Key messages
• We are confident that quality of life is improved with triple therapy (inhaled corticosteroids (ICS) plus long-acting beta2-agonists (LABA) plus long-acting muscarinic antagonists (LAMA)) compared to combination bronchodilator inhalers (LABA plus LAMA).
• We are moderately confident that compared to combination bronchodilator inhalers, triple therapy results in reduced symptoms and an increased risk of pneumonia.
• We have little confidence that triple therapy lowers rates of chronic obstructive pulmonary disease (COPD) flare-ups and the risk of death or improves lung function when compared to combination bronchodilator inhalers.
Why is this question important?
COPD is a common long-term lung disease that includes chronic bronchitis and emphysema. It is often associated with smoking. People with COPD experience persistent symptoms including breathlessness, cough, and phlegm production, and may suffer from COPD flare-ups where their symptoms become worse.
COPD can be treated with inhalers. Inhalers can contain one, two, or three different medications. These medications include long-acting bronchodilators (LABA and LAMA), which open (dilate) the airways; and ICS, which reduce inflammation in the airways. In some people who have persistent symptoms or frequent flare-ups, all three medications may be taken.
LABA and LAMA can be taken together in one inhaler. This is called a 'combination inhaler'. Combination inhalers have been found to improve adherence to treatment and patient outcomes. LABA and LAMA and ICS can also be taken together, which is known as 'triple therapy'.
We wanted to find out if triple therapy is better than combination therapy in people with stable COPD. Specifically, we wanted to know whether triple therapy improved patient outcomes and what side effects there might be.
How did we answer this question?
We looked for all randomised controlled trials (a type of study where participants are randomly assigned to one of two or more treatment groups) comparing treatment with triple therapy or combination inhaler treatment in people with stable COPD.
What did we find?
We found four studies including a total of 15,412 people with COPD. The studies compared triple therapy ICS/LABA/LAMA inhalers to combination LABA/LAMA inhalers. Most people in the studies were in their mid-sixties, had severe or very severe symptoms of COPD, and had had at least one recent COPD flare-up; there were more men than women in the included studies.
We are confident that quality of life is improved with triple therapy compared to combination inhalers. We are moderately confident that symptoms are reduced by triple therapy, and that people treated with triple therapy have an increased risk of pneumonia compared to those treated with combination inhalers. We have little confidence in the findings that triple therapy may lower rates of COPD flare-ups compared to combination inhalers; that there may be a lower risk of death with triple therapy compared to combination inhalers; or that triple therapy may reduce adverse events or improve lung function.
More research is needed, especially involving people with less severe COPD and those without recent COPD flare-ups.
How up-to-date is the evidence?
The evidence is current to 30 November 2022.
The available evidence suggests that triple therapy may reduce rates of COPD exacerbations (low-certainty evidence) and results in an improvement in health-related quality of life (high-certainty evidence) compared to combination LABA/LAMA inhalers, but probably confers an increased pneumonia risk as a serious adverse event (moderate-certainty evidence). Triple therapy probably improves respiratory symptoms and may improve lung function (moderate- and low-certainty evidence, respectively); however, these benefits do not appear to be clinically significant. Triple therapy may reduce the risk of all-cause mortality compared to combination LABA/LAMA inhalers (low-certainty evidence). The certainty of the evidence was downgraded most frequently for inconsistency or indirectness. Across the four included studies, there were important differences in inclusion criteria, trial medications, and duration of follow-up. Investigation of heterogeneity was limited due to the small number of included studies. We found limited data on the effects of triple therapy compared to combination LABA/LAMA inhalers in patients with mild-moderate COPD and those without a recent exacerbation history.
Management of chronic obstructive pulmonary disease (COPD) commonly involves a combination of long-acting bronchodilators including beta2-agonists (LABA) and muscarinic antagonists (LAMA). LABA and LAMA bronchodilators are now available in single-combination inhalers. In individuals with persistent symptoms or frequent exacerbations, inhaled corticosteroids (ICS) are also used with combination LABA and LAMA inhalers. However, the benefits and risks of adding ICS to combination LABA/LAMA inhalers as a triple therapy remain unclear.
To assess the effects of adding an ICS to combination LABA/LAMA inhalers for the treatment of stable COPD.
We searched the Cochrane Airways Group Register of Trials, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase up to 30 November 2022. We also searched ClinicalTrials.gov and the WHO ICTRPup to 30 November 2022.
We included parallel-group randomised controlled trials of three weeks' duration or longer that compared the treatment of stable COPD with ICS in addition to combination LABA/LAMA inhalers against combination LABA/LAMA inhalers alone.
We used standard Cochrane methodological procedures. The primary outcomes were acute exacerbations of COPD, respiratory health-related quality of life, pneumonia and other serious adverse events. The secondary outcomes were symptom scores, lung function, physical capacity, and mortality. We used GRADE to assess certainty of evidence for studies that contributed data to our prespecified outcomes.
Four studies with a total of 15,412 participants met the inclusion criteria. The mean age of study participants ranged from 64.4 to 65.3 years; the proportion of female participants ranged from 28% to 40%. Most participants had symptomatic COPD (COPD Assessment Test Score ≥ 10) with severe to very severe airflow limitation (forced expiratory volume in one second (FEV1) < 50% predicted) and one or more moderate-to-severe COPD exacerbations in the last 12 months. Trial medications differed amongst studies. The duration of follow-up was 52 weeks in three studies and 24 weeks in one study. We assessed the risk of selection, performance, and detection bias to be low in the included studies; one study was at high risk of attrition bias, and one study was at high risk of reporting bias.
Triple therapy may reduce rates of moderate-to-severe COPD exacerbations compared to combination LABA/LAMA inhalers (rate ratio (RR) 0.74, 95% confidence interval (CI) 0.67 to 0.81; n = 15,397; low-certainty evidence). Subgroup analysis stratifying by blood eosinophil counts showed there may be a greater reduction in rate of moderate-to-severe COPD exacerbations with triple therapy in participants with high-eosinophils (RR 0.67, 95% CI 0.60 to 0.75) compared to low-eosinophils (RR 0.87, 95% CI 0.81 to 0.93) (test for subgroup differences: P < 0.01) (high/low cut-offs: 150 eosinophils/µL in three studies; 200 eosinophils/µL in one study). However, moderate-to-substantial heterogeneity was observed in both high- and low-eosinophil subgroups. These subgroup analyses are observational by nature and thus results should be interpreted with caution. Triple therapy may be associated with reduced rates of severe COPD exacerbations (RR 0.75, 95% CI 0.67 to 0.84; n = 14,131; low-certainty evidence).
Triple therapy improved health-related quality of life assessed using the St George's Respiratory Questionnaire (SGRQ) by the minimal clinically important difference (MCID) threshold (4-point decrease) (35.3% versus 42.4%, odds ratio (OR) 1.35, 95% CI 1.26 to 1.45; n = 14,070; high-certainty evidence). Triple therapy may result in fewer symptoms measured using the Transition Dyspnoea Index (TDI) (OR 1.33, 95% CI 1.13 to 1.57; n = 3044; moderate-certainty evidence) and improved lung function as measured by change in trough FEV1 (mean difference 38.68 mL, 95% CI 22.58 to 54.77; n = 11,352; low-certainty evidence). However, these benefits fell below MCID thresholds for TDI (1-unit decrease) and trough FEV1 (100 mL), respectively.
Triple therapy is probably associated with a higher risk of pneumonia as a serious adverse event compared to combination LABA/LAMA inhalers (3.3% versus 1.9%, OR 1.74, 95% CI 1.39 to 2.18; n = 15,412; moderate-certainty evidence). In contrast, all-cause serious adverse events may be similar between groups (19.7% versus 19.7%, OR 0.95, 95% CI 0.87 to 1.03; n = 15,412; low-certainty evidence). All-cause mortality may be lower with triple therapy (1.4% versus 2.0%, OR 0.70, 95% CI 0.54 to 0.90; n = 15,397; low-certainty evidence).