Triple (ICS/LABA/LAMA) vs. Dual (ICS/LABA) Therapy for Persistent, Uncontrolled Asthma: A Systematic Review and Meta-Analysis
Bibliographic record
Abstract
Introduction: Among patients with moderate-severe asthma, the benefits and harms of adding long-acting muscarinic antagonists (LAMA) to inhaled corticosteroids (ICS) and long-acting bronchodilators (LABA) remains unclear. Recent randomized clinical trials (RCTs) have evaluated the safety and efficacy of LAMA add-on to ICS and LABA, also known as triple therapy, but prior systematic reviews and meta-analysis did not capture the majority of these trials, resulting in imprecise and inconclusive findings. The latest asthma recommendations are based on 2-3 studies from prior to 2017 (n=907-1301) and one LAMA type. Therefore, the objective of this study was to systematically synthesize the efficacy and safety of triple (ICS-LABA-LAMA) vs. dual therapy (ICS-LABA) in children, adolescents, and adults with persistent, uncontrolled asthma. PROSPERO:CRD42020172608. Methods: MEDLINE, EMBASE, CENTRAL, ICTRP, FDA and EMA databases from November 2017 to December 8, 2020 were searched without language restriction. Two investigators independently selected RCTs comparing triple vs. dual therapy in patients with moderate-severe asthma. Two reviewers independently extracted data and assessed risk of bias. We used random-effects meta-analyses, including individual patient-level exacerbation data, and to assess evidence certainty, the GRADE approach. The primary outcome included in the study were severe exacerbations (risk ratio [RR], incidence rate ratio [IRR], hazard ratio [HR]). The secondary outcomes included asthma control, quality of life, FEV 1 , and adverse events. Results: We included 20 RCTs using 3 LAMA types that enrolled 11,826 children, adolescents, and adults. Compared with dual therapy, preliminary metaanalysis showed that triple therapy with add-on LAMA decreased the number of severe asthma exacerbations (RR 0.80, 95% CI 0.71 to 0.90, high certainty) and increased time-to-first event (HR 0.84, 95%CI 0.78-0.90, high certainty). The symptom scores measured in ACQ5, ACQ6, ACQ7 and ACT in the triple therapy group was improved compared to the dual treatment group was (Mean Difference [MD] 0.05, 95%CI 0.07-0.01 units better, high certainty). In addition, FEV 1 in the triple therapy group was increased compared to the ICS-LABA therapy (FEV 1 MD 80mL, 95% CI 60 to 90mL, high certainty). Serious and non-serious adverse events were similar between groups. Findings were robust to trial sequential, subgroup and sensitivity analyses. Conclusions: In moderate-severe asthma, high certainty evidence shows that triple therapy safely reduces severe exacerbations with modest improvements in other patient-important outcomes. This supports add-on LAMA in patients at high risk for future exacerbation.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.019 | 0.035 |
| Meta-epidemiology (narrow) | 0.003 | 0.002 |
| Meta-epidemiology (broad) | 0.027 | 0.041 |
| Bibliometrics | 0.009 | 0.008 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.004 | 0.002 |
| Open science | 0.003 | 0.002 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".