Table 2 Strengths and limitations of selected RCTs of ICS in patients with COPD.
From: Rational use of inhaled corticosteroids for the treatment of COPD
Pharmacotherapy | Key trials/reference (year) | Key findings | Main critique | Reference to GOLD COPD documents |
|---|---|---|---|---|
ICS alone | Yang IA, et al. Cochrane Database Syst Rev (2012)43 | RCTs of ICS vs. placebo >6 months: • Modest decrease in exacerbations • No decrease in FEV1 decline or mortality • Increased pneumonia risk | Exacerbation benefit overestimated due to ICS withdrawal effect47 | GOLD Report 2011 “ICS monotherapy not recommended in COPD as it is less effective than LABA/ICS (Evidence A)”45 |
LABA/ICS | TORCH (2007)44 • 3-year survival study • Moderate–severe COPD (FEV1 < 60%), SAL/FP500 vs. its mono-components and placebo | All-cause mortality (complete survival follow-up): • HR LABA/ICS vs. placebo 0.825 (95% CI 0.681, 1.002), p = 0.052) • Primary endpoint not achieved • Incomplete (discontinuation) follow-up for all non-primary (non-survival) endpoints Pneumonia events: • LABA/ICS and ICS groups (18–20%) • LABA and placebo groups (12–13%) | • Placebo is not “usual care” • 2-week run-in with ICS and LABA withdrawal (28% dropout) • ICS withdrawal (45–50%) • LABA withdrawal (35%) • Factorial (2*2 analysis) not published by study authors but otherwise calculated to show survival benefit attributable to LABA, not ICS, component47 | GOLD REPORT 2023—Efficacy of ICS alone4 “In the TORCH trial, a trend toward higher mortality was observed for patients treated with fluticasone propionate alone compared to those receiving placebo or salmeterol plus fluticasone propionate combination” |
Adding LAMA | Canadian OPTIMAL Study (2007)49 • 52-week, 3-arm exacerbation RCT • Moderate–severe COPD (FEV1 < 65%); ≥1 exacerbation/year; past asthma excluded - LAMA (Tio, n = 156) - LAMA/LABA (Tio/SAL; n = 148) - LAMA + LABA/ICS (Tio + SAL/FP250; n = 145) | • Proportion of patients who experienced moderate–severe exacerbations: - LAMA (62.8%) - LAMA + LABA (64.8%) - LAMA + LABA/ICS (60%) - Rate ratios not significantly different • Hospitalisations lower in LAMA + LABA/ICS vs LAMA group: - HR 0.67 (95% CI 0.45, 0.99) • 40% premature discontinuation in non-ICS arms | • First trial of triple therapy in COPD, non-pharma sponsored • Complete (intent-to-treat) follow-up • High withdrawal rate in non-ICS arms related to ICS withdrawal on randomisation (75% pre-study ICS use) • No exacerbation benefit in ICS-naïve subjects (per-study non-users)47 | Study not cited |
LAMA/LABA vs. LABA/ICS | FLAME (2016)50 • 52-week, 2-arm exacerbation RCT - Moderate–severe COPD (FEV1 25–60%); >1 exacerbation/year; past asthma excluded. - LAMA/LABA (GLY/IND; n = 1680) - LABA/ICS (SAL/FP250; n = 1682) | • 4-week LAMA (Tio) run-in associated with 32% dropout rate • Annual rate of all COPD exacerbations: - 11% lower in LAMA/LABA group than LABA/ICS group (RR 0.89; 95% CI 0.83, 0.96; p = 0.003) • Incidence of pneumonia: - 3.2% in LAMA/LABA group and 4.8% in LABA/ICS group | • Study design tending to exclude ICS responders • Run-in bias (4-week Tio run-in; all ICS and LABA discontinued) • Past asthma excluded • Subjects with blood eosinophil count >600 cells/µl excluded • The reported HR for time to first exacerbation may represent a magnification of the real effect51 | No referral to this study regarding ICS use in COPD |
