LOW DOSE INHALED CORTICOSTEROIDS AND THE PREVENTION OF DEATH FROM ASTHMA. Low-dose inhaled corticosteroids and the prevention of death from asthma

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1 ii74 * Thorax 2001;56(Suppl II):ii74 ii78 LOW DOSE INHALED CORTICOSTEROIDS AND THE PREVENTION OF DEATH FROM ASTHMA Department of Respiratory Diseases, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium J C Kips R A Pauwels Correspondene to: Dr J Kips johan.kips@rug.a.be ASTHMA Introdutory artile J C Kips, R A Pauwels Low-dose inhaled ortiosteroids and the prevention of death from asthma S Suissa, P Ernst, S Benayoun, M Baltzan, B Cai Bakground: Although inhaled ortiosteroids are effetive for the treatment of asthma, it is unertain whether their use an prevent death from asthma. Methods: We used the Saskathewan Health data bases to form a population-based ohort of all subjets from 5 44 years of age who were using antiasthma drugs during the period We followed subjets until the end of 1997, their 55th birthday, death, emigration, or termination of health insurane overage, whihever ame first. We onduted a nested ase-ontrol study in whih subjets who died of asthma were mathed with ontrols within the ohort aording to the length of follow-up at the time of death of the ase patient (the index date), the date of study entry, and the severity of asthma. We alulated rate ratios after adjustment for the subjet s age and sex; the number of presriptions of theophylline, nebulized and oral beta-adrenergi agonists, and oral ortiosteroids in the year before the index date; the number of anisters of inhaled beta-adrenergi agonists used in the year before the index date; and the number of hospitalizations for asthma in the two years before the index date. Results: The ohort onsisted of 30,569 subjets. Of the 562 deaths, 77 were lassified as due to asthma. We mathed the 66 subjets who died of asthma for whom there were omplete data with 2681 ontrols. Fifty-three perent of the ase patients and 46% of the ontrol patients had used inhaled ortiosteroids in the previous year, most ommonly low-dose belomethasone. The mean number of anisters was 1.18 for the patients who died and 1.57 for the ontrols. On the basis of a ontinuous dose-response analysis, we alulated that the rate of death from asthma dereased by 2% with eah additional anister of inhaled ortiosteroids used in the previous year (adjusted rate ratio 0.79; 95% onfidene interval 0.65 to 0.97). The rate of death from asthma during the first three months after disontinuation of inhaled ortiosteroids was higher than the rate among patients who ontinued to use the drugs. Conlusions: The regular use of low-dose inhaled ortiosteroids is assoiated with a dereased risk of death from asthma. (N Engl J Med 2000;343:332 6) AS AN INFLAMMATORY DISORDER OF THE AIRWAYS As insight into the pathogenesis of asthma inreases, so does the appreiation of the omplexity of the disease. Detailed morphologial analysis of asthmati airways reveals a ombination of aute inflammatory hanges haraterised by vasodilatation, inreased vasular permeability and an influx of ativated inflammatory ells, together with more hroni strutural alterations, so-alled airway remodelling. 1 This proess is thought to be largely orhestrated by allergen speifi Th2 ells and to involve a wide range of inflammatory ells as well as strutural tissue elements. However, the preise funtional role of eah of the ells and the mediators, ytokines, or growth fators they release within this inflammatory proess needs to be examined further. In addition, it is still not lear exatly how the various omponents of this inflammatory proess relate to the linial and lung funtion harateristis of the disease. It follows that the proper evaluation of a treatment strategy in asthma should not be based on a single outome measure. Instead, several indies of disease ativity should be assessed as they might all represent another aspet of the disease proess and therefore respond diverently to treatment. Ideally, this evaluation should inlude linial markers that reflet short term disease ontrol suh as symptoms, baseline fored expiratory volume in one seond (FEV 1 ), bronhial responsiveness, exaerbation rate, or disease related quality of life, in addition to a diret assessment of the degree of airway inflammation. This evaluation then needs to be omplemented by the long term monitoring in large groups of patients of asthma related Thorax: first published as on 1 September Downloaded from on 12 January 2019 by guest. Proteted by opyright.

2 Low dose inhaled ortiosteroids and prevention of death from asthma mortality and health are utilisation elements suh as hospital admissions or emergeny department visits. 2 Inhaled gluoortiosteroids in asthma Most of the above mentioned data are available for inhaled steroids. Numerous studies onsistently show in both hildren and adults that, ompared with monotherapy with short ating agonists, inhaled steroids are superior at improving symptoms, lung funtion, bronhial responsiveness, and the quality of life, 3 6 as well as reduing the number of exaerbations As onfirmed by several biopsy studies, these linial evets are aompanied by an evet on aute inflammation, with a redution in plasma exudation and ellular influx as well as a more limited dose dependent evet on airway remodelling Moreover, larger population studies indiate that the use of inhaled steroids protets against severe exaerbations requiring hospitalisation and redues the likelihood of readmission or death following disharge from hospital Analysis of the Saskathewan Health Insurane data indiates that treatment with inhaled steroids also diminishes the risk of fatal and near fatal asthma in the ommunity. 23 The study by Suissa et al (introdutory artile) further strengthens this onept by establishing that the use of inhaled steroids is assoiated with a redution in asthma related mortality. 24 This is in line with studies from the UK that have reported a redution in asthma mortality in patients aged 65 years or less in onjuntion with inreased presription of inhaled steroids. 25 The onfirmation that treatment with inhaled steroids is assoiated with redued asthma related mortality in a large ommunity survey obviously is of interest and further underlines the potential of inhaled steroids in the treatment of asthma. At the same time, this study raises a number of unanswered questions. Mortality in asthma Asthma related mortality is a rare event. The inidene over the past 30 years in industrialised ountries has varied from <1 to 8 per inhabitants per year Mortality in the USA has traditionally been lower than in European ountries inluding the UK. 27 However, whereas in the UK a derease in mortality has been observed in nearly all age groups from 1983 to despite the inrease in the prevalene of asthma, 28 mortality in the USA has risen by 46% from 1980 to In addition, the USA data indiate that asthma mortality ontinues to avet non-white subjets, urban areas, and the deprived population disproportionately. 30 It needs to be remembered that, even in these patient groups, the overall asthma related mortality is low ompared with other pulmonary diseases suh as lung aner or hroni obstrutive pulmonary disease (COPD). Some studies have even questioned the impat of asthma on expeted longevity. Most studies, however, onfirm that asthma is assoiated with inreased mortality, mainly from respiratory diseases inluding status asthmatius and onomitant COPD Notwithstanding the potential for diagnosti inauray, 37 this presumably reflets in large part the additional risk assoiated with igarette smoking. From the desription of ases of fatal and non-fatal asthma it appears that asthma deaths an be divided into two groups: a few ases experiene a sudden attak without apparent worsening 39 but, in the majority, a more gradual deterioration leading to inreasing airflow obstrution over a period of several hours to days has been observed. 40 The risk fators that have been identified relate mainly to this latter group and inlude environmental as well as patient and physiian related fators. 41 Exposure to high levels of outdoor allergens has been shown to inrease the risk of respiratory arrest from asthma. 42 This might also explain the observation in Britain that the inidene of asthma related deaths in young patients shows a seasonal inrease in the summer. 25 Although inreased hospital admissions have been related to pollution, longer term studies do not support the relationship between mortality rate and the onentration of air pollutants. 43 Probably more important than environmental fators are patient and physiian related elements. 44 The most onsistent risk fator for fatal asthma is admission to hospital beause of asthma in the previous 12 months, partiularly if there was a need for mehanial ventilatory support. Most of these patients are onsidered to have severe asthma, although unontrolled asthma would seem to be a more appropriate label. 45 Even patients onsidered to have mild asthma are at risk of fatal attaks if their asthma is poorly ontrolled. Various elements an ontribute to the lak of proper asthma ontrol. Patient related fators inlude poor pereption and reporting of symptoms, psyhiatri aseness, poor soioeonomi status, low level of eduation, and suboptimal ompliane with treatment. It is oneivable that the ombination of these diverent elements results in limited aess to are and/or poor adherene to proper treatment regimens. In addition, studies onduted in the 1980s, suh as the retrospetive analysis performed by the British Thorai Soiety panel on asthma deaths, have drawn attention to defiienies in aspets both of primary and hospital based are Problems highlighted inluded failure to diagnose asthma, undertreatment, and inadequaies in severity assessment or treatment of fatal attaks At the same time it was shown that, by inreasing the availability of dediated pre-hospital emergeny servies and the aessibility to hospital emergeny are, asthma related mortality an be evetively redued. Nearly 20 years have elapsed sine these observations and during that period intensive evorts have been made, towards both the publi and health are professionals, to inrease the awareness of the high prevalene and morbidity assoiated with asthma. Consensus reports on the diagnosis and treatment of asthma that inlude patient orientated eduation have been widely disseminated. 60 It an be postulated that this has resulted over the past two deades in an overall inrease in the quality of asthma are, of whih the inreased presription of inhaled steroids is only one element. The observation that asthma mortality has dereased despite the inrease in prevalene in ountries suh as the UK would seem to support this hypothesis. However, this does not mean that we should beome omplaent. Reent surveys in Europe, Australia, Canada, and the USA have shown that asthma management is still not optimal One of the striking observations emerging from the AIRE study is that, whereas most of the patients used as needed β 2 agonists, even in the group of patients with severe symptoms only 25% used inhaled steroids. 64 Both insuyient presription and the unwillingness of patients to use the presribed ompounds are likely to ontribute to the low use of steroids. Studies based on questionnaires as well as general pratie reords indiate that maintenane treatment is still insuyiently presribed by physiians Data from a similarly designed Canadian study indiate that most patients do not understand the *ii75 Thorax: first published as on 1 September Downloaded from on 12 January 2019 by guest. Proteted by opyright.

3 Kips, Pauwels ii76 * Learning points Evaluation of the effiay of treatment in asthma should be based on as wide a range of outome measures as possible. Inhaled steroids remain the most effetive form of asthma treatment urrently available. Low doses of inhaled steroids are ost effetive in the treatment of asthma. At present there are no data to indiate that ombined treatment with long ating agonists and steroids inreases asthma mortality. Most ases of fatal asthma are probably preventable. Reent surveys indiate that asthma management is still suboptimal throughout Europe. rationale for using inhaled steroids and most of them have signifiant fears onerning their side evets. 69 In addition, the ost of steroids and resentment to the use of regular mediation an further diminish patient adherene to inhaled steroids The study by Suissa et al further adds to the evidene that inhaled steroids, even at low doses, are ost evetive at improving asthma ontrol. 72 In addition, the safety of low to moderate doses of inhaled steroids, even when used over a long period, is inreasingly being reognised. 73 Reiteration of this information to both physiians and patients would therefore seem very appropriate. It has been shown that speifi eduation programmes fousing on the pratial implementation of onepts introdued in the guidelines inrease the presription rate and adherene to steroids, improving the overall degree of asthma ontrol How do inhaled steroids redue asthma mortality? A final element that needs to be onsidered in relation to the study by Suissa et al is whether the observed evet on mortality is speifi to the use of inhaled steroids. As already mentioned, it is unlear to what extent the observed evet is onfounded by an inrease in overall quality of asthma are. The initial report based on the Saskathewan data indiates that the risk of fatal or near fatal asthma was lower in patients who had been presribed more than one anister of inhaled steroids per month. The risk profile for asthma related mortality in this group was not lower in the number of patients who had been presribed less than one anister per month, nor was there any diverene in the number of speialist visits by the two groups. 23 Similarly, ontrolling for the rate of routine ambulatory are did not appreiably alter the reported protetive evet of inhaled steroids on hospital admissions. 19 When aggregated, these and other observations seem to indiate that the evets obtained an be attributed to the pharmaologial ativities of inhaled steroids. Exatly how inhaled steroids redue the likelihood of developing a life threatening asthma attak is unknown. Severe asthma exaerbations are thought to reflet exessive airway narrowing. 41 Inhaled steroids have been shown to redue the degree of maximal airway narrowing in asthma but the dose response harateristis of inhaled steroids on this aspet of airway physiology have not been fully established. In epidemiologial studies the risk of asthma mortality has been shown to orrelate with blood eosinophil ounts and lung funtion variability. 35 The responsiveness of peak flow riteria and sputum eosinophil ounts to low doses of inhaled steroids has been onviningly demonstrated The evet of inhaled steroids on hospital admissions also ompares favourably with the evet of romones or theophylline, two mediations that have some anti-inflammatory evets but less pronouned than those of inhaled steroids. It is noteworthy with respet to the inreased asthma mortality rate assoiated with smoking that smoking might redue the anti-inflammatory evet of inhaled steroids. 86 Another potentially interfering element that needs to be onsidered is the onomitant use of β 2 agonists. There is onsensus that the exessive use of short ating agonists is a marker of inreased risk of an adverse asthma outome. However, the ausal assoiation between short ating agonists and inreased asthma mortality is a highly debated issue whih we do not wish to develop further here. More importantly, in view of the inreased use of ombination produts, is the potential influene on asthma mortality of presribing long ating agonists with inhaled steroids. Currently available evidene indiates that ombined treatment with inhaled steroids and long ating agonists, but not short ating agonists, improves asthma ontrol and redues the number of exaerbations In addition, treatment with long ating agonists does not seem to worsen the severity of the exaerbations 91 nor to mask progression of the underlying airway inflammation, judged by sputum eosinophil ounts. 92 To what extent these observations an be extrapolated to more severe exaerbations that require hospital admission and mortality is at present unknown. Based on a reent ase ontrol study it would seem that the use of salmeterol by patients with hroni severe asthma is not assoiated with a signifiantly inreased risk of developing a near fatal asthma attak. 93 Moreover, the introdution of fixed ombinations of inhaled steroids with long ating agonists not only asertains the onomitant use of inhaled steroids but should also inrease ompliane with them. The added benefit of the inreased use of inhaled ortiosteroids is likely to outweigh the hypothetial drawbak assoiated with the use of long ating agonists on long term asthma ontrol. Large sale surveillane data will undoubtedly larify this issue further. Conlusion The data by Suissa et al one more underline the ost evetiveness of low doses of inhaled steroids on asthma ontrol. EVorts should be ontinued to publiise this finding. Thorax: first published as on 1 September Downloaded from on 12 January 2019 by guest. Proteted by opyright.

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