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Inhaled Corticosteroids Increase the Risk of
Pneumonia in Patients with Chronic Obstructive
Pulmonary Disease A National C...
Outline
• Introduction
• Materials and methods
• Results
• Discussion
• Conclusion
2
Introduction
3
Chronic Obstructive Pulmonary Disease (COPD)
• Chronic inflammation of bronchial tree causing
major mortalities and disabi...
Pharmacologic Management of COPD
5
Ref: Am J Respir Crit Care Med. 2013;187:347-365
ICS/LABA: improve lung function and he...
Long-Term Safety of ICS
• Increase the risk of pneumonia
▫ Controversial
• Meta-analysis, 2014
▫ Fluticasone: odds ratio (...
Why Discrepancy?
• Different study designs and definition of pneumonia
among individual clinical trial
• Pneumonia is simp...
What Recent Cohort Studies Said?
8
Ref: PLoS One. 2014; 9(5): e97149. Ref: Thorax 2013;68:1029-1036.
However…
• None of these studies
▫ Control the confounding effect of COPD severity
• The severity of COPD and the dose of ...
10
Medicine 94(42):e1723
Impact factor: 2.133 Ranking: 40/155、25.8%
Taiwan National Health Insurance Research
Database (NHIRD)
Strength Weakness
• Large sample size
▫ 97% of Taiwan’s populat...
Materials and Methods
The Institutional Review Board of
Taipei Medical University approved
the study (TMU REC: 201503024)
...
Two Parts of the Study
13
Follow up until pneumonia developed,
Dec 31st, 2007 or lost to follow up
Continuous use:
No inte...
Definition of Pneumonia
Pneumonia
Chest
radiography
Prescriptions Diagnosis
14
ICD-9-CM codes 480-486 and
A-codes A321
Pne...
Co-Morbidities
• Malignancy
• Diabetes mellitus
• End stage renal disease (ESRD)
• Liver cirrhosis
• Autoimmune diseases
•...
Statistical Analysis
All analyses were performed using
SAS (SAS Institute Inc., Cary,
NC, USA)
16
Dose Calculation
• The prescription duration of individual drugs
▫ The defined daily doses(DDDs)
• ICS
▫ an equivalent dos...
First Part (COPD Cohort)
18
First COPD Dx
First AE
AS the enrollment date
During 365 days from enrollment date to index da...
ICS Cohort
• To ensure pts in a relatively stable condition either
before or after treatment modification, and to avoid
th...
Results
20
Characteristics of the COPD Pts with AE
21
Factors Predicting the Development of Pneumonia
22
ICS Cohort
23
The Impact of ICS Use on Pneumonia Events
24
On average, prescribing ICS for
9.1 (1/[0.21–0.10]) person-
years increased 1...
Discussion
25
Major Important Findings
• The use of ICS has an independent and dose-
dependent effect of increasing the risk of pneumoni...
ICS for COPD Patients
• GOLD guidelines: ICS/LABA for group C or D patients
• Short- and long-term side effects?
• A Highe...
Data from Meta-Analyses
• Not all meta-analyses have the same conclusions
▫ Combined 43 randomized controlled trials
 Bud...
Retrospective Cohort Studies
• Lack of randomization
• But
▫ Much larger patient numbers
▫ Some patients with underlying c...
Data form Observational Studies
• The impact of ICS on the risk of pneumonia in COPD
patients
▫ Estimated relative risk: 1...
Limitations from Those Studies
• Without judicious control of the severity of COPD
▫ Overestimated
▫ ICS usually for sever...
Strengths of Our Studies-1
• The first study
▫ Investigating the impact of ICS on the risk of
pneumonia by using time-depe...
Strengths of Our Studies-2
• The first study
▫ Providing longitudinal data on the incidence rate of
pneumonia and AE befor...
Other Factors
• Baseline pneumonia event, recent frequency of AE,
and oral aminophylline use
▫ Increased the risk of pneum...
Limitations of Our Studies
• Retrospective claims data
▫ The diagnoses of COPD and its severity, as well as
pneumonia
 Su...
Conclusion
• This study demonstrates the association between ICS
use and pneumonia in patients with COPD and
history of AE...
The 2017 GOLD Report
37
Hightlighted boxes and arrows: preferred treatment pathways
As ICS increases the risk for developi...
Future Works
Other
side
effects
COPD
ICS
38
Ex:
Cataracts
Osteoporosis
Thank you for listening
39
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Inhaled Corticosteroids Increase the Risk of Pneumonia in Patients with Chronic Obstructive Pulmonary Disease A National Cohort Study

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Inhaled Corticosteroids Increase the Risk of Pneumonia in Patients with Chronic Obstructive Pulmonary Disease A National Cohort Study

  1. 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 1
  2. 2. Outline • Introduction • Materials and methods • Results • Discussion • Conclusion 2
  3. 3. Introduction 3
  4. 4. Chronic Obstructive Pulmonary Disease (COPD) • Chronic inflammation of bronchial tree causing major mortalities and disabilities • Persistent decline of lung function 4 Ref: Am J Respir Crit Care Med. 2013;187:347-365
  5. 5. Pharmacologic Management of COPD 5 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. 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 6 Ref: Cochrane Database Syst Rev. 2014, Lancet. 2009;374(9691):712.
  7. 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. 7
  8. 8. What Recent Cohort Studies Said? 8 Ref: PLoS One. 2014; 9(5): e97149. Ref: Thorax 2013;68:1029-1036.
  9. 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. 9
  10. 10. 10 Medicine 94(42):e1723 Impact factor: 2.133 Ranking: 40/155、25.8%
  11. 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? 11 Ref: Journal of Food and Drug Analysis, Vol 15, No. 2, 2007, Pages 99-108
  12. 12. Materials and Methods The Institutional Review Board of Taipei Medical University approved the study (TMU REC: 201503024) 12
  13. 13. Two Parts of the Study 13 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. 14. Definition of Pneumonia Pneumonia Chest radiography Prescriptions Diagnosis 14 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. 15. Co-Morbidities • Malignancy • Diabetes mellitus • End stage renal disease (ESRD) • Liver cirrhosis • Autoimmune diseases • Pneumoconiosis • Acquired immunodeficiency syndrome • Organ transplantation • Low-income status 15 Ref: Chest. 2015;147:520-528.
  16. 16. Statistical Analysis All analyses were performed using SAS (SAS Institute Inc., Cary, NC, USA) 16
  17. 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 17 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. 18. First Part (COPD Cohort) 18 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. 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 19 ICS use ICS Discontinuation 3 months 3 months 3 months Calculate and compare the incidence rate of pneumonia by pairted t test
  20. 20. Results 20
  21. 21. Characteristics of the COPD Pts with AE 21
  22. 22. Factors Predicting the Development of Pneumonia 22
  23. 23. ICS Cohort 23
  24. 24. The Impact of ICS Use on Pneumonia Events 24 On average, prescribing ICS for 9.1 (1/[0.21–0.10]) person- years increased 1 pneumonia event.
  25. 25. Discussion 25
  26. 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 26
  27. 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. 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 28
  29. 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 29
  30. 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 30
  31. 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 31
  32. 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 32
  33. 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 33
  34. 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 34
  35. 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 35
  36. 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. 36
  37. 37. The 2017 GOLD Report 37 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. 38. Future Works Other side effects COPD ICS 38 Ex: Cataracts Osteoporosis
  39. 39. Thank you for listening 39

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