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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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Outline• Introduction•Materials and methods•Results•Discussion•Conclusion

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Introduction

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Chronic Obstructive Pulmonary Disease (COPD)

•Chronic inflammation of bronchial tree causing major mortalities and disabilities

•Persistent decline of lung function

Ref: Am J Respir Crit Care Med. 2013;187:347-365

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Pharmacologic Management of COPD

Ref: Am J Respir Crit Care Med. 2013;187:347-365

ICS/LABA: improve lung function and health statusPossibly reduce the frequency of acute exacerbation (AE) and mortality

More severe

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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

pneumoniaRef: Cochrane Database Syst Rev. 2014, Lancet. 2009;374(9691):712.

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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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What Recent Cohort Studies Said?

Ref: PLoS One. 2014; 9(5): e97149. Ref: Thorax 2013;68:1029-1036.

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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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Medicine 94(42):e1723Impact factor: 2.133 Ranking: 40/155、 25.8%

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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?

Ref: Journal of Food and Drug Analysis, Vol 15, No. 2, 2007, Pages 99-108

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Materials and MethodsThe Institutional Review Board of Taipei Medical University approved the study (TMU REC: 201503024)

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Two Parts of the Study

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, 496A-code A325

ICD-9-CM: the International Classification of Diseases, 9th revesion, clinical modification

COPD-specific medications:Corticosteroids, long or short actingBeta-agonists, anti-cholinergics, aminophylline

AE: emergency department visits or admissions with COPD diagnoses and prescription of systemic corticosteroids

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Definition of Pneumonia

Pneumonia

Chest radiography

Prescriptions

Diagnosis ICD-9-CM codes 480-486 and

A-codes A321Pneumonia-specific antibioticsSystemic beta-lactams and/or beta-lactamase inhibitors, fluoroquinolones, macrolides, and carbapenems.

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Co-Morbidities• Malignancy• Diabetes mellitus• End stage renal disease (ESRD)• Liver cirrhosis• Autoimmune diseases• Pneumoconiosis• Acquired immunodeficiency syndrome• Organ transplantation• Low-income status

Ref: Chest. 2015;147:520-528.

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Statistical AnalysisAll analyses were performed using SAS (SAS Institute Inc., Cary,NC, USA)

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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

Ref: 1. WHO Collaborating Centre for Drug Statistics Methodology. Guidelines for ATC classification and DDD assignment 2015. Oslo; 20142. Eur Respir J. 2008;31:143–178.

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First Part (COPD Cohort)First COPD Dx

First AEAS the enrollment date

During 365 days from enrollment date to index dateCalculate 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 period1. age, co-morbidities2. Prescribed medications

Using time-dependent Cox proportional hazards modelSignificance for entry and stay were set at 0.15. Statistical significance was set at a 2-sided P<0.05.

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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

ICS use ICS Discontinuation

3 months 3 months 3 months

Calculate and compare the incidence rate of pneumonia by pairted t test

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Results

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Characteristics of the COPD Pts with AE

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Factors Predicting the Development of Pneumonia

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ICS Cohort

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The Impact of ICS Use on Pneumonia Events

On average, prescribing ICS for9.1 (1/[0.21–0.10]) person-years increased 1 pneumonia event.

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Discussion

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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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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.

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.

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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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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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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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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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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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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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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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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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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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The 2017 GOLD Report

Hightlighted boxes and arrows: preferred treatment pathways

As ICS increases the risk for developing pneumoniaIn 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

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Future Works

Other side

effects

COPD

ICS

Ex:CataractsOsteoporosis

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Thank you for listening