1. For patients with moderate-to-severe asthma, budesonide-formoterol combination therapy was not associated with a higher risk of serious asthma-related events than budesonide alone.
2. Budesonide-formoterol combination therapy demonstrated superior efficacy compared to budesonide monotherapy.
Evidence Rating Level: 1 (Excellent)
Study Rundown: There is controversy regarding a possible association between the chronic use of long-term beta agonists (LABAs) and mortality in asthmatics. In response, the Food and Drug Administration (FDA) required LABA manufacturers to conduct studies examining the safety of glucocorticoid-LABA combination therapy. This study is one of the four mandated by the FDA which analyzed the safety and efficacy of formoterol-budesonide compared to budesonide alone. There was no significant difference between patients who received budesonide-formoterol versus patients who received budesonide alone. Asthma exacerbations were significantly reduced in the budesonide-formoterol group versus budesonide alone group. This study is in agreement with the safety profile published earlier for glucocorticoid-LABA combination therapy and glucocorticoid monotherapy.
This was a multi-center, randomized, double-blind study. A large enough study group was included to overcome the statistical rarity of serious asthma-related adverse events. Limitations included the support of a pharmaceutical sponsor in data collection and analysis and that a 26-week study period may be too short to rule out all long-term adverse events.
In-Depth [randomized controlled trial]: This multi-center, randomized controlled trial had 11,551 patients in the final intention-to-treat analysis. Patients were randomized to receive either formoterol-budesonide or budesonide alone for 26 weeks. Safety (primary endpoint) was defined as a composite of asthma-related deaths, intubations, and hospitalizations. Additional safety measurements included serious adverse events and discontinuations due to adverse events or exacerbations. Efficacy (secondary endpoint) was based on the first asthma exacerbation, defined by the need for systemic glucocorticoids for at least 3 days, hospitalization, or an emergency department visit that resulted in glucocorticoid administration. Asthma control was assessed by the six-item Asthma Control Questionnaire.
Patients in the budesonide-formoterol group had 43 serious asthma-related events versus 40 events in the budesonide monotherapy group, which demonstrated noninferiority HR 1.07 (95%CI 0.70 to 1.65). Results of other safety measures in the combined therapy group versus monotherapy group, respectively, were; 6 patients versus 8 for reported deaths, 1.6% versus 2.3% discontinued treatment from adverse events, and 0.9% versus 1.2% discontinued treatment due to exacerbations. The risk of asthma exacerbation (secondary endpoint of efficacy) was 16.5% lower with combination budesonide-formoterol therapy than budesonide therapy alone (HR 0.84; 95%CI 0.74 to 0.94; p = 0.002).
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