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Asthma is a common chronic respiratory illness worldwide, consisting of longstanding airway inflammation with acute exacerbations. Traditionally, asthma has been managed in a step-wise fashion, with older guidance recommending short-acting beta-agonists (SABAs) as required for mild cases, and the addition of regular inhaled corticosteroids (ICS) for more persistent symptoms 1. Since 2019, GINA has highlighted the risks of SABA-only treatment, and advised for a combination ICS and long-acting beta agonist (LABA), to be used as required with mild symptoms, and regularly for more persistent symptoms 2. Long-acting muscarinic agonists (LAMAs) are considered a later add-on therapy if initial stages of therapy are not sufficient to control symptoms. This Cochrane review addresses the approach to a patient with residual asthma symptoms despite the use of a first-line preventer therapy (MD-ICS), a common consultation in both the primary and secondary care setting. ICS are the mainstay treatment for persistent asthma. Escalating treatment is required when asthma is not controlled with ICS therapy alone, which would include, but is not limited to, adding a long-acting beta2-agonist (LABA) or a LAMA or doubling the dose of ICS. To assess the efficacy and safety of adding a LABA or LAMA to ICS therapy versus doubling the dose of ICS in adolescents and adults whose asthma is not well controlled on medium-dose (MD) ICS using a network meta-analysis (NMA), and to provide a ranking of these treatments according to their efficacy and safety. We searched the Cochrane Airways Trials Register, CENTRAL, MEDLINE, Embase, Global Health, ClinicalTrials.gov and the World Health Organization ICTRP for pre-registered randomised controlled trials (RCTs) from January 2008 to 19 December 2022. We searched for studies including adolescents and adults with uncontrolled asthma who had been treated with or were eligible for MD-ICS, comparing it to high-dose (HD) ICS, ICS/LAMA or ICS/LABA. We excluded cluster- and cross-over RCTs. Studies were of at least 12 weeks duration. We conducted a systematic review and network meta-analysis according to a previously published protocol. We used Cochrane's Screen4ME workflow to assess search results. We used Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of evidence. The primary outcome is asthma exacerbations (moderate and severe). We included 38,276 participants from 35 studies (median duration 24 weeks range 12–78; mean age 44.1; 38% male; 69% white; mean forced expiratory volume in one second 2.1 L and 68% of predicted). MD- and HD-ICS/LABA likely reduce and MD-ICS/LAMA possibly reduces moderate to severe asthma exacerbations compared to MD-ICS (hazard ratio HR 0.70, 95% credible interval CrI 0.59–0.82; moderate certainty; HR 0.59, 95% CrI 0.46–0.76; moderate certainty; and HR 0.56, 95% CrI 0.38–0.82; low certainty, respectively), whereas HD-ICS probably does not (HR 0.94, 95% CrI 0.70–1.24; moderate certainty). There is no clear evidence to suggest that any combination therapy or HD-ICS reduces severe asthma exacerbations compared to MD-ICS (low to moderate certainty). This study suggests no clinically meaningful differences in the symptom or quality of life score between dual combinations and monotherapy (low to high certainty). MD- and HD-ICS/LABA increase or likely increase the odds of Asthma Control Questionnaire (ACQ) responders at 6 and 12 months compared to MD-ICS (odds ratio OR 1.47, 95% CrI 1.23–1.76; high certainty; and OR 1.59, 95% CrI 1.31–1.94; high certainty at 6 months; and OR 1.61, 95% CrI 1.22–2.13; moderate certainty and OR 1.55, 95% CrI 1.20–2.00; high certainty at 12 months, respectively). MD-ICS/LAMA probably increases the odds of ACQ responders at 6 months (OR 1.32, 95% CrI 1.11–1.57; moderate certainty). No data were available at 12 months. There is no clear evidence to suggest that HD-ICS increases the odds of ACQ responders or improves the symptom or quality of life score compared to MD-ICS (very low to high certainty). There is no evidence to suggest that ICS/LABA or ICS/LAMA reduces asthma-related or all-cause serious adverse events (SAEs) compared to MD-ICS (very low to high certainty). HD-ICS results in or likely results in little or no difference in the included safety outcomes compared to MD-ICS as well as HD-ICS/LABA compared to MD-ICS/LABA. The pairwise meta-analysis shows that MD-ICS/LAMA likely reduces all-cause adverse events (AEs) and results in a slight reduction in treatment discontinuation due to AEs compared to MD-ICS (risk ratio RR 0.86, 95% confidence interval (CI) 0.77–0.96; 4 studies, 2238 participants; moderate certainty; and RR 0.51, 95% CI 0.26–0.99; 4 studies, 2239 participants; absolute risk reduction 10 fewer per 1000 participants; moderate certainty, respectively). The NMA evidence is in agreement with the pairwise evidence on treatment discontinuation due to AEs, but very uncertain on all-cause AEs, due to imprecision and heterogeneity. The review findings suggest that MD- or HD-ICS/LABA and MD-ICS/LAMA reduce moderate to severe asthma exacerbations and increase the odds of ACQ responders compared to MD-ICS, whereas HD-ICS probably does not. The evidence is generally stronger for MD- and HD-ICS/LABA than for MD-ICS/LAMA primarily due to a larger evidence base. There is no evidence to suggest that ICS/LABA, ICS/LAMA or HD-ICS/LABA reduces severe asthma exacerbations or SAEs compared to MD-ICS. MD-ICS/LAMA likely reduces all-cause AEs and results in a slight reduction in treatment discontinuation due to AEs compared to MD-ICS. The above findings may assist in deciding on a treatment option during the stepwise approach of asthma management. Longer-term safety of higher than MD-ICS needs to be addressed in phase 4 or observational studies given that the median duration of included studies was 6 months. Despite GINA recommendations to initiate ICS/LABA from the outset of treatment 2, many patients will, in line with older BTS/SIGN guidance, be prescribed ICS-only treatment 1. When this is insufficient to control asthma symptoms, doctors should confirm the diagnosis of asthma, assess compliance with medication, inhaler technique and counsel patients to avoid triggers. Once these areas have been addressed, the evidence presented in this review suggests that adding either LABA or LAMA to MD-ICS results in a reduction in moderate to severe asthma exacerbation, whereas a simple increase in the dose of ICS likely does not (see Figure 1). This is an important learning point as a clinician may be tempted to simply increase the dose of the ICS that the patient is already taking for reasons of familiarity, convenience or acceptability to the patient. There is also a significant cost differential, as ICS inhalers are significantly cheaper than combination inhalers (Table 1). The recommendation for early addition of a second medication represents a difference from the management of other common chronic conditions, for example, regarding hypertension, the BNF advises maximising the dose of each agent before adding additional medication 3. Clenil Modulite 100 2 puffs BD £4.45 Clenil Modulite 200 2 puffs BD £9.70 (2 × cost low-dose Clenil) Fostair 100 2 puffs BD £29.32 (6.6 × cost low-dose Clenil) Soprobec 100 2 puffs BD £3.34 Soporobec 200 2 puffs BD £7.29 (2.2 × cost low-dose Soprobec) Seretide 50 2 puffs BD £17.46 (3.9 × cost low-dose Clenil) QVAR 50 2 puffs BD £4.72 QVAR 100 2 puffs BD £10.33 (2.2 × cost low-dose QVAR) Easyhaler Budesonide 100 2 puffs BD £5.32 Easyhaler Beclomethasone 200 2 puffs BD £8.96 (1.7 × cost low-dose Easyhaler) Fostair 100 NEXThaler 2 puffs BD £29.32 (5.5 × cost low-dose Easyhaler) Pulmicort 100 Turbohaler 2 puffs BD £8.55 Pulmicort 200 Turbohaler 2 puffs BD £17.10 (2 × cost low-dose Pulmicort) Symbicort Turbohaler 200/6 2 puffs BD £28.30 (5 × cost low-dose Easyhaler DPI) Flixotide 100 Accuhaler 2 puffs BD £8.04 Flixotide 250 Accuhaler 2 puffs BD £8.46 (similar cost of low-dose Flixotide) Revlar Ellipta 92 one puff OD £22.00 (4.13 × cost low-dose Easyhaler) The advice to add in a second agent, is reflected in BTS/SIGN 1 and American NIH 4 guidelines which recommend adding LABA to low-dose ICS if the patient has uncontrolled symptoms, in contrast to GINA 2 which recommends low-dose ICS/LABA from the outset. This review did not find significant superiority of MD-ICS/LABA compared to MD-ICS/LAMA either at medium or high dose. Both combinations were found to reduce moderate–severe exacerbations compared to HD-ICS alone. Despite this, all guidelines prioritise LABA as the first add-on therapy to ICS. Reviews have demonstrated the benefit of adding LAMA to this combination of ICS/LABA 5, but guidelines reserve this as a specialist-only treatment 1, 2. The use of ICS/LAMA (without LABA) is only recommended in guidance where there has been no benefit to adding the LABA, or if the LABA is either not tolerated or unavailable 2. The universal recommendation for ICS/LABA is likely due to the limited number of studies performed on ICS/LAMA 3, 4. The reason for both the paucity of evidence for LAMA, and the addition of LAMAs at later step in the guidelines (which rely on this evidence) may be that, in contrast to many combination inhalers available for ICS/LABA (Table 1), there are no commercially available combination ICS/LAMA inhalers. We know that asthma adherence is maximised by simplifying regimens, so addition of a second inhaler to provide the LAMA is likely to reduce adherence and therefore asthma control. Of the two LAMA studies included in this review, one excluded participants who were at risk of non-compliance 6, and the other notes that adherence within clinical trials is higher than in routine clinical practice 7. 50% of patients are estimated to be incompletely adherent to their medications 2, so while this review found that the impact of ICS/LABA was not significantly different to ICS/LAMA, in practice, a single combination device containing ICS/LABA is likely to be superior. There is a need for further evidence around the use of ICS/LAMA as this may allow it a firmer place in national and international asthma guidelines. Baigel and Gregory drafted and revised this article together. The authors would like to thank Dr Robert Boyle for his help in preparing the manuscript. Dr Gregory has no conflicts of interest to declare. Dr Baigel has received funding from Reckitt Benckiser and ALK towards her Master's in Allergy and Immunology, and has received funding for international conference attendance from Reckitt Benckiser.
Baigel et al. (Wed,) studied this question.
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