A retrospective analysis of the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) trial data was performed, grading patients by the 2013 Global initiative for chronic Obstructive Lung Disease (GOLD) severity groups. The number of antibiotics/systemic corticosteroids courses and hospitalizations/ emergency department (ED) visits for COPD in the preceding year, baseline forced expiratory volume in 1 second (FEV1) and St. George’s Respiratory Questionnaire (SGRQ) score were used to grade patients: 357 (6.3%), 1421 (24.9%), 299 (5.2%), and 3636 (63.7%) in Groups A–D, respectively. Mean FEV1 was higher and SGRQ scores lower with tiotropium than usual care (control) in all GOLD groups at all post-baseline time points during treatment. In the control group, mean (95% confidence interval [CI]) exacerbation rates per patient per year were highest in Group D (1.01 [0.96, 1.07]), similar in Groups B (0.63 [0.57, 0.69]) and C (0.72 [0.59, 0.87]), and lowest in Group A (0.48 [0.39, 0.59]). Tiotropium significantly prolonged time to first exacerbation versus control in Groups B and D (hazard ratios [95% CI]: 0.79 [0.69, 0.91] and 0.89 [0.82, 0.96]); in Groups A and C, similar effects were observed, reflecting the small size of these groups. The number of exacerbations per patient-year was lower with tiotropium than control in all GOLD groups (rate ratios 0.64, 0.72, 0.91, and 0.89 for Groups A–D; p<0.005 for all but Group C (p=0.4978). The incidence rate of major adverse cardiac events was higher in Group D than in Groups A–C but lower within the group in patients treated with tiotropium. In conclusion, tiotropium improved lung function and health status, and reduced exacerbation rates in patients in all GOLD groups. Abstract

A retrospective analysis of the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) trial data was performed, grading patients by the 2013 Global initiative for chronic Obstructive Lung Disease (GOLD) severity groups. The number of antibiotics/systemic corticosteroids courses and hospitalizations/emergency department (ED) visits for COPD in the preceding year, baseline forced expiratory volume in 1 second (FEV1) and St. George's Respiratory Questionnaire (SGRQ) score were used to grade patients: 357 (6.3%), 1421 (24.9%), 299 (5.2%), and 3636 (63.7%) in Groups A-D, respectively. Mean FEV1 was higher and SGRQ scores lower with tiotropium than usual care (control) in all GOLD groups at all post-baseline time points during treatment. In the control group, mean (95% confidence interval [CI]) exacerbation rates per patient per year were highest in Group D (1.01 [0.96, 1.07]), similar in Groups B (0.63 [0.57, 0.69]) and C (0.72 [0.59, 0.87]), and lowest in Group A (0.48 [0.39, 0.59]). Tiotropium significantly prolonged time to first exacerbation versus control in Groups B and D (hazard ratios [95% CI]: 0.79 [0.69, 0.91] and 0.89 [0.82, 0.96]); in Groups A and C, similar effects were observed, reflecting the small size of these groups. The number of exacerbations per patient-year was lower with tiotropium than control in all GOLD groups (rate ratios 0.64, 0.72, 0.91, and 0.89 for Groups A-D; p < 0.005 for all but Group C (p = 0.4978). The incidence rate of major adverse cardiac events was higher in Group D than in Groups A-C but lower within the group in patients treated with tiotropium. In conclusion, tiotropium improved lung function and health status, and reduced exacerbation rates in patients in all GOLD groups.

Introduction Effects of interventions on patient-reported outcomes may be subjective and modulated by patients’ expectations regarding treatment efficacy. The ‘gold standard’ for minimising such biases are double-blind randomised controlled trials. We analysed the effects of tiotropium on health-related quality of life in chronic obstructive pulmonary disease (COPD) in placebo-controlled trials and assessed whether trial design (double-blind versus open-label) is a relevant modifier of the effects of tiotropium. Methods Trials of ≥6 months’ duration investigating the effect of tiotropium versus placebo on health-related quality of life in COPD (assessed using St George’s Respiratory Questionnaire [SGRQ]) were identified from the Boehringer Ingelheim clinical trial database and by a systematic literature search in MEDLINE, with a cut-off date of 30 November 2011. As a clinical end point, the mean difference between treatment groups in SGRQ total score was assessed. Trials were grouped according to double-blind or open-label design. We performed a network meta-analysis including standard methodology to test for interaction to evaluate whether trial design is a potential modifier of effect size or its direction. Results We identified 12 trials in which tiotropium had been administered double-blind and three trials with open-label application. The overall effect for mean difference versus placebo in SGRQ total score was -2.98 units (95% confidence interval [CI): -3.49, -2.47). For the double-blind trial subgroup, mean difference versus placebo was -3.20 (95% CI: -3.75, -2.65) compared to -1.67 (95% CI: -3.02, - 0.32) for open-label trials. The p-value for interaction between subgroup and effect on SGRQ total score was 0.04. Conclusions In patients with COPD, trial design (double-blind versus open-label) was a statistically significant modifier of the effect of inhaled tiotropium on health-related quality of life. The modification was quantitative, resulting in a substantial underestimation of the effect of tiotropium on SGRQ total score when the administration had been open-label compared to the ‘gold standard’ double-blind. A subjective end point such as quality of life is particularly susceptible to bias due to patients’ expectations towards the efficacy of an intervention. Therefore, the validity of studies using non-blinded designs to investigate such end points must be questioned.

BACKGROUND:Tiotropium is an anticholinergic bronchodilator for symptom relief and reducing exacerbations with an established safety profile in patients with chronic obstructive pulmonary disease (COPD). Using data from the 4-year Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) study, we re-evaluated the safety of tiotropium HandiHaler® in patients who experienced recent myocardial infarction (MI), heart failure or unstable rhythm disorder during the study.METHODS:A post-hoc analysis of all-cause mortality and serious cardiac adverse events (cardiac SAEs), including cardiac deaths and death unknown, was conducted in patients who had experienced cardiac arrhythmia, MI or cardiac failure during UPLIFT® and who completed the study. Descriptive analyses were performed.RESULTS:Most patients experiencing cardiac events, for which they would have been excluded at baseline, remained in the trial. Kaplan-Meier analyses revealed a trend to later occurrence of cardiac SAEs with tiotropium HandiHaler® versus placebo. Patients who experienced a cardiac event and continued in UPLIFT® were not found to be at subsequently increased risk of all-cause mortality or cardiac SAEs with tiotropium treatment. Evaluation of deaths by major adverse cardiac events composite endpoints also showed that patients treated with tiotropium were not at increased risk of mortality or cardiac SAEs compared with placebo.CONCLUSIONS:Risk of cardiac events, mortality or SAEs was not increased by tiotropium in patients experiencing cardiac events for which they would have been excluded at study baseline. The findings support the cardiac safety of tiotropium HandiHaler® in patients with COPD.

The 2013 GOLD classification system for COPD distinguishes four stages: A (low symptoms, low exacerbation risk), B (high symptoms, low risk), C (low symptoms, high risk) and D (high symptoms, high risk). Assessment of risk is based on exacerbation history and airflow obstruction, whatever results in a higher risk grouping. The previous system was solely based on airflow obstruction. Earlier studies compared the predictive performance of new and old classification systems with regards to mortality and exacerbations. The objective of this study was to compare the ability of both classifications to predict the number of future (total and severe) exacerbations and mortality in a different patient population, and to add an outcome measure to the comparison: lung function decline.

INTRODUCTION:Tiotropium is prescribed for the treatment of chronic obstructive pulmonary disease (COPD) and delivered via HandiHaler(®) (18 μg once daily) or Respimat(®) Soft Mist™ inhaler (5 μg once daily). The recent TIOtropium Safety and Performance In Respimat(®) (TIOSPIR™) study demonstrated that both exhibit similar safety profiles. This analysis provides an updated comprehensive safety evaluation of tiotropium(®) using data from placebo-controlled HandiHaler(®) and Respimat(®) trials.METHODS:Pooled analysis of adverse event (AE) data from tiotropium HandiHaler(®) 18 μg and Respimat(®) 5 μg randomized, double-blind, parallel-group, placebo-controlled, clinical trials in patients with COPD (treatment duration ≥4 weeks). Incidence rates, rate ratios (RRs), and 95% confidence intervals (CIs) were determined for HandiHaler(®) and Respimat(®) trials, both together and separately.RESULTS:In the 28 HandiHaler(®) and 7 Respimat(®) trials included in this analysis, 11,626 patients were treated with placebo and 12,929 with tiotropium, totaling 14,909 (12,469 with HandiHaler(®); 2,440 with Respimat(®)) patient-years of tiotropium exposure. Mean age was 65 years, and mean prebronchodilator forced expiratory volume in 1 second (FEV1) was 1.16 L (41% predicted). The risk (RR [95% CI]) of AEs (0.90 [0.87, 0.93]) and of serious AEs (SAEs) (0.94 [0.89, 0.99]) was significantly lower in the tiotropium than in the placebo group (HandiHaler(®) and Respimat(®) pooled results), and there was a numerically lower risk of fatal AEs (FAEs) (0.90 [0.79, 1.01]). The risk of cardiac AEs (0.93 [0.85, 1.02]) was numerically lower in the tiotropium group. Incidences of typical anticholinergic AEs, but not SAEs, were higher with tiotropium. Analyzed separately by inhaler, the risks of AE and SAE in the tiotropium groups remained lower than in placebo and similarly for FAEs.CONCLUSION:This analysis indicates that tiotropium is associated with lower rates of AEs, SAEs, and similar rates of FAEs than placebo when delivered via HandiHaler(®) or Respimat(®) (overall and separately) in patients with COPD.

Background: Subgroup analyses of patients with concomitant cardiovascular (CV) diseases may help characterise safety profiles of COPD maintenance therapies. Aims and objectives : To compare the serious cardiac adverse event (SCAE) profiles, including fatalities, of patients with baseline CV conditions in a pooled analysis of 4 double-blind, randomized, parallel-group clinical trials of tiotropium HandiHaler® (HH) vs salmeterol metered dose inhaler (MDI). Methods: Incidence rates (IR): number of patients with event divided by 100 patient-years at risk. Rate ratios (RR) and 95% confidence intervals (CI): derived from Cochran-Mantel-Haenszel test stratified by study. Results: In total, 8836 patients were included. The IRs of SCAEs, and fatalities from cardiac diseases, during treatment by CV conditions at baseline are in the table. SCAEs* Fatalities Condition at baseline (No. patients) Tiotropium (IR) Salmeterol (IR) RR (95% CI) Tiotropium (IR) Salmeterol (IR) RR (95% CI) CV medication (4741) 3.58 3.45 1.03 (0.74, 1.43) 0.71 0.74 0.96 (0.47, 1.95) Cardiac, total (2239) 6.04 5.47 1.11 (0.76, 1.61) 1.58 1.03 1.53 (0.69, 3.36) - Coronary artery disease (1664) 6.54 5.59 1.17 (0.78, 1.77) 1.54 1.20 1.29 (0.54, 3.05) - Cardiac arrhythmia (324) 10.70 10.71 1.04 ( 0.46, 2.33) 2.82 2.37 1.17 (0.24, 5.78) Hypertension (3979) 3.75 3.38 1.11 (0.78, 1.57) 0.78 0.84 0.94 (0.45, 1.95) IR expressed in 100 patient-years. *MedDRA Version 14.1. Conclusion: Tiotropium once daily via HH showed a comparable cardiac safety profile to salmeterol MDI in subgroups with CV conditions at baseline.

Background: Several long-acting bronchodilators (BDs) were introduced recently as maintenance therapy for COPD. However, a direct comparison of the effects of these newer agents with existing therapy from long-term studies is lacking. Aims and objectives: To investigate if patient selection affects the magnitude of effects observed in clinical studies in COPD. Methods: Subgroup analysis of the UPLIFT® trial using in/exclusion criteria similar to clinical programs of other long-acting BDs (OLB), ie, exclusion of GOLD IV patients and concomitant long-acting β 2 -agonists. Spirometry and SGRQ: mixed-model repeated measures ANOVA with random subject effects; number of events: Poisson regression with correction for overdispersion. Results: Baseline patient characteristics are shown in the table. For UPLIFT total vs OLB subgroup, minimum, maximum improvements tiotropium versus placebo over 4 yrs were: trough FEV 1 , 0.09-0.10L vs 0.10-0.13L; SGRQ total score, -2.30 to -3.35 vs -2.14 to -4.14. Overall exacerbation rate (per pt-yr) in tiotropium/placebo groups differed between UPLIFT total (0.74/0.87) and OLB subgroup (0.43/0.48), rate ratios for tiotropium vs placebo were 0.86 and 0.89 respectively. Conclusion: Efficacy results in COPD placebo-controlled clinical trials are influenced by included patient population characteristics and/or allowed concomitant medication. Cross-trial efficacy comparisons should take this into account.

Background: Guidelines recommend long-acting bronchodilators as preferred options for maintenance treatment of COPD. Cardiovascular (CV) safety of these treatments is of interest. Aims and objectives: To compare the CV safety of tiotropium vs the long-acting β2-agonist salmeterol in a large number of patients (pts) with COPD. Methods: Pooled analysis of 4 double-blind, randomized, parallel-group clinical trials comparing the CV adverse event profile of tiotropium HandiHaler® (HH) vs salmeterol metered dose inhaler (MDI). Incidence rates (IR): number of pts with event divided by pt-years at risk. Rate ratios (RR) and 95%CI: derived from Cochran-Mantel-Haenszel test stratified by study. Results: In total, 8836 pts were included; 25.3% had a cardiac disorder and 53.7% used CV medication at baseline. IRs (per 100 pt-yrs) for tiotropium vs salmeterol were: all-cause mortality, 1.74 vs 2.08 (RR: 0.84, 95% CI: 0.61, 1.16); fatal major adverse cardiac events (MACE), including death unknown, 0.72 vs 0.92 (RR: 0.78, 95% CI: 0.47, 1.28). IRs of serious adverse CV events during treatment for selected major CV diagnoses are in the table. View this table: Conclusion: Tiotropium HH once daily showed a comparable CV safety profile to salmeterol MDI treatment in a pooled analysis of double-blind, randomized, parallel group studies.

The research letter by Walker et al 1 questions the generalisability of the results of the 4-year UPLIFT trial comparing tiotropium versus placebo based on potential eligibility for UPLIFT at time of discharge of a COPD patient population in New Zealand hospitalised for an exacerbation. The authors state that 38% of their study population would have been excluded from UPLIFT. The authors' assertion regarding the limited generalisability of UPLIFT's findings to clinical practice is not valid for several reasons. First, patients hospitalised for COPD exacerbations are not representative of the general COPD population. An epidemiological analysis from The Netherlands2 reported that 2.1% and 4.4% of COPD patients (mean age, 68 years) starting treatment with HandiHaler and Respimat, respectively, had a COPD-related hospitalisation in the year preceding the analysis. Analysis of an elderly Canadian COPD population3 showed that 9.8% were recently hospitalised for acute respiratory conditions. These epidemiological data suggest that the COPD population studied by Walker et al is not representative of the general COPD population. …

Background: Exacerbations are a defining outcome of chronic obstructive pulmonary disease (COPD). We evaluated the effect of tiotropium on COPD exacerbations and related hospitalizations among patients from the USA enrolled in clinical trials.Methods: Data were pooled from six randomized, double-blind, placebo-controlled trials (6 to >= 12 months' duration) of tiotropium in patients with COPD. Exacerbations were defined retrospectively as an increase in or new onset of >1 respiratory symptom lasting for >= 3 days and requiring treatment with systemic corticosteroids and/or antibiotics. Time to first exacerbation or hospitalization and exacerbation rates were analyzed at 6 months, and at 1 year for studies >= 1 year.Results: In total, 4355 patients (tiotropium, 2268, placebo, 2087; mean age 66.5 years; forced expiratory volume in 1 s [FEV1] 1.03 L [35.5% predicted]) were analyzed at 6 months and 2455 at 1 year (tiotropium 1317, placebo 1138; mean age 65.5 years; FEV1, 1.03 L [37.0% predicted]). Tiotropium delayed time to first exacerbation or first hospitalized exacerbation at 6 months (hazard ratios [HRs], 0.80, 0.65, respectively; p < 0.001 vs placebo) and 1 year (HRs, 0.73 and 0.55; p < 0.001 vs placebo) and reduced exacerbation rates and hospitalization rates (6 months: HRs, 0.79, 0.64; 1 year: HRs, 0.78, 0.56, respectively; all p < 0.01 vs placebo). Tiotropium significantly reduced exacerbations, irrespective of inhaled corticosteroid use at baseline. Tiotropium was not associated with an increased risk of cardiac-related events.Conclusions: Tiotropium significantly reduced the risk and rates of exacerbations and hospitalizations among US patients with COPD. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.

Background: Frequent COPD exacerbations are linked to rapid decline in lung function. Little is known about the impact of a single exacerbation on rate of decline. Aims and objectives: To examine the effect of a single COPD exacerbation on rate of decline in lung function, using data from a 4-y, randomized, double-blind, placebo-controlled trial of tiotropium in moderate-to-very severe COPD (UPLIFT®). Methods: Retrospective analysis of annual rate of decline in pre- and postbronchodilator (BD) forced expiratory volume in 1s (FEV 1 ) and forced vital capacity (FVC), before and after first COPD exacerbation (increase in/new onset of >1 respiratory symptom lasting ≥3 days and treated with antibiotic/systemic corticosteroids). Eligible patients (pts) had ≥3 pulmonary function tests (PFTs) before (≥24 days after treatment start) and ≥3 months after the exacerbation (no further exacerbations permitted for next 3 PFT measurements). Rate of decline was calculated by linear regression and P -values by Wilcoxon signed-rank test. Results: 462 pts were eligible (mean age 64 y, 78% male, mean baseline FEV 1 1.19 L and FEV 1 /FVC 0.44). Mean annual rate of decline in pre- and post-BD FEV 1 and pre-BD FVC significantly increased (Table). Conclusion: A single exacerbation can lead to a significantly larger rate of decline in lung function in COPD pts 1-2 years post exacerbation.

Background: GOLD recently updated their COPD severity classification to include risk of exacerbations. Increased risk is typically defined by a FEV 1 of 1 ≥50% pred and 0-1 exacerbation in the previous year (A+B). Aims and objectives: To examine the effect of tiotropium 18 µg qd via Handihaler® in GOLD low risk patients (pts) using data from a 4-y, randomized, double-blind, placebo-controlled trial in COPD (UPLIFT®). Methods: Retrospective analysis of exacerbations, lung function and QoL (SGRQ) in low-risk pts (pts with a baseline postbronchodilator [BD] FEV 1 %pred ≥50% and ≤1 oral steroid/antibiotic course in the previous year). Pts with high risk (FEV 1 %pred Results: 2012 pts were analyzed (mean age 64.5±8.6 y, male 74%, mean (±SD) baseline postBD FEV 1 1.65 (0.37) L and FEV 1 %pred (±SD) 58.9 (5.8). The HR (tiotropium vs control) for time to first exacerbation was 0.76 (95% CI, 0.68; 0.86; P P P 1 was 110 mL (95% CI, 84; 136; P 1 were significantly improved at all time points. The above-mentioned endpoints were also significantly improved in the high-risk population. Conclusion: Tiotropium qd was effective throughout 4 y in reducing exacerbations and improving lung function and QoL in low-risk pts with COPD (GOLD A+B).

Chronic obstructive pulmonary disease (COPD) exacerbations are associated with systemic consequences. Data from a 4-year trial (Understanding Potential Long-term Impacts on Function with Tiotropium [UPLIFT®], n = 5,992) were used to determine risk for nonlower respiratory serious adverse events (NRSAEs) following an exacerbation.

BACKGROUND:Data have highlighted the potential bias introduced by withdrawal of inhaled corticosteroids at randomization in chronic obstructive pulmonary disease trials examining inhaled corticosteroids. Analyses were conducted to determine whether this was true of inhaled anticholinergic withdrawal in tiotropium trials.METHODS:A pooled analysis of randomized, double-blind, placebo-controlled, parallel-group tiotropium trials of at least six months' duration was performed. Trials had similar inclusion and exclusion criteria. Exacerbation definition was standardized. Patients were divided into two groups, ie, D (anticholinergics discontinued at randomization, previously prescribed) and ND (anticholinergics not discontinued, not previously prescribed).RESULTS:Demographics were balanced between the D (n = 5846) and ND (n = 6317) groups, except for higher cumulative smoking (56 pack-years versus 48 pack-years), lower forced expiratory volume in one second (FEV(1))/forced vital capacity (43% versus 48%), and lower baseline FEV(1) (35.8% predicted versus 42.4% predicted) in the D group. In both groups, tiotropium reduced the risk for an exacerbation (hazard ratio [HR] = 0.83, P < 0.0001 [D] versus 0.79, P < 0.0001 [ND]) and a hospitalized exacerbation (HR = 0.85, P = 0.0467 versus 0.79, P = 0.0094). Tiotropium reduced the number of exacerbations per patient-year (rate ratio [RR] = 0.82, P < 0.0001 [D] versus RR = 0.80, P < 0.0001 [ND]) and associated hospitalizations per patient-year (RR = 0.88, P = 0.015 [D] versus RR = 0.74, P < 0.0001 [ND]).CONCLUSION:Tiotropium reduced exacerbations in patients who did and did not have anticholinergics discontinued upon randomization in clinical trials.

Der Vergleich des Anteils an Patienten mit einer klinisch relevanten Änderung ist etabliert zur Bewertung der klinischen Relevanz von Therapieeffekten in Studien.

The article by Adams et al.1Adams S.G. Anzueto A. Briggs D.D. Leimer I. Kesten S. Evaluation of withdrawal of maintenance tiotropium in COPD.Respiratory Medicine. 2009; 103: 1415-1450Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar is flawed due to incorrect statistical analysis, in their use of analysis of covariance. This compares the means of normal populations assuming equal unknown variances. The Central Limit Theorem justifies the normality assumption for inferences on means, but unknown do not have to be homogeneous. This makes the analysis of covariance unsuitable for general mean comparison. As Linnik2Linnik Yu.V. Latest investigations on Behrens-Fisher problem.Sankhya A. 1966; 28: 15-24Google Scholar has shown that two-sample t-statistics based on their standard deviations and the difference between their sample means do not exist when variances are unknown, this problem is not avoided by futilely3Kendall M.G. Stuart A. The advanced theory of statistics. vol. 2. Charles Griffin and Co., London1973: 484Google Scholar testing for the equality of variances. Nor is it circumvented by avoiding normality using nonparametric rank tests such as the Wilcoxon test. Being a comparison of distributions, these rank tests say nothing about the means if significant and are biased to one side4Lehmann E.L. Testing statistical hypotheses. John Wiley and Sons Inc, New York1959Google Scholar in a two-sided test. Tsakok5Tsakok A.D. A solution to the generalized Behrens-Fisher problem.Metron. 1978; 36: 79Google Scholar has solved the Behrens–Fisher problem of comparing the means of normal populations with unknown variances at exact significance levels. It is also shown5Tsakok A.D. A solution to the generalized Behrens-Fisher problem.Metron. 1978; 36: 79Google Scholar to be more effective in detecting significant mean differences even with unknown equal variances. Its exposition6Tsakok A.D. Comment on visual acuity.Ophthalmic Epidemiology. 2002; 9: 347Crossref PubMed Scopus (10) Google Scholar is available. The software GSP implements the Tsakok technique, and is used to compare means at 0.02 (one significant figure) significance level per pair. For Table 3,1Adams S.G. Anzueto A. Briggs D.D. Leimer I. Kesten S. Evaluation of withdrawal of maintenance tiotropium in COPD.Respiratory Medicine. 2009; 103: 1415-1450Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar there are significant mean differences between the tiotropium group and placebo in their St George Respiratory Questionaire (SGRQ) total score and their rescue medication at 3-week follow-up. The attention given to the data means that they deserve correct analysis. The Tsakok articles are reprinted7Tsakok A.D. Statistics and the unified field. AD Tsakok Mathematical Centre, London1987Google Scholar with further results. None.