The Proceedings of the American Thoracic Society 1:167-170 (2004)
© 2004 The American Thoracic Society
Clinical Effects of Inhaled Corticosteroids in Chronic Obstructive Pulmonary Disease
Paul W. Jones
St. George's Hospital Medical School, London, United Kingdom
Correspondence and requests for reprints should be addressed to Paul W. Jones, M.B.B.S., Ph.D., F.R.C.P., Professor of Respiratory Medicine, St. George's Hospital Medical School, London SW 17 0RE, UK. E-mail pjones{at}sghms.ac.uk
 |
ABSTRACT
|
|---|
Chronic obstructive pulmonary disease (COPD) has multiple pathophysiologic effects that are not confined to the lungs. Similarly, treatment for COPD may have a number of different beneficial effects, and although each of these may be small, their cumulative effect may add up to a worthwhile overall outcome. Many of the effects of COPD are only weakly related to FEV1, and there is good evidence that health status questionnaires are the best overall measures of disease severity. Recently it has been shown, using such instruments, that health status in patients with COPD deteriorates progressively and at a measurable rate. Fluticasone reduces that decline, an effect that may take months to be detectable but continues to develop over 3 years. The effect of fluticasone on health appears to be due to a reduction in exacerbations coupled with its small effect on FEV1.
Key Words: dyspnea • exacerbations • health status
|
EFFECTS ON DYSPNEA
|
|---|
Chronic obstructive pulmonary disease (COPD) results from multiple pathophysiologic processes in the lungs, but it is also a multisystem disease with structural and functional changes taking place in other organs. Breathlessness is the characteristic symptom of COPD, and it has a complex etiology linked to the work of breathing (1, 2). However, while expiratory airflow limitation is the prime characteristic of COPD, bronchodilator-induced reductions in breathlessness at rest have been shown to correlate better with changes in forced inspiratory flow than with changes in FEV1 (3). During exercise, the reduction in breathlessness after bronchodilator treatment correlates better with improvement in inspiratory capacity than with improvement in FEV1 (4, 5). For this reason, breathlessness should be measured, rather than inferred from surrogates. Direct measurements of breathlessness require a laboratory setting, but the impact of breathlessness on daily life (i.e., respiratory-induced disability) can be assessed using methods such as the Baseline Dyspnea Index (BDI) and the Transitional Dyspnea Index (TDI) (6).
There have been relatively few studies of the effect of inhaled corticosteroids (ICSs) in COPD on dyspnea. However, a recent study of a fluticasone/salmeterol combination provided data on dyspnea measured using the TDI in patients who received fluticasone alone (7). At the end of 6 months, the benefits with this combination compared with those of placebo were at the threshold of clinical significance using this instrument, TDI score: fluticasone 1.3 units; placebo 0.4 units (p = 0.002). Two phases of response could be seen: an initial improvement over the first week, then a slower progressive improvement of a slightly smaller magnitude. The time course and magnitude of improvement were almost identical to the results seen in the salmeterol arm of the same study.
|
EFFECTS ON EXACERBATIONS
|
|---|
Exacerbations are an important feature of COPD, and their frequency increases with disease severity (8), although patients appear to underreport them (9). In patients with moderate to severe COPD, prospective data collection with diary cards revealed a median exacerbation rate of three per year, with a range of one to eight per year (9). Following a single exacerbation, lung function can take several weeks to recover (10), and recovery of health status can take even longer (11). Exacerbation frequency is clearly an important factor in this disease.
A 6-month study of fluticasone showed a reduction in the severity of COPD exacerbations (12), but the true effect of an ICS on exacerbations became apparent only after the results of the 3-year ISOLDE study (Inhaled Steroid in Obstructive Lung Disease in Europe) of fluticasone (13) and subsequent 1-year studies of ICS plus long-acting ß2-agonist (14, 15). On average, fluticasone reduced the exacerbation rate by about 25% compared with placebo (13, 14), and budesonide reduced the rate by 15% compared with placebo (15).
There are a number of major outstanding issues concerning ICS and exacerbations. The first is the definition of an exacerbation. There is no universal agreement, but the major ICS studies have used an operational definition based upon a worsening of symptoms and the treatment required: moderate exacerbations are those that can be treated with oral corticosteroids and/or antibiotics, severe exacerbations are those requiring hospital admission. This method of classification does not identify the type of exacerbation. It is not clear, therefore, whether ICS have the same mechanism of action in preventing exacerbations as the long-acting ß2-agonists or tiotropium. The three 1-year trials of ICS plus ß2-agonist show a consistent pattern—the exacerbation rate was lower with the combination of these two agents than when either was given alone (14–16). There are a number of possible mechanisms to account for this apparent additive effect: (1) The individual drugs were not at the top of their dose–response curve for this outcome; (2) They have different, and additive, mechanisms of action; or (3) The different agents were preventing different types of exacerbation. Nothing is known of the effect of ICS on the severity of exacerbations, although in one 6-month placebo-controlled study of fluticasone, there were more mild exacerbations (self managed by patient at home) in the fluticasone group, but fewer moderate and severe exacerbations (12). One interpretation of this result is that fluticasone reduced the severity of exacerbations. This important observation requires confirmation.
|
EFFECTS ON HEALTH STATUS
|
|---|
Impaired health in COPD results from the cumulative effect of many different disease processes (Figure 1). However, this means that there are also multiple points at which therapy may have an effect. Although none of these effects may be very large, they may be cumulative. Health impairment is largely reflected in patients' symptoms and their account of the effects of the disease on their bodily functions, daily activity, and sense of well-being. Quantification of the level of patients' health impairment, to produce a numerical estimate of their health status, is achieved through the use of carefully designed questionnaires, such as the St. George's Respiratory Questionnaire (SGRQ), which is widely used to assess the effects of pharmacologic treatment, and the Chronic Respiratory Questionnaire (CRQ), which is used extensively in rehabilitation. There is now a large body of evidence that health status instruments provide a valid estimate of the impact of the disease (17), including the fact that SGRQ scores are significant predictors of death in COPD, even after age, FEV1, and body mass index have been taken into account (18, 19). These questionnaires are perhaps one of the best measures of the overall impact of COPD on the patient's health and well-being. They produce information that is entirely complementary to FEV1, because the correlation between them and FEV1 is weak, both between and within patients (17). In fact, the FEV1 is one of the poorest physiologic correlates of health status (17). By contrast, exercise performance and dyspnea are much stronger correlates. This is reviewed extensively elsewhere (17).
COPD is characterized by progressive deterioration. FEV1 in individuals with COPD declines faster than in those without COPD, and it is now known that health status declines at a measurable rate (20). In patients with a mean postbronchodilator FEV1 of 50% predicted value who were treated with a bronchodilator alone, the SGRQ score deteriorated at a rate of 3.2 units per year (20). This is much faster than would have been expected from the age-associated worsening of SGRQ score reported from a cross-sectional study of subjects without COPD (21). The mechanisms of the deterioration have yet to be fully established, although the rate of decline in FEV1 and the exacerbation frequency have both be shown to be factors (22).
The effects of ICS on health status appear to be complex. Analysis of data from the ISOLDE study (13) showed no significant difference between treatment groups after 6 months, although the placebo-treated patients deteriorated by a small amount (
1 unit on the SGRQ) and the fluticasone-treated patients improved by about the same amount. It is a little difficult to interpret these results, because nearly all patients had received a 2-week course of prednisolone 0.6 mg/kg before starting the study medication. More recently, measurements of health status were made soon after initiation of ICS therapy given without oral corticosteroids (14). Differences from placebo may be apparent after 2 weeks of treatment (Figure 2), the time course of this effect being same as that seen with salmeterol (14). These initial gains may not be sustained over the longer term because of the progressive deterioration that occurs over time (20). However, when measured over 3 years in the ISOLDE study (13), fluticasone did slow the overall rate of deterioration in COPD compared with placebo by approximately 40% (Figure 3).
View larger version (19K):
[in this window]
[in a new window]
|
Figure 2. Changes in health status measured using the SGRQ during the first 8 weeks of treatment with fluticasone. A reduction in SGRQ score indicates improvement. A four-unit change is clinically significant. Adapted by permission from Calverley and coworkers (14).
|
|
View larger version (17K):
[in this window]
[in a new window]
|
Figure 3. Changes in health status measured using the SGRQ score with placebo and fluticasone (p = 0.003). A rising score indicates worsening health status. A four-unit change is clinically significant. Adapted by permission from Burge and colleagues (13).
|
|
|
POSSIBLE MECHANISMS OF HEALTH GAIN DUE TO ICS
|
|---|
The time course of changes in health status with ICSs suggests the presence of at least two different mechanisms. The short-term changes seem to be related to improved airway function, which can be detected within 1 week of treatment initiation (14, 15), as well as to improvements in breathlessness over the same period (7). The long-term effect of ICSs on health in COPD appears to be due to a different mechanism. The most striking observation from the ISOLDE study is that the difference in the health status of placebo- and fluticasone-treated patients became progressively wider over time (Figure 3). This difference suggests a benefit that takes time to accumulate, and the most obvious candidate mechanism is a reduction in exacerbations. A recent re-analysis of the ISOLDE data suggests that this is the case: most of the reduction in the rate of deterioration in health status is attributable to the effect of fluticasone on reducing exacerbations (22) .
A model of the relationship between COPD exacerbations and health status decline is shown in Figure 4. It reflects ISOLDE data showing that health status deteriorates over time even in patients who have no exacerbations (mean reduction in SGRQ score 1.9 units/year). In patients who experience exacerbations less than 1.5 times a year, the decline in health status is greater (mean reduction in SGRQ score 2.4 units/year). In the model, I have assumed that health deteriorates between exacerbations at the same rate in all patients, by 1 SGRQ unit on each occasion. That figure is based on the known magnitude and time course of recovery from acute exacerbations (11). It is only a very small proportion ( 5%) of the acute effect, and only a quarter of the change detectable clinically by a patient or physician (23). This model shows how failure to recover by only a very small amount could produce the cumulative effect implied by the measured faster rate of deterioration that occurs even in patients who experience exacerbations only once per year.
View larger version (22K):
[in this window]
[in a new window]
|
Figure 4. Model of health status changes over time in two patients, one with no exacerbations and one with a single exacerbation per year. A rising score indicates worsening health status.
|
|
|
CONCLUSIONS
|
|---|
ICSs have only a small effect on FEV1, but this therapy is associated with a worthwhile reduction in exacerbations, improvement in dyspnea, and health status benefits. The time course and magnitude of the early symptomatic responses to ICSs is similar to those of long-acting bronchodilators. Long-term use of ICSs reduces the progressive rate of deterioration in health that characterizes COPD, apparently because it reduces the number of exacerbations.
|
ACKNOWLEDGMENTS
|
|---|
P.W.J. has held a consultancy agreement with GlaxoSmithKline (GSK) and sat on Advisory Boards for GSK, Novartis, and AstraZeneca (AZ); in each case the fees have been less than $5,000 p.a.; and has received fees for speaking at conferences and symposia organized by GSK, Boehringer Ingelheim, Pfizer, Novartis, and AZ, receiving less than $5,000 p.a. per company year; and has presented as an expert witness for Boehringer Ingelheim and currently receives grants from Boehringer and GSK.
(Received in original form February 18, 2004; accepted in final form September 21, 2004)
|
REFERENCES
|
|---|
- Killian KJ, Jones NL. Respiratory muscles and dyspnea. Clin Chest Med 1988;9:237–248.[Medline]
- O'Donnell DE. Exertional breathlessness is chronic respiratory disease. In: Mahler DA, editor. Dyspnea. New York: Marcel Dekker; 1998. p. 97–147.
- Taube C, Burghart L, Paasch K, Kirsten DK, Jörres RA, Magnussen H. Factor analysis of changes in dyspnea and lung function parameters after bronchodilation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:216–220.[Abstract/Free Full Text]
- Belman MJ, Botnick WC, Shin JW. Inhaled bronchodilators reduce dynamic hyperinflation during exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996;153:967–975.[Abstract]
- O'Donnell DE, Lam M, Webb KA. Spirometric correlates of improvement in exercise performance after anticholinergic therapy in chronic obsructuve pulmonary disease. Am J Respir Crit Care Med 1999;160: 542–549.[Abstract/Free Full Text]
- Mahler DA, Weinberg DH, Wells CK, Feinstein AR. Measurements of dyspnea: contents, interobserver correlates of two new clinical indices. Chest 1984;85:751–758.[Abstract/Free Full Text]
- Mahler DA, Wire P, Horstman D, Chang C-N, Yates J, Fischer T, Shah T. Effectiveness of fluticsone proprionate and salmeterol combination delivered via the diskus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;166:1084–1091.[Abstract/Free Full Text]
- Jones PW, Willits LR, Burge PS, Calverley PMA. Disease severity and the effect of fluticasone proprionate on chronic obstructive pulmonary disease exacerbations. Eur Respir J 2003;21:1–6.[Free Full Text]
- Seemungal TAR, Donaldson GC, Paul EA, Bestall JC, Jefferies DJ, Wedzicha JA. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157:1418–1422.[Medline]
- Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161: 1608–1613.[Medline]
- Spencer S, Jones PW. Time course of recovery of health status following an infective exacerbation of chronic bronchitis. Thorax 2003;58:589–593.[Abstract/Free Full Text]
- Paggiaro PL, Dahle R, Bakran I, Frith L, Hollingworth K, Efthimiou J. Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. International COPD Study Group. Lancet 1998;351:773–780.[CrossRef][Medline]
- Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000;320:1297–1303.[Abstract/Free Full Text]
- Calverley PMA, Pauwels R, Vestbo J, Jones PW, Pride N, Gulsvick A. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease. Lancet 2003;361:449.[CrossRef][Medline]
- Szafranski W, Cukier A, Ramirez A, Menga G, Sansores R, Nahabedian S, Peterson S, Olsson H. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J 2003;21:74–81.[Abstract/Free Full Text]
- Calverley PMA, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J 2003;22:912–919.[Abstract/Free Full Text]
- Jones PW. Health status measurement in chronic obstructive pulmonary disease. Thorax 2001;56:880–887.[Abstract/Free Full Text]
- Domingo-Salvany A, Lamarca R, Ferrer M, Garcia-Aymerich J, Alonso J, Félez M, Khalaf A, Marrades RM, Monsó E, Serra-Batlles J, et al. Health-related quality of life and mortality in male patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;166:680–685.[Abstract/Free Full Text]
- Oga T, Nishimura K, Tsukino M, Sato S, Hajiro T. Analysis of the factors related to mortality in chronic obstructive pulmnary disease. Am J Respir Crit Care Med 2003;167:544–549.[Abstract/Free Full Text]
- Spencer S, Calverley PMA, Burge PS, Jones PW. Health status deterioration in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:122–128.[Abstract/Free Full Text]
- Ferrer M, Villasante C, Alonso J, Sobradillo V, Gabriel R, Vilagut G, Masa JF, Viejo JL, Jiménez-Ruiz CA, Miravitlles M. Interpretation of quality of life scores from the St George's Respiratory Questionnaire. Eur Respir J 2002;19:405–413.[Abstract/Free Full Text]
- Spencer S, Calverley PMA, Burge PS, Jones PW. Impact of preventing exacerbations on deterioration of health status in COPD. Eur Respir J 2004;23:1–5.[Free Full Text]
- Jones PW. Interpreting thresholds for a clinically significant changes in health status in asthma and COPD. Eur Respir J 2002;19:398–404.[Abstract/Free Full Text]
TOP
ABSTRACT
EFFECTS ON DYSPNEA
/
mismatch refers to decreasing ventilation and increasing cardiac output.