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Etiology

Regular use of β-agonists was associated with an increased risk for death and near-death from asthma

ACP J Club.1992 July-Aug;117:26. doi:10.7326/ACPJC-1992-117-1-026


Source Citation

Spitzer WO, Suissa S, Ernst P, et al. The use of β-agonists and the risk of death and near death from asthma. N Engl J Med. 1992 Feb 20;326:501-6.


Abstract

Objective

To ascertain whether β-agonist bronchodilator use is associated with increased risk for death and near-death from asthma.

Design

Matched case-control study of patients drawn from a cohort who were prescribed medication for asthma.

Setting

Saskatchewan, Canada.

Patients

12 301 patients (age range 5 to 54 y), who had had ≥ 10 prescriptions for asthma medications (fenoterol, albuterol, metaproterenol, terbutaline, theophylline compounds, ipratropium bromide, and inhaled beclomethasone), were considered. Case patients (n = 129) were those in this cohort who had fatal or near-fatal asthma (arterial partial pressure of CO2 > 6.0 kPa [45 mm Hg], nonelective intubation during an acute asthma attack, or both). Controls, up to 8 per case patient, were those receiving asthma medication who did not have fatal or near-fatal asthma. Controls (n = 655) were matched for region, amount of social assistance, age, date of entry, and hospitalization.

Assessment of risk factors

Health insurance files provided information on β-agonist use, including dosage, other medications, and additional health care use.

Main outcome measures

Odds ratios for association of asthma medication and fatal and near-fatal asthma, adjusted for health care use and nonasthma medication.

Main results

Case patients were similar to control patients with respect to age and sex but were hospitalized more often and used more medications. Adjusted odds ratios indicate that both fenoterol (6.1, 95% CI 3.1 to 12.2) and albuterol (4.1, CI 2.1 to 8.0) taken by metered-dose inhaler were associated with an increased risk for death from asthma or near-fatal asthma. Smaller, but still increased risks for death or near-fatal asthma were found for albuterol taken by nebulizer, other inhaled β-agonists, theophylline, and oral corticosteroids. No increased risks were found for oral β-agonists or for inhaled corticosteroids and cromolyn considered together. Each increase of 1 metered-dose inhaler of β-agonists per month was associated with a more than 2-fold increase in the risk for fatal and near-fatal asthma.

Conclusions

Fatal and near-fatal asthma were associated with regular β-agonist use, especially with fenoterol and albuterol. Greater use led to increased risks for death. Cromolyn and inhaled or oral corticosteroids were not associated with increased risk.

Source of funding: Boehringer-Ingelheim Pharmaceuticals.

Address for article reprint: Dr. W.O. Spitzer, McGill University, Purvis Hall, 1020 Pine Avenue West, Montreal, Quebec H3A 1A2, Canada.


Commentary

This study supersedes the New Zealand case-control studies reporting an increased risk for death associated with inhaled fenoterol. By accessing a computerized prescription database, with dates and amounts of drug dispensed, drug exposure was more accurately determined. Further, because some asthmatic patients in the Canadian study did not use either fenoterol or salbutamol, the risk associated with exposure to this class of medications has now been determined. All available β-agonists, when used in higher doses, substantially increased the risk for death from asthma.

More severe asthma is likely to be treated with more drugs and is also more likely to be fatal. There was, however, no increased risk for death with oral steroids after adjustment for other drug therapy. This finding militates against the association with β-agonists being simply related to severity.

A recent randomized controlled trial (1) showed that asthma control deteriorated when use of β-agonist was increased from as-needed (mean, 2.9 puffs per d) to regular doses (mean, 10.0 puffs per d). On balance, these and other studies suggest that increasing the dose of inhaled β-agonists, especially the more potent fenoterol, increases the severity of asthma and the risk for death. The striking increase in risk for death, as exposure to either β-agonist increased from 1 to ≥ 2 inhalers per month, is consistent with this hypothesis.

Whatever the mechanism, patients using high doses of any inhaled β-agonist risk making their asthma worse and having a fatal outcome. Management should be carefully reviewed to reduce reliance on β-agonists.

Malcolm R. Sears, MB, ChB
McMaster UniversityHamilton, Ontario, Canada


Reference

1. Sears MR, Taylor DR, Print CG, et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet. 1990;336:1391-6.