Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Tiotropium improved lung function more than did ipratropium in chronic obstructive pulmonary disease

PDF

ACP J Club. 2000 Nov-Dec;133:101. doi:10.7326/ACPJC-2000-133-3-101


Source Citation

van Noord JA, Bantje Th A, Eland ME, Korducki L, Cornelissen PJ, on behalf of the Dutch Tiotropium Study Group. A randomised controlled comparison of tiotropium and ipratropium in the treatment of chronic obstructive pulmonary disease. Thorax. 2000;55:289-94. [PubMed ID: 10722768]


Abstract

Question

In patients with stable chronic obstructive pulmonary disease (COPD), what is the long-term effectiveness and safety of tiotropium compared with those of ipratropium?

Design

Randomized {allocation concealed*}†, blinded (patient and outcome assessor),* controlled trial with 13 weeks of follow-up.

Setting

14 centers in the Netherlands.

Patients

288 patients ≥ 40 years of age (mean age 64 y, 83% men) who were current or past smokers with a diagnosis of COPD and stable airways obstruction, an FEV1 < 65% of the predicted normal rate, and a ratio of FEV1 to forced vital capacity (FVC) of < 70%. Exclusion criteria included a history of asthma, allergic rhinitis, or atopy; a recent history of myocardial infarction, heart failure, or cardiac arrhythmia requiring drug treatment; upper respiratory tract infection in the past 6 weeks; and hypersensitivity to anticholinergic drugs. 90% completed all tests.

Intervention

191 patients were assigned to tiotropium, 18 µg once daily, delivered by a dry-powder inhaler system; and 97 were assigned to ipratropium, 40 µg 4 times daily, delivered by a metered-dose inhaler. Each group also received placebo doses of the other treatment.

Main outcome measures

Lung function, peak expiratory flow (PEF), use of concomitant salbutamol, and adverse effects.

Main results

Trough, peak, and mean FEV1 response and trough and mean FVC response showed greater improvement with tiotropium than with ipratropium (Table). Morning and evening PEF was consistently better with tiotropium (P < 0.05). Use of concomitant salbutamol was lower in the tiotropium group (P < 0.05). The groups did not differ for adverse effects.

Conclusions

In patients with chronic obstructive pulmonary disease, tiotropium improved lung function more than did ipratropium. The safety profiles of the 2 drugs were similar.

*See Glossary.

†Information provided by the author.

Source of funding: Boehringer Ingelheim BV.

For correspondence: Dr. J.A. van Noord, Department of Respiratory Diseases, Atrium Medisch Centrum, Henri Dunantstraat 5, 6419 PC Heerlen, The Netherlands. FAX 31-455767534.


Table. Tiotropium vs ipratropium at 13 weeks in chronic obstructive pulmonary disease (lung function improvement, in liters, compared with baseline at start of study)‡

Outcomes Tiotropium Ipratropium Mean difference (95% CI)
FEV1 trough 0.16 0.03 0.13 (0.08 to 0.18)
FEV1 peak (at 50 d) 0.38 0.30 0.08 (0.02 to 0.15)
FEV1 mean (over 6 h) 0.26 0.18 0.08 (0.03 to 0.13)
FVC trough 0.39 0.18 0.21 (0.10 to 0.32)
FVC mean (at 50 d) 0.62 0.45 0.17 (0.50 to 0.29)

‡FVC = forced vital capacity.


Commentary

The anticholinergic agent ipratropium bromide is front-line therapy for patients with nonasthmatic COPD (1). In most of these patients, ipratropium used alone is more effective as a bronchodilator than is an inhaled β-agonist used alone. (Combination therapy, however, is often more effective than either agent used alone.) Ipratropium bromide has a relatively short duration of action, requiring inhalation every 6 to 8 hours. In addition, ipratropium nonselectively inhibits all 3 of the known muscarinic receptors in the human airway (M1, M2, and M3). This is of theoretical concern because the M2 receptor normally acts as a feedback inhibitory receptor; blockade of the M2 receptor results in increased acetylcholine release in the airway and could attenuate or reverse the bronchodilation achieved by blockade of the M1 and M3 receptors (2). The clinical relevance of this issue is uncertain.

Tiotropium is a potent and long-lasting muscarinic antagonist that has “kinetic selectivity” for M1 and M3 receptors over M2 receptors (2). A single dose of inhaled tiotropium produces bronchodilation for 24 hours in patients with COPD (3) and attenuates methacholine-induced bronchoconstriction for 48 hours in patients with asthma (4). Once-daily dosing for 4 weeks in stable patients with COPD provides sustained bronchodilation with an excellent safety profile (5).

The study by van Noord and colleagues provides important data, showing the superiority of tiotropium (18 µg once/d) over the usual dose of ipratropium (40 µg 4 times/d). Patients were permitted to use many of their own usual medications (including methylxanthines, inhaled steroids, and oral steroids up to 10 mg of prednisone/d) during the course of the trial, showing the effectiveness of tiotropium in a meaningful clinical context. Tiotropium, not yet approved for use in the United States, appears to have great potential in the long-term maintenance therapy of COPD.

Herbert P. Wiedemann, MD
The Cleveland Clinic Foundation
Cleveland, Ohio, USA


References

1. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1995;152:S77-121.

2. Barnes PJ. The pharmacological properties of tiotropium. Chest. 2000;117:S63-6.

3. Maesen FP, Smeets JJ, Sledsens TJ, Wald FD, Cornelissen PJ. Tiotropium bromide, a new long-acting antimuscarinic bronchodilator: a pharmacodynamic study in patients with chronic obstructive pulmonary disease (COPD). Dutch Study Group. Eur Respir J. 1995;8:1506-13.

4. O’Connor BJ, Towse LJ, Barnes PJ. Prolonged effect of tiotropium bromide on methacholine-induced bronchoconstriction in asthma. Am J Respir Crit Care Med. 1996; 154:876-80.

5. Littner MR, Ilowite JS, Tashkin DP, et al. Long-acting bronchodilation with once-daily dosing of tiotropium (Spiriva in stable chronic obstructive pulmonary disease). Am J Respir Crit Care Med. 2000;161:1136-42.