Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD

Abstract

BACKGROUND Triple fixed-dose regimens of an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting β 2-agonist (LABA) for chronic obstructive pulmonary disease (COPD) have been studied at single dose levels of inhaled glucocorticoid, but studies at two dose levels are lacking. METHODS In a 52-week, phase 3, randomized trial to evaluate the efficacy and safety of triple therapy at two dose levels of inhaled glucocorticoid in patients with moderate-tovery-severe COPD and at least one exacerbation in the past year, we assigned patients in a 1:1:1:1 ratio to receive twice-daily inhaled doses of triple therapy (inhaled glucocorticoid [320 μg or 160 μg of budesonide], a LAMA [18 μg of glycopyrrolate], and a LABA [9.6 μg of formoterol]) or one of two dual therapies (18 μg of glycopyrrolate plus 9.6 μg of formoterol or 320 μg of budesonide plus 9.6 μg of formoterol). The primary end point was the annual rate (the estimated mean number per patient per year) of moderate or severe COPD exacerbations, as analyzed in the modified intention-to-treat population with the use of on-treatment data only. RESULTS The modified intention-to-treat population comprised 8509 patients. The annual rates of moderate or severe exacerbations were 1.08 in the 320-μg-budesonide triple-therapy group (2137 patients), 1.07 in the 160-μg-budesonide triple-therapy group (2121 patients), 1.42 in the glycopyrrolate-formoterol group (2120 patients), and 1.24 in the budesonide-formoterol group (2131 patients). The rate was significantly lower with 320-μg-budesonide triple therapy than with glycopyrrolateformoterol (24% lower: rate ratio, 0.76; 95% confidence interval [CI], 0.69 to 0.83; P<0.001) or budesonide-formoterol (13% lower: rate ratio, 0.87; 95% CI, 0.79 to 0.95; P = 0.003). Similarly, the rate was significantly lower with 160-μg-budesonide triple therapy than with glycopyrrolate-formoterol (25% lower: rate ratio, 0.75; 95% CI, 0.69 to 0.83; P<0.001) or budesonide-formoterol (14% lower: rate ratio, 0.86; 95% CI, 0.79 to 0.95; P = 0.002). The incidence of any adverse event was similar across the treatment groups (range, 61.7 to 64.5%); the incidence of confirmed pneumonia ranged from 3.5 to 4.5% in the groups that included inhaled glucocorticoid use and was 2.3% in the glycopyrrolate-formoterol group. CONCLUSIONS Triple therapy with twice-daily budesonide (at either the 160-μg or 320-μg dose), glycopyrrolate, and formoterol resulted in a lower rate of moderate or severe COPD exacerbations than glycopyrrolate-formoterol or budesonide-formoterol. (Funded by AstraZeneca, ETHOS ClinicalTrials.gov number, NCT02465567.

<p>Current Status of the Treatment of COPD in China: A Multicenter Prospective Observational Study</p>

“…Many studies have shown that dual or triple therapy will produce a statistically significant improvement in FEV 1 and reduce the exacerbation risk compared among different groups. [35][36][37] Unfortunately, in our study, the lung function of FEV 1 /FVC, symptoms of dyspnea and exacerbations after 1-year of follow-up were not improved, even worse compared to the baseline. The FEV 1 and CAT scores were stable.…”

Pharmacotherapy and Lung Function Decline in Patients with Chronic Obstructive Pulmonary Disease. A Systematic Review

“…We cannot address the reasons why the different treatments might influence the rate of decline of FEV 1 , although as we illustrate, treatment reduces exacerbation rates, which are associated with lung function decline (8,31). Recent data have shown that maximizing the therapy that is usually given to patients with COPD and more severe disease and exacerbations can reduce the risk of these events and of dying (32,33); these findings are consistent with this complementary evidence from the published literature. This systematic review is useful because it addressed one single research question, used studies with a large number of patients, had a high-quality control of the primary outcome (FEV 1 ) and followed patients over a long enough period of time to provide an answer to the research question.…”

<p>Prescribing Pathways to Triple Therapy: A Retrospective Observational Study of Adults with Chronic Obstructive Pulmonary Disease in the UK</p>

“…This is supported by double-blind, randomized controlled trials that have shown benefits of triple therapy versus LAMA/LABA and ICS/LABA combination therapies in reducing exacerbation rates. [22][23][24][25] Additionally, all-cause mortality data from the ETHOS and IMPACT studies have shown a beneficial effect for triple therapy compared with LAMAs/LABAs. 22,25 Adherence levels in our study (as defined by PDC) were high, with adherent patients experiencing significantly increased exacerbation rates versus non-adherent patients.…”

“…[22][23][24][25] Additionally, all-cause mortality data from the ETHOS and IMPACT studies have shown a beneficial effect for triple therapy compared with LAMAs/LABAs. 22,25 Adherence levels in our study (as defined by PDC) were high, with adherent patients experiencing significantly increased exacerbation rates versus non-adherent patients. This is to be expected, as patients are more likely to adhere to medication if they are experiencing exacerbations that are not under control.…”