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Pooled Clinical Trial Analysis of Tiotropium Safety^*

^* From Boehringer Ingelheim Pharmaceuticals (Drs. Kesten and Lanes), Ridgefield, CT; Epidemiology Consulting LLC (Dr. Jara), LLC, Danbury, CT; and Analytic Consulting Solutions (Mr. Wentworth), Wakefield, RI.

Correspondence to: Steven Kesten, MD, FCCP, Therapeutic Program Director, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd, Ridgefield, CT 06877-0368; e-mail: skesten{at}rdg.boehringer-ingelheim.com

Abstract

Background: 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.

Methods: 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.

Results: 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).

Conclusions: 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: COPD • drug safety • tiotropium

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