Discontinuation of Inhaled Corticosteroids from Triple Therapy in COPD: Effects on Major Outcomes in Real World Clinical Practice.

Recent reports provide evidence-based guidelines for the withdrawal of inhaled corticosteroids (ICS) in COPD, but data on patients treated with ICS-based triple therapy are sparse and contradictory. We assessed the effect of ICS discontinuation on the incidence of severe exacerbation and pneumonia in a real-world population of patients with COPD who initiated triple therapy. We identified a cohort of patients with COPD treated with LAMA-LABA-ICS triple therapy during 2002-2018, age 50 or older, from the UK's CPRD database. Subjects who discontinued ICS were matched 1:1 on time-conditional propensity scores to those continuing ICS and followed for one year. Hazard ratios (HR) of severe exacerbation and pneumonia were estimated using Cox regression. The cohort included 42,667 patients who discontinued ICS matched to 42,667 who continued ICS treatment. The hazard ratio of a severe exacerbation with ICS discontinuation relative to ICS continuation was 0.86 (95% CI: 0.78-0.95), while for severe pneumonia it was 0.96 (95% CI: 0.88-1.05). The incidence of severe exacerbation after ICS discontinuation was numerically higher than after continuation among patients with two or more exacerbations in the prior year (HR 1.09; 95% CI: 0.94-1.26) and among those with FEV1 <30% predicted (HR 1.29; 95% CI: 1.04-1.59). This large real-world study in the clinical setting of COPD treatment suggests that certain patients on triple therapy can be safely withdrawn from ICS and remain on bronchodilator therapy. As residual confounding cannot be ruled out, ICS discontinuation is not warranted for patients with multiple exacerbations and with very severe airway obstruction.

Triple Inhaler versus Dual Bronchodilator Therapy in COPD: Real-World Effectiveness on Mortality.

Randomized trials of triple therapy including an inhaled corticosteroid (ICS) for chronic obstructive pulmonary disease (COPD) reported remarkable benefits on mortality compared with dual bronchodilators, likely resulting from ICS withdrawal at randomization. We compared triple therapy with dual bronchodilator combinations on major COPD outcomes in a real-world clinical practice setting. We identified a cohort of COPD patients, age 50 or older, treated during 2002-2018, from the United Kingdom's Clinical Practice Research Datalink. Patients initiating treatment with a long-acting muscarinic antagonist (LAMA), a long-acting beta2-agonist (LABA) and an ICS on the same day, were compared with patients initiating a LAMA and LABA, weighted by fine stratification of propensity scores. Subjects were followed-up one year for all-cause mortality, severe exacerbation and pneumonia. The cohort included 117,729 new-users of LAMA-LABA-ICS and 26,666 of LAMA-LABA. The adjusted hazard ratio (HR) of all-cause mortality with LAMA-LABA-ICS compared with LAMA-LABA was 1.17 (95% CI: 1.04-1.31) while for severe exacerbation and pneumonia it was 1.19 (1.08-1.32) and 1.29 (1.16-1.45) respectively. However, mortality was not elevated with triple therapy among patients with asthma diagnosis (HR 0.99; 95% CI: 0.74-1.34), with two or more prior exacerbations (HR 0.88; 95% CI: 0.70-1.11), and with FEV1 percent predicted >30%. In a real-world setting of COPD treatment, triple therapy initiation was not more effective than dual bronchodilators at preventing all-cause mortality and severe COPD exacerbations. Triple therapy may be unsafe among patients without prior exacerbations, in whom ICS are not recommended, with no asthma diagnosis and with very severe airflow obstruction.Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2021.1977789 .

Comparative Effectiveness and Safety of LABA-LAMA vs LABA-ICS Treatment of COPD in Real-World Clinical Practice.

BACKGROUND: Long-acting ß2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are recommended as initial maintenance treatments for COPD, with their combination (LABA-LAMA) advocated as the disease progresses. Randomized trials comparing the effectiveness of this combination with the alternative combination of LABA with inhaled corticosteroid (LABA-ICS) have reported conflicting data, while there are no real-world comparative effectiveness and safety studies of these regimens in clinical practice settings. METHODS: We identified a cohort of patients with COPD during 2002-2015, age 55 years or older, from the United Kingdom's Clinical Practice Research Datalink. Patients initiating LABA-LAMA on the same day (no ICS) were matched on time-conditional high-dimensional propensity scores with patients initiating LABA-ICS on the same day (no LAMA), and monitored for 1 year for the occurrence of a moderate or severe COPD exacerbation and severe pneumonia. RESULTS: The cohort included 1,977 initiators of LABA-LAMA matched with 1,977 initiators of LABA-ICS. The hazard ratio (HR) of moderate or severe COPD exacerbation associated with LABA-LAMA initiation, relative to LABA-ICS initiation, was 1.04 (95% CI, 0.90-1.20), while for a severe exacerbation it was 0.94 (95% CI, 0.65-1.36). The incidence of severe pneumonia requiring hospitalization was lower with LABA-LAMA initiation (HR, 0.66; 95% CI, 0.41-1.05), particularly in the on-treatment analysis (HR, 0.66; 95% CI, 0.50-0.87). CONCLUSIONS: In a real-world clinical practice setting of COPD treatment, combined LABA-LAMA inhalers appear to be as effective as combined LABA-ICS inhalers in preventing COPD exacerbations. However, a LABA-LAMA combination may be preferred because it is associated with fewer severe pneumonias.

Comparative effectiveness of LABA-ICS versus LAMA as initial treatment in COPD targeted by blood eosinophils: a population-based cohort study.

BACKGROUND: Long-acting ß2 agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are the recommended initial maintenance treatment for chronic obstructive pulmonary disease (COPD), with almost all LABAs dispensed in fixed combination with inhaled corticosteroids (LABA-ICS). We compared the effectiveness and safety of LABA-ICS versus LAMA treatment initiation as a function of blood eosinophilia, a potential biomarker of ICS effectiveness, in a real-world setting. METHODS: In this population-based cohort study, we identified a cohort of patients with COPD initiating treatment with a LAMA or LABA-ICS during 2002-15, age 55 years or older, from the UK's Clinical Practice Research Datalink. We excluded patients who initiated treatment with both bronchodilators on the same date. All patients required at least 1 year of medical history and a measure of blood eosinophil concentration before cohort entry, defined by the date of the first cohort-defining bronchodilator prescription. Patients initiating a LAMA were matched on high-dimensional propensity scores with patients initiating a LABA-ICS. They were followed up for 1 year for the occurrence of a moderate or severe COPD exacerbation and for severe pneumonia. Sensitivity analyses included, among others, repeating the analysis among patients with two blood eosinophil concentration measures and stratification by concurrent asthma and previous exacerbations. FINDINGS: The base cohort included 539 643 patients with a prescription for LABAs or LAMAs from Jan 1, 2002, to Dec 31, 2015, of whom 18 500 were initiated on LABA-ICS and 13 870 on LAMAs. Propensity score analysis resulted in 12 366 initiators of LAMAs (mainly tiotropium) matched to 12 366 initiators of LABA-ICS. The hazard ratio (HR) of COPD exacerbation associated with LABA-ICS initiation, relative to LAMA initiation, was 0·95 (95% CI 0·90-1·01). In patients with blood eosinophil concentrations of less than 2% of white blood cell count, the HR was 1·03 (95% CI 0·93-1·13) and for those with eosinophil concentrations of 2-4%, the HR was 1·00 (0·91-1·10). For patients with eosinophil concentrations of more than 4%, the HR was 0·79 (0·70-0·88). The incidence of pneumonia increased with LABA-ICS initiation (HR 1·37 [95% CI 1·17-1·60]) and was similar across all eosinophil concentrations. Sensitivity analyses were consistent with these findings, but the incidence of exacerbation with LABA-ICS among the 2766 (11%) of all 24 732 patients with two or more COPD exacerbations during the baseline year was marginally lower (HR 0·87 [95% CI 0·79-0·97]). INTERPRETATION: In this real-world, clinical practice, observational study, initial COPD treatment with LABA-ICS inhalers was only more effective than with LAMAs in patients with high blood eosinophil concentrations (>4%) or counts (>300 cells per µL) and possibly in frequent exacerbators. Because of the increased risk of pneumonia associated with the ICS component, initiation with a LAMA should be preferred in patients with blood eosinophil concentrations of less than 4%. FUNDING: Canadian Institutes of Health Research, Canadian Foundation for Innovation.