Inhaled corticosteroids, bone mineral density and fracture in older people
Hubbard R, Tattersfield A
Division of Respiratory Medicine, University of Nottingham, Nottingham, UK
The efficacy of inhaled corticosteroids in the treatment of asthma has been firmly established in a variety of settings. The majority of asthma management plans now recommend the use of inhaled corticosteroids at an early stage. This means that most patients with asthma will be prescribed an inhaled corticosteroid at some point in time and many patients with asthma will use these drugs for several years.Inhaled corticosteroids are also used in the treatment of other conditions, particularly chronic obstructive pulmonary disease (COPD). Since inhaled corticosteroids are absorbed into the systemic circulation, they can have systemic adverse effects, such as suppression of the hypothalamic-pituitary-adrenal axis and increasing the risk of bruising. However, perhaps the greatest concern for patients is whether the regular use of inhaled corticosteroids has an adverse impact on the bone mineral density and increases the risk of fracture. There is now accumulating evidence from epidemiological studies that the use of inhaled corticosteroids is inversely related to bone mineral density in a dose-dependent fashion. However, data from two clinical trials of moderately high doses of inhaled corticosteroids in patients with COPD have produced conflicting results and while the larger study of triamcinolone found a significant impact of this drug on bone mineral density, a smaller study of budesonide found no effect.Epidemiological research into the relationship between inhaled corticosteroids and fracture is at an early stage. To date, only three studies in this area have been reported, all of which have used different approaches to try to minimise the impact of bias and confounding. There is a lack of consistency between the final estimates of the impact of inhaled corticosteroids on fracture risk. However, taken together these data suggest that the short to medium term use of inhaled corticosteroids is associated with a small adverse effect on bone. Doctors and patients need to be aware of this risk and balance it against the known beneficial effects of inhaled corticosteroids.
Inhaled corticosteroids and the risk of a first exacerbation in COPD patients
de Melo MN, Ernst P, Suissa S
Dept of Epidemiology and Biostatistics, McGill University, Montreal, Quebec, Canada
The role of inhaled corticosteroids (ICS) in asthma is well established, but their benefit in the management of chronic obstructive pulmonary disease (COPD) is still controversial. The current study assessed whether ICS are effective in preventing a first exacerbation of COPD. A cohort of newly treated COPD patients was formed from the Administrative Databases of Saskatchewan Health. The outcome was the occurrence of a first moderate or severe exacerbation from 1990-1999. Moderate exacerbations involved prescriptions for an antibiotic and an oral corticosteroid on the same day. Severe exacerbations were hospitalisations with a primary discharge diagnosis of COPD. A nested case-control design was used and matched on year of birth and cohort entry. Rate ratios (RR) were further adjusted for use of other medication and other confounders. There were 995 exacerbations among 4,455 subjects. The rate of a first exacerbation was increased with any use of ICS in the year prior to the index date (RR: 1.27; 95% CI: 1.08-1.48) and with current use (RR: 1.51; 95% CI: 1.22-1.87), and it increased with increasing daily doses of ICS. Inhaled corticosteroids do not seem to be beneficial in reducing the risk of a first exacerbation of chronic obstructive pulmonary disease.
The presence of emphysema does not affect the systemic bioactivity of inhaled fluticasone in severe chronic obstructive pulmonary disease
Lee DK, Lipworth BJ
Asthma & Allergy Research Group, Department of Clinical Pharmacology, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, Scotland, United Kingdom
AIMS: To assess the systemic bioactivity of fluticasone proprionate (FP) 2000 micro g daily on sensitive adrenal and bone markers in severe chronic obstructive pulmonary disease (COPD) patients with or without significant emphysema. METHODS: Ten patients without emphysema (COPD group: age 55 years, FEV(1) 51% predicted and DL(CO) 83% predicted) and 10 patients with emphysema (COPDE group: age 59 years, FEV(1) 43% predicted and DL(CO) 49% predicted) received FP 2000 micro g daily via a spacer for 2 weeks. There was a 1-week washout period prior to FP treatment where patients were given salmeterol and oxitropium, after stopping their usual inhaled corticosteroids for the duration of the study. Measurements including overnight 10 h urinary cortisol excretion corrected for creatinine (OUCC) and serum osteocalcin concentrations were performed at baseline following washout and after 2 weeks of FP. RESULTS: Values for OUCC and serum osteocalcin concentrations pre- and post-FP were not significantly different between the COPD and COPDE groups. There was significant suppression of OUCC (nmol mmol(-1)) by FP treatment within the COPD group (P = 0.03): 7.86 vs 4.64 (95% CI on the difference 0.47, 5.98), and within the COPDE group (P = 0.006): 7.13 vs 4.27 (95% CI on the difference: 1.03, 4.69). Likewise, there was significant suppression of osteocalcin concentration (nmol l(-1)) by FP treatment within the COPD group (P = 0.04): 7.24 vs 6.34 (95% CI on the difference: 0.01, 1.78), and within the COPDE group (P = 0.03): 6.92 vs 5.72 (95% CI on the difference: 0.12, 2.29). CONCLUSIONS: Severe COPD patients who are receiving high dose FP are susceptible to the development of systemic adverse effects, irrespective of the presence of emphysema.
Inhaled corticosteroids in chronic obstructive pulmonary disease: is there a long-term benefit?
Highland KB
Division of Pulmonary, Critical Care, Allergy and Clinical Immunology, Medical University of South Carolina, Charleston, South Carolina, USA. highlakb@musc.edubr
PURPOSE OF REVIEW: The use of inhaled corticosteroids is one of the most controversial issues in COPD pharmacotherapy. Experts disagree about the benefits and harms of ICS for patients with COPD, yet a majority of patients with COPD are being treated with inhaled corticosteroids. This is a review of the most recent literature on this subject. RECENT FINDINGS: Evidence suggests that ICS, with or without a long-acting beta2-agonist, are cost-effective in reducing exacerbation rates and retarding the decline in health status of COPD patients, although they do not significantly modify the rate of decline in FEV1 or change mortality. This discrepancy is likely related to the differences in pathology of COPD when compared with asthma. Evidence also suggests that ICS may be safe regarding the effects on adrenals and bone mineral density. We have yet to identify reliable criteria for predicting a response to ICS in COPD, but it has become clear that in mild disease, no beneficial effect has been demonstrated. SUMMARY: In contrast to asthma, inhaled corticosteroids should not be used as a first-line medication in patients with COPD. Identification of patients with COPD who might benefit from long-term treatment with ICS remains paramount.
Inhaled corticosteroids in COPD: determinants of use and trends in patient persistence with treatment
Blais L, Bourbeau J, Sheehy O, LeLorier J
Centre de recherche, Centre hospitalier de l'Universite de Montreal-Hotel Dieu, Montreal, Quebec. lucie.blais@umontreal.ca
METHODS: The determinants of a new treatment with inhaled corticosteroids and secular trends in patient persistence with treatment among chronic obstructive pulmonary disease (COPD) patients were investigated. A cohort of 3768 physician-diagnosed, elderly COPD patients was selected between 1990 and 1996 from the health care administrative database of the Regie de l'assurance maladie du Quebec. A nested case-control design was used to identify patient and physician characteristics that were associated with a new treatment with inhaled corticosteroids. Treatment persistence with inhaled corticosteroids was also estimated using Kaplan-Meier analysis. In addition to that, changes in treatment persistence over time, from 1990 to 1995, were investigated by estimating the yearly proportion of patients persisting for less than one year. RESULTS: Within the cohort, the yearly percentage of patients filling at least one prescription for inhaled corticosteroids was 42.2% in 1990 and increased to 53.1% in 1995 (P=0.001). Using a conditional logistic regression model, it was found that the patients most likely to initiate a treatment with inhaled corticosteroids were those who had severe COPD (rate ratio [RR] 1.7; 95% CI 1.4 to 2.0), those who were hospitalized for COPD (RR 10.0; 95% CI 5.6 to 17.9), those who consulted a respirologist in the previous month (RR 2.3; 95% CI 1.6 to 3.3) or those who visited more than three different physicians in the previous three months (RR 1.6; 95% Cl 1.3 to 1.9). The proportion of patients persisting with inhaled corticosteroids for less than one year rose by 19.4%, from 47.6% in 1990 to 67.0% in 1995 (P=0.011; test for trend). CONCLUSIONS: The use of inhaled corticosteroids increased while patient persistence decreased between 1990 and 1995. Disease severity, as well as recent consultation to a respirologist and multiple visits to a physician, were associated with a strong likelihood of being prescribed inhaled corticosteroids. The cost of this practice is far from negligible, while their clinical impact is still uncertain.
Cost-effectiveness of inhaled corticosteroids for chronic obstructive pulmonary disease according to disease severity
Sin DD, Golmohammadi K, Jacobs P
Institute of Health Economics, Department of Medicine, University of Alberta, Edmonton, Canada. don.sin@ualberta.ca
PURPOSE: Inhaled corticosteroids reduce exacerbations in patients with chronic obstructive pulmonary disease (COPD), but their cost-effectiveness is not known. METHODS: We used a Markov model to determine, from a societal perspective, the cost-effectiveness of four treatment strategies involving inhaled corticosteroids: no use regardless of COPD severity; use in all disease stages; use in patients with stage 2 or 3 disease (forced expiratory volume in 1 second [FEV(1)] minor 50% of predicted); and use in patients with stage 3 disease (FEV(1) minor 35% of predicted). Data from the literature were used to estimate mortality, exacerbation, and disease progression rates, as well as the costs associated with care and quality-adjusted life-years (QALYs), according to disease stage and use or nonuse of inhaled corticosteroids. A time horizon of 3 years was used. RESULTS: Use of inhaled corticosteroids in patients with stage 2 or 3 disease was associated with a cost of 17,000 dollars per QALY gained. In stage 3 patients, use resulted in a cost of 11,100 dollars per QALY gained. Providing inhaled corticosteroids to all COPD patients was associated with a less favorable cost-effectiveness ratio. Results were robust to various assumptions in a Monte Carlo simulation. CONCLUSION: In patients with COPD, use of inhaled corticosteroids in those with stage 2 or 3 disease for 3 years results in improved quality-adjusted life expectancy at a cost that is similar to that of other therapies commonly used in clinical practice.
Inhaled corticosteroids with/without long-acting beta-agonists reduce the risk of rehospitalization and death in COPD patients
Soriano JB, Kiri VA, Pride NB, Vestbo J
Worldwide Epidemiology, GlaxoSmithKline Research and Development, Greenford, UK
INTRODUCTION: In patients with COPD who have recently been hospitalized for their disease, we examined whether treatment with inhaled corticosteroids without or with long-acting beta-adrenoceptor agonists (beta-agonists) reduced rehospitalization and mortality. STUDY DESIGN: Retrospective cohort analysis in the UK General Practice Research Database. METHODS: We compared rehospitalization for a COPD-related medical condition or death within 1 year after first hospitalization, in 3636 COPD patients receiving prescriptions for inhaled corticosteroids or long-acting beta-agonists compared with 627 reference patients with COPD who were prescribed short-acting bronchodilators only. RESULTS: Rehospitalization within a year occurred in 13.2% of the reference COPD patients, 14.0% of users of long-acting beta-agonists only, 12.3% of users of inhaled corticosteroids only, and 10.4% of users of inhaled corticosteroids and long-acting beta-agonists. Death within a year occurred in 24.3% of the reference COPD patients, 17.3% of users of long-acting beta-agonists only, 17.1% of users of inhaled corticosteroids only, and in 10.5% of users of inhaled corticosteroids and long-acting beta-agonists. In multivariate analyses the risk of rehospitalization or death was reduced by 10% in users of long-acting beta-agonists only (NS), by 16% in users of inhaled corticosteroids only, and by 41% in users of combined inhaled corticosteroids and long-acting beta-agonists (both p < 0.05). CONCLUSION: Use of inhaled corticosteroids with/without long-acting beta-agonists was associated with a reduction of rehospitalization or death in COPD patients.
Is there a role for systemic corticosteroids in the management of stable chronic obstructive pulmonary disease?
Wood-Baker R.
Royal Hobart Hospital & University of Tasmania, Hobart, Tasmania, Australia. Richard.WoodBaker@utas.edu.au
COPD, encompassing both chronic bronchitis and emphysema, usually results from exposure to tobacco smoke. Smoking causes infiltration of the airways with leukocytes, an imbalance between proteases and their naturally occurring inhibitors and local cytokine secretion in the lung, which leads to airway inflammation and alveolar destruction. Corticosteroids have a range of anti-inflammatory actions, particularly inhibition of cytokine secretion, which suggests that they may be effective in COPD. However, data from the highest quality studies available do not show any evidence of significant improvement in symptoms of patients with COPD treated with systemic corticosteroids.A meta-analysis found that about 10% of patients with stable COPD showed an improvement in lung function following treatment with short-term systemic corticosteroids compared with placebo. Exercise capacity in patients with COPD was evaluated in four studies, only one of which found a significant improvement with oral corticosteroids compared with placebo. Long-term systemic corticosteroid treatment in patients with stable COPD has not been found to alter the rate of decline in FEV(1). Although systemic corticosteroids are associated with a range of adverse effects, the data do not allow precise quantification of their contribution to morbidity. However, studies show an increased risk of osteoporosis in COPD. Recent studies have also found an association between oral corticosteroid administration and mortality in patients with stable COPD, but it is not clear if this is a cause and effect relationship.Current data do not support long-term administration of systemic corticosteroids to all patients with stable COPD. Results of studies suggest that short-term oral corticosteroid administration may identify a sub-population of patients with COPD who may benefit through a reduction in the decline in FEV(1) and better control of symptoms by long-term administration of inhaled corticosteroids; these findings need to be tested by further research.
Fracture risk associated with inhaled corticosteroid use in chronic obstructive pulmonary disease
Lee TA, Weiss KB.
MidwestCenter for Health Services and Policy Reseach, HinesVA Hospital, Hines, IL60141, USA. lee@research.hines.med.va.gov
Patients with chronic obstructive pulmonary disease (COPD) are frequently treated with inhaled corticosteroids (ICS). However, the impact of ICS use on fracture risk remains unclear in these patients. This nested case-control study examines the association between ICS use and nonvertebral fractures in Veterans Affairs patients with COPD. From a cohort of 40,157 patients with a COPD diagnosis between October 1, 1998 and September 30, 1999, and that used services in the preceding 12-month period but did not have a COPD diagnosis, 1,708 cases with nonvertebral fractures were identified and matched to 6,817 control patients. Patients were 94% male, and average age was 62.7 years. ICS exposure was identified through prescription records and converted to beclamethasone equivalents. In conditional logistic regression models, exposure to ICS at any time during follow-up was not associated with an increased fracture risk (adjusted odds ratio = 0.97; 95% confidence interval, 0.84-1.11). However, current high-dose ICS users (> or = 700 microg per day) had an increased risk of fractures compared with patients with no exposure (adjusted odds ratio = 1.68; 95% confidence interval, 1.10-2.57). In patients with COPD, current use of high-dose ICS was associated with an increased risk of nonvertebral fractures.
Inhaled corticosteroids reduce the progression of airflow limitation in chronic obstructive pulmonary disease: a meta-analysis
Sutherland ER, Allmers H, Ayas NT, Venn AJ, Martin RJ
Department of Medicine, National Jewish Medical and Research Center and the University of Colorado Health Sciences Center, Denver, Colorado, USA. sutherlande@njc.org
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a syndrome of chronic progressive airflow limitation which occurs as a result of chronic inflammation of the airways and lung parenchyma. However, the role of inhaled corticosteroids in the treatment of COPD is controversial. We hypothesised that inhaled corticosteroids reduce the progression of airflow limitation in COPD. METHODS: A comprehensive literature search was conducted and data were analysed using random effects methodology. The effect of inhaled steroids on annual change in forced expiratory volume in 1 second (FEV1) was determined for all trials, for trials with high dose treatment regimens, and for trials in subjects with moderate to severe airflow limitation. RESULTS: Data from eight controlled clinical trials of > or =2 years were included (n=3715 subjects). Meta-analysis of all study data revealed that inhaled corticosteroids reduce the rate of FEV1 decline by 7.7 ml/year (95% confidence interval (CI) 1.3 to 14.2, p=0.02). Meta-analysis of studies with high dose regimens revealed a greater effect of 9.9 ml/year (95% CI 2.3 to 17.5, p=0.01) compared with the meta-analysis of all studies. CONCLUSIONS: Inhaled corticosteroid treatment for > or =2 years slows the rate of lung function decline in COPD. The effect observed with high dose regimens is greater than that with all regimens combined. These data suggest a potential role for inhaled corticosteroids in modifying the long term natural history of COPD.
Inhaled corticosteroids in the long-term management of patients with chronic obstructive pulmonary disease
Sin DD, Man SF
The Department of Medicine, Pulmonary Division, University of Alberta, Edmonton, Alberta, Canada. don.sin@ualberta.ca
Chronic obstructive pulmonary disease (COPD) is a major problem in the elderly population, with approximately 10% of the population affected. Since COPD is an inflammatory disorder of the pulmonary system, corticosteroids might be expected to improve clinical outcomes of the disease. Data from large, well designed randomised clinical trials in which approximately one third of patients were > or =65 years of age indicate that inhaled corticosteroids do not modify the natural history of COPD, as measured by the rate of decline in forced expiratory volume in 1 second (FEV1). However, these same studies also suggest that corticosteroids reduce the frequency of clinical exacerbations by nearly a third (compared with placebo). This beneficial effect is particularly pronounced among those with an FEV1 less than 50% of the predicted value. Withdrawal of inhaled corticosteroids, on the other hand, leads to increased symptoms and elevates the risk of exacerbations by 50% above baseline levels. Patients' health-related quality of life is also improved by the use of inhaled corticosteroids. It is clear that inhaled corticosteroids elevate the risk of thrush, dysphonia and skin bruising by 2-fold compared with placebo. In addition, the sum of evidence suggests a modest deleterious effect for inhaled corticosteroids on bone mineral density, especially for formulations that have an increased rate of systemic absorption. However, the clinical evidence of this observation is uncertain. The effect of inhaled corticosteroids on fracture risk is controversial with some observational studies suggesting a possible association. Whether inhaled corticosteroids increase the risk of ophthalmic complications (cataracts and glaucoma) is also uncertain. In conclusion, the current evidence indicates that inhaled corticosteroid therapy produces short- and long-term clinical benefits in COPD patients with moderate-to-severe disease and should be used as adjunctive therapy for elderly patients with COPD who experience frequent exacerbations or have moderately reduced lung function.
Inhaled corticosteroids in chronic obstructive pulmonary disease and risk of death and hospitalization: time-dependent analysis
Fan VS, Bryson CL, Curtis JR, Fihn SD, Bridevaux PO, McDonell MB, Au DH
Department of Medicine, University of Washington, Seattle, WA98108. vfan@u.washington.edu
Observational studies of inhaled corticosteroids in chronic obstructive pulmonary disease (COPD) have shown improved survival whereas randomized trials have not. It has been suggested that this difference may be due to immortal time bias. To investigate this further, we performed a prospective cohort study of patients with COPD, using time-dependent methods to determine whether use of inhaled corticosteroids more than 80% of the time reduced the risk of all-cause mortality and COPD exacerbations. Of 8,033 patients, 2,686 (33%) received inhaled corticosteroids. We did not find a significant reduction in mortality for average inhaled steroid use at either low (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.69-1.33) or medium/high dose (HR, 0.86; 95% CI, 0.67-1.10). Similarly, recent inhaled corticosteroid use was not associated with a reduction in mortality at low (HR, 0.80; 95% CI, 0.60-1.07) or medium/high doses (HR, 0.88; 95% CI, 0.71-1.09). There was no association between inhaled corticosteroid use and hospitalizations or exacerbations due to COPD. Patients using medium/high-dose inhaled corticosteroids did not have a significantly lower risk of COPD hospitalizations (HR, 0.85; 95% CI, 0.64-1.13) or COPD exacerbations (HR, 1.13; 95% CI, 0.94-1.36). In a time-dependent study of outpatients with COPD, adherence to inhaled corticosteroid use was not associated with a decreased risk of mortality or exacerbations.
Inhaled corticosteroids and hospitalisation due to exacerbation of COPD
Bourbeau J, Ernst P, Cockcoft D, Suissa S
Respiratory Epidemiology Unit, Joint Depts of Epidemiology and Biostatistics, and Occupational Health, McGillUniversity, Montreal, QC, Canada
Previous studies have provided conflicting evidence as to the possible benefits of inhaled corticosteroids in the treatment of chronic obstructive pulmonary disease (COPD). Using the Saskatchewan healthcare databases subjects were identified who were aged > or = 55 yrs, initiating regular treatment for COPD but without any prior treatment for asthma. In the current nested case-control analysis, the authors concentrated on 1,742 subjects with a first hospitalisation for COPD after January 1, 1990 and examined whether the use of inhaled corticosteroids was associated with a change in the risk of a subsequent hospitalisation for COPD. The cases consisted of 846 patients with a subsequent hospitalisation for COPD. These were matched on age, time since the prior hospitalisation and use of other respiratory therapy to all possible person moments in the cohort without rehospitalisation. After further adjustment for comorbidity, sex, calendar year and intensity of other drug therapy, inhaled corticosteroids were not significantly associated with risk of a subsequent COPD hospitalisation. Even relatively high doses of inhaled corticosteroids, >800 microg of beclomethasone or the equivalent per day, were not associated with the risk of COPD hospitalisation. No reduction in chronic obstructive pulmonary disease exacerbations requiring hospitalisation, in relation to the use of inhaled corticosteroids, were observed.
Lack of long-term adverse adrenal effects from inhaled triamcinolone: Lung Health Study II
Eichenhorn MS, Wise RA, Madhok TC, Gerald LB, Bailey WC, Tashkin DP, Scanlon PD; Lung Health Study Research Group
Henry Ford Hospital, Detroit, MI, USA
STUDY OBJECTIVE: Inhaled corticosteroids (ICS) are widely used in the treatment of COPD. One of the potential adverse effects of their use is the development of adrenal suppression. Our study aimed to determine the effects of ICS on adrenal function over 3 years of use in patients with COPD. METHODS: Two hundred twenty-one subjects were recruited from the 1,116 patients already enrolled in Lung Health Study II and were randomized to receive either triamcinolone, 1,200 microg, or placebo daily. Basal cortisol levels and cortisol levels at 30 min and 60 min following cosyntropin injection were measured at study entry and after 1 year and 3 years of participation. RESULTS: Basal cortisol levels in the placebo group were higher than in those receiving active drug at all time points and rose through the study period. There was no suppression of cortisol levels after cosyntropin stimulation at any study point in any subgroup. CONCLUSION: Use of inhaled triamcinolone, 1,200 microg/d, over 3 years does not suppress baseline adrenal function or diminish adrenal responsiveness to cosyntropin stimulation.
Long-term effects of inhaled corticosteroids on FEV1 in patients with chronic obstructive pulmonary disease. A meta-analysis.
Highland KB, Strange C, Heffner JE
Division of Pulmonary, Critical Care, Allergy and Clinical Immunology, Medical University of South Carolina, 96 Jonathan Lucas Street, 812 CSB, Box 250623, Charleston, South Carolina 29425, USA. highlakb@musc.edu
BACKGROUND: There is no consensus on the effectiveness of inhaled corticosteroids for the treatment of chronic obstructive pulmonary disease (COPD). PURPOSE: To evaluate the long-term effects of inhaled corticosteroids on the rate of FEV1 decline in patients with COPD. DATA SOURCES: MEDLINE, EMBASE, CISCOM, and AMED databases and the Cochrane Library (1966 to December 2002), reference lists from identified articles, and consultation with experts. Searches were not limited to the English language. STUDY SELECTION: Randomized, placebo-controlled trials that examined the rate of FEV1 decline as a primary outcome in patients with COPD. DATA EXTRACTION: Two reviewers independently extracted the data by using predetermined criteria. DATA SYNTHESIS: For the six studies that met the inclusion criteria, the summary estimate for the difference in FEV1 decline between the placebo and treatment groups was -5.0 +/- 3.2 mL/y (95% CI, -11.2 to 1.2 mL/y; P = 0.11). CONCLUSIONS: The use of inhaled corticosteroids was not associated with the rate of FEV1 decline in 3571 patients followed for 24 to 54 months.
Inhaled corticosteroid effects on bone metabolism in asthma and mild
chronic obstructive pulmonary disease.
Jones A, Fay JK, Burr M, Stone M, Hood K, Roberts G.
Department of General Practice, University of Wales College of Medicine,
Dept. of General Practice, Llanedeyrn Health Centre, Cardiff, UK, CF23 7PN.
BACKGROUND: Inhaled corticosteroids form the main therapy for asthma, but
there is increasing concern about the potential systematic effects of
long-term inhaled corticosteroids including their effect on bone metabolism
and bone loss. OBJECTIVES: To determine the effect of inhaled
corticosteroids use on biochemical markers of bone turnover, bone mineral
density and the development of fractures. SEARCH STRATEGY: We searched the
Cochrane Airways Group trials register, electronic reference databases, UK
National Research Register, bibliographies of included studies, and
contacted pharmaceutical companies. SELECTION CRITERIA: Randomised trials
of the effect of inhaled steroid versus placebo on markers of bone function
and metabolism, in adults with asthma or mild COPD. DATA COLLECTION AND
ANALYSIS: Trial quality was assessed and data extracted from the papers
included (2 reviewers per paper) and from additional data supplied by the
authors. MAIN RESULTS: Of 438 references found, seven met the inclusion
criteria. Three studies were in healthy subjects asthma or COPD. The
patients were generally less than 60 years old and the male:female ratio
was 2:1. There was no evidence of increased risk of loss of bone mineral
density (BMD) or fractures. There was no significant change in osteocalcin
at conventional doses of inhaled corticosteroids (Standardised Mean
Difference [SMD] -0.34 (95% Confidence Interval [CI] -0.72, 0.04), although
a statistically significant change was seen in those studies using
experimental doses of inhaled steroid in excess of the doses recommended by
the British Thoracic Society SMD 0.97 (95% CI -1.61, -0.34). A
statistically significant change in parathyroid hormone seen in one small
short trial (n=10, 6 weeks) may have been due to the trial design and
outcome measurements used. REVIEWER'S CONCLUSIONS: In patients with asthma
or mild COPD, there is no evidence of an effect of inhaled corticosteroid
at conventional doses given for two or three years on BMD or vertebral
fracture. Higher doses were associated with biochemical markers of
increased bone turnover, but data on BMD and fractures at these doses are
not available. There is a need for further, even longer term prospective
studies of conventional and high doses of inhaled corticosteroids.
Medicines Evaluation Unit, North-west Lung Research Centre, South Manchester University Hospital Trust, Wythenshawe, Manchester, and Clinical Pharmacology and Drug Development, GlaxoSmithKline, Greenford, UK.
AIMS: We have previously shown that the systemic exposure to inhaled fluticasone
propionate (FP) is reduced in asthmatics compared with healthy subjects.
We have now compared its pharmacokinetics in patients suffering from chronic
obstructive pulmonary disease (COPD, n = 10) and matched healthy subjects (n = 13).
METHODS: A double-blind, randomized, cross-over study design was used.
Plasma FP and serum cortisol were measured for 12 h after subjects received
hydrofluoroalkane FP 1000 micro g day-1 inhaled (via an MDI and spacer) for 7 days
and following a single 1000- micro g intravenous dose. RESULTS: The pharmacokinetics
differed in the two groups. After inhalation, geometric least square means were
significantly lower in the COPD group for the plasma AUC
(1961 vs 2996 pg ml-1 h-1 for COPD and controls, respectively; P = 0.03) and the Cmax
(235 vs 421 pg ml-1 for COPD and controls, respectively; P = 0.03).
Suppression of serum cortisol concentration over 12 h was greater in healthy controls.
Weighted mean serum cortisol concentration (nmol l-1) in healthy subjects and COPD was 93
and 170, respectively (P = 0.03). The intravenous pharmacokinetic parameters for FP were
comparable in the two groups, resulting in similar suppression of serum cortisol.
CONCLUSIONS: We conclude that the altered pharmacokinetics of inhaled fluticasone propionate
in COPD caused less hypothalamic-pituitary-adrenal suppression than in healthy controls.
This is further evidence that the systemic effects of inhaled corticosteroids should be
assessed in patients and not healthy subjects.
Effectiveness of Inhaled Corticosteroids in COPD: Immortal Time Bias in Observational Studies.
Suissa S.
Division of Clinical Epidemiology, McGill University Health Centre, Royal Victoria Hospital, Montreal, Quebec, Canada; Epidemiology, Biostatistics and Medicine, McGill University, Montreal, Quebec, Canada.
Recent large-scale cohort studies that reported an important reduction in
mortality and COPD morbidity with inhaled corticosteroids may be biased.
We used a population-based cohort of Saskatchewan residents 55 years of age or over,
first hospitalised for COPD during 1990-97, to study this potential bias.
These 979 subjects were followed for a year from discharge until their first readmission
for COPD or death (389 subjects). Inhaled corticosteroid exposure was any dispensing within
90 days after discharge. Cox's proportional hazards model was used to compare the
time-fixed analysis employed in the recent studies with an alternative time-dependent analysis.
The time-fixed adjusted rate ratio was 0.69 (95% Cl: 0.55-0.86) for inhaled corticosteroid use
within 90 days while the time-dependent rate ratio was 1.00 (95% Cl: 0.79-1.26).
With the time-fixed analysis, the rate ratios were affected by the choice of the exposure period,
decreasing from 0.98 for a 15-day exposure period to 0.51 for 365 days,
but remained stable between 1.06 and 0.94 with the time-dependent analysis.
Inhaled corticosteroid use after hospitalisation for COPD was not found to reduce mortality and morbidity.
Recent observational reports of reductions in mortality and morbidity with inhaled corticosteroids
are biased by their inappropriate allocation of exposure and immortal time.
PMID: 12663327 [PubMed - as supplied by publisher]
Inhaled corticosteroids and survival in chronic obstructive pulmonary disease: does the dose matter?
Sin DD, Man SF.
Dept of Medicine, Pulmonary Division, University of Alberta, Edmonton, Canada. don.sin@ualberta.ca
Recent data suggest that inhaled corticosteroids reduce the number of clinical
exacerbations in chronic obstructive pulmonary disease (COPD). It remains unknown
whether a dose/response relationship exists. The present study was conducted to
evaluate the long-term impact of varying doses of inhaled corticosteroids on COPD
mortality. Hospital discharge data were used to identify all patients
aged > or = 65 yrs recently hospitalised due to COPD in Alberta, Canada (n = 6,740).
The relative risk (RR) for all-cause mortality was compared across different dose categories of
inhaled corticosteroids (none and low, medium and high doses) following hospital discharge.
Inhaled corticosteroid therapy after discharge was associated with a 25% relative reduction in
risk for all-cause mortality (RR 0.75, 95% confidence interval (CI) 0.68-0.82).
Patients on medium- or high-dose therapy showed lower risks for mortality than those on low doses
(RR 0.77, 95% CI 0.69-0.86 for low dose; RR 0.48, 95% CI 0.37-0.63 for medium dose;
and RR 0.55, 95% CI 0.44-0.69 for high dose). Use of inhaled corticosteroids following hospital
discharge for chronic obstructive pulmonary disease was associated with a significant reduction
in the overall mortality rate. Low- was inferior to medium- or high-dose therapy in protecting
against mortality in chronic obstructive pulmonary disease.
Disease severity and the effect of fluticasone propionate on chronic obstructive pulmonary disease exacerbations.
Jones PW, Willits LR, Burge PS, Calverley PM; Inhaled Steroids in Obstructive Lung Disease in Europe study investigators.
Division of Physiological Medicine, St George's Hospital Medical School, London, UK. pjones@sghms.ac.uk
Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with worse health and increased healthcare utilisation.
The Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study in COPD showed a 26% reduction in the yearly rate of
exacerbations in patients treated with fluticasone propionate (FP) compared to placebo, but did not indicate which patients
showed greatest benefit. In this study the patients were stratified into mild and moderate-to-severe COPD using the
American Thoracic Society criterion of forced expiratory volume in one second (FEV1) 50% predicted, and the total number of
exacerbations and those requiring treatment with oral corticosteroids were examined.
There were 391 (195 FP) patients with mild COPD and 359 (180 FP) patients with moderate-to-severe disease.
The exacerbation rate was highly skewed in mild disease, but more normally distributed in moderate-to-severe disease.
FP reduced the overall exacerbation rate in moderate-to-severe disease (FP median rate 1.47 yr(-1), placebo 1.75 yr(-1)),
but not in mild disease (FP 0.67 yr(-1), placebo 0.92 yr(-1)).
FP use was associated with fewer patients with > or = 1 exacerbation x yr(-1) being treated with oral corticosteroids
(mild: FP 8%, placebo 16%; moderate-to-severe: FP 17%, placebo 30%).
Effects of fluticasone propionate on exacerbations were seen predominantly in patients with a postbronchodilator forced expiratory volume in one
second < 50% predicted. These data support recommendations in the Global Initiative for Chronic Obstructive Disease treatment guidelines that
inhaled corticosteroids should be considered in patients with moderate-to-severe chronic obstructive pulmonary disease who experience recurrent exacerbations.
Survival in COPD patients after regular use of fluticasone propionate and salmeterol in general practice.
Soriano JB, Vestbo J, Pride NB, Kiri V, Maden C, Maier WC.
Worldwide Epidemiology Dept, GlaxoSmithKline Research and Development, Greenford, Middlesex, UK. joan.b.soriano@gsk.com
Despite substantial evidence regarding the benefits of combined use of inhaled corticosteroids
and long-acting beta2-agonists in asthma, such evidence remains limited for chronic obstructive
pulmonary disease (COPD). Observational data may provide an insight into the expected survival in
clinical trials of fluticasone propionate (FP) and salmeterol in COPD. Newly physician-diagnosed
COPD patients identified in primary care during 1990-1999 aged > or = 50 yrs, of both sexes and
with regular prescriptions of respiratory drugs were identified in the UK General Practice Research Database.
Three-year survival in 1,045 COPD patients treated with FP and salmeterol was compared with that in 3,620 COPD
patients who regularly used other bronchodilators but not inhaled corticosteroids or long-acting beta2-agonists.
Standard methods of survival analysis were used, including adjustment for possible confounders.
Survival at year 3 was significantly greater in FP and/or salmeterol users (78.6%) than in the
reference group (63.6%). After adjusting for confounders, the survival advantage observed was highest in
combined users of FP and salmeterol (hazard ratio (HR) 0.48 (95% confidence interval 0.31-0.73)),
followed by users of FP alone (HR 0.62 (0.45-0.85)) and regular users of salmeterol alone (HR 0.79 (0.58-1.07))
versus the reference group. Mortality decreased with increasing number of prescriptions of FP and/or salmeterol.
In conclusion, regular use of fluticasone propionate alone or in combination with salmeterol is associated with
increased survival of chronic obstructive pulmonary disease patients managed in primary care.
Effect of discontinuation of inhaled
corticosteroids in patients with chronic obstructive
pulmonary disease: the COPE study.
van der Valk P, Monninkhof E, van der Palen J,
Zielhuis G, van Herwaarden C.
Department of Pulmonary Medicine, Medisch Spectrum
Twente, Enschede, The Netherlands. valkpapa@knmg.nl
The aim of this double-blind single center study
(the COPE study) was to investigate the effect of
discontinuation of the inhaled corticosteroid fluticasone
propionate (FP) on exacerbations and health-related
quality of life in patients with chronic obstructive
pulmonary disease. After 4 months of treatment with
FP (1,000 microg/day), 244 patients were randomized
to either continue FP or to receive placebo for
6 months: 123 patients continued FP (FP group),
and 121 received placebo (placebo group). In the
FP group, 58 (47%) patients developed at least one
exacerbation compared with 69 (57%) in the placebo
group. The hazard ratio of a first exacerbation
in the placebo group compared with the FP group
was 1.5 (95% confidence interval [CI] 1.1-2.1).
In the placebo group 26 patients (21.5%) experienced
rapid recurrent exacerbations and were subsequently
unblinded and prescribed FP compared with 6 patients
(4.9%) in the FP group (relative risk = 4.4; 95%
CI 1.9-10.3). Over a 6-month period, a significant
difference in favor of the FP group was observed
in the total score (+2.48 95% CI 0.37-4.58), activity
domain (+4.64 95% CI 1.60-7.68), and symptom domain
(+4.58 95% CI 1.05-8.10) of the St. George's Respiratory
Questionnaire. This study indicates that discontinuation
of FP in patients with chronic obstructive pulmonary
disease is associated with a more rapid onset and
higher recurrence-risk of exacerbations and a significant
deterioration in aspects of Health-Related Quality
of Life.
Controlled trial of inhaled fluticasone
propionate in moderate to severe COPD.
Thompson WH, Carvalho P, Souza JP, Charan NB.
Department of Medicine, University of Washington,
Seattle, Washington, USA.
Inhaled corticosteroids are often used in the treatment
of stable chronic obstructive pulmonary disease (COPD),
however, studies of these agents have had mixed results.
Previous trials have often excluded subjects with
bronchodilator response, have failed to evaluate effect
on gas exchange, and have usually looked at only post-
rather than prebronchodilator forced expiratory volume
(FEV). Our objective was to better assess the efficacy
of topical corticosteroids in the treatment of COPD.
We used a prospective, randomized, double-blinded,
placebo-controlled, crossover study at the Outpatient
Department, Department of Veterans Affairs Medical
Center. Thirty-six COPD patients with a mean (+/-
SD) FEV1 of 1.10 +/- 0.43 L, with or without significant
bronchodilator response participated in the study.
Subjects received a 3-month course of inhaled fluticasone
propionate (220 micro g/puff) or identical-appearing
placebo by metered-dose inhaler at 2 puffs twice daily,
followed by crossover to the alternative inhaler for
an additional 3 months. Fluticasone treatment resulted
in a higher prebronchodilator FEV1 (1.17 +/- 0.08
L [mean +/- SEM] versus 1.07 +/- 0.08 L, p = 0.001),
a higher PaO2 (66.6 +/- 1.4 mmHg versus 63.6 +/- 1.6
mmHg, p = 0.002), and a better dyspnea score on the
chronic respiratory questionnaire (3.70 +/- 0.18 versus
3.47 +/- 0.19, p = 0.03). A trend towards fewer exacerbations
with fluticasone did not quite meet statistical significance
(p = 0.11). Inhaled fluticasone over 3 months improved
prebronchodilator airflow obstruction and oxygenation
while decreasing dyspnea in moderate to severe COPD.
Postbronchodilator FEV1 was not significantly changed.
Effects of fluticasone
propionate on inflammatory cells in COPD: an ultrastructural
examination of endobronchial biopsy tissue.
Gizycki MJ, Hattotuwa KL, Barnes N, Jeffery PK.
Lung Pathology Unit, Imperial College School of Medicine
at the Royal Brompton Hospital, London, UK London
Chest Hospital, London, UK.
BACKGROUND: Inhaled corticosteroids (ICS) markedly
reduce bronchial mucosal inflammation in asthma but
whether they have an anti-inflammatory effect in airway
tissue in chronic obstructive pulmonary disease (COPD)
is unknown. METHODS: A study of endobronchial biopsy
samples was conducted as part of a double blind, placebo
controlled, randomised trial of parallel design. Patients
had mild to moderately severe COPD (FEV(1) 25-80%
of predicted) and were given 3 months treatment with
ICS, fluticasone propionate (FP; 500 micro g twice
daily, n=14) or placebo (n=10). Biopsy tissue taken
at baseline and after treatment was examined by transmission
electron microscopy to count the numbers of all ultrastructurally
distinct inflammatory cells. RESULTS: Compared with
their baseline values, FP resulted in a significant
decrease (on average 65%) in the numbers of mucosal
mast cells (median 7.8 (range 1-33) v 2.8 (1-14),
p<0.05). The reductive effect of FP held true when
the post-treatment values of the placebo and FP groups
were compared: 8.8 (1-24) v 2.8 (1-14) (p<0.05).
Unexpectedly, there were significantly more neutrophils
in the FP than in the placebo group: 4.0 (0-23) v
1.7 (0-8), respectively (p<0.05). There were no
alterations to other cell types including mononuclear
cells. Symptoms markedly improved in the patients
treated with FP for 3 months. CONCLUSION: Fluticasone
propionate given for 3 months to patients with COPD
has selective effects on the inflammatory cells in
the bronchial mucosa: the reduction in mast cell numbers
may account for the improvement in symptoms over this
time.
Department of Pulmonary and Intensive Care Medicine,
Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
verhoeveng@mcrz.nl
BACKGROUND: Treatment of chronic obstructive pulmonary
disease (COPD) with inhaled corticosteroids does not
appear to be as effective as similar treatment of
asthma. It seems that only certain subgroups of patients
with COPD benefit from steroid treatment. A study
was undertaken to examine whether inhaled fluticasone
propionate (FP) had an effect on lung function and
on indices of inflammation in a subgroup of COPD patients
with bronchial hyperresponsiveness (BHR). METHODS:
Twenty three patients with COPD were studied. Patients
had to be persistent current smokers between 40 and
70 years of age. Non-specific BHR was defined as a
PC(20) for histamine of <or=8 mg/ml. Patients received
either 2 x 500 microg FP or placebo for 6 months.
Expiratory volumes were measured at monthly visits,
BHR was determined at the start of the study and after
3 and 6 months, and bronchial biopsy specimens were
taken at the start and after 6 months of treatment.
Biopsy specimens from asymptomatic smokers served
as controls. RESULTS: In contrast to asthma, indices
of BHR were not significantly influenced by treatment
with FP. Forced expiratory volume in 1 second (FEV(1))
showed a steep decline in the placebo group but remained
stable in patients treated with FP. FEV(1)/FVC, and
maximal expiratory flows at 50% and 25% FVC (MEF(50),
MEF(25)) were significantly increased in the FP treated
patients compared with the placebo group. Biopsy specimens
were analysed for the presence of CD3+, CD4+, CD8+,
MBP+, CD15+, CD68+, CD1a, and tryptase cells. FP treatment
resulted in marginal reductions in these indices of
inflammation. CONCLUSION: In patients with COPD and
BHR, FP has a positive effect on indices of lung function
compared with placebo. Bronchial inflammation analysed
in bronchial biopsy specimens is only marginally reduced.
The effects of inhaled corticosteroids
in chronic obstructive pulmonary disease: a systematic
review of randomized placebo-controlled trials.
Alsaeedi A, Sin DD, McAlister FA.
Division of Pulmonary Medicine, University of Alberta,
Edmonton, Alberta T6G 2B7, Canada.
Although inhaled corticosteroids are commonly used
to treat patients with chronic obstructive pulmonary
disease (COPD), their effect on clinical outcomes
such as exacerbation and mortality is unknown. This
systematic review was conducted to determine whether
inhaled corticosteroids improve clinical outcomes
for patients with stable COPD.All placebo-controlled
randomized trials of inhaled corticosteroids given
for at least 6 months for stable COPD were identified
by searching MEDLINE (1966-2000), EMBASE (1980-2001),
CINAHL (1982-2000), SIGLE (1980-2000), the Cochrane
Controlled Trial Registry, and the bibliographies
of published studies. We independently extracted data
from each of the studies using a specified protocol,
and determined the summary risk ratios (RRs) and 95%
confidence intervals (CIs) for exacerbations and deaths.Nine
randomized trials (3976 patients with COPD), including
four with a systemic steroid run-in phase, were identified.
Use of inhaled corticosteroid therapy reduced the
rate of exacerbations (RR = 0.70; 95% CI: 0.58 to
0.84), with similar benefits in those who were and
were not pretreated with systemic steroids. Inhaled
corticosteroid therapy was also associated with increased
rates of oropharyngeal candidiasis (RR = 2.1; 95%
CI: 1.5 to 3.1), skin bruising (RR = 2.1; 95% CI:
1.6 to 2.8), and lower mean cortisol levels. No effects
were seen on all-cause mortality (RR = 0.84; 95% CI:
0.60 to 1.18) in the five trials that measured this
outcome.This systematic review demonstrates a beneficial
effect of inhaled corticosteroids in reducing rates
of COPD exacerbation. Further research is required
to define the long-term effects of these medications
and the benefit/risk ratio for patients with COPD.
Lung Pathology Unit, Imperial College School of Medicine
at the Royal Brompton Hospital, London, United Kingdom.
Inhaled corticosteroids (ICS) are effective in the
treatment of asthma and markedly reduce the numbers
of inflammatory cells in bronchial biopsies. However,
the effect of ICS on the inflammatory profile of biopsies
in smokers with chronic obstructive pulmonary disease
(COPD) is unknown. We have performed a double-blind,
placebo-controlled, randomized study to compare fluticasone
propionate (FP) 500 microg twice daily via a dry powder
inhaler and placebo (P) over a 3-month period in subjects
with COPD. Fiberoptic bronchoscopy and bronchial biopsy
was carried out at baseline and after the 3 months
of treatment. Thirty-one subjects completed the trial
and 30 paired biopsies were available for analysis.
Compared with P (n = 14), subjects on inhaled FP (n
= 16) had no significant reductions in the primary
endpoints: CD8+, CD68+ cells, or neutrophils, considered
to be of importance in COPD. However, there was a
reduction in the CD8:CD4 ratio in the epithelium and
of the numbers of subepithelial mast cells in the
FP group. CD4+ cells were significantly raised in
the P group in both subepithelium and epithelium.
Symptoms significantly improved, and there were significantly
fewer exacerbations in subjects on FP, compared to
subjects on P. The data indicate that inhaled fluticasone
does affect selected aspects of airway inflammation
in COPD, and this may explain, in part, the decrease
in exacerbations seen in long-term studies with fluticasone
propionate.
Inhaled corticosteroid therapy
reduces the risk of rehospitalization and all-cause
mortality in elderly asthmatics.
Sin DD, Tu JV.
Institute for Clinical Evaluation Sciences (ICES),
Sunnybrook and Women's College Health Science Center,
University of Toronto, Ontario, Canada.
Elderly patients with asthma have relatively high
rates of hospitalization and mortality. Although inhaled
corticosteroids have been shown to improve outcomes
among younger patients with asthma, their usefulness
in elderly patients has not been established. Therefore,
a population-based study of patients 65 yrs of age
or older, who have been hospitalized at least once
with asthma in Ontario, Canada was conducted to determine
the impact of inhaled corticosteroids on rehospitalization
for asthma and all-cause mortality rates. Data from
the Canadian Institute of Health Information was used
to capture all patients 65 yrs of age and older who
were hospitalized at least once, with the most responsible
diagnosis of asthma in Ontario, Canada between fiscal
year 1992 and 1996. This database was then linked
with drug claims, physician billing and mortality
databases. In total, 6,254 consecutive elderly patients
with asthma were identified. Sixty percent of these
patients were given at least one prescription for
inhaled corticosteroids within 90 days postdischarge
from their index hospitalization for asthma. Users
of inhaled corticosteroids postdischarge were 29%
(95% confidence interval (CI) 20%-38%) less likely
to be readmitted to hospital for asthma and 39% (95%
CI, 20%-53%) less likely to experience all-cause mortality
compared to those who did not receive these drugs
postdischarge over a one year follow-up period. These
findings suggest that inhaled corticosteroids are
beneficial in reducing the risk for rehospitalization
and all-cause mortality in elderly patients with asthma
who have recently been hospitalized for their disease.
Should inhaled corticosteroids
be used in the long term treatment of chronic obstructive
pulmonary disease?
Burge S.
Birmingham Heartlands Hospital, England.
Chronic obstructive pulmonary disease (COPD) is a
progressive disease with alveolar destruction (emphysema)
and bronchiolar fibrosis (obstructive bronchitis)
in variable proportions. Reducing disease progression,
as assessed by forced expiratory volume in I second
(FEV1) decline, health-related quality of life, exacerbation
rate and mortality, is a more realistic outcome than
physiological improvement. This paper reviews all
the published studies of at least 100 patients followed
for at least 2 years. Studies have included patients
with mild COPD (Copenhagen City Lung Study) to advanced
symptomatic disease [Inhaled Steroids in Obstructive
Lung Disease (ISOLDE)], with 2 studies of those with
relatively early symptoms [European Respiratory Society
Study on Chronic Obstructive Pulmonary Disease (EUROSCOP)
and Lung Health-21. Exacerbation frequency, and probably
severity, are reduced by high dose inhaled corticosteroids.
Exacerbations are only frequent in more advanced disease,
limiting the use of this outcome in EUROSCOP and Lung
Health-2. Exacerbations are associated with reduced
health-related quality of life. ISOLDE clearly showed
a reduced rate in decline of the disease-specific
St George's Respiratory Questionnaire with fluticasone
propionate, partly related to the reduced exacerbations.
The symptom component of the score showed the greatest
difference between placebo and fluticasone propionate.
None of the larger studies were able to reproduce
the statistically significant reduction in the rate
of decline in FEV1 suggested by the smaller, earlier
studies. This might at least in part be as a result
of the statistical modelling used which cannot adequately
compensate for those with more rapidly progressive
disease dropping out earlier. The equivalent doses
of inhaled corticosteroids differed approximately
fivefold between the major studies. The more positive
results were obtained with higher doses. Oropharyngeal
adverse effects were similar to those seen in patients
with asthma; bruising was increased in one study with
budesonide, otherwise adverse effects were similar
to placebo. Bone loss was specifically studied in
subgroups of patients in EUROSCOP and Lung Health-2.
Budesonide 800 microg/day was associated with less
bone loss than placebo, whereas triamcinolone 1200
microg/day was associated with excess bone loss. High
dose inhaled corticosteroids have a favourable risk/benefit
ratio in patients with advanced disease, particularly
those with frequent exacerbations, and no benefit
for those with very mild disease. It is not possible
from the data to make firm recommendations for the
important intermediate group where delaying progression
is likely to lead to greatest benefit. I believe high
dose inhaled steroids are warranted for those with
intermediate severity COPD, who have frequent exacerbations
or significant COPD-related symptoms.
Effects of withdrawal of inhaled
steroids in men with severe irreversible airflow obstruction.
O'Brien A, Russo-Magno P, Karki A, Hiranniramol
S, Hardin M, Kaszuba M, Sherman C, Rounds S.
Division of Pulmonary and Critical Care Medicine,
Pharmacy Service, Providence Veterans' Affairs Medical
Center, Rhode Island Hospital, RI 02908, USA.
Inhaled corticosteroid therapy has proven efficacy
for asthmatics, but the benefit for patients with
chronic obstructive pulmonary disease (COPD) is less
well supported. We hypothesized that withdrawal of
inhaled steroids in elderly patients with severe irreversible
airway obstruction would not lead to a deterioration
in respiratory function. We designed a prospective,
double-blind, randomized, placebo-controlled, crossover
study to follow spirometry, quality of life questionnaire,
six-minute (6-min) walk test, and sputum markers of
inflammation during a 6-wk placebo treatment period
and a 6-wk treatment period with beclomethasone dipropionate
(BDP), 336 microg/d. There were 24 men receiving BDP
who entered the study; 15 completed the study. Their
mean age was 66.9 +/- 1.9 yr, and mean FEV(1) was
1.61 +/- 0.1 L (47% of predicted). There was a significant
decrease in the mean FEV(1 )while using the placebo
inhaler (1.70 L versus 1.60 L, baseline versus placebo:
95% CI, 0.002 to 0.195; p < 0.05). There was a
decrease in the mean percentage change in FEV(1) for
the study subjects during the placebo treatment period
as compared with the BDP treatment period (-6.28 versus
5.03%, placebo versus BDP: 95% CI, -23.38 to 0.76;
p = 0.06). Six-minute walk test results and sputum
analysis for cell count and differential were not
significantly different during placebo and BDP treatment
periods. Borg scale assessment of dyspnea after exercise
was increased while using the placebo inhaler as compared
with baseline, and decreased during the BDP treatment
period. Chronic Respiratory Disease Questionnaire
(CRQ) scores revealed no significant difference between
placebo and BDP. This study has demonstrated that
in elderly patients with severe irreversible airway
obstruction, withdrawal of inhaled corticosteroid
therapy leads to a deterioration in ventilatory function
and increased exercise-induced dyspnea.
Effect of inhaled triamcinolone
on the decline in pulmonary function in chronic obstructive
pulmonary disease.
The Lung Health Study Research Group.
BACKGROUND: Chronic obstructive pulmonary disease
(COPD) results from a progressive decline in lung
function, which is thought to be the consequence of
airway inflammation. We hypothesized that antiinflammatory
therapy with inhaled corticosteroids would slow this
decline. METHODS: We enrolled 1116 persons with COPD
whose forced expiratory volume in one second (FEV1)
was 30 to 90 percent of the predicted value in a 10-center,
placebo-controlled, randomized trial of inhaled triamcinolone
acetonide administered at a dose of 600 microg twice
daily. The primary outcome measure was the rate of
decline in FEV1 after the administration of a bronchodilator.
The secondary outcome measures included respiratory
symptoms, use of health care services, and airway
reactivity. In a substudy of 412 participants, we
measured bone density in the lumbar spine and femur
at base line and one and three years after the beginning
of treatment. RESULTS: The mean duration of follow-up
was 40 months. The rate of decline in the FEV1 after
bronchodilator use was similar in the 559 participants
in the triamcinolone group and the 557 participants
in the placebo group (44.2+/-2.9 vs. 47.0+/-3.0 ml
per year, P= 0.50). Members of the triamcinolone group
had fewer respiratory symptoms during the course of
the study (21.1 per 100 person-years vs. 28.2 per
100 person-years, P=0.005) and had fewer visits to
a physician because of a respiratory illness (1.2
per 100 person-years vs. 2.1 per 100 person-years,
P=0.03). Those taking triamcinolone also had lower
airway reactivity in response to methacholine challenge
at 9 months and 33 months (P=0.02 for both comparisons).
After three years, the bone density of the lumbar
spine and the femur was significantly lower in the
triamcinolone group (P < or = 0.007). CONCLUSIONS:
Inhaled triamcinolone does not slow the rate of decline
in lung function in people with COPD, but it improves
airway reactivity and respiratory symptoms and decreases
the use of health care services for respiratory problems.
These benefits should be weighed against the potential
long-term adverse effects of triamcinolone on bone
mineral density.
Randomised, double blind, placebo
controlled study of fluticasone propionate in patients
with moderate to severe chronic obstructive pulmonary
disease: the ISOLDE trial.
Burge PS, Calverley PM, Jones PW, Spencer
S, Anderson JA, Maslen TK.
Department of Respiratory Medicine, Birmingham
Heartlands Hospital, Birmingham B9 5SS. burgeps@aol.com
OBJECTIVES: To determine the effect of long term inhaled
corticosteroids on lung function, exacerbations, and
health status in patients with moderate to severe
chronic obstructive pulmonary disease. DESIGN: Double
blind, placebo controlled study. SETTING: Eighteen
UK hospitals. Participants: 751 men and women aged
between 40 and 75 years with mean forced expiratory
volume in one second (FEV(1)) 50% of predicted normal.
Interventions: Inhaled fluticasone propionate 500
microgram twice daily from a metered dose inhaler
or identical placebo. Main outcome measures: Efficacy
measures: rate of decline in FEV(1) after the bronchodilator
and in health status, frequency of exacerbations,
respiratory withdrawals. Safety measures: morning
serum cortisol concentration, incidence of adverse
events. RESULTS: There was no significant difference
in the annual rate of decline in FEV(1 )(P=0.16).
Mean FEV(1) after bronchodilator remained significantly
higher throughout the study with fluticasone propionate
compared with placebo (P<0.001). Median exacerbation
rate was reduced by 25% from 1.32 a year on placebo
to 0.99 a year on with fluticasone propionate (P=0.026).
Health status deteriorated by 3.2 units a year on
placebo and 2.0 units a year on fluticasone propionate
(P=0.0043). Withdrawals because of respiratory disease
not related to malignancy were higher in the placebo
group (25% v 19%, P=0.034). CONCLUSIONS: Fluticasone
propionate 500 microgram twice daily did not affect
the rate of decline in FEV(1) but did produce a small
increase in FEV(1). Patients on fluticasone propionate
had fewer exacerbations and a slower decline in health
status. These improvements in clinical outcomes support
the use of this treatment in patients with moderate
to severe chronic obstructive pulmonary disease.
Publication Types:
* Clinical Trial
* Multicenter Study
* Randomized Controlled Trial
Department of Thoracic Medicine, National Heart and
Lung Institute, Imperial College, London.
Inhaled corticosteroids are widely prescribed for
the treatment of stable chronic obstructive pulmonary
disease (COPD), despite lack of proven efficacy. Because
COPD involves airway inflammation and probable protease-antiprotease
imbalance, we examined the effect of high dose fluticasone
propionate on markers of activity of both pathogenetic
mechanisms. Thirteen patients with COPD were treated
with fluticasone propionate (500 microg twice a day)
for 4 wk, delivered via MDI and spacer, in a double-blind
crossover study. There was no clinical benefit in
terms of lung function or symptom scores, and induced
sputum inflammatory cells, percentage neutrophils,
and IL-8 levels were unchanged. Sputum supernatant
elastase activity, matrix metalloproteinase (MMP)-1,
MMP-9, and the antiproteases secretory leukoprotease
inhibitor (SLPI) and tissue inhibitor of metalloproteinase
(TIMP)-1 were similarly unaffected by treatment. These
results add to previous evidence that inhaled steroids
have no anti-inflammatory action in stable COPD. Furthermore,
inhaled steroids do not appear to redress the protease-antiprotease
imbalance that is thought to be important in the pathogenesis
of airway obstruction.
Long-term treatment with inhaled
budesonide in persons with mild chronic obstructive
pulmonary disease who continue smoking. European Respiratory
Society Study on Chronic Obstructive Pulmonary Disease.
Pauwels RA, Lofdahl CG, Laitinen LA, Schouten JP,
Postma DS, Pride NB, Ohlsson SV.
Department of Respiratory Diseases, University Hospital,
Ghent, Belgium. romain.pauwels@rug.ac.be
BACKGROUND: Although patients with chronic obstructive
pulmonary disease (COPD) should stop smoking, some
do not. In a double-blind, placebo-controlled study,
we evaluated the effect of the inhaled glucocorticoid
budesonide in patients with mild COPD who continued
smoking. After a six-month run-in period, we randomly
assigned 1277 subjects (mean age, 52 years; mean forced
expiratory volume in one second [FEV1], 77 percent
of the predicted value; 73 percent men) to twice-daily
treatment with 400 microg of budesonide or placebo,
inhaled from a dry-powder inhaler, for three years.
RESULTS: Of the 1277 subjects, 912 (71 percent) completed
the study. Among these subjects, the median decline
in the FEV1 after the use of a bronchodilator over
the three-year period was 140 ml in the budesonide
group and 180 ml in the placebo group (P=0.05), or
4.3 percent and 5.3 percent of the predicted value,
respectively. During the first six months of the study,
the FEV1 improved at the rate of 17 ml per year in
the budesonide group, as compared with a decline of
81 ml per year in the placebo group (P<0.001).
From nine months to the end of treatment, the FEV1
declined at similar rates in the two groups (P=0.39).
Ten percent of the subjects in the budesonide group
and 4 percent of those in the placebo group had skin
bruising (P<0.001). Newly diagnosed hypertension,
bone fractures, postcapsular cataracts, myopathy,
and diabetes occurred in less than 5 percent of the
subjects, and the diagnoses were equally distributed
between the groups. CONCLUSIONS: In patients with
mild COPD who continue smoking, the use of inhaled
budesonide is associated with a small one-time improvement
in lung function but does not appreciably affect the
long-term progressive decline.
Long-term effect of inhaled budesonide
in mild and moderate chronic obstructive pulmonary
disease: a randomised controlled trial.
Vestbo J, Sorensen T, Lange P, Brix A, Torre P,
Viskum K.
Department of Respiratory Medicine, Hvidovre Hospital,
Denmark. jvestbo@inet.uni2.dk
BACKGROUND: Little is known about the long-term efficacy
of inhaled corticosteroids in chronic obstructive
pulmonary disease (COPD). We investigated the efficacy
of inhaled budesonide on decline in lung function
and respiratory symptoms in a 3-year placebo-controlled
study of patients with COPD. METHODS: We used a parallel-group,
randomised, double-blind, placebo-controlled design
in a singlecentre study, nested in a continuing epidemiological
survey (the Copenhagen City Heart Study). Inclusion
criteria were as follows: no asthma; a ratio of forced
expiratory volume in 1 s (FEV1) and vital capacity
of 0.7 or less; FEV1 which showed no response (<15%
change) to 1 mg inhaled terbutaline or prednisolone
37.5 mg orally once daily for 10 days. 290 patients
were randomly assigned budesonide, 800 microg plus
400 microg daily for 6 months followed by 400 microg
twice daily for 30 months, or placebo for 36 months.
The mean age of the participants was 59 years and
the mean FEV1 2.37 L or 86% of predicted. The main
outcome measure was rate of FEV1 decline. Analyses
were by intention to treat. FINDINGS: The crude rates
of FEV1 decline were slightly smaller than expected
(placebo group 41.8 mL per year, budesonide group
45.1 mL per year). The estimated rates of decline
from the regression model did not differ significantly
(49.1 mL vs 46.0 mL per year; difference 3.1 mL per
year [95% CI -12.8 to 19.0]; p=0.7). Before the study,
the minimum relevant difference was defined as 20
mL per year; this difference was outside the 95% CI.
No effect of inhaled budesonide was seen on respiratory
symptoms. 316 exacerbations occurred during the study
period, 155 in the budesonide group and 161 in the
placebo group. Treatment was well tolerated. INTERPRETATION:
Inhaled budesonide was of no clinical benefit in COPD
patients recruited from the general population by
screening. We question the role of long-term inhaled
corticosteroids in the treatment of mild to moderate
COPD.
Long term effects of inhaled corticosteroids
in chronic obstructive pulmonary disease: a meta-analysis.
van Grunsven PM, van Schayck CP, Derenne JP, Kerstjens
HA, Renkema TE, Postma DS, Similowski T, Akkermans
RP, Pasker-de Jong PC, Dekhuijzen PN, van Herwaarden
CL, van Weel C.
Department of General Practice and Social Medicine,
University of Nijmegen, The Netherlands.
BACKGROUND: The role of inhaled corticosteroids in
the long term management of chronic obstructive pulmonary
disease (COPD) is still unclear. A meta-analysis of
the original data sets of the randomised controlled
trials published thus far was therefore performed.
The main question was: "Are inhaled corticosteroids
able to slow down the decline in lung function (FEV1)
in COPD?" METHODS: A Medline search of papers published
between 1983 and 1996 was performed and three studies
were selected, two of which were published in full
and one in abstract form. Patients with "asthmatic
features" were excluded from the original data. Ninety
five of the original 140 patients treated with inhaled
corticosteroids (81 with 1500 micrograms beclomethasone
daily, six with 1600 micrograms budesonide daily,
and eight with 800 micrograms beclomethasone daily)
and 88 patients treated with placebo (of the initial
144 patients) were included in the analysis. The effect
on FEV1 was assessed by a multiple repeated measurement
technique in which points of time in the study and
treatment effects (inhaled corticosteroids compared
with placebo) were investigated. RESULTS: No baseline
differences were observed (mean age 61 years, mean
FEV1 45% predicted). The estimated two year difference
in prebronchodilator FEV1 was +0.034 l/year (95% confidence
interval (CI) 0.005 to 0.063) in the inhaled corticosteroid
group compared with placebo. The postbronchodilator
FEV1 showed a difference of +0.039 l/year (95% CI
-0.006 to 0.084). No beneficial effect was observed
on the exacerbation rate. Worsening of the disease
was the reason for drop out in four patients in the
treatment group compared with nine in the placebo
group. In the treatment group six of the 95 subjects
dropped out because of an adverse effect which may
have been related to the treatment compared with two
of the 88 patients in the placebo group. CONCLUSIONS:
This meta-analysis in patients with clearly defined
moderately severe COPD showed a beneficial course
of FEV1 during two years of treatment with relatively
high daily dosages of inhaled corticosteroids.
The effect of high-dose inhaled
beclomethasone dipropionate in patients with stable
COPD.
Nishimura K, Koyama H, Ikeda A, Tsukino M, Hajiro
T, Mishima M, Izumi T.
Department of Respiratory Medicine, Graduate School
of Medicine, Kyoto University, Japan.
BACKGROUND: The benefits of inhaled corticosteroids
in the management of COPD are less apparent than they
are in asthma therapy, and the potential for adverse
systemic effects of high-dose inhaled corticosteroids
has been recognized recently. It is therefore essential
to know the maximal obtainable benefits in order to
assess the risk/benefit ratio of this treatment. PURPOSE:
The aim of this study was to investigate the maximal
obtainable benefits of high-dose inhaled corticosteroids,
3 mg/d of beclomethasone dipropionate (BDP), when
used in combination with adequate doses of regular
bronchodilators in patients with stable COPD. STUDY
DESIGN: Thirty patients with stable COPD completed
a randomized, double-blind, placebo-controlled cross-over
trial with either 3 mg/d of BDP or with a matching
placebo using a metered-dose inhaler with a spacer
device for 4 weeks during each treatment period. All
of the patients continued to inhale both 400 microg
of salbutamol qid and 80 microg of ipratropium bromide
qid. RESULTS: The mean prebronchodilator FEV1 was
0.97+/-0.35 L during the placebo period and 1.08+/-0.38
L during the BDP period (p < 0.001). While on BDP,
five patients demonstrated a response in their FEV1
of more than 8.5% of the predicted value, which was
above the range that covered 95% of the distribution
of the placebo response. The mean absolute improvement
in the FEV1 in these 5 objective responders was 0.34+/-0.10
L, compared to 0.06+/-0.09 L in the 25 objective nonresponders.
Symptom scores for wheezing and dyspnea were significantly
better with BDP than with placebo. Hoarseness and
sore throat were associated more with BDP treatment.
CONCLUSION: Although a considerable minority of patients
benefited substantially from this treatment, the overall
outcome does not seem to justify the widespread use
of this treatment in the light of increasing recognition
of the potential adverse systemic effects of high-dose
inhaled corticosteroids.
Multicentre randomised placebo-controlled
trial of inhaled fluticasone propionate in patients
with chronic obstructive pulmonary disease. International
COPD Study Group.
Paggiaro PL, Dahle R, Bakran I, Frith L, Hollingworth
K, Efthimiou J.
Respiratory Pathophysiology, University of Pisa, Italy.
BACKGROUND: The efficacy of inhaled corticosteroids
in the treatment of chronic obstructive pulmonary
disease (COPD) remains controversial because of a
lack of placebo-controlled studies. We compared the
effect of inhaled fluticasone propionate with placebo
in the treatment of patients with COPD. METHODS: We
used a randomised, double-blind, placebo-controlled
design. We enrolled from 13 European countries, New
Zealand, and South Africa, 281 outpatient current
or ex-smokers, aged between 50 and 75 years. They
had a forced expiratory volume in 1 s (FEV1) of between
35% and 90% of predicted normal values, a ratio of
FEV1 to forced vital capacity of 70% or less and bronchodilator
reversibility of less than 15%, as well as a history
of chronic bronchitis. Patients were randomly assigned
fluticasone propionate 500 microg (n=142) or placebo
(n=139) twice daily via a metered-dose inhaler for
6 months. The main outcome measures were the number
of patients who had at least one exacerbation by the
end of treatment, the number and severity of exacerbations,
clinic lung function, diary card symptoms and peak
expiratory flow and 6 min walking distance. FINDINGS:
51 (37%) patients in the placebo group compared with
45 (32%) in the fluticasone propionate group had had
at least one exacerbation by the end of treatment
(p=0.449). Significantly more patients had moderate
or severe exacerbations in the placebo group than
in the fluticasone propionate group (86% vs 60%, p<0.001).
Diary-card and clinic morning peak expiratory flows
improved significantly in the fluticasone propionate
group (p<0.001, p=0.048, respectively), as did
clinic FEV1 (p<0.001), forced vital capacity (p<0.001),
and mid-expiratory flow (p=0.01). Symptom scores for
median daily cough and sputum volume were significantly
lower with fluticasone propionate treatment than with
placebo (p=0.004 and p=0.016, respectively). At the
end of treatment, patients on fluticasone propionate
had increased their 6 min walking distance significantly
more than those on placebo (p=0.032). Fluticasone
propionate was tolerated as well as placebo, with
few adverse effects and without a clinically important
effect on mean serum cortisol concentration. INTERPRETATION:
Fluticasone propionate may be of clinical benefit
in patients with COPD over at least 6 months. Inhaled
corticosteroids may have an important role in the
long-term treatment of COPD.
