[show abstract][hide abstract] ABSTRACT: The changes in inspiratory capacity (IC) over time in chronic obstructive pulmonary disease (COPD) patients are unknown. The Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) trial included IC measurements.
IC analysis from UPLIFT® (N = 5992) was performed at 1 and 6 months, and every 6 months through 4 years. Annualized rate of decline in pre- and post-bronchodilator IC and mean differences at each time point were analyzed by mixed-effects models. The relationships between baseline IC and exacerbation rate and mortality were explored using Cox regression analysis.
Baseline characteristics: age, 65 years; 75% men; post-bronchodilator forced expiratory volume in 1 second, 1.32 L (48% predicted); pre- and post-bronchodilator IC, 2.03 and 2.33 L. Mean IC rate of decline (mL/year) was 34 ± 2 (1.7% of baseline) and 50 ± 3 (2.1% of baseline) pre- and post-bronchodilator, respectively, without significant between-group differences. Morning pre-bronchodilator (trough) IC improved with tiotropium versus placebo: 124 mL (1 month), 103 mL (1 year), 107 mL (2 years), 98 mL (3 years), and 97 mL (4 years) (all p < 0.001). Post-bronchodilator improvements were similar between treatment groups. Lower baseline IC values were associated with reduced time to first exacerbation. For the lowest quartile (n = 1413) the values in months were 14.3 (11.7-17.0) for tiotropium and 10.3 (8.8-11.7) for controls (p < 0.01).
IC declines from approximately 34 to 50 mL/year in patients with stage II to IV COPD. Tiotropium treatment does not change the IC decline rate but provides 24-hour improvements in IC sustained over the long term. Trough IC differences suggest that tiotropium provides sustained decrease in end-expiratory lung volume.
Respiratory research 08/2012; 13:66. · 3.64 Impact Factor
[show abstract][hide abstract] ABSTRACT: GOLD stage II COPD encompasses patients with FEV₁ 50-80% predicted. A published trials review suggested that benefits of maintenance therapy are limited to patients with FEV₁ <60% predicted. We previously reported data demonstrating the efficacy of tiotropium in GOLD stage II disease in the 4-year UPLIFT® trial, and present here a further analysis of a sub-category of GOLD stage II patients with post-bronchodilator FEV1 ≥60% predicted from UPLIFT®. Outcomes included pre- and post-bronchodilator spirometry, exacerbations, SGRQ and mortality. Of the 5,992 UPLIFT® cohort, 1,210 (632 tiotropium, 578 control) had baseline post-bronchodilator FEV₁ ≥60% predicted (range 60-78%), mean age was 64 years, 70% were men, and mean SGRQ total score was 39.9 units. Mean annual rate of post-bronchodilator FEV₁ decline was 41 (tiotropium) and 49 (control) mL/year (P = 0.07); corresponding pre-bronchodilator values were 32 and 37 mL/year (P = 0.24). Morning pre-drug FEV₁ and FVC improvements for tiotropium versus control were 87-127 mL and 139-186 ml, respectively (P < 0.001, all time-points). SGRQ total score improvements (tiotropium-control) were 2.0-3.4 units (P < 0.05 for all); a higher percentage of patients had an improvement of ≥4 units with tiotropium (P <0.05). Tiotropium reduced risk for an exacerbation (HR [95% CI] = 0.83 [0.71, 0.96]) and mortality for the 4-year protocol-defined treatment period (HR [95% CI] = 0.66 [0.45, 0.96]). Tiotropium treatment provides clinical efficacy in patients with GOLD stage II disease with an FEV₁ ≥60% predicted, supporting current GOLD guidelines for COPD treatment. (ClinicalTrials.gov number NCT00144339).
[show abstract][hide abstract] ABSTRACT: Placebo-controlled clinical trials on COPD are characterized by premature discontinuation. At present, no clear insight into this phenomenon is available.
To obtain better insight into the phenomenon of premature discontinuation.
We analyzed the pattern of discontinuation in the UPLIFT-trial.
Premature discontinuation was substantial and greater in the placebo than in the tiotropium group (45 vs. 37%, p < 0.001). Patients discontinuing were characterized by more severe COPD (p < 0.0001), greater number of pack years (p < 0.002), smaller pre-bronchodilator and post-bronchodilator FEV(1) (p < 0.0001 for both), and worse SGRQ scores (p < 0.0001). Rates of decline of FEV(1) and SGRQ were greater in non-completers (p < 0.0001 for both). The latter differences increased over time indicating that the evolution of variables in time was related to trial completion. The risks of exacerbations and hospitalizations were greater in non-completers. In logistic regression analysis BMI, post-bronchodilator FEV(1), male gender and treatment with tiotropium were positively related to trial completion, whereas age, worse SGRQ, female gender, current smoking and assignment to the placebo group were negatively related.
Assignment to the control group is related to premature discontinuation. Discontinuation was important and selective in this large trial. Pulmonary function, health-related quality of life and smoking are the most important other variables related to discontinuation. The evolution of variables during the trial is also related to discontinuation. Complete follow-up of discontinued patients may provide better insight into the efficacy of medication in future trials.
Respiratory medicine 04/2011; 105(10):1523-30. · 2.33 Impact Factor
[show abstract][hide abstract] ABSTRACT: Whilst recent large-scale studies have provided much evidence on the natural history and therapeutic response in patients with chronic obstructive pulmonary disease (COPD), relatively little is known about the effect in younger patients. We report a pre-specified post-hoc analysis of 356 patients with COPD ≤ 50 years old from the four year randomised, double blind placebo controlled Understanding Potential Long Term Impact on Function with Tiotropium (UPLIFT) trial. Inclusion criteria included a post-bronchodilator forced expiratory volume in 1 s (FEV(1)) of ≤70%, FEV(1)/FVC < 0.70, age ≥40 years, and smoking history of ≥10 pack years. Younger patients had a mean FEV(1) of 1.24 L (39% predicted) and an impaired health-related quality of life (St. George's Respiratory Questionnaire (SGRQ)) compared to the entire UPLIFT population. There were 40.2% women and 51.1% current smokers in the younger age group. Tiotropium was associated with a sustained improvement in spirometry and SGRQ. Mean decline in post-bronchodilator FEV(1) was 58 ml/year (placebo) vs. 38 ml/year (tiotropium) (p = 0.01). Corresponding values for pre-bronchodilator FEV(1) were 41 ml/year (placebo) compared with 34 ml/year (tiotropium) (p = 0.34). The hazard ratio (95%CI) for an exacerbation in the younger age group was 0.87(0.68, 1.13)). The rate of exacerbations was reduced by tiotropium (rate ratio (95%CI) = 0.73(0.56, 0.95)). Tiotropium resulted in sustained bronchodilation, improved quality of life, and a decreased exacerbation rate in younger patients. Tiotropium also resulted in a significant reduction in the decline in post-bronchodilator FEV(1), suggesting possible disease modification by tiotropium in younger patients with COPD.
Respiratory medicine 11/2010; 104(11):1659-67. · 2.33 Impact Factor
[show abstract][hide abstract] ABSTRACT: The aim of the present study was investigate the long-term effect of tiotropium as first maintenance respiratory medication in chronic obstructive pulmonary disease (COPD). A 4-yr, randomised, multicentre, double-blind, parallel-group, placebo-controlled trial (Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) was conducted. Analysis focused on the effect of tiotropium versus matching placebo in the 810 (13.5%) COPD patients not on other maintenance treatment (long-acting beta-agonists, inhaled corticosteroids, theophyllines or anticholinergics) at randomisation. Spirometry, health-related quality of life (St George's Respiratory Questionnaire (SGRQ) score), exacerbations of COPD and mortality were also analysed. 403 patients (mean+/-sd age 63+/-8 yrs, post-bronchodilator forced expiratory volume in 1 s (FEV(1)) 53+/-12% predicted) received tiotropium and 407 (64+/-8 yrs of age, post-bronchodilator FEV(1) 51+/-12% pred) received placebo. Post-bronchodilator FEV(1) decline was 42+/-4 mL.yr(-1) in the tiotropium group and 53+/-4 mL.yr(-1) in the placebo group (p = 0.026). At 48 months, the morning pre-dose FEV(1) was 134 mL higher in the tiotropium group compared to the placebo group (p<0.001). SGRQ total score declined more slowly in the tiotropium group (difference of 1.05+/-0.34 units.yr(-1); p = 0.002). This was particularly significant for the impact (difference of 1.08+/-0.37 units.yr(-1); p = 0.004) and activity (1.44+/-0.40 units.yr(-1); p<0.001) domains, but not for symptoms (0.26+/-0.50 units.yr(-1); p = 0.6). At 48 months, the difference in total score was 4.6 units (p<0.001) with tiotropium compared to placebo. In patients with COPD who are not on maintenance therapy, tiotropium is associated with significant benefits in disease progression.
European Respiratory Journal 02/2010; 36(1):65-73. · 6.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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 microg; 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 (FEV(1)) and in postbronchodilator FEV(1), 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.
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 FEV(1) 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 FEV(1) 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 FEV(1) 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).
Tiotropium seemed to reduce the rate of decline of postbronchodilator FEV(1) 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.
Boehringer Ingelheim and Pfizer Pharmaceuticals.
The Lancet 09/2009; 374(9696):1171-8. · 39.06 Impact Factor
[show abstract][hide abstract] ABSTRACT: UPLIFT (Understanding Potential Long-Term Improvements in Function with Tiotropium), a 4-yr trial of tiotropium in chronic obstructive pulmonary disease, allowed for assessment of smoking status on long-term responses to maintenance bronchodilator therapy. 5,993 patients were randomised (tiotropium/placebo). Lung function, St George's Respiratory Questionnaire, exacerbations and adverse events were followed. Patients were characterised as continuing smokers (CS), continuing ex-smokers (CE), or intermittent smokers (IS) based on self-reporting smoking behaviour. 60%, 14% and 26% of patients were CE, CS and IS, respectively. The rate of forced expiratory volume in 1 s (FEV(1)) decline for placebo patients was most rapid in CS (-52+/-4, -37+/2 and -23+/2 mL.yr(-1) in CS, IS, and CE, respectively). Tiotropium did not alter FEV(1) decline, but was associated with significant improvements in pre- and post-bronchodilator FEV(1) over placebo that persisted throughout the 4-yr trial for each smoking status (pre-bronchodilator: 127, 55 and 97 mL at 48 months in CS, IS and CE, respectively; p< or =0.0003). Tiotropium reduced exacerbation risk in CS (HR (95% CI) 0.80 (0.67-0.95)), in CE (0.85 (0.79-0.92)) and trended towards significance in IS (0.89 (0.79-1.00)). At 4 yrs, St George's Respiratory Questionnaire for tiotropium patients improved the most in CS (-4.63 units, p = 0.0006) and the least in IS (-0.60 units, p = 0.51), [corrected] compared with control. Tiotropium provided long-term benefits irrespective of smoking status, although differences among categories were observed.
European Respiratory Journal 08/2009; 35(2):287-94. · 6.36 Impact Factor