systematic literature review of systemic corticosteroid use for asthma management

Systematic Literature Review of Systemic Corticosteroid Use for Asthma Management

Affiliations.

• 1 Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona Health Sciences, Tucson, Arizona.
• 2 Lung Division, Royal Brompton Hospital, London, United Kingdom.
• 3 Department of Primary Care Respiratory Medicine, University of Aberdeen, Aberdeen, United Kingdom.
• 4 Observational and Pragmatic Research Institute, Singapore.
• 5 Department of Respiratory Diseases, University of Montpellier, Montpellier, France.
• 6 Research Evaluation Unit, Oxford PharmaGenesis Ltd., Oxford, United Kingdom.
• 7 Evidera, Waltham, Massachusetts.
• 8 AstraZeneca, Luton, United Kingdom; and.
• 9 AstraZeneca, Gaithersburg, Maryland.
• PMID: 31525297
• PMCID: PMC6999108
• DOI: 10.1164/rccm.201904-0903SO

Systemic corticosteroid use to manage uncontrolled asthma and its associated healthcare burden may account for important health-related adverse effects. We conducted a systematic literature review to investigate the real-world extent and burden of systemic corticosteroid use in asthma. We searched MEDLINE and Embase databases to identify English-language articles published in 2010-2017, using search terms for asthma with keywords for oral corticosteroids and systemic corticosteroids. Observational studies, prescription database analyses, economic analyses, and surveys on oral/systemic corticosteroid use in children (>5 yr old), adolescents (12-17 yr old), and adults with asthma were included. We identified and reviewed 387 full-text articles, and our review included data from 139 studies. The included studies were conducted in Europe, North America, and Asia. Overall, oral/systemic corticosteroids were commonly used for asthma management and were more frequently used in patients with severe asthma than in those with milder disease. Long-term oral/systemic corticosteroid use was, in general, less frequent than short-term use. Compared with no use, long-term and repeated short-term oral/systemic corticosteroid use were associated with an increased risk of acute and chronic adverse events, even when doses were comparatively low. Greater oral/systemic corticosteroid exposure was also associated with increased costs and healthcare resource use. This review provides a comprehensive overview of oral/systemic corticosteroid use and associated adverse events for patients with all degrees of asthma severity and exposure duration. We report that oral/systemic corticosteroid use is prevalent in asthma management, and the risks of acute and chronic complications increase with the cumulative oral corticosteroid dosage.

Keywords: asthma; oral corticosteroids; severe asthma; systematic literature review; systemic corticosteroids.

Publication types

• Research Support, Non-U.S. Gov't
• Systematic Review
• Adrenal Cortex Hormones / administration & dosage*
• Adrenal Cortex Hormones / adverse effects*
• Asthma / drug therapy*
• Child, Preschool
• Adrenal Cortex Hormones

• Help & FAQ

Systematic Literature Review of Systemic Corticosteroid Use for Asthma Management

• Institute of Applied Health Sciences
• Applied Health Sciences
• University of Arizona
• Royal Brompton Hospital
• Hôpital Arnaud de Villeneuve
• Oxford PharmaGenesis Ltd
• Evidera Waltham
• AstraZeneca
• AstraZeneca, US

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

Systemic corticosteroid use to manage uncontrolled asthma and its associated health care burden may account for important health-related adverse effects. We conducted a systematic literature review to investigate the real-world extent and burden of systemic corticosteroid use in asthma. We searched MEDLINE® and Embase® databases to identify English-language articles published from 2010-2017, using search terms for asthma with key words for oral corticosteroids and systemic corticosteroids. Observational studies, prescription database analyses, economic analyses, and surveys on oral/systemic corticosteroid use for children (aged >5 years), adolescents (aged 12-17 years), and adults with asthma were included. We identified and reviewed 387 full-text articles, and our review included data from 139 studies. The included studies were conducted in Europe, North America, and Asia. Overall, oral/systemic corticosteroid use was common in asthma management and more frequent for patients with severe asthma compared with patients with milder disease. Long-term oral/systemic corticosteroid use was, in general, less frequent than short-term use. Compared with no use, long-term and repeated short-term oral/systemic corticosteroid use were associated with increased risk of acute and chronic adverse events (AEs), even when doses were comparatively low. Greater oral/systemic corticosteroid exposure was also associated with increased costs and health care resource utilization. This review provides a comprehensive overview of oral/systemic corticosteroid use and associated AEs for patients with all degrees of asthma severity and exposure duration. We report that oral/systemic corticosteroid use is prevalent in asthma management, and risks of acute and chronic complications increase with cumulative OCS dosage.

Bibliographical note

• Oral Corticosteroids
• Severe Asthma
• Systematic Literature Review
• Systematic Corticosteroids
• Systemic corticosteroids
• Oral corticosteroids
• Severe asthma
• Systematic literature review
• EMERGENCY-DEPARTMENT VISITS
• INHALED CORTICOSTEROIDS
• SEVERE ALLERGIC-ASTHMA
• FLUTICASONE PROPIONATE/SALMETEROL
• oral corticosteroids
• TO-TREAT ASTHMA
• ADD-ON THERAPY
• PRESCRIPTION PATTERNS
• ORAL CORTICOSTEROIDS
• severe asthma
• ACTING BETA-AGONISTS
• HEALTH-CARE UTILIZATION
• systematic literature review
• systemic corticosteroids

Access to Document

• 10.1164/rccm.201904-0903SO Licence: CC BY

This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage and reprints, please contact Diane Gern ([email protected]).

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• Adrenal Cortex Hormones Medicine & Life Sciences 100%
• Asthma Medicine & Life Sciences 96%
• Systematic Reviews Medicine & Life Sciences 91%
• Northern Asia Medicine & Life Sciences 18%
• Databases Medicine & Life Sciences 13%
• Patient Acceptance of Health Care Medicine & Life Sciences 13%
• Health Resources Medicine & Life Sciences 12%
• Risk Management Medicine & Life Sciences 12%

T1 - Systematic Literature Review of Systemic Corticosteroid Use for Asthma Management

AU - Bleecker, Eugene R

AU - Menzies-Gow, Andrew N

AU - Price, David B

AU - Bourdin, Arnaud

AU - Sweet, Stephen

AU - Martin, Amber L

AU - Alacqua, Marianna

AU - Tran, Trung N

N1 - Writing and editing assistance, including preparation of a draft manuscript under the direction and guidance of the authors, incorporating author feedback, and manuscript submission, was provided by Debra Scates, Ph.D., of JK Associates, Inc., and Michael A. Nissen, E.L.S., of AstraZeneca. This support was funded by AstraZeneca.

PY - 2020/2/1

Y1 - 2020/2/1

N2 - Systemic corticosteroid use to manage uncontrolled asthma and its associated health care burden may account for important health-related adverse effects. We conducted a systematic literature review to investigate the real-world extent and burden of systemic corticosteroid use in asthma. We searched MEDLINE® and Embase® databases to identify English-language articles published from 2010-2017, using search terms for asthma with key words for oral corticosteroids and systemic corticosteroids. Observational studies, prescription database analyses, economic analyses, and surveys on oral/systemic corticosteroid use for children (aged >5 years), adolescents (aged 12-17 years), and adults with asthma were included. We identified and reviewed 387 full-text articles, and our review included data from 139 studies. The included studies were conducted in Europe, North America, and Asia. Overall, oral/systemic corticosteroid use was common in asthma management and more frequent for patients with severe asthma compared with patients with milder disease. Long-term oral/systemic corticosteroid use was, in general, less frequent than short-term use. Compared with no use, long-term and repeated short-term oral/systemic corticosteroid use were associated with increased risk of acute and chronic adverse events (AEs), even when doses were comparatively low. Greater oral/systemic corticosteroid exposure was also associated with increased costs and health care resource utilization. This review provides a comprehensive overview of oral/systemic corticosteroid use and associated AEs for patients with all degrees of asthma severity and exposure duration. We report that oral/systemic corticosteroid use is prevalent in asthma management, and risks of acute and chronic complications increase with cumulative OCS dosage.

AB - Systemic corticosteroid use to manage uncontrolled asthma and its associated health care burden may account for important health-related adverse effects. We conducted a systematic literature review to investigate the real-world extent and burden of systemic corticosteroid use in asthma. We searched MEDLINE® and Embase® databases to identify English-language articles published from 2010-2017, using search terms for asthma with key words for oral corticosteroids and systemic corticosteroids. Observational studies, prescription database analyses, economic analyses, and surveys on oral/systemic corticosteroid use for children (aged >5 years), adolescents (aged 12-17 years), and adults with asthma were included. We identified and reviewed 387 full-text articles, and our review included data from 139 studies. The included studies were conducted in Europe, North America, and Asia. Overall, oral/systemic corticosteroid use was common in asthma management and more frequent for patients with severe asthma compared with patients with milder disease. Long-term oral/systemic corticosteroid use was, in general, less frequent than short-term use. Compared with no use, long-term and repeated short-term oral/systemic corticosteroid use were associated with increased risk of acute and chronic adverse events (AEs), even when doses were comparatively low. Greater oral/systemic corticosteroid exposure was also associated with increased costs and health care resource utilization. This review provides a comprehensive overview of oral/systemic corticosteroid use and associated AEs for patients with all degrees of asthma severity and exposure duration. We report that oral/systemic corticosteroid use is prevalent in asthma management, and risks of acute and chronic complications increase with cumulative OCS dosage.

KW - Asthma

KW - Oral Corticosteroids

KW - Severe Asthma

KW - Systematic Literature Review

KW - Systematic Corticosteroids

KW - Systemic corticosteroids

KW - Oral corticosteroids

KW - Severe asthma

KW - Systematic literature review

KW - EMERGENCY-DEPARTMENT VISITS

KW - INHALED CORTICOSTEROIDS

KW - SEVERE ALLERGIC-ASTHMA

KW - asthma

KW - FLUTICASONE PROPIONATE/SALMETEROL

KW - oral corticosteroids

KW - TO-TREAT ASTHMA

KW - ADD-ON THERAPY

KW - PRESCRIPTION PATTERNS

KW - ORAL CORTICOSTEROIDS

KW - severe asthma

KW - ACTING BETA-AGONISTS

KW - HEALTH-CARE UTILIZATION

KW - systematic literature review

KW - systemic corticosteroids

UR - http://www.scopus.com/inward/record.url?scp=85078634867&partnerID=8YFLogxK

U2 - 10.1164/rccm.201904-0903SO

DO - 10.1164/rccm.201904-0903SO

M3 - Article

C2 - 31525297

SN - 1073-449X

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

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Use of Systemic Corticosteroids for Reasons Other than Asthma in Subjects with Asthma

Associated data.

All data generated or analyzed during this study are included in this article and its online suppl. files (for all online suppl. material, see www.karger.com/doi/10.1159/000518461 ). Further enquiries can be directed to the corresponding author.

Backgrounds

Recent studies have reported increased risks of adverse events from systemic corticosteroids even with only low-dose or short-term use. Some patients with asthma experience complications requiring systemic corticosteroids. However, few studies have examined issues associated with administration of systemic corticosteroids for reasons other than asthma among subjects with asthma.

We investigated patterns of systemic corticosteroid exposure for reasons other than asthma in subjects with asthma.

We retrospectively reviewed the records of adult subjects with asthma followed up for >1 year at Yokohama City University Hospital from January 1, 2010, to December 31, 2019. We investigated patterns and reasons for systemic corticosteroid use during follow-up. In addition, factors related to systemic corticosteroid use for reasons likely other than asthma were investigated.

Among the 568 subjects with asthma analyzed, 326 (57.4%) had received systemic corticosteroids for some reason. Among those 326 patients, 120 (36.8%) had received systemic corticosteroids for reasons likely other than asthma. Multivariable analysis revealed rheumatoid arthritis, eosinophilic granulomatosis with polyangiitis, other collagen vascular diseases, chronic rhinosinusitis, and malignancy as positively associated with systemic corticosteroid exposure for reasons likely other than asthma in subjects with asthma.

Conclusions

About 40% of systemic corticosteroid use in subjects with asthma was for reasons likely other than asthma. Clinicians should be aware of their asthma patients' exposures to systemic corticosteroids for nonasthma reasons, to avoid missing adverse events or underestimating the severity of asthma, and to reduce systemic corticosteroid use.

Introduction

Asthma is characterized by eosinophilic airway inflammation, and inhaled corticosteroids are the key drug class for the treatment of this pathology. However, systemic corticosteroids are required for exacerbations and/or maintenance in some cases of severe asthma [ 1 ]. About a quarter of subjects with asthma require short-term oral corticosteroids (OCS) during a 1-year period, and 20–60% of patients with severe or uncontrolled asthma are on long-term oral/systemic corticosteroids [ 1 ]. Recent studies have reported an increased risk of adverse events from systemic corticosteroids even among individuals with low-dose and/or short-term use of these drugs [ 1 , 2 , 3 , 4 , 5 , 6 ]. Clinicians therefore need to attend to their patients' exposures to systemic corticosteroids. Some asthmatic patients develop complications requiring systemic corticosteroids. However, few studies have examined exposures to systemic corticosteroids for reasons other than asthma in subjects with asthma. We therefore investigated patterns of systemic corticosteroid exposure for reasons likely other than asthma in subjects with asthma.

Materials and Methods

We retrospectively reviewed the electronic medical chart of adult subjects (≥18 years old) with physician-diagnosed asthma who were followed up for >1 year at outpatient clinic of Yokohama City University Hospital from January 1, 2010, to December 31, 2019. We then investigated patterns and reasons for systemic corticosteroid use during follow-up. We compared subjects with and without systemic corticosteroid use for reasons likely other than asthma. Factors related to systemic corticosteroid use for reasons likely other than asthma were also investigated. The dose of systemic corticosteroid was categorized as low (prednisolone-equivalents ≤5 mg/day) or high (prednisolone-equivalents >5 mg/day). Duration of systemic corticosteroid use was categorized as short (≤3 months) or long (>3 months). Systemic corticosteroids included oral, intravenous, and intramuscular corticosteroids. We collected the data of spirometry, peripheral eosinophils, and total IgE at the stable state of asthma within 2 years before or after the start of the study period. Specific IgE status at the diagnosis and/or during follow-up was also collected.

Data are presented as mean (range) unless otherwise specified. JMP version 11 software (SAS Institute, Cary, NC, USA) was used for statistical analyses. Comparisons were made using the Mann-Whitney U test for continuous variable, while categorical variables were compared using Pearson's χ 2 test or Fisher's exact test. To detect factors related to systemic corticosteroid exposure for reasons likely other than asthma, we performed multivariate analysis by logistic regression analysis for factors showing values of p < 0.1 in univariate analysis. Statistical significance was defined as a value of p < 0.05, and all tests were 2-tailed.

This study was approved by the institutional review board at Yokohama City University Hospital (approval no. B200500001). Due to the retrospective nature of this study, the need to obtain written informed consent was waived.

Figure ​ Figure1 1 shows the flow diagram for the study. A total of 569 subjects with asthma were followed up for >1 year. One subject was excluded because of attending a clinical trial and receiving unknown treatment. Thus, data from 568 subjects with asthma were analyzed, revealing that 326 of the 568 patients (57.4%; 95% confidence [CI]: 53.3–61.4%) received systemic corticosteroids for any reason. Among those 326 subjects, 120 patients (36.8%; 95% CI: 31.8–42.2%) received at least 1 dose of systemic corticosteroid for reasons likely other than asthma. Table ​ Table1 1 shows the characteristics of asthma in this population.

Flow diagram for the study.

Characteristics of asthma in the population

Data are presented as median (range) or patients n (%). FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; ICS, inhaled corticosteroid; LABA, long-acting β2 agonist; LAMA, long-acting anticholinergic agent; LTRA, leukotriene receptor antagonist.

Table ​ Table2 2 shows a comparison of the subjects with or without systemic corticosteroid exposure for reasons likely other than asthma. Subjects receiving systemic corticosteroids for reasons likely other than asthma were older (64 years [22–84 years] vs. 59 years [21–88 years]; p = 0.020) and more frequently showed rheumatoid arthritis (RA) (7.5% vs. 2.9%; p = 0.031), eosinophilic granulomatosis with polyangiitis (EGPA) (5.8% vs. 0.5%; p < 0.001), other collagen vascular diseases (CVDs) (20.8% vs. 1.8%; p < 0.001), chronic rhinosinusitis (CRS) (21.7% vs. 7.8%; p < 0.001), and malignancy (10.0% vs. 2.0%; p < 0.001).

Comparison of clinical features

Data are presented as median (range) or patients n (%). COPD, chronic obstructive pulmonary disease; CRS, chronic rhinosinusitis; CVD, collagen vascular disease; EGPA, eosinophilic granulomatosis with polyangiitis; GINA, global initiative for asthma; RA, rheumatoid arthritis.

Table ​ Table3 3 shows the causes requiring systemic corticosteroid use for reasons likely other than asthma. Main likely reasons for nonasthma use of systemic corticosteroids were RA ( n = 9, 7.5%), EGPA ( n = 7, 5.8%), other CVD ( n = 24, 20%), CRS ( n = 20, 16.7%), and malignancy ( n = 12, 10.0%).

Main reason, dose, and duration of systemic corticosteroid use for likely nonasthma

Main reasons ( n ≥ 5) are presented. Some subjects received systemic corticosteroids for both long and short durations and/or at low and high doses. Dose of corticosteroid was categorized as low (prednisolone-equivalents ≤5 mg/day) or high (prednisolone-equivalents >5 mg/day). Duration of systemic corticosteroid was categorized as short (≤3 months) or long (>3 months). CRS, chronic rhinosinusitis; CVD, collagen vascular disease; EGPA, eosinophilic granulomatosis with polyangiitis; RA, rheumatoid arthritis.

Table ​ Table4 4 shows factors related to systemic corticosteroid exposure for reasons likely other than asthma in subjects with asthma according to multivariable analysis. Age (odds ratio [OR] 1.02, 95% CI: 1.00–1.04; p = 0.033), duration of follow-up (OR 1.13, 95% CI: 1.05–1.22; p = 0.001), RA (OR 3.42, 95% CI: 1.30–8.98; p = 0.017), EGPA (OR 32.6, 95% CI: 6.31–168; p < 0.001), other CVD (OR 22.8, 95% CI: 9.04–52.3; p < 0.001), CRS (OR 4.97, 95% CI: 2.64–9.36; p < 0.001), and malignancy (OR 8.56, 95% CI: 3.15–23.2; p < 0.001) were positively associated with systemic corticosteroid exposure for reasons likely other than asthma in subjects with asthma.

Multivariable analysis for systemic corticosteroids use for likely nonasthma

COPD, chronic obstructive pulmonary disease; CRS, chronic rhinosinusitis; CVD, collagen vascular disease; EGPA, eosinophilic granulomatosis with polyangiitis; RA, rheumatoid arthritis; CI, confidence interval.

In this study, 57.4% of subjects with asthma received systemic corticosteroids during follow-up (median, 4.1 years). Of these, 36.8% received systemic corticosteroids for reasons likely other than asthma management. Factors identified as positively related to systemic corticosteroid use for reasons likely other than asthma were age, RA, EGPA, other CVD, CRS, and malignancy.

Systemic corticosteroid use is related to a wide variety of adverse events, even in low doses or with intermittent use [ 1 , 2 , 3 , 4 , 5 , 6 ]. Moreover, systemic corticosteroids for reasons other than asthma could contribute to better asthma control and clinician underestimation of the severity of the asthma. Clinicians should be aware of systemic corticosteroid use for reasons other than asthma, to ensure that adverse events are not missed and the severity of asthma is correctly evaluated.

As mentioned above, with the increasing evidence of adverse events following low-dose or intermittent use of systemic corticosteroids, reducing systemic corticosteroid use is increasingly being recognized as important. In recent studies, OCS use for asthma is relatively common, and the proportion of OCS was stable during the study periods [ 8 , 9 , 10 ]. However, reducing systemic corticosteroids administered for asthma is insufficient, as 36.8% of subjects with asthma received systemic corticosteroids, which uses other than asthma. This indicates the importance of reducing the use of systemic corticosteroids for reasons other than asthma. To achieve this goal, one target is the comorbidity of allergic diseases. The incidence of concomitant asthma and other allergic diseases is high [ 11 , 12 ]. In addition, some treatments are effective against both asthma and other allergic diseases [ 13 , 14 , 15 , 16 ]. Total management of allergic diseases is thus important to reduce systemic corticosteroid exposure. In this study, 22.5% of systemic corticosteroid use for reasons likely other than asthma was to control allergic diseases such as CRS and EGPA. These diseases have an etiology and treatment target in common with asthma. For example, dupilumab shows efficacy against both asthma and CRS [ 14 , 15 , 16 ]. Allergen immunotherapy is effective in allergic asthma and allergic rhinitis [ 17 , 18 ]. In addition, upper-airway disease activity has an impact on asthma control and treatment of upper-airway diseases improves asthma control [ 19 , 20 , 21 ]. Biologics or immunotherapy might spare systemic corticosteroid used for asthma, by not only directly improving asthma control but also indirectly improving upper-airway disease control. With a view to reducing exposures to systemic corticosteroids, total management of allergic diseases is clearly important.

In this study, CVD was another main likely reason for systemic corticosteroid use. Among CVDs, RA is common in the general population and studies have shown an association between asthma and RA, with asthma increasing the risk of RA [ 22 , 23 , 24 ]. Some studies suggested that the airway mucosal inflammation is related to anticitrullinated protein antibody production and seropositive RA development [ 25 , 26 ]. Zaccardelli et al. [ 26 ] reported anticitrullinated protein antibody elevation in asthma prior to RA diagnosis, suggesting that airway inflammation in asthma is also related to RA development. In fact, 3.9% of individuals with asthma in this study had RA, which seems higher than the rate in the general population [ 27 ]. Systemic steroids are also used for other CVDs, such as systemic lupus erythematosus. Asthma increases the risk of autoimmune diseases, including systemic lupus erythematosus and Sjögren's syndrome [ 24 ]. In subjects with asthma, systemic corticosteroid use for CVD also requires attention.

In the multivariable analysis, malignancy was another factor related to systemic corticosteroid use for reasons likely other than asthma. Systemic corticosteroids are used as anticancer agents (i.e., lymphoma) [ 28 ], antiemetics [ 29 ], and palliative care in oncology [ 30 ]. As cancer prognoses have improved [ 31 ], not only short-term but also long-term adverse events related to systemic corticosteroids require attention.

The prevalence of OCS use in general population is around 15% [ 32 ]. In this study, about 40% of subjects with asthma received systemic corticosteroids for reasons other than asthma. Compared to general population, subjects with asthma might have a higher risk of OCS exposure and require special attention.

This study has some limitations that require consideration when interpreting the results. First, the major limitation is the retrospective nature of the study. Neither diagnostic criteria for asthma nor timing of spirometry and blood test was predefined. Besides, some data are lacking. But the diagnosis of asthma was made by the pulmonologist and/or the allergist. In addition, the steroid prescription and the reason for prescription were recorded on an electronic chart. Thus, the data of systemic steroids' prescription are relatively firm. Second, this study was performed at a single university hospital. It could not be applicable to the asthma in general. However, this study included mild asthma (GINA step 1/2) and most of the comorbidities for which systemic corticosteroids were used were common diseases. Third, we could not clarify conditions of use for systemic corticosteroid prescribed at other hospitals and/or clinics. A greater proportion of subjects with asthma might thus be exposed to systemic corticosteroid use for reasons other than asthma. Fourth, recent advances in treatment for many fields might have allowed reductions in systemic corticosteroid use among subjects with asthma. Further study is needed in the future to clarify whether systemic corticosteroid use for reasons other than asthma is decreasing in subjects with asthma.

In conclusion, about 40% of subjects with asthma at a university hospital received at least 1 dose of systemic corticosteroids for reasons likely other than asthma during follow-up (median, 4.1 years). Clinicians should familiarize themselves with the exposure of their asthma patients to systemic corticosteroids for nonasthma uses, to avoid missing adverse events or underestimation of the severity of asthma, and to reduce the use of systemic corticosteroids.

Statement of Ethics

This research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. This study was approved by the institutional review board at Yokohama City University Hospital (approval no. B200500001). Due to the retrospective nature of this study, the need to obtain written informed consent was waived.

Conflict of Interest Statement

K. Watanabe received research grants and/or lecture fees from AstraZeneca, KYORIN Pharmaceutical Co., Nippon Boehringer Ingelheim, and Novartis. N. Horita has nothing to declare. Y. Hara received research grants and/or lecture fees from AstraZeneca, GlaxoSmithKline, and Novartis. N. Kobayashi received research grants and/or lecture fees from AstraZeneca, GlaxoSmithKline, MSD, Nippon Boehringer Ingelheim, and Novartis. T. Kaneko received research grants and/or lecture fees from AstraZeneca, GlaxoSmithKline, KYORIN Pharmaceutical Co., Nippon Boehringer Ingelheim, and Novartis.

Funding Sources

There is no funding related to this article.

Author Contributions

K.W. contributed to the conception and design of the study; to the collection of patient data; to the analysis and interpretation of the data; and to drafting and finalizing the manuscript. N.H., Y.H., N.K., and T.K. contributed to the interpretation of the data and to finalizing the manuscript. All the authors have read and approved the final manuscript.

Data Availability Statement

Supplementary material.

Supplementary data