Outcomes for COPD pharmacological trials: from lung function to biomarkers

Methods

The ATS/ERS jointly created a Task Force on “Outcomes for COPD pharmacological trials: from lung function to biomarkers” to inform the COPD research community about the possible use and limitations of current outcomes and markers when evaluating the impact of a pharmacological therapy. Based on their review of the published literature, the following report has been prepared with individual sections that address specific outcomes and markers, and a summary of their recommendations.

Task Force selection

Task Force members were selected using the following criterion: worldwide recognised experts in COPD trials and in specific COPD outcomes. An initial list was prepared by those who developed the proposal and this list was integrated with other names suggested by the ERS Scientific Committee and by the three reviewers of the application, considering the expertise in COPD trials and in specific outcomes.

Outcomes assessed

The major sections of the present report are: Lung function; Patient-reported outcomes; Exacerbations; Exercise; Mortality; Social and economic burden; Imaging; Nonpulmonary markers; Minimal important difference; and Biomarkers. Each outcome measure was assessed by a group of authors using the set of criteria described in table 1⇓. This assessment was left to the discretion of the authors. Throughout this process, the authors have considered an “outcome” to mean a consequence of the disease that a patient normally experiences. This may be cough, dyspnoea, weight loss, exercise intolerance, exacerbations, impaired HRQoL, increased health resource use or mortality. Conversely, a “marker” is a measurement known to be associated with an outcome; for example, exercise capacity as tested in a laboratory is a marker of exercise intolerance in daily life 4.

Literature review

The authors searched the literature according to strategies that they developed independently. No central literature review or standardised evaluation for inclusion or exclusion of evidence was applied. Thus, while the ATS/ERS Task Force has adopted a comprehensive approach to reviewing the measures reported in the present report, it does acknowledge that not all measures and all evidence may have been included due to the amount of evidence available on each measure in the medical literature.

Introduction

COPD is characterised by physiological abnormalities, including airflow limitation, abnormalities in gas exchange and lung hyperinflation. These can be objectively assessed in the laboratory using measurements such as FEV₁, arterial oxygen tension (P_a,O2) and carbon dioxide arterial tension from blood gas determinations, as well as lung volumes measured at rest or during exercise. These markers serve as objective physiological measurements that aid in diagnosing disease, assessing its severity and analysing the mechanisms underlying some of its morbidity. In COPD, FEV₁ is used in diagnosis and staging, arterial blood gases are useful in defining respiratory failure and dynamic hyperinflation helps to explain exertional dyspnoea 6.

Unfortunately, it is not easy to determine whether a measured change reflects a true change in pulmonary status or is only a result of test variability. Appropriate concepts such as sensitivity to change or responsiveness should be applied. These concepts account for test variability or variability in the measurement of differences at two different time-points. Repeated measures indicating change from baseline will provide more confidence that real change has occurred.

Forced expiratory manoeuvre outcomes

FEV₁ is the volume of air that is forcibly exhaled in the first second, whereas forced vital capacity (FVC) is the total volume of air exhaled after a full inspiration. The methodology for obtaining forced expiratory manoeuvres and derived parameters have been standardised by the ATS and the ERS first separately and now also jointly 7. In the general population, reference equations based on the distribution of spirometric parameters in normal populations have been made available by the ATS 8, by the European Community for Coal and Steel (ECCS) 9 and by studies on different ethnic groups and age ranges 10. As such, it is important to carefully consider reference values that are most likely to represent the population to be tested in clinical practice or in multicentre clinical trials. In COPD patients, the FEV₁ has been used to classify COPD patients by severity 11 and to describe progression 12 of the disease.

FEV₁ and FVC have been shown to be highly reproducible in the vast majority of patients, with differences between highest and second highest values within 150 mL or 6%, if obtained by well-trained technicians. Variability coefficients for FEV₁ and FVC over time (within days, weeks or years) have been reported 10. When taking into consideration the degree of change in FEV₁ that would be considered clinically meaningful by the regulators, a change of 5–10% from baseline values is considered to be clinically important. During advisory committee meetings of the US Food and Drug Administration for new COPD drugs, a change of <3% of the baseline has been deemed to be not clinically important 13. According to ATS/ERS recommendations for the interpretation of lung function tests 10, the change in FEV₁ should be ≥20% in short-term trials (of weeks of duration) and ≥15% in long-term trials (≥1 yr) to be confident that a clinically meaningful change has occurred (a summary of these recommendations can be found in the Minimal important difference section).

Forced expiratory volume in six seconds (FEV₆) has recently been suggested as an alternative to FVC. It has been found to be ∼25% less variable than FVC 14. The operating characteristics of this measurement continue to be defined according to reference values recently published 15, 16. The diagnostic accuracy for defining airflow obstruction or restriction seems good 17, 18, although this depends on the population tested and the use of appropriate lower limit thresholds to define normality 19. It has been suggested that different fixed thresholds (FEV₁/FEV₆ <73% and FEV₆ <82%) 20 are more appropriate than the currently utilised thresholds for obstruction in international guidelines (FEV₁/FVC <70% and FVC <80% predicted).

In terms of health outcomes for the general population, a low pre-bronchodilator FEV₁ has been found to be a predictor of mortality for all causes and cardiovascular mortality 21–25. In COPD patients, post-bronchodilator FEV₁ is poorly correlated with patient-centred outcomes, such as dyspnoea, exercise performance and HRQoL at baseline or after pharmacological interventions 26–31. However, FEV₁ has the advantage of being the most repeatable lung function parameter and one that measures changes in both obstructive and restrictive types of lung disease 7. Therefore, FEV₁ has been proposed as a measure to be used for adopting treatment strategies in COPD based on severity classification 15.

The European Medicines Agency 1 specifies that strict airways reversibility criteria must be applied to patient inclusion in clinical trials (e.g. ≤12–15% FEV₁ reversibility post-bronchodilator), with a pre-bronchodilator FEV₁/FVC ratio ≤70% and FEV₁ within 30–70% pred (post-bronchodilator). The ATS/ERS recommendation is that an increase in FEV₁ and/or FVC >12% and 200 mL compared with baseline during a single testing session suggests a significant bronchodilatation 10. However, although changes in FEV₁ and FVC have been suggested to assess the reversibility of airway obstruction, a negative response to a single administration of bronchodilator should not be used to determine the need for long-term bronchodilator treatment due to the lack of sensitivity of the parameters derived from full forced expiratory manoeuvres 32 and the variability of response over time 33. FEV₁, FVC and FEV₁/FVC ratio have all been used as predictors of the outcome of lung volume reduction surgery 34.

During exacerbations of COPD, measurement of FEV₁ is possible but it does not seem to be useful for the early detection of exacerbations 35. However, even small changes in post-bronchodilator FEV₁ following acute treatment were found to be associated with meaningful clinical outcomes 36–38.

FEV₁ has been used as a primary variable in the vast majority of multicentre trials, though an increase in FVC is also considered as proof of bronchodilatation 10, since physiologically relevant changes occur in a number of COPD patients who respond to bronchodilators with an increase of FVC without changes in FEV₁ 9, 39. Reliable values of FVC may be difficult to obtain in severe COPD patients who are unable to sustain prolonged expiration for a period >6 s; therefore, FEV₆ may be used instead of FVC. The rate of decline of FEV₁ has been shown to be decreased by smoking cessation 12.

With respect to feasibility, spirometry can be undertaken using different types of equipment, provided the standard requirements are met 7. Simple spirometry is only moderately time-consuming, with an average of 10–20 min per session 40. The reproducibility of spirometric measurements is critically dependent on the ability of the technician 7. Thus, specific training is mandatory for the technical staff and also for physicians who wish to undertake spirometry testing 36. The cost of spirometers is widely variable, but relatively inexpensive portable equipment can be used for large clinical trials, provided accuracy requirements are met 7.

When spirometry is performed, patients can experience some discomfort, light-headedness or even syncope. Airway obstruction may occur if multiple prolonged exhalations are required for the measurement of FVC. The use of FEV₆ may prevent these events in more severe patients. There is also potential for infection transmission during pulmonary function testing but direct evidence has not been provided 41. Measures to reduce the risk of infection have been identified and should be followed 41.

Lung volumes

Functional residual capacity (FRC) is the volume of gas remaining in the lung at the end of tidal expiration. In healthy subjects at rest, the FRC corresponds to the relaxation volume (V_r) of the respiratory system. In COPD, FRC may be increased because the V_r is increased (static hyperinflation) or the end-tidal lung volume exceeds V_r (dynamic hyperinflation). Inspiratory capacity (IC) is the maximum volume of gas that can be inspired from end-tidal expiration, which is the difference between total lung capacity (TLC) and FRC. Residual volume (RV) is the volume of gas remaining in the lung at the end of a maximal expiration. In COPD, RV may be increased due to airway closure or extreme flow limitation.

The methods for measuring absolute lung volume and its subdivisions have been standardised in a joint ATS/ERS document 7, 42. In the general population, reference equations based on the distribution of FRC and RV in normal populations have been published by the ECCS 9. Published reference values are summarised in the ATS/ERS joint document on interpretation of pulmonary function tests 10. Differences in ethnicity are not well characterised. Most laboratories use reference values recommended by ECCS 9 or an ATS/ERS workshop 43. There are no equations for predicting IC; it is thus determined by the subtraction of predicted TLC from predicted FRC. Currently, there are no frequency distribution data available for any of these spirometry measures in COPD patients.

The reproducibility of FRC has been reported, with coefficients of variation ranging 3.5–6.7% for plethysmography and 4.9–10.4% for helium dilution, without apparent differences between normal and obstructed subjects 44. The coefficients of variation of RV measurements ranged 9.5–12.4% for plethysmography and 2.4–14% for helium dilution. However, no data are available for FRC or RV reproducibility in absolute values. Inter-laboratory differences seem to be as important as intra-individual differences. For IC, the short-term variability (95% confidence interval (CI)) in subjects with chronic airway obstruction at rest was 220–150 mL or 10–4.5% pred 32, 45.

In COPD patients, FRC increments 46 or IC decrements 29, 45, 47–54 have been shown to correlate better than increased FEV₁ with exercise tolerance and dyspnoea, and HRQoL, both at baseline 45, 47, 51, 52 and after pharmacological 29, 46, 49, 50, 53 or surgical 48, 54 interventions. When related to TLC, IC has been reported to be an independent predictor of mortality in COPD of different severity 55. Changes in RV have been shown to be a major determinant of response to lung volume reduction surgery 56, but its usefulness in large studies has yet to be determined.

Changes in lung volumes can occur in COPD patients after treatment with bronchodilators, even in the absence of changes in FEV₁ 32, 57. Small increases in IC after bronchodilator therapy, which signify a reduction in end-expiratory lung volume, are associated with reduced mechanical loading and increased functional strength of the inspiratory muscles. This in turn results in a decreased work of breathing and a reduced oxygen debt. Furthermore, an increased resting IC (of the order of 0.3 L or 10% pred) would be indicative of a greater ability to expand tidal volume during exercise, with a resultant increase in ventilatory capacity 29, 49, 58. Reduced operating volumes during exercise enhance the neuromechanical coupling of the respiratory system (i.e. the relationship between neural drive and mechanical response), thereby relieving respiratory discomfort. The net effect of these physiological benefits is an improvement in the patient's ability to engage in exercise 59. Several studies have also indicated that long-acting bronchodilators can reduce hyperinflation in COPD, as measured by RV, FRC and IC, in a manner that is somewhat similar to that seen with lung volume reduction surgery 49, 60, 61.

During recovery from mild exacerbations, both FRC and RV were found to decrease, while IC increased and TLC remained constant 38. Therefore, IC can be used to reflect changes in lung hyperinflation during acute exacerbations. Studies have confirmed that TLC does not change during more severe exacerbations 38, 62.

These variables can be measured in multicentre trials, possibly in selected centres. For acute interventions, in which TLC can be assumed to be constant 63–65, changes in IC are a good surrogate for changes in FRC. For chronic interventions, in which TLC may not be constant, changes in IC may not mirror changes in FRC 60.

In terms of feasibility, FRC and RV measurements require a body plethysmograph or spirometers with inert gas analysers. Either method can be used, provided the equipment meets the standard requirements 42. However, they are not interchangeable, since moderate-to-severe airflow obstruction dilution methods tend to underestimate and body plethysmography tends to overestimate TLC. IC can be measured during simple spirometry if a closed circuit system is used. Dilution methods are too time-consuming for serial measurements, whereas body plethysmography is much less time-consuming and does not add much time to that necessary for simple spirometry. IC is part of the spirometric manoeuvre and only requires a few stable breaths before its measurement. The reproducibility of pulmonary function test measurements is critically dependent on the ability of the technician 41. Measurement of absolute lung volumes is technically more demanding than simple spirometry and specific training is necessary. The equipment for measuring lung volumes is substantially more expensive than simple spirometers. Body plethysmographs are more expensive than dilution equipment but the extra cost may be neutralised by time saving.

Gas exchange

The diffusing capacity of the lung for carbon monoxide (D_L,CO) is a measure of carbon monoxide (CO) transfer from the airspace to pulmonary capillary blood; it is expressed as the total uptake of CO by the lung per unit of time and per unit of driving pressure 66, 67.

The methodology of the single-breath method has been standardised by the ATS and the ERS first separately 66, 67 and then jointly 68. For the general population, reference equations based on the distribution of D_L,CO values in normal populations have been made available by studies on different ethnic groups and age ranges 69–71. D_L,CO has been used to quantify the extent of emphysema in COPD patients 72. Measurements have been made before and after rehabilitation 73 and have been used to assess patients for lung volume reduction surgery 74, 75.

The measure of D_L,CO is reproducible even if the inter-laboratory coefficient of variation is larger than for spirometry measurements. Acceptable D_L,CO test criteria have been standardised 68. A coefficient of variation of 3–4% has been reported in repeated measurements in normal subjects and in patients with abnormal spirometric patterns. An inter-sessional D_L,CO variability of ≤9% over time has been reported 76–79.

The influence of D_L,CO on health outcome has not been established in the general population, whereas in COPD patients it has been used in the evaluation of surgical risk, particularly for lung cancer and other thoracic surgery 80. D_L,CO has also been used in studies evaluating the effects of lung volume reduction surgery 74, 75, rehabilitation 73 and therapy for α₁-antitrypsin deficiency 81, 82. However, it is a measure that can only be performed in stable conditions rather than during exacerbations of COPD.

D_L,CO has been used as a primary outcome variable in multicentre trials, particularly in studies of lung volume reduction surgery 75, 76. It can be measured using different types of equipment, provided they meet the standard requirements 66, 67. The measurement takes 15–30 min and its reproducibility is critically dependent on the ability of the technician and on the achievement of acceptable test criteria 66, 67. Therefore, specific training is mandatory for the technical staff 66, 67. The cost of D_L,CO equipment is variable but rather expensive. It is not available in primary care although it can be used for limited clinical trials, provided accuracy requirements are met 66, 67. Discomfort, light-headedness or even syncope may occur if multiple prolonged exhalations are required for measurement of D_L,CO. There is also the possibility of infection transmission, although direct evidence has not been provided. General considerations for pulmonary function testing also apply to D_L,CO equipment and procedures 41.

P_a,O2 is a measurement of arterial oxygen partial pressure and it can be determined by direct blood sampling. Some investigators have utilised arterialised earlobe capillary blood to assess P_a,O2, although potential for underestimation of arterial oxygenation has been suggested by several groups 83, 84. Conversely, arterial oxygen saturation (S_p,O2) can be measured directly 85–87 or indirectly with the aid of pulse oximetry 88, 89.

Neither the ATS nor the ERS have standardised the methodology for both these variables. However, there are many studies in the literature that consider the methodology, techniques and equipment required to measure arterial blood gases 85, 90, 91. The frequency distribution of blood gas values has been established for the general population; reference equations based on the distribution of P_a,O2in normal populations have been made available by studies on different ethnic groups and age ranges 92, 93. In COPD patients, P_a,O2 has been used to define respiratory failure (P_a,O2 <7.98 kPa (<60 mmHg)) and it was included for adopting treatment strategies in COPD based on severity classification and disease progression 11. In terms of measurement reproducibility, modern blood gas analysers are automated self-diagnostic instruments that require minimal maintenance. Calibration of the machine's electrodes is important to correct for any drift in the measurements over time 85–87. A coefficient of variation of 3–4% has been reported for many available pulse oximeters 90, 91.

In terms of health outcomes, P_a,O2 is useful for predicting survival status in hospitalised COPD patients with exacerbations 94, 95. Conversely, S_p,O2 is commonly used in sleep studies 96, 97. P_a,O2 has been used in many studies evaluating the effects of treatment in severe COPD patients. Since pulse oximetry is a noninvasive technique, S_p,O2 can be easily determined in large studies that occur in primary care settings 98–102. As mentioned previously, P_a,O2 is an important variable that can be measured in severe, uncooperative COPD patients with exacerbations 103. S_p,O2 can also be easily used to monitor these patients 104, 105. Both variables can be obtained in all patients with or without comorbidities.

P_a,O2 and S_p,O2 can be useful in multicentre trials in severe COPD patients, provided the same equipment is used in each setting and standard requirements are met 85, 91. Both variables take little time to measure and the only training that is required is related to arterial blood sampling 86, 87. The cost of the equipment for the measurement of P_a,O2 and arterial oxygen saturation is variable but rather expensive. S_p,O2 that is obtained by pulse oximetry is relatively inexpensive and is available in almost all patient care settings. There are safety issues with arterial puncture for blood gas analysis, such as local pain, discomfort, light-headedness, nerve damage or syncope. Although the risk of bleeding may be increased, this procedure has been successfully performed in individuals who have been treated with therapeutic anticoagulation 106.

Safety and technical considerations

In general, pulmonary function testing can be physically demanding for a minority of patients when considering the influence on common comorbidities, e.g. ischaemic heart disease, diabetes mellitus or psychiatric disturbances. It is recommended that patients are not tested within 1 month of myocardial infarction 42. Conversely, measurements may be suboptimal in the presence of various comorbidities, such as chest or abdominal pain, facial abnormalities, stress incontinence or psychiatric disturbances. With respect to safety issues, claustrophobia may occur during body plethysmography. The potential also exists for infection transmission but direct evidence has not been provided 41.

Measurements of absolute lung volumes may also be suboptimal in the presence of various comorbidities, such as chest or abdominal pain, facial abnormalities, stress incontinence or psychiatric disturbances.

Conclusions

Based on the review of lung function measurements, FEV₁ remains a primary end-point that regulatory authorities regard as an acceptable measure of efficacy for COPD pharmacological trials, particularly in combination with instruments that encompass symptomatic-based end-points 1. However, since lung hyperinflation and its reduction in response to a bronchodilator are not reflected in routine spirometry, IC could also be included in COPD trials, particularly where changes in lung physiology are expected. In hyperinflated patients, RV or FVC are useful measures for the identification of a therapeutic response that may not be determined from measuring FEV₁. It has also been highlighted that measuring IC after a pharmacological intervention without plethysmographic determination of the static lung volumes may not be an adequate reflection of the underlying changes in these volumes 53. Arterial blood gases are useful outcomes in interventional studies that might affect respiratory drive or impair ventilation–perfusion relationships in the lungs.

Introduction

The development of COPD may affect several aspects of a patient's health 107. These consequences of illness can be regarded as a process of illness progression, which normally starts at the development of physiological or biological abnormalities, resulting in symptoms and physical limitations that are noticed and reported by the patients. Eventually, patients will have to face their inability to take part in their usual activities, which will influence their perception of their health and ultimately their general well-being 108.

As a consequence, a number of clinical and physiological outcomes, such as dyspnoea, functional status, HRQoL and health status, are recognised as being important for the characterisation of response to treatment 109. For instance, dyspnoea is the primary reason for patients seeking medical care. Measurements of dyspnoea provide an insight into the practical effects of treatment on everyday life, reflecting whether or not patients perceive an improvement in this primary symptom of COPD. Patients with COPD frequently decrease their activity in order to avoid the unpleasant sensation of breathlessness. Functional status measurement reveals the number of activities that a patient can perform, something not reflected in measurements of FEV₁ or dyspnoea.

Health status and HRQoL

Health status measurement provides a standardised method of assessing the impact of disease on patients' daily lives, activity and well-being. The term “quality of life” is often used loosely in this context, but this is inappropriate. The factors that determine an individual's quality of life are varied. Even in very ill people, health usually forms only a minor determinant of an individual's quality of life, with employment, finances, family and social factors being collectively more important 110. “HRQoL” is a more specific term.

Health status and HRQoL measurements are designed to allow comparisons across patients and studies. This means that all patients in all studies must be measured in the same way using a common instrument and unit of measurement. The measurements must be made without bias, i.e. the instrument should apply to relevant patients equally. Essentially, health status and HRQoL are instruments for use in groups of patients; they may also be used to assess individuals, but it should be understood that they will provide a standardised assessment of their health, not their quality of life.

The reader is also directed to the ATS Quality of Life website 111 as a useful source of information and to access detail of some of the questionnaires summarised herein.

Dyspnoea

Dyspnoea, or breathlessness, can be measured based on the principles of psychophysics (stimulus–response relationship). In general, two different approaches have been used to measure dyspnoea in clinical trials: clinical ratings based on activities of daily living and ratings during an exercise task.

The purposes of measuring dyspnoea in pharmacological trials include differentiating between individuals who have less dyspnoea and those who have more (a discriminative instrument), and determining how much dyspnoea has changed (an evaluative instrument). For the assessment of treatment efficacy, the two important measurement criteria of an evaluative instrument are responsiveness and construct validity 141. Responsiveness refers to the ability to detect change; if a treatment results in an improvement in dyspnoea, both the investigator and the clinician want to be confident that they can detect the difference, even if it is small. For construct validity, changes in dyspnoea scores should correlate with expected changes in other variables, such as lung function and exercise performance, consistent with theoretically derived predictions. However, the magnitude of the correlations is typically modest, indicating that dyspnoea ratings and measures of lung function represent different constructs.

Conclusions

A number of clinical and physiological outcomes, such as dyspnoea, functional status and health status, are recognised as being important for the characterisation of response to treatment. Instruments used to measure dyspnoea should rely on patient-reported outcomes, be multidimensional where possible, adhere to standardised methodology and ideally be computerised. Instruments that are third-party rated may prove less compelling than validated patient-rated instruments. These recommendations should be upheld if the evaluation of dyspnoea in COPD is to provide consistently reliable data in future clinical trials 109. Health is an abstract concept but it is possible to produce standardised health status measures that have true interval-scaling properties (i.e. the questionnaire behaves like a ruler). While there is a relationship between reduced lung function and impaired health 174, this is not sufficiently strong for spirometric measures to provide a reliable estimate of HRQoL 175. For that reason, measurements of health status must be performed using specifically designed questionnaires. Unfortunately, recent evidence indicates the possibility of an improvement in health status in COPD patients even after a regular treatment with placebo 176, whereas a meta-analysis of the published clinical trials indicates that SGRQ is only able to differentiate between health condition and presence of COPD, but it is not a real indicator of the severity of the disease according to the severity of airway obstruction 177. At this time, the poor correlation between changes in FEV₁ and in quality-of-life scores indicates the need for using a multidimensional approach.

Introduction

The chronic and progressive course of COPD is often aggravated by short periods of increasing symptoms, particularly increasing cough, dyspnoea and production of sputum that can become purulent. The majority of these COPD exacerbations are caused by bronchial infection and, if frequent, have been demonstrated to have a negative impact on HRQoL in patients with COPD 178–181. Furthermore, acute exacerbations are the most frequent cause of medical visits, hospital admissions and death among patients with COPD 182. One of the main objectives of COPD treatment is to reduce the frequency and severity of exacerbations. Unfortunately, there is no validated diagnostic test or biomarker of exacerbations 183; therefore, the diagnosis of an exacerbation must be based on a clinical definition that includes the most frequent symptoms observed during these episodes. Definition of exacerbations and their severity need to be standardised to allow comparisons between different interventions in different settings 184.

Evaluating the frequency of exacerbations

Due to seasonal variation, an evaluation of exacerbation frequency requires a period of ≥1 yr 179. The methods for recording exacerbation frequency as a variable have not been standardised, but various methods have been used in several clinical trials of inhaled corticosteroids and/or bronchodilators in COPD 152, 154, 190, 191, 195–198.

In observational studies of COPD patients, a skewed distribution of this variable has been found with a large number of patients having 0–2 exacerbations per yr and a small number of patients having ≥10 exacerbations per yr 179, 194, 198. The mean number of exacerbations is generally related to the severity of the baseline disease and the definition used, and in observational studies ranges 1–2.5 episodes per yr 179, 194, 198. If unreported exacerbations are included, severe patients (GOLD III) have a mean of 3.43 exacerbations per yr and GOLD II patients have a mean of 2.68 per yr 194.

In the short term (i.e. weeks or months), this variable does not appear to be reproducible due to the small number of episodes per yr; the probability of repeating an episode in weeks or months is small. However, in the long term, patients with frequent exacerbations in the past have a large probability of suffering frequent exacerbations in the future 194, 199. In COPD patients, there is also a short-term 36 and a long-term impact of exacerbations on HRQoL 178–180, 200. The magnitude of this impact is directly related to the frequency of exacerbations 178–180, 200. In addition, poor HRQoL is a risk factor for frequent exacerbations 179. Numerous clinical trials have also shown that it is sensitive to treatment effect, with apparent reduction in the frequency of exacerbations 152, 154, 190, 191, 195, 197, 198. Comorbidities, particularly cardiac diseases, are a risk factor for poor outcome of the exacerbation 201 but, to date, there is no evidence that comorbidities are a risk factor for frequent exacerbations.

With respect to the feasibility of measuring the frequency of exacerbations, simpler methods are more likely to be used in multicentre trials. A questionnaire in the form of a diary card is needed in order to capture the unreported exacerbations from patients and another questionnaire for investigators to quantify the reported exacerbations 178, 194. The questionnaires take <1 min each to complete. No additional equipment or training is required.

The statistical methodology used to calculate the annual ratio of exacerbations in a given cohort and to compare the different ratios between treatment arms in clinical trials must be described in detail, since great and significant differences have been reported when different approaches have been used 202.

Evaluating the severity of exacerbations of COPD

The methodology surrounding the use of severity of exacerbations as a variable has not been standardised. The criteria for hospital admission may vary from country to country and in different hospitals. In addition, the use of systemic steroids and/or antibiotics for exacerbations has different patterns in different areas. The severity of exacerbations is closely related to the severity of the baseline disease, i.e. severe COPD patients are more likely to be hospitalised due to an exacerbation. Therefore, distribution of severity of exacerbations parallels distribution of severity of COPD in a given population. Up to 50% of exacerbations may be unreported to the physician and managed at home (mild exacerbations), 40–45% are moderate exacerbations and <10% are severe exacerbations 178, 194, 198, 203. This variable is not reproducible in the short term but, in the long term, COPD patients who experience severe exacerbations have an increased risk of experiencing more severe exacerbations in the future 194, 204. In COPD patients, this variable does influence health outcome since severe exacerbations, which require hospital admission, do have an impact on health status 179. Many RCTs have also demonstrated improvements in the severity of exacerbations with pharmacotherapy compared with placebo in patients with COPD 152, 154, 195, 197, 198. It is possible that cardiac disease may influence the severity of the exacerbation. Patients with cardiac disease have an increased risk of hospitalisation due to an episode 205 and have an increased risk of mortality 206.

The severity of exacerbations can be measured in multicentre trials. This is based on medical resource utilisation observed in numerous RCTs of pharmacotherapy compared with placebo 152, 154, 187, 190, 195–198. It requires the use of a questionnaire or a diary card for the patient to detect the unreported (mild) exacerbations; and a questionnaire is also used for the investigator to collect information on reported (moderate-to-severe) exacerbations 178, 194. Both take <1 min to complete and require no additional equipment or training costs.

Conclusions

The definition of exacerbations for clinical trials with anti-infectives should include the recognition of symptoms related to the likelihood of infectious aetiology. However, the definition used in clinical trials of pharmacotherapy in stable COPD is not restricted to exacerbations of infectious aetiology. The proposed definition of an exacerbation of COPD is an increase in respiratory symptoms over baseline that usually requires medical intervention. This definition requires the patient to be encouraged to recognise exacerbations and increase their own therapy or present to healthcare professionals. Patient diary cards are useful for recognising these episodes. The definition of severity is as follows: 1) mild, which involves an increase in respiratory symptoms that can be controlled by the patient with an increase in the usual medication; 2) moderate, which requires treatment with systemic steroids and/or antibiotics; and 3) severe, which describes exacerbations that require hospitalisation or a visit to the emergency department. The severity of exacerbations is largely based on the degree of healthcare utilisation and this definition has the disadvantage of having different criteria for hospital admission or different patterns of use of antibiotics and/or oral steroids in different settings or countries. At this time, no biological marker for the risk of exacerbation or severity exists that can be used in clinical practice or for an RCT.

Introduction

In chronic cardiopulmonary diseases the ability to exercise is an important clinical outcome in its own right and a marker of other significant outcomes. Exercise tolerance is significantly impaired in many patients with COPD and is an important determinant of HRQoL 119, 207. In COPD patients, exercise tolerance cannot be predicted by resting lung function measurements (e.g. FEV₁) and exercise testing is useful in the clinical setting to assess the degree of impairment, prognosis and the effects of interventions. Exercise capacity is mostly limited by ventilatory constrains, lung gas exchange inefficiency leading to increased exercise ventilatory demand, lung dynamic hyperinflation and dyspnoea sensation 208, 209. Deconditioning and/or malnutrition leading to peripheral muscle dysfunction and leg fatigue may also contribute significantly to reduced exercise capacity 210.

The ability of exercise to provoke breathlessness is used in the MRC dyspnoea scale to estimate symptom intensity (see section on Dyspnoea) 144 and exercise impairment is an important predictor of mortality 211, 212.

The severity and cause of exercise intolerance are best assessed by performing detailed physiological measurements in the laboratory (minute ventilation, breathing pattern, oxygen uptake, carbon dioxide production, oxygen saturation and other derived indexes; all during exercise). Simpler field tests, where it is normal simply to record the duration of exercise or the distance covered in a fixed time period, can also be utilised. Laboratory test protocols can be either incremental with a steady rise in the intensity of the workload or constant work rate tests (“endurance”), where the workload is undertaken at a fixed percentage of a previously established maximum. Incremental testing is less sensitive to interventions than endurance exercise, which is usually conducted at ∼75% of the symptom-limited peak oxygen uptake (V′_O2,peak) or peak work rate 213, 214. Field tests, such as the widely used 6-min walking test (6MWT), represent an alternative in which patients are encouraged to walk as far as they are able to for the period of the test 215. In addition to the distance covered, it is useful to record, at the beginning and end of exercise, the intensity of breathlessness (and sometimes leg fatigue) using a modified Borg category scale or a VAS (see section on Dyspnoea), cardiac frequency and S_p,O2. Differences in physiological adaptation to cycling and to walking have been reported in COPD in patients with increased dyspnoea and arterial oxygen desaturation during walking exercise 216, 217.

All exercise tests have been shown to have good validity, specificity, reliability 49, 50, predictive ability 212, discriminative ability and evaluative ability 218.

Laboratory exercise testing

Laboratory exercise testing is conducted under standardised conditions, with the recording of cardiac frequency, minute ventilation, respiratory frequency and breathing pattern, oxygen uptake and carbon dioxide production (from which the anaerobic threshold can be estimated 219), exercise duration and maximum workload performed. Lung volumes can be measured noninvasively using optoelectronic plethysmography 220 but the most common method involves the measurement of IC (assuming the TLC to be constant during exercise). Care is needed in how this measurement is conducted 64 but in individual laboratories its reproducibility is good 65. The intensity of respiratory sensation, breathlessness and the presence of leg fatigue are recorded using a category ratio scale (see section on Dyspnoea) at rest and at intervals during exercise (commonly at 1 min or just before a planned increase in workload). It is useful to note the principal symptom limiting exercise performance 216, 217. Cardiac frequency, blood pressure, oxygen saturation and ECG are also recommended.

According to ERS and ATS/American College of Chest Physicians guidelines for cardiopulmonary exercise testing 208, 209, patients rest for a few minutes breathing quietly on the equipment before beginning light exercise, which increases in intensity in a ramp fashion. Cycle and treadmill exercise have been used interchangeably, although the former has been mostly used in COPD clinical studies, as the work rate for incremental and endurance tests is easier to quantify. As the exercise period should last 10–12 min, the work rate increment should be selected carefully. In COPD studies the usual rate of workload increase is 10 W·min⁻¹, although slower or faster rates are possible in the very sick and the very fit patients, respectively. The maximal incremental exercise test is also utilised to determine the appropriate work rate to be used in an endurance protocol (i.e. 75% peak work rate).

The measurement of respiratory and metabolic variables together with various exercise protocols is standard, although there is no universal agreement on the rate of increase of work during exercise, which tends to be individual to the purpose of the investigation. Although the statistical frequency distributions of these measures have not yet been determined in the general population or in COPD patients, they are reproducible in the short term as well as in the long term, where changes can reflect disease progression. In the general population, exercise is an important determinant of overall cardiovascular mortality 221, and in COPD patients mortality has been related to V′_O2,peak in this group 212. Many studies have also demonstrated that interventions, such as rehabilitation 222, 223, lung volume reduction surgery 224 and oxygen 225, 226 and heliox 227 administration, and treatment with bronchodilator drugs 49, 50 improve exercise-related indices. These have been largely demonstrated with an endurance test outcome rather than incremental testing. However, exercise testing should not be peformed during exacerbations of COPD due to the obvious patient practicalities. The presence of comorbidities, which themselves limit exercise performance, e.g. intermittent claudication or exertional chest pain, precludes exercise testing with any test modality. Coexisting occult cardiac disease can be identified during exercise from abnormalities in cardiovascular variables (i.e. cardiac frequency, ECG and blood pressure).

With respect to the practicality of implementing exercise testing, it can be performed in multicentre studies, providing there is strict quality control of data collection centrally. Studies with ≤100 patients that have been conducted in six or more centres have now been reported with good data quality 49. It can be expected that >90% of COPD patients would be able to carry out exercise testing in a study. In order to undertake such testing, appropriate laboratory space is necessary. An electrically braked cycle ergometer or a treadmill with facility to operate at a gradient is required. Aditionally, an appropriate flow meter and gas analysers, which are commonly part of commercial computerised exercise-recording systems, will be needed. Ideally, any exercise test should measure a physiological variable in a breath-by-breath fashion. Testing with this modality requires 45–60 min to fully complete a test and allow the patient to rest. Training is necessary for the operators, who would normally be physiological measurement technicians, graduate students or equivalent. Costing varies from centre to centre but is not insignificant.

Field tests

Conclusions

Exercise capacity is another important clinical outcome that could be measured in COPD pharmacological trials. Several methods for evaluating exercise capacity have been developed. The 6MWT is a relatively simple test that has been used extensively in trials to evaluate possible benefits of pharmacological intervention. More standardised tests have patients walking at a specific speed on the treadmill or performing cycle ergometry. Exercise duration, power output (in watts) and oxygen consumption (in mL·kg⁻¹·min⁻¹) are also standard measures of exercise capacity.

Introduction

Mortality provides the best possible outcome to measure. Reliable, relatively easy to measure and of great importance, it has been the gold standard in the evaluation of predictors and therapies. In COPD, several studies evaluated predictors of mortality. Four reports have shown improvements in mortality with COPD therapies: two trials evaluating oxygen for hypoxaemic patients 246, 247, one patient level meta-analysis trial of inhaled corticosteroids 248, and one of lung volume reduction surgery in a small subgroup of patients 218.

Cause of death in patients with COPD

Patients dying as a consequence of severe COPD do not regularly have COPD listed on their death certificates, making COPD-specific mortality a difficult outcome measure 249, 250. Patients with advanced COPD are often recorded as dying from other causes, sometimes trivial insults, such as hospital admissions for unrelated events (e.g. fractures), or therapeutic mishaps, such as sedation, uncontrolled oxygen or maintenance treatment withdrawal. COPD is also an independent risk factor for cardiovascular deaths 251, 252. All-cause mortality is probably the best COPD outcome measure.

Adjudication of the cause of death

The correct determination of the cause of death remains important, however, as it may help generate hypotheses regarding the mechanism by which a variable in question affects the outcome or the influence that a treatment under study may have on the outcome.

Very little has been published in the area of accurately defining the cause of death. As a matter of fact, only one study 196 was found in the COPD literature where a methodology for the adjudication of the actual cause of death was described. In contrast, adjudication committees for the cause of death and a description of their methods are frequent in cardiovascular trials 253, 254. The discrepancy between the original and the adjudicated cause of death in some of those studies has reached 20% 196. There is emerging consensus that large clinical trials evaluating death as an outcome should have an independent adjudicating committee 255 consisting of at least three members 256. More members do not appear to increase the accuracy of classification 254.

Predictors of mortality

In table 2⇓, the variables that represent predictors of mortality are presented along with the stage (GOLD–ATS/ERS) included in the studies and whether it predicts all-cause and respiratory mortality 5, 55, 212, 249, 257–269.

With mortality as an outcome, the variables listed represent surrogate outcomes. They could be used as surrogates for mortality, especially if their changes reflect changes in mortality. A case in point is correction of oxygen in hypoxaemic patients, which alters the mortality rate. Unfortunately, surrogates often do not show a relationship or even contradictory results when compared with important patient outcomes.

Thus, the relative strength of the variables remains difficult to ascertain. Recent data do suggest that, at least for the body mass index (B), obstruction (O), dyspnoea (D) and exercise endurance (E) index (BODE index), changes in its value after intervention confer changes in prognosis 270, 271. More studies are needed to confirm these preliminary findings. What is clear is that variables that differ from FEV₁ are predictors of mortality and some, such as BODE, may be better than lung function alone.

Conclusions

Mortality remains the most important and robust clinical outcome in COPD research. Several variables different from the degree of airflow obstruction independently predict mortality in patients with COPD. Accurate determination in studies assessing mortality as an outcome requires the correct adjudication of the cause of death. The adjudication committee should consist of three individuals.

Introduction

An economic evaluation is not an outcome measure as such, but rather a specific type of analysis that compares costs and effects between two or more interventions and integrates the differences in costs and effects into a cost-effectiveness ratio. Cost is a cumulative variable that includes a wide variety of different types of healthcare utilisation and other resource use, all of which can be measured in different ways. These data are increasingly important in various jurisdictions in order to support coverage and reimbursement decisions by health authorities.

Because economic evaluations require high-quality data on outcome measures, a detailed description of the methods, data acquisition and handling and reporting requirements are relevant to the remit of the ATS/ERS Task Force.

There are several educational books and guidelines on economic evaluation 272–274 and there are reviews of economic evaluations of COPD interventions 275, 276. The purpose of the present section is to focus on: 1) the aspects of economic evaluations that are typical or specifically relevant to COPD in the context of pharmacological trials; 2) the issues around the measurement and valuation of healthcare utilisation; 3) the measurement and valuation of productivity costs; 4) the outcomes typically used in economic evaluation; 5) the interpretation of the cost-effectiveness ratio; and 6) the epidemiological models of COPD specifically developed to estimate cost-effectiveness of COPD interventions. Most economic evaluations of COPD interventions were conducted alongside randomised clinical trials. An increasing number of cost-effectiveness analyses are using models to estimate cost-effectiveness.

Use of healthcare resources

Productivity losses

Outcomes in economic evaluation

Incremental cost-effectiveness ratio

COPD progression simulation models

Models may follow up on the empirical assessment of cost-effectiveness alongside clinical trials, for example when there is a need to extend the time horizon of a clinical trial in order to capture all relevant economic end-points. Simulation models can be used to project disease burden or estimate cost-effectiveness of interventions 277. The Burden of Lung Disease model is designed as a burden-estimation tool for use by policy makers and local researchers. In addition, recent work describes estimates for the cost-effectiveness of COPD interventions 294, 302–305. These models are called “state transition models” or “Markov models” 306, which simulate the progression of COPD over different stages of disease severity and model the probability to experience COPD exacerbations. This interest in COPD models is also driven by the need to adapt the model input (e.g. the prevalence distribution of COPD severity or the average length of hospital stay) before transferring the cost-effectiveness results from one country or setting to another country or setting.

Conclusions

Cost-effectiveness analyses evaluate the net changes in costs and outcomes that will result from using a new treatment in a particular group of patients, compared with an existing treatment. In particular, where the drug is more expensive, it is necessary to determine whether the increase in cost is justified by the resultant improvement in patient-centred outcomes. Unfortunately, in COPD pharmacological trials the presence of protocol-induced visits may lead to increased monitoring of patients with associated improvements in health behaviour and compliance, which may lead to an underestimation of costs compared with what would occur in a more naturalistic setting. Furthermore, the clinical trials have a double-masked design, so the results are unlikely to reflect compliance and patient preference differences that might be seen in a comparison of treatments. The relatively short time period of trials, in particular, places important limitations on the accuracy of the cost estimates, as expensive hospitalisations may have occurred outside the study period. Moreover, few studies determine all resource use and potential downstream cost. In any case, without an evaluation of new agents using summary outcomes, such as QALYs, as the measure of effectiveness, it is difficult to gauge the value of pharmacological therapy in individuals with COPD.

Introduction

FEV₁ is a nonspecific end-point that does not distinguish the relative contribution to airflow obstruction arising from emphysema, chronic obstructive bronchitis, asthma and bronchiectasis. As has been recently suggested, progress toward specific treatments for COPD might be accelerated by moving beyond measurements of airflow limitation to the precise diagnosis of the specific targets responsible for the airflow limitation 307. Computed tomography (CT) imaging provides a means of accurately characterising lung parenchymal changes and the nature of the image data facilitates quantitative assessment. Although comparison between plain radiography and CT has shown that for clinical purposes the plain film still has an important role in the evaluation of COPD 308, CT is more sensitive than plain radiography in diagnosing emphysema, and correlates with the presence and severity of emphysema better than nonspecific physiological parameters, such as FEV₁ and D_L,CO/alveolar volume 309, 310. Longitudinal studies indicate that densitometric indices relate to the decline in FEV₁ 311 but, in addition, are a more sensitive measure of emphysema progression than pulmonary function tests and health status 312–315. Furthermore, the addition of CT evaluation of measurements of airway wall thickening has greatly contributed to the in vivo morphological study of COPD 316. Recent data show that by quantifying both the extent of emphysema and of airway remodelling, high-resolution CT (HRCT) is useful in differentiating COPD patients who have predominant parenchymal disease from those who have predominant airway pathology 317, 318. The importance of determining the relative contribution of emphysema and conductive airway remodelling in individual subjects with COPD is further highlighted by a study showing that neutrophil counts in the induced sputum are significantly associated with CT indices of peripheral airway dysfunction but not with the severity of emphysema, as assessed by both CT and D_L,CO 319. Consequently, quantitative CT presents the first real opportunity to measure accurately and repeatedly in vivo lung pathological changes related to specific mechanisms of airflow limitation in COPD.

General principles of CT lung parenchyma and airways analysis

Various indices have been used to quantify lung density changes by CT. Mean lung density (MLD) is calculated by averaging the density of all pixels in the image that represent the entire lung. It has been validated by correlation with lung function tests 320–323. The percentile point is defined as the cut-off density value in Hounsfield units (HU), for which a predetermined percentage of all voxels has a lower value and, as with MLD, is also influenced by density changes in all lung structures 324, 325. Only the fifth percentile point has been correlated with pathology 326 and lung function tests 327, although in the assessment of emphysema progression there is similar sensitivity between the 10th and 20th percentile 328. The voxel index (VI), also referred to as Density Mask after the software program developed by General Electric Medical Systems (Milwaukee, WI, USA), or the “relative area”, is defined as the proportional area under the curve of the histogram below a predetermined threshold. It is not influenced by changes in the attenuation value of voxels that remain beyond the designated threshold. Different thresholds have been applied and validated by comparative studies using pathological standards 329–333 and physiology 331, 332, 334–337.

The percentage wall area and the ratio of wall thickness to whole diameter of the right upper lobe bronchus 316, 318 or all depicted bronchi of >2 mm in diameter 317 have been used to evaluate airway wall thickening. These measurements have been shown to be reliable in the assessment of the conductive airway remodelling that is characteristic of COPD, and in defining the relative contribution of emphysema and airway disease to physiological impairment. HRCT-pathological correlation has shown that CT measurements of airways with an internal perimeter ≥0.75 cm could be used to estimate the dimensions of the small peripheral conductive airways 338. Recent studies have attempted to address standardisation of the methodology of airway measurements by CT 339–342.

Inherent errors in the evaluation of airways that are oriented obliquely to the axial plane may be overcome through the use of dedicated software that has been shown to be accurate in the three-dimensional computation of the central axis of the bronchi and in its two-dimensional lumen and wall contour segmentation 342.

Variability of quantitative CT indices

With respect to scanner performance, the density of the lungs is much lower than that of water or bone and falls in a range where not all manufacturers have optimised their scanners. Some systems, for instance, have large and varying offsets at air density 343, 344. The lung, consisting of air-filled cavities of almost zero density within nearly water-equivalent tissue, is very heterogenous and gives rise to the nonlinear partial volume effect, which may cause an underestimation of lung density 345.

Several physiological variables affect lung density. Lung volume is the main confounder and the physiological variable that is probably most pertinent to the reproducibility of densitometry in long-term studies. Gross lung density can vary by as much as 80–100 HU from full inspiration to end expiration 346, 347.

At this time, the methodology has not been standardised. A number of issues remain unresolved. First, there needs to be control of or correction for variability in inspiratory level. Incorporation of a respiratory gating device consisting of a spirometer and a microcomputer has been proposed as a means of controlling ventilatory volume during image acquisition 348. In an evaluation of this procedure, however, it was concluded that the repeatability of lung densitometry could not be improved by spirometric control 349. A similar technique using a pneumotachometer allows the patient to breathe between acquisitions and scanning is initiated on return to a pre-selected inspiratory level 350. An alternative approach is to standardise densitometric measurements for lung volume using a technique that acquires two volume scans at different lung volumes. The relationship between lung density and logarithmically transformed volume of air in the lungs measured from CT images is linear and thus lung density can be calculated for a specified lung volume using linear regression 328. This approach of volume correction has been shown to improve reproducibility 351, 352, but its use in long-term studies may mask some of the lung density loss secondary to emphysema-related hyperinflation. The routine use of these volume-control methods in densitometric studies remains contentious 350–355.

Consistent measurements are most likely to be achieved at maximum inspiration 353 because variation in CT lung density is lowest at full inspiration 356; in cooperative patients, breath-holding at maximum inspiration is most reproducible 357. A study aimed at investigating the relationship between HRCT lung attenuation measurements (employing spirometric lung volume control), pulmonary dysfunction and dyspnoea severity in patients with COPD 358, has shown that pulmonary dysfunction in COPD cannot be assessed by a single modality of lung attenuation measurements. In particular, the inspiratory level at which spirometrically gated measurements of HRCT lung attenuation are acquired influences the relationship with physiological measurements and dyspnoea perception in COPD: inspiratory measurements assess the extent of emphysematous tissue loss, expiratory measurements may reflect airflow limitation and lung hyperinflation with attendant dyspnoea perception 358.

Secondly, there are issues with the optimum image acquisition protocol. CT numbers are recognised to be unreliable 359 and are dependent on scanner type, model, object positioning within the scanner gantry and various physical factors (e.g. kilovoltage, current-time product, slice thickness and reconstruction algorithm) 343, 359–361. Furthermore, it is recognised that spatial uniformity of CT numbers over the entire subject area may only be achievable for certain combinations of parameters 362.

The optimum acquisition protocol remains contentious. Scanner settings for optimal visual resolution and density resolution 363 are mutually exclusive and, although a standardised densitometry protocol has been developed that gives comparable results in different CT scanners 361, 364, this is at the expense of visual interpretation.

Finally, delineation methods are perhaps the most important component of imaging software. Semi-automated image-processing programs, such as the “seeded-region growing” method 365, reduce interobserver variability compared with the manual outlining of complex structures 366. Software incorporating an internal calibration step may allow correction of errors in scanner calibration 344, 360, 367 and the generation of audit trails for regulation and electronic security ensure integrity 368.

There is no convincing evidence with regard to whether analysis of the whole lung is superior to single or limited slice assessment. Studies based on visual point-counting scores 369 suggest that adequate assessment cannot be obtained from one lung slice alone, although limited evidence from densitometric studies 328, 370 suggests that similar results may be obtained for the whole lung and single or limited slice analysis.

The optimum densitometric index for use in longitudinal trials remains contentious. The MLD is subject to noise 364 and is less sensitive to progression than other indices 371. The sensitivity of the VI is influenced by threshold 328, 344, whereas the percentile point is less dependent on the choice of percentile 328, 372. Other techniques have been described but are less well validated than the aforementioned methods 373–375.

The normal range of lung density has been determined in relationship to age and height 327, 376, 377. This supports the sensitivity of changes in disease that are independent of either age or height 326. However, more recent studies have demonstrated age-related changes in both airspace dimensions 378–380 and CT lung density measurements. CT densitometry is reproducible in the short term 314, 343, 351–353, 381, 382 and also likely in the long term 344, 367.

During exacerbations of COPD, accurate and precise measurements of emphysema cannot be performed. Lung density will be altered by the influence of changes in airways resistance on gas trapping and by the presence of interstitial changes resulting from infection. In addition, increased dyspnoea will influence the ability to breath-hold. In the case of coexisting illnesses, lung density will be altered by respiratory (e.g. pneumonia, pulmonary embolism, asthma, interstitial lung disease) and nonrespiratory (e.g. cardiac failure and other causes of pulmonary oedema) comorbidities.

With regard to patient safety, CT examination does entail exposure to ionising radiation. Historically considered to be a high-dose examination 383, modern scanners and protocols have allowed great reduction in effective dose delivery without loss of fidelity. Conventional HRCT (1.5-mm images at 10-mm intervals with 140 kVp and 175 mAs) delivers an effective dose of 0.98 mSv, which is ∼12 times that of a posteroanterior and lateral chest radiograph 384. Volumetric protocols entail several times this dose but the use of low-dose multidetector imaging, employing tube currents as low as 8 mAs, reduces the dose to below that recommended in studies of mild-to-moderate risk (1–10 mSv) 385.

The exposure to ionising radiation with CT scanning causes concerns about the risk/benefit ratio, but estimates of this ratio can only be approximate. The damaging effects of ionising radiation are assumed to follow a linear dose–effect relationship and estimates of risk are largely extrapolated from data obtained from extremely high-dose exposure 386. The so-called “linear-no threshold” hypothesis 387 allows estimation of risk by extrapolation and rightly adopts a cautious stance towards safety. Nevertheless, this hypothesis has been questioned 388 and the explanation of risk may be more relevant and more meaningful to the lay person if expressed as multiples of the natural background radiation using the background-equivalent radiation time unit 389. The risk/benefit of using CT scanning in patients exposed to ionising radiation in the absence of a clinical indication underlies the need of standardising the use of low-radiation dose protocols in the context of COPD clinical trials 390. Conversely, the life-time mortality risk from cancer of an average 50–70-yr-old COPD patient after exposure to a low-dose chest CT is sufficiently low 390, 391 to justify the use of the technique in carefully controlled studies aimed to: 1) define the in vivo lung morphological changes underlying airflow limitation; 2) identify different clinical phenotypes of the disease; and 3) understand its natural history more clearly and the possible effects of preventative and pharmacological intervention. The risk/benefit balance of CT studies in the absence of routine clinical indication is compounded by the lack of consensus on whether the risk of low levels of exposure (<100 mSv) can be extrapolated from the complications arising from extreme levels of exposure, such as nuclear explosions or accidents.

Conclusions

Although CT densitometric evaluation allows the measurement of the progression of emphysema and the evaluation of airway wall thickening, a number of concerns have been raised regarding its use in COPD clinical trials. These mainly relate to the unresolved issues of the repeated exposure of patients to ionising radiation and the high costs involved in its frequent use. Another issue is that this methodology has not been fully validated yet. CT densitometric evaluation could be limited to a select group of patients in which the impact of treatment on airway remodelling and the progression of emphysema can be potentially studied.

Introduction

There is a growing realisation that COPD is a multiorgan-system disease. In particular, there is accumulating evidence that the skeletal muscles do not function normally, contributing to exercise intolerance. This is important because skeletal muscle dysfunction may well be a remediable source of exercise intolerance 392. The fat-free mass (FFM) is also a significant determinant of exercise capacity in patients with COPD. With the recognition that extra-pulmonary aspects of COPD are important, standardised markers of skeletal muscle function and lean body mass must be considered. Loss of skeletal muscle mass is the main cause of weight loss in COPD, whereas loss of fat mass contributes to a lesser extent 393.

Body weight and FFM

BMI is a measure of body weight corrected for body height (body weight×height⁻²; in kg·m⁻²), whereas the FFM index (FFMI) is a measure of FFM corrected for body height (FFM×height⁻²; in kg·m⁻²) 394.

These measures have been standardised. BMI is widely used in health and disease as a measure of body weight adjusted to height 266. FFM includes all compartments of the body except fat mass. It consists of muscle tissue, bone tissue and body fluids, and it can be easily measured using bioelectrical impedance analysis. More sophisticated measures are dual X-ray analysis or deuterium and bromide dilution 394–400. Statistical frequency distributions have been established for both measures. For BMI and FFMI in the general population and in the COPD patient population, the World Health Organization and COPD researchers have specified a number of ranges that represent certain nutritional states, as outlined in table 3⇓ 261, 266, 399, 401. Measuring BMI is highly reproducible when using the same equipment. In the case of FFMI, it is also reproducible but dependent on the method used 398, 402.

In the general population, these measures have been found to influence health outcome. Decreased BMI and FFMI are associated with impaired physical functioning. Obesity correlates with increased cardiovascular comorbidity and diabetes mellitus, but the shape of the association is not linear 403. In COPD patients, a decreased BMI and especially a decreased FFMI are associated with impaired muscle function, exercise capacity and health status and with decreased survival 261, 266, 397, 404, 405. BMI can be increased by diet or nutritional supplementation 244, 406–408, whereas FFMI can be increased by training (rehabilitation) 409 and/or anabolic therapies, such as anabolic steroids 410. During exacerbations of COPD, BMI and FFMI can be measured especially using bioelectrical impedance analysis 411. However, it must be taken into account that fluid shifts can take place during exacerbations, which might affect FFM measurement. FFM depletion and involuntary weight loss are associated with an enhanced systemic inflammatory response 412–414. Osteoporosis is commonly associated with FFM depletion 415.

The variables BMI and FFMI can easily be used in multicentre trials, with the restriction that the same equipment should be used throughout the centres. Measurements of these variables require a height rod, a weighing beam scale and bioelectrical impedance equipment. The process takes only 5 min and involves little training or cost.

Measurement of quadriceps muscle function

Quadriceps muscle weakness has been observed in patients with COPD 416, 417 and has been related to exercise intolerance 418, utilisation of healthcare resources 419 and survival in patients with moderate-to-severe COPD 420. Therefore, treatment of quadriceps muscle weakness is very important in the management of patients with moderate-to-severe COPD 421–423.

Many different techniques have been used to measure quadriceps muscle weakness in clinical trials. Volitional and nonvolitional quadriceps muscle force can be measured.

Isometric assessments involve patients sitting with their hip in 90° flexion with a lever connected to the lower leg by a strap (with two fingers above the lateral malleolus). The lever has to be moved towards the knee angle of interest (e.g. 60° knee flexion) and the patient is then asked to extend the leg with as much force as possible for 4–6 s.

In COPD patients, no standardisation of this technique has been conducted. With respect to reproducibility in the short term, there have only been a few studies with small samples of patients to suggest that this is indeed the case 424. In terms of the influence of quadriceps muscle function on the health outcome of COPD patients, it is known that patients with moderate-to-severe COPD who had been admitted to hospital at least twice in the year prior to the study had significantly lower isometric quadriceps muscle force than those without hospital admission 419. However, the actual cost of healthcare resource utilisation was not studied. Quadriceps muscle function appears to be a sensitive measure of treatment effect attributable to specific lower limb training, and multiple international clinical trials, including patients with COPD, have used a computerised dynamometer to assess isometric quadriceps muscle force before and after an exercise training programme 421. Limited data are available with regard to muscle function testing in pharmacological intervention studies. Improvements in muscle bulk and strength are reported after hormonal replacement therapy in elderly males and COPD patients 425, 426.

In the case of isokinetic assessments, COPD patients sit with their hip in 90° flexion and a lever is connected to the lower leg by a strap (with two fingers above the lateral malleolus). The lever has to be moved from 90° to 0° knee flexion with as much force as possible; gravity will bring the leg back into the starting position. This can be repeated 15–30 times to assess quadriceps muscle endurance 417.

Femoral nerve magnetic stimulation requires that patients lie on a specially modified couch with their knees bent at 90°. The ankle on their dominant side is placed in an inextensible strap connected to a strain gauge. The signal is amplified and passed to a personal computer running the software program LabVIEW (Instron Deutschland GmbH, Darmstadt, Germany). Stimulation of the femoral nerve is carried out using a custom-made double 70-mm branding iron design coil connected via a Y-connector to two Magstim 200 Mono Pulse electromagnets (Magstim Co. Ltd, Whitland, UK). The output of two magnets combined in this fashion is equivalent to 120% of the output of a single unit. Stimulations are delivered spaced ≥20 s apart to avoid twitch-on-twitch potentiation.

Conclusions

The observed relationships between weight loss, muscle wasting and muscle weakness 394, 427, which are independent of FEV₁, as well as the known close relationship between respiratory muscle weakness and dyspnoea, indicate the importance of adequately recording and reporting all patient characteristics in sufficient detail during pharmacological trials. This enables investigators to better understand the physical status of their patients, particularly the state of their peripheral muscles in the context of COPD. Unfortunately, BMI and FFMI are the only standardised measures available. Measurements of quadriceps muscle function are not yet standard, mainly due to the expense and need for a trained operator.

Introduction

With the increased interest in COPD and increasing number of reports of clinical trials, physicians are faced with the almost daily challenge of evaluating published reports of therapies for this disorder. Evaluating the clinical significance of such studies requires a firm grasp of statistics. The concept of minimal clinically important difference (MCID) in outcomes of therapy for patients with COPD has been proposed as a tool to assist clinicians and researchers in understanding the results of clinical trials. The minimal important difference (MID) has been defined by a group of clinical epidemiologists at McMaster University as “the smallest difference in score in the outcome of interest that informed patients or informed proxies perceive as important, either beneficial or harmful, and which would lead the patient or clinician to consider a change in management.” The description of the MID precludes making MID estimates for outcomes that are remote from those important, in themselves, to patients, such as spirometry or laboratory exercise capacity. Further, the definition suggests that only if there were reasons to question the reliability or accuracy of data from patients could proxies be relied on to provide estimates of the MID 428–430. The MID should optimally be determined in a population of subjects similar to that in which the MID is to be applied. Thus, the MID for various measures to be used in outcome studies of COPD should be determined from populations with COPD. The severity of the population and homogeneity of the population in which MID is estimated are also important factors to consider.

There are three basic methods for estimating MID: 1) statistical- or distribution-based methods that focus on the variance and distributional properties of scores in an untreated population of patients with the disease of interest; 2) panel-based estimates from healthcare professionals and patients; and 3) external- or anchor-based methods, which compare changes in the outcome of interest to other clinically important outcomes. Statistical methods for estimating MID include a half sd, se of measurement (the product of the sd and the square root of one, i.e. reliability of the measure), effect size (the average change divided by the baseline sd) and standardised response mean (the average change divided by the sd of that change) 431–433. The original method to determine the MID relied on anchor-based approaches, while panel-based methods are infrequently used. Leidy and Wyrwich 434 have recently suggested “triangulation methodology” to describe the need to consider all three estimation methods along with expert input to identify a final MID. In addition, the uncertainty around the point estimate for the MID should be considered and provided.

MID estimates for some outcome measures in studies of COPD are summarised in table 4⇓.

Health status and HRQoL

Dyspnoea

Exercise

Lung function and FEV₁

The universally used measure of lung function in clinical studies of COPD is FEV₁. However, this measure of pulmonary function, currently recognised as only one of the key components necessary to fully characterise patients with COPD, has statistically significant but weak correlations with other patient-centred outcomes, such as dyspnoea 436. Therefore, FEV₁ is only one (and an imperfect) method of assessing outcomes that are important to patients in more recent studies in patients with COPD. Despite its widespread use and the large number of clinical investigations that have simultaneously measured FEV₁ and other patient-centred outcomes, there has been relatively little effort to determine an MID for FEV₁. Furthermore, the definition of the MID calls into question the value of pulmonary function measures as being important for patients or leading to change in management. Nevertheless, as recently reviewed by Donohue 466, an MID for FEV₁ of 100 mL can be suggested. However, a more rigorously defined MID for FEV₁ is needed. A single MID estimate may be difficult to establish for several reasons. First, baseline severity of the underlying disease assessed by FEV₁ is likely to be important. In this regard, change in FEV₁ after bronchodilator therapy is less marked in terms of absolute change in FEV₁ in patients with lower baseline lung function. Secondly, some patients have a greater degree of response to short-acting β-agonists, which may be associated with a widely variable response to other therapeutic agents. Thirdly, FEV₁ has been used as an outcome at different time-points after therapy. FEV₁ can be a short-term outcome measuring peak response over minutes to hours, a longer-term outcome over hours or days, as a “trough” response prior to the next treatment dose, and as a very long-term outcome over years. Fourthly, a recent study 467 indicated a greater variation in spirometry performed in clinical practice settings compared with pulmonary function laboratories.

Other pulmonary function measures

Due to the cost and complexity of measuring lung volumes, diffusing capacity and arterial blood gases, these features have not been widely employed in research studies of therapeutic outcomes in COPD studies. Therefore, there is limited information regarding the MID for pulmonary function measures other than FEV₁. However, there has recently been an increased interest in the assessment of hyperinflation and associated measurement of static and dynamic lung volumes in response to bronchodilators and lung volume reduction surgery 49, 58, 224. Some of these investigations have concurrently measured lung volumes, exercise capacity and quality of life, and could be further analysed to develop external measure-based estimates of MID, particularly for selected lung volume measures. Oxygenation is also a potentially important outcome. Substantial improvements in oxygenation may be associated with reducing or eliminating the need for supplemental oxygen therapy, which is critically important to patients. In addition, reduction in oxygen need may lead to a reduction in healthcare costs, a factor of importance to payers of healthcare and society.

Conclusions

The MID for outcome measures is a promising method to assist clinicians and investigators in the interpretation of therapeutic trials. However, the MID for some of the outcome measures (pulmonary function) should be more rigorously evaluated according to standard methods before they can be universally applied.

Introduction

A biomarker refers to the measurement of any molecule or material (e.g. cells, tissue) that reflects the disease process. In COPD, several types of biomarker have been measured that are related to disease pathophysiology and the inflammatory and destructive process in the lung. Pulmonary biomarkers have been measured in bronchial biopsies, bronchoalveolar lavage (BAL), sputum and exhaled breath. Plasma biomarkers are discussed in the Nonpulmonary markers section. A review of >600 published studies suggests that few of these biomarkers have been validated and there is little information about reproducibility and the relationship to disease development, severity or progression 177, 472. In evaluating pulmonary biomarkers it is important to compare findings in patients with COPD with cigarette smokers matched for exposure who do not have significant airflow limitation (normal smokers) and with age-matched nonsmoking normal subjects. This is rarely performed accurately, making interpretation of abnormal findings difficult. The advantages and disadvantages of various pulmonary biomarkers in COPD have recently been reviewed 473.

Bronchial biopsies

Although the inflammation in COPD predominately involves lung parenchyma and small airways, bronchial biopsies appear to reflect the cellular abnormalities seen in the peripheral lung 474, 475. Bronchial biopsies have been useful for documenting the structural changes, cellular patterns and expression of inflammatory proteins in patients with COPD. In stable COPD there is increased infiltration of macrophages and activated T-lymphocytes, particularly of CD8+ T-lymphocytes 474, 476, which express interferon-γ, inducible protein-10 and interleukin (IL)-9 477, 478. Moreover, these lymphocytes express chemokine receptors associated to a type-1 response, such as CXC chemokine receptor 3, in contrast to lymphocytes in asthma, which express chemokine receptors typical of a type-2 response, such as CC chemokine receptor 4 479. While a prominent neutrophilia is present in the airway lumen of patients with COPD in stable conditions, it is not observed at the tissue level, except in patients with severe airflow limitation 480. Finally, during exacerbations of the disease, an increased recruitment of eosinophils and neutrophils has been described, which is associated with upregulation of specific chemoattractants, such as regulated on activation, normal T-cell expressed and secreted and CXC chemokine ligand 5 481–483.

Several studies have assessed the potential anti-inflammatory effects of treatments in bronchial biopsies of patients with COPD. These studies usually involve either a baseline biopsy and a second biopsy after a defined period of treatment, or a single biopsy at the end of active treatment with a biopsy in a parallel group of patients taking placebo therapy. Overall, inhaled corticosteroids seem to have little effect on the airway inflammation typical of COPD, while they are able to reduce mast cells, an effect which is associated with a reduction in exacerbation numbers 484, 485. More encouraging results have been obtained after treatment with either a phosphodiesterase-4 inhibitor or with the combination of corticosteroids and bronchodilators 486, 487. However, further studies are required to establish whether the airway inflammation in COPD can be successfully eradicated and whether this would result in a significant clinical improvement.

Bronchoalveolar lavage

BAL has the advantage, unlike bronchial biopsies, of sampling inflammation in the lung periphery. BAL can generally be safely performed 490, providing careful assessment is performed and guidelines are adhered to. In general, fluid recovery is greater in patients with less extensive emphysema, as assessed by diffusion capacity 491. BAL may be performed in the same patients as bronchial biopsy, thus providing additional and complementary information.

Sputum

Many COPD patients produce suitable sputum spontaneously, but spontaneous sputum may contain a high proportion of dead cells 502, which potentially provide misleading cell counts and mediator measurements 503, 504. For this reason, induced sputum has usually been the procedure of choice. It should be recognised that sputum obtained after inhaling nebulised hypertonic saline may have a different composition than mucus and may be more similar to a washing of the proximal airways. The procedure is tolerated by patients with FEV₁ >30% pred. However, airflow obstruction is often observed 505, 506 and cannot be totally prevented by pre-medication with β₂-agonists 507.

Exhaled gases

Measuring biomarkers in the breath is a very attractive approach to monitoring COPD airways inflammation as it is noninvasive and makes repeated sampling possible 529, 530. However, there are important issues regarding reproducibility and sensitivity that need to be addressed before this approach can be recommended as an outcome measurement.

Exhaled breath condensate

Many mediators have now been detected in exhaled breath condensate (EBC), which has the advantage that it is easy to perform and completely noninvasive 543. Several factors affect the measurement and recommendations have recently been formulated by an ERS/ATS Task Force 544. A limitation of the technique is the variability of the measurement and the low concentrations of mediators detected.

Blood

In recent years, researchers have hypothesised that a “low-grade” systemic inflammation may play an important role in the pathogenesis of systemic complications observed in chronic respiratory diseases such as COPD 248, 252, 268, 563–568. In the Third National Health and Nutrition Examination Survey of the US population 564, a number of markers of systemic inflammation were shown to be associated with active smoking and reduced FEV₁. The markers investigated were C-reactive protein (CRP), fibrinogen, leukocytes and platelets in serum and plasma. However, their level of involvement has since been questioned due to the cross-sectional methodology used and the lack of information regarding the temporal aspects and biological plausibility of this observed association 569. Previous studies 566, 568, 570–584 have suggested roles for systemic CRP, fibrinogen, leukocytes, TNF-α, IL-6 and IL-8 in COPD and its exacerbations, but more longitudinal randomised controlled studies with larger sample sizes are needed to confirm their specificity and sensitivity as biomarkers in patients with reduced lung function 441.

Regulatory issues

Many drugs are now in development as potential anti-inflammatory therapies for COPD 585. However, as there is no effective anti-inflammatory treatment for COPD, it is uncertain how much and how rapidly clinical parameters will change in patients. This makes it important to develop reliable biomarkers to quantify inflammation in COPD patients and to validate these against some other measure of disease activity and progression. For assessment of anti-inflammatory treatments it is important to identify biomarkers that indicate the efficacy of the drug on components of the inflammatory process before proceeding to large and prolonged clinical trials. Biomarkers can facilitate drug development in a number of ways, such as: 1) providing evidence that a drug can reach its target and modify that target in some positive way; 2) identifying criteria for dose selection for phase-2 and -3 studies; 3) providing “go-no-go” decisions at early stages of the drug-development process; 4) identifying populations that are more likely to benefit from a drug; and 5) predicting safety problems.

There are several types of drugs that can be developed for COPD based on whether the drug is intended to improve airflow obstruction, provide symptom relief, modify or prevent exacerbations, alter disease progression, or modify lung structure. The efficacy end-points that are currently used in phase-3 studies to support registration of a drug for COPD are based on measures that translate to direct benefit of some aspects of the disease that is important to patients, such as improvement of symptoms, functional capacity, HRQoL or survival. With the possible exception of drugs that are intended to improve airflow obstruction, whose efficacy can be relatively easily assessed by measuring FEV₁ in short-term studies, drugs of other types are likely to require prolonged studies, often extending to many years. These studies become rather risky and expensive endeavours and this further underscores the need for the development of biomarkers.

The biomarkers described elsewhere in the present report are not sufficiently validated to date for use as evidence of efficacy in phase-3 studies or for supporting specific labelling claims. Nevertheless, these biomarkers are reflective of the disease and have potential use for regulatory purpose. Carefully selected biomarkers with or without a patient-centred clinically meaningful end-point can be used in early phase studies, such as proof-of-action or proof-of-concept studies, based on which a rational decision can be made on further development of the drug. Biomarkers can also be used in either early phase studies or phase-3 studies to support the drug's putative mode of action. In addition, use of the biomarkers in phase-3 studies in conjunction with clinically meaningful end-points may help validate the use of the biomarker, or even help elevate a biomarker to a surrogate end-point status.

Conclusions

Although many pulmonary biomarkers have been described in COPD patients, there is little information regarding reproducibility and correlation with other outcome measurements in COPD (i.e. dyspnoea, HRQoL, exacerbation frequency and mortality). In the future, these biomarkers need to be assessed in normal smokers and age-matched normal subjects and linked to disease stage (and rate of FEV₁ decline), clinical phenotype (emphysema versus small airway disease), smoking status (current versus ex-smokers), clinical status (stable versus exacerbation) and treatment (effect of corticosteroids, theophylline, etc.). Further research in this area is important as pulmonary biomarkers may be useful in the future for predicting clinical outcomes of COPD and for assessing new therapies which may modify the inflammatory/destructive disease process.