Intraclass Difference in Pneumonia Risk with Fluticasone and Budesonide in COPD: A Systematic Review of Evidence from Direct-Comparison Studies

BACKGROUND: Inhaled corticosteroids (ICS) are widely used and recommended to treat chronic obstructive pulmonary disease (COPD). While generally considered safe, several studies demonstrated an increased risk of pneumonia with the use of ICS in COPD patients. Although all ICS indicated for COPD carry the class labeling warning of increased pneumonia risk, evidence suggests an intraclass difference in the risk of pneumonia between inhaled budesonide and fluticasone. To date, systematic reviews of direct-comparison studies have not been performed to assess if an intraclass difference exists. RESEARCH QUESTION: This review investigated whether there is an intraclass difference in risk of pneumonia between inhaled fluticasone and budesonide, the 2 most commonly used ICS in COPD. STUDY DESIGN AND METHODS: A search of the medical literature was conducted in PubMed and Embase for the time period of 01/01/69–05/31/19. The search strategy combined terms that defined the patient/disease type, exposures, outcome, and the study/publication type. Descriptive and comparative statistics reported for fluticasone- and budesonide-containing products in each study, including data for pneumonia event subgroups, were extracted and reported by dose, seriousness, or practice setting. Controlled clinical trials and observational studies meeting the inclusion criteria were assessed for methodologic quality by using the appropriate tool from the list of study quality assessment tools developed by the National Institutes of Health. RESULTS: The summary relative risk (RR) ratio across 5 included studies (57,199 patients) was 1.13 (95% CI: 1.09–1.19), representing a 13.5% increased risk of pneumonia among fluticasone users compared to budesonide users. Similarly, summary RR ratio for serious pneumonia implied a 14.4% increased risk of serious pneumonia among fluticasone users compared to budesonide users (pooled RR: 1.14; 95% CI: 1.09–1.20). INTERPRETATION: There is likely a clinically important intraclass difference in the risk of pneumonia between fluticasone- and budesonide-containing inhaled medications in COPD.