Abstract
Only a few therapies have been shown to prolong survival in specific patients with COPD. In recent years, the IMPACT and the ETHOS trials suggested that triple therapy (a combination of inhaled corticosteroid (ICS), long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) given in a single inhaler) may reduce mortality compared with dual bronchodilation.
These results need however to be interpreted with caution. These trials were not powered by design to evaluate the impact of triple therapy on mortality as mortality was a secondary outcome. In addition, mortality reduction has to be put in perspective with the low mortality rate in both studies (<2%). Furthermore, a key methodological issue is that up to 70–80% of patients had ICS withdrawal at the enrolment in the LABA/LAMA arms, but none in the ICS-containing treatment arms. It is possible that ICS withdrawal may have contributed to some early death events. Finally, the inclusion and exclusion criteria of both trials were designed to select patients likely to respond to ICS.
There are no conclusive data yet that triple therapy reduces mortality in COPD. Future, well-designed and -powered trials are needed to validate the findings on mortality.
Abstract
To date, there are no conclusive data that triple therapy limits mortality in COPD. Future, well-designed and -powered trials are needed to validate the findings around mortality. https://bit.ly/3ZtzmT1
Commentary on
Lipson DA, et al. Once-daily single-inhaler triple versus dual therapy in patients with COPD. N Engl J Med 2018; 378: 1671–1680.
Rabe KF, et al. Triple inhaled therapy at two glucocorticoid doses in moderate-to-very-severe COPD. N Engl J Med 2020; 383: 35–48.
Context
COPD is an airway disease with persistent respiratory symptoms that causes globally ∼3 million deaths every year [1]. Tobacco exposure has been proven to be the main risk factor for the development of COPD [2]. With the increasing prevalence of smoking in developing countries, and ageing populations in high-income countries, prevalence of COPD is expected to rise over the next 40 years. By 2030, there may be over 4.5 million deaths annually from COPD and related conditions [1]. Only smoking cessation in mild and moderate COPD patients [3], vaccination, long-term oxygen therapy in severely hypoxaemic COPD patients, and lung volume reduction surgery in selected COPD patients with emphysema were found to have a consistent benefit on mortality [4–6]. Pharmacological treatment choices such as inhaled bronchodilators are central to symptom management and are commonly given on a regular basis to prevent or reduce symptoms. However, none of the individual studies that were powered to evaluate the effects of pharmacological treatments on COPD mortality have detected a significant survival benefit [7–10].
In recent years, two large randomised controlled trials provided new evidence on reduction of exacerbations with combination therapy including an inhaled corticosteroid (ICS), a long-acting muscarinic antagonist (LAMA) and a long-acting β2-agonist (LABA) given in a single inhaler (triple therapy). These trials are called the IMPACT (“Informing the Pathway of COPD Treatment”) and ETHOS (“Efficacy and Safety of Triple Therapy in Obstructive Lung Disease”) trials [11, 12]. These trials also suggested a reduction in mortality with triple therapy compared with dual bronchodilation [11–14].
Here we describe the methods and results of the IMPACT and ETHOS trials with a specific focus on the impact of triple therapy on COPD mortality and discuss the strengths and limitations of these trials and how their design could have affected their findings.
Methods
Impact
The IMPACT trial [11] was a phase 3, multicentre, randomised, double-blind, placebo-controlled trial. Patients of 40 years of age or older, with physician-diagnosed symptomatic COPD, assessed with a COPD Assessment Test (CAT) score ≥10, and forced expiratory volume in 1 s (FEV1) <50% and a history of one moderate or severe exacerbation in the previous year, or an FEV1 of 50–80% of the predicted normal value and at least two moderate exacerbations or one severe exacerbation in the previous year, were included. Participants were randomised in a 2:2:1 ratio to receive either a triple therapy including fluticasone furoate (FF) at a dose of 100 μg, umeclidinium (UMEC) at a dose of 62.5 μg, and vilanterol (VI) at a dose of 25 μg, or with FF/VI (at doses of 100 μg and 25 μg, respectively) or UMEC/VI (at doses of 62.5 μg and 25 μg, respectively) for 52 weeks (table 1). The primary endpoint was the annual rate of moderate or severe COPD exacerbations. The two co-primary treatment comparisons were triple therapy versus UMEC/VI, and triple therapy versus FF/VI with a superiority hypothesis with triple therapy on reducing exacerbations. The predefined key secondary endpoints were the FEV1 and change of the St. George's Respiratory Questionnaire (SGRQ).
Main characteristics of the IMPACT and ETHOS trials
Ethos
The ETHOS trial [12] was a phase 3, multicentre, randomised, double-blind, placebo-controlled trial. Patients of 40 years of age or older, with physician-diagnosed symptomatic COPD, assessed with CAT score ≥10, and FEV1 <50% and a history of one moderate or severe exacerbation in the previous year, or an FEV1 of 50–65% of the predicted normal value and at least two moderate exacerbations or one severe exacerbation in the previous year, were included. Patients were randomised to 320 µg of budesonide (BUD), glycopyrrolate and formoterol (320 µg BUD/GLY/FOR), 160 µg BUD/GLY/FOR, GLY/FOR or 160 µg BUD/FOR administered in a single inhaler (randomised 1:1:1:1) for 52 weeks (table 1) [12, 14]. The primary endpoint was the annual rate of moderate or severe COPD exacerbations with a superiority hypothesis with triple therapy over dual therapy. The predefined key secondary endpoints were time to death (all-cause), SGRQ response and changes in pre-bronchodilator FEV1.
Results
In the phase 3, 52-week IMPACT study, 10 355 patients with symptomatic COPD and a history of exacerbations were randomised 2:2:1 to treatment with FF/UMEC/VI, FF/VI or UMEC/VI, administered in a single inhaler [11]. Triple versus dual therapy significantly reduced the annual moderate/severe exacerbations. The rate of moderate or severe exacerbations in the triple-therapy group was 0.91 per year, as compared with 1.07 per year in the FF/VI (rate ratio with triple therapy 0.85 (95% CI 0.80–0.90); 15% difference; p<0.001) (table 2). Improvements from baseline with FF/UMEC/VI compared with UMEC/VI were also maintained throughout the study for both trough FEV1 and SGRQ. In addition, the data from the IMPACT trial showed that FF/UMEC/VI reduced risk of all-cause mortality compared with LAMA/LABA (UMEC/VI). The hazard ratio for triple therapy versus UMEC/VI was 0.58 (95% CI 0.38–0.88; 42% difference; unadjusted p=0.01), and the hazard ratio for FF/VI versus UMEC/VI was 0.61 (95% CI 0.40–0.93; 39% difference; unadjusted p=0.02) [11, 13].
Main outcomes of the IMPACT and ETHOS trials
In the ETHOS trial, 16 033 patients were screened of which 8588 were randomised to either 320 µg BUD/GLY/FOR (n=2157), 160 µg BUD/GLY/FOR (n=2137), GLY/FOR (n=2143) or 160 µg BUD/FOR (n=2151). Population characteristics were similar to those of the IMPACT trial (table 2). In the overall population, the ETHOS trial showed similar results to the IMPACT trial. Triple therapy (either 320 and 160 µg BUD/GLY/FOR) significantly reduced annual exacerbations compared with GLY/FOR (rate ratio 0.76 (95% CI 0.69–0.83); p<0.001) or 160 µg BUD/FOR (rate ratio 0.87 (95% CI 0.79–0.95); p=0.003) [12, 14] (table 2). In addition, triple therapy showed significant improvement in both FEV1 and SGRQ compared with dual therapy but without reaching minimal clinically important differences (MCID). Finally, the ETHOS trial reported a hazard ratio of all-cause mortality over 1 year of 0.51 (95% CI 0.33–0.80) comparing triple therapy (BUD/GLY/FOR) with dual bronchodilator therapy (GLY/FOR) [12, 14].
Commentary
COPD is a leading cause of mortality worldwide and several large trials have evaluated whether COPD-related treatments reduce mortality. Although rarely powered by design to investigate mortality, various previous randomised controlled trials have assessed the effect of different bronchodilators on mortality in COPD as well. No statistically significant difference in mortality was observed with LABA/ICS, LABA alone or ICS alone compared with placebo in previous trials [7, 10]. Even the SUMMIT trial (Study to Understand Mortality and Morbidity in COPD) involving patients with moderate COPD with heightened cardiovascular risk which was powered to study all-cause mortality, did not show a significant effect for FF/VI compared with FF (hazard ratio 0.91 (95% CI 0.77–1.08); p=0.284) or VI alone (hazard ratio 0.96 (95% CI 0.81–1.14); p=0.655) [7].
Besides smoking cessation, only few therapies have been shown to prolong survival in specific patients with COPD including long-term oxygen therapy, vaccination and lung volume reduction surgery in selected patients [1, 4, 5]. The IMPACT and ETHOS trials suggested for the first time that bronchodilators could also improve mortality [11–14]. Both trials reported a markedly large (40–50%) reduction of mortality with LAMA/LABA/ICS over LAMA/LABA combinations in patients with COPD [11–14]. These results need, however, to be interpreted with caution.
First, in both trials, mortality was a secondary or an exploratory outcome. Therefore, these trials were not powered by design to evaluate the impact of triple therapy on mortality. Furthermore, mortality reduction has to be put in perspective with the low mortality rate in both studies. Indeed, mortality findings were based on 164 deaths out of 8588 participants (mortality rate of 1.9%) in ETHOS and 138 deaths out of 10 355 participants (mortality rate of 1.3%) in IMPACT [11–14].
Second, both the ETHOS and IMPACT trials have shown a significant reduction in mortality with triple therapy in the first year of treatment. However, by stratification over follow-up time, some discrepancies have to be pointed out [13–15]. Indeed, during the first 90 days after treatment initiation, there was a significantly lower proportion of deaths in the triple therapy group than in the dual therapy group in both the IMPACT and ETHOS studies (rate ratio of mortality of 0.24 (95% CI 0.12–0.48) and 0.37 (0.15–0.95), respectively). By contrast, during the subsequent 91–365 days of follow-up, the death rate was more similar or no longer statistically significant for triple and dual therapy (rate ratio 1.03 (0.71–1.50) and 0.86 (0.57–1.31) for the IMPACT and ETHOS trials, respectively) [13–15]. This would suggest that triple therapy only has a protective effect during the first 3 months of use, with no sustained benefit thereafter when the large majority of deaths occurred, or that withdrawal of ICS has an acute harmful effect compared to maintenance of ICS. Therefore, several methodological issues have been raised to explain this controversial benefit of triple therapy [16]. A key methodological issue is the management of treatment of patients at enrolment. Treatment had to be discontinued at randomisation for all patients. However, up to 70–80% of patients had ICS withdrawal at the enrolment of both the ETHOS and IMPACT studies (table 1) in the LABA/LAMA arms but none of the patients in the ICS containing treatment arms. By comparison, only 33% of patients had ICS before inclusion in SUMMIT [7]. It is possible that ICS discontinuation may have contributed to some early death events. This effect of ICS discontinuation is especially prominent in IMPACT where, in the first month, the incidence rate of first exacerbation under LAMA/LABA was higher than under LAMA/LABA/ICS. This may be due to the fact that in both the IMPACT and ETHOS trials, patients had raised eosinophil counts at baseline (table 1). In these patients, especially those with blood eosinophils over 300 cells·µL−1, ICS discontinuation increases exacerbations and might therefore contribute to a higher mortality [17].
Third, the inclusion and exclusion criteria of both ETHOS and IMPACT were designed to select patients likely to respond to ICS. Patients with a previous history of asthma or atopy were not excluded. In addition, up to one-fifth of patients in the IMPACT study and almost one-third in ETHOS had significant bronchodilator reversibility (table 1). This is in contrast to other trials, such as FLAME [18], that included patients that were less likely to respond to ICS, as they excluded patients with a current or previous diagnosis of asthma or atopy or allergic rhinitis, or patients with respiratory symptoms before the age of 40 years, or patients with eosinophils ≥600 cells per mm3. Furthermore, the patients included in IMPACT and ETHOS were more symptomatic with more frequent moderate or severe exacerbations compared with previous trials [11, 12]. In both trials, more than half of patients had two or more moderate or severe exacerbations during the year before inclusion. By contrast, a recent pooled analysis from six randomised controlled trials including COPD patients with a lower exacerbation risk (e.g. <20% of patients reported ≥2 exacerbations in the prior year) showed contrasting results [19]. No statistically significant difference in time to death was observed between LAMA/LABA (3133 patients) and LAMA/LABA/ICS (3133 patients) after propensity score matching including exacerbation history in the previous year (hazard ratio for LAMA/LABA 1.06 (95% CI 0.68–1.64); p=0.806). This suggests triple therapy may predominantly benefit selected patients with a high risk of exacerbation (>2 exacerbations per year).
Therefore, the difference of inclusion criteria and baseline characteristics of patients in the ETHOS and IMPACT trials may have affected all outcomes and also mortality compared with previous trials.
Implications for research and practice
The management of COPD should be based on a systematic approach to identify the phenotype and comorbidities that can influence the prognosis. The current COPD treatment guidelines recommend a stepwise approach and personalisation of treatments [1]. In patients with symptomatic severe COPD (FEV1 <50%) and a history of exacerbations, triple therapy has shown a reduction of exacerbations over a LAMA–LABA association. However, as discussed above, there are no conclusive data yet that triple therapy reduces mortality. Even if there is mortality benefit, this may be driven by maintaining corticosteroid therapy in ICS responsive groups. Therefore, future studies need to consider ICS responsiveness to evaluate the effect of ICS withdrawal on mortality. Furthermore, following an adaptive selection method that aims at avoiding the previous medications' withdrawal effect will be important for future studies to evaluate the effect of triple therapies [20].
Conclusion
There are no conclusive data yet that triple therapy causally reduces mortality in COPD. In both the ETHOS and IMPACT trials, even if a potential reduction in mortality was observed (secondary outcome), there are several methodological issues that prompt to interpret these results with caution. Therefore, reduction of exacerbations in symptomatic patients with severe COPD and a history of exacerbations should remain the main objective of triple therapy. Future, well designed and powered trials are needed to validate the findings on mortality.
Footnotes
Conflict of interest: T. Soumagne reports personal fees from GSK, Menarini, AstraZeneca, Sanofi-Aventis, ALK and non-financial support from Menarini, outside the submitted work. L. Lahousse reports honoraria paid to her institution for lectures from IPSA (non-profit organisation facilitating lifelong learning for healthcare providers) and a fee for external expert consultation paid to her institution from AstraZeneca, outside the submitted work. The other authors did not have conflicts of interest to declare.
- Received November 11, 2022.
- Accepted January 5, 2023.
- Copyright ©ERS 2023
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