INHALED STEROIDS FOR COPD?

Transcription

1 Thorax 2001;56(Suppl II):ii2 ii6 INHALED STEROIDS FOR COPD? A E Tattersfield, T W Harrison ii2 * Division of Respiratory Mediine, City Hospital, Nottingham NG5 1PB, UK A E Tattersfield T W Harrison Correspondene to: Professor A E Tattersfield Introdutory artiles Randomised, double blind, plaebo ontrolled study of flutiasone propionate in patients with moderate to severe hroni obstrutive pulmonary disease: the ISOLDE trial P S Burge, P M A Calverley, P W Jones, S Spener, J A Anderson, T K Maslen on behalf of the ISOLDE study investigators Objetives: To determine the effet of long term inhaled ortiosteroids on lung funtion, exaerbations, and health status in patients with moderate to severe hroni obstrutive pulmonary disease. Design: Double blind, plaebo ontrolled study. Setting: Eighteen UK hospitals. Partiipants: 751 men and women aged between 40 and 75 years with mean fored expiratory volume in one seond (FEV 1 ) 50% of predited normal. Interventions: Inhaled flutiasone propionate 500 µg twie daily from a metered dose inhaler or idential plaebo. Main outome measures: Effiay measures: rate of deline in FEV 1 after the bronhodilator and in health status, frequeny of exaerbations, respiratory withdrawals. Safety measures: morning serum ortisol onentration, inidene of adverse events. Results: There was no signifiant differene in the annual rate of deline in FEV 1 (p=0.16). Mean FEV 1 after bronhodilator remained signifiantly higher throughout the study with flutiasone propionate ompared with plaebo (p=0.001). Median exaerbation rate was redued by 25% from 1.32 a year on plaebo to 0.99 a year with flutiasone propionate (p=0.026). Health status deteriorated by 3.2 units a year on plaebo and 2.0 units a year on flutiasone propionate (p=0.0043). Withdrawals beause of respiratory disease not related to malignany were higher in the plaebo group (25% v 19%, p=0.034). Conlusions: Flutiasone propionate 500 µg twie daily did not affet the rate of deline in FEV 1 but did produe a small inrease in FEV 1. Patients on flutiasone propionate had fewer exaerbations and a slower deline in health status. These improvements in linial outomes support the use of this treatment in patients with moderate to severe hroni obstrutive pulmonary disease. (BMJ 2000;320: ) Sputum eosinophilia and short-term response to prednisolone in hroni obstrutive pulmonary disease: a randomised ontrolled trial C E Brightling, W Monteiro, R Ward, D Parker, M D L Morgan, A J Wardlaw, I D Pavord Bakground: Some patients with hroni obstrutive pulmonary disease (COPD) respond to ortiosteroid therapy. Whether these patients have different airway pathology from other COPD patients is unlear. We tested the hypothesis that response to prednisolone is related to the presene of eosinophili airway inflammation. Methods: We did a randomised, double-blind, rossover trial. Patients who had COPD treated with bronhodilators only were assigned plaebo and 30 mg prednisolone daily for 2 weeks eah, in a random order, separated by a 4-week washout period. Before and after eah treatment period, we assessed patients with spirometry, symptom sores, the hroni respiratory disease questionnaire (CRQ), inremental shuttle walk test, and indued sputum. Analysis was done by intention to treat. Findings: 83 patients were reruited, of whom 67 were randomised. The geometri mean sputum eosinophil ount fell signifiantly after prednisolone (from 2.4% to 0.4%; mean differene sixfold [95% CI ]) but not after plaebo. Other sputum ell ounts did not hange. After stratifiation into tertiles by baseline eosinophil ount, postbronhodilator fored expiratory volume in 1 s (FEV 1 ) and total sores on the CRQ improved progressively after prednisolone from the lowest to the highest eosinophili tertile, ompared with plaebo. The mean hange in postbronhodilator FEV 1, total CRQ sore, and shuttle walk distane with prednisolone ompared with plaebo in the highest tertile was 0.19 L ( ), 0.62 ( ), and 20 m (5 35), respetively. Interpretation: Our findings suggest that eosinophili airway inflammation ontributes to airflow obstrution and symptoms in some patients with COPD and that the short-term Thorax: first published as on 1 September Downloaded from on 13 June 2018 by guest. Proteted by opyright.

2 Inhaled steroids for COPD? effets of prednisolone are due to modifiation of this feature of the inflammatory response. The possibility that sputum eosinophilia identifies a subgroup of patients who partiularly respond to long-term treatment with inhaled ortiosteroids should be investigated. (Lanet 2000;356: ) Bakground Chroni obstrutive pulmonary disease (COPD) avets at least people in the UK and is the fifth most ommon ause of death. 1 It results from the inflammatory response in the lung that follows exposure to noxious gases and partiles, partiularly igarette smoke, and is haraterised by progressive airflow obstrution that varies little from day to day or in response to bronhodilators or ortiosteroids. The main pathologial features are hroni inflammation and strutural hanges in the airways, and emphysema due to the body s inability to ounter the inreased release of protease enzymes from neutrophils and marophages. Although hroni airway inflammation is found in both asthma and COPD, the nature of the inflammation divers. Eosinophils, mast ells and lymphoytes, partiularly CD4 T ells, predominate in asthmati airways whereas the inflammatory response in COPD is dominated by neutrophils, partiularly in more severe disease, with some inrease in marophages and lymphoytes, predominantly CD8 ells. 2 Cigarette smoking is the most important ause of COPD, but only a relatively small proportion of smokers develop linially important airflow obstrution. The rate of deline in fored expiratory volume in 1 seond (FEV 1 ) is used to predit suh patients, with values ranging from 30 ml/year or less in healthy subjets to over 100 ml/year in some heavy smokers. 3 There is marked heterogeneity in the FEV 1 response between smokers, however, showing that fators other than igarette smoke help to determine the rate of deline in FEV 1, inluding other exogenous fators suh as air pollution and oupational exposures. Endogenous fators are also important and inlude, at a mehanisti level, alpha-1 antitrypsin defiieny 4 and the MZ phenotype, 5 sputum neutrophilia, 6 plasma ortisol onentrations, 7 and a poor response to bronhodilators. 8 Duth workers in the 1960s suggested that patients with asthma and smokers with irreversible COPD shared a ommon allergi predisposition and bronhial hyperresponsiveness (known as the Duth hypothesis ). 9 Several studies have looked at the assoiation between smoking, rate of deline in FEV 1, and features of allergy and, although the findings are somewhat variable, in general smoking has been assoiated with higher eosinophil ounts and inreased IgE levels A low FEV 1 and inreased rate of deline in FEV 1 have also been assoiated with higher blood eosinophil ounts and IgE levels and positive skin tests in some but not all studies. Bronhial responsiveness to non-speifi stimuli suh as histamine shows a lose orrelation with FEV 1 in subjets with COPD, refleting the dependene of bronhial responsiveness measurements on airway alibre. After ontrolling for baseline lung funtion, however, bronhial responsiveness has been shown to predit the subsequent rate of deline in FEV 1 in several large studies There is still debate as to whether the inrease in bronhial responsiveness is responsible for the aelerated fall in FEV 1, as antiipated by the Duth hypothesis, or whether it mirrors the fall in FEV 1 beause of its dependene on airway geometry. The latter suggestion was supported by a four year follow up of 27 patients with COPD in whih both perentage predited FEV 1 and bronhial responsiveness remained stable in patients who stopped smoking but both fell in parallel in those who ontinued to smoke. 20 Any treatment that is able to redue the rate of deline in FEV 1 will postpone the time when patients develop exerise limitation and symptoms. So far only smoking essation has been shown to be evetive. 21 Sine the inflammatory response within the lung appears to be responsible for the damage to airways and alveoli, a treatment that redued the inflammatory response would be expeted to redue the rate of deline in FEV 1. Sine inhaled ortiosteroids redue inflammation in asthma, the question of whether they might redue inflammation and hene the deline in FEV 1 in patients with COPD has been pursued. The ISOLDE study The study by Burge and olleagues (ISOLDE study, introdutory artile 1) is one of four plaebo ontrolled studies that have addressed the question of whether regular use of an inhaled ortiosteroid an redue the rate of deline in FEV 1 in patients with COPD. A meta-analysis of 95 patients in three small studies had given equivoal results. 26 In the ISOLDE study the evet of a relatively large dose of flutiasone propionate (1000 µg/day) and plaebo were ompared in 751 subjets with moderately severe COPD (mean age 64 years, mean post-salbutamol FEV l); the main end point was the rate of deline of post-bronhodilator FEV 1. Before starting treatment with flutiasone or plaebo, subjets reeived oral prednisolone 0.6 mg/kg/day for 2 weeks and this was assoiated with a mean inrease in post-bronhodilator FEV 1 of 60 ml. Three months into the study the mean post-bronhodilator FEV 1 had fallen below the pre-prednisolone baseline level in the plaebo group but remained above the baseline level in the subjets taking flutiasone. However, there was no diverene between the two groups in the deline in post-bronhodilator FEV 1 over the 3 years of the study. With respet to seondary end points, flutiasone was assoiated with a smaller deline in health status (assessed with the St George s respiratory questionnaire), fewer exaerbations (defined as a requirement for oral ortiosteroids and/or antibiotis; 0.99 v 1.32/year), and fewer withdrawals due to non-malignant respiratory disease (19% v 25%). These findings need to be ompared with those in the other three studies that have looked at the evet of regular inhaled ortiosteroid use on deline in FEV 1 in patients with COPD All four studies were large and of at least 3 years duration, but there were some diverenes in methodology, patient entry riteria, and dose of inhaled ortiosteroid as shown in table 1. Despite these diverenes, all four studies showed no benefit from the inhaled ortiosteroid for the main end point that is, rate of deline in FEV 1 (table 2). Both the ISOLDE and EUROSCOP studies showed a small initial inrease in FEV 1 in the inhaled ortiosteroid group but this was not seen in the other two studies. The inhaled ortiosteroid had no signifiant evet on any seondary end point in the study by Vestbo et al, 24 but triaminolone was assoiated with a small redution in symptoms, unsheduled physiian visits for respiratory problems, and bronhial responsiveness in the Lung Health Study. 25 Some systemi adverse evets were evident in three of the four studies an inrease in bruising, a redution in morning serum *ii3 Thorax: first published as on 1 September Downloaded from on 13 June 2018 by guest. Proteted by opyright.

3 Tattersfield, Harrison Table 1 Details of four long term plaebo ontrolled studies looking at effet of inhaled ortiosteroids on deline in FEV 1 ii4 * Study No of patients, withdrawals (%), mean age, study duration (years) Dose inhaled steroid (µg/day) and devie ortisol levels in the ISOLDE study, and a redution in bone mineral density in the Lung Health Study 25 but not in the EUROSCOP study. 23 These four studies have therefore answered the primary question they addressed by showing learly that inhaled ortiosteroids do not have any worthwhile evet on the rate of deline in FEV 1 in patients with COPD. That leaves us with the seondary end points suh as symptoms, measures of health status, and exaerbations. Of the two studies reporting symptoms, Vestbo et al 24 found no diverene between groups whereas the Lung Health Study 25 found a small redution in some symptoms, although this did not translate into any improvement in health status. In ontrast, the ISOLDE study showed a smaller deline in health status in the inhaled ortiosteroid group. 22 Exaerbations were reported in two of the studies, with no diverene between groups in the Copenhagen study 24 ompared with a redution of 0.33 exaerbations/year with flutiasone in the ISOLDE study. 22 No redution in exaerbations had been seen in an earlier 6 month study although their severity appeared to be redued with flutiasone. 27 There are some important diverenes between the ISOLDE study and the other three long term studies whih might aount for some of the diverenes in seondary outomes. The dose of inhaled ortiosteroid was high in the ISOLDE study and the patients were older and had more severe COPD; the plaebo group therefore had more exaerbations and the study had more power to detet a diverene in exaerbations. Bronhodilator reversibility was also fairly high, raising the question of whether the ISOLDE study inluded more subjets with an element of asthma, in addition to smoking related COPD, than the other studies. This also raises the question of whether there is a small Mean FEV 1 Bronhodilator (% predited) reversibility in postbronhodilator ml (% of baseline)* Rate of deline in FEV 1 (ml/year) Ative Plaebo Differene (95% CI) p value Burge et al (2000) ; 48%; 64; 3 Flutiasone (10%) ( 20 to 3) 0.16 µg; MDI + spaer Pauwels et al (1999) ; 29%; 52; 3 Budesonide (3.6%) (no 95% CI) 0.39 µg; Turbuhaler Vestbo et al (1999) ; 30%; 59; 3 Budesonide (7.7%) ( 19 to 13) µg for 0.5 years, 800 µg for 2.5 years; Turbuhaler Lung Health Study Researh Group (2000) ; 6%; 56; 3.3 (mean) Triaminolone 1200 µg; MDI (6.65%) ( 11 to 5) 0.5 FEV 1 = fored expiratory volume in one seond; MDI = metered dose inhaler; CI = onfidene interval. *Calulated from FEV 1 values in papers (after salbutamol 400 µg or terbutaline 1 mg ). Table 2 subgroup of patients who might benefit in terms of redued exaerbations and symptoms within the COPD population and whether suh patients an be identified. The study by Vestbo and olleagues, 24 the most onviningly negative of the four studies, was the only one to exlude patients if they had a 15% inrease in FEV 1 in response to a 10 day ourse of prednisolone. Sputum eosinophils and response to prednisolone Brightling et al 28 addressed the question of how the linial response to prednisolone 30 mg daily for 2 weeks relates to sputum eosinophil ount in patients with COPD, studying 67 patients (mean age 66 years, mean FEV l) in a plaebo ontrolled rossover study. Prednisolone was assoiated with a sixfold redution in sputum eosinophil ount (no hange after plaebo) and a signifiant inrease in various end points, although the magnitude of these evets was small ompared with plaebo (150 ml for post-bronhodilator FEV 1 ; 12 m for shuttle walk distane). When patients were divided into tertiles aording to their initial sputum eosinophil ount the response to prednisolone was greatest in those with the highest eosinophil ount, but the diverene between the highest and lowest tertiles was still fairly modest (190 ml for FEV 1 ; 20 m for the shuttle test). The findings are similar to those seen in a previous smaller study. 29 Although sputum eosinophilia has been assoiated with a greater bronhodilator response and inreased exhaled nitri oxide (NO), 30 Brightling and olleagues disount mislassifiation by asthma to aount for their findings sine they went to some lengths to exlude patients with asthma, Effet of an inhaled ortiosteroid in patients with COPD in four long term plaebo ontrolled studies Burge et al 22 (ISOLDE) Pauwels et al 23 (EUROSCOP) Vestbo et al 24 Lung Health Study 25 Effiay variables: Primary Deline in FEV 1 No effet No effet No effet No effet Seondary Symptoms NR NR No effet Fewer new symptoms, dyspnoea slightly less Exaerbations Redued (25%)* NR No effet NR Quality of life Smaller deline with ICS NR NR No differene overall (1 of 8 worse with ICS) Visits to A&E, physiians NR NR NR No effet on A&E or total visits, unsheduled dotor visits redued by ICS Bronhial responsiveness NR NR NR Redued Adverse effets: Morning ortisol Redued NR NR NR Bone mineral density NR No effet (n=194) NR Redued (n=359) Bruising Inreased (signifiane not given) Inreased NR Inreased Thorax: first published as on 1 September Downloaded from on 13 June 2018 by guest. Proteted by opyright. NR = not reported; ICS = inhaled ortiosteroid. *Also redued withdrawals for non-malignant respiratory onditions (19% v 25%).

4 Inhaled steroids for COPD? Learning points Inhaled ortiosteroids do not alter the deline in FEV 1 in patients with COPD who ontinue to smoke. Inhaled ortiosteroids may have a small effet on other linial end points although the findings in different studies have not been onsistent. Whether this is due to differenes in drug, dose, or patients studied is not lear. Nor is it lear whether any suh effet ours in a small subgroup with some features of asthma. Patients with COPD who have eosinophils in their sputum but without other features of asthma are more likely to show a linial response, albeit modest, to 30 mg prednisolone for 2 weeks. Whether suh patients benefit from regular inhaled ortiosteroids has not been shown. COPD is a large publi health problem so any small benefits from inhaled ortiosteroids in COPD need to be weighed arefully against potential adverse effets in this group of patients. Before their widespread use an be reommended, more information is needed on whether a high dose is needed to obtain benefit, the balane of benefiial and adverse effets in relation to dose, and whether a subgroup who benefit an be identified. These studies are a reminder that smoking essation is the only intervention that has been shown to affet the underlying disease proess in COPD and redue the deline in lung funtion over time. inluding anyone with respiratory problems during hildhood. Furthermore, the range of eosinophil ounts appears to have a reasonably normal distribution, suggesting that the patients were a fairly homogeneous group. A more likely explanation aording to the authors is that smoking, whilst reruiting neutrophils to the airways, also reruits eosinophils but to a varying extent between patients. They also question whether COPD might start as an eosinophili bronhitis, and that this is assoiated with a more rapid deline in FEV 1 and the development of COPD. Brightling and olleagues question whether indued sputum might be used to identify patients who would be more likely to benefit from an inhaled ortiosteroid. They showed an inrease in FEV 1 with prednisolone as was seen at the start of the ISOLDE study, and it may well be that muh of the small early inrease in FEV 1 seen in the ISOLDE and EUROSCOP studies was due to a subgroup of patients with sputum eosinophilia. However, the patients in the ISOLDE study who responded to prednisolone did not show a redued rate of deline in FEV 1 nor, as far as is reported, any other long term benefit. The measurement of sputum eosinophils annot therefore yet be justified as a useful linial measure. A further onsideration would be whether the test s repeatability, whih is reasonable when arried out in speialist entres, an be maintained if it were to be used more widely. Clinial impliations The ruial question, oming bak to the longer term studies, is whether inhaled ortiosteroids should be presribed to patients with COPD on the basis of the benefit seen in some of the seondary end points in the ISOLDE and Lung Health studies. The benefiial evets have not been entirely onsistent between studies and are at best relatively modest, so they have to be balaned against the ost of treatment and the risk of systemi adverse evets from high dose inhaled ortiosteroids in this group of patients. The duration of treatment will, in general, be less in COPD than in asthma, but patients with COPD are older and hene already at risk of problems suh as atarats and osteoporoti frature. The risk is likely to be less with drugs that have a high first pass metabolism suh as flutiasone and budesonide when ompared with triaminolone, 31 and this may explain why a redution in bone mineral density was deteted in the Lung Health study but not in the EUROSCOP study. Little is known about the extent of pulmonary absorption of diverent inhaled ortiosteroids in patients with COPD. Taken together, the studies suggest that there probably are some small benefits from the long term use of inhaled ortiosteroids, but they also suggest that a high dose of inhaled ortiosteroid may be required to ahieve these evets and it is not lear whether it is only a subgroup of patients within the COPD population who benefit. Although the most onvining evidene of benefit omes from the ISOLDE study, this is still very modest, bearing in mind that publiations invariably emphasise positive results and this study had the highest withdrawal rate. For example, exaerbations were only redued by 0.33/year by flutiasone that is, one exaerbation every 3 years. This ompares with a redution of 0.79 exaerbations/year with oral muolyti drugs in a reent meta-analysis. 32 If a high dose of inhaled ortiosteroid is required to ahieve these small evets, it is diyult to justify their use for patients with mild to moderate COPD or, indeed, for the small redution in frequeny of exaerbations seen in the ISOLDE study. Can they be justified on the basis of the quality of life data from this study? 33 This is also diyult sine the Lung Health Study, whih was slightly larger, showed no benefit in quality of life measures and a small euphoriant evet from flutiasone annot be exluded, partiularly as the questionnaire was unable to detet a diverene in health *ii5 Thorax: first published as on 1 September Downloaded from on 13 June 2018 by guest. Proteted by opyright.

5 Tattersfield, Harrison ii6 * status between patients who ontinued to smoke and those who stopped. It may be that patients with more severe COPD, those having more frequent exaerbations, and those with sputum eosinophilia would benefit more from an inhaled ortiosteroid, but these questions need to be answered before drugs that are ostly and may have adverse evets are reommended for widespread use. COPD is a very large publi health problem and more information is needed, partiularly on the evet of diverent doses of inhaled ortiosteroids on linial end points, health status, and adverse evets so that any benefits an be plaed in perspetive. Perhaps the most important message from these studies is that more evetive treatment is needed for patients with COPD. Having said that, no drug an or is ever likely to produe anything like the benefiial health evets seen with smoking essation. The authors thank Rihard Hubbard for omments on the manusript. 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