Short-Acting Beta-2-Agonist Exposure and Severe Asthma Exacerbations: SABINA Findings From Europe and North America

SABINA North American and European Study contributors

doi:10.1016/j.jaip.2022.02.047

Short-Acting Beta-2-Agonist Exposure and Severe Asthma Exacerbations: SABINA Findings From Europe and North America

SABINA North American and European Study contributors

Medicine

Research output: Contribution to journal › Article › peer-review

56 Citations (Scopus)

Abstract

Background: Expert national/global asthma management recommendations raise the issue whether a safe threshold of short-acting beta-2 agonist (SABA) use without concomitant inhaled corticosteroids (ICS) exists. Objective: To examine SABA and maintenance therapy associations with severe asthma exacerbations across North America and Europe. Methods: Observational analyses of 10 SABa use IN Asthma (SABINA) datasets involving 1,033,564 patients (≥12 y) from Canada, France, the Netherlands, Poland, Spain, the United Kingdom, and the United States. Negative binomial models (incidence rate ratio [IRR] [95% CI adjusted for prespecified-covariates]) evaluated associations between SABA and exacerbations. Results: Across severities, 40.2% of patients were prescribed/possessed 3 or more SABA canisters/y. Per the Global Initiative for Asthma (GINA) 2018 definitions, steps 3 to 5–treated patients prescribed/possessing 3 or more versus 1 or 2 SABAs experienced more severe exacerbations (IRR 1.08 [95% CI 1.04‒1.13], U.S. Medicare; IRR 2.11 [95% CI 1.96‒2.27], Poland). This association was not observed in all step 1 or 2–treated patients (the Netherlands, IRR 1.25 [95% CI 0.91‒1.71]; U.S. commercial, IRR 0.92 [95% CI 0.91‒0.93]; U.S. Medicare, IRR 0.74 [95% CI 0.71‒0.76]). We hypothesize that this inverse association between SABA and severe exacerbations in the U.S. datasets was attributable to the large patient population possessing fewer than 3 SABA and no maintenance therapy and receiving oral corticosteroid bursts without face-to-face health care provider encounters. In U.S. SABA monotherapy–treated patients, 3 or more SABAs were associated with more emergency/outpatient visits and hospitalizations (IRR 1.31 [95% CI 1.29‒1.34]). Most GINA 2 to 5–treated study patients (60.6%) did not have maintenance therapy for up to 50% of the time; however, the association of 3 or more SABAs and severe exacerbations persisted (IRR 1.32 [95% CI 1.18‒1.49]) after excluding these patients and the independent effect was further confirmed when U.K. SABA data were analyzed as a continuous variable in patients with up to 100% annual coverage for ICS-containing medications. Conclusions: Increasing SABA exposure is associated with severe exacerbation risk, independent of maintenance therapy. As addressed by GINA, based on studies across asthma severities where as-needed fast-acting bronchodilators with concomitant ICS decrease severe exacerbations compared with SABA, our findings highlight the importance of avoiding a rescue/reliever paradigm utilizing SABA monotherapy.

Original language	English
Journal	Journal of Allergy and Clinical Immunology: In Practice
DOIs	https://doi.org/10.1016/j.jaip.2022.02.047
Publication status	Accepted/In press - 2022

Bibliographical note

Funding Information:
Writing and editorial support was provided by Cactus Life Sciences (part of Cactus Communications, Mumbai, India) in accordance with Good Publication Practice (GPP3) guidelines ( http://www.ismpp.org/gpp3 ) and fully funded by AstraZeneca. AstraZeneca was involved in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication. Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data-sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

Funding Information:
Funding: This work was funded by AstraZeneca.Conflicts of interest: J. K. Quint's research group received funds from AstraZeneca for some of this work, and J. K. Quint has received fees for speaking from AstraZeneca. J. W. H. Kocks reports grants, personal fees, and nonfinancial support from AstraZeneca, Boehringer Ingelheim, COVIS, and GlaxoSmithKline; grants and personal fees from Chiesi and Novartis; and grants from MundiPharma and TEVA outside the submitted work, all paid to his institution; also holds 72.5% of shares in the General Practitioners Research Institute. M. Kupczyk reports personal fees from AstraZeneca during the conduct of the study; grants from AstraZeneca; and personal fees from AstraZeneca, Chiesi, GlaxoSmithKline, Novartis, Lekam, Alvogen, Emma, Nexter, and Berlin Chemie outside the submitted work. V. Plaza, in the last 3 years, received honoraria for speaking at sponsored meetings from AstraZeneca, Boehringer Ingelheim, MSD, and Chiesi; received travel assistance from AstraZeneca, Chiesi, and Novartis; served as a consultant for ALK, AstraZeneca, Boehringer Ingelheim, MSD, MundiPharma, and Sanofi; and received funding/grant support for research projects from a variety of government agencies and not-for-profit foundations, as well as AstraZeneca, Chiesi, and Menarini. C. Raherison-Semjen reports a professional relationship with AstraZeneca, ALK, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Intermune, MundiPharma, Novartis, TEVA, and Zambon. B. Walker has received honoraria and served on advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Sanofi. E. Penz has served on advisory boards and received honoraria and consulting fees from AstraZeneca, GlaxoSmithKline, Sanofi Genzyme, and Boehringer Ingelheim. N. L. Lugogo received consulting fees for advisory board participation from Amgen, AstraZeneca, Genentech, GSK, Novartis, Regeneron, Sanofi, and Teva; honoraria for nonspeakers bureau presentations from GSK and AstraZeneca; and travel support from AstraZeneca; her institution received research support from Amgen, AstraZeneca, Avillion, Gossamer Bio, Genentech, GSK, Regeneron, Sanofi, and Teva. S. Arnetorp, J. Nuevo, C. Cabrera, I. Gilbert, and R. J. P. van Der Valk are employees of AstraZeneca. S. Arnetorp and C. Cabrera also hold stocks of AstraZeneca. I. Gilbert also holds shares and options of AstraZeneca. R. J. P. van Der Valk also holds shares of GlaxoSmithKline and shares and options of AstraZeneca.The authors acknowledge Tamsin Morris, BSc Hons and Yang Xu, Pharmacy (AstraZeneca, UK) for their insights on the U.K. analyses, Mena Soliman, MSc (AstraZeneca, Canada) for his assistance with interpreting the Canada data, and Antonio Valero, MD (Barcelona, Spain) and Jesús Molina, PhD (Madrid, Spain) for their assistance with interpreting the Spanish dataset. The authors are grateful to Eleni Rapsomaniki, PhD (AstraZeneca, UK) for her assistance with designing and running the stratification analyses. The authors also thank Laura Pillot, PharmD (AstraZeneca, France) and Delphine Leynaud, Pharmaceutical Marketing (AstraZeneca, France) for their assistance in coordinating data collection from France, and Mieke Bastiaanse, MSc (AstraZeneca, the Netherlands) for supporting data collection from the Netherlands. The authors also thank the Scientific Committee of the ASTHMAPOP study (France): Alain Didier, MD, Armine Izadifar, MD, Maud Russier, Jean-Pierre Aubert, MD, and Christine Rolland, Masters (Intercultural Communication). Writing and editorial support was provided by Cactus Life Sciences (part of Cactus Communications, Mumbai, India) in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3) and fully funded by AstraZeneca. AstraZeneca was involved in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication. Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data-sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

Funding Information:
Conflicts of interest: J. K. Quint’s research group received funds from AstraZeneca for some of this work, and J. K. Quint has received fees for speaking from AstraZeneca . J. W. H. Kocks reports grants, personal fees, and nonfinancial support from AstraZeneca , Boehringer Ingelheim , COVIS, and GlaxoSmithKline; grants and personal fees from Chiesi and Novartis; and grants from MundiPharma and TEVA outside the submitted work, all paid to his institution; also holds 72.5% of shares in the General Practitioners Research Institute. M. Kupczyk reports personal fees from AstraZeneca during the conduct of the study; grants from AstraZeneca; and personal fees from AstraZeneca , Chiesi , GlaxoSmithKline , Novartis , Lekam, Alvogen, Emma, Nexter, and Berlin Chemie outside the submitted work. V. Plaza, in the last 3 years, received honoraria for speaking at sponsored meetings from AstraZeneca , Boehringer Ingelheim , MSD , and Chiesi; received travel assistance from AstraZeneca , Chiesi , and Novartis; served as a consultant for ALK, AstraZeneca , Boehringer Ingelheim , MSD , MundiPharma, and Sanofi; and received funding/grant support for research projects from a variety of government agencies and not-for-profit foundations, as well as AstraZeneca , Chiesi , and Menarini. C. Raherison-Semjen reports a professional relationship with AstraZeneca, ALK, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Intermune, MundiPharma, Novartis, TEVA, and Zambon. B. Walker has received honoraria and served on advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Sanofi. E. Penz has served on advisory boards and received honoraria and consulting fees from AstraZeneca , GlaxoSmithKline , Sanofi Genzyme , and Boehringer Ingelheim . N. L. Lugogo received consulting fees for advisory board participation from Amgen, AstraZeneca, Genentech, GSK, Novartis, Regeneron, Sanofi, and Teva; honoraria for nonspeakers bureau presentations from GSK and AstraZeneca; and travel support from AstraZeneca; her institution received research support from Amgen, AstraZeneca, Avillion, Gossamer Bio, Genentech, GSK, Regeneron, Sanofi, and Teva. S. Arnetorp, J. Nuevo, C. Cabrera, I. Gilbert, and R. J. P. van Der Valk are employees of AstraZeneca. S. Arnetorp and C. Cabrera also hold stocks of AstraZeneca. I. Gilbert also holds shares and options of AstraZeneca. R. J. P. van Der Valk also holds shares of GlaxoSmithKline and shares and options of AstraZeneca.

Publisher Copyright:
© 2022 The Authors

ASJC Scopus Subject Areas

Immunology and Allergy

PubMed: MeSH publication types

Journal Article
Observational Study
Research Support, Non-U.S. Gov't

Access to Document

10.1016/j.jaip.2022.02.047

Cite this

@article{214366e952904ea6a51bc41e4980acae,

title = "Short-Acting Beta-2-Agonist Exposure and Severe Asthma Exacerbations: SABINA Findings From Europe and North America",

abstract = "Background: Expert national/global asthma management recommendations raise the issue whether a safe threshold of short-acting beta-2 agonist (SABA) use without concomitant inhaled corticosteroids (ICS) exists. Objective: To examine SABA and maintenance therapy associations with severe asthma exacerbations across North America and Europe. Methods: Observational analyses of 10 SABa use IN Asthma (SABINA) datasets involving 1,033,564 patients (≥12 y) from Canada, France, the Netherlands, Poland, Spain, the United Kingdom, and the United States. Negative binomial models (incidence rate ratio [IRR] [95% CI adjusted for prespecified-covariates]) evaluated associations between SABA and exacerbations. Results: Across severities, 40.2% of patients were prescribed/possessed 3 or more SABA canisters/y. Per the Global Initiative for Asthma (GINA) 2018 definitions, steps 3 to 5–treated patients prescribed/possessing 3 or more versus 1 or 2 SABAs experienced more severe exacerbations (IRR 1.08 [95% CI 1.04‒1.13], U.S. Medicare; IRR 2.11 [95% CI 1.96‒2.27], Poland). This association was not observed in all step 1 or 2–treated patients (the Netherlands, IRR 1.25 [95% CI 0.91‒1.71]; U.S. commercial, IRR 0.92 [95% CI 0.91‒0.93]; U.S. Medicare, IRR 0.74 [95% CI 0.71‒0.76]). We hypothesize that this inverse association between SABA and severe exacerbations in the U.S. datasets was attributable to the large patient population possessing fewer than 3 SABA and no maintenance therapy and receiving oral corticosteroid bursts without face-to-face health care provider encounters. In U.S. SABA monotherapy–treated patients, 3 or more SABAs were associated with more emergency/outpatient visits and hospitalizations (IRR 1.31 [95% CI 1.29‒1.34]). Most GINA 2 to 5–treated study patients (60.6%) did not have maintenance therapy for up to 50% of the time; however, the association of 3 or more SABAs and severe exacerbations persisted (IRR 1.32 [95% CI 1.18‒1.49]) after excluding these patients and the independent effect was further confirmed when U.K. SABA data were analyzed as a continuous variable in patients with up to 100% annual coverage for ICS-containing medications. Conclusions: Increasing SABA exposure is associated with severe exacerbation risk, independent of maintenance therapy. As addressed by GINA, based on studies across asthma severities where as-needed fast-acting bronchodilators with concomitant ICS decrease severe exacerbations compared with SABA, our findings highlight the importance of avoiding a rescue/reliever paradigm utilizing SABA monotherapy.",

author = "{SABINA North American and European Study contributors} and Quint, {Jennifer K.} and Sofie Arnetorp and Kocks, {Janwillem W.H.} and Maciej Kupczyk and Javier Nuevo and Vicente Plaza and Claudia Cabrera and Chantal Raherison-Semjen and Brandie Walker and Erika Penz and Ileen Gilbert and Lugogo, {Njira Lucia} and {van der Valk}, {Ralf J.P.} and Andrew Fong and Christina Qian and Caroline Fabry-Vendrand and Chantal Touboul and Dorota Brzostek and Ekaterina Maslova and Filip Surmont and Helena Goike and Hitesh Gandhi and Korevaar, {J. C.} and Joseph Tkacz and Karissa Johnston and {Peres da Costa}, Keith and {van Dijk}, L. and M. Vervloet and Michael Pollack and Paul Hernandez and Silvia Boarino and Noorduyn, {Stephen G.} and Wendy Beekman-Hendricks and Weesie, {Y. M.}",

note = "Funding Information: Writing and editorial support was provided by Cactus Life Sciences (part of Cactus Communications, Mumbai, India) in accordance with Good Publication Practice (GPP3) guidelines ( http://www.ismpp.org/gpp3 ) and fully funded by AstraZeneca. AstraZeneca was involved in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication. Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca{\textquoteright}s data-sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure Funding Information: Funding: This work was funded by AstraZeneca.Conflicts of interest: J. K. Quint's research group received funds from AstraZeneca for some of this work, and J. K. Quint has received fees for speaking from AstraZeneca. J. W. H. Kocks reports grants, personal fees, and nonfinancial support from AstraZeneca, Boehringer Ingelheim, COVIS, and GlaxoSmithKline; grants and personal fees from Chiesi and Novartis; and grants from MundiPharma and TEVA outside the submitted work, all paid to his institution; also holds 72.5% of shares in the General Practitioners Research Institute. M. Kupczyk reports personal fees from AstraZeneca during the conduct of the study; grants from AstraZeneca; and personal fees from AstraZeneca, Chiesi, GlaxoSmithKline, Novartis, Lekam, Alvogen, Emma, Nexter, and Berlin Chemie outside the submitted work. V. Plaza, in the last 3 years, received honoraria for speaking at sponsored meetings from AstraZeneca, Boehringer Ingelheim, MSD, and Chiesi; received travel assistance from AstraZeneca, Chiesi, and Novartis; served as a consultant for ALK, AstraZeneca, Boehringer Ingelheim, MSD, MundiPharma, and Sanofi; and received funding/grant support for research projects from a variety of government agencies and not-for-profit foundations, as well as AstraZeneca, Chiesi, and Menarini. C. Raherison-Semjen reports a professional relationship with AstraZeneca, ALK, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Intermune, MundiPharma, Novartis, TEVA, and Zambon. B. Walker has received honoraria and served on advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Sanofi. E. Penz has served on advisory boards and received honoraria and consulting fees from AstraZeneca, GlaxoSmithKline, Sanofi Genzyme, and Boehringer Ingelheim. N. L. Lugogo received consulting fees for advisory board participation from Amgen, AstraZeneca, Genentech, GSK, Novartis, Regeneron, Sanofi, and Teva; honoraria for nonspeakers bureau presentations from GSK and AstraZeneca; and travel support from AstraZeneca; her institution received research support from Amgen, AstraZeneca, Avillion, Gossamer Bio, Genentech, GSK, Regeneron, Sanofi, and Teva. S. Arnetorp, J. Nuevo, C. Cabrera, I. Gilbert, and R. J. P. van Der Valk are employees of AstraZeneca. S. Arnetorp and C. Cabrera also hold stocks of AstraZeneca. I. Gilbert also holds shares and options of AstraZeneca. R. J. P. van Der Valk also holds shares of GlaxoSmithKline and shares and options of AstraZeneca.The authors acknowledge Tamsin Morris, BSc Hons and Yang Xu, Pharmacy (AstraZeneca, UK) for their insights on the U.K. analyses, Mena Soliman, MSc (AstraZeneca, Canada) for his assistance with interpreting the Canada data, and Antonio Valero, MD (Barcelona, Spain) and Jes{\'u}s Molina, PhD (Madrid, Spain) for their assistance with interpreting the Spanish dataset. The authors are grateful to Eleni Rapsomaniki, PhD (AstraZeneca, UK) for her assistance with designing and running the stratification analyses. The authors also thank Laura Pillot, PharmD (AstraZeneca, France) and Delphine Leynaud, Pharmaceutical Marketing (AstraZeneca, France) for their assistance in coordinating data collection from France, and Mieke Bastiaanse, MSc (AstraZeneca, the Netherlands) for supporting data collection from the Netherlands. The authors also thank the Scientific Committee of the ASTHMAPOP study (France): Alain Didier, MD, Armine Izadifar, MD, Maud Russier, Jean-Pierre Aubert, MD, and Christine Rolland, Masters (Intercultural Communication). Writing and editorial support was provided by Cactus Life Sciences (part of Cactus Communications, Mumbai, India) in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3) and fully funded by AstraZeneca. AstraZeneca was involved in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication. Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data-sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure Funding Information: Conflicts of interest: J. K. Quint{\textquoteright}s research group received funds from AstraZeneca for some of this work, and J. K. Quint has received fees for speaking from AstraZeneca . J. W. H. Kocks reports grants, personal fees, and nonfinancial support from AstraZeneca , Boehringer Ingelheim , COVIS, and GlaxoSmithKline; grants and personal fees from Chiesi and Novartis; and grants from MundiPharma and TEVA outside the submitted work, all paid to his institution; also holds 72.5% of shares in the General Practitioners Research Institute. M. Kupczyk reports personal fees from AstraZeneca during the conduct of the study; grants from AstraZeneca; and personal fees from AstraZeneca , Chiesi , GlaxoSmithKline , Novartis , Lekam, Alvogen, Emma, Nexter, and Berlin Chemie outside the submitted work. V. Plaza, in the last 3 years, received honoraria for speaking at sponsored meetings from AstraZeneca , Boehringer Ingelheim , MSD , and Chiesi; received travel assistance from AstraZeneca , Chiesi , and Novartis; served as a consultant for ALK, AstraZeneca , Boehringer Ingelheim , MSD , MundiPharma, and Sanofi; and received funding/grant support for research projects from a variety of government agencies and not-for-profit foundations, as well as AstraZeneca , Chiesi , and Menarini. C. Raherison-Semjen reports a professional relationship with AstraZeneca, ALK, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Intermune, MundiPharma, Novartis, TEVA, and Zambon. B. Walker has received honoraria and served on advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Sanofi. E. Penz has served on advisory boards and received honoraria and consulting fees from AstraZeneca , GlaxoSmithKline , Sanofi Genzyme , and Boehringer Ingelheim . N. L. Lugogo received consulting fees for advisory board participation from Amgen, AstraZeneca, Genentech, GSK, Novartis, Regeneron, Sanofi, and Teva; honoraria for nonspeakers bureau presentations from GSK and AstraZeneca; and travel support from AstraZeneca; her institution received research support from Amgen, AstraZeneca, Avillion, Gossamer Bio, Genentech, GSK, Regeneron, Sanofi, and Teva. S. Arnetorp, J. Nuevo, C. Cabrera, I. Gilbert, and R. J. P. van Der Valk are employees of AstraZeneca. S. Arnetorp and C. Cabrera also hold stocks of AstraZeneca. I. Gilbert also holds shares and options of AstraZeneca. R. J. P. van Der Valk also holds shares of GlaxoSmithKline and shares and options of AstraZeneca. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

doi = "10.1016/j.jaip.2022.02.047",

language = "English",

journal = "Journal of Allergy and Clinical Immunology: In Practice",

issn = "2213-2198",

publisher = "Elsevier",

}

TY - JOUR

T1 - Short-Acting Beta-2-Agonist Exposure and Severe Asthma Exacerbations

T2 - SABINA Findings From Europe and North America

AU - SABINA North American and European Study contributors

AU - Quint, Jennifer K.

AU - Arnetorp, Sofie

AU - Kocks, Janwillem W.H.

AU - Kupczyk, Maciej

AU - Nuevo, Javier

AU - Plaza, Vicente

AU - Cabrera, Claudia

AU - Raherison-Semjen, Chantal

AU - Walker, Brandie

AU - Penz, Erika

AU - Gilbert, Ileen

AU - Lugogo, Njira Lucia

AU - van der Valk, Ralf J.P.

AU - Fong, Andrew

AU - Qian, Christina

AU - Fabry-Vendrand, Caroline

AU - Touboul, Chantal

AU - Brzostek, Dorota

AU - Maslova, Ekaterina

AU - Surmont, Filip

AU - Goike, Helena

AU - Gandhi, Hitesh

AU - Korevaar, J. C.

AU - Tkacz, Joseph

AU - Johnston, Karissa

AU - Peres da Costa, Keith

AU - van Dijk, L.

AU - Vervloet, M.

AU - Pollack, Michael

AU - Hernandez, Paul

AU - Boarino, Silvia

AU - Noorduyn, Stephen G.

AU - Beekman-Hendricks, Wendy

AU - Weesie, Y. M.

N1 - Funding Information: Writing and editorial support was provided by Cactus Life Sciences (part of Cactus Communications, Mumbai, India) in accordance with Good Publication Practice (GPP3) guidelines ( http://www.ismpp.org/gpp3 ) and fully funded by AstraZeneca. AstraZeneca was involved in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication. Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data-sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure Funding Information: Funding: This work was funded by AstraZeneca.Conflicts of interest: J. K. Quint's research group received funds from AstraZeneca for some of this work, and J. K. Quint has received fees for speaking from AstraZeneca. J. W. H. Kocks reports grants, personal fees, and nonfinancial support from AstraZeneca, Boehringer Ingelheim, COVIS, and GlaxoSmithKline; grants and personal fees from Chiesi and Novartis; and grants from MundiPharma and TEVA outside the submitted work, all paid to his institution; also holds 72.5% of shares in the General Practitioners Research Institute. M. Kupczyk reports personal fees from AstraZeneca during the conduct of the study; grants from AstraZeneca; and personal fees from AstraZeneca, Chiesi, GlaxoSmithKline, Novartis, Lekam, Alvogen, Emma, Nexter, and Berlin Chemie outside the submitted work. V. Plaza, in the last 3 years, received honoraria for speaking at sponsored meetings from AstraZeneca, Boehringer Ingelheim, MSD, and Chiesi; received travel assistance from AstraZeneca, Chiesi, and Novartis; served as a consultant for ALK, AstraZeneca, Boehringer Ingelheim, MSD, MundiPharma, and Sanofi; and received funding/grant support for research projects from a variety of government agencies and not-for-profit foundations, as well as AstraZeneca, Chiesi, and Menarini. C. Raherison-Semjen reports a professional relationship with AstraZeneca, ALK, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Intermune, MundiPharma, Novartis, TEVA, and Zambon. B. Walker has received honoraria and served on advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Sanofi. E. Penz has served on advisory boards and received honoraria and consulting fees from AstraZeneca, GlaxoSmithKline, Sanofi Genzyme, and Boehringer Ingelheim. N. L. Lugogo received consulting fees for advisory board participation from Amgen, AstraZeneca, Genentech, GSK, Novartis, Regeneron, Sanofi, and Teva; honoraria for nonspeakers bureau presentations from GSK and AstraZeneca; and travel support from AstraZeneca; her institution received research support from Amgen, AstraZeneca, Avillion, Gossamer Bio, Genentech, GSK, Regeneron, Sanofi, and Teva. S. Arnetorp, J. Nuevo, C. Cabrera, I. Gilbert, and R. J. P. van Der Valk are employees of AstraZeneca. S. Arnetorp and C. Cabrera also hold stocks of AstraZeneca. I. Gilbert also holds shares and options of AstraZeneca. R. J. P. van Der Valk also holds shares of GlaxoSmithKline and shares and options of AstraZeneca.The authors acknowledge Tamsin Morris, BSc Hons and Yang Xu, Pharmacy (AstraZeneca, UK) for their insights on the U.K. analyses, Mena Soliman, MSc (AstraZeneca, Canada) for his assistance with interpreting the Canada data, and Antonio Valero, MD (Barcelona, Spain) and Jesús Molina, PhD (Madrid, Spain) for their assistance with interpreting the Spanish dataset. The authors are grateful to Eleni Rapsomaniki, PhD (AstraZeneca, UK) for her assistance with designing and running the stratification analyses. The authors also thank Laura Pillot, PharmD (AstraZeneca, France) and Delphine Leynaud, Pharmaceutical Marketing (AstraZeneca, France) for their assistance in coordinating data collection from France, and Mieke Bastiaanse, MSc (AstraZeneca, the Netherlands) for supporting data collection from the Netherlands. The authors also thank the Scientific Committee of the ASTHMAPOP study (France): Alain Didier, MD, Armine Izadifar, MD, Maud Russier, Jean-Pierre Aubert, MD, and Christine Rolland, Masters (Intercultural Communication). Writing and editorial support was provided by Cactus Life Sciences (part of Cactus Communications, Mumbai, India) in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3) and fully funded by AstraZeneca. AstraZeneca was involved in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication. Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data-sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure Funding Information: Conflicts of interest: J. K. Quint’s research group received funds from AstraZeneca for some of this work, and J. K. Quint has received fees for speaking from AstraZeneca . J. W. H. Kocks reports grants, personal fees, and nonfinancial support from AstraZeneca , Boehringer Ingelheim , COVIS, and GlaxoSmithKline; grants and personal fees from Chiesi and Novartis; and grants from MundiPharma and TEVA outside the submitted work, all paid to his institution; also holds 72.5% of shares in the General Practitioners Research Institute. M. Kupczyk reports personal fees from AstraZeneca during the conduct of the study; grants from AstraZeneca; and personal fees from AstraZeneca , Chiesi , GlaxoSmithKline , Novartis , Lekam, Alvogen, Emma, Nexter, and Berlin Chemie outside the submitted work. V. Plaza, in the last 3 years, received honoraria for speaking at sponsored meetings from AstraZeneca , Boehringer Ingelheim , MSD , and Chiesi; received travel assistance from AstraZeneca , Chiesi , and Novartis; served as a consultant for ALK, AstraZeneca , Boehringer Ingelheim , MSD , MundiPharma, and Sanofi; and received funding/grant support for research projects from a variety of government agencies and not-for-profit foundations, as well as AstraZeneca , Chiesi , and Menarini. C. Raherison-Semjen reports a professional relationship with AstraZeneca, ALK, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Intermune, MundiPharma, Novartis, TEVA, and Zambon. B. Walker has received honoraria and served on advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Sanofi. E. Penz has served on advisory boards and received honoraria and consulting fees from AstraZeneca , GlaxoSmithKline , Sanofi Genzyme , and Boehringer Ingelheim . N. L. Lugogo received consulting fees for advisory board participation from Amgen, AstraZeneca, Genentech, GSK, Novartis, Regeneron, Sanofi, and Teva; honoraria for nonspeakers bureau presentations from GSK and AstraZeneca; and travel support from AstraZeneca; her institution received research support from Amgen, AstraZeneca, Avillion, Gossamer Bio, Genentech, GSK, Regeneron, Sanofi, and Teva. S. Arnetorp, J. Nuevo, C. Cabrera, I. Gilbert, and R. J. P. van Der Valk are employees of AstraZeneca. S. Arnetorp and C. Cabrera also hold stocks of AstraZeneca. I. Gilbert also holds shares and options of AstraZeneca. R. J. P. van Der Valk also holds shares of GlaxoSmithKline and shares and options of AstraZeneca. Publisher Copyright: © 2022 The Authors

PY - 2022

Y1 - 2022

N2 - Background: Expert national/global asthma management recommendations raise the issue whether a safe threshold of short-acting beta-2 agonist (SABA) use without concomitant inhaled corticosteroids (ICS) exists. Objective: To examine SABA and maintenance therapy associations with severe asthma exacerbations across North America and Europe. Methods: Observational analyses of 10 SABa use IN Asthma (SABINA) datasets involving 1,033,564 patients (≥12 y) from Canada, France, the Netherlands, Poland, Spain, the United Kingdom, and the United States. Negative binomial models (incidence rate ratio [IRR] [95% CI adjusted for prespecified-covariates]) evaluated associations between SABA and exacerbations. Results: Across severities, 40.2% of patients were prescribed/possessed 3 or more SABA canisters/y. Per the Global Initiative for Asthma (GINA) 2018 definitions, steps 3 to 5–treated patients prescribed/possessing 3 or more versus 1 or 2 SABAs experienced more severe exacerbations (IRR 1.08 [95% CI 1.04‒1.13], U.S. Medicare; IRR 2.11 [95% CI 1.96‒2.27], Poland). This association was not observed in all step 1 or 2–treated patients (the Netherlands, IRR 1.25 [95% CI 0.91‒1.71]; U.S. commercial, IRR 0.92 [95% CI 0.91‒0.93]; U.S. Medicare, IRR 0.74 [95% CI 0.71‒0.76]). We hypothesize that this inverse association between SABA and severe exacerbations in the U.S. datasets was attributable to the large patient population possessing fewer than 3 SABA and no maintenance therapy and receiving oral corticosteroid bursts without face-to-face health care provider encounters. In U.S. SABA monotherapy–treated patients, 3 or more SABAs were associated with more emergency/outpatient visits and hospitalizations (IRR 1.31 [95% CI 1.29‒1.34]). Most GINA 2 to 5–treated study patients (60.6%) did not have maintenance therapy for up to 50% of the time; however, the association of 3 or more SABAs and severe exacerbations persisted (IRR 1.32 [95% CI 1.18‒1.49]) after excluding these patients and the independent effect was further confirmed when U.K. SABA data were analyzed as a continuous variable in patients with up to 100% annual coverage for ICS-containing medications. Conclusions: Increasing SABA exposure is associated with severe exacerbation risk, independent of maintenance therapy. As addressed by GINA, based on studies across asthma severities where as-needed fast-acting bronchodilators with concomitant ICS decrease severe exacerbations compared with SABA, our findings highlight the importance of avoiding a rescue/reliever paradigm utilizing SABA monotherapy.

AB - Background: Expert national/global asthma management recommendations raise the issue whether a safe threshold of short-acting beta-2 agonist (SABA) use without concomitant inhaled corticosteroids (ICS) exists. Objective: To examine SABA and maintenance therapy associations with severe asthma exacerbations across North America and Europe. Methods: Observational analyses of 10 SABa use IN Asthma (SABINA) datasets involving 1,033,564 patients (≥12 y) from Canada, France, the Netherlands, Poland, Spain, the United Kingdom, and the United States. Negative binomial models (incidence rate ratio [IRR] [95% CI adjusted for prespecified-covariates]) evaluated associations between SABA and exacerbations. Results: Across severities, 40.2% of patients were prescribed/possessed 3 or more SABA canisters/y. Per the Global Initiative for Asthma (GINA) 2018 definitions, steps 3 to 5–treated patients prescribed/possessing 3 or more versus 1 or 2 SABAs experienced more severe exacerbations (IRR 1.08 [95% CI 1.04‒1.13], U.S. Medicare; IRR 2.11 [95% CI 1.96‒2.27], Poland). This association was not observed in all step 1 or 2–treated patients (the Netherlands, IRR 1.25 [95% CI 0.91‒1.71]; U.S. commercial, IRR 0.92 [95% CI 0.91‒0.93]; U.S. Medicare, IRR 0.74 [95% CI 0.71‒0.76]). We hypothesize that this inverse association between SABA and severe exacerbations in the U.S. datasets was attributable to the large patient population possessing fewer than 3 SABA and no maintenance therapy and receiving oral corticosteroid bursts without face-to-face health care provider encounters. In U.S. SABA monotherapy–treated patients, 3 or more SABAs were associated with more emergency/outpatient visits and hospitalizations (IRR 1.31 [95% CI 1.29‒1.34]). Most GINA 2 to 5–treated study patients (60.6%) did not have maintenance therapy for up to 50% of the time; however, the association of 3 or more SABAs and severe exacerbations persisted (IRR 1.32 [95% CI 1.18‒1.49]) after excluding these patients and the independent effect was further confirmed when U.K. SABA data were analyzed as a continuous variable in patients with up to 100% annual coverage for ICS-containing medications. Conclusions: Increasing SABA exposure is associated with severe exacerbation risk, independent of maintenance therapy. As addressed by GINA, based on studies across asthma severities where as-needed fast-acting bronchodilators with concomitant ICS decrease severe exacerbations compared with SABA, our findings highlight the importance of avoiding a rescue/reliever paradigm utilizing SABA monotherapy.

UR - http://www.scopus.com/inward/record.url?scp=85130474448&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85130474448&partnerID=8YFLogxK

U2 - 10.1016/j.jaip.2022.02.047

DO - 10.1016/j.jaip.2022.02.047

M3 - Article

C2 - 35364341

AN - SCOPUS:85130474448

SN - 2213-2198

JO - Journal of Allergy and Clinical Immunology: In Practice

JF - Journal of Allergy and Clinical Immunology: In Practice

ER -

Short-Acting Beta-2-Agonist Exposure and Severe Asthma Exacerbations: SABINA Findings From Europe and North America

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