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An Obvious Paradigm

2021; Elsevier BV; Volume: 160; Issue: 4 Linguagem: Inglês

10.1016/j.chest.2021.06.025

1931-3543

Mario Cazzola, Maria Gabriella Matera,

Pneumonia and Respiratory Infections

FOR RELATED ARTICLE, SEE PAGE 1255Many clinicians initiate treatment of COPD by prescribing long-acting beta agonist/inhaled corticosteroid fixed-dose combinations (LABA/ICS FDCs), despite the growing evidence supporting the use of LABA/long-acting muscarinic antagonist (LAMA) FDCs in the early stage of the disease.1Maniscalco M. Martucci M. Fuschillo S. de Felice A. D’Anna S.E. Cazzola M. A case scenario study on adherence to COPD GOLD recommendations by general practitioners in a rural area of southern Italy: The “progetto PADRE”.Respir Med. 2020; 170: 105985Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar This approach may be appropriate if it takes into account the specific characteristics of the patient to be treated, as personalized therapy requires. FOR RELATED ARTICLE, SEE PAGE 1255 Obviously, each prescription must maximize clinical efficacy without causing adverse events,2Maxwell S.R. Rational prescribing: the principles of drug selection.Clin Med (Lond). 2016; 16: 459-464Crossref PubMed Scopus (19) Google Scholar but this is not always predictable, regardless of the type of combination chosen. Besides, the most appropriate choice between the many available LABA/LAMA and LABA/ICS FDCs is difficult mainly because of the paucity of head-to-head comparison studies.3Calzetta L. Matera M.G. Cazzola M. Pharmacological mechanisms leading to synergy in fixed-dose dual bronchodilator therapy.Curr Opin Pharmacol. 2018; 40: 95-103Crossref PubMed Scopus (41) Google Scholar This paucity can be overcome partly by the use of large national registries that can serve as the basis for rigorous observational studies, provided that the big number of confounding variables is addressed adequately, possibly with the use of the inverse probability treatment weighting propensity score approach.4Mitchell J.D. Gage B.F. Fergestrom N. Novak E. Villines T.C. Inverse probability of treatment weighting (propensity score) using the Military Health System Data Repository and national death index.J Vis Exp. 2020; https://doi.org/10.3791/59825Crossref Scopus (2) Google Scholar In this issue of CHEST, Wang et al5Wang M.T. Lai J.H. Huang Y.L. et al.Comparative effectiveness and safety of different types of LABA/LAMA versus LABA/ICS fixed-dose combinations in COPD: a propensity score-inverse probability of treatment weighting cohort study.Chest. 2021; 160: 1255-1270Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar used Taiwanese national health claims from 2014 to 2017 to compare some LABA/LAMA and LABA/ICS FDCs in COPD following the inverse probability treatment weighting approach. The two LABA/LAMA FDCs considered (indacaterol/glycopyrronium and vilanterol/umeclidinium) appeared to be more effective than salmeterol/fluticasone, but not formoterol/budesonide and formoterol/beclomethasone, in reducing the risk of exacerbation of COPD (ECOPD). The occurrence of severe pneumonia was significantly greater in subjects who received salmeterol/fluticasone than in those who received LABA/LAMA FDCs. This difference did not appear when LABA/LAMA FDCs were compared with the other two LABA/ICS FDCs. In addition, no difference in cardiovascular risk was observed among the five treatments. The fact that these results were produced with the use of data derived from real-world professional practices is surely their real plus. They confirm the conclusion of some randomized controlled trials that have shown that several LABA/LAMA FDCs are more effective than salmeterol/fluticasone in reducing the risk of ECOPDs.6Calzetta L. Di Marco F. Blasi F. et al.Impact of ICS/LABA and LABA/LAMA FDCs on functional and clinical outcomes in COPD: a network meta-analysis.Pulm Pharmacol Ther. 2019; 59: 101855Crossref PubMed Scopus (9) Google Scholar They also decrease potential doubts about the external validity of randomized controlled trial data and the ability to extrapolate them widely to real-world patients. However, we must highlight that the lack of reference to dissimilarities in the inhalers that are used to deliver the different FDCs and of the categorization of responses taking into account the COPD phenotypes somewhat lowers their value. In addition, we should also note that they contrast with the reiterated evidence of increased cardiovascular risk with indacaterol compared with formoterol, regardless of the presence of glycopyrronium.7Rogliani P. Matera M.G. Ritondo B.L. et al.Efficacy and cardiovascular safety profile of dual bronchodilation therapy in chronic obstructive pulmonary disease: a bidimensional comparative analysis across fixed-dose combinations.Pulm Pharmacol Ther. 2019; 59: 101841Crossref PubMed Scopus (20) Google Scholar The ability of dual bronchodilation to decrease the frequency of ECOPDs can be explained by mentioning several mechanisms that are activated by concomitant administration of a LABA and a LAMA, such as reducing pulmonary hyperinflation, restoring the dynamics of lung function, and decreasing the release of nonneuronal acetylcholine from choline acetyltransferase-expressing epithelial cells in response to inflammatory stimuli.8Beeh K.M. Burgel P.R. Franssen F.M.E. et al.How do dual long-acting bronchodilators prevent exacerbations of chronic obstructive pulmonary disease?.Am J Respir Crit Care Med. 2017; 196: 139-149Crossref PubMed Scopus (59) Google Scholar There is experimental documentation that dual bronchodilation produces a synergistic inhibition of airway smooth muscle tone by significantly increasing cyclic adenosine monophosphate levels in bronchi and epithelial cells and decreasing the amount of nonneuronal acetylcholine released from the epithelium.9Cazzola M. Calzetta L. Puxeddu E. et al.Pharmacological characterisation of the interaction between glycopyrronium bromide and indacaterol fumarate in human isolated bronchi, small airways and bronchial epithelial cells.Respir Res. 2016; 17: 70Crossref PubMed Scopus (66) Google Scholar Rather, it is more difficult to explain why dual bronchodilation is more effective than a LABA/ICS combination in the prevention of ECOPDs only when the latter includes salmeterol. It is likely that the pharmacologic differences between the LABAs included in the FDCs that were considered in this study may have played a key role. Basically, β2-agonists of higher intrinsic efficacy elicit a greater response.10Cazzola M. Page C.P. Calzetta L. Matera M.G. Pharmacology and therapeutics of bronchodilators.Pharmacol Rev. 2012; 64: 450-504Crossref PubMed Scopus (325) Google Scholar Salmeterol, a partial β2-agonist, has low intrinsic efficacy compared with indacaterol and formoterol, which are full or nearly full agonists, and vilanterol, which, although being a partial β2-agonist, has higher intrinsic efficacy than salmeterol.10Cazzola M. Page C.P. Calzetta L. Matera M.G. Pharmacology and therapeutics of bronchodilators.Pharmacol Rev. 2012; 64: 450-504Crossref PubMed Scopus (325) Google Scholar Also, the ability of formoterol, but not salmeterol, to reverse corticosteroid insensitivity by attenuating the oxidative stress that characterizes COPD and by inhibiting phosphoinositide-3-kinase δ is not negligible.11Rossios C. To Y. Osoata G. Ito M. Barnes P.J. Ito K. Corticosteroid insensitivity is reversed by formoterol via phosphoinositide-3-kinase inhibition.Br J Pharmacol. 2012; 167: 775-786Crossref PubMed Scopus (48) Google Scholar This results in an increase in histone deacetylase 2 action and, consequently, in the efficiency of glucocorticoid receptor-mediated repression of genes encoding proinflammatory proteins. In any case, it should be emphasized that full or near full β2-agonists (formoterol, indacaterol) should elicit a greater cardiac response than partial β2-agonists (salmeterol, vilanterol),12Matera M.G. Calzetta L. Puxeddu E. Rogliani P. Cazzola M. A safety comparison of LABA+LAMA vs LABA+ICS combination therapy for COPD.Expert Opin Drug Saf. 2018; 17: 509-517Crossref PubMed Scopus (5) Google Scholar but this difference did not emerge in the study of Wang et al.5Wang M.T. Lai J.H. Huang Y.L. et al.Comparative effectiveness and safety of different types of LABA/LAMA versus LABA/ICS fixed-dose combinations in COPD: a propensity score-inverse probability of treatment weighting cohort study.Chest. 2021; 160: 1255-1270Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar A statistically significant reduction in the risk of pneumonia with LABA/LAMA compared with LABA/ICS has been documented repeatedly.12Matera M.G. Calzetta L. Puxeddu E. Rogliani P. Cazzola M. A safety comparison of LABA+LAMA vs LABA+ICS combination therapy for COPD.Expert Opin Drug Saf. 2018; 17: 509-517Crossref PubMed Scopus (5) Google Scholar Pneumonia should be considered as the most relevant adverse event of LABA/ICS combinations. Apparently, there are intra-ICS class differences in pneumonia risks, and differences in lipophilicity/hydrophilicity of ICSs determine the risk of pneumonia in COPD.13Janson C. Stratelis G. Miller-Larsson A. Harrison T.W. Larsson K. Scientific rationale for the possible inhaled corticosteroid intraclass difference in the risk of pneumonia in COPD.Int J Chron Obstruct Pulmon Dis. 2017; 12: 3055-3064Crossref PubMed Scopus (45) Google Scholar Indeed, the more prolonged pulmonary retention of fluticasone propionate compared with beclomethasone or budesonide results in greater local immunosuppression, which may enhance susceptibility to respiratory infections by increasing the pathogenic microbiome burden in the airways and lungs and consequently lead to the occurrence of pneumonia.13Janson C. Stratelis G. Miller-Larsson A. Harrison T.W. Larsson K. Scientific rationale for the possible inhaled corticosteroid intraclass difference in the risk of pneumonia in COPD.Int J Chron Obstruct Pulmon Dis. 2017; 12: 3055-3064Crossref PubMed Scopus (45) Google Scholar The study of Wang et al5Wang M.T. Lai J.H. Huang Y.L. et al.Comparative effectiveness and safety of different types of LABA/LAMA versus LABA/ICS fixed-dose combinations in COPD: a propensity score-inverse probability of treatment weighting cohort study.Chest. 2021; 160: 1255-1270Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar confirms the role of intra-ICS class differences in the risk of pneumonia. However, this risk is also influenced significantly by several factors, including age (≥65 years), being a current smoker, BMI <25 kg/m2, severe airflow obstruction, and a history of previous exacerbations and pneumonias, with patients with more severe COPD having a higher risk of pneumonia.14Crim C. Dransfield M.T. Bourbeau J. et al.Pneumonia risk with inhaled fluticasone furoate and vilanterol compared with vilanterol alone in patients with COPD.Ann Am Thorac Soc. 2015; 12: 27-34Crossref PubMed Scopus (115) Google Scholar Unfortunately, Wang et al5Wang M.T. Lai J.H. Huang Y.L. et al.Comparative effectiveness and safety of different types of LABA/LAMA versus LABA/ICS fixed-dose combinations in COPD: a propensity score-inverse probability of treatment weighting cohort study.Chest. 2021; 160: 1255-1270Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar did not test the impact of these factors on the risk of pneumonia for each of the FDCs examined; therefore, a solid conclusion cannot be drawn. Anyway, regardless of any other consideration about the methodologic strengths and weaknesses of the study, we are convinced that the study by Wang et al,5Wang M.T. Lai J.H. Huang Y.L. et al.Comparative effectiveness and safety of different types of LABA/LAMA versus LABA/ICS fixed-dose combinations in COPD: a propensity score-inverse probability of treatment weighting cohort study.Chest. 2021; 160: 1255-1270Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar despite its limitations, suggests that the treatment algorithms recommended in the COPD guidelines/strategies are open to criticism and therefore need to be at least partially amended, because they always refer to classes of drugs to be used rather than to individual molecules with their own unique pharmacologic characteristics. In fact, the pharmacodynamics and pharmacokinetics of any LABA, LAMA, or ICS included in a specific FDC may make this combination more effective than others of the same type and even FDCs of different types, regardless of what is expected by the application of COPD guideline/strategy algorithms. We firmly believe that individual molecules, regardless of whether they are bronchodilators or ICSs, should be chosen for their pharmacologic characteristics rather than for their belonging to a specific pharmacologic class. This obviously also applies to combinations. In fact, each combination has a specific efficacy/safety profile that needs to be considered. In our opinion, it would be appropriate to also consider this seemingly new, but obvious, concept and consider it a paradigm when treating a patient with COPD. In any case, it is imperative that pragmatic head-to-head trials focused on the impact of different LABA/LAMA and LABA/ICS FDCs, with their own pharmacodynamics and pharmacokinetics, on the risk of ECOPDs, pneumonia, and cardiovascular adverse events are made mandatory, while still taking into account the phenotype of the subject to be treated. This will generate crucial information to further improve the possibility of personalized therapy in patients with COPD. Comparative Effectiveness and Safety of Different Types of Inhaled Long-Acting β2-Agonist Plus Inhaled Long-Acting Muscarinic Antagonist vs Inhaled Long-Acting β2-Agonist Plus Inhaled Corticosteroid Fixed-Dose Combinations in COPD A Propensity Score-Inverse Probability of Treatment Weighting Cohort StudyCHESTVol. 160Issue 4PreviewBoth LABA/LAMAs vs SAL/FP are associated with a lower exacerbation rate and pneumonia risk, but exhibit similar effectiveness and safety outcomes compared with FF/BDP or FF/BUD, suggesting that comparative effects may differ by individual components of the dual therapies in COPD. Full-Text PDF