Pooled Clinical Trial Analysis of Tiotropium Safety


      Marketing approval of pharmaceutical products is often based on data from several thousand subjects or fewer. Evaluation of safety is greatly enhanced by augmenting the safety database with postapproval studies.


      We conducted a pooled analysis of adverse event data from 19 randomized, double-blind, placebo-controlled trials with tiotropium in patients with obstructive lung disease. We computed incidence rates and rate ratios (RRs) for various reported adverse event end points of interest. Patients contributed person-time to the analysis as long as they were in the study until 30 days after treatment (tiotropium, placebo), or until they had the event of interest, whichever came first. Studies were pooled using the Mantel-Haenszel estimator, and we used 95% confidence intervals (CIs) to assess the precision of effect estimates.


      The pooled trial population includes 4,435 tiotropium patients and 3,384 placebo patients contributing 2,159 person-years of exposure to tiotropium and 1,662 person-years of exposure to placebo. Dyspnea, dry mouth, COPD exacerbation, and upper respiratory tract infection were the most commonly reported events. There was a higher relative risk of dry mouth in the tiotropium group (RR, 3.60; 95% CI, 2.56 to 5.05). There was a lower risk of dyspnea (RR, 0.64; 95% CI, 0.50 to 0.81) and COPD exacerbation (RR, 0.72; 95% CI, 0.64 to 0.82) in patients receiving tiotropium compared to patients receiving placebo. Other results of interest are as follows: (1) all-cause mortality (RR, 0.76; 95% CI, 0.50 to 1.16); (2) cardiovascular mortality (RR, 0.57; 95% CI, 0.26 to 1.26); and (3) respiratory mortality (RR, 0.71; 95% CI, 0.29 to 1.74). The relative risk of urinary retention was 10.93 (95% CI, 1.26 to 94.88).


      Pooling of adverse event data from preapproval and postapproval tiotropium clinical trials increase the precision of effect estimates and supports the present safety profile of tiotropium.

      Key words


      CI (confidence interval), RR (risk ratio), URTI (upper respiratory tract infection)
      To read this article in full you will need to make a payment


      Subscribe to CHEST
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Disse B
        • Speck GA
        • Rominger KL
        • et al.
        Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease.
        Life Sci. 1999; 64: 457-464
        • Casaburi R
        • Mahler DA
        • Jones PW
        • et al.
        A long-term evaluation of once-daily tiotropium in chronic obstructive pulmonary disease.
        Eur Respir J. 2002; 19: 217-224
        • Vincken W
        • van Noord JA
        • Greefhorst APM
        • et al.
        Improved health outcomes in patients with COPD during 1 yr’s treatment with tiotropium.
        Eur Respir J. 2002; 19: 209-216
        • Brusasco V
        • Hodder R
        • Miravitlles M
        • et al.
        Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD.
        Thorax. 2003; 58: 399-404
        • Donohue JF
        • van Noord JA
        • Bateman ED
        • et al.
        A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol.
        Chest. 2002; 122: 47-55
        • O’Donnell D
        • Flüge T
        • Gerken F
        • et al.
        Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD.
        Eur Respir J. 2004; 23: 832-840
        • Maltais F
        • Hamilton A
        • Marciniuk D
        • et al.
        Improvements in symptom-limited exercise performance over 8 h with once-daily tiotropium in patients with COPD.
        Chest. 2005; 128: 1168-1178
        • Niewoehner DE
        • Rice K
        • Cote C
        • et al.
        Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator.
        Ann Intern Med. 2005; 143: 319-326
      1. Spiriva HandiHaler tiotropium bromide inhalation powder [US package insert]. Boehringer Ingelheim International GmbH, Ingelheim, Germany2004
      2. Atrovent (ipratropium bromide) inhalation aerosol [US package insert]. Boehringer Ingelheim International GmbH, Ingelheim, Germany2002
        • Morganroth J
        • Golisch W
        • Kesten S
        Electrocardiographic monitoring in COPD patients receiving tiotropium.
        COPD. 2004; 1: 181-190
        • Rothman KJ
        • Greenland S
        Measures of disease frequency.
        Modern epidemiology. Lippincott-Raven Publishers, Philadelphia, PA1998: 29-46 (Rothman, KJ Greenland, S eds 2nd ed.)
        • Fleiss JL
        The statistical basis of meta-analysis.
        Stat Methods Med Res. 1993; 2: 121-145
        • Casaburi R
        • Kukafka D
        • Cooper CB
        • et al.
        Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD.
        Chest. 2005; 127: 809-817
        • Hasani A
        • Toms N
        • Agnew JE
        • et al.
        The effect of inhaled tiotropium bromide on lung mucociliary clearance in patients with COPD.
        Chest. 2004; 125: 1726-1734
        • Calverley PMA
        • Lee A
        • Towse L
        • et al.
        The effect of tiotropium bromide on circadian variation in airflow limitation in chronic obstructive pulmonary disease.
        Thorax. 2003; 58: 855-860
        • 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: 1136-1142
        • Maesen FPV
        • Smeets JJ
        • Sledsens TJH
        • et al.
        Tiotropium bromide, a new long-acting antimuscarinic bronchodilator: a pharmacodynamic study in patients with chronic obstructive pulmonary disease.
        Eur Respir J. 1995; 8: 1506-1513
        • Celli B
        • Zu Wallack R
        • Wang S
        • et al.
        Improvements in resting inspiratory capacity and hyperinflation with tiotropium in COPD with increased static lung volumes.
        Chest. 2003; 124: 1743-1748
        • McNicholas WT
        • Calverly PMA
        • Lee A
        • et al.
        Long-acting inhaled anticholinergic therapy improves sleeping oxygen saturation in COPD.
        Eur Respir J. 2004; 23: 825-831
        • Brown JE
        • Taylor P
        Muscarinic receptor agonists and antagonists.
        Goodman and Gilman’s the pharmacological basis of therapeutics. McGraw-Hill Book, New York, NY2001: 162-168 (Gilman, AG Hardman, JG Limbird, LE eds 10th ed.)
        • Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. NHLBI/WHO workshop report. Bethesda, MD: National Heart, Lung, and Blood Institute, April 2001
        (Accessed November 5, 2004)
        • Celli BR
        • Mac Nee W
        ATS/ERS Task Force Committee Members. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper.
        Eur Respir J. 2004; 23: 932-946
        • Anthonisen NR
        • Connett JE
        • Enright PL
        • et al.
        Hospitalizations and mortality in the Lung Health Study.
        Am J Respir Crit Care Med. 2002; 166: 333-339
        • Anthonisen NR
        • Connett JE
        • Kiley JP
        • et al.
        Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1, the Lung Health Study.
        JAMA. 1994; 272: 1497-1505
        • Lanes S
        • Golisch W
        • Mikl J
        Ipratropium and Lung Health Study.
        Am J Respir Crit Care Med. 2003; 167: 801
        • Salpeter SR
        • Ormiston TM
        • Salpeter EE
        Cardiovascular effects of B-agonists in patients with asthma and COPD.
        Chest. 2004; 125: 2309-2321
        • Psaty BM
        • Furberg CD
        Cox-2 inhibitors: lessons in drug safety.
        N Engl J Med. 2005; 352: 1133-1135
        • Center for Drug Evaluation and Research, United States Food and Drug Administration. FDA public health advisory, worsening depression and suicidality in patients being treated with antidepressant medications
        (Accessed December 11, 2004)