Risk of pneumonia with budesonide-containing treatments in COPD: an individual patient-level pooled analysis of interventional studies

Abstract

BackgroundConcerns have been raised that treatment of COPD with inhaled corticosteroids may increase pneumonia risk. Responding to a request from the European Medicines Agency Pharmacovigilance Risk Assessment Committee, a pooled analysis of interventional studies compared pneumonia risk with inhaled budesonide-containing versus non-budesonide-containing treatments and the impact of other clinically relevant factors.MethodsAstraZeneca-sponsored, parallel-group, double-blind, randomized controlled trials meeting the following criteria were included: >8 weeks’ duration; ≥60 patients with COPD; inhaled budesonide treatment arm (budesonide/formoterol or budesonide); and non-budesonide-containing comparator arm (formoterol or placebo). Primary and secondary outcomes were time to first pneumonia treatment-emergent serious adverse event (TESAE) and treatment-emergent adverse event (TEAEs), respectively, analyzed using Cox regression models stratified by study.ResultsEleven studies were identified; 10,570 out of 10,574 randomized patients receiving ≥1 dose of study treatment were included for safety analysis (budesonide-containing, n=5,750; non-budesonide-containing, n=4,820). Maximum exposure to treatment was 48 months. The overall pooled hazard ratio (HR), comparing budesonide versus non-budesonide-containing treatments, was 1.15 for pneumonia TESAEs (95% confidence interval [CI]: 0.83, 1.57) and 1.13 for pneumonia TEAEs (95% CI: 0.94, 1.36). The annual incidence of pneumonia TESAEs was 1.9% and 1.5% for budesonide-containing and non-budesonide-containing treatments, respectively. Comparing budesonide/formoterol with non-budesonide-containing treatment, the HRs for pneumonia TESAEs and TEAEs were 1.00 (95% CI: 0.69, 1.44) and 1.21 (95% CI: 0.93, 1.57), respectively. For budesonide versus placebo, HRs were 1.57 for pneumonia TESAEs (95% CI: 0.90, 2.74) and 1.07 for pneumonia TEAEs (95% CI: 0.83, 1.38).ConclusionThis pooled analysis found no statistically significant increase in overall risk for pneumonia TESAEs or TEAEs with budesonide-containing versus non-budesonide-containing treatments. However, a small increase in risk with budesonide-containing treatment cannot be ruled out; there is considerable heterogeneity in study designs and patient characteristics, particularly in the early budesonide studies, and each study contributes <40 pneumonia TESAEs.

Effect of budesonide/formoterol pressurized metered-dose inhaler on exacerbations versus formoterol in chronic obstructive pulmonary disease: The 6-month, randomized RISE (Revealing the Impact of Symbicort in reducing Exacerbations in COPD) study

“…A metaanalysis of 7 studies with >7000 patients found no increase in pneumonia rates following budesonide treatment with or without a LABA component in patients with COPD [20]. A recently updated pooled analyses of 11 studies with >10,000 patients also found no statistically significant increase in overall risk of pneumonia treatment-emergent AEs following budesonide treatment (with or without a LABA) in patients with COPD versus non-budesonide comparators (formoterol or placebo) [21]. Our findings suggest that the ICS component of budesonide/formoterol pMDI 320/9 mg combination treatment provides clinical benefit for patients with COPD without an apparent causal relationship for the development of pneumonia.…”

Role of eosinophils in airway inflammation of chronic obstructive pulmonary disease

“… 84 – 89 , 102 In addition, potential differences in risk for pneumonia may be affected by the specific ICS used. 86 , 103 , 104 Therefore, considering a patient’s prior history of pneumonia may be important when choosing ICS therapy as part of the COPD-treatment regimen.…”

Comparison of fluticasone propionate and budesonide on COPD macrophage and neutrophil function

“… 3 – 7 On the other hand, most double-blind, randomized controlled studies with budesonide treatment alone or in combination with the LABA formoterol reported no increased risk of pneumonia when compared with formoterol alone or placebo. 8 Furthermore, large observational, population-based studies in real-world, clinical practice with COPD patients have suggested a higher risk of pneumonia for therapy with FP than with budesonide. 9 – 12 Similarly, a recent evaluation of meta-analyses that considered the risk of pneumonia related to treatment of COPD patients with FP or budesonide showed an association with FP causing a statistically significant increased risk of pneumonia, whereas budesonide showed no association.…”