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01.12.2016 | Research article | Ausgabe 1/2016 Open Access

BMC Pulmonary Medicine 1/2016

Effectiveness of initiating extrafine-particle versus fine-particle inhaled corticosteroids as asthma therapy in the Netherlands

BMC Pulmonary Medicine > Ausgabe 1/2016
Thys van der Molen, Dirkje S. Postma, Richard J. Martin, Ron M. C. Herings, Jetty A. Overbeek, Victoria Thomas, Cristiana Miglio, Richard Dekhuijzen, Nicolas Roche, Theresa Guilbert, Elliot Israel, Wim van Aalderen, Elizabeth V. Hillyer, Simon van Rysewyk, David B. Price
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s12890-016-0234-0) contains supplementary material, which is available to authorized users.
An erratum to this article can be found at http://​dx.​doi.​org/​10.​1186/​s12890-016-0270-9.

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.

Authors’ contributions

All authors were involved in the conception or design of the study; or the acquisition, analysis, or interpretation of study data; and, drafting the study or revising it; and, giving final approval for publication. The authors are responsible for all aspects of this study. DBP led the study design process, which was guided by Steering Committee discussions. The Steering Committee was composed of study authors representing the SASG: RJM, DSP, NR, WvA, RD, and TvdM. CM and VT were responsible for the data acquisition and analyses. SvR wrote the manuscript.



Most randomised clinical trials typically exclude a significant proportion of asthma patients, including those at higher risk of adverse events, with comorbidities, obesity, poor inhaler technique and adherence, or smokers. However, these patients might differentially benefit from extrafine-particle inhaled corticosteroids (ICS). This matched cohort, database study, compared the effectiveness of extrafine-particle with fine-particle ICS in a real-life population initiating ICS therapy in the Netherlands.


Data were from the PHARMO Database Network, comprising pharmacy and hospital discharge records, representative of 20 % of the Dutch population. The study population included patients aged 12 − 60, with a General Practice-recorded diagnosis for asthma (International Classification of Primary Care code R96), when available, ≥2 prescriptions for asthma therapy at any time in their recorded history, and receiving first prescription of ICS therapy as either extrafine-particle (ciclesonide or hydrofluoroalkane beclomethasone dipropionate [BDP]) or fine-particle ICS (fluticasone propionate or non-extrafine-particle-BDP). Patients were matched (1:1) on relevant demographic and clinical characteristics over 1-year baseline. Primary outcomes were severe exacerbation rates, risk domain asthma control and overall asthma control during the year following first ICS prescription. Secondary outcomes, treatment stability and being prescribed higher versus lower category of short-acting β2 agonists (SABA) dose, were compared over a 1-year outcome period using conditional logistic regression models.


Following matching, 1399 patients were selected in each treatment cohort (median age: 43 years; males: 34 %). Median (interquartile range) initial ICS doses (fluticasone-equivalents in μg) were 160 (160 − 320) for extrafine-particle versus 500 (250 − 500) for fine-particle ICS (p < 0.001). Following adjustment for residual confounders, matched patients prescribed extrafine-particle ICS had significantly lower rates of exacerbations (adjusted rate ratio [95 % CI], 0.59 [0.47–0.73]), and significantly higher odds of achieving asthma control and treatment stability in the year following initiation than those prescribed fine-particle ICS, and this occurred at lower prescribed doses. Patients prescribed extrafine-particle ICS had lower odds of being prescribed higher doses of SABA (0.50 [0.44–0.57]).


In this historical, matched study, extrafine-particle ICS was associated with better odds of asthma control than fine-particle ICS in patients prescribed their first ICS therapy in the Netherlands. Of importance, this was reached at significantly lower prescribed dose.
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