View metadata, citation and similar papers at core.ac.uk ARTICLE IN PRESS brought to you by CORE provided by Elsevier - Publisher Connector Respiratory Medicine (2007) 101, 476–480

Effects of replacing oxitropium with tiotropium on pulmonary function in patients with COPD: A randomized study

Cristoforo IncorvaiaÃ, Gian Galeazzo Riario-Sforza, Chiara Pravettoni, Natale Dugnani, Fulvia Paterniti, Laura Pessina, Mario Fumagalli

Unit of Pulmonary Rehabilitation, ICP Hospital, via Bignami 1, Viale Molise 69, Milan, Italy

Received 3 February 2006; accepted 6 July 2006

KEYWORDS Summary COPD; Background: Inhaled are first line drugs in the treatment of chronic Pulmonary function; obstructive pulmonary disease (COPD). is a recently introduced long- Drug treatment; acting agent able to reduce dyspnoea and COPD exacerbations and to ; improve pulmonary function and quality of life. We designed a study to compare the short- Tiotropium; term efficacy of tiotropium bromide with that of oxitropium bromide in improving Oxitropium pulmonary function in patients with COPD. Methods: Eighty patients were randomized either to continue oxitropium 800 mcg/day or to receive tiotropium 18 mcg/day. Seventy-six (39 in the tiotropium and 37 in the oxitropium group) completed the study. Plethysmography was performed at baseline and after 72 h in all patients. The changes in functional parameters in the two groups were compared by the Mann–Whitney U-test. Results: There were no differences between the two groups regarding age (72.5 vs. 74.2 years), male/female ratio (25/14 vs. 23/14) and pulmonary function at baseline. The changes in spirometric parameters were significantly greater in tiotropium- than in oxitropium-treated patients: mean forced expiratory volume in 1 s (FEV1) increased significantly by 15% vs. 3% (P ¼ 0:017), mean FVC by 10.5% vs. 2.2% (P ¼ 0:044), and FEF 25, 50, and 75 by 34% vs. 14% (Po0.05), 33% vs. 7% (Po0.05), and 50% vs. 6% (Po0.0001), respectively; mean FRC and RV decreased nonsignificantly by 7.5% and 10% with tiotropium vs. 4.3% and 6.5% with oxitropium, respectively. Conclusion: The replacement of oxitropium with tiotropium significantly increases pulmonary function in patients with COPD. The improvement involves also small airways that have not been investigated thus far. & 2006 Elsevier Ltd. All rights reserved.

ÃCorresponding author. Tel./fax: +39 02 5513852. E-mail address: [email protected] (C. Incorvaia).

0954-6111/$ - see front matter & 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmed.2006.07.008 ARTICLE IN PRESS

Effects of replacing oxitropium with tiotropium on pulmonary function in patients with COPD 477

Introduction Methods

Inhaled bronchodilators, namely b2-agonists and anticholi- Pulmonary function nergics, are the mainstay of treatment for chronic obstruc- The FEV1, the FVC, the expiratory flows at low volumes (FEF tive pulmonary disease (COPD).1–3 They are able to improve 25, 50, and 75), the FRC, and the residual volume (RV) were symptoms and exercise capacity,4 and to decrease the measured by an automated pulmonary function testing frequency of COPD exacerbations.5,6 center (6200 Autobox DL, Sensor Medics, Yorba Linda, CA, Tiotropium bromide is a second-generation anticholiner- USA) in accordance with recognized standards.15 Variables gic agent that is structurally related to ipratropium were measured at inclusion and after 72 h: this interval was bromide. Its main distinguishing characteristic is slow chosen to avoid confounding by pulmonary rehabilitation dissociation from Hm1 and Hm3 muscarinic receptors,7 procedures.16 The last dose before repeat measurement which results in sufficiently prolonged pharmacological was given 3 h before for oxitropium and 1 h before for activity8 to allow once daily administration. After the first tiotropium. dose, mean time to onset of its bronchodilating effect is 30 min and mean time to peak effect is about 3 h. Statistical analysis Subsequent doses increase efficacy even further until maximum bronchodilating activity is achieved after 1 week.9 The differences in the absolute changes of respiratory A number of clinical studies have demonstrated the parameters between post- and pre-intervention in tiotro- efficacy of tiotropium in reducing dyspnoea and COPD pium- and oxitropium-treated patients were analysed by the exacerbations and in improving quality of life.10–12 More- Mann–Whitney U-test, setting a P value lower than 0.05 as over, significant effects on pulmonary function have been significant. reported, namely increase in forced expiratory volume in 1 s 13 (FEV1) and forced vital capacity (FVC), and decrease in functional residual capacity (FRC), which indicates that the Results drug reduces lung hyperinflation.14 The objective of this study was to assess short-term Of the 80 patients included, four did not perform the changes in pulmonary function, including small airways second plethysmography, three (two in the oxitropium and variables, in patients with COPD on treatment with another one in the tiotropium group) because they withdrew anticholinergic agent, oxitropium bromide, during either the informed consent and one (in the oxitropium group) continuation of treatment with oxitropium bromide or because family problems made compliance with the replacement treatment with tiotropium bromide. rehabilitation program difficult. Thus, 76 patients (39 in the tiotropium and 37 in the oxitropium group) were Materials and methods evaluated for the study. Thirteen patients of the oxitropium group did not use any spacer device and were instructed to use it. The baseline characteristics of the two treatment Patients groups are shown in Table 1: the two groups were well matched. Eighty patients referred to the Unit of Pulmonary Rehabi- The changes in each parameter vs. baseline are reported litation of the ICP Hospital in Milan were included in the in Table 2. The increases in mean FEV1, FVC, and FEF 25, 50, study. To be included, patients had to be in stable and 75 were significantly higher in patients treated with conditions, with no exacerbations for at least 2 months, in 1 tiotropium than in those treated with oxitropium, whereas GOLD stage 2–4 according to FEV1 values, and on treatment the decrease in mean FRC and RV was larger in tiotropium with only oxitropium bromide as . Treatment treated patients but did not reach statistical significance. with other bronchodilators or inhaled corticosteroids was an This is depicted in Fig. 1. exclusion criterion. The patients were randomized either to continuation of treatment with oxitropium (800 mcg daily) or to replacement of oxitropium with tiotropium (18 mcg Discussion daily). In patients maintained on treatment with oxitro- pium, the inhalation technique was optimized by using A considerable body of evidence collected following the spacer devices, if they had not been already introduced. The introduction of tiotropium bromide into clinical practice need to inhale the drug every 6 h was stressed. Patients makes it a first-line drug for the treatment of COPD.9–14 initiating treatment with tiotropium were instructed to use A recent meta-analysis of nine randomized controlled the dry powder inhaler device. studies has clearly shown that the drug ameliorates

Table 1 Baseline characteristics of the two treatment groups.

Treatment No. of patients Gender Age FEV1 (% predicted) FVC (% predicted)

Oxitropium 37 23 m, 14 f 74.277.1 49.2716.3 72.6715.3 Tiotropium 39 25 m, 14 f 72.576.5 44.3713.3 77.8719.2 ARTICLE IN PRESS

478 C. Incorvaia et al.

Table 2 Changes in mean values of functional parameters in patients treated with oxitropium and tiotropium.

Parameter Oxitropium Tiotropium

Baseline Post-treatment % difference Baseline Post-treatment % difference

FEV1 9497301 9777299 +3 9217385 10597498 +15 FVC 19177604 19607575 +2.2 19807706 21887826 +10.5 FRC 430871706 412471600 4.3 457771648 423471446 7.5 RV 368971444 345071346 6.5 370471706 333071298 10.1 FEF25 12627905 144271015 +14.3 10897866 146171131 +34.1 FEF50 5417355 5797388 +7 4167292 5527461 +32.6 FEF75 178781 1897110 +6.2 1497110 2247181 +50.3

20.0 p = 0.017 p = 0.039 Oxitropium Tiotropium 15.0

10.0

5.0 FRC RV 0.0 FEV1 FVC

percent difference percent -5.0

-10.0

n.s. n.s. -15.0 (A) functional parameters

60.0 p < 0.05 p < 0.05 p < 0.0001 50.0 Oxitropium Tiotropium 40.0

30.0

percent difference percent 20.0

10.0

0.0 FEF25 FEF50 FEF75 (B) functional parameters

Figure 1 Changes in mean values of FEV1, FVC, FRC, and RV (A) and of FEF25, 50, and 75 (B) in patients treated with oxitropium and tiotropium. symptoms and related quality of life, reduces the incidence The improvement in spirometric parameters achieved of disease exacerbations and improves pulmonary function, with tiotropium was apparent not only as compared to as well as increasing exercise capacity.17 placebo-treated patients,13,14 but also in subjects treated ARTICLE IN PRESS

Effects of replacing oxitropium with tiotropium on pulmonary function in patients with COPD 479 with other bronchodilators. For example, the early increase as measured by FRC and RV, did not achieve statistical in mean FEV1 in patients treated with tiotropium was significance; this may have been due to the short period of significantly higher compared to those treated with the observation—3 days. This short period was planned to avoid long-acting b2-agonist salmeterol12 and an improvement in confounding effects by the pulmonary rehabilitation proto- FEV1 value was observed even in patients regularly treated col, but may have been not long enough to reach maximum with the other b2-agonist .18 The superiority in improvement, which was achieved with tiotropium in other respect of the first-generation anticholinergic ipratropium is studies after 42 days14 and 28 days.22 A recent study showed made unmistakable by the meta-analysis,17 while to our that also shorter durations of treatment with tiotropium, knowledge no comparison with oxitropium is available. In starting from 1 week, are sufficient to significantly improve respect to ipratropium, oxitropium has a longer pharmaco- IC but not RV,23 and this offers support to our findings. logical action which enables twice a-day dosing and is as In conclusion, the results of our study confirm the greater effective as ipratropium in terms of the bronchodilating efficacy of tiotropium in respect of previous generation activity.19 anticholinergic agents in the treatment of COPD, and In the present study we compared the short-term effects suggest that the drug possesses a significant effect on small on pulmonary function parameters of the introduction of airways thus far not investigated. tiotropium in patients with COPD, randomizing the subjects either to continue treatment with oxitropium—after opti- mizing the dosage and the inhaling technique—or to replace References it with tiotropium. In oxitropium-treated subjects small increases in FEV1, FVC, and FEF 25, 50, and 75 were found, 1. Pauwels RA, Buist AS, Calverley PMA, Jenkins CR, Hurd SS. as well as small decreases in FRC and RV, which were likely Global strategy for the diagnosis, management and prevention to be due to the optimization of treatment. The changes of chronic obstructive pulmonary disease. NHLB/WHO Global were greater in tiotropium-treated patients: mean FEV1 Initiative for Chronic Obstructive Lung Disease (GOLD) workshop increased significantly by 15% vs. 3% in oxitropium-treated report. Am J Respir Crit Care Med 2001;163:1256–76. patients, mean FVC by 10.5% vs. 2.2%, FEF 25 by 34% vs. 14%, 2. Rand Sutherland E, Cherniak RM. Management of chronic FEF 50 by 33% vs. 7%, and FEF 75 by 50% vs. 6%. By contrast, obstructive pulmonary disease. N Engl J Med 2004;350: 2689–97. mean FRC decreased nonsignificantly by 7.5% with tiotro- 3. Weder MM, Donohue JF. Role of bronchodilators in chronic pium vs. 4.3% with oxitropium, and RV decreased nonsigni- obstructive pulmonary disease. Semin Respir Crit Care Med ficantly by 10% vs. 6.5%. 2005;26:221–34. This degree of improvement is not unexpected, because 4. Belman MJ, Botnick WC, Shin JW. Inhaled bronchodilators even higher values were reported in placebo-controlled reduce dynamic hyperinflation during exercise in patients with studies. For example, the first dose of tiotropium increased chronic obstructive pulmonary disease. Am J Respir Crit Care mean FEV1 by 16% and mean FVC by 17% in patients with Med 1996;153:67–75. stable COPD.13 In a long-term study the addition of 5. Friedman M, Witek Jr. TJ, Serby CW, et al. Pharmacoeconomic tiotropium to other standard drug treatments was able to evaluation of a combination of ipratropium plus albuterol 10 compared to ipratropium alone and albuterol alone in chronic increase mean FEV1 up to 22% and mean FVC up to 12%. In obstructive pulmonary disease. Chest 1999;115:635–41. our study, also the difference in FEF 25, 50, and 75 between 6. Rennard SI, Anderson W, ZuWallack R, et al. Use of a long-acting tiotropium- and oxitropium-treated patients was significant: inhaled beta2-adrenergic agonist, xinafoate, in tiotropium produced larger increase in these parameters, patients with chronic obstructive pulmonary disease. Am which are related to small airways calibre, with a P J Respir Crit Care Med 2001;163:1087–92. valueo0.05 for FEF 25 and FEF 50, and o0.0001 for FEF 75. 7. Disse B, Reichl R, Speck G, Traunecker W, Rominger KL, Hammer To the best of our knowledge, previous evaluations on the R. Ba 679 Br, a novel long-acting anticholinergic bronchodilator: effects of tiotropium on small airways are not available. The preclinical and clinical aspects. Life Sci 1993;52:537–44. improvement we observed, particularly for FEF75, which 8. Maesen FPV, Smeets JJ, Sledsens TJH, Wald FDM, Cornelissen was the most marked among the spirometric measurements, PJG. Tiotropium bromide, a new long-acting antimuscarinic is likely to be linked to the efficiency of the dry powder bronchodilator: a pharmacodynamic study in patients with chronic obstructive pulmonary disease (COPD). Eur Respir inhaler device in delivering the drug into the airways and to J 1995;8:1506–13. the interaction with muscarinic receptors in the smooth 20 9. Barnes PJ. Tiotropium bromide. Expert Opin Invest Drugs muscle of small airways. The importance of this portion of 2001;10:733–40. the respiratory tract was recently claimed by a study, in 10. Casaburi R, Mahler DA, Jones PW, et al. A long term evaluation which bioptic evidence disclosed a close correlation of once daily inhaled tiotropium in chronic obstructive between severity of small airway obstruction and clinical pulmonary disease. Eur Respir J 2002;19:217–24. severity of COPD.21 Consequently, future investigation on 11. Vincken W, van Noord JA, Greefhorst APM, et al. Improvement the efficacy of drug treatment should take into account the in health status in patients with COPD during one year changes occurring in small airway calibre. The dilation of treatment with tiotropium. Eur Respir J 2002;19:209–16. small airways is expected to reduce the air trapping and 12. Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for six months with then the hyperinflation parameters. Previous studies re- once daily tiotropium compared with twice daily salmeterol in ported that treatment with tiotropium achieves a significant patients with COPD. Thorax 2003;58:399–404. decrease in lung hyperinflation, as measured by the 13. Casaburi R, Briggs Jr. DD, Donohue JF, Serby CW, Menjoge SS, inspiratory capacity (IC), an event usually associated with Witek Jr. TJ. The spirometric efficacy of once-daily dosing with 14,22 improvement in exertional dyspnoea. In the present tiotropium in stable COPD: a 13-week multicenter trial. The US study the decrease in hyperinflation induced by tiotropium, Tiotropium Study Group. Chest 2000;118:1294–302. ARTICLE IN PRESS

480 C. Incorvaia et al.

14. O’Donnell, Fluge T, Gerken F,et al. Effects of tiotropium on lung 19. Peel ET, Anderson G, Cheong B, Broderick N. A comparison of hyperinflation, dyspnoea and exercise tolerance in COPD. Eur oxitropium bromide and in . Eur Respir J 2004;23:832–40. J Respir Dis 1984;65:106–8. 15. American Thoracic Society. Standardization of spirometry: 20. Barnes PJ. Muscarinic receptor subtypes in airways. Life Sci 1994 update. Am J Respir Crit Care Med 1995;152: 1993;52:521–7. 1107–36. 21. Hogg JC, Chu F, Utokaparch S, et al. The nature of small airways 16. Riario-Sforza GG, Incorvaia C, Paterniti F, Dugnani N, Fumagalli obstruction in chronic obstructive pulmonary disease. N Engl M. Different outcome of pulmonary rehabilitation in patients J Med 2004;350:2645–53. with COPD with or without exacerbations. Monaldi Arch Chest 22. Celli B, ZuWallack R, Wang S, Kesten S. Improvement in resting Dis 2005;63:129–32. inspiratory capacity and hyperinflation with tiotropium in COPD 17. Barr RG, Bourbeau J, Camargo CA, Ram FS. Inhaled tiotropium patients with increased static lung volumes. Chest 2003;124: for stable chronic obstructive pulmonary disease. Cochrane 1743–8. Database Syst Rev 2005;CD002876. 23. Santus P, Centanni S, Verga M, Di Marco F, Matera MG, Cazzola 18. Cazzola M, Noschese P, Salzillo A, De Giglio C, D’Amato G, M. Comparison of the acute effect of tiotropium versus a Matera MG. Bronchodilator response to formoterol after regular combination therapy with single inhaler /formoterol tiotropium or to tiotropium after regular formoterol in COPD on the degree of resting pulmonary hyperinflation. Respir Med patients. Respir Med 2005;99:524–8. 2006;100:1277–81.