Long-acting β-agonists: a review of formoterol safety data from asthma clinical trials

Safety concerns regarding inhaled adrenergic compounds date back to the late 1940s. Up to five-fold increases in mortality among users of inhaled adrenalin 1 and high-dose isoprenaline 2–4 were reported in 1948 and the 1960s, respectively. A more recent mortality epidemic in New Zealand, beginning in 1976 5, led to a series of case–control studies 6–8 that indicated an increased risk of fatal asthma associated with prescription of fenoterol. A study in Saskatchewan (Canada) found an increased risk of mortality with increasing use of both fenoterol and salbutamol 9. Although cardiac adverse events were frequently considered responsible for the increased risk, a 1-yr clinical trial showed increased airway responsiveness and worsened asthma control during regular treatment with fenoterol added to usual therapy compared with β-agonist used only as needed for symptom relief 10, 11. However, subsequent US and UK trials of regular versus as needed salbutamol did not detect sustained adverse effects on asthma control 12, 13. Nevertheless, during the 1990s, consensus guidelines increasingly advocated use of short-acting β₂-agonists (SABAs) only as needed for symptom relief 14–16.

The introduction of the long-acting β₂-agonists (LABAs) salmeterol and formoterol prompted questions regarding the possibility of safety issues. Clinical trials showed substantial benefit from adding LABAs to inhaled corticosteroid (ICS) therapy, exceeding that of doubling or even further increasing the dose of ICS 17–19. At the same time, the Serevent Nationwide Surveillance (SNS) trial in the UK reported a nonsignificant three-fold excess of asthma-related deaths in patients using regular salmeterol compared with regular salbutamol over 16 weeks 20. Of the patients studied, 69% were using ICS at baseline. A controlled study that employed stepwise reduction of ICS to permit inflammation to gradually increase demonstrated the potential for LABAs to mask clinical evidence of progressive inflammation 21. In the USA, the Food and Drug Administration (FDA) approved salmeterol as monotherapy, as well as for use in combination with other therapies, but required a post-marketing clinical trial in order to address safety concerns raised by the SNS study. The US study was halted prematurely in 2003, when an interim analysis indicated that addition of salmeterol to usual therapy was associated with an increase in both severe exacerbations and mortality compared with placebo 22. Post hoc subgroup analyses suggested that the increased mortality was confined to patients not prescribed ICS at baseline (nine deaths with salmeterol and none with placebo, compared with four and three deaths, respectively, among patients using ICS at baseline). However the use of ICS was not recorded during the treatment period.

In three placebo-controlled trials (n = 1,613) with formoterol (Foradil^TM; Novartis Pharmaceuticals, Basle, Switzerland), a higher dose (24-μg metered dose twice daily) tended to be associated with more serious asthma exacerbations than a lower dose (12 μg twice daily) 23. However, a large phase IV, randomised placebo-controlled trial (n = 2,085) of Foradil^TM found all doses of formoterol to be associated with fewer exacerbations than placebo, with no indication of any dose–response relationship 24.

Following a safety review of LABAs 25, the Pulmonary-Allergy Drugs Advisory Committee (PADAC) of the FDA recommended additional safety labelling information for this class. In November 2005, the FDA directed US manufacturers of salmeterol- and formoterol-containing products to update existing product labels with new warnings 26.

The PADAC review included formoterol data only from Novartis trials, as only that preparation (Foradil^TM) was then marketed in the USA. However, the AstraZeneca clinical database for formoterol is much larger than that available through Novartis trials. The formoterol Turbuhaler (Oxis®; AstraZeneca, Lund, Sweden) is currently licensed in 82 countries and the combined ICS/LABA budesonide/formoterol Turbuhaler (Symbicort®; AstraZeneca) in 101 countries.

The present article reports a comprehensive review of safety data obtained in completed AstraZeneca trials (up to December 2006) involving formoterol with respect to the risks of asthma-related and cardiac-related death and serious adverse events (SAEs), as well as all-cause mortality. Three questions were posed of the data. 1) What are the risks of exposure to formoterol compared to other treatment regimens that do not include a LABA (non-LABA)? 2) What are the risks of exposure to formoterol when given in combination with ICS compared to treatment with non-LABA plus ICS? 3) What are the risks of exposure to formoterol without ICS compared with formoterol in combination with ICS? The use of other treatments (e.g. SABAs) was not taken into account.

In order to achieve the largest possible data set, and mimic a real-life situation in which patients may not adhere to guidelines, the primary analysis of the present study focused on question 1. However, given that all guidelines state that LABAs should be used in asthma management in combination with ICS, and as use of ICS may be regarded as a potential confounder in studies of LABA safety, question 2 was added as a post hoc analysis to determine risks associated with the addition of LABA to treatment with ICS versus non-LABA with ICS.

METHODS

Data source

All AstraZeneca trials (completed by December 2006) in patients with asthma involving the use of formoterol either alone as maintenance or reliever therapy or in combination with budesonide were identified through the company database. This consisted of 78,339 patients participating in 117 trials (fig. 1⇓). This large data set was then subjected to reduction in order to bring about more uniformity. The first step excluded trials in which treatment was short. Since an adverse effect of treatment on asthma severity may require exposure over many months, the main analysis included all randomised controlled trials with durations of 3–12 months, performed either as centrally run trials or trials run by marketing companies in different countries (locally run). In order to focus on adverse effects associated with formoterol in comparison with those of non-LABA regimens, treatment arms involving randomisation to the other LABA, salmeterol, were excluded from the main analyses (fig. 1⇓). The remaining trials included those from the centrally run AstraZeneca clinical development programmes for formoterol Turbuhaler (14 trials), budesonide/formoterol Turbuhaler (19 trials) and budesonide/formoterol pressurised metered-dose inhaler (pMDI; 11 trials), and 20 trials conducted by local AstraZeneca marketing companies with formoterol Turbuhaler or budesonide/formoterol Turbuhaler. Details of these 64 trials, involving 72,174 randomised patients, are provided in tables E-1–E-3 of the supplementary material. After excluding the 4,170 patients randomised to salmeterol, the resulting overall data set included 68,004 patients, of whom 49,906 were randomised to formoterol-containing products and 18,098 to non-LABA products (fig. 1⇓).

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Fig. 1—

Flow chart showing all patients involved in AstraZeneca trials with formoterol (FORM). LABA: long-acting β₂-agonist; RELIEF: Real life effectiveness of Oxis Turbuhaler as needed in asthmatic patients during six months; ICS: inhaled corticosteroid.

A supplementary analysis of all identified AstraZeneca asthma trials, regardless of duration or study design, was also performed in order to ensure that no important safety signals were missed by selecting only trials of 3–12 months’ duration. These included all centrally run trials in asthmatic patients, including long-term safety studies, emergency department trials in acute severe asthma, pharmacokinetic and high-dose tolerance studies, methacholine-induced bronchoconstriction studies and trials in a prematurely terminated (due to device malfunction) formoterol pMDI programme. All identified locally run parallel-group trials in asthmatic patients were also included. There were no exclusions of salmeterol-randomised patients in the supplementary analysis. Results from this supplementary analysis are summarised in the present article and further described in the supplementary material.

RESULTS

DISCUSSION

The primary purpose of the present analysis was to determine whether or not use of formoterol was associated with an increased risk of asthma mortality in the largest possible data set from clinical trials, including some patients not on regular treatment with ICS. The present analysis involved 68,004 patients from the AstraZeneca clinical trial programme for formoterol and budesonide/formoterol, providing ∼23,600 person-yrs of exposure to formoterol. Although an RR of 1.57 did not show a significantly increased risk of death, mortality is a rare event in such trials and estimates of risk should be interpreted with caution given that the trials were not powered on these events. More confidence can be placed in the rates for SAEs, for which the numbers of events were substantially greater. The use of formoterol was associated with a significant reduction in asthma-related nonfatal SAEs among both patients in the whole data set and those prescribed ICS at baseline (global ICS analysis), with the RRs being 0.68 and 0.63, respectively.

When analysing the safety of LABAs, two questions are important. What is the overall risk of death if patients are given a LABA regardless of other therapy? What is the relative risk when a LABA, such as formoterol, is added to standard treatment with ICS? Eight asthma-related deaths in 23,600 person-yrs of formoterol exposure in the overall data set yielded a mortality rate of 0.34 per 1,000 person-yrs. The risk of asthma-related death comparing all formoterol-exposed patients with all non-LABA-exposed patients in the overall analysis was 1.57 (95% CI 0.31–15.1). The other question posed in the present analysis regarded the risk of formoterol compared with non-LABA when both were used with concomitant ICS, as per international asthma guidelines. The global ICS analysis (tables 1⇑ and 2⇑) showed an RR of 2.32, but this was also not significant and was associated with wide CIs. This included all patients using ICS at least at baseline, but it also included both the RELIEF trial 30, in which use of ICS after trial entry was not documented (ICS could be discontinued or started), and trials comparing different strategies of using combination ICS/LABA therapies in which there were no non-LABA-randomised patients. Hence the global analysis could be viewed as less appropriate despite the larger number of patients. The analysis based on the smaller randomised ICS data set (table 3⇑), which retained all patients with known ICS exposure during treatment and a non-LABA comparator arm, had three asthma-related deaths in 11,773 formoterol-randomised patients compared to none among the non-LABA-randomised patients. Mortality risk cannot be accurately estimated with only three deaths, albeit all in the formoterol arm, and the calculated RR becomes infinite. However, the absolute rate of asthma mortality is low (0.48 per 1,000 treatment-yrs). The significantly lower risk found for asthma SAEs for formoterol versus non-LABA added to ICS treatment is similar to the findings of a recent meta-analysis by Jaeschke et al. 31.

The data set was explored to assess the relative risk of using formoterol alone. However, the data were insufficient to address this, the third, question. Ideally, this question would be addressed by examining trials in which patients were randomised to formoterol with ICS versus formoterol without ICS. The only AstraZeneca trials using this design were those performed in the USA, where monotherapy with individual components of combination therapy is required by the FDA. However, the 384 patients randomised to formoterol without ICS in these trials were too few to analyse with any meaning. Overall, <8% of all formoterol-treated patients in AstraZeneca asthma trials were not exposed to ICS.

When comparing all formoterol-exposed patients to all non-LABA-exposed patients in the overall data set, no increased risks of cardiac-related deaths (table 1⇑) or cardiac-related non-fatal SAEs (table 2⇑) were observed. Similarly, when examined by ICS use by either the global ICS or randomised ICS method, there was no increased risk of cardiac SAEs with regimens of formoterol with ICS versus non-LABA with ICS (tables 2⇑ and 3⇑).

Hospital admission is a recognised marker of risk of asthma mortality 32, 33. Although these were not analysed separately, the significant reduction in asthma-related SAEs with formoterol, >90% of which were hospitalisations, speaks against a relationship between formoterol and increased asthma mortality.

The main limitation of the present study was the lack of sufficient power to form a definitive conclusion regarding the risk of death for patients treated with formoterol. Although use of formoterol, largely with ICS, was not associated with a significantly increased risk of asthma-related deaths, the power was too low to conclude that there was no association with formoterol, even with data on >68,000 patients. Given the observed asthma mortality rate of ∼0.3 per 1,000 person-yrs and the overall sample sizes in the present study of formoterol-exposed (49,906) and non-exposed patients (18,098), corresponding to 23,600 and 9,200 treatment-yrs, respectively, the present study had a 42, 70 and 88% power for detecting three-, four- and five-fold increases in the risk. The study was also unable to adequately address the issue of age, sex and ethnicity factors, which could be important in modifying the risk of death. The AstraZeneca database lacks sufficient numbers to specifically address the risk in the formoterol-exposed Black population, but no increase in mortality or incidence of asthma-related SAEs was seen in the small numbers of Black subjects.

The present report also does not provide the same weight of evidence as would a large randomised controlled trial of formoterol safety. The report was compiled as an observational study, using data from randomised controlled trials. Several factors need to be considered with respect to their potential for introducing bias into these findings. Data were derived from formoterol arms of numerous trials, and comparator data from arms in the same or different trials. Many trials did not have non-LABA arms or non-ICS arms. There may have been differences in asthma severity and indications for ICS treatment in the different trials, impacting outcomes. Patients entered into most of these trials were required to be in a relatively stable condition with no recent exacerbation or requirement for oral corticosteroid; it is not possible to know to what extent these entry criteria may have selected a population at lower risk of SAEs from treatment. Some deaths and SAEs were assessed and coded as asthma-related or cardiac-related in open trials in which the assigned treatment was known.

Analyses of multiple trial data sets are difficult because of differences in study design and selection criteria, including severity of disease and treatment. A further criticism of the present study is that it did not include all trials involving formoterol. Novartis formoterol trials were not included in the present review as the primary data from their published and unpublished trials were not available to the present authors. Furthermore, possible differences in the formulation and delivery of the two preparations of formoterol could confound or invalidate the analyses. The dose-related increase in nonfatal asthma-related SAEs observed in the Novartis phase III formoterol programme 23 was not confirmed in their phase IV trial comprising 2,085 patients 24, nor in the present review of almost 50,000 formoterol-treated patients. On the contrary, the risk of SAEs in the AstraZeneca trials decreased with higher formoterol doses, an effect that may also be attributable to the higher dose of concomitant ICS generally used with higher doses of formoterol. Conversely, the data from the present study reflect the full breadth of experience with formoterol in AstraZeneca trials in many different populations and situations, including one very large trial (RELIEF), in which formoterol could be used freely as reliever medication and also in addition to maintenance formoterol in some patients 30.

The findings reported here contrast with the report of Salpeter et al. 34, who undertook a meta-analysis of LABA trials with durations of ≥3 months in which LABA was compared with placebo therapy. They concluded that significantly increased mortality and morbidity were associated with both LABAs. However, their analyses included only one of the trials 35 included in the present primary analysis and one additional trial 36 included in the present supplementary analysis, out of a total of 117 AstraZeneca trials in the present review, and specifically excluded many relevant trials, as noted in several responses 37 to the original report of Salpeter et al. 34. One single trial, the Salmeterol Multicenter Asthma Research Trial (SMART), accounted for >26,000 (78%) patients included in their meta-analysis, whereas the two AstraZeneca trials that were included contributed only 753 (2%) patients. In a critique of the paper, Chinchilli 38 made the following comment: “Given the domination by the SMART trial, however, it may be incorrect to claim that this constitutes a systematic overview to investigate the risks of LABAs on asthma-related deaths”.

The conclusion of Salpeter et al. 34 also differs markedly from that of two recent Cochrane analyses on this topic 39, 40. These analyses included trials in which ICS was uniformly used by all patients, and concluded that add-on LABA was both effective and safe. A more recent Cochrane analysis 41 examined trials of LABAs for chronic asthma in adults and children in which the background therapy contained varied or no ICS, and excluded those in which patients were uniformly taking ICS. In this latter review of 67 trials, a median of only 62% were taking ICS. The benefits of add-on LABA on asthma control were seen both with and without ICS therapy, but the authors identified potential safety issues with LABA without ICS, again based almost exclusively on the trial of Nelson et al. 22, in which excess mortality was seen among patients without ICS at baseline. The Asthma Guidelines Committee of the Canadian Thoracic Society carefully reviewed the meta-analysis of Salpeter et al. 34, and affirmed the safety of LABA used in conjunction with ICS 42.

In summary, the present study is the largest analysis to date of trials involving the long-acting β₂-agonist formoterol. Numerous studies have shown the benefit of adding a long-acting β₂-agonist compared with doubling or further increasing the dose of inhaled corticosteroid 18, 19, 36 and the greater benefits to most outcomes of adding a long-acting β₂-agonist compared with adding a leukotriene antagonist 43. International asthma treatment guidelines and the US Food and Drug Administration now emphasise that long-acting β₂-agonist should not be used as monotherapy in asthma but always together with an inhaled corticosteroid 44. The reduction in asthma-related serious adverse events associated with use of formoterol compared with non-long-acting β₂-agonist, and the lack of any dose–response relation with serious adverse events, provides some reassurance regarding the safety of formoterol used largely with inhaled corticosteroid, but, given the infrequency of deaths, the power of the present study is insufficient to conclude with confidence that there is no association between formoterol and mortality. Further studies of mortality in asthma are required in order to permit better assessment of risks so that these can be compared against the widely accepted benefits that long-acting β₂-agonists have brought to the management of patients with asthma.

Support statement

M.R. Sears reviewed the trial data, including details of all deaths, and was primarily responsible for writing this article and for the medical content. S. Suissa was responsible for the statistical and pharmacoepidemiological content. A. Ottosson and F. Radner were responsible for extraction, validation and analysis of data from the AstraZeneca trials. All authors read and approved the final manuscript.

Statement of interest

Statements of interest for all authors of this manuscript can be found at www.erj.ersjournals.com/misc/statements.shtml