UPLIFT: A 4-Year Trial of Efficacy and Safety of Tiotropium in Chronic Obstructive Pulmonary Disease

27 Oct, 16

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Introduction

The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial was designed to assess the benefits of tiotropium in reducing the rate of decline in FEV₁ in patients with chronic obstructive pulmonary disease (COPD). Tiotropium is a once-daily, inhaled anticholinergic drug that delivers long-lasting 24-hour improvements in airflow and hyperinflation in patients with COPD.

Aim

The trial focused on the long-term effects of tiotropium therapy on the clinically important end points of health-related quality of life (HRQoL), exacerbations, related hospitalizations, and mortality.

Patients Profile

N=5993
Age of ≥ 40 years
Smoking history of at least 10 pack-years
Post-bronchodilator FEV₁ of ≤ 70% of the predicted value
FEV₁ / FVC of ≤ 70% or less
Exclusion criteria: History of asthma, a COPD exacerbation or respiratory infection within 4 weeks before screening, a history of pulmonary resection, use of supplemental oxygen for more than 12 hours per day, and the presence of a coexisting illness that could preclude participation in the study or interfere with the study results

Method

Study Design

A 4-year, randomized, double blind, placebo-controlled, parallel-group trial involving patients with moderate-to-very-severe COPD
The patients were from 490 investigational centers set in 37 countries

Dosing

Patients were divided into 2 groups:
- Those who received 18 ?g of tiotropium; or
- Those who received a matching placebo once daily
The patients received doses via HandiHaler inhalation device
All respiratory medications, except other inhaled anticholinergic drugs, were permitted during the trial
At the end of the study, all patients were given 40 ?g of ipratropium (two inhaler actuations) four times daily and to return for a final assessment after 30 days

End-point

Primary end points: yearly rate of decline in the mean FEV1:
- Before the use of a study drug and short-acting bronchodilators in the morning (prebronchodilator) and
- After the use of a study drug (postbronchodilator) from day 30 (steady state) until completion of double-blind treatment
Secondary end points:
- Rate of decline in the mean forced vital capacity (FVC) and slow vital capacity (SVC)
- Health-related quality of life, as measured by the total score on St. George’s Respiratory Questionnaire (SGRQ)
- Exacerbations of COPD and related hospitalizations. Rate of death from any cause and from lower respiratory conditions

Results

Rate of Decline in Lung Function

The mean absolute improvements in FEV₁ in the tiotropium group were maintained throughout the trial (ranging from 87 to 103 mL before bronchodilation and from 47 to 65 mL after bronchodilation), as compared with the placebo group (P<0.001).
After day 30, the differences between the two study groups in the rate of decline in the mean FEV₁ and FVC before and after bronchodilation remained non-significant.

Figure 1: Annual rates of decline in FEV1

Figure 2: Annual rates of decline in FVC

Health-Related Quality of Life

The mean absolute total score on the SGRQ was improved (i.e. lower) in the tiotropium group, at each time point throughout the 4-year period (ranging from 2.3 to 3.3 units, P<0.001) as compared with the placebo group.

Figure 3: Percent of patients showing improvements of ≥4 units in SGRQ scores at 1 year

Exacerbations

Exacerbations were defined as an increase in or the new onset of more than one respiratory symptom (cough, sputum, sputum purulence, wheezing, or dyspnea) lasting 3 days or more and requiring treatment with an antibiotic or a systemic corticosteroid.
Tiotropium was found to be associated with a reduction in the mean number of exacerbations of 14% (P<0.001) and a significant delay in the time to the first hospitalization for an exacerbation.

Figure 4: Delay in time to first exacerbation (months)

Mortality

During a period of 4 years plus 30 days (1470 days) of the study, a total of 941 patients died: 14.9% in the tiotropium group and 16.5% in the placebo group.

Figure 5: Mortality statistics

Safety

Tiotropium showed reduced respiratory morbidity (including a decreased risk of respiratory failure) and reduced cardiac morbidity as compared to the placebo

Table 1: Safety profile of tiotropium

Variables	Tiotropium	Placebo
Adverse events reported	92.6%	92.3%
Serious adverse events	51.6%	50.2%
Fatal events	12.8%	13.7%

Table 2: Incidence rate of serious cardiac adverse events per 100 patient-years

Adverse Event	Tiotropium (N = 2986)	Placebo (N = 3006)	Relative Risk for Tiotropium vs. Placebo
Cardiac	3.56	4.21	0.84 †
Angina	0.51	0.36	1.44
Atrial fibrillation	0.74	0.77	0.95
Cardiac failure	0.61	0.48	1.25
Congestive heart failure	0.29	0.48	0.59 †
Coronary artery disease	0.21	0.37	0.58
Myocardial infarction	0.69	0.97	0.71†

† P<0.05

The most frequent adverse events encountered were due to lower respiratory causes, including COPD exacerbations, pneumonia and dyspnea, myocardial infarction and stroke development.
Other adverse events consistent with the known safety profile of tiotropium, like dry mouth and constipation, were also observed

Conclusions

Tiotropium was shown to improve lung function, quality of life, and exacerbations during a 4-year period despite the non-significant reduction in rate of decline in FEV1; in patients with COPD.

N Engl J Med. 2008; 359(15):1543-54

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