INHALED BETA AGONISTS AND DEATH FROM ASTHMA: REVISITING THE CONTROVERSY

To the Editor:

Abramson and colleagues present the results from a case-control study examining the impact of asthma medications and other management strategies on asthma mortality (1). Written management plans were associated with decreased risk of fatal asthma. The authors also found higher blood salbutamol (albuterol) concentrations in cases of fatal asthma than in control subjects. The authors then implicated inhaled beta agonist (IBA) toxicity as a cause of death from asthma.

This article joins a long debate about the role of IBA toxicity in fatal asthma. In my view, the authors' conclusions are misleading. On the basis of their data, it is not possible to separate the acute effects of IBAs from strong confounding by poor asthma control. Many features of case subjects suggest that they had inadequate asthma control in the time predating their fatal event. Case subjects were less likely to have been hospitalized during the past month for asthma, to have consulted a general practitioner, or to have used "inhaled symptomatic" medications during the past month or for their last asthma attack. In fact, case subjects were less likely to use every class of asthma drug for their last attack, ranging from inhaled symptomatic to oral preventive medications (Table 5). These data are most consistent with suboptimal treatment of asthma, leading to poor asthma control. As a consequence, the higher salbutamol blood levels among cases may be the result of poor asthma control and greater acute illness severity.

Previous literature indicates that confounding by poor asthma control may explain the apparent deleterious effects of IBAs. In a cohort of HMO members with asthma, Donahue and colleagues demonstrated that greater IBA use was associated with asthma hospitalization only among nonusers of inhaled corticosteroids (2). We have also found that IBA use was related to a greater risk of intensive care unit admission and endotracheal intubation for acute asthma exacerbation only among those not using inhaled corticosteroids (3). As a consequence, the relation between IBA use and adverse asthma outcomes may reflect severe, uncontrolled asthma and not direct drug-related toxicity.

Why does this matter? Focusing attention on the possible toxicity of IBAs may do more harm than good. The clinical problem is likely not overtreatment with IBAs, but undertreatment with inhaled corticosteroids (4) and other efficacious strategies. As the authors' data suggest, the critical issue is that asthma patients receive appropriate medical management, including written management plans. In this view, asthma patients are more likely to die from undertreatment than from overtreatment.

University of California, San Francisco, San Francisco, California

1. Abramson MJ, Bailey MJ, Couper FJ, Driver JS, Drummer OH, Forbes AB, McNeil JJ, Walters EH. Are asthma medications and management related to deaths from asthma? Am J Respir Crit Care Med 2001; 163: 12-18 [Abstract/Free Full Text].

2. Donahue JG, Weiss ST, Livingston JM, Goetsch MA, Greineder DK, Platt R. Inhaled steroids and the risk of hospitalization for asthma. JAMA 1997; 277: 887-891 [Abstract/Free Full Text].

3. Eisner MD, Lieu TA, Chi F, Capra AM, Mendoza G, Blanc PD. Beta agonists, inhaled steroids, and the risk of intensive care unit admission for asthma. Eur Respir J 2001; 17: 233-240 [Abstract/Free Full Text].

4. Suissa S, Ernst P, Benayoun S, Baltzan M, Cai B. Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med 2000; 343: 332-336 [Abstract/Free Full Text].

From the Authors:

We controlled for confounding by chronic asthma severity using validated markers (hospital admissions in the last year and usual oral steroid medication), although there was insufficient data to adjust for confounding by the severity of the acute attack (1). Furthermore, when we also adjusted for the features highlighted by Dr. Eisner as indicating poor asthma control (general practitioner visits, inhaled symptomatic medication, and hospitalization in the last month), there was very little change in the ratio of blood salbutamol levels. The cases still had geometric mean salbutamol levels 2.41 (95% CI:1.35-4.30) times higher than the control patients.

The previous North American studies are not directly comparable. The cohort study of HMO members with asthma (2) found an increased risk of hospitalization among patients dispensed more than eight -agonist inhalers per year. Although this effect was significantly attenuated by coprescription of inhaled steroids, it was still present among patients who received inhaled steroids. The recently published further analysis of the Saskatchewan cohort (3) could not directly address the role of -agonists, because cases and controls were matched for the dispensing of -agonists from metered dose inhalers and nebulizers. Nonetheless, this evidence that even quite modest doses of inhaled steroids can reduce the risk of hospitalization or death is compelling. Unfortunately, we were not able to examine the inhaled steroid dose- response relationship in our case-control study.

The difference in interpretation relates to the causal pathways from dispensing and use of asthma medication to death. We believe that many asthma deaths result from the combination of poor management with inadequate preventive medication and excessive reliance on self-administered -agonists during the fatal attack. Our point is that these are just the two sides of the same coin. Both sides need to be addressed if asthma mortality is to be further reduced.

1. Abramson M, Bailey M, Couper F, Driver J, Drummer OH, Forbes A, McNeil J, Walters EH. the Victorian Asthma Mortality Study Group. Asthma medications and managements are related to deaths from asthma. Am J Respir Crit Care Med 2001; 163: 12-18 .

2. Donahue JG, Weiss ST, Livingston JM, Goetsch MA, Greineder DK, Platt R. Inhaled steroids and the risk of hospitalization for asthma. JAMA 1997; 277: 887-891 .

3. Suissa S, Ernst P, Benayoun S, Baltzan M, Cai B. Low-dose inhaled corticosteriods and the prevention of death from asthma. N Engl J Med 2000; 343: 332-336 .