Risk of mortality associated with formoterol: a systematic review and meta-analysis

Area of Science:

• Pulmonary Medicine
• Pharmacovigilance
• Clinical Trials

Background:

• Long-acting beta-agonists (LABAs) are commonly prescribed for asthma.
• Concerns exist regarding a potential association between LABA use and increased asthma mortality.
• Systematic reviews and meta-analyses are crucial for evaluating drug safety.

Purpose of the Study:

• To systematically review and meta-analyze randomized controlled trials (RCTs) of formoterol in asthma.
• To assess the risk of all-cause mortality and asthma-specific death associated with formoterol compared to non-LABA treatments.
• To evaluate the safety profile of formoterol concerning asthma mortality.

Main Methods:

• Systematic review of RCTs with a duration of at least 4 weeks comparing formoterol to non-LABA comparators.
• Inclusion of data from the AstraZeneca Formoterol Clinical Trial Safety Database and Novartis FDA Formoterol Briefing Document.
• Meta-analysis using simple contingency tables, Peto's one-step method, and Bayesian analysis.

Main Results:

• A total of 62 studies with 49,327 subjects were included, reporting 42 deaths (9 from asthma).
• Simple contingency table analysis showed an odds ratio for all-cause mortality of 1.1 (95% CI 0.6-2.2) and for asthma death of 2.7 (95% CI 0.5-26.7) with formoterol.
• Alternative analytical methods yielded similar risk estimates with wide confidence/credible intervals, indicating insufficient statistical power.

Conclusions:

• The study lacked sufficient statistical power to definitively determine if formoterol increases mortality risk.
• However, point estimates suggest a 2.0- to 3.2-fold increased risk of asthma death, which warrants caution.
• These findings support existing evidence that LABA use may elevate asthma mortality risk under certain conditions.