分享老師的研究發表

1. Inhaled Corticosteroids Increase the Risk of
Pneumonia in Patients with Chronic Obstructive
Pulmonary Disease A National Cohort Study
加護病房查房日誌
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2. Outline
• Introduction
• Materials and methods
• Results
• Discussion
• Conclusion
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3. Introduction
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4. Chronic Obstructive Pulmonary Disease (COPD)
• Chronic inflammation of bronchial tree causing
major mortalities and disabilities
• Persistent decline of lung function
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Ref: Am J Respir Crit Care Med. 2013;187:347-365

5. Pharmacologic Management of COPD
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Ref: Am J Respir Crit Care Med. 2013;187:347-365
ICS/LABA: improve lung function and health status
Possibly reduce the frequency of acute exacerbation (AE) and mortality
More severe

6. Long-Term Safety of ICS
• Increase the risk of pneumonia
▫ Controversial
• Meta-analysis, 2014
▫ Fluticasone: odds ratio (OR) 1.78 (95 % CI 1.5-2.12)
▫ Budesonide: OR 1.62 (95 % CI 1.0-2.62)
• Meta-analysis, 2009
▫ Budesonide is not associated with increased risk of
pneumonia
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Ref: Cochrane Database Syst Rev. 2014, Lancet. 2009;374(9691):712.

7. Why Discrepancy?
• Different study designs and definition of pneumonia
among individual clinical trial
• Pneumonia is simply an adverse event, not a primary
endpoint
• A large cohort study may be more suitable than
available meta-analyses to understand this issue.
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8. What Recent Cohort Studies Said?
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Ref: PLoS One. 2014; 9(5): e97149. Ref: Thorax 2013;68:1029-1036.

9. However…
• None of these studies
▫ Control the confounding effect of COPD severity
• The severity of COPD and the dose of each drug may
vary with time
▫ A time-dependent approach is a more suitable
statistical method.
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10. 10
Medicine 94(42):e1723
Impact factor: 2.133 Ranking: 40/155、25.8%

11. Taiwan National Health Insurance Research
Database (NHIRD)
Strength Weakness
• Large sample size
▫ 97% of Taiwan’s population
• Relatively inexpensive
• Real-world practice
▫ Medical service utilization
▫ Prescription drug use
• Longitudinal histories
• Over-the-counter drugs?
• A secondary database
• Lag time
• Disease severity?
▫ Surrogate data
• Laboratory data?
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Ref: Journal of Food and Drug Analysis, Vol 15, No. 2, 2007, Pages 99-108

12. Materials and Methods
The Institutional Review Board of
Taipei Medical University approved
the study (TMU REC: 201503024)
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13. Two Parts of the Study
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Follow up until pneumonia developed,
Dec 31st, 2007 or lost to follow up
Continuous use:
No interruption for more than 30 days
COPD: ICD-9-CM codes 491, 492, 496
A-code A325
ICD-9-CM: the International Classification of Diseases, 9th revesion, clinical modification
COPD-specific medications:
Corticosteroids, long or short acting
Beta-agonists, anti-cholinergics, aminophylline
AE: emergency department visits or
admissions with COPD diagnoses and
prescription of systemic corticosteroids

14. Definition of Pneumonia
Pneumonia
Chest
radiography
Prescriptions Diagnosis
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ICD-9-CM codes 480-486 and
A-codes A321
Pneumonia-specific antibiotics
Systemic beta-lactams and/or
beta-lactamase inhibitors,
fluoroquinolones, macrolides,
and carbapenems.

15. Co-Morbidities
• Malignancy
• Diabetes mellitus
• End stage renal disease (ESRD)
• Liver cirrhosis
• Autoimmune diseases
• Pneumoconiosis
• Acquired immunodeficiency syndrome
• Organ transplantation
• Low-income status
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Ref: Chest. 2015;147:520-528.

16. Statistical Analysis
All analyses were performed using
SAS (SAS Institute Inc., Cary,
NC, USA)
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17. Dose Calculation
• The prescription duration of individual drugs
▫ The defined daily doses(DDDs)
• ICS
▫ an equivalent dose of budesonide 800 μg
• Systemic corticosteroids
▫ Prednisolone in mg
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Ref:
1. WHO Collaborating Centre for Drug Statistics Methodology. Guidelines for ATC classification and DDD assignment 2015. Oslo; 2014
2. Eur Respir J. 2008;31:143–178.

18. First Part (COPD Cohort)
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First COPD Dx
First AE
AS the enrollment date
During 365 days from enrollment date to index date
Calculate the baseline frequency AE and pneumonia
events
Index date Follow up pneumonia or not
Record the co-morbidities
1996 2007
Time-dependent variables from 120 to 30 days
before the end of each period
1. age, co-morbidities
2. Prescribed medications
Using time-dependent Cox proportional hazards model
Significance for entry and stay were set at 0.15.
Statistical significance was set at a 2-sided P<0.05.

19. ICS Cohort
• To ensure pts in a relatively stable condition either
before or after treatment modification, and to avoid
the potential confounding effects lasting from
previous status
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ICS use ICS Discontinuation
3 months 3 months 3 months
Calculate and compare the incidence rate of pneumonia by pairted t test

20. Results
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21. Characteristics of the COPD Pts with AE
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22. Factors Predicting the Development of Pneumonia
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23. ICS Cohort
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24. The Impact of ICS Use on Pneumonia Events
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On average, prescribing ICS for
9.1 (1/[0.21–0.10]) person-
years increased 1 pneumonia
event.

25. Discussion
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26. Major Important Findings
• The use of ICS has an independent and dose-
dependent effect of increasing the risk of pneumonia
▫ After controlling for COPD severity and time-
dependent analysis
• The incidence rate of pneumonia increases during
ICS use and has a decreasing trend after ICS
discontinuation
▫ While the incidence rate of AE continues to decrease
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27. ICS for COPD Patients
• GOLD guidelines: ICS/LABA for group C or D patients
• Short- and long-term side effects?
• A Higher risk of pneumonia while using ICS
▫ TOwards a Revolution in COPD Health (TORCH)
▫ Investigating New Standards for Prophylaxis in
Reducing Exacerbations (INSPIRE)
• Some studies demonstrate the opposite.
27
Ref: 1. N Engl J Med. 2007;356:775–789. 2. Am J Respir Crit Care Med. 2008;177:19–26. 3. Drugs. 2008;68:1975–2000. 4. Drugs. 2009;69:549–565. 5.
Am J Respir Crit Care Med. 2009;180:741–750.

28. Data from Meta-Analyses
• Not all meta-analyses have the same conclusions
▫ Combined 43 randomized controlled trials
 Budesonide: OR 1.62, 95 % CI 1.0-2.62
 Fluticasone: OR 1.78, 95 % CI 1.50-2.12
• Reasons of the discrepancy
▫ Pneumonia: adverse event report from clinical trials
 Not every pneumonia confirmed by chest radiography and
microbiologic data
 TORCH (72 %), INSPIRE (58 %)
▫ Heterogeneous of study design
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29. Retrospective Cohort Studies
• Lack of randomization
• But
▫ Much larger patient numbers
▫ Some patients with underlying co-morbidities
 Excluded in clinical trials
• Real-world situation
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30. Data form Observational Studies
• The impact of ICS on the risk of pneumonia in COPD
patients
▫ Estimated relative risk: 1.11 to 3.26
▫ Some showed a positive dose-response relationship
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31. Limitations from Those Studies
• Without judicious control of the severity of COPD
▫ Overestimated
▫ ICS usually for severely impaired lung function
 Higher risk of respiratory tract infection
• The dose of ICS is averaged in a certain period and
arbitrarily categorized into 2 or 3 levels
▫ In the real-world, it could vary with time
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32. Strengths of Our Studies-1
• The first study
▫ Investigating the impact of ICS on the risk of
pneumonia by using time-dependent variables
 The dynamic characteristics of COPD severity and
medications
• Surrogates for controlling COPD severity
▫ Baseline pneumonia events
▫ Baseline and recent frequency of AE
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33. Strengths of Our Studies-2
• The first study
▫ Providing longitudinal data on the incidence rate of
pneumonia and AE before, during and after ICS use
 AE decreases gradually
 Pneumonia increases significantly during ICS use
 Consistent with current knowledge
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34. Other Factors
• Baseline pneumonia event, recent frequency of AE,
and oral aminophylline use
▫ Increased the risk of pneumonia
▫ Those may correlate with the severity of COPD
• Aging, DM, malignancy, low-income and oral
corticosteroid use
▫ Immunosuppression
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35. Limitations of Our Studies
• Retrospective claims data
▫ The diagnoses of COPD and its severity, as well as
pneumonia
 Surrogate indicators: baseline AE, pneumonia
• Without some possible confounding factors
▫ Ex: nutritional status
• Real-world findings
▫ Could be applied to the majority of COPD patients
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36. Conclusion
• This study demonstrates the association between ICS
use and pneumonia in patients with COPD and
history of AE.
• ICS should be judiciously used in indicated COPD
patients.
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37. The 2017 GOLD Report
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Hightlighted boxes and arrows: preferred treatment pathways
As ICS increases the risk for developing pneumonia
In some patients, our primary choice is LABA/LAMA
Group D patients are at higher risk of developing pneumonia
when receiving treatment with ICS
Ref: Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. Available from: http://goldcopd.org

38. Future Works
Other
side
effects
COPD
ICS
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Ex:
Cataracts
Osteoporosis

39. Thank you for listening
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