With COPD, based on current data, it still is not possible to get one to make a clear choice between treatment with the combination LABA + LAMA or the combination ICS + LABA.
GOLD 2024 no longer gives place to the combination ICS + LABA. However, a Cochrane Review and a cohort study in JAMA did not yield unambiguous results, so we cannot conclude that the combination LABA + LAMA is more effective in terms of symptom relief or reduction in the number of exacerbations than the combination ICS + LABA.
The combination ICS + LABA then causes again more frequent pneumoniawithout increasing mortality.
Introduction
The drug treatment of chronic obstructive pulmonary disease (COPD) includes:
According to guidelines1-4, the first step of treatment consists of a bronchodilator.
What is the recommended approach if a bronchodilator is not sufficient to relieve symptoms and/or if exacerbations occur? Addition of another bronchodilator (combination LABA + LAMA) or an ICS (combination ICS + LABA)?
In this article we discuss the results of two publications from 2023 in which both combinations are compared: a Cochrane Review5 (update of a Cochrane Review discussed in the 2018 Folia on the treatment of stable COPD), and a cohort study that appeared in JAMA6.
Cochrane Review
Protocol
In the 2023 update, 8 studies were added (total 19 studies, 2 unsponsored studies). Most studies were double-blind RCTs, with the exception of 2 open studies. A total of 22,354 patients with stable COPD were included. The participants were predominantly men (70%), with an average age of 64 years and with an ESW (one second value) of 51% of the predicted value. In 13 studies, patients with moderate to severe COPD without recent exacerbations were included. In 4 studies, only patients who had recently experienced an exacerbation were included, which amounts to 65% of the total number of participants.
Treatment with the combination LABA + LAMA or with the combination ICS + LABA was evaluated for a period of 6 to 52 weeks.
Results
In contrast to the 2017 Cochrane, the 2023 update shows no advantage of the LABA + LAMA combination over the ICS + LABA combination in terms of exacerbations or quality of life.
In the 2023 review, the results are as follows:
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For the primary endpoints “exacerbations”, “quality of life” and “serious side effects” there was no difference between the two combinations. The “ESW” improved more with LABA + LAMA than with ICS + LABA.
- ≥ 1 exacerbation: OR 0.91 (95% CI from 0.78 to 1.06), moderate certainty (heterogeneity).
- Quality of life (SGRQ score): MD -0.57 (95% CI from -1.36 to 0.21), moderate degree of certainty (heterogeneity).
- Serious adverse events: OR 1.02 (95% CI from 0.91 to 1.15), high confidence.
- ESW: MD 0.07 (95% CI from 0.05 to 0.08), moderate degree of certainty (heterogeneity).
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The other results were secondary endpoints. No difference was seen in the occurrence of a clinically relevant improvement in quality of life (defined as a difference of ≥4 points in the SGRQ score).
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Pneumonia occurred more frequently in patients receiving ICS + LABA (5% versus 3% under LABA+LAMA, NNH=50). The overall mortality was slightly higher with LABA + LAMA (1.4% versus 1% under ICS + LABA, NNH=250).
- Pneumonia: 5% with ICS + LABA versus 3% with LABA + LAMA. OR 0.61 (95% CI from 0.52 to 0.72), high confidence.
- Global mortality: 1% with ICS + LABA versus 1.4% with LABA + LAMA. OR 1.35 (95% CI from 1.05 to 1.75), moderate certainty (low number of events).
- Clinically relevant improvement in quality of life (difference of ≥4 points on the SGRQ score):
OR 1.06 (95% CI from 0.90 to 1.25), moderate confidence.
Limits
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According to the authors of the Cochrane Review, the reliability of these results is moderate to high. The risk of bias is generally low, except for conflicts of interest (17 of the 19 studies were sponsored).
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Pre-specified subgroup analyzes could not be performed according to COPD severity because insufficient data were available on participants in the different studies.
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No study evaluated the risk of hospitalization for exacerbation.
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The studies varied with regard to the exclusion of patients with asthma or with eosinophilia. Since these patient groups more often benefit from treatment with ICS, the results may be biased in favor of ICS.
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Regarding the higher mortality among LABA + LAMA, the authors point out that the number of events was low. This is a secondary endpoint that requires further investigation. To our knowledge, this is the only study showing higher mortality under LABA + LAMA than under ICS + LABA.5
Cohort Study (JAMA)
Protocol
The study in the JAMA was published is a propensity score matched cohort study, based on data from an American insurance company. 137,833 patients with a diagnosis of COPD were included (mean age 70 years, minimum 40 years at inclusion, 50.4% women). Patients with a diagnosis of asthma or patients receiving triple therapy with ICS + LABA + LAMA were excluded. They had been registered in the database for at least one year and were included in the study as soon as they were prescribed a LABA + LAMA or an ICS + LABA for the first time. 30,216 pairs of patients were used for the analysis.
Adjustments were made for numerous confounding variables.
Results
There were two primary endpoints.
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The first primary endpoint was the occurrence of a first moderate to severe exacerbation. A moderate exacerbation was defined in the study as an exacerbation that required the patient to take oral corticosteroids for 5 to 14 days. A severe exacerbation was defined as an exacerbation requiring hospitalization.
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The second primary endpoint was the occurrence of pneumonia requiring hospitalization.
For both endpoints, results favored the LABA + LAMA combination: -8% for moderate to severe exacerbations and -20% for pneumonia hospitalizations compared to ICS + LABA.
- Moderate to severe exacerbation: – 8%, HR 0.92 (95% CI from 0.89 to 0.96). Absolute reduction of 43 events per 1000 person years.
- Hospital admission for pneumonia: -20%, HR 0.80 (95% CI from 0.75 to 0.86). Absolute reduction of 21.9 events per 1000 person years.
The results on the exacerbation endpoint were no longer statistically significant when analyzing pre-specified subgroups, such as GOLD stage, history of exacerbation or eosinophilia.
Limits
In addition to the fact that it is an observational study, the study has other limitations, according to the authors.
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The duration of follow-up was short: up to one year until the endpoint occurred.
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The analyzes were based on the delivery of the specialties on medical prescription. This does not necessarily mean that the medicine was administered and that the administration was done correctly.
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Patients who received the ICS + LABA combination generally had more severe COPD and had more limited access to care than patients who received the LABA + LAMA combination. This may be the cause of the higher number of adverse events in the ICS + LABA group. The authors do not rule out residual confounding.6
Commentary from the BCFI
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It remains difficult for COPD patients to choose between treatment with the combination LABA + LAMA versus the combination ICS + LABA.
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GOLD 2024 no longer gives place to the combination ICS + LABA. However, the most recent studies discussed in this article do not clearly show that the combination LABA + LAMA is more effective than the combination ICS + LABA in terms of symptom relief or reduction in the number of exacerbations.
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The studies do confirm the higher risk of pneumonia with the combination ICS + LABA, without an increase in the number of deaths.
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The Cochrane Review shows for the first time a higher global mortality with LABA + LAMA. The causes of death are not stated. Given the small number of events, these results should be interpreted with caution. Since we are talking about global mortality, additional research on this would be useful.
List of fixed combinations LABA+LAMA / ICS+LABA with COPD as indication in the SKP
LABA + LAMA
See also Directory
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Aclidinium + formoterol: Duaklir®
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Glycopyrronium + indacaterol: Ultibro®
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Tiotropium + olodaterol: Spiolto®, Yanimo®
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Umeclidinium + vilanterol: Anoro®
ICS + LABA
See also Directory
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Formoterol + budesonide: Symbicort®, Airbufo®, Bufomix®
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Formoterol + beclometason: Inuvair®
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Salmeterol + fluticason: Seretide Diskus®, Airflusal®, Flutisamix®
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Vilanterol + fluticason: Relvar®
Sources
1 https://goldcopd.org/2024-gold-report/
2 https://bestpractice.bmj.com/topics/en-gb/7/treatment-algorithm
3 https://richtlijnen.nhg.org/standaarden/copd#volledige-tekst-medicamenteuze-behandeling-copd
4 https://www.nice.org.uk/guidance/ng115/chapter/Recommendations#managing-stable-copd
5 Fukuda N, Horita N, Kaneko A, Goto A, Kaneko T, Ota E, Kew KM. Long‐acting muscarinic antagonist (LAMA) plus long‐acting beta‐agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2023, Issue 6. Art. No.: CD012066. DOI: 10.1002/14651858.CD012066.pub3. Accessed 19 January 2024.
6 Feldman WB, Avorn J, Kesselheim AS, Gagne JJ. Chronic Obstructive Pulmonary Disease Exacerbations and Pneumonia Hospitalizations Among New Users of Combination Maintenance Inhalers. JAMA Intern Med. 2023;183(7):685–695. doi:10.1001/jamainternmed.2023.1245
2024-03-14 20:37:48
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