SHORT-TERM VS CONVENTIONAL

GLUCOCORTICOID THERAPY IN ACUTE EXACERBATIONS

OF COPD

Melanie Mier PGY4

COPD A common, preventable and treatable

disease Characterized by persistent airflow

limitation that is usually progressive associated with an enhanced chronic

inflammatory response in the airways and the lung to noxious particles or gases

Exacerbations and comorbidities contribute to the overall severity in individual patients

Mechanisms Underlying Airflow Limitation in COPD

Small Airways Disease• Airway inflammation• Airway fibrosis, luminal

plugs• Increased airway

resistance

Parenchymal Destruction• Loss of alveolar

attachments• Decrease of elastic recoil

AIRFLOW LIMITATION

Burden of COPD

COPD is a leading cause of morbidity and mortality worldwide.

The burden of COPD is projected to increase in coming decades due to continued exposure to COPD risk factors and the aging of the world’s population.

COPD is associated with significant economic burden.

Risk factors for COPD

Aging Populations

Genes

Infections

Socio-economic status

SYMPTOMS

chronic coughshortness of breath

EXPOSURE TO RISKFACTORS

tobaccooccupation

indoor/outdoor pollution

SPIROMETRY: Required to establish diagnosis

Diagnosis of COPD

è

sputum

presence of a post-bronchodilator FEV1/FVC < 0.70 confirms the presence of persistent airflow limitation and

thus of COPD

Symptoms

Dyspnea: Progressive, persistent and characteristically worse with exercise.

Chronic cough: May be intermittent and may be unproductive.

Chronic sputum production: COPD patients commonly cough up sputum.

Spirometry: Obstructive Disease

Volu

me,

liters

Time, seconds

5

4

3

2

1

1 2 3 4 5 6

FEV1 = 1.8L

FVC = 3.2L

FEV1/FVC = 0.56

Normal

Obstructive

© 2014 Global Initiative for Chronic Obstructive Lung Disease

COPD flow loop

Classification of Severity of Airflow Limitation in COPD*

In patients with FEV1/FVC < 0.70:

GOLD 1: Mild FEV1 > 80% predicted

GOLD 2: Moderate 50% < FEV1 < 80% predicted

GOLD 3: Severe 30% < FEV1 < 50% predicted

GOLD 4: Very Severe FEV1 < 30% predicted

*Based on Post-Bronchodilator FEV1

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Therapeutic Options: COPD Medications

Beta2-agonists

Short-acting beta2-agonists

Long-acting beta2-agonists

Anticholinergics

Short-acting anticholinergics

Long-acting anticholinergics

Combination short-acting beta2-agonists + anticholinergic in one inhaler

Combination long-acting beta2-agonists + anticholinergic in one inhalerMethylxanthines

Inhaled corticosteroids

Combination long-acting beta2-agonists + corticosteroids in one inhaler

Systemic corticosteroids

Phosphodiesterase-4 inhibitors© 2014 Global Initiative for Chronic Obstructive Lung Disease

Treatment Bronchodilator medications are central to symptomatic

management of COPD The principal bronchodilator treatments are

beta2-agonists, anticholinergics, theophylline or combination therapy

Long-acting inhaled bronchodilators reduce exacerbations and related hospitalizations and improve symptoms and health status.

Regular treatment with inhaled corticosteroids improves symptoms, lung function and quality of life and reduces frequency of exacerbations for COPD patients with an FEV1 < 60% predicted

Treatment An inhaled corticosteroid combined with a long-

acting beta2-agonist is more effective than the individual components in improving lung function and health status and reducing exacerbations in moderate to very severe COPD

Addition of a long-acting beta2-agonist/inhaled glucorticosteroid combination to an anticholinergic (tiotropium) appears to provide additional benefits

Chronic treatment with systemic corticosteroids should be avoided because of an unfavorable benefit-to-risk ratio

Exacerbation

An acute event characterized by worsening of the patients respiratory symptoms that is beyond normal day to day variations and leads to a change in medication

Risk of exacerbation

Two or more exacerbations within the last year or an FEV1 < 50 % of predicted value are indicators of high risk.

One or more hospitalizations for COPD exacerbation should be considered high risk.

Impact on symptoms

and lungfunction

Negativeimpact on

quality of life

Consequences Of COPD Exacerbations

Increasedeconomic

costs

Acceleratedlung function

decline

IncreasedMortality

EXACERBATIONS

© 2014 Global Initiative for Chronic Obstructive Lung Disease

Most common causes of COPD exacerbations are viral URIs and infection of the tracheobronchial tree

Diagnosis relies exclusively on clinical presentation of the patient

Goal of treatment is to minimize the impact of the current exacerbation and prevent future exacerbations

Exacerbation assessments ABG: PaO2 < 8.0 kPa with or with out PaCO2 >

6.7 kPa when breathing room air indicates respiratory failure.

CXR: exclude alternative diagnosis EKG: may aid in diagnosis of coexisting cardiac

problem CBC: identify polycythemia, anemia, or bleeding Purulent sputum during exacerbation: indication to

begin empirical antibiotic treatment Biochemical tests: detect electrolyte disturbances,

diabetes, and poor nutrition Spirometry: not recommended during an exacerbation

Treatment Oxygen: titrate to improve the patients hypoxemia

with a target saturation of 88-92% Bronchodilators: Short acting inhaled beta2

agonists with or without short acting anticholinergics Systemic Corticosteroids: shorten recovery time,

improve lung function and arterial hypoxemia and reduce the risk of early relapse, treatment failure, and length of hospital stay. A dose of 40mg of prednisone a day for 5 days is recommended

Antibiotics: given to patients with increased dyspnea, increased sputum volume, and increased sputum purulence or who require mechanical ventilation

Indications for hospitalization Marked increased in intensity of

symptoms Onset of new physical signs Failure of an exacerbation to respond to

initial medical management Presence of serious comorbidities Frequent exacerbations Older age Insufficient home support

Steroids

shorten recovery time, improve lung function and arterial hypoxemia and reduce the risk of early relapse, treatment failure, and length of hospital stay.

A dose of 40mg of prednisone a day for 5 days is recommended??

REDUCE Randomized clinical trial Tested the hypothesis that in patients

presenting to the ED with acute exacerbation of COPD, a 5 day course of systemic glucocorticoid treatment would not result in an inferior clinical outcome compared with conventional 14 day treatment, but would significantly decrease glucocorticoid exposure and reduce untoward effects

Why care about steroids? Long term use of glucocorticoids is in an

independent risk factor for increased mortality in COPD

Given the adverse effect of glucocorticoids and the potentially large number of exacerbations occurring in patients with COPD, glucocorticoid exposure should be minimized

Adverse effects of glucocorticoids

Design From March 2006 through February

2011 consecutive patients with exacerbated COPD were screened for eligibility at ED of 5 Swiss hospitals

Inclusion criteria: exacerbation of COPD as defined by 2 of the following:Change in baseline dyspnea, cough, or

sputum quality or purulenceAge older than 40 yearsSmoking history of 20 pack years or more

Exclusion criteria: History of asthmaFEV1/FVC greater than 70% as evaluated

by bedside post-bronchodilator spirometry prior to randomization

Radiological diagnosis of pneumoniaEstimated survival of less than 6 mos due to

severe comorbidityPregnancy or lactationInability to give written consent

Study Drugs, Randomization,and Masking

Randomly assigned either 5 or 14 days of systemic glucocorticoids using a centralized secured study website

Used a computer generated randomization list based onAge stratified blocks of 6Presence or absence of systemic

glucocorticoid treatment prior to studySeverity of COPD according to the GOLD

classification

All patients received 40mg of IV methylprednisolone on day 1

Followed by 40mg of oral prednisone daily from day 2-5

From day 6 to 14 patients received 40mg oral prednisone or matching placebo once daily

Patients, caregivers, outcome assessors, data collectors, the biostatistician and all other investigators remained blinded

All patients received a broad spectrum antibiotic for 7 daysAn inhaled, nebulized short acting bronchodilator

4-6 times prn while inpatient Inhaled glucocorticoids twice daily combined

with inhaled Beta agonist twice daily plus tiotropium once daily

CPT, supplemental O2, and ventilation used as needed

Additional steroids could be given at discretion of physician

End points assessed daily during hospitalization and on days 6, 15, 30, 90, and 180

End points Primary endpoint:

time to next COPD exacerbation during a follow up of 6 months (during index exacerbation or during follow up)

Secondary endpoints:All cause mortalityChange in FEV1Cumulative glucocorticoid doseClinical performance (questionnaire)

Assessed length of hospital stay and severity Assessed glucocorticoid associated adverse events:

New or worsening hyperglycemiaNew or worsening HTNNew infectionOther potentially related adverse events

Statistical Analysis Modified Delphi technique to define non-inferiority regarding

primary endpoint 11 board certified specialists who defined a 15% absolute

difference in the percentage of patients with a re-exacerbation during the 6 month follow up period as the clinically tolerable upper limit

According to the non-inferiority definition the true proportion of patients under experimental treatment experiencing a COPD exacerbation must not exceed 65% Translate to critical hazard ratio of 1.515 based on n exponential

proportional hazards survival model Differences in time to next exacerbation or time to death were

assessed using Kaplan-Meier method in combination with the log rank test and Cox proportional hazards model.

Non-inferiority was concluded if the 2 sided 90% confidence interval for the HR between the short term and the conventional treatment group in an intention to treat and per protocol analysis was below 1.515.

Primary endpoint Time to re-exacerbation did not differ

between groups Figure 2

The HR of re-exacerbation between the short term and conventional treatment group was 0.95 in intention to treat and 0.93 in the per-protocol analysis, meeting the non-inferiority criteria

Median time to re-exacerbation was was 43.5 days in the short term group and 29 days in the conventional group

Estimates of re-exacerbation rates were 37.2% in the short term and 38.4% in the conventional group

Secondary end points

Overall survival did not differ between the groups

Figure 3

Table 3

During hospital stay there was no difference in the requirement for mechanical ventilation.

Shortterm treatment group had shorter hospital stay by 1 day (8 vs 9)

Short term group had mean cumulative dose of 379mg and conventional group mean of 793mg

New or worsened hyperglycemia was observed in 74 pts in short term and 74 in conventional group

HTN developed or worsened in 15 pts in the short term group and 23 pts in the conventional group

No differences in infection rates or other potentially glucocorticoid related adverse effects like GI bleed, insomnia, fractures, psychiatric sx, or heart failure

Limitations No standard glucocorticoid regimen for treatment of

COPD exacerbations at time of trial design All patients were treated with inhaled long acting beta

agonists, glucocorticoids and tiotropium – overtreatment Less HTN in short term treatment patients, difference

was not significant Focused on hyperglycemia and HTN during

hospitalization, too short of time period to really assess these

All patients received antibiotics regardless of sputum purulence

Most patients had severe or very severe COPD All patients were current or past smokers

Final summary of results

A 5 day glucocorticoid treatment course was non-inferior to a 14 day course in respect to re-exacerbation during a 6 month follow up

No significant difference in recovery of lung function and disease related symptoms but shorter course resulted in a significantly reduce glucocorticoid exposure

References Leuppi, J, Schuetz P. Short-term vs conventional

glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease. JAMA. 2013;309(21):2223-2231.

Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of COPD. http://www.goldcopd.org/guidelines/guidelines-resources.htm

http://www.hindawi.com/journals/ije/2012/485376.fig.002.jpg

Google

And now, the statistics discussion…

Hazard Ratios

What is hazard? What is a hazard ratio?How is hazard different from relative risk?How can it be interpreted?

Hazard

h(t)- “the probability that an individual who is under observation at a time (t) has an event at that time”

Hazard Ratios

“A measure of how often a particular event happens in one group compared to how often it happens in another group, over time. Hazard ratios are often used in clinical trials to measure survival at any point in time in a group of patients who have been given a specific treatment compared to a control group given another treatment or a placebo.”

Interpretation

“A hazard ratio of one means that there is no difference in survival between the two groups. A hazard ratio of greater than one or less than one means that survival was better in one of the groups.”

HR= 1HR= 0.5HR= 2

Resources

http://www.medicine.ox.ac.uk/bandolier/painres/download/whatis/what_are_haz_ratios.pdf

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC478551/pdf/1409-03.pdf

http://www.cancer.gov/dictionary?cdrid=618612

http://www.youtube.com/watch?v=z1b2hFzXsrU