COPD: The ICS Triple Therapy Debate Heats Up

The maintenance inhalers available for obstructive lung disease are long-acting beta-agonists (LABAs), long-acting muscarinic antagonists (LAMAs), and inhaled corticosteroids (ICSs). We use all three to treat chronic obstructive pulmonary disease (COPD). When and how to use one, two, or all three varies by disease severity and, as it turns out, personal opinion. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) statement provides flow charts with a tidy grading system that uses capital letters. The addition or subtraction of each inhaler medicine is simple and rote. For all its popularity though, GOLD isn’t the only game in town.
For the academic bent on overcomplicating the simple, the GOLD statement warrants discussion. Beyond mere quibbling, the use of LAMAs or LABAs is not controversial, but ICSs are different. Their efficacy is conditional and overstated, they traditionally have been considered an add-on, and they increase pneumonia rates (we’re pretty sure). The role of ICSs in COPD continues to evolve as we learn more about phenotyping and move toward precision medicine.
The modern debate over ICSs in COPD has the catnip required to produce an academic catfight. It pits “statements” against “guidelines” and expert opinion against the systematic analysis of pooled randomized controlled trial (RCT) data, with a healthy dose of bench vs bedside. Practicing physicians are convinced the academics telling them what to do read journals in a bubble while residents and students see their patients. For their part, the academic experts believe the docs at the bedside spend their time playing Patch Adams while distributing theophylline. Phenotyping is limited to blue bloaters vs pink puffers.
ICS use for COPD was common before publication of the WISDOM trial in 2014. Knowing ICSs were associated with pneumonia (and other harms), the WISDOM investigators tested whether patients on LAMA/LABA/ICS could safely discontinue the ICS. The answer? Sort of. Exacerbation rates in the withdrawal group met their predefined criteria for noninferiority. They had a persistent decrease in lung function, though, and a statistically significant decline in quality of life (of questionable clinical importance). The 2016 FLAME trial found that LAMA/LABA therapy was superior to ICS/LABA therapy and that ICSs increased pneumonia risk. WISDOM and FLAME dealt ICSs a body blow.
ICS treatment began punching off the ropes. In 2018, a series of papers found that triple therapy was superior to dual bronchodilator regimens. A systematic analysis of all three concluded that ICSs increase pneumonia, but the risk is offset by a reduction in acute exacerbations (AECOPD) when targeting the proper patient, with “proper” being defined as someone who exacerbates through LAMA/LABAs.
That same year, CHEST featured a pro-con debate over ICS withdrawal. As is often the case, the authors reviewed the same data and reached the same conclusion. Yes, the ICS should be withdrawn if patients are on triple therapy, but only if they have a low serum eosinophil count and are free of exacerbations. Eosinophils had been gaining traction as a COPD biomarker and would make their appearance in subsequent GOLD statements.
More recently, there’s been a flurry of new publications on ICSs, COPD, and GOLD, including a new pro– con debate in CHEST. The new debate was meant to address differences between the latest GOLD Statement and the Canadian Thoracic Society (CTS) guidelines on COPD. The debate centers on how quickly to start triple therapy and how to use eosinophils.
The hawks want everyone with group E COPD to receive triple therapy including ICSs, whereas the doves see a role for LAMA/LABA and targeting by eosinophils. The dove who wrote the con paper argues that 65%-80% of patients in RCTs comparing triple therapy and dual therapy with LAMA/LABA had to discontinue the ICS prior to enrollment. Participants weren’t treatment-naive, and the need for withdrawal confounds interpretation. When RCT results were analyzed by eosinophil count, the reduction in exacerbations was greater with higher counts; therefore, they recommended LAMA/LABA therapy (without ICS) for group E COPD with low eosinophil counts. The con author is a PhD, and he invokes a comparatively more rigid interpretation of the data. His conclusions mirror the GOLD statement more than the CTS guidelines.
The CTS guidelines end up more hawkish, in line with the authors of the pro side of the CHEST debate. Ironically, CTS ends up hawkish despite operating within the rigid confines of guideline science. Theirs is a more synthesized, quantitative summary of the data, but because none of the RCTs used eosinophils to guide therapy, they don’t recommend it. Everyone in group E gets triple therapy, just as the less data-driven pro authors recommend. Incidentally, a study just published in the Annals of the American Thoracic Society would seem to support the pro authors and the CTS guideline. 
It’s fascinating to see how different, intelligent interpretations of the existing data can lead brilliant academics to different conclusions. There seems to be a move away from “step-up” therapy and toward prevention in those at high risk. Whether they realize it or not, I see practicing clinicians endorsing this concept by voting with their prescription pads (I’m old enough to have actually used one). When a patient is hospitalized for AECOPD, they’re discharged on triple therapy. No hesitation if eosinophil levels are low, and no need to wait for LAMA/LABA failure. If this is consistent with your practice, there’s literature to back you up. 
Aaron B. Holley, MD, is a professor of medicine at Uniformed Services University in Bethesda, Maryland, and a pulmonary/sleep and critical care medicine physician at MedStar Washington Hospital Center in Washington, DC. He covers a wide range of topics in pulmonary, critical care, and sleep medicine.