Marketing approval of pharmaceutical products is often based on efficacy and safety data from several thousand subjects. After approval, information may be obtained from larger numbers of patients from Phase IV clinical trials enhancing the ability to detect rare adverse events.
We pooled data on adverse events from 19 randomized, double-blind, placebo-controlled trials with tiotropium in patients with COPD (17 studies) and asthma (2 studies) using data available in project database as of May 2004. Heterogeneity of incidence rate ratios was examined by trial prior to pooling. We computed incidence rates of selected adverse events and Maentel-Haenszel incidence rate ratio estimates, and used 95% confidence intervals for precision of effect estimates. Patients were included while in the study until 30 days post-treatment (tiotropium, placebo) or until they had the event of interest, whichever came first.
Pooled population includes 7,819 patients (4,435 tiotropium; 3,384 placebo), contributing 2,159 person-years of exposure to tiotropium; 1,662 person-years of exposure to placebo. Dyspnea, dry mouth, COPD exacerbation and upper respiratory tract infection were the most common events. There was decreased relative risk of dyspnea (RR=0.64, 95%CI=0.05, 0.81) and COPD exacerbation (RR=0.72, 95%CI=0.64, 0.82) with tiotropium compared with placebo. Among heart rate and rhythm disorders, risk of tachycardia was slightly elevated with tiotropium (RR=1.68, 95%CI=0.69, 4.11). Serious cardiac conditions, such as cardiac arrest and myocardial infarction did not occur more frequently with tiotropium. There was an elevated risk of urinary retention (RR=10.93, 95%CI=1.26, 94.88) with tiotropium. There was lower risk of all cause mortality (RR=0.76, 95%CI=0.50, 1.16), cardiovascular mortality (RR=0.57, 95%=0.26, 1.26) and respiratory mortality (RR=0.71, 95%CI=0.29, 1.74) with tiotropium.
The benefit/risk profile of tiotropium is characterized by decreased risk of dyspnea and COPD exacerbation and increased risk of dry mouth and urinary retention. Pooling of adverse event data from tiotropium clinical trials supports the present safety profile of tiotropium.
Pooling of adverse event data from pre- and post-registration clinical trials has value in understanding the safety of recently approved medications.
Steven Kesten, Grant monies (from industry related sources) Funded by Boehringer Ingelheim and Pfizer.; Employee S. Kesten and S. Lanes are employees of Boehringer Ingelheim.; Consultant fee, speaker bureau, advisory committee, etc. M. Jara and C. Wentworth are consultants for Boehringer Ingelheim.