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      Tiotropium HandiHaler ® in the treatment of COPD: A safety review

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          Abstract

          Background

          Tiotropium is a long-acting inhaled anticholinergic developed for the treatment of chronic obstructive pulmonary disease (COPD) and has been available since 2002. We sought to update an evaluation of the safety of tiotropium in the HandiHaler ® formulation as significant clinical trial data have become available over time.

          Methods

          Pooled analysis of adverse event reporting from phase III and IV tiotropium HandiHaler ® clinical trials with the following characteristics was performed: randomized, double-blind, parallel group, placebo-controlled design, tiotropium 18 μg once-daily dosing, COPD indication, duration of at least four weeks. Incidence rates by treatment group, rate differences (tiotropium–placebo), and 95% confidence intervals were determined.

          Results

          Twenty-six trials were identified involving 17,014 patients. Mean age was 65 years, mean forced expiratory volume in one second was 1.16 L (41% predicted), 76% men. Total exposure to study drug was 11,958 patient-years (tiotropium) and 10,578 patient-years (placebo). Tiotropium was associated with a reduced risk (expressed as rate difference [95% confidence interval] per 100 patients-years at risk) for an adverse event (−17.5 [−22.9, −12.2]), serious adverse event (−1.41 [−2.81, −0.00]) and a fatal event (−0.63 [−1.14, −0.12]). A reduced risk was present for adverse events that were cardiac (−0.79 [−1.48, −0.09]), lower respiratory (−14.2 [−17.0, −11.5]) and for a composite endpoint of major adverse cardiovascular events (−0.45 [−0.85, −0.05]). Typical expected inhaled anticholinergic effects such as dry mouth, constipation, and urinary difficulties were observed in the safety database.

          Conclusion

          The safety data review does not indicate an increased risk for death or cardiovascular morbidity during tiotropium treatment in patients with COPD.

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          Most cited references 32

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          A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.

          Currently available inhaled bronchodilators used as therapy for chronic obstructive pulmonary disease (COPD) necessitate multiple daily dosing. The present study evaluates the long-term safety and efficacy of tiotropium, a new once-daily anticholinergic in COPD. Patients with stable COPD (age 65.2+/-8.7 yrs (mean+/-SD), n=921) were enrolled in two identical randomized double-blind placebo-controlled 1-yr studies. Patients inhaled tiotropium 18 microg or placebo (mean screening forced expiratory volume in one second (FEV1) 1.01 versus 0.99 L, 39.1 and 38.1% of the predicted value) once daily as a dry powder. The primary spirometric outcome was trough FEV1 (i.e. FEV1 prior to dosing). Changes in dyspnoea were measured using the Transition Dyspnea Index, and health status with the disease-specific St. George's Respiratory Questionnaire and the generic Short Form 36. Medication use and adverse events were recorded. Tiotropium provided significantly superior bronchodilation relative to placebo for trough FEV1 response (approximately 12% over baseline) (p<0.01) and mean response during the 3 h following dosing (approximately 22% over baseline) (p<0.001) over the 12-month period. Tiotropium recipients showed less dyspnoea (p<0.001), superior health status scores, and fewer COPD exacerbations and hospitalizations (p<0.05). Adverse events were comparable with placebo, except for dry mouth incidence (tiotropium 16.0% versus placebo 2.7%, p<0.05). Tiotropium is an effective, once-daily bronchodilator that reduces dyspnoea and chronic obstructive pulmonary disease exacerbation frequency and improves health status. This suggests that tiotropium will make an important contribution to chronic obstructive pulmonary disease therapy.
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            The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial.

            Randomized clinical trials have not yet demonstrated the mortality benefit of smoking cessation. To assess the long-term effect on mortality of a randomly applied smoking cessation program. The Lung Health Study was a randomized clinical trial of smoking cessation. Special intervention participants received the smoking intervention program and were compared with usual care participants. Vital status was followed up to 14.5 years. 10 clinical centers in the United States and Canada. 5887 middle-aged volunteers with asymptomatic airway obstruction. All-cause mortality and mortality due to cardiovascular disease, lung cancer, and other respiratory disease. The intervention was a 10-week smoking cessation program that included a strong physician message and 12 group sessions using behavior modification and nicotine gum, plus either ipratropium or a placebo inhaler. At 5 years, 21.7% of special intervention participants had stopped smoking since study entry compared with 5.4% of usual care participants. After up to 14.5 years of follow-up, 731 patients died: 33% of lung cancer, 22% of cardiovascular disease, 7.8% of respiratory disease other than cancer, and 2.3% of unknown causes. All-cause mortality was significantly lower in the special intervention group than in the usual care group (8.83 per 1000 person-years vs. 10.38 per 1000 person-years; P = 0.03). The hazard ratio for mortality in the usual care group compared with the special intervention group was 1.18 (95% CI, 1.02 to 1.37). Differences in death rates for both lung cancer and cardiovascular disease were greater when death rates were analyzed by smoking habit. Results apply only to individuals with airway obstruction. Smoking cessation intervention programs can have a substantial effect on subsequent mortality, even when successful in a minority of participants.
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              Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American Thoracic Society.

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                Author and article information

                Journal
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                1176-9106
                1178-2005
                2009
                2009
                29 November 2009
                : 4
                : 397-409
                Affiliations
                [1 ] Boehringer Ingelheim Pharmaceuticals; Ridgefield, CT, USA
                [2 ] Caritas St. Elizabeth’s Medical Center, Boston, MA, USA
                [3 ] University of Leuven, Leuven, Belgium
                [4 ] Boehringer Ingelheim GmbH, Ingelheim, Germany
                [5 ] David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
                Author notes
                Correspondence: Steven Kesten, Boehringer-Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd, Ridgefield, CT, 06877-0368, USA, Tel +1 203 791 5983, Fax +1 203 837 5983, Email steven.kesten@ 123456boehringer-ingelheim.com
                Article
                copd-4-397
                2793068
                20037679
                © 2009 Kesten et al, publisher and licensee Dove Medical Press Ltd

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                Categories
                Review

                Respiratory medicine

                tiotropium, chronic obstructive pulmonary disease, mortality, safety

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