asthma mortality in portugal

Treat Respir Med 2006; 5 (2): 143-147ORIGINAL RESEARCH ARTICLE 1176-3450/06/0002-0143/$39.95/0

© 2006 Adis Data Information BV. All rights reserved.

Asthma Mortality in PortugalImpact of Treatment with Inhaled Corticosteroids and LeukotrieneReceptor Antagonists

Magda Nunes de Melo,1 Zilda Mendes,1 Paula Martins1 and Samy Suissa2

1 Centro de Estudos de Farmacoepidemiologia, Associacao Nacional das Farmacias, Lisbon, Portugal2 Division of Clinical Epidemiology, Pharmacoepidemiology Unit, Royal Victoria Hospital, McGill University Health

Center, Montreal, Quebec, Canada

Objective: To determine whether the use of inhaled corticosteroids or leukotriene receptor antagonists (LTRAs)Abstracthas had an impact on asthma mortality in Portugal during the period 1991–2001.Methods: A population-based ecological study was conducted for the period 1991–2001. Yearly asthma deathrates were computed for all ages. Data on sales of inhaled corticosteroids and LTRAs were obtained andexpressed in defined daily doses (DDDs)/year. The association between the yearly rate of asthma deaths andconsumption of these medications was estimated using Poisson regression.Results: The rate of asthma death decreased steadily from 39.4 per million inhabitants in 1991 to 14.2 in 2001.At the same time, the use of inhaled corticosteroids in the population increased from 5.8 to 22.2 million DDDsper year. The adjusted rate ratio of asthma death was 0.85 (95% CI 0.78, 0.92) for every additional 5 millionDDDs of inhaled corticosteroids per year and 0.84 (95% CI 0.70, 1.02) for every additional 5 million DDDs ofLTRAs per year.Conclusion: The increasing use of inhaled corticosteroids and leukotriene receptor antagonists during the 1990sin Portugal appears to have contributed to the reduction in asthma mortality in that country.

During the past decade asthma mortality rates have been declin- bursed by the National Health System from the ninety-fourthposition to the fortieth position by the year 2002. Portugal, likeing in several countries.[1-5] It is believed that inhaled corticoste-most countries supporting drug plans, operates within a tightroids have contributed to this decline, as these drugs have becomebudget and seeks to ensure that expenditures have a positivethe treatment of choice in the management of asthma.[6-11] Evi-return. To date, the impact of inhaled corticosteroids or LTRAs ondence has shown that inhaled corticosteroids are very effective inmajor asthma outcomes in the Portuguese population has not beencontrolling the symptoms of asthma, reducing airway inflamma-investigated.tion and hyper-responsiveness.[9] Inhaled corticosteroids have also

The aim of our study was to determine whether the use ofbeen associated with a reduction in the rate of asthma hospitaliza-anti-inflammatory therapy, namely inhaled corticosteroids andtion[12,13] and rehospitalization,[14,15] and with a reduction in theLTRAs, had an impact on asthma mortality in Portugal during thedeath rates from asthma.[16-18]

period 1991–2001.In Portugal, inhaled corticosteroids have been ranked among

the top 100 drugs, with the highest expenditure to the National MethodsHealth System. Leukotriene receptor antagonists (LTRAs), themost recent novel class of anti-asthma drugs, were introduced in

Study DesignPortugal in 1998 and are recommended either as adjunct treatmentto inhaled corticosteroids[11,19] or as an alternative to corticoste- A population-based ecological study was conducted to corre-roids in mild asthma.[19] Since their introduction in Portugal in late the consumption of inhaled corticosteroids and LTRAs with1998, LTRAs have risen in expenditure rankings of drugs reim- asthma mortality in Portugal, during the period 1991–2001. We

144 Nunes de Melo et al.

estimated the yearly rate of asthma death over this period and estimate rate differences associated with LTRAs and inhaledverified whether the rate changed with the use of inhaled cortico- corticosteroid consumption. All models included an adjustmentsteroids and LTRAs. In particular, we evaluated whether the for extra-Poisson year-to-year variability. Because the populationchange in asthma mortality was associated with the time of intro- in Portugal is relatively small (10 million), we did not stratify theduction of LTRAs into the Portuguese market (both montelukast analyses by age. Confidence intervals were computed at the 95%and zafirlukast were marketed in Portugal in 1998). level. All analyses were performed using SAS software version

8.2 (1999–2001) developed by the SAS Institute, in Cary, NorthData Measurements Carolina, USA.

Annual data on the size of the population and the number ofResultsasthma deaths (International Classification of Diseases, ninth revi-

sion [ICD-9] codes 493.0 to 493.9[20]) were obtained directly from The average annual asthma death rate was 25.9 deaths perthe Portuguese Institute of National Statistics. Data on sales of million people during the period 1991–2001. This rate decreasedinhaled corticosteroids and LTRAs were obtained directly from steadily from 39.4 in 1991 to 14.2 deaths per million people inIMS-Health Portugal. All drug sales were standardized to total 2001. The average asthma death rate for the total population wasdefined daily doses (DDDs) consumed per year in Portugal. The 28.9 per million during the period prior to the introduction ofDDD is defined as the assumed average maintenance dose per day LTRAs (1991–8) and 17.9 per million thereafter (1999–2001), forfor a drug used in its main indication in adults.[21] DDDs for all a rate reduction of 38% (table I). The group older than 64 yearstherapeutic agents under study have been set by the WHO Collab- contributed to 78% of all deaths, and their average death rateorating Centre for Drug Statistics Methodology.[22] Thus, the decreased from 151.8 per million before the introduction ofDDDs/year were first calculated for each individual preparation LTRAs to 88.7 per million after the introduction of LTRAs.and combined to obtain estimates of total DDDs/year for the two Concurrent with the gradual reduction in the asthma death ratedifferent drug categories under study, namely inhaled corticoste- during the period 1991–2001, sales of inhaled corticosteroids roseroids and LTRAs. from 5.8 million to 22.2 million DDDs per year. Figure 1 and

figure 2 depict the yearly asthma death rate per million inhabitantsData Analysis

for all ages, along with annual sales in millions of DDDs/year ofinhaled corticosteroids and LTRAs, respectively. The consump-Rates of asthma death were computed as the ratio of the numbertion of inhaled corticosteroids and LTRAs (on the market sinceof deaths to the total population in each calendar year. Poisson1998) increased steadily while asthma death rates declined (figureregression models were used for all analyses. For the secular trend1 and figure 2).analysis, log-linear models were used to estimate the rate ratio of

asthma death before and after the introduction of LTRAs. To Table II shows the results of the Poisson regression analysis forcorrelate the total annual drug consumption with the correspond- the crude effect of each drug and adjusted for each other. Theing annual rate of asthma death, a log-linear model was fitted to adjusted rate ratio of asthma death was 0.85 (95% CI 0.78, 0.92)estimate rate ratios. A linear excess risk model was used to for every 5 million DDDs of inhaled corticosteroids per year and

Table I. Overall asthma death rates and drug sales standardized to total defined daily doses (DDDs) per year in Portugal during the period 1991–2001

Parameter Time period

before introduction of LTRAs in after introduction of LTRAs inPortugal (1991–8) Portugal (1999–2001)

No. of years 8 3

Asthma death rate

rate per million inhabitants 28.9 17.9

95% CI 25.5, 32.3 13.8, 21.9

Drug sales (DDDs × 106 per year)a

inhaled corticosteroids 11.2 ± 4.1 20.4 ± 1.8

LTRAs 0 7.2 ± 0.9

a Data are presented as mean ± standard deviation.

LTRAs = leukotriene receptor antagonists.

© 2006 Adis Data Information BV. All rights reserved. Treat Respir Med 2006; 5 (2)

Impact of Anti-Inflammatory Drugs on Asthma Mortality 145

This study has several methodologic limitations. One pertainsto the limited validity inherent in ecologic designs.[24] The use ofaggregate data makes it impossible to establish a direct linkbetween the individual patients exposed to a particular agent (inthis case, anti-inflammatory therapy) and the outcome under study(asthma mortality). On the other hand, ecologic studies can beuseful in assessing the impact of a drug at the population level andare important for generating hypotheses. Our conclusion that theseinterventions have contributed to the decrease of asthma deathrates in Portugal is supported by causality studies that associatedthe use of inhaled corticosteroids with decreased asthma mortali-

05

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1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001

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ate

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0

5

10

15

20

25

Sal

es (

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of D

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s/ye

ar)Asthma death rate

Sales of inhaled corticosteroids

Fig. 1. Yearly asthma death rate per million people in Portugal during theperiod 1991–2001, and sales of inhaled corticosteroids in defined dailydoses (DDDs)/year.

ty.[16,18] The present study, however, could not separate the effectof inhaled corticosteroid use from that of LTRA consumption on0.84 (95% CI 0.70, 1.02) for every 5 million DDDs of LTRAs perasthma mortality.year. These correspond to reductions in the asthma death rate of

4.6 per million inhabitants, with every 5 million DDDs of inhaled Potential misclassification in the coding of cause of death mustcorticosteroids per year, and of 2.5 deaths per million inhabitants be considered when analyzing mortality data. The steady decreasewith every 5 million DDDs of LTRAs per year. in asthma mortality observed during the entire study period was

slightly more pronounced after 1998. This could result either fromDiscussion

a reduction in the risk of asthma death or from better diagnosis ofthe cause of death for conditions that resemble asthma. A Portu-We found that asthma mortality in Portugal decreased steadilyguese mortality report observed an unexpected change in theduring the 1990s. Concurrently, the use of anti-inflammatorynumber of deaths from bronchitis in 1998 and noted that it couldmedications, including inhaled corticosteroids and LTRAs, in-be due to transference in the number of deaths among patients withcreased during this past decade (1991–2001), indicating a signifi-respiratory diseases because of more refined diagnosis.[25] Howev-cant impact of inhaled corticosteroids on asthma mortality. Theer, the fact that the age distribution of asthma deaths remainedeffect of LTRAs on the asthma death rate, although of a slightly

higher magnitude than that observed with inhaled corticosteroids, relatively constant between 1991 and 2001 (data not shown) doeswas similar in the adjusted model for both drugs; nevertheless, the not support the notion of such a shift in diagnostic classification.95% confidence interval for the effect of LTRA on asthma death Evidence has shown that diagnoses of asthma mortality are wellrate crossed the null value. established in the 5- to 34-year age group and that accuracy of

Several other countries, including the UK, Israel, Japan and these diagnoses decline with increasing age, with false-positiveNew Zealand, have observed similar reductions in asthma deaths reporting rates of >30% in patients aged ≥65 years.[26] It is possibleand their association with the use of anti-inflammatory ther- that our asthma deaths rates were overestimated, as the majority ofapy.[2,3,5,23] The study from Japan, however, was the only investi- asthma deaths occurred in the age group ≥65 years (data notgation on the effects of LTRAs, in addition to inhaled corticoste- shown). We were not able to correlate asthma mortality rates forroids, on asthma mortality.[5] Most studies have focused on asthmamortality among the younger 5- to 34-year age group, whichrepresents only a small proportion of all asthma deaths. In Portu-gal, a country of only 10 million inhabitants, only 4% of all asthmadeaths occur in this age group. Thus, in terms of numbers andpercentages, the relevant public health question, on the impact ofthese drugs on asthma mortality, should be directed at overallasthma mortality rather than mortality in the small younger sub-group of patients. This study is the first to show an impact ofinhaled corticosteroids and LTRAs on asthma mortality over allage groups, including patients over 64 years of age, who accountfor 78% of all asthma deaths in Portugal. It is likely that this agegroup experienced the greatest benefit from these drugs.

05

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1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001

Calendar year

Asthma death rateSales of LTRAs

0123456789

Dea

th r

ate

(per

mill

ion

peop

le)

Sal

es (

mill

ions

of D

DD

s/ye

ar)

Fig. 2. Yearly asthma death rate per million people in Portugal during theperiod 1991–2001, and sales of leukotriene receptor antagonists (LTRAs)in defined daily doses (DDDs)/year.


146 Nunes de Melo et al.

Table II. Rate ratio (RR) and rate difference (RD) of asthma deaths in Portugal, associated with the use of inhaled corticosteroids and leukotriene receptorantagonists (LTRAs) during the period 1991–2001

RRa 95% CI RDb 95% CI

Crude analysis

Inhaled corticosteroids 0.80 0.75, 0.85 –5.8 –7.2, –4.4

LTRAs 0.65 0.52, 0.80 –9.6 –13.5, –5.7

Adjusted analysisc

Inhaled corticosteroids 0.85 0.78, 0.92 –4.6 –7.0, –2.3

LTRAs 0.84 0.70, 1.02 –2.5 –6.7, 1.7

a RR of asthma deaths per additional 5 million DDDs of inhaled corticosteroids or LTRAs per year.

b RD of asthma deaths per million people per year associated with every additional 5 million DDDs of inhaled corticosteroids or LTRAs per year.

c One model with both drug consumption variables (sales of inhaled corticosteroids and sales of LTRAs) so that the effect of one drug is adjustedfor the effect of the other drug on asthma mortality.

DDDs = defined daily doses.

the 5- to 34-year age group with the use of inhaled corticosteroids should be investigated further using more rigorous individual-based epidemiologic designs rather than ecologic studies.or LTRAs because mortality rates in this age group were very low.

When interpreting sales data expressed in DDDs two assump-Acknowledgmentstions must be made.[21] Firstly, that the patient actually uses the

medication once it has been dispensed, and secondly that the dosesWe would like to acknowledge IMS-Health Portugal for supplying theused for the treatment of the condition under investigation, in this

drug sales data. Many thanks are due to Dr Jose Mouronho (Instituto Nacionalcase asthma, are the average maintenance doses. Prescription

de Estatistica, Lisbon, Portugal) for providing the information on asthmapatterns for anti-inflammatory therapy for asthma patients in Por- deaths and size of the Portuguese population. Magda Melo, Zilda Mendes and

Paula Martins are employees of the Associacao Nacional das Farmacias,tugal have not yet been studied to allow comparison between theLisbon, Portugal, which funds the Centro de Estudos de Farmacoepidemio-DDDs and the actual prescribed daily doses. Moreover, since ourlogia (CEFAR, Lisbon, Portugal). Dr Suissa is the recipient of a Distinguished

sales data are not linked to the patients or to the indication, itInvestigator award from the Canadian Institutes of Health Research (CIHR).

cannot be assumed that all inhaled corticosteroids analyzed in this The authors declared no conflict of interest.study were used only for the treatment of asthma. Reports that15% of patients receiving inhaled corticosteroids had an indication

Referencesother than asthma,[2] and that 85% of patients with COPD were1. Bucknall CE, Slack R, Godley CC, et al. Scottish confidential inquiry into asthma

receiving inhaled corticosteroid therapy,[27] indicate that these deaths (SCIAD), 1994-6. Thorax 1999 Nov; 54 (11): 978-842. Campbell MJ, Cogman GR, Holgate ST, et al. Age specific trends in asthmadrugs are used widely for other indications besides asthma. Thus, a

mortality in England and Wales, 1983-95: results of an observational study.proportion of the inhaled corticosteroids studied are likely to have BMJ 1997 May 17; 314 (7092): 1439-41

3. Goldman M, Rachmiel M, Gendler L, et al. Decrease in asthma mortality rate inbeen used in the treatment and management of respiratory condi-Israel from 1991-1995: is it related to increased use of inhaled corticosteroids? J

tions other than asthma, such as COPD. Conversely, we do not Allergy Clin Immunol 2000 Jan; 105 (1 Pt 1): 71-44. Picard E, Barmeir M, Schwartz S, et al. Rate and place of death from asthma amongknow what percentage of asthma patients in Portugal use inhaled

different ethnic groups in Israel: national trends 1980 to 1997. Chest 2002 Oct;corticosteroids. A study on asthma and chronic bronchitis in 122 (4): 1222-7

5. Suissa S, Ernst P. Use of anti-inflammatory therapy and asthma mortality in Japan.patients enrolled in sentinal-general practitioners’ practices inEur Respir J 2003 Jan; 21 (1): 101-4Portugal showed that in 1996 only 31.4% of patients with asthma

6. Boulet LP, Becker A, Berube D, et al. Canadian asthma consensus report, 1999.used inhaled corticosteroids as maintenance therapy.[28] Canadian Asthma Consensus Group. CMAJ 1999 Nov 30; 161 (11 Suppl.):

S1-61In our study we observed an association between sales of 7. British Thoracic Society. Guidelines for asthma management. Thorax 1997; 52:

S1-21inhaled corticosteroids and LTRAs, and asthma mortality in Portu-8. Makino SFK, Miyamoto T, Ohta K. Asthma prevention and management guide-

gal during the period 1991–2001. The effect of LTRAs on reduc- lines. Ministry of Health and Welfare, Japan. Int Arch Allergy Immunol 2000;121 Suppl. 1: 1-77ing asthma mortality was slightly less compared with inhaled

9. Barnes PJ. Current issues for establishing inhaled corticosteroids as the antiinflam-corticosteroids and ought to be explored further. The implicationmatory agents of choice in asthma. J Allergy Clin Immunol 1998 Apr; 101 (4 Pt

that this effect was observed across all age groups is novel and 2): S427-33


Impact of Anti-Inflammatory Drugs on Asthma Mortality 147

10. Hargreave FE, Dolovich J, Newhouse MT. The assessment and treatment of 21. WHO Collaborating Centre for Drug Statistics Methodology. Guidelines forasthma: a conference report. J Allergy Clin Immunol 1990 Jun; 85 (6): DDDs. 2nd ed. Oslo, Norway: WHO Collaborating Centre for Drug Statistics1098-111 Methodology, 1993

22. WHO Collaborating Centre for Drug Statistics Methodology. Anatomic Therapeu-11. Global Initiative for Asthma. Pocket guide for asthma management and prevention.tic Chemical (ATC) classification index with Defined Daily Doses (DDDs).Bethesda (MD): NIH, 2003. Report No.: Updated from NHLBI/WHO Work-January 2001 ed. Oslo, Norway: WHO Collaborating Centre for Drug Statisticsshop Report: Global Strategy for Asthma Management and Prevention issuedMethodology, 2001January 1995 and revised 2002. NIH Publication No. 02-3659

23. Garrett J, Kolbe J, Richards G, et al. Major reduction in asthma morbidity and12. Suissa S, Ernst P, Kezouh A. Regular use of inhaled corticosteroids and the longcontinued reduction in asthma mortality in New Zealand: what lessons haveterm prevention of hospitalisation for asthma. Thorax 2002 Oct; 57 (10): 880-4been learned? Thorax 1995 Mar; 50 (3): 303-1113. Blais L, Suissa S, Boivin J, et al. First treatment with inhaled corticosteroids and

24. Rothman KJ, Greenland S. Modern epidemiology. 2nd ed. Philadelphia (PA):the prevention of admissions to hospital for asthma. Thorax 1998; 53: 1025-9Lippincott Williams & Wilkins, 199814. Sin DD, Tu JV. Inhaled corticosteroid therapy reduces the risk of rehospitalization

25. Nogueira PJ, Falcao JM. Causas de morte com alteracoes inesperadas em 1998. 1stand all-cause mortality in elderly asthmatics. Eur Respir J 2001 Mar; 17 (3):ed. Lisboa: Instituto Nacional de Saude Dr. Ricardo Jorge; Ministerio da Saude,380-5200115. Alsaeedi A, Sin DD, McAlister FA. The effects of inhaled corticosteroids in

26. Masoli M, Fabian D, Holt S, et al. Global burden of asthma. Allergy 2004; 59:chronic obstructive pulmonary disease: a systematic review of randomized469-78placebo-controlled trials. Am J Med 2002; 113: 59-65

27. Jackevicius CA, Chapman KR. Prevalence of inhaled corticosteroid use among16. Suissa S, Ernst P, Benayoun S, et al. Low-dose inhaled corticosteroids and thepatients with chronic obstructive pulmonary disease: a survey. Annprevention of death from asthma. N Engl J Med 2000 Aug 3; 343 (5): 332-6Pharmacother 1997 Feb; 31 (2): 160-417. Kips JC, Pauwels RA. Low dose inhaled corticosteroids and the prevention of

28. Monsanto A, Ascensao P. Bronquite cronica e asma. Luso: Reuniao anual dosdeath from asthma. Thorax 2001 Sep; 56 Suppl. 2: ii74-8Medicos Sentinela, 199718. Lanes SF, Garcia Rodriguez LA, Huerta C. Respiratory medications and risk of

asthma death. Thorax 2002 Aug; 57 (8): 683-619. Lipworth BJ. Leukotriene-receptor antagonists. Lancet 1999 Jan 2; 353 (9146):

Correspondence and offprints: Samy Suissa, Division of Clinical Epidemiol-57-62ogy, Royal Victoria Hospital, 687 Pine Avenue West, R.4.29, Montreal, QC,20. International Classification of Diseases 9th revision – clinical modification. Ann

Arbor (MI): Commission on Professional and Hospital Activities, 1991 Canada H3A 1A1.


asthma mortality in portugal

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