salmeterol plus ipratropium. Another study has on September 23, 2021 by guest. Protected copyright. induced by 600 µg oxitropium after pretreat- recently reported that a regimen of 12 µg ment with 50 µg salmeterol or placebo were formoterol plus 40 µg ipratropium was sup- always statistically diVerent (p<0.0001) from erior to 40 or 80 µg ipratropium, but no statis- their baseline and post-inhalational values tically significant diVerence was observed (table 2). between the combination regimen and 12 or 8 Analysis of variance of FEV1 values induced 24 µg formoterol. It is possible that the by 600 µg oxitropium bromide or placebo (six subjects studied in these two specific clinical puVs) across all four treatments was significant situations were at the top of their bronchodila- (p = 0.002). The comparison between sal- tion response curve after inhalation of salm- meterol + 600 µg oxitropium and salmeterol + eterol or formoterol. However, it must also be placebo (six puVs) showed a mean diVerence of stressed that the dose of ipratropium bromide 0.128 l (95% CI of diVerences 0.096 to 0.159) needed to produce near maximal bronchodila- that was statistically significant (p<0.0001). tion is several times higher than the normal V 19 The mean di erence between the highest FEV1 dosage. Consequently, the full therapeutic after salmeterol + 600 µg oxitropium and that potential of combined salmeterol or formoterol after placebo + 600 µg oxitropium was also plus an anticholinergic drug can only be estab- statistically significant (p<0.01). In fact, the lished using doses higher than those currently

increase in FEV1 induced by 600 µg oxitro- recommended in the marketing of antimus- pium after pretreatment with salmeterol carinic agents. tended to be greater than that after placebo The results of the present study show that (0.111 l; 95% CI of diVerences 0.044 to acute pretreatment with 50 µg salmeterol does 0.177). It should also be noted that treatment not block the possibility of inducing further with 200 µg oxitropium after salmeterol was bronchodilation with oxitropium bromide signiﬁcantly (p<0.01) more eVective than when a higher than normal dosage of the 1086 Cazzola, Di Perna, Centanni, et al

anticholinergic drug is used. Our data suggest 4 Cazzola M, Spina D, Matera MG. The use of bronchodilators in stable chronic obstructive pulmonary disease. Pulm that the inhalation of 600 µg oxitropium may Pharmacol Ther 1997;10:129–44.

â Thorax: first published as 10.1136/thx.54.12.1083 on 1 December 1999. Downloaded from be required to achieve a further bronchodila- 5 Cazzola M, Matera MG. Should long-acting 2-agonists be considered an alternative first choice option for the tion when inadequate relief is obtained after treatment of stable COPD? Respir Med 1999;93:227–9. â 50 µg salmeterol. 6 Cazzola M, Donner CF, Matera MG. Long-acting 2- In this study we used oxitropium bromide as agonists and theophylline in stable chronic obstructive pulmonary disease. Thorax 1999;54:730–6. the anticholinergic agent because it is an eVec- 7 Matera MG, Caputi M, Cazzola M. A combination with 20 21 clinical recommended dosages of salmeterol and ipratro- tive bronchodilator in COPD, exhibits a V 22 pium is not more e ective than salmeterol alone in patients certain dose response relationship, and, more with chronic obstructive pulmonary disease. Respir Med important, FEV reaches a plateau after 1996;90:497–9. 1 8 Sichletidis L, Kottakis J, Marcou S, et al. Bronchodilatory administration of a cumulative dose of only six responses to formoterol, ipratropium, and their combina- puVs of oxitropium (600 µg) in patients with tion in patients with stable COPD. Int J Clin Pract 1999;53: 19 185–8. COPD. 9 American Thoracic Society. Standards for the diagnosis and In conclusion, the results of this study care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995;152: S72–120. suggest that higher than normal doses of an 10 American Thoracic Society. Standardization of spirometry: anticholinergic drug must be used for further 1987 update. Am Rev Respir Dis 1987;136:1285–98. relief of bronchospasm in patients with COPD 11 Chapman KR. Clinical implications of anticholinergic bronchodilator therapy in COPD. Res Clin Forums 1991;13 when a single conventional inhaled dose of sal- (2 part 1):43–50. meterol is given first. However, we should 12 Campbell S. For COPD a combination of ipratropium bromide and albuterol sulfate is more eVective than albuterol stress that this study remains an observation of base. Arch Intern Med 1999;159:156–60. an acute eVect and is limited to the eVects on 13 Brown IG, Chan CS, Kelly CA, et al. Assessment of the clinical usefulness of nebulised ipratropium bromide in airway obstruction. Further larger studies are patients with chronic airflow limitation. Thorax 1984;39: needed to verify the impact of regularly sched- 272–6. 14 Marlin GE. Studies of ipratropium bromide and fenoterol uled salmeterol combined with higher than the administered by metered-dose inhaler and aerosolized conventional dosage of an anticholinergic solution. Respiration 1986;50(Suppl 2):290–3. agent on spirometric values. It will also be 15 Barros MJ, Rees PJ. Bronchodilator responses to salbutamol followed by ipratropium bromide in partially reversible air- interesting to examine the impact of such a flow obstruction. Respir Med 1990;84:371–5. combination on dyspnoea, improvement in 16 Cazzola M, Santangelo G, Piccolo A, et al.EVect of salmeterol and formoterol in patients with chronic quality of life, exercise capacity, and activities obstructive pulmonary disease. Pulm Pharmacol 1994;7: of daily living. 103–7. 17 Matera MG, Cazzola M, Vinciguerra A, et al. A comparison of the bronchodilating eVects of salmeterol, salbutamol and The authors thank Dr Paolo Fina for statistical analysis. ipratropium bromide in patients with chronic obstructive pulmonary disease. Pulm Pharmacol 1995;8:267–71 . 18 Cazzola M, Matera MG, Di Perna F, et al. A comparison of This study received no funding from the pharmaceutical indus- bronchodilating eVects of salmeterol and oxitropium try. bromide in stable chronic obstructive pulmonary disease. Respir Med 1998;92:354–7. 1 COPD Guidelines Group of the Standards of Care 19 Ikeda A, Nishimura K, Koyama H, et al. Comparative dose- Committee of the BTS. BTS guidelines for the manage- response study of three anticholinergic agents and fenoterol

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