Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial

doi:10.1016/S0140-6736(09)61298-8

The Lancet

Volume 374, Issue 9696, 3–9 October 2009, Pages 1171-1178

https://doi.org/10.1016/S0140-6736(09)61298-8 Get rights and content

Summary

Background

The beneficial effects of pharmacotherapy for chronic obstructive pulmonary disease (COPD) are well established. However, there are few data for treatment in the early stages of the disease. We examined the effect of tiotropium on outcomes in a large subgroup of patients with moderate COPD.

Methods

The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study was a randomised, double-blind, placebo-controlled trial undertaken in 487 centres in 37 countries. 5993 patients aged 40 years or more with COPD were randomly assigned to receive 4 years of treatment with either once daily tiotropium (18 μg; n=2987) or matching placebo (n=3006), delivered by an inhalation device. Randomisation was by computer-generated blocks of four, with stratification according to study site. In a prespecified subgroup analysis, we investigated the effects of tiotropium in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II disease. Primary endpoints were the yearly rates of decline in prebronchodilator forced expiratory volume in 1 s (FEV₁) and in postbronchodilator FEV₁, beginning on day 30 until completion of double-blind treatment. The analysis included all patients who had at least three measurements of pulmonary function. This study is registered with ClinicalTrials.gov, number NCT00144339.

Findings

2739 participants (mean age 64 years [SD 9]) had GOLD stage II disease at randomisation (tiotropium, n=1384; control, n=1355), with a mean postbronchodilator FEV₁ of 1·63 L (SD 0·37; 59% of predicted value). 1218 patients in the tiotropium group and 1157 in the control group had three or more measurements of postbronchodilator pulmonary function after day 30 and were included in the analysis. The rate of decline of mean postbronchodilator FEV₁ was lower in the tiotropium group than in the control group (43 mL per year [SE 2] vs 49 mL per year [SE 2], p=0·024). For prebronchodilator pulmonary function, 1221 patients in the tiotropium group and 1158 in the control group had three or more measurements and were included in the analysis. The rate of decline of mean prebronchodilator FEV₁ did not differ between groups (35 mL per year [SE 2] vs 37 mL per year [SE 2]; p=0·38). Health status, measured with the St George's Respiratory Questionnaire, was better at all timepoints in the tiotropium group than in the control group (p≤0·006 for all timepoints). Time to first exacerbation and time to exacerbation resulting in hospital admission were also longer in the tiotropium group than in the control group (hazard ratio 0·82, 95% CI 0·75–0·90, and 0·74, 0·62–0·88, respectively).

Interpretation

Tiotropium seemed to reduce the rate of decline of postbronchodilator FEV₁ in patients with GOLD stage II COPD. This finding and the other improvements in outcomes suggest that treatment of COPD should begin at an early stage of the disease.

Funding

Boehringer Ingelheim and Pfizer Pharmaceuticals.

Introduction

The introduction of longacting β₂ agonists,¹ inhaled steroids,1, 2, 3, 4, 5 fixed combination products,1, 6, 7, 8 and a longacting anticholinergic drug9, 10, 11, 12 has substantially improved treatment of patients with chronic obstructive pulmonary disease (COPD). These agents improve pulmonary function and quality of life, and reduce the frequency of exacerbations.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 Reduction of exacerbations is especially important because they can accelerate the progression of the disease.13, 14 There are also data to suggest that treatment with a longacting anticholinergic drug¹² and a combination product⁶ might reduce mortality. Additionally, treatment with a longacting anticholinergic drug was shown to reduce cardiovascular morbidity¹² and incidence of respiratory failure.¹² Most of these studies, however (apart from some that investigated inhaled corticosteroids2, 3, 4), mainly included patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage III and IV disease (mean forced expiratory volume in 1 s [FEV₁] ranging from 36% to 45% of predicted value). By contrast, little is known about treatment of COPD at earlier stages, such as GOLD stage II (moderate disease).

One fairly small (n=224) and short-term study showed that in patients with GOLD stage II COPD who were recruited in general practice, treatment with tiotropium improved FEV₁ and forced vital capacity (FVC) compared with placebo.¹⁵ Another recent study showed that exercise limitation and dyspnoea were present in patients with GOLD stage I disease.¹⁶ Studies on activity measurement have consistently shown inactivity early in the disease (ie, GOLD stage I and II).17, 18, 19 Since comorbidities also start early in COPD, there is a case for earlier treatment.²⁰ However, there is currently no clear evidence of the benefit of earlier treatment of COPD, although a recent study suggested that dyspnoea and hyperinflation during exercise could be improved in patients with symptomatic stage I disease with inhaled ipratropium.²¹

We investigated the effect of long-term treatment with tiotropium on outcomes in patients with GOLD stage II COPD, by use of data from the recently published Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial.¹² The UPLIFT trial provided us with the largest group of patients with GOLD stage II disease treated with a longacting anticholinergic drug in a randomised placebo-controlled study.

Section snippets

Patients

The design and main results of the UPLIFT trial have been reported elsewhere.12, 22 Briefly, the study was a 4-year, randomised, double-blind, placebo-controlled, parallel-group study in patients with moderate to severe COPD. Patients with a clear diagnosis of COPD, including a differential diagnosis with asthma, were eligible for inclusion. Eligibility criteria also included an age of 40 years or more, a smoking history of 10 pack-years or more, a postbronchodilator FEV₁ of 70% or less of the

Results

Of 5993 randomised patients, 2739 (46%) had GOLD stage II COPD (figure 1). A higher proportion of patients in the control group (35%) discontinued study treatment than did patients in the tiotropium group (31%; p=0·024). Table 1 shows the baseline characteristics of study participants in the tiotropium and control groups by disease stage. The most relevant concomitant drugs used by patients with GOLD stage II disease at baseline and during the study are shown in table 2.

In the tiotropium group,

Discussion

This subgroup analysis of the UPLIFT trial showed that in patients with GOLD stage II COPD, tiotropium seemed to reduce the rate of decline of postbronchodilator FEV₁ and the risk of exacerbations. Additionally, lung function and health-related quality of life were better in the tiotropium group than in the control group throughout the trial. Our findings suggest that treatment with a longacting anticholinergic drug has substantial benefits in patients with moderate COPD, and therefore provide

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Citation Excerpt :
Compared with GOLD stage III or IV, the UPLIFT study revealed that tiotropium bromide can reduce the annual lung function decline rate and improve the symptoms of COPD patients in GOLD stage II.12,84 Furthermore, in the tiotropium bromide group, the time to the first acute exacerbation and the time to hospitalization caused by acute exacerbation were extended, and the acute exacerbation risk was reduced.12 The Mesure de l’Influence de Spiriva1 sur les Troubles Respiratoires Aigus a Long terme (MISTRAL) study showed that in the subgroup of patients with moderate COPD with FEV1 ≥ 50%, the frequency of exacerbations in the tiotropium bromide group was lower than that in the placebo group (1.21 vs. 1.97, P < 0.01).93
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ArticlesEffect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Patients

Results

Discussion

Lancet

Lancet

Chest

Chest

Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking

N Engl J Med

Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease

N Eng J Med

Randomised, double blind, placebo-controlled study of fluticasone in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial

BMJ

Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease

N Engl J Med

Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease

Eur Respir J

Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease

Eur Respir J

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

Eur Respir J

Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium

Eur Respir J

Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial

Ann Intern Med

Articles
Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial