A 4-Year Trial of Tiotropium in Chronic Obstructive Pulmonary Disease

Carl Stuart.

Stuart Medical Series.

                          A 4-Year Trial of Tiotropium in Chronic Obstructive Pulmonary Disease (COPD).

The full item is published in The New England Journal of Medicine; October 9, 2008; Volume 359, Issue number 15; Pages 1543-1554. Authors: Donald.P. Tashkin, M.D., Bartolome Celli, M.D., Stephen Senn,Ph.D., Deborah Burkhart, B.S.N., Steven Kessen, M.D., Shailendra Menjoge, Ph.D., and Marc Decramer, M.D., Ph.D.

Background.

Most drugs used to manage COPD, apart from single daily dose of Tiotropium, have been shown not to modify the low FEV₁(Forced expiratory volume in  1 second) . Previous controlled clinical trials and retrospective analysis have shown that the bronchodilation caused by tiotropium does improve airflow within the respiratory tract, thus, leading to adequate lung inflation. In this UPLIFT (Understanding potential long-term impact on function with tiotropium) trial; the researchers studied the effects of tiotropium on FEV_1, and its related impact on the overall quality of health of a COPD patient (as can be measured by reduced mortality, reduced rates of exacerbation and hospitalization; and improved quality of life).

Methods.

This was a randomized, parallel-group, placebo-controlled, double-blind 4-year trial that involved moderately ill-to-severely ill COPD patients. All the 5933 patients that were selected belonged to 37 nationalities, were more than 40 years old, had a smoking history of more than 10 pack-years, had a post-bronchodilator FEV ₁ predictive value of 70% or less; and FVC:FEV₁ ratio greater than 1.43.  The main exclusion criteria used were asthmatic patients, COPD exacerbation, lower tract respiratory infections, previous pulmonary resection, more than 12 hours utilization of supplemental oxygen; and co-existing respiratory co-morbidities. Most patients had ceased smoking prior to randomization, and those who continued smoking were recorded during each visit.

The two co-primary variable pulmonary endpoint parameters that were selected were the annual rate of decline of FEV₁ before and after use of bronchodilators from the 30^th  day into the study till completion of UPLIFT trial; and the secondary outcome biomarkers, such as, FVC( forced vital capacity), SVC (slow vital capacity), SGRQ (St. George’s Respiratory Questionnaire) score; and, exacerbations of COPD and its related incidence of co-morbidity, hospitalization and mortality.

The subjects inhaled either 18 µg of tiotropium or an equivalent amount of placebo. Also, use of all respiratory drugs was allowed in this trial with the exception of inhalational anticholinergics. Upon completion of the study, 40 µg of inhalational ipratropium for 6-hourly use was prescribed to each subject for 30 days and then they were asked to return upon completion of the prescription period.

Eligible subjects were assigned into two equal groups using centralized randomization. One group received tiotropium while the other received placebos. Clinical visits occurred after 4 weeks and 12 weeks upon commencement of the trial. Thereafter, clinical visits occurred after every 3 months. Pre-bronchodilator and post-bronchodilator spirometry was done during each clinical visit. SGRQ score was done prior to pre-bronchodilator spirometry.

                                    Results.

There was a mean absolute and sustained improvement in the respiratory functions, as measured by FEV₁ in the group that received tiotropium as compared to the group that received the placebo. However, 4 weeks after the study commenced; both the pre-bronchodilation and post-bronchodilation rate of decline in mean FEV₁ between the tiotropium group and placebo group were insignificant. The mean absolute SGRQ total score improved in the tiotropium group as compared to the placebo group. Moreover, use of tiotropium was associated with reduced incidence of exacerbations, respiratory failure and related hospitalizations.

Discussion.

This study showed that lung function is significantly improved by tiotropium use; and this ultimately leads to improvements in the health-related quality of life and lower incidence of exacerbations.  Moreover, there was a significant reduction in the annual rate of decline of FEV₁ in this study as compared to other prospective long-term interventional studies; such as EUROSCOP (European Respiratory Society Study on Chronic Obstructive Pulmonary Disease) trial, BRONCUS (Bronchitis Randomized on N-Acetylcysteine Cost-Utility Study) trial, ISOLDE (Inhaled steroid in Obstructive Lung Disease in Europe) trial; and, the Lung Health Study II.

            The ceiling effect that was evident with tiotropium usage in reducing the annual rate of decline in FEV₁ does not negate the fact that there is sustained mean absolute improvement in lung function that occurs due to the intrinsic properties of tiotropium that promote repair and regeneration of lung tissue. This improvement is manifested by reduced incidence of exacerbations of COPD, reduced respiratory co-morbidities; and, reduced incidence of associated hospitalizations, hence improving the overall quality of life. This information is pointed out to the general public in order to enlighten them on the importance of using tiotropium in the management of COPD.