The US Food and Drug Administration Health Alert on Long-acting Beta-agonists: Is It Evidence Based or Biased?
The US Food and Drug Administration has recently issued a boxed warning on long-acting β2-agonists (LABAs) that these drugs can increase the risk of severe asthma-related adverse events including deaths. This action was prompted by the findings of the Salmeterol Multi-center Asthma Research Trial which revealed the use of salmeterol was associated with a >4-fold increased risk in the incidence of asthma-related deaths when compared with a matched-placebo over a 28-week unsupervised treatment period. However, this increased risk was only seen in patients who didn't take inhaled corticosteroids (ICS) at entry to the study. Other pharmaco-epidemiologic, case-controlled and clinical studies, however, have failed to demonstrate any significant association between LABAs and asthma-related deaths. It is likely that while unsupervised use of LABAs in patients who are not treated with ICS, especially when their disease is not well controlled, may potentially be detrimental and therefore should not be recommended, the combined use of this class of drugs with ICS is safe and effective.
Keyword : Asthma deaths and SMART; Long-acting β2-agonists
The Food and Drug Administration (FDA) of the United States (US) requested manufacturers of Advair Diskus, Foradil Aerolizer, and Serevent Diskus to update their existing product labels with new warnings and a Medication Guide (FDA-approved patient information) for patients to alert health care professionals and patients that these medicines may increase the risk of severe asthma exacerbation and asthma-related deaths (ARDs) on November 18, 2005.1 All these medications involved contained a long-acting beta-agonist (LABA), either salmeterol or formoterol. This action of FDA was prompted by the results of the Salmeterol Multi-center Asthma Research Trial (SMART) that was conducted in the US from 1996 to 2003 involving more than 25,000 subjects.2
SMART was a multi-center, randomised, double-blind, parallel-group, placebo-controlled, single visit surveillance study conducted over a period of 28 weeks. The demographics of the subjects are shown in Table 1. Males and non-pregnant females >=12 years of age, with a clinical diagnosis of asthma who had no previous use of inhaled LABA were enrolled into the study. Patients were allowed to continue with their usual anti-asthma drugs, except LABAs. Salmeterol 42 mcg twice-daily via metered dose inhaler (MDI) added to concurrent pharmacotherapy was compared with a matched placebo twice-daily via MDI added to concurrent therapy. In both groups, 47% of patients were taking inhaled corticosteroid (ICS) at entry to the study.
The SMART study was terminated when an interim analysis conducted on the then enrolled 26,355 patients showed a statistically significant increase in the risk of ARD, a secondary outcome variable, in the salmeterol group when compared to the placebo group (13 vs 3 deaths, relative risk [RR] 4.37, 95% CI 1.25-15.34). In addition, another secondary outcome variable, the combined ARD or respiratory life-threatening adverse events (intubation and mechanical ventilation, LAEs), was also higher in the salmeterol group (37 vs 22 events, RR 1.71, 95% CI 1.01-2.89). The primary outcome variable - combined respiratory related deaths or LAEs - however, did not differ between the two groups. A summary of the SMART data is shown in Table 2. African American patients were found to have the highest risk of developing all the above-mentioned major outcome variables when compared to the other ethnic groups. Subgroup analysis also found a difference among subjects who were treated with ICS at entry to the study and those without. In the ICS users, all the primary or secondary outcome variables were not significantly different between the salmeterol and placebo groups. These patients in fact had a lower relative risks for all the above-mentioned outcome variables when compared to the total study population. In contrast, subjects who were not on ICS at baseline in the salmeterol treatment arm had a considerably higher incidence of the secondary outcome variables.
Apart from occasional reports in the lay press of deaths associated with the use of salmeterol, the SMART dataset is hitherto the only randomised, placebo-controlled clinical study to suggest that this drug may increase the risks of fatal and near-fatal asthma. Although data from an earlier similar study involving >25,000 patients in the UK - the Serevent Nationwide Surveillance Study (SNS) - revealed a similar trend of increased deaths related to asthma in the salmeterol group than the placebo group (12/16,787 vs 2/8,393 respectively), the difference failed to reach statistical significance.3 A recent case-control study conducted in 33 health authorities or health boards in Great Britain (which together provided health care services to 27% of the general population) revealed that although asthma mortality was positively associated with long term use of inhaled short acting beta-agonists (SABAs) (1-5 years before the index event; odds ratio 2.52 [95% CI:1.28-4.98]), there was no evidence of adverse effects on mortality with medium (4-12 months prior to index event) to long term use of LABAs.4 If anything, there appeared to be a reduced risk of asthma death associated with this class of drugs after controlling for asthma severity (odds ratio 0.74 [0.55-1.01], p=0.06). The lack of association between LABAs and severe adverse events is in accord with earlier similar studies.5-8 Not withstanding the limitations of a case-control study - difficulty in controlling for disease severity, associated chronic obstructive pulmonary disease, etc, - this latest case-control study has much greater power (532 deaths) than either the SMART (13 in salmeterol group and 3 in placebo group) or SNS (12 in salmeterol group and 2 in salbutamol group) in examining the relationship between fatal asthma and anti-asthma medications.
The SMART study was designed to have only a single clinic visit. At study entry, at least 60% of subjects had evidence of poorly controlled asthma with nocturnal awakening >=1 night/week but only 47% were taking ICS (Table 1). In the absence of other protocol-defined office visits other than just telephone calls 4 weekly during the 28-week treatment period, the treatment of the patients was largely unsupervised. This practice of asthma-care, though common in real life,9,10 is against what is recommended by the guidelines.11,12 While the SMART dataset precludes a firm conclusion to be drawn for the mechanisms underlying the excess in severe asthma-related events associated with salmeterol treatment, it does suggest that the unsupervised use of LABAs in patients with poorly controlled asthma, particularly in the non-ICS users, may potentially be detrimental. These findings, therefore, concur with current asthma guidelines that LABAs should only be prescribed in conjunction with ICS and should never be used as monotherapy in asthma. Furthermore, although LABAs possess some steroid-sparing effects, they cannot completely substitute for ICS in the treatment of persistent asthma.13,14 Currently, combination formulations of ICS and LABAs are available (Seretide and Symbicort). Thus, such therapies ensure an appropriate dose of ICS will always be given together with a LABA at the same time. Indeed, the safety and efficacy of such combined formulations have been validated by a number of clinical studies, whether they are given as fixed or variable doses.15-17
Although the US FDA has rightly emphasised that combination therapy is mainly indicated for asthma patients whose disease is not adequately controlled by ICS alone, it is debatable to state that this should only be used for this group of patients. A recent meta-analysis on 18 studies have shown that the addition of a LABA to ICS in steroid-naive patients with mild to moderate airflow obstruction is as safe as treatment with ICS alone.18 While no differences were seen between these 2 treatment groups in terms of rescue b2-agonist use or exacerbation rates, the combination regime does improve lung function and symptom-free days than those treated with ICS alone.
The authors would like to thank Prof. Richard Beasley for his valuable advice in preparing this manuscript.
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