COPD Landmark Trial UPLIFT: Meeting Important End Points

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

18th Annual Congress of the European Respiratory Society

Berlin, Germany / October 4-8, 2008

The landmark UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) trial showed for the first time that appropriate treatment in chronic obstructive pulmonary disease (COPD) produced benefits including improvements in lung function and health-related quality of life (HRQoL) and reduced exacerbations and hospitalizations that were maintained long term. Mean absolute improvements in forced expiratory volume in one second (FEV<sub>1</sub> )were seen with tiotropium throughout the trial, although there was no significant reduction in the rate of decline in FEV<sub>1</sub>. Tiotropium, the only available once-daily inhaled long-acting anticholinergic agent, also reduced mortality in COPD patients. These benefits were seen in all stages of disease, but had not previously been demonstrated in a clinical trial in early stage – stage II according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. “These findings will likely lead to a change in the management of COPD patients, with physicians seeing patients earlier and treating them more aggressively,” predicted UPLIFT principal investigator Dr. Marc Decramer, Professor of Medicine, and Chief Respiratory Division, Katholieke Universiteit, Leuven, Belgium. The trial also confirmed the agent’s safety profile seen in earlier studies. There were no major side effects and no increases in risk of stroke or myocardial infarction (MI) associated with it over the four years of the trial. “This is very reassuring for a treatment that will have to be given chronically to patients,” Dr. Decramer commented.

UPLIFT Trial Design

The trial results were presented by Dr. Decramer and co-principal investigator Dr. Donald Tashkin, Professor of Medicine and Medical Director, Pulmonary Function Laboratory, David Geffen School of Medicine, University of California, Los Angeles, and published simultaneously (Tashkin et al. N Engl J Med 2008; 359:1543-54).

UPLIFT was based on earlier studies that had demonstrated improvements in exercise tolerance, HRQoL, and rates of dyspnea and exacerbations with tiotropium in COPD patients over periods of six weeks to 12 months. A retrospective analysis of one-year placebo-controlled trial data had suggested that tiotropium might slow the rate of decline in FEV<sub>1</sub>. “We wanted to do a real-life study to answer these questions,” Dr. Decramer told the audience. Consequently, patients in UPLIFT were allowed to take any respiratory medications during the trial except other inhaled anticholinergics.

From January 2003, a total of 5993 patients at 487 sites in 37 countries were randomly assigned in a double-blind fashion to receive either tiotropium 18 µg or matching placebo q.d. delivered via an inhalation device. The average age of these patients was 65 years, 75% were men, and 30% were current smokers. They included a large proportion (46%) with GOLD stage II disease, 44% with stage III and 8% with stage IV. The trial was completed in February 2008 with 1887 (74%) patients on tiotropium and 1648 (64%) on placebo. Dropout rates were similar to those in other COPD clinical trials, Dr. Decramer reported. At this time point, medication was stopped and patients given open-label ipratropium 40 µg q.i.d. for use during the 30-day follow-up period.

Improved Lung Function

The rate of FEV<sub>1</sub> decline, the primary end point of the trial did not differ between the two treatment groups throughout the trial. The rates in both groups were very low, which the investigators attributed to the high rate of use of inhaled corticosteroids or long-acting beta-agonists: 62% and 60%, respectively, at baseline, rising to 74% and 72% during the trial. Post-hoc analysis of the patients who were not on these agents at baseline showed mean improvements in rates of decline with tiotropium in prebronchodilator FEV<sub>1</sub> (5 mL/year) and post-bronchodilator FEV<sub>1</sub> (7 mL/year; P=0.048 vs. control). Dr. Decramer suggested that there might be a ceiling effect, so that FEV<sub>1</sub> could not be improved beyond the normal rate of decline (20-30 mL/year). Improvements seen in other spirometric end points, including forced vital capacity (FVC) and slow vital capacity (SVC), followed the same pattern and were maintained throughout the study, although there was no effect on rate of decline.

Significant improvements were seen in secondary end points of mean FEV<sub>1</sub>, FVC, and SVC measured at one month and then every six months (P<0.001 for all measurements). Average FEV<sub>1</sub> improvements were 87-103 mL prebronchodilation and 47-65 mL post-bronchodilation. Of particular interest was the clear improvement seen with active therapy in patients with GOLD stage II disease: 100-119 mL (prebronchodilator) and 52-82 mL (post-bronchodilator). “It is reassuring that even in early stages of the disease we can treat COPD patients and that our treatment is effective,” Dr. Decramer noted. The rate of decline in FEV<sub>1</sub> in GOLD stage II patients on tiotropium was improved by a mean of 6 mL/year, a statistically significant difference vs. controls (P=0.02). “It appears that in GOLD stage II there is a greater rate of decline in lung function than in stages III and IV, and that is a strong argument for early intervention,” he suggested.

Quality of Life and Exacerbations/Hospitalizations

HRQoL as measured by the St. George’s Respiratory Questionnaire (SGRQ), was significantly improved with tiotropium at all time points during the trial (2.2 to 3.3 units, P<0.001 vs. placebo). More patients on active therapy had improvements in SGRQ score of <u>></u>4 units, an improvement regarded as clinically meaningful, at one, two, three and four years (P<0.001 vs. placebo for all comparisons). Scores improved compared with placebo for all SGRQ domains.

Time to first exacerbation was significantly delayed in the active treatment group compared with placebo and the risk for exacerbations was reduced by 14% vs. placebo (HR 0.86, 95% CI:0.81-0.91; P<0.001). A significant reduction (14%) was also seen with tiotropium in the mean number of exacerbations per patient- year (HR 0.86, 95% CI:0.81-0.91; P<0.001). The total numbers of hospitalizations for exacerbations were small in the trial, but the risk for an exacerbation leading to hospitalization was reduced by 14% (HR 0.86, 95% CI:0.78-0.95; P=0.002). There was no difference in exacerbations between patients taking or not taking anticholinergics at baseline, showing that the reduction in the risk of exacerbations was not due to their stopping these medications at the start of the trial.

Significant Reductions in Mortality

Compared with placebo, tiotropium was associated with a significant 16% reduction in the probability of death from any cause from the first to last day of treatment (HR 0.84, 95% CI:0.73-0.97; P=0.016). “Such a significant reduction is a novel finding, not previously shown with pharmacotherapy,” remarked Dr. Decramer. Intention to treat analysis up to day 1440 also revealed a significant 13% all-cause mortality reduction (HR 0.87, 95% CI: 0.76-0.99, P=0.034). Twenty deaths occurred during the follow-up period, most (16) in the tiotropium group, nine of which occurred within 35 days of the last dose of the agent, possibly attributable to withdrawal of tiotropium, Dr. Tashkin suggested. There were significant reductions in lower respiratory, cardiac, and vascular fatal events and sudden cardiac death of 19% (P=0.033) at 1440 days and 17% at 1470 days (P=0.055).

Safety Profile Confirmed

The most common serious adverse events in the tiotropium group were dry mouth and constipation, known adverse effects of the drug. Neither on-treatment nor intention to treat analyses showed an increased risk for any type of stroke, with rate ratios of <1 in all analyses, suggesting that tiotropium was actually associated with a decrease in risk of stroke. “There is no signal at all that tiotropium is associated with an increased risk of stroke,” Dr. Tashkin confirmed. There was also no evidence for an association with increased MI risk, with a significant 29% reduction (relative risk 0.71, 95 % CI:0.52-0.99; P<0.05) in MI as well as a significant 16% reduction in serious cardiac events overall. The incidence of exacerbations, dyspnea, and respiratory failure were also significantly reduced in the tiotropium group (all P<0.05 vs. placebo).

Additional studies are needed to determine whether cardiovascular mortality and morbidity, which is known to occur in GOLD stage II COPD, can be prevented by treating stage I and II disease. Dr. Decramer suggested testing this by performing a randomized clinical trial comparing aggressive vs. more lenient treatment in these patients.

We Appreciate Your Feedback
Please take 30 seconds to help us better understand your educational needs.
Are you a healthcare professional practicing in Canada?
What type of healthcare professional best describes you?
Did you find this publication to be of educational value?
What is you preferred format for receiving and reading a report?
Would you like to have video available with the report?
Suggested future topics: