Inhaled triple therapy (TT) with long-acting β2-agonists (LABA), long-acting muscarinic antagonists (LAMA), and inhaled corticosteroids (ICS) has been established as a relevant therapeutic option in the management of patients with chronic obstructive pulmonary disease (COPD) and frequent exacerbations.1 Randomized clinical trials (RCTs) have consistently demonstrated its efficacy in reducing exacerbations, improving lung function and quality of life, and, to a lesser extent, providing survival benefits compared with dual therapies (LAMA–LABA).1,2 However, translating these results into routine clinical practice constitutes a genuine challenge, influenced by the complexity and heterogeneity of patients treated outside the context of an RCT.3
In this context, observational studies (OS) provide a valuable complementary perspective by including populations representative of routine clinical practice.4,5 A high burden of comorbidities, advanced age, polypharmacy, or low treatment adherence are some of the characteristics commonly considered exclusion criteria in RCTs, yet they play a crucial role in the outcomes that can be expected.6,7 This largely explains why the benefits observed with TT compared with dual bronchodilation in OS are not as consistent as those described in RCTs. This discrepancy reflects the heterogeneity of the populations studied. Nevertheless, despite the aforementioned limitations, there is solid evidence on the benefits of TT administered via a single device versus multiple devices.8,9 Treatment simplification has been associated with a lower discontinuation rate and a reduction in exacerbations, an aspect of particular relevance in populations with polypharmacy.
In routine clinical practice, physicians are often required to identify the most appropriate therapeutic option for each patient. In this context, evidence from OS is particularly valuable, as it provides comparative information in settings closer to real-world clinical practice. Nevertheless, data from these studies should be interpreted with caution, particularly when comparing the effectiveness of different TT combinations, as indirect comparisons suggest differences in efficacy in the absence of direct comparative studies.10 One key aspect to consider is the indication of TT in the analyzed population. Many studies use prescription of the drug in patients labeled as COPD as the main inclusion criterion, an approach that is not without limitations. Low adherence to clinical practice guidelines has been widely reported, with poor symptom control, rather than the presence of exacerbations, being one of the main reasons for escalation to TT despite maximal bronchodilation.11 Sarcopenia, malnutrition, and cardiovascular comorbidity are some of the conditions that are often omitted or only partially captured in many OS, and whose presence may contribute to poor symptom control7,12 and influence the outcomes obtained. Moreover, several OS base the diagnosis of COPD on large population registries in which, in many cases, confirmatory spirometry is not available. This fact, which reflects what frequently occurs in routine clinical practice,13 represents a relevant factor that may affect study results. Added to this is the heterogeneity in the definition of exacerbation, the selection criteria employed, the care setting (primary versus hospital care), the duration of follow-up, and the characterization of prior treatments, all of which hinder direct comparison of results and limit the extrapolation of conclusions. Furthermore, OS are subject to biases inherent to their design, such as indication bias, which may influence the interpretation of their findings.
Moreover, the response to TT, and particularly to the ICS component, is clearly modulated by factors such as peripheral blood eosinophil count or the coexistence of bronchial asthma.14 These variables are frequently not adequately recorded, and their absence may reduce the validity of the results. This aspect becomes particularly relevant when higher mortality or increased pneumonia rates are suggested with TT use, as these outcomes may reflect the patient's baseline severity rather than an adverse effect directly attributable to the treatment.15 Advanced age, a high burden of comorbidities (particularly diabetes mellitus), or significant airflow obstruction are well-recognized factors in the development of respiratory infections and are widely represented in patients with COPD and frequent exacerbations, especially those who have required hospitalization.16 In this patient profile, inappropriate use of ICS may worsen the situation, requiring caution both in indication and in the selection of the molecule. In the absence of RCTs directly comparing different TT combinations, some OS suggest a lower risk of pneumonia associated with the use of extrafine-particle TT compared with other ICS.17
An additional aspect that has been rarely addressed in both RCTs and OS is the microbiological characterization through sputum culture. The presence of bronchial colonization by potentially pathogenic microorganisms, such as Haemophilus influenzae, Streptococcus pneumoniae, or Pseudomonas aeruginosa, has been associated with an increased risk of exacerbations, hospitalizations, and worse prognosis, and could significantly influence the response to TT.18,19 The systematic inclusion of microbiological information in future OS would allow a more precise interpretation of adverse events and contribute to a more appropriate selection of patients eligible to receive TT.
On the other hand, the timing of TT initiation remains a matter of debate, with conflicting results.20,21 Initiating this therapy in patients without a clearly defined exacerbation phenotype may lead to unnecessary exposure to ICS, whereas delayed introduction in patients with frequent exacerbations may limit its potential benefit. Therefore, the decision regarding the optimal timing for TT initiation will require a careful assessment of the patient's profile, weighing potential risks against expected benefits.
In conclusion, TT remains an effective and valuable strategy in patients with COPD and frequent exacerbations, particularly when administered via a single device, which promotes adherence and treatment simplification. Evidence from OS highlights the complexity and heterogeneity of patients in real-world clinical practice, where multimorbidity, polypharmacy, advanced age, suboptimal symptom control, or bronchial colonization are more the rule than the exception. These characteristics not only influence clinical response but also the risk of adverse events, underscoring the need to interpret data with caution and always within the individual context of each patient.
Declaration of generative AI and AI-assisted technologies in the manuscript preparation processArtificial intelligence tools were used exclusively to support editing and linguistic refinement of the manuscript. AI tools did not influence the scientific content, data interpretation, or clinical recommendations.
FundingThis manuscript did not receive any funding.
Authors’ contributionsAll authors contributed equally to this editorial and approved the final version.
Conflicts of interestJMFG has received honoraria for speaking engagements and funding for conference attendance from AstraZeneca, Laboratories Esteve, Laboratorios Bial, MundiPharma, Boehringer Ingelheim, Ferrer, Menarini, Rovi, GSK, Chiesi, Novartis, and Gebro Pharma. BAN declares conflicts of interest for having received consulting fees, research grants, or lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, Grifols, GSK, Laboratorios Bial, Laboratorios Menarini, and Sanofi. JMD has received fees for lectures and funding for conference attendance from AstraZeneca, BIAL, Boehringer Ingelheim, Chiesi, FAES, Fresenius-Kabi, Gebro, GSK, Janssen, Menarini, Novartis, Sanofi, Roche, Teva, Pfizer, and Zambon.
