Comparison Among Different Inhalers in COPD

FOR RELATED ARTICLE, SEE PAGE 799Despite the high prevalence and disease burden of COPD and the decades of experience and research with inhaler treatments, much about inhaler therapy remains unclear. Our understanding of what matters in categorizing COPD has evolved, and we are redefining COPD based on patient-centered clinical outcomes. Patients with COPD are categorized based on their exacerbation frequency and symptom severity; current guidelines recommend inhaler treatment aimed at reducing symptoms and exacerbations.1Global Initiative for Obstructive Lung Disease (GOLD). COPD report: 2023.https://goldcopd.org/2023-gold-report-2/Date accessed: February 20, 2023Google Scholar FOR RELATED ARTICLE, SEE PAGE 799 For patients with two or more exacerbations in 1 year (or a single exacerbation that leads to hospitalization, group E) and those with symptoms (group B), a combination of long-acting muscarinic antagonists and long-acting β2-agonists (LAMA/LABA) is recommended to reduce symptoms and exacerbations.1Global Initiative for Obstructive Lung Disease (GOLD). COPD report: 2023.https://goldcopd.org/2023-gold-report-2/Date accessed: February 20, 2023Google Scholar But uncertainty regarding the differences among LAMA/LABA combinations in clinical effectiveness and side-effects remains. If we are prescribing a LAMA/LABA combination and, as guidelines recommend, taking into account access, cost, and patient preference, does it really matter which LAMA/LABA combinations we pick? In this issue of CHEST, Lin et al2Weng C.-F. Wu C.-C. Wu M.-H. Lin F.-J. Comparison of clinical outcomes among different fixed-dose combinations of long-acting muscarinic antagonists and long-acting β2-agonists (LAMA/LABA) in patients with COPD.Chest. 2023; 163: 799-814Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar attempt to answer that question in a retrospective cohort study of nearly 45,000 patients with COPD who were newly prescribed a LAMA/LABA combination. They compared three LAMA/LABA combinations: glycopyrronium/indacaterol (GLY/IND), umeclidinium/vilanterol (UMEC/VI), and tiotropium/olodaterol (TIO/OLO), all covered by the National Health Insurance in Taiwan. They used propensity score matching and Cox regression models to assess differences in acute exacerbation of COPD and differences in cardiovascular adverse effects. Was there a difference? It seems so. Compared with those who were prescribed TIO/OLO, patients who were prescribed GLY/IND or UMEC/VI had lower risk of an acute exacerbation of COPD (hazard ratio, 0.77 and 0.76, respectively). What about the cardiovascular outcomes? “I am not worried about cardiovascular safety when I prescribe these medications,” many of you may be thinking. “My main concern is whether they are effective at improving symptoms and reducing exacerbations.” Perhaps. But as we evolve in our thinking about COPD causes and symptoms, we may rethink how we view the overlap between COPD and cardiovascular outcomes. Because tobacco use and air pollution are causal factors in both COPD and cardiovascular disease, many patients have both comorbidities. Indeed, even our relatively “hard” outcomes, such as COPD exacerbations that lead to hospitalization, are more confusing up close as patients get treatment for both, COPD and cardiovascular disease, during many hospitalizations. And sure, we do not worry about cardiovascular risks when we prescribe LABA/LAMA inhalers, but we did not used to worry about cardiovascular risks of prescribing macrolides either.3Ray W.A. Murray K.T. Hall K. et al.Azithromycin and the risk of cardiovascular death.N Engl J Med. 2012; 366: 1881-1890Crossref PubMed Scopus (780) Google Scholar Certainly, the question of cardiovascular risk with the use of tiotropium and other LAMAs has been raised before.4Shin J. Lee J.H. Effects of tiotropium on the risk of coronary heart disease in patients with COPD: a nationwide cohort study.Sci Rep. 2022; 12: 1-10Crossref PubMed Scopus (1) Google Scholar, 5Celli B. et al.Cardiovascular safety of tiotropium in patients with COPD.Chest. 2010; 137: 20-30Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 6Michele T.M. Pinheiro P. Iyasu S. The safety of tiotropium: the FDA’s conclusions.N Engl J Med. 2010; 363: 1097-1099Crossref PubMed Scopus (98) Google Scholar In this study, Lin et al2Weng C.-F. Wu C.-C. Wu M.-H. Lin F.-J. Comparison of clinical outcomes among different fixed-dose combinations of long-acting muscarinic antagonists and long-acting β2-agonists (LAMA/LABA) in patients with COPD.Chest. 2023; 163: 799-814Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar found that, compared with those patients who started TIO/OLO, patients who took GLY/IND had fewer cardiovascular events (hazard ratio, 0.70); this difference appeared to be driven by patients aged 65 and older and was present only when follow-up duration was longer than 6 months. Is this the final word on choosing one inhaler over the other? No. The study has several important limitations. First, despite the propensity score matching for a laundry list of factors, the possibility remains that it is not the inhaler per se that led to the differences in observed outcomes, but some other factor that led to the differences in prescribing patterns. Although this concern is less significant in a place with a nationalized health insurance program and a complete prescription data set, confounding by indication remains a major concern in these types of studies. Second, although the overall prescription data are complete, there are no data on actual medication adherence by the patients nor of lung function or tobacco exposure history. And finally, triple therapy (LABA/LAMA/ICS) medications were not reimbursed in Taiwan until March 2020; thus, it is unclear how many patients who were treated with LABA/LAMA in this study would have been treated with triple therapy in other settings and therefore how generalizable these results are elsewhere. So, what do we make of this? Professor Pope,7Arden Pope III, C.A. Health effects of air pollution: Utah Clean Air Conference.https://www.youtube.com/watch?v=e498gZ4AMXQGoogle Scholar when describing his air pollution work at a conference, said the number one criticism he gets is that “these effects [of air pollution on health] are too small to matter.” The number two criticism he gets is that “these effects are too big. They can’t possibly be real.” On the surface these differences among LAMA/LABA combination inhalers seem trivial, surely hardly something to get excited about when prescribing to an individual, especially if there is a difference in cost or another reason to prefer one inhaler over another. On the other hand, when we look at these seemingly small differences over the number of people who take these medications worldwide, not only is the potential impact of such differences in efficacy and risk huge, but also it is shameful that with that many people’s lives at stake and that much money spent in this market, we have little certainty or high-quality data on which to base these decisions. The work by Lin et al2Weng C.-F. Wu C.-C. Wu M.-H. Lin F.-J. Comparison of clinical outcomes among different fixed-dose combinations of long-acting muscarinic antagonists and long-acting β2-agonists (LAMA/LABA) in patients with COPD.Chest. 2023; 163: 799-814Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar is not the final stroke of clarity in this field, but it is an important step forward. It sheds light on some differences among LAMA/LABA inhalers in both efficacy and cardiovascular events and adds to our incomplete, but growing, understanding of the magnitude and importance of differences within a class of medications. None declared. Comparison of Clinical Outcomes Among Different Fixed-Dose Combinations of Long-Acting Muscarinic Antagonists and Long-Acting β2-Agonists in Patients With COPDCHESTVol. 163Issue 4PreviewOur results revealed that the risk of severe AE was lower among patients with COPD receiving UMEC/VI or GLY/IND than among those receiving TIO/OLO, whereas the incidence of cardiovascular events was similar across groups but was slightly lower in GLY/IND users when compared with TIO/OLO users. Further research will be required to confirm these findings. Full-Text PDF