Correspondence: David Price, Observational and Pragmatic Research Institute, 5 Coles Lane, Cambridge, CB24 3BA, UK, Email [email protected]

In response to the study titled “Inhaled Corticosteroid particle size and risk of hospitalization rue to exacerbations and all-cause mortality in patients with chronic obstructive respiratory disease. A Nationwide cohort study”. Heerfordt et al.1

Having previously reported that the use of extrafine particle ICS, compared to standard size preparations, is associated with reduced hospital admission for pneumonia Heerfordt el al now report that extrafine particle ICS do not reduce the risk of exacerbations or all-cause mortality in the same database.1 In a subgroup analysis of the more recent paper the authors suggest a potential benefit if the extra fine particles come from an MDI inhaler.

We feel that the current paper has a number of limitations. The number of people using extrafine particle ICS in this dataset is low at 4.2%, and it seems likely to us that this represents a highly selected group of patients. Although the baseline demographic table (Table 1 in the Heertfordt paper),1 suggests the patient groups are similar it seems likely to us that patients who received extrafine particle ICS inhalers may well have been moved to these treatments because of problems with standard inhalers. The impact of this selection bias would be to have a more severe group of patients in the extrafine group and to bias the results away from a beneficial impact of these drugs.

There is no ideal way to circumvent this problem of selection bias, and the authors can be commended for trying several different approaches including prospensity score matching and multivariate adjusted models.1 Both of these approaches moved the unadjusted models, which tended to show a protective effect of extrafine particle ICS, towards unity. In order to understand the associations more fully it would be informative to know which of the covariables were responsible for these changes by undertaking a series of bivariate models, and by inspecting the effect estimates as more variables are adjusted using the “change-in-estimates” method.2,3 In simply adding all of the variables together at once we have lost an opportunity to explain these findings.

It is not clear to us from the methods exactly when the exposure period was defined – and if exposures occurred after the study start date it is possible that issues with immortal time bias will also exist. As with all cohort studies a full description of the start and stop dates, and the period of exposure considered would make the paper more informative.4 Because exposure to ICS particle type was defined based on highest cumulative exposure from the year prior to cohort entry, adjustment for covariates such as ICS equivalent dose from the same period may introduce overadjustment bias, whereby there is control for intermediate variables on a causal path from exposure to outcome.5

An alternative approach would be to undertake a “new user” analysis where the exposure status of the patient is defined on the basis of the first inhaler they were prescribed.6 A degree of selection bias is still possible with such an approach but the problem of people with more problematic disease being moved between treatments is removed.

Calculating dose equivalents for ICS studies is not straightforward, but for this study again some broad classification of dose as low, medium or high would be helpful.

Richard Hubbard, Victoria Carter, and William Henley are employees of the Observational and Pragmatic Research Institute (OPRI).

David Price has advisory board membership with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Viatris, Teva Pharmaceuticals; consultancy agreements with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Viatris, Teva Pharmaceuticals; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Chiesi, Viatris, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, and UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Inside Practice, GlaxoSmithKline, Medscape, Viatris, Novartis, Regeneron Pharmaceuticals and Sanofi Genzyme, Teva Pharmaceuticals; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Novartis, Medscape, Teva Pharmaceuticals.; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 92.61% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); is peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation Programme, and Health Technology Assessment; and he was an expert witness for GlaxoSmithKline. The authors report no other conflicts of interest in this communication.

1. Heerfordt CK, Rønn C, Eklöf J, et al. Inhaled corticosteroids particle size and risk of hospitalization due to exacerbations and all-cause mortality in patients with chronic obstructive pulmonary disease. A nationwide cohort study. Int J Chron Obstruct Pulmon Dis. 2024;19:2169–2179. doi:10.2147/COPD.S453524

2. Wang Z. Two postestimation commands for assessing confounding effects in epidemiological studies. Stata J. 2007;7(2):183–196. doi:10.1177/1536867x0700700203

3. Greenland S, Pearce N. Statistical foundations for model-based adjustments. Annu Rev Public Health. 2015;36(1):89–108. doi:10.1146/annurev-publhealth-031914-122559

4. Roche N, Reddel H, Martin R, et al. Quality standards for real-world research. Focus on observational database studies of comparative effectiveness. Ann Am Thorac Soc. 2014;11(Supplement 2):S99–104. doi:10.1513/AnnalsATS.201309-300RM

5. Schisterman EF, Cole SR, Platt RW. Overadjustment bias and unnecessary adjustment in epidemiologic studies. Epidemiology. 2009;20(4):488–495. doi:10.1097/EDE.0b013e3181a819a1

6. Wang MT, Lai JH, Huang YL, et al. 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 study. Chest. 2021;160(4):1255–1270. doi:10.1016/j.chest.2021.05.025