Case-Control Study Ofprescribed Fenoterol

170 Thorax 1990;45:170-175 Case-control study of prescribed fenoterol and death from asthma in New Zealand, 1977-81 Thorax: first published as 10.1136/thx.45.3.170 on 1 March 1990. Downloaded from N Pearce, J Grainger, M Atkinson, J Crane, C Burgess, C Culling, H Windom, R Beasley Abstract A recent New Zealand case-control study,' A previous New Zealand case-control conducted by our group, tested the hypothesis study of asthma deaths in the 5-45 year that the unsupervised self administration of age group during 1981-3 found that pres- fenoterol by inhalation increases the risk of cription of fenoterol (by metered dose death from asthma. This hypothesis arose inhaler) was associated with an increased primarily from epidemiological evidence link- risk of death in patients with severe ing the sale of fenoterol to the epidemic of asthma. One major criticism ofthis study deaths from asthma that New Zealand has was that drug data for the cases and experienced since the late 1970s,' 2 and controls came from different sources. A experimental evidence that fenoterol is a less new case-control design has been used to selective beta2 agonist than salbutamol, the evaluate the same hypothesis, with a dif- most commonly used beta agonist.3 The possi- ferent set of asthma deaths, the same ble mechanisms ofaction remain to be clarified, source for drug information being used but several potential mechanisms are apparent; for both cases and controls. This depen- these depend on whether the association is with ded on identifying deaths from asthma long term use of fenoterol or use in the acute during 1977-81 from national mortality attack. Long term use may be associated with records, and ascertaining which patients tachyphylaxis, as was suggested with isopren- from those who died had been admitted to aline,4 or with increases in airway hyperrespon- a major hospital for asthma during the 12 siveness following beta agonist treatment,5 months before death. The study was con- which may lead to more severe asthma. fined to this subgroup, which accounted Repeated self administration of high doses of a for about 20% of all asthma deaths in the longer acting and less selective beta2 agonist areas served by a major hospital. For each during an acute attack could result in delay in of the eligible patients who died four age seeking medical advice,6 hypokalaemia,7 and matched controls were selected from adverse cardiac effects,3 particularly when http://thorax.bmj.com/ patients admitted to hospital for asthma hypoxaemia is present.8 Hypoxaemia may be during the year that the death occurred made worse because beta agonists may disturb who had also had an admission for ventilation-perfusion relationships.9 asthma in the previous 12 months. For the The previous study related to the period 58 cases and 227 control subjects informa- August 1981-July 1983, and compared the tion on prescribed drugs was collected prescribed drug treatment ofpatients who died from the hospital records relating to the of asthma with that of patients with severe previous admission. The odds ratio of asthma who did not die. The findings were on October 4, 2021 by guest. Protected copyright. asthma death in patients prescribed consistent with the hypothesis that inhaled inhaled fenoterol was 1-99 (95% con- fenoterol increases the risk of death in patients fidence interval 112-3-55, p = 0 02). As in with severe asthma. We could not, however, the previous study, subgroups defined by exclude all possible sources ofbias, particularly markers of chronic asthma severity were as information on prescribed asthma drugs was Department of also considered. The inhaled fenoterol obtained from different sources for the cases Community Health odds ratio was 2-98 (95% CI 1-15-7 70, p = and controls. We have now examined the N Pearce in three or more further in a study of deaths from C Culling 0 02) patients prescribed hypothesis categories of asthma drugs, 3-91 (95% CI asthma in New Zealanders aged 5-45 years Department of Medicine, Wellington 179-8 54, p < 0-01) in patients with a during 1977-81. Information on drugs pres- School ofMedicine, previous admission for asthma in the past cribed for asthma has been obtained from the Wellington, New 12 months, and 5 83 (95% CI 1-62-21-0, p = same sources for both cases and controls, the Zealand J Grainger 0-01) in patients prescribed oral cortico- major potential source of bias in the previous M Adtinson steroids at the time of admission. In study thus being avoided. J Crane patients with the most severe asthma C Burgess H Windom (defined by a previous admission for R Beasley asthma during the past 12 months and Methods Address for reprint requests: prescribed oral corticosteroids at time of Dr N Pearce, Departnent of admission) the inhaled fenoterol odds SELECTION OF SUBJECTS Community Health, < Cases The cases all Wellington School of ratio was 9-82 (95% CI 2-23-43 4, p 0 01). potential comprised Medicine, PO Box 7343 These findings add further support to the patients aged 5-45 years who died from asthma Wellington South, New in the Zealand hypothesis that inhaled fenoterol in- New Zealand during period January with 1977-July 1981, and who had been admitted Accepted 13 November creases the risk of death in patients 1989. severe asthma. for asthma to a major hospital during the 12 Case control study ofprescribedfenoterol and deathfrom asthma in New Zealand, 1977-81 171 months before death. The study was confined tion that identified cases and controls was to those aged 5-45 years as before,' as death deleted. Two members of the study team (CB from asthma is a reasonably clearcut diagnosis and JC) then made a blind assessment of the in this age range.'0 Asthma deaths (ICD code drugs at admission and discharge. In one case were identified and six controls no information was available 493) from registrations at the Thorax: first published as 10.1136/thx.45.3.170 on 1 March 1990. Downloaded from National Health Statistics Centre. For each on the drugs at discharge, and they were death the records of hospitals to which the assumed to be the same as the drugs at admis- patient was likely to have been admitted in an sion. Information from subsequent chest clinic acute attack were then searched to identify any and outpatient visits was available for some admission for asthma in the previous 12 cases and controls, but this was relatively months. Ifsuch an admission was identified the incomplete. Thus, unless otherwise specified, death was included in the study, and the all findings refer to -drugs prescribed at dis- admission closest to the date of death was used. charge. The- study was based on the same major hos- As in the previous study, the possibility of pitals that we used in the previous study, with confounding or effect modification by severity the exception of Dunedin Public Hospital, for was assessed by considering various subgroups which ethical approval to examine the records defined by markers of chronic severity: (1) was not obtained. As before, admissions to prescription of three of more categories of smaller hospitals were not considered. asthma drugs (oral or aerosolised beta agonists, Controls For each case potential controls, nebulised beta agonists, theophyllines, sodium matched for age within five years, were selected cromoglycate or inhaled corticosteroids, oral at random from patients discharged from the corticosteroids); (2) a hospital admission for same hospital with the diagnosis of asthma in asthma during the previous 12 months (that is, the year in which the death occurred. The in the 12 months before the admission when the admission records for each potential control prescribed medication was recorded); (3) pre- were then examined to determine whether the scription of oral corticosteroids. When dis- patient had had a previous hospital admission charged most patients were taking several for asthma during the 12 months before the drugs, including oral corticosteroids. Thus we admission under consideration. If such an considered it most appropriate to define admission was found the patient was included chronic severity in terms of the drugs being as a control. For each case the first four controls prescribed at the time of admission. As before, meeting this criterion were selected. If suf- the main drug treatment of interest (fenoterol ficient controls could not be obtained the and other asthma drugs) related to the drugs acceptable age range was widened to 10 years. prescribed at discharge. For seven cases with an admission to hospitals in Auckland, Christchurch, or Hamilton insuf- DATA ANALYSIS ficient controls were available and 22 of their The Mantel-Haenszel procedure" was used to http://thorax.bmj.com/ controls were selected from another hospital in calculate odds ratios and test based confidence the same area. For all cases and controls the intervals (CI),'2 and Rothman's adaptation of admission was considered to have been this procedure'3 was used to perform a matched primarily for asthma, as indicated by the dis- analysis. Logistic regression'4 was also used to charge coding. calculate odds ratios adjusted for age, gender, ethnicity, and other potential confounders. INFORMATION ON PRESCRIBED DRUGS For both cases on and controls information on October 4, 2021 by guest. Protected copyright. prescribed drugs for self administration was Results extracted from records relating to the previous Death registrations were identified from adtiission-that is, the admission within the 12 National Health Statistics Centre records for months before death for the cases and the 366 New Zealand residents with a recorded corresponding prior admission for the control address and aged 5-45 years who died from subjects.

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