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Measuring Symptom Response to Pharmacological Interventions in Patients With COPD: a Review of Instruments Used in Clinical Trials

Posted on: Friday, 25 February 2005, 15:00 CST

SUMMARY

Objectives: To identify and evaluate the instruments used to measure the effect of pharmacological intervention on symptoms of chronic obstructive pulmonary disease (COPD) in clinical trials.

Design: An extensive literature search was conducted for articles published in English in a peer-reviewed journal from 1995 to March 2002 which described a randomised controlled clinical trial measuring symptoms of COPD in response to pharmacological interventions.

Patients: Patients with any severity of COPD.

Interventions: Any pharmacological intervention for treatment of COPD.

Measurements and results: A total of 43 eligible articles were identified. The individual symptoms most frequently measured were dyspnoea/ breathlessness, chest tightness or discomfort and exacerbations. There was considerable variability in the methods, terminology and symptom measurement instruments used. The most widely used instruments for measuring dyspnoea were the Borg scale, the Baseline Dyspnoea Index and the Transitional Dyspnoea Index. None of the instruments used had published evidence of rigorous psychometric testing.

Conclusions: Numerous methods have been employed to assess the symptoms of COPD in clinical trials, making it difficult to compare the results of different trials. No single measurement instrument predominates, and none of the measures identified in the review have undergone rigorous psychometric testing in this patient population. There is a clear need for a fully developed and validated tool for measuring the effecls of therapeutic interventions on symptoms in COPD in clinical trials.

Introduction

Chronic obstructive pulmonary disease (COPD) imposes a substantial burden on patients, their families, healthcare systems and society in general. In the US, the total direct costs of COPD were estimated at $15.5 billion in 1993(1). The prevalence of COPD is forecast to increase in most high-income countries, as a result of ageing populations and past smoking behaviour2. By 2020, COPD is expected to be the fifth most important cause of disability across the world, as measured by disability-adjusted life-years (DALYs)3. This rise in prevalence will further increase the human and economic costs of COPD.

Minimising this burden of disease will require development, selection and optimal use of effective treatments for COPD. A rational, evidence-based assessment of treatment options depends on a reliable method, or methods, of measuring the effect of treatment on the disease. Some aspects of COPD, such as lung function, can be measured by well-established objective methods such as forced expiratory volume in 1 s (FEV^sub 1^). However, such a measure does not reflect all aspects of the disease, and does not necessarily capture important features such as the patient's symptoms. Several studies have found only a weak correlation between FEV^sub 1^ and measures of impairment such as exercise tolerance and perceived dyspnoea on exertion4-6. Thus, the ability of FEV^sub 1^ to describe the full impact of symptoms on patients and their families, and to assess important economic parameters such as the need for healthcare and support services, may be limited. Clinical trials of treatments for COPD need to measure symptom severity directly. Some healthrelated quality of life (HRQL) instruments include a symptom scale, but this is not their primary aim. A scientifically developed and validated symptom scale for daily use is needed.

There is now increasing recognition by regulatory authorities in the US and Europe that all patientreported outcome measures (which include symptom scales and HRQL questionnaires, among others) should be thoroughly developed and validated, and guidance on development standards has been issued7,8. Patient-reported outcomes are entirely subjective, relying on patients' evaluation of their own experience, and, therefore, need very careful development to provide evidence that they are truly measuring the parameter that they intended to measure. This is particularly relevant to the evaluation of symptoms, as most available tools have traditionally been devised by individual researchers or institutions and have not usually been subjected to rigorous psychometric testing. Regulatory authorities have expressed concern over the use of ad hoc HRQL instruments with unknown psychometric characteristics9, and many of the same concerns also apply to the assessment of individual symptoms or the use of symptom scales.

The scientific practices that should be followed in developing and evaluating a symptom scale are similar to those set out by Revicki et al.10 for the development of an HRQL instrument. The development process should include testing of internal consistency, test-retest reliability, validity, responsiveness and assessment of likely clinical significance10. An internal consistency reliability co-efficient (Cronbach's a) of > 0.70 and a test-retest reliability co-efficient of > 0.70 over 2 weeks is considered to demonstrate acceptable reliability10. Validity evaluates the degree to which the instrument actually measures what it is intended to measure, responsiveness is the extent to which an instrument accurately reflects changes in the patient's condition and clinical significance assesses the practical value of an observed change10.

Although several tools are in use for assessing symptoms in COPD, there has, to our knowledge, been no recent systematic review of the tools available or the evidence for their validation.

This review analyses the instruments used to measure symptom severity in published clinical trials of pharmacological intervention in COPD, with the aim of determining what measures are available and the extent to which they have data on psychometric properties.

Materials and methods

Search Strategy

Searches were conducted using MEDLINE, CINAHL, HealthStar, EMBASE and the Cochrane Library, using the terms (as Medical Sub-Headings and text words, whenever appropriate]: (lung diseases, obstructive OR bronchitis OR pulmonary emphysema OR COPD OR chronic bronchitis OR emphysema OR chronic obstructive pulmonary disease) AND (randomized controlled trial OR clinical trial OR controlled clinical trial). This database search was limited to the period 1995 to March 2002. The search was complemented by searching the personal collections of the investigators and scanning the reference lists of identified articles, meta-analyses and systematic reviews.

Eligibility Criteria

Articles meeting all the following criteria were selected by two of us (Carlos Rizo and Paola Cubillos):

* report published as a full report in English in a peer- reviewed journal

* randomised controlled trial (parallel or crossover design)

* trial comparing one or more pharmacological intervention(s) in COPD, or attempting to validate one or more tool(s) to assess symptoms of COPD

* trial including patients with COPD of any severity and presenting data on the impact of pharmacological intervention (s) on COPD symptoms, and if possible data on the psychometric properties of tools to assess the symptoms of COPD

* trial presenting data on patients with COPD of any severity, but not aggregated with data from patients with other respiratory disorders.

Articles were excluded if they presented pharmacokinetic or pharmacodynamic data only, or if they did not provide separate data on symptoms.

Data Extraction

Data extraction was performed by three independent reviewers with clinical and methodological expertise. They resolved any differences by consensus, referring to the information in the original report. The following items were extracted and included in the present analysis: citation details; symptoms measured; tools used for symptom measurement; frequency of measurement and any mention of efforts made to validate the tools. Symptoms were defined as events that can only be measured by the person experiencing them; i.e. dyspnoea/breathlessness is a symptom, whereas cough is not. However, where events were rated by the person experiencing them (e.g. a patient rating for cough severity), they were also included as symptoms. Where the validation of a tool was by reference to other papers, these articles were obtained and reviewed.

Quality Assessment

The methodological quality of the trials was assessed using a 3- item validated scale11. This scale assesses studies according to the following criteria:

* Is the study described as randomised? (Score 0 for no, 1 for yes but with no description of the methods, and 2 for yes if the methods were described and considered appropriate).

* Is the study described as double-blind? (Score 0 for no, 1 for yes but with no description of the methods, and 2 for yes if the methods were described and considered appropriate).

* Docs the study provide a description of withdrawals and drop- outs? (Score 0 for no, and 1 if the number of and reasons for withdrawals and dropouts in each of the groups were stated).

The minimum score (lowest quality) was 0 points and the maximum (highest quality) 5 points. Scores of 2 points or lower indicate poor methodological quality11.

Data Analysis

The extracted data were tabulated and summarised. Due to substantial heterogeneity between trials, a metaanalysis was not performed.

Results

A total of 43 studies meet\ing all the criteria were identified and included in the review12-54. Additional results from the study published by Boyd et al.16 were published by Jones and Bosh55.

The majority of studies (25/43) achieved a quality score of 3 or more, indicating reasonable methodological quality. Three studies obtained the maximum quality score15,17,36.

Most of the studies were small, with 17 having a sample size of less than 50 patients and a further nine having a sample size of 50- 99 patients. All but six studies used the term 'COPD' to describe the patients, with five using only the term 'chronic bronchitis' and one including patients with 'emphysema' or 'chronic bronchitis'.

Symptom Measures

The symptoms measured in each of the studies are listed in Table 1, together with the instruments used to measure them. The symptoms most frequently measured were dyspnoea/breathlessness, chest tightness or discomfort, and exacerbations. The terminology used was variable, for example, dyspnoea was also described as shortness of breath or breathlessness. The methods used were also highly variable, even when measuring similar symptoms. For example, in some studies dyspnoea was measured at rest and in others it was measured after exertion. Some studies included measurement of dyspnoea in the morning, some during the day, and some during the night. Dyspnoea was assessed using a single question, questionnaires, visual analogue scales, or as one domain of a HRQL questionnaire (such as the Chronic Respiratory Questionnaire [CRQ] developed by Guyatt) (Table 1).

Development and Validation of the Instruments Used

There was no mention of validation efforts for single questions, such as asking the patient to rate breathlessness on a scale on 0- 3. It could be argued that these questions do not require validation as they have face validity. Of the scales used to measure symptoms, validation efforts were mentioned only for the Borg Dyspnoea Scale, the Dyspnoea Baseline Index, and the Transition Dyspnoea Index (Table 1). The Mahler Dyspnoea Index cited by Weir et al.53 was found to be an alternative name for the Dyspnoea Baseline Index when traced back through the citations. The article(s) cited in support of validation efforts for each scale were reviewed and are described below.

Table 1. Sumptoms measured in each study

Table 1. Sumptoms measured in each study

Table 1. Sumptoms measured in each study

Table 1. Sumptoms measured in each study

Table 1. Sumptoms measured in each study

Table 1. Sumptoms measured in each study

The Borg Dyspnoea Scale was developed to provide a method of rating perceived exertion on a scale of 1-10, with various points on the scale 'anchored' to verbal descriptions that were considered by the author to be 'simple and understandable by most people'56. It was described as showing a close correlation with measures of blood lactate and muscle lactate56.

The Dyspnoea Baseline Index and the Transition Dyspnoea Index were developed by Mahler et al.57 to provide a method of assessing dyspnoea at a fixed time (the Dyspnoea Baseline Index) and measuring subsequent changes over time (the Transition Dyspnoea Index). Each index rates functional impairment, magnitude of task needed to evoke dyspnoea, and magnitude of effort needed to invoke dyspnoea. At baseline these are each rated from O (severe) to 4 (unimpaired), and summed to a total score ranging from O to 12. Transitions or changes from baseline are rated from -3 (major deterioration) to +3 (major improvement), and summed to give a total score ranging from -9 to +9. The indices showed a good correlation with 12 min walking distance, but poorer correlation with FEV^sub 1^ and forced vital capacity (FVC)57. A subsequent study showed that the Baseline Dyspnoea Index correlated well with two other measures of dyspnoea, the oxygen cost diagram and the Medical Research Council (MRC) scale58, and the indices have been recommended by an outcomes committee of the American Association of Cardiovascular and Pulmonary Rehabilitation59.

There was no reference to detailed psychometric testing of any of these scales.

Several of the other articles included in this review cited references in support of their chosen symptom measures12,31- 34,43,48-50 and these references were obtained and reviewed. One of these was a general discussion of visual analogue scales, and the remainder were citations of other trials that had used the same instrument, with either no mention of validation or a reference to a further study (these secondary references were not followed up).

Discussion

This report presents data from an extensive systematic search for clinical trials that included some measure of symptoms in COPD. The most striking finding is the variability of the measurement methods in use. Dyspnoea/breathlessness was the most widely measured symptom, but it was described by multiple terms (breathlessness, shortness of breath, dyspnoea), measured at various times of day and with or without exertion and assessed using single questions, questionnaires, visual analogue scales and as part of a HRQL questionnaire. Although many methods have been used for assessing symptoms in COPD, it appears that these have yet to be standardised into a single definitive measure or set.

Few symptom measurement tools have been fully developed and validated. The Borg Dyspnoea Scale and the pair of indices developed by Mahler's research group (the Baseline Dyspnoea Index and the Transition Dyspnoea Index) have gained widespread acceptance since their publication in 1982 and 1984 respectively, but do not appear to have been subjected to detailed psychometric study. This finding is not altogether unexpected, as it reflects the way in which symptom measurement instruments are traditionally derived, as empirical tools by individual researchers or institutions. Although validation methods are well established in the development of HRQL tools60 and the importance of linguistic and cultural adaptation is well known, symptom measurement tools appear to have not generally received the same attention61.

Most of the symptom measures employed were narrowly focused on one or a few attributes of COPD (e.g. breathlessness), and, therefore, would be limited in their ability to capture the full impact of COPD and/or its treatment. Furthermore, the multiplicity of measures in use makes it difficult to compare results between different studies, even studies that set out to measure the same symptom. For example, how could one compare the results of Tashkin et al.47 assessing shortness of breath as mild, moderate or severe, with results from Poole et al.39 using a visual analogue scale to assess breathlessness, with those of Weir et al.53 measuring dyspnoea using the Mahler Baseline Dyspnoea Index? Thus, the lack of a widely accepted tool for measuring symptoms in COPD forms a substantial handicap to research synthesis in the field.

There is a clear need for a fully developed and validated tool for measuring symptoms in COPD. Ideally, such a tool should incorporate both the patients' and clinicians' goals as defined in the Global Obstructive Lung Disease (GOLD) guidelines62 and should be developed according to current recommendations governing patient- reported outcome measures10. One possibility is to use the symptom domain in the two disease-specific questionnaires, the CRQ and the St George's Respiratory Questionnaire (SGRQ). The dyspnoea domain of the CRQ has been used as a daily measure in one study by Cook et al., however, no information on psychometric properties is reported22. Since completing the present research, we have noted the recent publication of two measurement tools the Breathlessness, Cough and Sputum Scale (BCSS)64 and the Clinical COPD Questionnaire (CCQ)63, which may be potentially useful in future studies.

The BCSS is a patient-reported 3-item measure in which breathlessness, cough and sputum are each rated on a scale of 0-4, with higher scores indicating worse symptoms. However, it was not derived using a formal item generation and reduction process, which is a limitation. The individual item and total scores were found to have high internal consistency and reliability (Cronbach's α 0.95-0.99 over time, intra-class correlation co-efficient 0.74- 0.78) and the scale showed evidence of concurrent, convergent, divergent and discriminant validity64. Secondary analyses of data from three clinical trials showed that the BCSS score was both reproducible over time in clinically stable patients, and sensitive to change in patients who responded to treatment.

The CCQ was developed specifically to assess clinical control either as a weekly or as a daily measure in patients with COPD63. The instrument is a self-administered 10-item scale which reflects the GOLD treatment goals and was scientifically developed and validated using established psychometric methods. Briefly, qualitative research with patients and clinicians was used to generate possible items, which were evaluated by 67 international experts and reduced to a scale of 10 items grouped into three domains. Cross-sectional data showed high internal consistency (Cronbach's α 0.91) and high discriminant validity (significantly higher scores in patients with more severe COPD than in patients with milder COPD or healthy smokers). The CCQ score showed moderate to high correlations with both a disease-specific and a generic HRQL instrument instrument (SGRQ and Short-Form 36, respectively), SGRO and lower correlations with lung function measurements. Test-retest reliability was high (intra-class correlation co-efficient 0.94), and the CCQ score showed a clear improvement over 2 months in smokers who successfully gave up smoking, indicating that the scale has good longitudinal responsiveness63. The minimal clinically important difference has been estimated to be 0.5 (Thys van der Molen, personal communication).

Conclusion

This review has \shown that numerous methods are employed to assess the symptoms of COPD in clinical trials, making it difficult or impossible to compare the results of different trials. No single measurement instrument predominates, and none of the measures identified in the review have undergone rigorous psychometric testing. There is a clear need for a fully developed and validated tool for measuring the effect of pharmacological interventions on symptoms in COPD.

Disclosure of Financial Support

The research was conducted by Foresight Consultants, a division of Foresight Links Corporation. Foresight Consultants was commissioned by AstraZeneca to perform an independent review of this topic, through an unrestricted contract. Representatives from AstraZeneca participated in the review design and reporting, but not in the study selection or appraisal or in the analysis of the data.

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2818_5, Accepted for publication: 29 October 2004

Published Online: 24 November 2004

doi: 10.1185/030079904X15165

Alejandro Jadad1, Carlos Rizo1, Paola Cubillos2 and Elisabeth Sthl3

1 Centre for Global eHealth Innovation, Toronto, Canada

2 Consultant, Foresight Links Corporation, Ontario, Canada

3 AstraZeneca R&D, Lund, Sweden

Address for correspondence: Dr Alejandro Jadad, Centre for Global eHealth Innovation, Toronto General Hospital, R. Fraser Elliott Building, 4th Flr., 190 Elizabeth Street, Toronto, ON, M5G 2C4, Canada. Tel: +1 416 340 4800 Ext. 6903; Fax: +1 416 340 3595; email: ajadad@uhnres.utoronto.ca

Key words: Chronic obstructive pulmonary disease (COPD) - Measurement - Symptoms Systematic review

Copyright Librapharm Dec 2004

Source: Current Medical Research and Opinion

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