Transcript Inhaled corticosteroids in COPD What are we really doing?

Treatment of COPD
What are we really
doing?
Questions
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Is all COPD created equal?
Is there a “right” way to treat my patient?
What are the outcomes I can expect for
my treatments?
Does anything affect mortality in my
patients?
Are there any downsides to treatments?
How do I assess my patient’s prognosis?
Recommended website
Official guidelines
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Global initiative for chronic
obstructive lung disease (GOLD)
www.goldcopd.org
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Pocket guide, Iphone app
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Does your patient have COPD?
Diagnosis of COPD
SYMPTOMS
shortness of breath
chronic cough
sputum
EXPOSURE TO RISK
FACTORS
tobacco
occupation
indoor/outdoor pollution
SPIROMETRY: Required to establish
diagnosis
© 2015 Global Initiative for Chronic Obstructive Lung Disease
Spirometry refresher:
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FEV1; amount of air that can be exhaled in
1 second
FVC total amount of air that can be
exhaled in one breath
Most patients should be able to exhale
>70% of their vital capacity in one second.
If they can’t, they have airflow obstruction
and their FEV1/FVC ratio is <70%
Global Strategy for Diagnosis, Management and Prevention of COPD
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
© 2015 Global Initiative for Chronic Obstructive Lung Disease
GOLD risk stratification
based on
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Functional status
Using CAT or MRC scales
 Presence of dyspnea with with normal
ambulation
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Severity of airflow obstruction
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Mild/moderate vs severe
Number of exacerbations
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<2 vs >1 or needing hospitalization
Global Strategy for Diagnosis, Management and Prevention of
COPD
Modified MRC (mMRC)Questionnaire
© 2015 Global Initiative for Chronic Obstructive Lung Disease
Global Strategy for Diagnosis, Management and Prevention of COPD
GOLD 3
A
GOLD 2
GOLD 1
ICS + LABA
or
and
LAMA
LAMA
SAMA prn
LABA
or
or
SABA prn
LAMA
CAT < 10
mMRC 0-1
D
B
CAT > 10
mMRC > 2
© 2015 Global Initiative for Chronic Obstructive Lung Disease
2 or more
or
> 1 leading
to hospital
admission
1 (not leading
to hospital
admission)
0
Exacerbatoins
C
GOLD 4 ICS + LABA
per yearr
Manage Stable COPD: Pharmacologic Therapy
RECOMMENDED FIRST CHOICE
Global Strategy for Diagnosis, Management and
Prevention of COPD
Combined Assessment
of COPD
When assessing risk, choose the highest risk
according to GOLD grade or exacerbation history.
One or more hospitalizations for COPD
exacerbations should be considered high risk.)
Patient
Characteristic
A
Spirometric
Classification
Exacerbations
per year
CAT
mMRC
Low Risk
Less Symptoms
GOLD 1-2
≤1
< 10
0-1
B
Low Risk
More Symptoms
GOLD 1-2
≤1
> 10
>2
C
High Risk
Less Symptoms
GOLD 3-4
>2
< 10
0-1
D
High Risk
More Symptoms
GOLD 3-4
>2
> 10
© 2015 Global Initiative for Chronic Obstructive Lung Disease
>2
Modified Stepwise Approach to
Treatment
MILD
MODERATE
SEVERE
VERY SEVERE
FEV1>80%
FEv1 50-79%
FEV1 30-49%
FEV1<30% or failure
Smoking cessation; Reduce risk factors; Vaccination
Pulmonary Rehab based on functional status
O2
Surgery
Short acting bronchodilators PRN if respiratory symptoms
Long acting bronchodilators
ICS, if freq. exac (≥ 2/yr.)
Azithromycin/roflumilast/NAC
Available Drugs
SABA
Albuterol
Levalbuterol
LABA
Salmeterol
Formoterol
Beta-2 agonists
SAMA
Arformoterol
Olodaterol
Vilanterol
Ipratropium
Antimuscarinics
LAMA
Tiotropium
Aclidinium
Umeclidinium
Budesonide
Fluticasone
Mometasone
Roflumilast
Theophylline
azithromycin
ICS
PDEI
BUT, ALL COPD IS NOT
CREATED EQUAL!
Obstructive Diseases
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Asthma: functional dx
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Emphysema: anatomic dx
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Reversible airflow obstruction
Inflammation prominent
Permanent obstruction
Destruction of the
respiratory bronchioles and
alveoli
Chronic Bronchitis:
symptomatic dx
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Sputum production 3
months/year for 2 years
Asthma/COPD overlap syndrome
Chronic
bronchitis
emphysema
ACOS
asthma
Asthma/COPD overlap syndrome
(ACOS)
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Adults > 40, usually smokers
May have a h/o childhood asthma
Often have marked variability in symptoms
Partial reversibility of airflow obstruction on
bronchodilator testing
Very little hard data about how to treat this
specific group of patients
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Patients with improvement in FEV1>10% excluded
from most studies
ICS should probably be used earlier
WILL TREATING MY PATIENT
ACCORDING TO GUIDELINES
AFFECT OUTCOME?
GOLD statement
 None of the existing medications for COPD
have been shown to modify the long-term
decline in lung function that is the hallmark of
this disease (Evidence A). Therefore,
pharmacotherapy for COPD is used to
decrease symptoms and/or complications.
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http://www.goldcopd.org
Therapeutic outcomes:
What really makes a difference
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Smoking cessation: all patients should be
encouraged to quit
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Pharmacologic aids improve success
Oxygen therapy in patients with daytime
hypoxemia
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Benefit of oxygen therapy in patients with
exercise desaturation is not known
Oxygen therapy
COT
Cumulative
Survival
(%)
NOT
MRC
O2
MRC
controls
• PaO2 < 55 or
• PaO2 = 56-59
with evidence of
pulmonary
hypertension,
polycythemia or
cor pulmonale
Months
Flenley DC. Chest. 1985;87:99-103
Smoking and COPD
Males
Females
Former
smokers
30 ml/year
22 ml/year
Current
smokers
66 ml/year
54 ml/year
Anthonisen NR, et.al. Am J Respir Crit Care Med 166:675-9, 2002.
Inhaled steroids in COPD
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Possible Benefits
Improvement in lung function
 Decrease in exacerbations
 Improvement in quality of life
 Decrease in lung cancer
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Possible drawbacks
Increased pneumonia
 Cost
 Cataracts
 Osteoporosis
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Do inhaled
corticosteroids
improve pulmonary
function in COPD?
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change in lung function
ISOLDE trial
Randomized double blind placebo controlled
study in 751 pts with moderate to severe COPD
(FEV1 50% pred) over 3 year period
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Excluded pts with >10% change in FEV1 post BD
Included smokers and non-smokers
2 week run in trial with oral prednisone
Treated with fluticasone 500 mcg bid vs placebo
43% withdrew from ICS and 53% from placebo
groups, most commonly for exacerbations
ISOLDE trial
Change in lung function
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No change in rate of decline between ICS
and placebo
Pts treated with ICS had higher FEV1
throughout the study (average of 30cc)
All patients deteriorated when ICS were
withdrawn during run-in phase
Response to oral prednisone didn’t predict
response to ICS
Change in FEV1
No Caption Found
Burge, P S et al. BMJ 2000;320:1297-1303
Copyright ©2000 BMJ Publishing Group Ltd.
TORCH Trial
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6112 pts with moderate to severe COPD
Current or former smokers
 < 10% response to BD
 Followed for 3 years
 44% pts withdrew from placebo, 34% from
tx groups
NEJM
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Randomized to:
2007;356:775
Fluticasone 500 mcg bid alone
 Salmeterol alone
 Fluticasone plus salmeterol combination
 Placebo
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Change in FEV1
TORCH Trial
All therapy arms had an improvement in first 6 months.
Adjusted mean change in FEV1 over 3 years (liters):
- .062 placebo
- .021 Salmeterol
- .015 Fluticasone
+.029 Sal/Flu
All treatment groups statistically better than the next
group, though changes are modest
No difference in rate of decline between the groups.
Change in FEV1
TORCH trial
TORCH study
Mortality data
TORCH Study
Causes of death
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35% pulmonary causes
27% cardiovascular causes
21% cancer
If ICS don’t
dramatically increase
pulmonary function or
survival, what about
quality of life?
ISOLDE trial; fluticasone in moderatesevere COPD
SGRQ data
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Questionnaire designed to specifically evaluate
health status in respiratory disease
Increase in score with worsened health status
Change of > 4 points is considered significant
Placebo pts in ISOLDE trial worsened at a faster
rate than treated pts (3.2 vs 2.0 points/yr
p=.004)
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? Is this clinically significant
Change in health status
No Caption Found
ISOLDE trial
Burge, P S et al. BMJ 2000;320:1297-1303
Copyright ©2000 BMJ Publishing Group Ltd.
TORCH study
change in health status
SGRQ
NEJM 2007;356:775
Change in quality of life in pts with
severe COPD and recurrent
exacerbations
42% SFC vs 30% SAL had
improvement of > 4pts
AJRCCM 2007;175:144
OK, so what can ICS
really do?
TORCH study
Exacerbations
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Yearly exacerbation rate 0.85 combination
therapy vs 1.13 placebo.
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25% reduction corresponds to NTT of 4 pts to
prevent 1 exacerbation/yr
Combination treatment group exacerbation
rate lower than all other groups
Hospitalization rates lower in combination
and salmeterol groups than in placebo (0.16
vs 0.19)
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NTT is 32 to prevent 1 hospitalization/yr
Time to recurrent
exacerbation
AJRCCM 2007;17544
ICS and exacerbations
Meta-analysis
Ann Fam Med 2006;4:253
WHY DO WE CARE ABOUT
EXACERBATIONS?
COPD Exacerbations : Mortality
1016 pts with severe COPD exacerbation
60
(PaCO2 > 50 mm Hg)
49%
50
Mortality (%)
43%
40
33%
30
20%
20
11%
10
0
Hospital
stay
60 days
180 days
1 year
2 years
Connors AF Jr et al. Am J Respir Crit Care Med. 1996;154:959-67
COPD exacerbations: Survival
Probability of surviving
1.0
0.8
No exacerbation
0.6
p<0.001
1–2 exacerbations
0.4
p=0.07
3–4 exacerbations
0.2
0.0
0
10
20
30
40
Time (months)
Soler-Cataluña JJ et al. Thorax. 2005;64:925-31
50
60
p<0.0001
Lung cancer and ICS
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Cohort study of 10,500 veterans with
COPD
Median f/u time 4 years
 423 cases of lung cancer
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20% had been prescribed ICS, only 5%
adherent (517 pts)
Risk adjusted for smoking status, age,
comorbidity, other cancers and BD
AJRCCM
canister use
2007;175:712
Lung cancer and Triamcinolone use
Adjusted Hazard ratio (95% CI)
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Pts on < 1200 mcg/day HR 1.13 (0.67-1.9)
Pts on > 1200 mcg/day HR 0.39 (0.160.96)
Continuous per 100mcg/day HR 0.96
(0.94-1)
Is there something different about the pts
treated with ICS (more asthmatics?)
Is there a delay in dx of lung cancer in ICS
pts if they seek less medical care?
Prospective randomized study would be
useful, but likely not feasible
OK, so what’s the
down side?
Effect of ICS on pneumonia
incidence
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TORCH trial: 19% vs 13% in fluticasone
containing regimens (p<.001)
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No prospective definition of pneumonia
included
Nested case control study 175,000
Canadian COPD pts also found
increased risk of hospitalization for
pneumonia
Risk of hospitalization for
pneumonia with ICS use
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Current ICS user
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Rate ratio 1.7
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High dose ICS
Medium dose ICS
Low dose ICS
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Rate ratio 2.25
Rate ratio 1.63
Rate ratio 1.50
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ARJCCM 2007; 176:162
Risk of cataracts with ICS
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Increased occurrence not seen in prospective
studies
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Population based studies do show association
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May be exposure time too short
Less firm if pts treated with systemic steroids are
excluded
Lifetime dose important
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May not be relevant in most COPD pts
Ann fam med
2006;4:253
Risk of Osteoporosis with ICS
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Some decrease in bone mineral density,
particularly associated with triamcinolone
use
Risk of fractures does not appear to be
increased in prospective studies
Cochrane review
2007:CD002991
ICS in COPD
Drawbacks
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Pneumonia rate may be increased
May be a dose related phenomenon
 Is benefit preserved with lower doses?
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Cost/benefit ratio is not well defined
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Particularly in combination with LABD
Cataracts and increased fractures
probably not an issue in this specific pt
population
Conclusions
Benefits of ICS in COPD
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High dose ICS may improve lung function
and quality of life, but effects are small
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Exacerbation rate appears to be reduced,
particularly with more severe disease
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Pulmonary function may decline if ICS are
abruptly withdrawn
Would this have a mortality effect in larger study?
Is it outweighed by pneumonia incidence?
Benefit may be better in patients with
bronchodilator response (ACOS) since they
were excluded from studies
Lung cancer rate may be reduced
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Prospective data are needed
WHAT ABOUT
ANTICHOLINERGIC
(ANTIMUSCARINIC) AGENTS?
Tiotropium
Delays Next
Exacerbation/
Hospitalization
Niewoehner, D. E. et. al. Ann Intern Med 2005;143:317-326
Cardiac Risk, Ipratroprium, Tiotropium
Better tolerated than beta-agonists
 Meta-analysis - increased CV deaths in
patients on anti-muscarinics
 UPLIFT - 4 yr trial - decreased fatal
cardiovascular event risk with Tiotropium
 Clinical trial safety database
Tiotropium – no increased risk

Celli. Am J Respir Crit Care Med. 2009;180(10):948
Celli. Chest. 2010;137(1)20
Antimuscarinic agents:
conclusion
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They seem to reduce exacerbation rate.
Likely do NOT increase cardiovascular risk
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May reconsider risk in patients with unstable
cardiovascular disease
Long acting agents (LAMAs); tiotropium,
aclidinium, umeclidinium should NOT be
used with atrovent
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Competition for receptors may reduce efficacy
What about long acting beta
agonists (LABA)?
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Beware the black box!
Increased risk of death associated LABA
use found only in asthmatics
Do not need to be combined with inhaled
steroids (ICS) in COPD patients

Still, patients will ask about it, and it may be
difficult to use LABAs without ICS
OK; MY PATIENT IS ON 3
DIFFERENT INHALERS AND
STILL MISERABLE. IS THERE
ANYTHING ELSE?
Theophilline
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Positive effects for COPD
Stimulate respiratory center
 May improve diaphragmatic function
 Anti-inflammatory
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Negative effects for COPD
Increases GERD
 Narrow therapeutic window
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Cardiac tachyarrhthmias
Significant drug-drug interactions
Roflumilast
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Unknown exact mechanism
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Selectively inhibits phosphodiesterase Type 4
leading to increased intracellular cAMP
Decreases exacerbations in patients with
chronic bronchitis
Use with caution in liver disease,
depression (suicide)
N-acetyl cysteine (NAC) and
exacerbation rates
Lancet resp medicine 2014:
187
Azithromycin
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Randomized controlled trial of 1142
patients with COPD either on oxygen or
with exacerbation during the last year had
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Decreased exacerbation rate
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NNT to prevent exacerbation 2.86
Mild improvement in QOL
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43% VS 36% had improvement>4pts in SGRQ
Colonization with macrolide resistant bacteria
found on f/u treatment
 Pts with prolonged QT or hearing impairment
excluded
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Possible worsening in hearing in treated pts
Proportion of Participants Free from Acute Exacerbations of
Chronic Obstructive Pulmonary Disease (COPD) for 1 Year,
According to Study Group.
Albert RK et al. N Engl J Med 2011;365:689-698.
Pulmonary rehabilitation
programs
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Decrease symptoms of dyspnea and
fatigue
Improve exercise tolerance and quality of
life
Decrease hospitalization rates
Do not affect rate of decline in FEV1
The longer the program is, the more
benefit
Continued exercise at home afterwards
increases benefit
Lung volume reduction
surgery (LVRS)
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Greatest benefit in patients with upper
lobe predominant emphysema and low
exercise capacity
7.9% 90 day mortality vs 1.9% control
28% had improved exercise capacity at 6
months

15% at 2 years
NETT. NEJM 2003: 348:2059-73
Endobronchial valve
placement
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Designed to cause progressive lobar
collapse; non-operative lung volume
reduction
In selected patients improved FEV1, 6mwt
and QOL at 6 months
Lots of adverse events; ptx, displacement
of valve, need for removal
Small study ?? Ready for “prime time”
Nejm 2015;
373:2325
Lung Transplant
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Age <=65
Maximal medical therapy
Have undergone pulmonary rehab
Body weight 80-120% of ideal
Favorable social factors
Costly
5 year mortality 50%
Lung Transplant
Contraindications
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Untreatable pulmonary infection
Malignancy within last 2 years
Significant dysfunction of other organs (heart)
Significant chest wall/spine deformity
Active smoking/drug and alcohol dependency
Unresolved psychosocial problems
(noncompliance)
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Need dedicated care giver to travel with them to
transplant center
HIV, Hep B, Hep C
Acute Exacerbation
Classification
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Level 1: Treatment at home
Level 2: Hospitalization
Clinical Factors Favoring Hospitalization
HR, RR, change in BP
Hypoxia/ hypercapnea
Significant comorbidities
Elderly
Poor home support
Inadequate outpatient
response
ER Visit in last 2 weeks

Level 3: ICU/Specialized Care
Acute Exacerbation
Treatment
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Oxygen for low saturations
Bronchodilators

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Steroids 14 day max
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MDI vs nebulizer
IV vs Oral
Improves spirometry, decreases relapse rate and
length of stay
No study on taper; 40 mg x5 days recommended
by GOLD
Education; MDI use
Antibiotics
Antibiotics in acute
exacerbation
 Indicated for
 Increased
sputum volume
 Increased purulence
 In
patients who require
mechanical ventilation
Antibiotics and Survival

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Retrospective cohort
of 50K COPD pts in
Netherlands
Median time to next
exacerbation
delayed
More benefit in
worse exacerbations
Fewer treatment
failures with newer
Abx
Roede et al. Thorax 2008: 63:968
NIPPV in Acute Exacerbations
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If pH<7.35, if tolerated
Decreases symptoms/
LOS/ mortality
Avoid in:

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CV instability,
Uncooperative patient,
ΔMS,
Copious secretions, high
aspiration risk,
Facial abnormalities
How long will my patient live?
PROGNOSTICATION IN COPD
BODE index for COPD
survival prediction

FEV1

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50-64% 1 point
36-49% 2 points
<35% 3 points
6MWT distance

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Dyspnea

Need to stop on level
ground:


1 point
Walking 100 yards:

2 points
250-349 M 1 point
 Breathless with ADLs:
150-249 M 2 points
 3 points
< 149 M
3 points  BMI <21: 1 point
Bode inex; 4 year survival
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0-2 points:
3-4 points:
5-6 points:
7-10 points:
80%
67%
57%
18%
Summary

Prevention is key
Smoking cessation
 Vaccinations, early treatment of
exacerbations



Only oxygen and smoking cessation
improve mortality
Stepwise treatment with:
Short acting bronchodilators
 Long acting bronchodilators
 Inhaled steroids
To reduce symptoms and exacerbations

Summary

Inhaled corticosteroids may be associated
with increased pneumonia risk




Patients may deteriorate if ICS are withdrawn
abruptly
Pulmonary rehab should be used in
symptomatic patients
COPD exacerbations portend a poor
prognosis
Consider transplant or LVRS in selected
patients
The
REAL
reason
dinosaurs
became
extinct...