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

¹ Firestone Institute for Respiratory Health, St Joseph's Healthcare and McMaster University, Hamilton, Ontario, Canada
² AstraZeneca R&D, Lund, Sweden
³ Dept of Epidemiology and Biostatistics, and Medicine, McGill University, Montreal, Canada

^* To whom correspondence should be addressed. E-mail: searsm{at}mcmaster.ca.

	Abstract

The safety of long-acting ₂-agonist (LABA) treatment in asthma has been questioned following reported increased respiratory deaths when salmeterol was added to usual pharmacotherapy. We examined whether asthma, cardiac or all-cause mortality or morbidity were increased with formoterol use.

The analysis included all AstraZeneca randomized, controlled, parallel-group asthma trials of 3–12 months duration involving formoterol. Risks associated with formoterol use compared with non-LABA treatment, overall and in combination with inhaled corticosteroids (ICS), were assessed using an intention-to-treat analysis of the rates and rate ratios of deaths and serious adverse events (SAEs). The main objective of this study was to compare asthma-related mortality in patients using formoterol and those not using formoterol.

There were eight asthma-related deaths (0.34 per 1000 patient-years) among 49, 906 formoterol-randomized patients (92% using ICS), and two (0.22 per 1000 patient-years) among 18, 098 patients (83% using ICS) not randomized to formoterol (RR 1.57, 95% CI 0.31–15.1) which was not statistically significant. Asthma-related SAEs (>90% of which were hospitalizations) were significantly lower among formoterol-randomized patients (0.75% vs. 1.10%; RR 0.68, 95% CI 0.57–0.81). There was no increase in asthma-related SAEs with increased daily doses of formoterol (9 vs 18 vs 36 mcg). There was no statistically significant difference in cardiac mortality (RR 0.34, 95% CI 0.12–1.02) or non-cardiac, non-asthma-related mortality (RR 2.35, 95% 0.69–12.5) in formoterol-randomized when compared to non-LABA-treated patients. All-cause mortality was similar (RR 0.95, 95% CI 0.50–1.92). In the data set in which all subjects were prescribed ICS at baseline, there were seven asthma-related deaths (0.32 per 1000 patient-years) among 46, 003 formoterol-randomized patients and one (0.14 per 1000 patient-years) among 13, 905 patients not randomized to formoterol (RR 2.32, 95% CI 0.30–105) which was also not statistically significant.

There were few asthma-related or cardiac-related deaths among patients randomized to formoterol, and all differences were not statistically significant compared with non-LABA-randomized patients. However, despite data on over 68, 000 patients, the power is insufficient to conclude no increased mortality with formoterol. Cardiac-related SAEs were not increased, and asthma-related SAEs were significantly reduced with formoterol.

Keywords:  Asthma, formoterol, inhaled corticosteroids, long-acting -agonist, morbidity, mortality, safety

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