- Email: [email protected]
A historical perspective of the New Zealand asthma mortality epidemics
The ALLERGY ARCHIVES Pioneers and Milestones Richard Beasley, DM, DSc
A historical perspective of the New Zealand asthma mortality epidemics The recent US Food and Drug Administration meeting into the safety of long-acting b-agonists provides the latest installment in the long-running controversy of the safety of b-agonist drugs in the treatment of asthma. A key component of the debate has been the identification that the b-agonist fenoterol was the major cause of the epidemic of deaths from asthma in New Zealand in the 1970s and 1980s. One could be excused for concluding that the research into the role of fenoterol in the epidemic generated more heat than light. This impression may have arisen because of an inability to consider all the scientific evidence, confusion concerning the relevant issues, and the influence of competing interests. In fact, the epidemiologic and experimental studies that identified the role of fenoterol in the New Zealand asthma mortality epidemic and the mechanisms whereby its use increased the risk of death have proved coherent and robust (Table I). The studies have also contributed to the knowledge of the optimal use of b-agonist therapy in the treatment of asthma. In the early 1960s, asthma mortality increased markedly in a number of countries, including New Zealand, Australia, and England. The weight of evidence suggested that the use of the isoprenaline forte inhaler was the major cause of the epidemics.1 Alternative hypotheses that were subsequently raised such as undertreatment with oral or inhaled corticosteroids were implausible, because such problems of undertreatment applied to most countries, irrespective of whether they experienced epidemics, over a long period before rather than during the epidemics. The mortality rate declined following warnings from regulatory bodies and a marked reduction in the sales of isoprenaline forte, as well as other changes in medical practice. Death from bronchodilator aerosols was designated one of the most important adverse drug reactions since thalidomide,2 and an editorial in the British Medical Journal3 entitled, ‘‘Asthma deaths: a question answered,’’ opined that the relationship between the increase in asthma deaths and sympathomimetic aerosols was strong, and recommended that
J ALLERGY CLIN IMMUNOL
the dose should not be increased in the absence of a normal response. A second asthma mortality epidemic began in the mid-1970s in New Zealand but not in other countries. Initial investigations concluded that the most likely explanation, as for the 1960s epidemics, was an increased case fatality rate related to changes in the management of asthma in New Zealand.4 In view of the circumstances of the 1960s epidemic, specific b-agonists were the prime suspects. To investigate the causes of this epidemic, a national asthma mortality survey was undertaken by the Medical Research Council of New Zealand Asthma Task Force between 1981 and 1983. This survey was the largest case series of asthma deaths ever undertaken. Unfortunately, despite the importance of examining the possible role of b-agonist therapy, this was not possible because of the absence of a control group. In their reports, the Asthma Task Force made contradictory statements about the relevance of bronchodilator drug therapy to mortality. For example, in its initial report,5 it was stated that excessive use of bronchodilator drugs did not account for the high mortality rates, whereas in a subsequent review,6 it was reported that excess reliance on bronchodilator treatment was the most likely explanation for the epidemic. Thus, the possible role of b-agonist drug therapy was not critically examined, and no single factor emerged from the national survey to explain the increased asthma mortality in New Zealand. More generally, the series of publications emanating from the mortality survey did not attempt to differentiate the circumstances associated with asthma deaths (such as delay, lack of objective measurements, underuse of inhaled or oral corticosteroids) and factors that may have led to a 3-fold increase in the number of deaths over a 4-year period (such as changes in specific b-agonist use). There was considerable a priori evidence to suggest that the nonselective b-agonist fenoterol may have been a cause of the asthma mortality epidemic. Firstly, fenoterol was marketed in a high-dose preparation, dispensing 200 lg per puff compared with salbutamol at 100 lg per puff. Because fenoterol is about twice as potent as salbutamol, this meant that fenoterol was effectively a forte preparation at 4 times the strength of salbutamol. Secondly, fenoterol (like isoprenaline) is a full agonist at the b-1 receptor, whereas salbutamol is a partial agonist. This would account for the observation that when used repeatedly, fenoterol had greater cardiac side effects than salbutamol, similar to those of isoprenaline.7 Thirdly, fenoterol was introduced into New Zealand in April 1976, and the epidemic began in the same year. There was a rapid increase in the fenoterol market share and a similar rapid increase in the death rate between 1976 and 1979. The close parallel between fenoterol sales and asthma deaths in the early years of the epidemic contrasted with those for total b-agonist sales, which only began to increase
225
January 2006
TABLE I. Epidemiologic evidence supporting the association between the epidemic of asthma deaths in New Zealand and fenoterol Type of studies Strength of association Consistency Biologically appropriate temporal relationships Dose-response Biological plausibility Analogy Ecological evidence
226
Cohort, case-control, and ecological studies; no randomized control trials Relative risk 1.5-13.3 (higher in severe subgroups) New Zealand, Canada, Germany, and Japan Yes Yes Acute and/or chronic pharmacologic effects greater than other commonly used b-agonist drugs 1960s epidemic—isoprenaline forte New Zealand sales of fenoterol vs onset and end of the epidemic of deaths
3 years after the epidemic had started. Fenoterol had the highest per capita sales in the world in New Zealand but represented less than 5% of the market in most other countries and was not available in the United States. Finally, in 2 case series of deaths from New Zealand, fenoterol use among patients who died was at least twice that expected from national sales.8,9 Thus, there was both epidemiologic and pharmacologic evidence suggesting that the use of high-dose fenoterol could be the main cause of the second New Zealand asthma mortality epidemic, similar to isoprenaline forte in the 1960s. In response to this evidence, our group undertook a case-control study of asthma deaths,10 the definitive epidemiologic method for testing such an hypothesis. The case-control design involved comparing the prescribed drug treatment of patients who died from asthma (cases) with that of a group of patients with nonfatal asthma of a similar chronic severity (controls). Matched controls were chosen from patients with a hospital admission with asthma, with this group having been shown to come from a similar population (in terms of severity) to those dying from asthma. Information was also collected on markers of chronic asthma severity. In this case-control study, the only treatment associated with a significantly increased risk of death was fenoterol.10 The possibility that the increased risk may have been the result of selective prescribing to patients with more severe asthma (ie, confounding by severity) was investigated by examining subgroups defined by markers of chronic asthma severity. In these subgroups, the relative risk of death in those using fenoterol was markedly increased, with a 13-fold increased risk in the most severe subgroup. These findings effectively excluded the possibility that the association between fenoterol and asthma death was a result of confounding by severity. In this situation, the fenoterol relative risk would have decreased when the analysis was increasingly restricted to the more severe subgroups.11 Unfortunately, it is necessary to mention some of the subsequent events that help to demonstrate why the findings became so controversial. The manuscript was submitted to the Lancet in February 1989 with a copy given to Boehringer Ingelheim (the manufacturer of fenoterol) on the written condition that the company
January 2006
would make no attempt to interfere with the paper’s publication. The responses from the Lancet and Boehringer Ingelheim contrasted. The Lancet accepted the manuscript for publication after receiving opinions from independent reviewers and requested only minor changes. Boehringer Ingelheim commissioned a series of reviews that were highly critical and widely distributed, including to the Lancet. The Lancet provided our group with the opportunity to respond, which resulted in a considerably more detailed discussion in the text addressing methodological issues. In the interim, Boehringer Ingelheim was also operating in other spheres. Considerable pressure was placed on the Department of Health in New Zealand regarding its planned response to the pending publication,12 threatening that ‘‘.unless the Department’s approach is modified we are left with no option but to take every step available to us to protect ourselves. the responsibility for the medical and legal consequences rest with you.’’ It would be an understatement to comment that the authors were left in no doubt of the range of dire consequences that they might face as a result of this publication or indeed if they continued to work in this area. The paper was published in the Lancet on April 29, 1989, and on that date, the New Zealand Department of Health sent out a letter advising doctors that ‘‘Fenoterol will not be withdrawn from the market, but doctors should review and perhaps modify the treatment of severe asthmatics.’’ This cautious advice was pre-empted by highly critical press releases from the company. Within weeks, both the Boehringer Ingelheim reviewers and some members of the Asthma Task Force published critical reviews in the Lancet.13,14 These contrasted markedly with the views of a group of independent reviewers, who also published in the Lancet15 that ‘‘Like earlier correspondents some of us were hired by Boehringer Ingelheim to review a draft of the fenoterol paper. Unlike these correspondents however, we did not attend the meeting convened by the company—and we have reached different conclusions.’’ The critical reviews also contrasted with the supportive reviews we received from eminent epidemiologists such as Sir Richard Doll before our paper’s publication.
J ALLERGY CLIN IMMUNOL
We were well aware that the major methodological problem with the first case-control study was that the data for prescribed medicines were obtained from different sources for the cases and controls. To overcome this problem, we undertook a second case-control study that restricted comparison of medication use to cases (deaths) and hospital admission controls who had had an admission for asthma during the previous 12-month period.16 This enabled the collection of prescribed information for cases and controls from hospital records for the previous admission, thereby overcoming the potential problem of information bias. In the second study, the relative risk of death associated with the use of fenoterol was increased 2-fold. As previously, the relative risk increased markedly when the analysis was restricted to the subgroups with the most severe asthma, once again showing that the increased risk with fenoterol was not a result of confounding by severity.11 A third case-control study in New Zealand examined the same hypothesis in the same age group during 1981 to 1987.17 Once again, the study was restricted to cases and controls who had had an admission for asthma in the previous 12 months. However, in this study, 2 control groups were used; control group A involved hospital admission controls (as before), whereas control group B was composed of a random (unmatched) sample of the study base (patients with asthma with an admission for asthma in the previous 12 months). Whichever control group was used, fenoterol was associated with an increased risk of asthma death, but the alternative control group suggested by critics of the previous studies yielded stronger relative risks than the approach used before. The controversy in New Zealand was effectively resolved in December 1989, when the Minister of Health, Helen Clark (later to become the longest serving Labour Prime Minister in New Zealand), announced that the drug was to be removed from the drug tariff. This action effectively led to the withdrawal of fenoterol from use in New Zealand. Similar action was taken in Australia in 1990, and the company subsequently reduced the dose of the drug in the United Kingdom and other countries. This restriction was associated with a significant fall in the asthma mortality rate in New Zealand (Fig 1).18 In the 5 years before its restriction, the New Zealand asthma mortality rate per 100,000 persons in the age group 5 to 34 years averaged 2.3, and the death rate was 2.2 in the first half of 1989. In the second half of 1989 (after warnings were issued about the safety of fenoterol), the death rate fell to 1.1. It fell further to 0.8 in 1990, when the availability of the drug was formally restricted, and it has remained at this level or lower since then. The dramatic fall in mortality temporarily associated with the restriction of fenoterol was inconsistent with other hypotheses that were subsequently suggested, such as a possible class effect of
J ALLERGY CLIN IMMUNOL
FIG 1. Trends in asthma mortality (per 100,000) in patients 5 to 34 years old in a number of different countries.
b-agonists or the underuse of inhaled corticosteroid therapy.18 This latter suggestion was never feasible, because mortality in New Zealand was the highest in the world at a time when it had among the highest use of inhaled corticosteroids per capita. Ironically, the strongest evidence in support of the New Zealand findings came from the Boehringer Ingelheim–funded study conducted in Canada by a group that included several members of the Boehringer Ingelheim consensus panel.19 This study showed that when the data were analyzed using the same methods used in the New Zealand studies, the fenoterol relative risk was 5.3, whereas the salbutamol relative risk was 1.0. The accompanying editorial in the New England Journal of Medicine concluded that there was enough doubt about the safety of fenoterol to avoid it altogether.19 However, confusion was created when the report of the study focused primarily on the possibility of a general b-agonist effect. It has been argued that these conclusions should be considered with caution because they did not involve the primary hypothesis of the study (which centered on fenoterol)20 and involved some complex multivariate analyses based on questionable assumptions.1,21 It has now been generally accepted that increasing b-agonist use is associated with a greater risk of death because it is a marker of poor asthma control. This important finding has contributed to the clinical recognition of unstable asthma and requirement for additional preventive therapy and medical review in patients with heavy b-agonist use (ie, in excess of 2 canisters per month). By their nature, epidemiologic studies such as those discussed are unable to identify the underlying mechanisms by which the high-dose preparations of fenoterol (and isoprenaline) led to asthma mortality epidemics in the populations in which they were widely used. There are 2 potential groups of mechanisms that have been proposed: those relating to the regular use leading to worsening asthma control, and those relating to their overuse in the situation of a life-threatening attack of asthma. Key New Zealand studies have provided evidence that both these groups
227
January 2006
of mechanisms are relevant to the increased mortality associated with the use of fenoterol. In contrast to salbutamol, the regular use of fenoterol has been shown to increase asthma severity,22 whereas both isoprenaline and fenoterol have been shown to have greater acute side effects than salbutamol that are likely to be particularly harmful in the presence of severe hypoxia.7,23 In conclusion, the research into the New Zealand asthma mortality epidemics was crucial in not only identifying but also addressing the underlying causes, which resulted in sustained falls in mortality. The research findings have also led to a greater understanding of the role of b-agonist therapy in asthma. Richard Beasley, DM, DSc Medical Research Institute of New Zealand PO Box 10055 Wellington New Zealand E-mail: [email protected]
REFERENCES
228
1. Pearce NE, Beasley R, Crane J, Burgess C. Epidemiology of asthma mortality. In: Holgate S, Busse W. Asthma and rhinitis. Oxford: Blackwell Scientific; 2000. p. 56-72. 2. Venning GR. Identification of adverse reactions to new drugs, I: what have been the important adverse reactions since thalidomide? BMJ 1983;286:199-202. 3. Editorial. Asthma deaths: a question answered. BMJ 1972;ii:443-4. 4. Jackson RT, Beaglehole R, Rea HH, Sutherland DC. Mortality from asthma: a new epidemic in New Zealand. BMJ 1982;285:771-4. 5. Sears MR, Rea HH, Beaglehole R, Gillies AJD, Holst PE, O’Donnell TV, et al. Asthma mortality in New Zealand: a two year national study. N Z Med J 1985;98:271-5. 6. Sears MR, Beaglehole R. Asthma morbidity and mortality: New Zealand. J Allergy Clin Immunol 1987;80:383-8. 7. Crane J, Burgess C, Beasley R. Comparison of the cardiovascular and hypokalaemic effects of inhaled salbutamol, fenoterol and isoprenaline. Thorax 1989;44:136-40. 8. Wilson JD, Sutherland DC, Thomas AC. Has the change to beta agonists combined with oral theophylline increased cases of fatal asthma? Lancet 1981;i:1235-7.
January 2006
9. Sears MR, Rea HH, Fenwick J, Gillies AJ, Holst PE, O’Donnell PE, et al. 75 deaths in asthmatics prescribed home nebulisers. BMJ 1987;294:477-80. 10. Crane J, Pearce N, Flatt A, Burgess C, Jackson R, Kwong T, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-1983: a case-control study. Lancet 1989;i:917-22. 11. Beasley R, Burgess C, Pearce N, Grainger J, Crane J. Confounding by severity does not explain the association between fenoterol and asthma death. Clin Exp Allergy 1994;24:660-8. 12. Pearce N. Adverse reactions: the fenoterol saga. In: Davis P, editor. For health or profit? Medicine, the pharmaceutical industry, and the state in New Zealand. Auckland: Oxford University Press; 1992. p. 75-97. 13. Buist AS, Burney PGJ, Feinstein AR, Horwitz RI, Lanes SF, Rebuck AS, et al. Fenoterol and fatal asthma [letter]. Lancet 1989;1:1071. 14. O’Donnell TV, Holst P, Rea HH, Sears MR. Fenoterol and fatal asthma [letter]. Lancet 1989;1:1070-1. 15. Sackett DL, Shannon HS, Browman GW. Fenoterol and fatal asthma [letter]. Lancet 1990;i:46. 16. Pearce N, Grainger J, Atkinson M, Crane J, Burgess C, Culling C, et al. Case-control study of prescribed fenoterol and death from asthma in New Zealand, 1977-1981. Thorax 1990;45: 170-5. 17. Grainger J, Woodman K, Pearce N, Crane J, Burgess C, Keane A, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-1987: a further case-control study. Thorax 1991; 46:105-11. 18. Pearce N, Beasley R, Crane J, Burgess C, Jackson R. End of the New Zealand asthma mortality epidemic. Lancet 1995;345:41-4. 19. Spitzer WD, Suissa S, Ernst P, Horwitz RI, Habbick B, Cockcroft D, et al. The use of beta agonists and the risk of death and near death from asthma. N Engl J Med 1992;326:501-6. 20. Horwitz RJ, Spitzer WO, Buist S, Cockroft D, Ernst P, Habbick B, et al. Clinical complexity and epidemiologic uncertainty in casecontrol research: fenoterol and asthma management. Chest 1991; 100:1586-91. 21. Pearce NE, Crane J, Burgess C, Beasley R, Jackson R. Fenoterol, beta agonists and asthma deaths [letter]. N Engl J Med 1992;327: 355-6. 22. Sears MR, Taylor DR, Print CG, Lake DC, Li QQ, Flannery EM, et al. Regular inhaled beta agonist treatment in bronchial asthma. Lancet 1990;336:1391-6. 23. Bremner P, Siebers R, Crane J, Pearce N, Beasley R, Burgess C. Partial versus full beta receptor agonism: a clinical study of inhaled albuterol and fenoterol. Chest 1996;109:957-62.
Received for publication October 20, 2005; accepted for publication October 25, 2005.
J ALLERGY CLIN IMMUNOL
A historical perspective of the New Zealand asthma mortality epidemics The recent US Food and Drug Administration meeting into the safety of long-acting b-agonists provides the latest installment in the long-running controversy of the safety of b-agonist drugs in the treatment of asthma. A key component of the debate has been the identification that the b-agonist fenoterol was the major cause of the epidemic of deaths from asthma in New Zealand in the 1970s and 1980s. One could be excused for concluding that the research into the role of fenoterol in the epidemic generated more heat than light. This impression may have arisen because of an inability to consider all the scientific evidence, confusion concerning the relevant issues, and the influence of competing interests. In fact, the epidemiologic and experimental studies that identified the role of fenoterol in the New Zealand asthma mortality epidemic and the mechanisms whereby its use increased the risk of death have proved coherent and robust (Table I). The studies have also contributed to the knowledge of the optimal use of b-agonist therapy in the treatment of asthma. In the early 1960s, asthma mortality increased markedly in a number of countries, including New Zealand, Australia, and England. The weight of evidence suggested that the use of the isoprenaline forte inhaler was the major cause of the epidemics.1 Alternative hypotheses that were subsequently raised such as undertreatment with oral or inhaled corticosteroids were implausible, because such problems of undertreatment applied to most countries, irrespective of whether they experienced epidemics, over a long period before rather than during the epidemics. The mortality rate declined following warnings from regulatory bodies and a marked reduction in the sales of isoprenaline forte, as well as other changes in medical practice. Death from bronchodilator aerosols was designated one of the most important adverse drug reactions since thalidomide,2 and an editorial in the British Medical Journal3 entitled, ‘‘Asthma deaths: a question answered,’’ opined that the relationship between the increase in asthma deaths and sympathomimetic aerosols was strong, and recommended that
J ALLERGY CLIN IMMUNOL
the dose should not be increased in the absence of a normal response. A second asthma mortality epidemic began in the mid-1970s in New Zealand but not in other countries. Initial investigations concluded that the most likely explanation, as for the 1960s epidemics, was an increased case fatality rate related to changes in the management of asthma in New Zealand.4 In view of the circumstances of the 1960s epidemic, specific b-agonists were the prime suspects. To investigate the causes of this epidemic, a national asthma mortality survey was undertaken by the Medical Research Council of New Zealand Asthma Task Force between 1981 and 1983. This survey was the largest case series of asthma deaths ever undertaken. Unfortunately, despite the importance of examining the possible role of b-agonist therapy, this was not possible because of the absence of a control group. In their reports, the Asthma Task Force made contradictory statements about the relevance of bronchodilator drug therapy to mortality. For example, in its initial report,5 it was stated that excessive use of bronchodilator drugs did not account for the high mortality rates, whereas in a subsequent review,6 it was reported that excess reliance on bronchodilator treatment was the most likely explanation for the epidemic. Thus, the possible role of b-agonist drug therapy was not critically examined, and no single factor emerged from the national survey to explain the increased asthma mortality in New Zealand. More generally, the series of publications emanating from the mortality survey did not attempt to differentiate the circumstances associated with asthma deaths (such as delay, lack of objective measurements, underuse of inhaled or oral corticosteroids) and factors that may have led to a 3-fold increase in the number of deaths over a 4-year period (such as changes in specific b-agonist use). There was considerable a priori evidence to suggest that the nonselective b-agonist fenoterol may have been a cause of the asthma mortality epidemic. Firstly, fenoterol was marketed in a high-dose preparation, dispensing 200 lg per puff compared with salbutamol at 100 lg per puff. Because fenoterol is about twice as potent as salbutamol, this meant that fenoterol was effectively a forte preparation at 4 times the strength of salbutamol. Secondly, fenoterol (like isoprenaline) is a full agonist at the b-1 receptor, whereas salbutamol is a partial agonist. This would account for the observation that when used repeatedly, fenoterol had greater cardiac side effects than salbutamol, similar to those of isoprenaline.7 Thirdly, fenoterol was introduced into New Zealand in April 1976, and the epidemic began in the same year. There was a rapid increase in the fenoterol market share and a similar rapid increase in the death rate between 1976 and 1979. The close parallel between fenoterol sales and asthma deaths in the early years of the epidemic contrasted with those for total b-agonist sales, which only began to increase
225
January 2006
TABLE I. Epidemiologic evidence supporting the association between the epidemic of asthma deaths in New Zealand and fenoterol Type of studies Strength of association Consistency Biologically appropriate temporal relationships Dose-response Biological plausibility Analogy Ecological evidence
226
Cohort, case-control, and ecological studies; no randomized control trials Relative risk 1.5-13.3 (higher in severe subgroups) New Zealand, Canada, Germany, and Japan Yes Yes Acute and/or chronic pharmacologic effects greater than other commonly used b-agonist drugs 1960s epidemic—isoprenaline forte New Zealand sales of fenoterol vs onset and end of the epidemic of deaths
3 years after the epidemic had started. Fenoterol had the highest per capita sales in the world in New Zealand but represented less than 5% of the market in most other countries and was not available in the United States. Finally, in 2 case series of deaths from New Zealand, fenoterol use among patients who died was at least twice that expected from national sales.8,9 Thus, there was both epidemiologic and pharmacologic evidence suggesting that the use of high-dose fenoterol could be the main cause of the second New Zealand asthma mortality epidemic, similar to isoprenaline forte in the 1960s. In response to this evidence, our group undertook a case-control study of asthma deaths,10 the definitive epidemiologic method for testing such an hypothesis. The case-control design involved comparing the prescribed drug treatment of patients who died from asthma (cases) with that of a group of patients with nonfatal asthma of a similar chronic severity (controls). Matched controls were chosen from patients with a hospital admission with asthma, with this group having been shown to come from a similar population (in terms of severity) to those dying from asthma. Information was also collected on markers of chronic asthma severity. In this case-control study, the only treatment associated with a significantly increased risk of death was fenoterol.10 The possibility that the increased risk may have been the result of selective prescribing to patients with more severe asthma (ie, confounding by severity) was investigated by examining subgroups defined by markers of chronic asthma severity. In these subgroups, the relative risk of death in those using fenoterol was markedly increased, with a 13-fold increased risk in the most severe subgroup. These findings effectively excluded the possibility that the association between fenoterol and asthma death was a result of confounding by severity. In this situation, the fenoterol relative risk would have decreased when the analysis was increasingly restricted to the more severe subgroups.11 Unfortunately, it is necessary to mention some of the subsequent events that help to demonstrate why the findings became so controversial. The manuscript was submitted to the Lancet in February 1989 with a copy given to Boehringer Ingelheim (the manufacturer of fenoterol) on the written condition that the company
January 2006
would make no attempt to interfere with the paper’s publication. The responses from the Lancet and Boehringer Ingelheim contrasted. The Lancet accepted the manuscript for publication after receiving opinions from independent reviewers and requested only minor changes. Boehringer Ingelheim commissioned a series of reviews that were highly critical and widely distributed, including to the Lancet. The Lancet provided our group with the opportunity to respond, which resulted in a considerably more detailed discussion in the text addressing methodological issues. In the interim, Boehringer Ingelheim was also operating in other spheres. Considerable pressure was placed on the Department of Health in New Zealand regarding its planned response to the pending publication,12 threatening that ‘‘.unless the Department’s approach is modified we are left with no option but to take every step available to us to protect ourselves. the responsibility for the medical and legal consequences rest with you.’’ It would be an understatement to comment that the authors were left in no doubt of the range of dire consequences that they might face as a result of this publication or indeed if they continued to work in this area. The paper was published in the Lancet on April 29, 1989, and on that date, the New Zealand Department of Health sent out a letter advising doctors that ‘‘Fenoterol will not be withdrawn from the market, but doctors should review and perhaps modify the treatment of severe asthmatics.’’ This cautious advice was pre-empted by highly critical press releases from the company. Within weeks, both the Boehringer Ingelheim reviewers and some members of the Asthma Task Force published critical reviews in the Lancet.13,14 These contrasted markedly with the views of a group of independent reviewers, who also published in the Lancet15 that ‘‘Like earlier correspondents some of us were hired by Boehringer Ingelheim to review a draft of the fenoterol paper. Unlike these correspondents however, we did not attend the meeting convened by the company—and we have reached different conclusions.’’ The critical reviews also contrasted with the supportive reviews we received from eminent epidemiologists such as Sir Richard Doll before our paper’s publication.
J ALLERGY CLIN IMMUNOL
We were well aware that the major methodological problem with the first case-control study was that the data for prescribed medicines were obtained from different sources for the cases and controls. To overcome this problem, we undertook a second case-control study that restricted comparison of medication use to cases (deaths) and hospital admission controls who had had an admission for asthma during the previous 12-month period.16 This enabled the collection of prescribed information for cases and controls from hospital records for the previous admission, thereby overcoming the potential problem of information bias. In the second study, the relative risk of death associated with the use of fenoterol was increased 2-fold. As previously, the relative risk increased markedly when the analysis was restricted to the subgroups with the most severe asthma, once again showing that the increased risk with fenoterol was not a result of confounding by severity.11 A third case-control study in New Zealand examined the same hypothesis in the same age group during 1981 to 1987.17 Once again, the study was restricted to cases and controls who had had an admission for asthma in the previous 12 months. However, in this study, 2 control groups were used; control group A involved hospital admission controls (as before), whereas control group B was composed of a random (unmatched) sample of the study base (patients with asthma with an admission for asthma in the previous 12 months). Whichever control group was used, fenoterol was associated with an increased risk of asthma death, but the alternative control group suggested by critics of the previous studies yielded stronger relative risks than the approach used before. The controversy in New Zealand was effectively resolved in December 1989, when the Minister of Health, Helen Clark (later to become the longest serving Labour Prime Minister in New Zealand), announced that the drug was to be removed from the drug tariff. This action effectively led to the withdrawal of fenoterol from use in New Zealand. Similar action was taken in Australia in 1990, and the company subsequently reduced the dose of the drug in the United Kingdom and other countries. This restriction was associated with a significant fall in the asthma mortality rate in New Zealand (Fig 1).18 In the 5 years before its restriction, the New Zealand asthma mortality rate per 100,000 persons in the age group 5 to 34 years averaged 2.3, and the death rate was 2.2 in the first half of 1989. In the second half of 1989 (after warnings were issued about the safety of fenoterol), the death rate fell to 1.1. It fell further to 0.8 in 1990, when the availability of the drug was formally restricted, and it has remained at this level or lower since then. The dramatic fall in mortality temporarily associated with the restriction of fenoterol was inconsistent with other hypotheses that were subsequently suggested, such as a possible class effect of
J ALLERGY CLIN IMMUNOL
FIG 1. Trends in asthma mortality (per 100,000) in patients 5 to 34 years old in a number of different countries.
b-agonists or the underuse of inhaled corticosteroid therapy.18 This latter suggestion was never feasible, because mortality in New Zealand was the highest in the world at a time when it had among the highest use of inhaled corticosteroids per capita. Ironically, the strongest evidence in support of the New Zealand findings came from the Boehringer Ingelheim–funded study conducted in Canada by a group that included several members of the Boehringer Ingelheim consensus panel.19 This study showed that when the data were analyzed using the same methods used in the New Zealand studies, the fenoterol relative risk was 5.3, whereas the salbutamol relative risk was 1.0. The accompanying editorial in the New England Journal of Medicine concluded that there was enough doubt about the safety of fenoterol to avoid it altogether.19 However, confusion was created when the report of the study focused primarily on the possibility of a general b-agonist effect. It has been argued that these conclusions should be considered with caution because they did not involve the primary hypothesis of the study (which centered on fenoterol)20 and involved some complex multivariate analyses based on questionable assumptions.1,21 It has now been generally accepted that increasing b-agonist use is associated with a greater risk of death because it is a marker of poor asthma control. This important finding has contributed to the clinical recognition of unstable asthma and requirement for additional preventive therapy and medical review in patients with heavy b-agonist use (ie, in excess of 2 canisters per month). By their nature, epidemiologic studies such as those discussed are unable to identify the underlying mechanisms by which the high-dose preparations of fenoterol (and isoprenaline) led to asthma mortality epidemics in the populations in which they were widely used. There are 2 potential groups of mechanisms that have been proposed: those relating to the regular use leading to worsening asthma control, and those relating to their overuse in the situation of a life-threatening attack of asthma. Key New Zealand studies have provided evidence that both these groups
227
January 2006
of mechanisms are relevant to the increased mortality associated with the use of fenoterol. In contrast to salbutamol, the regular use of fenoterol has been shown to increase asthma severity,22 whereas both isoprenaline and fenoterol have been shown to have greater acute side effects than salbutamol that are likely to be particularly harmful in the presence of severe hypoxia.7,23 In conclusion, the research into the New Zealand asthma mortality epidemics was crucial in not only identifying but also addressing the underlying causes, which resulted in sustained falls in mortality. The research findings have also led to a greater understanding of the role of b-agonist therapy in asthma. Richard Beasley, DM, DSc Medical Research Institute of New Zealand PO Box 10055 Wellington New Zealand E-mail: [email protected]
REFERENCES
228
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Received for publication October 20, 2005; accepted for publication October 25, 2005.
J ALLERGY CLIN IMMUNOL