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| |  Once-Daily Inhaled Tiotropium Has Some Benefits in Patients With Chronic Obstructive Pulmonary Disease: Presented at ERS By Chris Berrie BERLIN -- October 6, 2008 -- Treatment with the inhaled anticholinergic tiotropium significantly improves some markers of lung function and health-related quality of life (HRQoL), as well as reducing the risk of exacerbations and hospitalisations for patients with chronic obstructive pulmonary disease (COPD), according to results of a 4-year, multicentre, randomised, placebo-controlled, double-blind, parallel-arm, clinical trial. Furthermore, despite recent concerns related to the safety of inhaled anticholinergics, treatment with tiotropium was associated with reduced mortality and reduced cardiac and lower respiratory morbidity, said study investigators on October 5th at the European Respiratory Society (ERS) 18th Annual Congress. The results were presented here on October 6 on behalf of the Understanding Potential Long-Term Impacts on Function With Tiotropium (UPLIFT) study group by principal investigator Marc Decramer, MD, PhD, Respiratory Division, University of Leuven, Leuven, Belgium. "The hypothesis [of the study] was that tiotropium modifies the natural course of the disease in COPD," Dr. Decramer explained. The coprimary endpoints were the yearly decline in prebronchodilator and postbronchodilator forced expiratory volume at 1 second (FEV1) from day 30 to completion of double-blind treatment. Postbronchodilator spirometry used 4 puffs of ipratropium and 4 puffs of salbutamol, with waiting times of 90 and 30 minutes between administrations, respectively. Main secondary endpoints were time to first exacerbation and to first hospitalisation due to exacerbations. Further secondary endpoints included: spirometry, COPD exacerbations and hospitalisations, HRQoL using the St. George's Respiratory Questionnaire (SGRQ), and all-cause and lower respiratory mortality. The researchers randomised 3,006 patients to placebo (mean age, 65 years; male, 74%) and 2,987 to tiotropium 18 mcg by inhalation once daily (mean age, 65 years; male, 75%). All respiratory medications were permitted except inhaled anticholinergics in the placebo group, throughout the trial. At end of trial, patients received open-label ipratropium for the 30-day follow-up. At baseline, there was a relatively large proportion of Global Initiative on Obstructive Lung Disease (GOLD) stage 2 patients (46%) versus GOLD stages 3/4 (44%/8%). There were no significant differences between treatment groups for the baseline spirometry measures, both prebronchodilator and postbronchodilator, and for baseline and on-treatment respiratory medications. The study was completed by 1,648 placebo patients and 1,887 tiotropium patients, representing significantly different discontinuation rates of 45% and 36%, respectively (P < .001). Although mean values for prebronchodilator and postbronchodilator FEV1 and forced vital capacity showed significant (P < .0001) improvements for tiotropium treatment over placebo, the coprimary outcomes for FEV1 showed no significant differences between treatment groups. However, Dr. Decramer noted that for the patient subgroups with no long-acting beta2-agonists or inhaled corticosteroids at baseline, and with GOLD stage 2 at baseline, tiotropium benefit over placebo for the coprimary endpoint for postbronchodilator FEV1 reached significance (P = .048; P = .02, respectively). Finally, significant benefits of tiotropium over placebo were seen for SGRQ (range, 2.3-3.3 units), COPD exacerbation (hazard ratio [HR], 0.86; log-rank P < .0001), and COPD exacerbation hospitalisations (HR, 0.86; log-rank P < .002). In a separate presentation, safety data from the UPLIFT trial were discussed by the study's coprincipal investigator, Donald Tashkin, MD, Pulmonary Function Laboratory, Department of Pulmonary and Clinical Care, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. Dr. Tashkin indicated no differences between tiotropium and placebo for any adverse events (93% vs 92%, respectively), for serious adverse events (52% vs 50%), and for fatal events (13% vs 14%). "However, there was a difference in the percentage of participants who had adverse events that lead to discontinuation from the trial [21% vs 25%]." With inclusion of vital status for study discontinuations to end of study on day 1,440, the probability of death from any cause showed significant benefit for tiotropium over placebo both on treatment (HR, 0.84; log-rank P = .016), and on treatment plus vital status on day 1,440 (HR, 0.87; log-rank P = .034). However, following the 30-day follow-up, on day 1,470, this was a trend for benefit for tiotropium (HR, 0.89; log-rank P = .086). Dr. Tashkin said, "It is interesting to speculate that the reason for this disparity between the deaths in the tiotropium and control arms during this [30-day follow-up] period could be related to tiotropium withdrawal." Finally, using the same composite and fatal endpoints, tiotropium still provided significant benefit over placebo (HR, 0.78; 95% confidence interval [CI], 0.65-0.94; HR, 0.73; 95% CI, 0.56-0.95; respectively). In addition, independent analyses for stroke, myocardial infarction, and respiratory failure generally showed either significant benefit or beneficial trends for tiotropium treatment over control. This study's findings are being published in the New England Journal of Medicine online on October 6 (doi:10.1056/NEJMoa0805800) and in print on October 9, 2008. Funding for this study was provided by Boehringer Ingelheim Pharmaceuticals, Inc. and Pfizer Inc.
[Presentation title: Understanding the Potential Long-Term Impacts on Function With Tiotropium: the UPLIFT Trial - Design and Efficacy Data. Abstract 1276] [Presentation title: Understanding the Potential Long-Term Impacts on Function With Tiotropium: the UPLIFT Trial - Safety Data. Abstract 1277]
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