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. 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. 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. 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
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
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. Materials and Methods
The Institutional Review Board of
Taipei Medical University approved
the study (TMU REC: 201503024)
12
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
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. 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. 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
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. 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
28
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. 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. 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. 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. 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. 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. 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. 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. 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