Asmanet ARLS 5-1998 Astra Respiratory Literature Service Experts comments

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AstraZeneca Respiratory Literature Service
N°5 1998 (see other Expert comments on Asmanet)

For many years, AstraZeneca Draco laboratories have brought to the asthmolgist community an excellent "Respiratory Literature Service" (ARLS) with an alert to new references, selected summaries and comments by a group of experts. In 1997, AstraZeneca is extending this concrete service with Asmanet in order to take advantage of the Internet capabilities. The following comments have been edited ( HTML format) to smooth the reading with hypertext links to integrate the comment in the Asmanet server and the worldwide distributed library on asthma, such as : abstract of the commented paper, references as seen on Medline and others, author's e-mail ...

	Title	Authors	Journal	Reviewer
1	Comparative clinical study of inhaled beclomethasone dipropionate and triamcinolone acetonide in persistent asthma.	Bronsky E, Korenblat P, Harris AG, et al	Annals of Allergy, Asthma & Immunology 1998;80:295-302	Professor Duncan Geddes
2	Budesonide delivered by Turbuhaler is effective in a dose-dependent fashion when used in the treatment of adult patients with chronic asthma	Busse WW, Chervinsky P, Condemi J, et al	J Allergy Clin Immunol 1998;101:457-463	Professor Duncan Geddes
3	Prednisolone in acute childhood asthma: clinical responses to three dosages	Langton Hewer S, Hobbs J, Reid F, et al	Respir Med 1998;92:541-546	Professor Duncan Geddes
4	Computer-based models to identify high-risk children with asthma	Lieu TA, Quesenberry CP, Sorel ME, et al	Am J Respir Crit Care Med 1998;157:1173-1180	Professor Philippe Godard
5	Once-daily budesonide in mild asthma	Chisholm SL, Dekker FW, Knuistingh Neven A, et al	Respir Med 1998;92:421-425	Professor Philippe Godard
6	Growth in asthmatic children treated with fluticasone propionate	Allen DB, Bronsky EA, LaForce CF, et al	J of Pediatrics 1998;132:472-477	Professor Philippe Godard
7	Dose-related response to inhaled fluticasone propionate in patients with methacholine-induced bronchial hyperresponsiveness: a double-blind, placebo-controlled study	Noonan MJ, Chervinsky P, Wolfe J, et al	J of Asthma 1998 No. 2;35:153-164	Ass. Professor Leif Rosenhall
8	Growth in asthmatic children treated with fluticasone propionate	Allen DB, Bronsky EA, LaForce CF, et al	J Pediatr 1998;132:472-477	Professor John H. Toogood
9	Tolerance to the bronchoprotective effect of salmeterol 12 hours after starting twice daily treatment	Drotar DE, Davis EE, Cockcroft DW	Ann Allergy Asthma Immunol 1998;80:31-34	Professor John H. Toogood

AstraZeneca Draco laboratories is also supporting the European Federation of Asthma and Allergy Associations which can be seen at http://www.efanet.org/

Access for abstracts to Medline through Healthgate (http://www.healthgate.com/HealthGate/MEDLINE/search.shtml ) or through HealthWorld Medline Search (http://www.healthy.net/library/search/medline.htm )

or through http://www.ncbi.nlm.nih.gov/

...

Many clinicians, especially in North America, are uncertain about the relative potency and comparability of beclomethasone dipropionate and triamcinolone acetonide in the treatment of asthma. This clinical trial compared the two drugs over 56 days in 328 adults with mild to moderately severe disease. A dose of 336 m g day of beclomethasone dipropionate was superior to triamcinolone 800 m g/day in terms of FEV₁ , asthma symptom scores and weekly use of rescue bronchodilator. There was no difference in the frequency of adverse events.

While this study suggests that beclomethasone dipropionate is better than triamcinolone acetonide only a single dose was tested, namely the "usual recommended starting dose". Comparisons between drugs that do not define the dose response curve are of limited value and furthermore triamcinolone was administered via a spacer while the beclomethasone was not. These defects are regrettable since head to head comparisons between inhaled corticosteroids in large numbers of patients are relatively rare.

Bronsky E, Korenblat P, Harris AG, Chen R
Intermountain Clinical Research, Salt Lake City, Utah 84102, USA.

At this time, no placebo-controlled studies in the clinical literature compare the efficacy and safety of the most widely prescribed oral inhaled corticosteroids when dosed at their recommended daily doses. This study compared the efficacy and safety of beclomethasone dipropionate (BDP) 336 microg/day administered by metered dose inhaler (MDI) alone, and triamcinolone acetonide (TA) 800 microg/day by MDI with a built-in tube extender in adults with persistent asthma.
METHODS: This 56-day, randomized, double-blind, double-dummy, placebo-controlled, multicenter trial was conducted in 328 adults with mild to moderately severe asthma (FEV1 50% to 90% of predicted while maintained on inhaled corticosteroids). Patients were seen at a baseline visit and on study days 28 and 56. Efficacy variables included pulmonary function tests, physician and patient assessments of asthma condition, and use of rescue medication.
RESULTS: Statistically significant improvementsfrom baseline in most efficacy measures were demonstrated for both active treatments versus placebo, and with the following exception were the same between active treatments: mean increase in FEV1 in the beclomethasone dipropionate group was statistically significantly greater than in the triamcinolone acetonide group on day 28...

Studies which define the dose response curve for inhaled corticosteroids remain welcome. In this study 473 adults with chronic asthma were randomised to budesonide 200, 400, 800 or 1600 m g daily as compared with placebo. For all measures, there was a dose-related improvement up to a total daily dose of 400 m g. At higher doses, further improvements either did not occur or were so trivial as to be clinically unimportant.

Although there is continuing debate about which outcome measure is the most important for evaluation of an asthma treatment and this study did not examine exacerbations, nevertheless confirmation that the dose response curve is flat for symptoms, lung function and bronchodilator use will help discourage unnecessarily high dose prescribing.

Busse WW, Chervinsky P, Condemi J, Lumry WR, Petty TL, Rennard S, Townley RG
University Hospitals CSC, Madison, WI, USA.

BACKGROUND: Airway inflammation is a hallmark of asthma, therefore current treatment recommendations include the use of inhaled glucocorticosteroids (GCS). However, there is little evidence that the effects of inhaled GCS are dose dependent.
OBJECTIVES: The objective of this study was to assess the efficacy and safety of a second-generation GCS, budesonide, delivered by Turbuhaler, in adults with chronic asthma.
METHODS: In a 12-week, randomized, double-blind, multicenter, parallel-group study, 473 subjects 18 to 70 years of age received either placebo or budesonide (200, 400, 800, or 1600 microg total daily dose) administered twice daily. Primary efficacy end points were mean change from baseline for FEV1 and morning peak expiratory flow .Safety was assessed by reported adverse events and by a cosyntropin-stimulation test.
RESULTS: The mean baseline FEV1 was 63% to 66% of predicted normal value between groups...

The dose response curve to corticosteroid therapy in asthma is relatively flat. This has been shown for inhaled treatment but good, well powered studies for oral corticosteroids are few. This report shows that in 98 children admitted with acute severe asthma there was no difference in outcome between three groups randomised to receive prednisolone 0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg. Although the sample size was not as large as intended the authors argue convincingly that clinically important differences were not missed.

Although the authors recommend the lowest dose for future treatment of acute severe asthma in children the conclusion can be questioned on two grounds. First, there may be the occasional patient in whom higher doses are necessary. This possibility cannot be excluded without a vast clinical trial. Secondly, there was no evidence of disadvantage from using the higher dose. More information on the dose response curve for systemic corticosteroids in asthma would be welcome.

Langton Hewer S, Hobbs J, Reid F, Lenney W
Royal Alexandra Hospital for Sick Children, Brighton, U.K.

Ninety-eight children aged 1-15 years entered a randomized double-blind study investigating an appropriate dose of oral prednisolone in children admitted to hospital with an acute exacerbation of asthma. None of the children had recently been treated with oral prednisolone. Following admission, the children were randomized to receive prednisolone 0.5 mg kg-1, 1.0 mg kg-1 or 2.0 mg kg-1 in a single daily dose in addition to nebulized bronchodilators. Clinical asthma scores, oxygen saturations, pulse rate, duration of admission and number of nebulizers given were compared in the three treatment groups. Thirty-five children received 0.5 mg kg-1, 33 received 1.0 mg kg-1 and 30 received 2.0 mg kg-1. There were no significant differences in the pattern of recovery between the three treatment groups. There were no advantages in using higher doses of prednisolone. We recommend 0.5 mg kg-1 day-1 of prednisolone as an appropriate dose for treating an acute exacerbation of asthma.

The authors retrospectively analysed health care utilisation in a cohort of 16,520 children with asthma, aged 0-14 years. This cohort was selected from a computerised database of a Californian health-maintenance organisation (HMO), which contained data from 210,125 children in total. Models were developed to predict asthma related hospitalisation and emergency visits.

The paper is difficult to read because the statistical analyses are very sophisticated. The results are disappointing because only already known risk factors are reported (i.e., previous hospitalisations, six or more b-agonist inhaler units per 6 months, and more than three physicians prescribing asthma medication during prior 6 months ). The authors conclude that the predictive models may be useful in population-based efforts to improve asthma management.

Although the results are somewhat disappointing, the paper is fascinating because computerised data from an HMO may be used for other analyses. For example, the model can be easily adjusted to evaluate cost-effectiveness of interventions, such as case management, referrals to specialists, and clinician education.

However, imperative demands by cost supplying organisations with regard to an individual treatment should be strongly discouraged. The electronic reports used in the study lack important data such as the patient’s disease severity, allergic status, or other important clinical aspects which are subjective or non-quantitative.

The question arises as to how electronic case reports may be used. This needs to be thoroughly discussed. Electronic reports may be used for scientific purposes but they should be anonymised. For the treatment of an individual patient, data from electronic reports should never be conclusive. Only the general practitioner, together with the patient, can make a balanced decision on how to improve an individuals asthma management.

Lieu TA, Quesenberry CP, Sorel ME, Mendoza GR, Leong AB
Division of Research, Kaiser Permanente, Oakland, California 94611, USA. tal (at) dor.Kaiser.org

Effective management of populations with asthma requires methods for identifying patients at high risk for adverse outcomes. The aim of this study was to develop and validate prediction models that used computerized utilization data from a large health-maintenance organization (HMO) to predict asthma-related hospitalization and emergency department (ED) visits. In this retrospective cohort design with split-sample validation, variables from the baseline year were used to predict
asthma-related adverse outcomes during the follow-up year for 16,520 children with asthma-related utilization. In proportional-hazard models, having filled an oral steroid prescription (relative risk [RR]: 1.9; 95% confidence interval [CI]: 1.3 to 2.8) or having been hospitalized (RR: 1.7; 95% CI: 1.1 to 2.7) during the prior 6 mo, and not having a personal physician listed on the computer (RR: 1.6; 95% CI: 1.1 to 2.3) were associated with increased risk of future hospitalization. Classification trees identified previous hospitalization and ED visits, six or more beta-agonist inhalers (units) during the prior 6 mo, and three or more physicians prescribing asthma medications during the prior 6 mo as predictors...

The study by Chisholm et al. is very interesting for two reasons. First, it demonstrates that 200 m g once daily is equivalent to 100 m g twice daily. Secondly, it demonstrates that mild asthmatic patients benefit from a low dose of inhaled steroid. This became especially clear in the wash-out period where a significant deterioration in peak flow and symptoms was observed.

In the past, only severe asthmatics were given inhaled steroids at least twice daily. Nowadays, even less severe asthmatics are treated with inhaled steroids. Compliance might be a problem in patients with few symptoms.

Strategies to increase patient compliance are important. However, it is not clear whether once daily administration of inhaled steroids improves compliance compared to twice daily administration.

When the severity of asthma is so high that 800 m g/day is required for control, twice daily administration seems most appropriate. When asthma control has been obtained, it is possible to step down in dose and give only 400 or 200 m g once a day.

The time of dosing, whether morning or evening, is also important. Oral corticosteroids are administered in the morning because of circadian variations of cortisol. However, pharmacologically it has been demonstrated that evening dosing might be better. For inhaled steroids, there is no evidence that evening administration is better than morning administration. Moreover, the effect on the HPA axis is absent at low doses of 200 and 400 m g/day. Therefore, to increase compliance, the choice between evening and morning dosing is made by mutual agreement with the physician and patient considering the patients psychology and his ability to adhere to a certain treatment.

Chisholm SL, Dekker FW, Knuistingh Neven A, Petri H
Department of General Practice, Leiden University, The Netherlands.

Inhaled steroid therapy is the most important treatment in the management of chronic asthma and currently twice-daily administration is recommended in mild to moderate asthma. Compliance is often a problem in asymptomatic patients and may lead to reduced disease control. Our aim was to investigate whether budesonide 0.2 mg once daily administered via the Turbuhaler is as effective as 0.1 mg twice daily. A randomized, double-blind, parallel group study was carried out in which 76 adult patients with mild to moderate asthma (FEV1 86% of predicted) were allocated to budesonide once or twice daily. After a run-in period of 2 weeks on present inhaled steroid treatment (0.2-0.5 mg day-1) there was an 8 week treatment period, followed by a washout period in which patients received no steroid for 4 weeks unless a drop in morning peak flow of at least 20% occurred or the use of beta 2-agonists increased by 50%. Both treatment groups improved minimally in peak flow (1.7 and 4.31 min-1 in the once-daily and twice-daily groups respectively) but the differences between the two groups were not significant. Testing the reverse hypothesis revealed clinical equivalence. The 90% confidence interval of the difference in the change of peak flow from run-in was between +30 and -30 l min-1, the limits deemed to be clinically relevant....

A total of 268 prepubescent children (4 to 11 years old) have been treated during a one year prospective study with fluticasone, 50 mg, 100 mg or placebo twice daily. Mean height increased by around 6 cm per year and was identical in the three groups.

The aim of this study was to determine the effect of inhaled fluticasone on growth rate. No influence on growth was found. This is in accordance with the results of the meta-analysis of 21 studies as discussed in the paper¹. However, the authors underline that this study is the first prospective 1-year study.

Concerning the analysis of the results, a kind of a dose-effect relationship can be observed. Growth seems lower in the group using the "high" dose fluticasone. The authors did not provide individual results or the distribution of the results. Therefore, it might be questioned whether all children grew normally.

In daily clinical practice, it should be recommended that the growth of children using inhaled corticosteroids is checked carefully and that the possibility of growth suppression is explained to the parents.

Allen DB, Bronsky EA, LaForce CF, Nathan RA, Tinkelman DG, Vandewalker ML, Konig P
University of Wisconsin Children's Hospital, Madison 53792-4108, USA.

OBJECTIVE: To determine whether inhaled fluticasone propionate has long-term effects on growth in children with persistent asthma.
STUDY DESIGN: In a double-blind, randomized, parallel-group, multicenter study, 325 prepubescent children with persistent asthma and normal growth rates were treated with placebo or inhaled fluticasone propionate powder 50 microg or 100 microg administered twice daily by a breath-actuated device for 1 year. Growth was evaluated monthly, whereas other safety variables and pulmonary function were evaluated periodically.
RESULTS: The prepubescent patients showed no statistically significant differences in mean height, mean growth velocity, or mean skeletal age between any of the treatment groups at any time. Over a period of 1 year, mean height (+/- SE) increased 6.15 +/- 0.17 cm in the placebo group, 5.94 +/- 0.16 cm in the fluticasone propionate 50 microg group, and 5.73 +/- 0.13 cm in the fluticasone propionate 100 microg group (p = 0.308, overall).
CONCLUSIONS: Prepubescent children treated with fluticasone propionate 50 microg and 100 microg administered twice daily for 1 year grew at rates similar to placebo-treated control subjects and at rates equal to expected growth velocity for age.

All doctors who are treating asthma are impressed by the positive effects of inhaled steroids. However, it is difficult to decide which dose a particular patient should have in a particular situation.

When inhaled steroids were first introduced on the market, we used a very low dose, 50 mg, twice daily. Later, it was recognised that an increasing dose gives a better response in most patients.

This study clearly shows that fluticasone 50 mg twice daily had about the same effect as 100 mg twice daily regarding improvements in lung function. However, the effect on bronchial reactivity was significantly better with the higher dose.

Therefore, in clinical practice it is important to give sufficiently high doses of inhaled steroids. This will result in normalised lung function and also in decreased bronchial hyperreactivity which is caused by the airway inflammation.

In general, clinical studies designed to compare different drugs should include measurements of bronchial hyperreactivity, and not only measurements of lung function.

Title (7): Dose-related response to inhaled fluticasone propionate in patients with methacholine-induced bronchial hyperresponsiveness: a double-blind, placebo-controlled study. (partial abstract below from http://www.healthy.net/library/search/medline.htm )

Noonan MJ, Chervinsky P, Wolfe J, Liddle R, Kellerman DJ, Crescenzi KL
Allergy Associates Research Office, Portland, Oregon 97213, USA.

Dose-response relationships with inhaled corticosteroids in the treatment of asthma have been difficult to establish. A multicenter, double-blind, parallel-group study was conducted to evaluate the clinical efficacy and safety of low doses of inhaled fluticasone propionate (FP) in patients with mild to moderate asthma. Methacholine challenge testing was conducted in addition to measurement of traditional efficacy variables. After a single-blind screening period, 138 patients > or = 12 years of age were randomly assigned to receive placebo, FP 50 microg, or FP 100 microg, twice daily for 8 weeks. The results of methacholine challenge testing averaged over all visits favored FP 200 microg/day over placebo and FP 100 microg/day (p < 0.05); there were no significant differences between placebo and FP 100 microg/day. Mean changes from baseline to endpoint favored each dose of FP over placebo based on forced expiratory volume in 1 sec (FEV1), patient-measured peak expiratory flow (PEF), total symptom scores, and rescue bronchodilator use (p < 0.05); there were no differences in these parameters between the two doses of FP. The addition of methacholine challenge testing allowed definition of a dose-response relationship that was not apparent with traditional efficacy variables.

This carefully designed study found no statistically significant growth suppression from one year of fluticasone propionate (FP) treatment at a dose of 0.1 to 0.2 mg/day. Although the authors point out that a small effect on growth could not be definitely excluded by their data, other investigators using the same daily dose of FP, found no reduction in growth relative to cromoglycate-treated controls¹.

Furthermore, children whose growth rate had been observed to decline during treatment with beclomethasone or budesonide (0.2 to 0.4 mg/day), accelerated their growth rate after switching to a lower and equally effective antiasthmatic dose of FP (0.1 to 0.2 mg/day)².

This and previously published studies^1,2,3,4,5 demonstrate that tolerance quickly develops to the bronchoprotective effect of salmeterol on methacholine or allergen or exercise induced bronchoconstriction - and that this is not preventable by co-treatment with an inhaled steroid. Of concern is the possibility that this might augment an adverse effect of long-term salmeterol use on airways inflammation and the risk of developing chronic airflow limitation.

Until the clinical significance of these findings has been more fully established, they favour a conservative approach to the use of long-acting b-agonist bronchodilators as maintenance therapy, particularly in atopic subjects.

Drotar DE, Davis EE, Cockcroft DW
Department of Medicine, Royal University Hospital, Saskatoon, Canada.

BACKGROUND: Regular use of salmeterol has been associated with reduced bronchoprotective effect against methacholine as early as 24 hours after initiating treatment. OBJECTIVE: To determine whether loss of the bronchoprotective effect measured one hour after salmeterol could be demonstrated 12 hours following one previous dose. METHODS: Ten subjects with stable, mild asthma were enrolled in a randomized, placebo-controlled, double-blind, crossover study comparing two 2-dose treatment periods: (1) blinded salmeterol 50 microg inhaled at bedtime, followed by unblinded salmeterol 50 microg inhaled 12 hours later and (2) blinded placebo inhaled at bedtime, followed by unblinded salmeterol 50 microg inhaled 12 hours later. The methacholine PC20 was measured one hour after the morning salmeterol; FEV1 was measured just prior to the morning salmeterol dose and at the start of the methacholine inhalation test. RESULTS: The mean log methacholine PC20 recorded one hour after a single dose of salmeterol (1.20 +/- 0.17 SE) was significantly higher than the mean log methacholine PC20 recorded after two doses of salmeterol at 12-hour intervals (1.00 +/- 0.16 SE; P = .024). The mean FEV1 12 hours after salmeterol was significantly higher than the mean FEV1 recorded 12 hours after placebo (P = .0017), however, there was no significant difference between the FEV1 recordings one hour after the two unblinded doses of salmeterol.
CONCLUSIONS: ...

ARLS

Congrès Conçue et réalisée par: Michel Godard (at)

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Date de création: 1er Mars 1996 -Dernière mise à jour: 17/06/99Le secret des correspondances transmises sur le réseau Internet n'est pas garanti. Toute personne citée dispose d'un droit d'accès, de modification, de rectification et de suppression des données le concernant (art. 34 de laloi "Informatique et Libertés"n° 78-17 du 6 janvier 1978). Pour l'éxercer adressez-vous àMichel Godard (at)

Title (1) :	Comparative clinical study of inhaled beclomethasone dipropionate and triamcinolone acetonide in persistent asthma.
Authors:	Bronsky E, Korenblat P, Harris AG, et al Annals of Allergy, Asthma & Immunology 1998;80:295-302
Comments by:	Professor Duncan Geddes Royal Brompton Hospital London SW3 6NP, England

Title (2) :	Budesonide delivered by Turbuhaler is effective in a dose-dependent fashion when used in the treatment of adult patients with chronic asthma
Authors:	Busse WW, Chervinsky P, Condemi J, et al J Allergy Clin Immunol 1998;101:457-463
Comments by:	Professor Duncan Geddes Royal Brompton Hospital London SW3 6NP, England

Title (3) :	Prednisolone in acute childhood asthma: clinical responses to three dosages
Authors:	Langton Hewer S, Hobbs J, Reid F, et al Respir Med 1998;92:541-546
Comments by:	Professor Duncan Geddes Royal Brompton Hospital London SW3 6NP, England

Title (4) :	Computer-based models to identify high-risk children with asthma
Authors:	Lieu TA, Quesenberry CP, Sorel ME, et al Am J Respir Crit Care Med 1998;157:1173-1180
Comments by: (previous comment next comment)	Professor Philippe Godard Hôpital Arnaud de Villeneuve 34059 MONTPELLIER CEDEX 1 , France

Title (5) :	Once-daily budesonide in mild asthma
Authors:	Chisholm SL, Dekker FW, Knuistingh Neven A, et al Respir Med 1998;92:421-425
Comments by: (previous comment next comment)	Professor Philippe Godard Hôpital Arnaud de Villeneuve 34059 MONTPELLIER CEDEX 1 , France

Title (6 ) :	Growth in asthmatic children treated with fluticasone propionate
Authors:	Allen DB, Bronsky EA, LaForce CF, et al J of Pediatrics 1998;132:472-477
Comments by: (previous comment next comment)	Professor Philippe Godard Hôpital Arnaud de Villeneuve 34059 MONTPELLIER CEDEX 1 , France

Title (7) :	Dose-related response to inhaled fluticasone propionate in patients with methacholine-induced bronchial hyperresponsiveness: a double-blind, placebo-controlled study
Authors:	Noonan MJ, Chervinsky P, Wolfe J, et al J of Asthma 1998 No. 2;35:153-164
Comments by:	Ass. Professor Leif Rosenhall Hudding University Hospital S-141 86 Huddinge, Sweden

Title (8) :	Growth in asthmatic children treated with fluticasone propionate
Authors:	Allen DB, Bronsky EA, LaForce CF, et al J Pediatr 1998;132:472-477
Comments by:	Professor John H. Toogood Victoria Hospital LONDON, Ontario N6A 4G5, Canada

Title (9) :	Tolerance to the bronchoprotective effect of salmeterol 12 hours after starting twice daily treatment
Authors:	Drotar DE, Davis EE, Cockcroft DW Ann Allergy Asthma Immunol 1998;80:31-34
Comments by:	Professor John H. Toogood Victoria Hospital LONDON, Ontario N6A 4G5, Canada