Meaningful effect size and patterns of response of the transition dyspnea index

doi:10.1016/S0895-4356(02)00589-9

Journal of Clinical Epidemiology

Volume 56, Issue 3, March 2003, Pages 248-255

https://doi.org/10.1016/S0895-4356(02)00589-9 Get rights and content

Abstract

Ths object of this study was to examine validity, meaningful effect sizes, and patterns of response of the Transition Dyspnea Index (TDI) in a clinical trial cohort of chronic obstructive pulmonary disease (COPD) patients. The design was a retrospective analysis of data from a randomized, double-blind placebo-controlled clinical trial. We analyzed fifty clinical investigation sites in United States. There were 921 patients with stable COPD. Tiotropium 18 μg dry powder or matching placebo was used. Patients were allowed to remain on usual care less ipratropium bromide. Construct validity was demonstrated by significant correlations (P < .05) between Baseline Dyspnea Index (BDI) and other baseline measures, as well as between TDI and changes in other measures at the end of 1 year. Concurrent validity was observed by the significant correlation between TDI and dyspnea diary responses. Changes in TDI focal score were in the range of one unit when the group was stratified by a minimal change in the physician's global evaluation. Significantly less (P < .05) supplemental albuterol was observed in the group of responders defined by a one-unit improvement in TDI. Responders also had few exacerbations and better health status. The validity of the TDI is supported in a large clinical trial setting. A one-unit change in the TDI focal score represented the minimal important difference.

Introduction

Dyspnea is a common and troublesome manifestation of chronic obstructive pulmonary disease (COPD). Thus, relief of dyspnea and its impact on disability is an important goal of therapy 1, 2. Instruments are available that can discriminate the level of breathlessness as well as evaluate dyspnea over time, including over the course of therapeutic interventions [3]. An instrument with wide use in COPD is the Baseline and Transition Dyspnea Index (BDI/TDI) originally described in 1984 [4]. This multidimensional instrument has been shown to be responsive to a variety of therapeutic modalities including inspiratory muscle training 5, 6, exercise training and pulmonary rehabilitation 7, 8, 9, 10, lung volume reduction surgery [11] and bronchodilators 12, 13, 14.

In most of these studies, the instrument was used in a single setting, in a relatively small (i.e., n = 12–39) number of patients, and over a relatively short period of intervention. The TDI has recently been utilized to demonstrate improvement in breathlessness over a 1-year period in patients treated with the bronchodilator tiotropium [15]. Tiotropium is a long-acting anticholinergic agent [16] that provides sustained improvements in air flow and associated with reduced exacerbations and improved health status. The clinical trials in support of tiotropium's effectiveness provide a unique opportunity to evaluate the validity of the BDI/TDI instrument over an extensive period of 1 year. The purposes of this study were to examine the validity of the instrument in this setting, and to investigate the relationship of the TDI to other measures to establish the magnitude of response that has clinical importance.

Section snippets

Study protocols

Fifty clinical centers participated in two identical double-blind, placebo-controlled trials (required for regulatory purposes) to evaluate the 1-year safety and efficacy of tiotropium. The study groups consisted of outpatients of either gender who were ⩾40 years old and had a clinical diagnosis of COPD, as defined by the American Thoracic Society (ATS) [17]. Participants were required to have at least a 10 pack-year smoking history, clinically stable airway obstruction, and forced expiratory

Patients

Patient characteristics are listed in Table 2. The population was, on average age, approximately 65 years old, primarily male (65%), and had moderate to severe disease based on spirometric criteria (39% FEV₁ Predicted Normal for combined treatments). Further details of the population and the primary safety and efficacy findings are reported by Casaburi and colleagues [15].

General patterns of measures

BDI scores prior to treatment was 6.0 ± 0.1 (mean ± SE) for patients randomized to tiotropium and 6.2 ± 0.1 for those

Discussion

In the evaluation of pharmacotherapy for COPD, instruments should be used that are valid, results should be consistent and supported by related measures, and effects should be meaningful. As dyspnea is the major symptom of COPD, methods to evaluate intervention on dyspnea are critical for clinical research. Our analysis has confirmed the validity of the TDI in a large clinical trial setting. Using an anchor approach of physicians' global evaluation, we provide support for a one-unit change as

Acknowledgements

Presented, in part, at the American Thoracic Society Meeting, May 2001. Supported by Boehringer Ingelheim Pharmaceuticals, Inc.

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Assessment of dyspnea in sarcoidosis using the Baseline Dyspnea Index (BDI) and the Transition Dyspnea Index (TDI)
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The Borg and Modified Medical Research Council (mMRC) dyspnea scales have been used to evaluate dyspnea in sarcoidosis. The Baseline Dyspnea Index (BDI) and Transitional Dyspnea Index (TDI) are useful for the assessment of dyspnea in COPD. It is not known if the BDI-TDI accurately assesses dyspnea in sarcoidosis patients.
Data was analyzed from the Registry for Advanced Sarcoidosis (ReAS), a multi-national database enrolling patients with advanced sarcoidosis and a comparison group of sarcoidosis patients with non-advanced disease. At baseline, patients completed a BDI questionnaire along with spirometry, 6-min walk distance (6MWD), mMRC, Borg score, fatigue assessment score (FAS) and HRQoL assessments using Kings Sarcoidosis Questionnaire (KSQ) and St Georges Respiratory Questionnaire (SGRQ). At 12-months, patients with advanced disease completed a TDI questionnaire along with the other measures. Correlations between BDI and baseline variables, and between TDI and changes in baseline variables were evaluated.
There was significant correlation (p < 0.001 for all) between BDI and baseline 6MWD (rho = 0.336), FVC% (rho = 0.387), FEV1% (rho = 0.285), DLCO% (rho = 0.355), mMRC (rho = −0.721), Borg score (rho = −0.389), FAS (rho = −0.669), SGRQ (rho = −0.785), and KSQ (rho = 0.318 to 0.724). At follow-up, TDI correlated with BDI, but not with changes in pulmonary function or other dyspnea measures.
BDI scores correlated with pulmonary function, 6MWD, and other dyspnea measures. TDI scores did not correlate with changes in pulmonary function or other dyspnea measures. BDI may be a useful independent measure of dyspnea in sarcoidosis patients. The role of TDI needs further evaluation in longitudinal studies associated with changes in clinical parameters.
Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: Results from two multicentre, blinded, randomised controlled trials
2014, The Lancet Respiratory Medicine
Citation Excerpt :
These findings suggest that the increasing effect of umeclidinium monotherapy on trough FEV1 towards the later part of our study might have been an anomaly. In the present studies, all treatments produced meaningful improvements in symptoms of dyspnoea as measured by TDI, with an intrapatient increase from baseline greater than the MCID of 1·0.27 All treatments also produced meaningful improvements in health-related quality of life, as measured by the SGRQ.
Combination long-acting bronchodilator treatment might be more effective than long-acting bronchodilator monotherapy for the treatment of chronic obstructive pulmonary disease (COPD). We aimed to compare the efficacy and safety of umeclidinium (UMEC) plus vilanterol (VI) with tiotropium (TIO) monotherapy, UMEC monotherapy, or VI monotherapy in patients with moderate to very severe COPD.
In two multicentre, randomised, blinded, double-dummy, parallel-group, active-controlled trials, eligible patients (current or former smokers aged 40 years or older with an established clinical history of COPD) were randomly assigned in 1:1:1:1 ratio to UMEC 125 μg plus VI 25 μg, UMEC 62·5 μg plus VI 25 μg, TIO 18 μg, and either VI 25 μg (study 1) or UMEC 125 μg (study 2). All study drugs were used once daily for 24 weeks. TIO was delivered via the HandiHaler inhaler and all other active treatments were delivered via the ELLIPTA dry powder inhaler. Random assignment (by a validated computer-based system) was done by centre and was not stratified. All patients and physicians were masked to assigned treatment during the studies. The primary efficacy endpoint of both studies was trough forced expiratory volume in 1 s (FEV₁) on day 169, which was analysed in the intention-to-treat population. Both studies are registered with ClinicalTrials.gov, numbers NCT01316900 (study 1) and NCT01316913 (study 2).
1141 participants were recruited in study 1, and 1191 in study 2. For study 1, after exclusions, 208, 209, 214, and 212 patients were included in the intention-to-treat analyses for TIO monotherapy, VI monotherapy, UMEC 125 μg plus VI 25 μg, and UMEC 62·5 μg plus VI 25 μg, respectively. For study 2, 215, 222, 215, and 217 patients were included in the intention-to-treat analyses for TIO monotherapy, UMEC monotherapy, UMEC 125 μg plus VI 25 μg, and UMEC 62·5 μg plus VI 25 μg, respectively. In both studies, we noted improvements in trough FEV₁ on day 169 for both doses of UMEC plus VI compared with TIO monotherapy (study 1, UMEC 125 μg plus VI 25 μg: 0·088 L [95% CI 0·036 to 0·140; p=0·0010]; study 1, UMEC 62·5 μg plus VI 25 μg: 0·090 L [0·039 to 0·141; p=0·0006]; study 2, UMEC 125 μg plus VI 25 μg: 0·074 L [0·025 to 0·123; p=0·0031]; study 2, UMEC 62·5 μg plus VI 25 μg: 0·060 L [0·010 to 0·109; nominal p=0·0182]). Both doses of UMEC plus VI also improved trough FEV₁ compared with VI monotherapy (UMEC 125 μg plus VI 25 μg: 0·088 L [0·036 to 0·140; p=0·0010]; UMEC 62·5 μg plus VI 25 μg: 0·090 L [0·039 to 0·142; p=0·0006], but not compared with UMEC 125 μg monotherapy (UMEC 125 μg plus VI 25 μg: 0·037 L [−0·012 to 0·087; p=0·14]; UMEC 62·5 μg plus VI 25 μg: 0·022 L [−0·027 to 0·072; p=0·38]). All treatments produced improvements in dyspnoea and health-related quality of life; we noted no significant differences in symptoms, health status, or risk of exacerbation between UMEC plus VI and TIO. The most common on-treatment, severe-intensity adverse event in both studies was acute exacerbation of COPD (1–4 [<1–2%] patients across treatment groups in study 1 and 1–6 [<1–3%] patients in study 2). We recorded five to 15 (2–7%) on-treatment serious adverse events across treatment groups in study 1, and nine to 22 (4–10%) in study 2. We noted no substantial changes from baseline in vital signs, clinical laboratory findings, or electrocardiography findings in any of the treatment groups.
Combination treatment with once-daily UMEC plus VI improved lung function compared with VI monotherapy and TIO monotherapy in patients with COPD. Overall our results suggest that the combination of UMEC plus VI could be beneficial for the treatment of moderate to very severe COPD.
GlaxoSmithKline.
Efficacy and safety of indacaterol and tiotropium in COPD patients according to dyspnoea severity
2013, Pulmonary Pharmacology and Therapeutics
Guidelines for chronic obstructive pulmonary disease (COPD) recommend that treatment choices be based partly on symptoms.
A post-hoc analysis of pooled data from clinical studies compared the efficacy and safety of once-daily inhaled bronchodilators indacaterol (150 and 300 μg) and open-label tiotropium (18 μg) according to baseline dyspnoea severity on the modified Medical Research Council (mMRC) scale in patients with COPD (mMRC scores <2 = ‘less dyspnoea’; scores ≥2 = ‘more dyspnoea’). Outcomes were assessed after 26 weeks.
The analysis included 3177 patients. In patients with less dyspnoea: indacaterol (both doses) improved 24-h post-dose (‘trough’) forced expiratory volume in 1 s (FEV₁), transition dyspnoea index (TDI) and St George's Respiratory Questionnaire (SGRQ) total scores at week 26 and reduced the risk of COPD exacerbations vs placebo; and open-label tiotropium improved trough FEV₁ and TDI total score vs placebo at week 26. In patients with more dyspnoea: indacaterol (both doses) improved trough FEV₁, TDI and SGRQ total scores at week 26; indacaterol 300 μg was the only treatment to improve the TDI total score by more than the minimum clinically important difference (≥1 point) vs placebo; and open-label tiotropium improved trough FEV₁, TDI total score at week 26 and decreased the risk of COPD exacerbations vs placebo. In both subgroups, all treatments were well tolerated.
In patients with less dyspnoea, all treatments had similar effects. Indacaterol 300 μg may be a useful treatment option for patients with COPD who experience more severe breathlessness.
Effects of long-acting bronchodilators in COPD patients according to COPD severity and ICS use
2013, Respiratory Medicine
Indacaterol is a once-daily, long-acting β₂-agonist bronchodilator that improves dyspnoea and health status in patients with moderate-to-severe COPD. While its bronchodilator effects have been shown to be maintained in different patient subgroups, effects on clinical outcomes in certain subgroups are not yet defined.
Post-hoc analysis of pooled clinical study data to investigate efficacy and safety of indacaterol compared with placebo and other long-acting bronchodilators (formoterol, salmeterol, open-label tiotropium) in patient subgroups defined by COPD severity (GOLD stage II or III; n = 4082) and ICS use at baseline (no/yes; n = 4088). Efficacy outcomes were trough (24-h post-dose) FEV₁, dyspnoea (transition dyspnoea index; TDI) and health status (St George's Respiratory Questionnaire; SGRQ) after 26 weeks.
All active treatments significantly improved trough FEV₁ and dyspnoea compared with placebo, and all apart from open-label tiotropium improved health status compared with placebo. Among active treatments, indacaterol 150 μg had the best overall efficacy profile in the GOLD II and no-ICS subgroups. In the GOLD III and ICS subgroups, indacaterol 300 μg had the best overall efficacy, including a marked effect on dyspnoea (1.4-point improvement in TDI total score vs. placebo; p < 0.001). Within subgroups, the incidence of adverse events was similar between treatments.
Indacaterol maintained its efficacy regardless of disease severity or use of concurrent ICS. Indacaterol 150 μg had the best overall efficacy profile in the GOLD stage II patients while, in patients with more severe disease, indacaterol 300 μg provided useful improvements in dyspnoea.
Indacaterol therapy in patients with COPD not receiving other maintenance treatment
2012, Respiratory Medicine
Citation Excerpt :
Our results demonstrate that patients not receiving other maintenance therapy experienced significant improvements with indacaterol, relative to placebo, in trough FEV1, rescue medication use, dyspnoea and health status after 6 months of treatment. Reduced use of rescue medication has been postulated as an indirect measure of symptom control.16 Both indacaterol doses provided important benefits for these maintenance-naïve patients, although the 150 μg dose was significantly more effective than the 300 μg dose for improving health status (SGRQ score).
Recent findings of rapid lung function decline in younger patients with moderate COPD severity suggest the need for effective early treatment.
To evaluate the effectiveness of indacaterol as maintenance therapy in COPD patients not receiving other maintenance treatments.
Pooled data from three randomised, placebo-controlled studies provided a population of patients with moderate-to-severe COPD not receiving maintenance treatment at baseline and who received once-daily, double-blind treatment with indacaterol 150 μg, indacaterol 300 μg or placebo. Data from an open-label tiotropium treatment arm in one study were available for comparison. Efficacy evaluations included trough FEV₁, dyspnoea (transition dyspnoea index, TDI) and health status (St George's Respiratory Questionnaire, SGRQ) at 6 months and risk of COPD exacerbations.
The maintenance-naïve population comprised 232 (indacaterol 150 μg), 220 (indacaterol 300 μg) and 325 (placebo) patients, plus 156 (tiotropium) (30% of overall study population). Patients treated with indacaterol 150 and 300 μg had statistically significant improvements relative to placebo (p < 0.05) in trough FEV₁ (170 and 180 mL), TDI total score (1.27 and 1.04 points), rescue use and SGRQ total score (−6.1 and −2.5 units) at 6 months. Patients receiving tiotropium had statistically significant improvements versus placebo (p < 0.05) in trough FEV₁ (130 mL) and TDI total score (0.69 points). Exacerbations were rare and not significantly reduced by any treatment. Treatments were well tolerated.
Indacaterol, given to patients with moderate-to-severe COPD not receiving other maintenance treatments, provided effective bronchodilation with significant, clinically relevant improvements in dyspnoea and health status compared with placebo.
Profiling the effects of indacaterol on dyspnoea and health status in patients with COPD
2011, Respiratory Medicine
Citation Excerpt :
The TDI domains are rated from −3 (major deterioration) to 3 (major improvement) and summed to give a total score from −9 to 9. Negative scores indicate deterioration, and a change from BDI or difference between treatments of 1 point is regarded as the minimum clinically important difference (MCID).14–16 Results are also presented for the proportion of patients responding with a change from the baseline score of equal to or greater than the MCID (‘responder analysis’).
Indacaterol is a novel, inhaled, ultra-long-acting β₂-agonist bronchodilator for maintenance use in patients with COPD. The aim of this paper is to assess the effect of indacaterol on dyspnoea and health status, using pooled study data to evaluate the relative efficacy of indacaterol and existing bronchodilators.
Individual patient data were pooled from three randomized, placebo-controlled studies (NCT00393458; NCT00567996; NCT00463567), conducted in patients with moderate-to-severe COPD. Treatments were double-blind indacaterol 150 μg (n = 746) or 300 μg (n = 853) once-daily, formoterol 12 μg twice-daily (n = 556), salmeterol 50 μg twice-daily (n = 333) and placebo (n = 1185); and open-label tiotropium 18 μg once-daily (n = 415). Evaluation after 6 months' treatment was by transition dyspnoea index (TDI; minimum clinically important difference [MCID] ≥1 point), and St George’s Respiratory Questionnaire (SGRQ; MCID ≥4 units).
Differences from placebo in TDI total score were 1.01 (indacaterol 150 μg) 1.28 (indacaterol 300 μg), 0.74 (formoterol), 0.92 (salmeterol) and 0.88 (tiotropium) (all p < 0.05), with corresponding odds ratios versus placebo for exceeding the MCID from baseline of 1.91, 2.69, 2.02, 1.79 and 1.49 (all p < 0.05). Differences versus placebo in SGRQ total score were −4.4 (indacaterol 150 μg), −3.4 (indacaterol 300 μg), −2.8 (formoterol), −4.0 (salmeterol) and −1.7 (tiotropium) (all p < 0.05), with corresponding odds ratios versus placebo for exceeding the MCID of 1.95, 1.63, 1.54, 1.82 and 1.29 (all p < 0.05 apart from tiotropium).
Indacaterol provided clinically important improvements in dyspnoea and health status that were at least as good as and often better than those observed with existing bronchodilator treatments for COPD.

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Original articleMeaningful effect size and patterns of response of the transition dyspnea index

Abstract

Introduction

Section snippets

Study protocols

Patients

General patterns of measures

Discussion

Acknowledgements

Clin Chest Med

Chest

Chest

Chest

Chest

J Clin Epidemiol

Dyspnea. Mechanisms, assessment, and managementa consensus statement. American Thoracic Society

Am J Respir Crit Care Med

Clinical measurement of dyspnea

Targeted inspiratory muscle training improves respiratory muscle function and reduces dyspnea in patients with chronic obstructive pulmonary disease

Ann Intern Med

Inspiratory muscle training in chronic airflow limitationcomparison of two different training loads with a threshold device

Eur Respir J

Original article
Meaningful effect size and patterns of response of the transition dyspnea index