Table 1.
History of evidence for the use of ICS-containing treatment regimens in COPD
| Timeline | Intervention | Evidence |
|---|---|---|
| 1980s | N/A | • ICS were adopted in the management of COPD based on the fact that they were highly effective in asthma rather than scientific evidence11 asthma rather than scientific evidence11 |
| Late 1990s | ICS alone | • Early RCTs in patients with mild COPD (ie, FEV1 near 80% predicted) found no improvement in the decline of lung function over time and no reduction in the exacerbation rate with various ICS compared with placebo11,15,17,18 |
| 2000 | ICS alone | • ISOLDE was the first trial to demonstrate the beneficial effects of ICS (ie, fluticasone propionate) on exacerbation rate in patients with moderate-to-severe COPD (ie, FEV1 ≤50% predicted); albeit, there was no effect on the rate of decline in lung function19 |
| • The Lung Health Study, which also included patients with lower FEV1 (mean 56% predicted), found that patients treated with an ICS (ie, triamcinolone) reported fewer visits to a physician for respiratory illness73 | ||
| 2001 | ICS alone | • In a large population-based cohort study of 22,620 patients with COPD who were previously hospitalized, it was found that patients who received ICS within 90 days postdischarge had 24% fewer rehospitalizations and a 29% risk reduction for mortality during a 1-year follow-up20 |
| 2002 | ICS alone | • A meta-analysis of early RCTs reported a significant 30% overall reduction in exacerbations with ICS74 |
| ICS + LABA | • RCTs began evaluating ICS in combination with a LABA (ie, either budesonide/formoterol or fluticasone propionate/salmeterol)11,21,22 | |
| 2007 | ICS + LABAa | • In the landmark TORCH trial, a 3-year, randomized, double-blind trial comparing salmeterol plus fluticasone propionate vs placebo, salmeterol alone, or fluticasone propionate alone in patients with COPD (FEV1 <60% of predicted), it was found that:22 |
| ○ There was no significant benefit of ICS + LABA on all-cause mortality (primary end point); however, the statistical significance was borderline when compared with placebo (17.5% reduction; P=0.052) | ||
| ○ ICS + LABA significantly reduced the rate of exacerbations vs placebo (by 25%, P<0.001) and LABA or ICS alone (12%, P=0.002 and 9%, P=0.024, respectively) | ||
| ○ ICS + LABA had a much slower rate of decline in lung function compared with placebo (P≤0.003) and LABA or ICS alone (P<0.001, respectively) | ||
| ○ ICS + LABA significantly improved health status vs placebo, LABA, or ICS alone (P<0.001 for all) | ||
| Adding ICS + LABA to LAMAb | • The Canadian Optimal trial was a 1-year, randomized, double-blind, placebo-controlled study that evaluated the addition of ICS + LABA (fluticasone propionate/salmeterol), LABA, or placebo in 449 patients with moderate-to-severe COPD who were receiving LAMA (tiotropium)75 | |
| ○ The findings of this trial were conflicting in that the addition of ICS + LABA to LAMA did not statistically influence rates of COPD exacerbation, but did improve lung function, quality of life, and hospitalization rates | ||
| 2008 | ICS + LABA vs LAMAa | • The INSPIRE trial, a 2-year, randomized, double-blind, double-dummy parallel study, directly compared ICS + LABA (fluticasone propionate/salmeterol) and LAMA (tiotropium) in a total of 1,323 patients with severe COPD, and was the first to show that there was no difference in exacerbation rate between ICS + LABA and LAMA24 |
| 2009 | ICS + LABA + LAMAb | • In the CLIMB trial, a 12-week, randomized, double-blind, parallel-group, multicenter study, the efficacy and tolerability of adding a LAMA (tiotropium) to ICS + LABA (budesonide/formoterol) vs placebo was assessed in 660 patients with COPD after a 2-week run-in period76 |
| ○ The addition of ICS + LABA to a LAMA vs LAMA alone reduced severe exacerbations (by 62%; P<0.001), as well as provided a rapid and sustained improvement in lung function (P<0.001), health status, and symptoms | ||
| 2015 | ICS + LABA | • In the SUMMIT trial, a placebo-controlled, double-blind, randomized, parallel group, multicenter study, mortality risk on ICS + LABA (fluticasone furoate/vilanterol) was evaluated in 16,485 patients from 43 countries who had COPD with moderate airflow limitation (FEV1 50%–70% predicted) and either a history or risk of cardiovascular disease26 |
| ○ Risk of mortality was found to be 12.2% lower with ICS + LABA compared with placebo; albeit, this difference was not statistically significant (P=0.137) |
Notes:
a
Used as evidence to support recommendations for GOLD Group C.
b
Used as evidence to support recommendations for GOLD Group D despite concerns about conflicting findings and/or short-term duration of trials.
Abbreviations: COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroids; INSPIRE, Investigating New Standards for Prophylaxis in Reduction of Exacerbations; ISOLDE, Inhaled Steroids in Obstructive Lung Disease in Europe; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; N/A, not applicable; RCT, randomized controlled trial; SUMMIT, Study to Understand Mortality and MorbidITy in COPD; TORCH, TOwards a Revolution in COPD Health.