Discussion
In this real-life population-based study, matched patients initiating extrafine-particle ICS had significantly lower rates of severe exacerbations and significantly higher odds of achieving asthma control and treatment stability than those prescribed fine-particle ICS. Notably, the prescribed doses of extrafine-particle ICS were lower than fine-particle ICS at the initiation date (median dose, 160 vs. 500 μg per day, fluticasone-equivalents). In addition, patients prescribed extrafine-particle ICS showed lower odds of being prescribed higher doses of short-acting β2 agonists. Outcome data showed no significant differences between the study cohorts for medications prescribed for treating oral candidiasis, and for asthma-related hospital admissions. These findings suggest a significant improvement in asthma control for patients prescribed extrafine-particle ICS with unstable asthma. Such patients would typically be excluded from traditional RCTs.
Possible mechanisms to account for the superior effectiveness of extrafine-particle ICS observed in this study include improved airway drug deposition and distribution, including distally in the small airways, and improved inhaler device tolerance. These are each discussed in turn below.
Aerosol particle size now appears therapeutically important for controlling asthma symptoms [
14]. Evidence indicates that fine-particle ICS with a MMAD of <5 μm, but ≥2 μm, show lower total lung distribution and deposition than extrafine-particles with a MMAD <2 μm, which can deposit more in the small airways [
1,
2,
15]. More effective control of small airway inflammation might contribute to improved asthma control [
15].
Poor device technique by patients is a common problem observed by clinicians. Asthma control worsens as the number of mistakes in device technique increases [
16]. The combination of fine-particle ICS with poor device technique can lead to some of the ICS settling in the oropharynx, resulting in side-effects such as oropharyngeal candidiasis. However, lung deposition of EF-HFA-BDP remains adequate even in patients with poor inhaler device technique [
1]. This may be due to pMDI design incorporating hydrofluoroalkane propellant that produces a softer, warmer and longer duration spray. This particular method of delivery has proven more tolerant of poor inhaler technique than some metered dose inhalers emitting fine-particle ICS [
1]. Tolerance to inhalation errors may in turn promote improved adherence to therapy [
14].
This study has several strengths. To ensure all potentially relevant variables for characterizing patients were included, and that the key outcomes of interest could be evaluated, both the statistical analysis plan, study population and outcomes were conceived prior to any analyses [
11]. Imitating traditional RCT design, the study included an initiation date marking therapy initiation. The study inclusion and exclusion criteria were selected to minimize potential confounding factors such as other asthma therapies, and to identify patients from a large clinical population receiving initial ICS therapy. Patient matching was used to adjust for demographic and clinical differences between the study cohorts. An advantage of 1-year baseline and outcome periods is that this time-period allows for natural seasonal changes in respiratory disease, and for recording infrequent clinical events such as exacerbations and asthma-related hospitalizations [
11]. The results confirm both the study hypothesis and similar findings observed in real-life asthma control studies with patients in the UK and US [
8‐
10]. This seems to suggest that the present findings can be extrapolated to healthcare systems and prescribing patterns in different countries. Collectively, these studies provide balance to findings reported in some RCTs that extrafine-particle ICS is only equally effective as fine-particle ICS in achieving asthma control [
3,
4].
However, as with all real-life comparative database studies, this study has its limitations as well. Limitations could derive from using the PHARMO Database Network, including disease misclassification biases from the almost exclusive use of “asthma prescriptions” to individuate patients with asthma, and the impossibility to adjust for all potential confounders, such as potential confounding by severity for factors indiscernible from patient records or patient-reported outcomes. Asthma diagnosis data, defined as a General Practice recorded diagnosis for asthma (ICPC code R96), were available in the General Practice database for only 12.2 % of the study population. In addition, the results of this study only apply to healthier patients who survive at least 1 year following prescription date. Therefore, this study cannot exclude potential survivor bias [
11,
13,
17].
Although specific to respiratory disease, this study could not accurately assess lung function, or symptom control. However, short-acting β2 agonist prescriptions were included in the study as a substitute for asthma symptoms in the ‘overall asthma control’ measure, because short-acting β2 agonist use reflects symptom control [
18]. The control cutoff point of a mean short-acting β2 agonist use of ≥2 puffs per day corresponds to the level 2 category (2 of 4, with 1 being the best controlled) of the validated approach of Schatz et al. [
18] for short-acting β2 agonist canister dispensing to assess asthma symptom control. During the study period, 1399/2981 (47 %) eligible patients initiating extrafine-particle ICS therapy were matched, and 1399/8200 (17 %) of those initiating fine-particle ICS were matched, possibly indicating that patients in neither cohort were representative of those who initiate extrafine-particle or fine-particle ICS therapy in the Netherlands. Finally, although smoking status was not reported in the study due to poor availability within the PHARMO Database Network, possible COPD patients were included (e.g., patients prescribed long-acting muscarinic agents in addition to ICS), but constituted only 1.8 % of the total study population.
Competing interests
Thys van der Molen has received grants for research, travel, and reimbursement for presentations and advisory boards from AstraZeneca, GlaxoSmithKline, Almirall, Mundipharma, Boehringer Ingelheim, Chiesi, Teva Pharmaceuticals Europe B.V., and Novartis.
David B. Price has Board Membership with Aerocrine, Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Meda, Mundipharma, Napp, Novartis, and Teva Pharmaceuticals Europe B.V. Consultancy: Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Meda, Mundipharma, Napp, Novartis, Pfizer, Teva Pharmaceuticals Europe B.V., and Zentiva. Grants/Grants Pending with UK National Health Service, British Lung Foundation, Aerocrine, AstraZeneca, Boehringer Ingelheim, Chiesi, Eli Lilly, GlaxoSmithKline, Meda, Merck, Mundipharma, Novartis, Orion, Pfizer, Respiratory Effectiveness Group, Takeda, Teva Pharmaceuticals Europe B.V., and Zentiva. Payments for lectures/speaking: Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Meda, Merck, Mundipharma, Novartis, Pfizer, SkyePharma, Takeda, and Teva Pharmaceuticals Europe B.V. Payment for manuscript preparation: Mundipharma and Teva Pharmaceuticals Europe B.V. Patents (planned, pending or issued) with AKL Ltd. Payment for the development of educational materials: GlaxoSmithKline, and Novartis. Stock/Stock options: Shares in AKL Ltd, which produces phytopharmaceuticals. Owns 80 % of Research in Real Life Ltd and its subsidiary social enterprise Optimum Patient Care. Received Payment for travel/accommodations/meeting expenses from: Aerocrine, Boehringer Ingelheim, Mundipharma, Napp, Novartis, and Teva Pharmaceuticals Europe B.V. Funding for patient enrolment or completion of research: Almirral, Chiesi, Teva Pharmaceuticals Europe B.V., and Zentiva. Peer reviewer for grant committees: Medical Research Council (2014), Efficacy and Mechanism Evaluation program (2012), HTA (2014); and received unrestricted funding for investigator-initiated studies from Aerocrine, AKL Ltd, Almirall, Boehringer Ingelheim, Chiesi, Meda, Mundipharma, Napp, Novartis, Orion, Takeda, Teva Pharmaceuticals Europe B.V., and Zentiva.
Ron M.C. Herings and Jetty A. Overbeek are employees of the PHARMO Institute for Drug Outcomes Research. This independent research institute performs financially supported studies for government and related healthcare authorities and several pharmaceutical companies.
Victoria Thomas is an employee of Research in Real-Life (RiRL). Cristiana Miglio is a former employee of Research in Real-Life, Ltd (RiRL). RiRL conducted this study. RiRL has conducted paid research in respiratory disease on behalf of the following other organizations in the past 5 years: Aerocrine, AKL Ltd, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Meda, Mundipharma, Napp, Novartis, Orion, Takeda, Teva Pharmaceuticals Europe B.V., and Zentiva, a Sanofi company.
Richard Dekhuijzen has received over the past 3 years’ fees for speaking, education, participation in advisory boards or consulting, from: Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Mundipharma, Novartis, Pfizer, Teva Pharmaceuticals Europe B.V., and Zambon. Research grants: AstraZeneca, Boehringer Ingelheim, and Novartis.
Richard J. Martin has conducted consultancy work and/or received travel support and/or honoraria for attendance at advisory boards for: AstraZeneca, MedImmune, Merck, and Teva Pharmaceuticals Europe B.V. Received research grants: MedImmune, and the NHLBI. Received royalties from UpToDate.
The University of Groningen has received money for Dirkje S. Postma regarding an unrestricted educational grant for research from Astra Zeneca, and Chiesi. Travel to ERS and/or ATS has been partially funded by Astra Zeneca, Chiesi, GlaxoSmithKline, and Takeda. Fees for consultancies given to the University of Groningen from: Astra Zeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Takeda and Teva Pharmaceuticals Europe B.V. Travel and lectures in China paid by Chiesi.
Nicolas Roche has received fees over the past 3 years for speaking, education, and participation in advisory boards or consulting from: 3M, Aerocrine, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, MSDChibret, Mundipharma, Novartis, Pfizer, Sandoz, Sanofi, Stallergenes, Takeda, and Teva Pharmaceuticals Europe B.V. Research grants from: Boehringer Ingelheim, Novartis, and Pfizer.
Theresa Guilbert has received personal fees from the American Board of Pediatrics, GlaxoSmithKline, Merck, and Regeneron Pharmaceuticals, and Sanofi. Pediatric Pulmonary Subboard, grants and personal fees from Teva Pharmaceuticals Europe B.V. Grants: Abbott Laboratories, Array Biopharma, CDC, CF Foundation Therapeutics, CompleWare Corporation, DHHS, F. Hoffman-LaRoche, Forest Research Institute, KaloBios Pharmaceuticals, Medimmune, Mylan, NIH, Roche/Genetech, Roxane Laboratories, and UW-Madison Medical and Education Research Committee, and Vertex Pharmaceuticals. Royalties from UpToDate.
Elliot Israel reports having received speaking fees over the past 3 years’ fees from Merck. Fees for consulting from AstraZeneca and Merck. Non-financial participation in Advisory Boards or consulting for Novartis (as DSMB Member). Research grants from Genentech and NIH. Writing/editorial support for manuscript preparation from RiRL. Travel grant support from RiRL and Teva Pharmaceuticals Europe B.V. Specialty Pharmaceuticals, fees for expert testimony from: Campbell, Campbell, Edwards & Conroy, Ficksman & Conley, Fox Rothschild, LLP, and Ryan Deluca, LLP. Royalties from UpToDate. Deputy Editor for the American Journal of Respiratory and Critical Care Medicine.
Wim van Aalderen is a member of the Medical Advisory Board of AstraZeneca.
Elizabeth V. Hillyer is a consultant to RiRL and has received payment for writing and editorial support to Merck.
Simon van Rysewyk is an employee of the Observational & Pragmatic Research Institute Pte Ltd, and has no competing interests to declare.