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1
Update on COPD & Asthma Guidelines
Michael C. Peters, M.D. MAS
Division of Pulmonary & Critical Care Medicine
Cardiovascular Research Institute
University of California San Francisco
UCSF Primary Care Internal Medicine
San Francisco, CA
October 18, 2019
Disclosures
• NHLBI - Asthma Clinical Research Network
• NHLBI – Severe Asthma Research Program
• NHLBI- Precise Network
2
Update on the Management of COPD
What is COPD
• Disease state characterized by airflow limitation
that is not fully reversible*
– Post-Bronchodilator FEV1/FVC <0.7
• Generally caused by cigarette smoke
– Biomass fuels (developing world)
– α1-antitypsin deficiency
– Pollution, chronic infection
• Bronchiectasis, cystic fibrosis are not included
in the definition
3
Rate of Deaths per 100,000 in
the USA 2005-2011
Heart Disease
Cancer
COPD/Chronic respiratory
Rate
Year2005 2006 2007 2008 2009 2010 2011
Cancer Death by Site
Lung 85,920 (27%)
Prostate 26,120 (8%)
Colorectal 26,020 (8%)
Pancreas 21,450 (7%)
Liver 18,280 (6%)
MENLung 72,120 (26%)
Breast 40,450 (14%)
Colorectal 23,170 (8%)
Pancreas 20,330 (7%)
Ovary 14,240 (5%)
WOMEN
American Cancer Society 2016
4
Simel and RennieEvidence-based Clinical DiagnosisMcGraw Hill, 2008GOLD 2019
•CHRONIC Obstructive Pulmonary Disease
• NEED SPIROMETRY: FEV1/FVC < 0.70
Spirometry and COPD
Simel and RennieEvidence-based Clinical DiagnosisMcGraw Hill, 2008GOLD 2019
•CHRONIC Obstructive Pulmonary Disease
• NEED SPIROMETRY: FEV1/FVC < 0.70
Spirometry and COPD
Definition Has Limitations
5
Original Article
Clinical Significance of Symptoms in Smokers with Preserved Pulmonary Function
N Engl J MedVolume 374(19):1811-1821
May 12, 2016
Observational study 2734 current and former smokersand controls who never smoked
Examined whether current or former smokers withpreserved lung function had symptoms or suffered COPD exacerbations
Respiratory Symptoms Smokers with Normal Pulmonary Function
Woodruff PG et al. N Engl J Med 2016;374:1811-1821
Symptom Scores
6
Prevalence of Symptoms and Risk of Respiratory Exacerbations
Woodruff PG et al. N Engl J Med 2016;374:1811-1821
- Patient First
- Spirometry helps confirm diagnosis
- No benefit to spiro “screening”
- No symptoms no need
Spirometry and COPD (Take
Home Point)
Anthonisen JAMA 1994
Qaseen, Ann Int Med 2011
USPTF JAMA 2016
GOLD 2019
7
COPD Assessment Goals
• Diagnosis
– Exposure History
– Airflow Limitation (confirmation)
• Determine Severity (Patient First)
– Symptoms
• Cough, sputum production, Dyspnea, Exacerbations
• Co-morbidities
– CVD, skeletal muscle dysfunction, metabolic
syndrome, lung cancer screening
GOLD Criteria
Risk
GO
LD
Cla
ssif
icat
ion
of A
irfl
ow L
imit
atio
n
(C) (D)
(B)(A)
4
3
2
1
≥2 or
1
0
Risk
Exac
erb
atio
n H
isto
ry
mMRC 0-1CAT < 10
mMRC ≥ 2CAT ≥10Symptoms
(mMRC or CAT score)
When assessing risk, choose the highest risk according to GOLD grade or exacerbation history
Patient Category
Characteristics Spirometric Classification
Exacerbations per year
mMRC CAT
A Low Risk, Less Symptoms GOLD 1-2 ≤1 0-1 <10
B Low Risk, More Symptoms GOLD 1-2 ≤1 ≥2 ≥10
C High Risk, Less Symptoms GOLD 3-4 ≥2 0-1 <10
D High Risk, More Symptoms GOLD 3-4 ≥2 ≥2 ≥10
GOLD Guidelines 2019
≥1 leading to hospital admission
(no hospital admission)
8
Risk
GO
LD
Cla
ssif
icat
ion
of A
irfl
ow L
imit
atio
n(C) (D)
(B)(A)
4
3
2
1
≥2 or
1
0
Risk
Exac
erb
atio
n H
isto
ry
mMRC 0-1CAT < 10
mMRC ≥ 2CAT ≥10Symptoms
(mMRC or CAT score)
When assessing risk, choose the highest risk according to GOLD grade or exacerbation history
GOLD Guidelines 2019
≥1 leading to hospital admission
(no hospital admission)
Take Home
• Don’t fear GOLD
• Treat the patient
– Symptoms
– Exacerbations
– Spirometry for confirmation
9
Bronchodilator Options• Short
– SABA (Short Acting Beta Agonist)– Albuterol
– SAMA (Short Acting Muscarinic Antagonists)– Ipratropium
• Long
– LABA (Long Acting Beta Agonist)– Formoterol (Symbicort)
– Salmetrol (Advair)
– Indacaterol (Arcapta)
– Vilanterol (Breo)
– LAMA (Long Acting Muscarinic Antagonists)– Tiotroprium (Spiriva)
– Umeclidinium (Incruse Ellipta)
– Glycopyrronium (Seebri)
Interventional Options• Smoking Cessation
– Ask
– Assess
– Assist
• Pulmonary Rehab
– Most important following an exacerbation
• Vaccinations
– Influenza
– Pneumococcal
10
Additional Options• Inhaled Corticosteroids (ICS)
• Azithromycin
• Phosodiesterase-4 inhibitor (Roflumilast)
What treatment is the most
effective for preventing COPD
exacerbations?
A) Roflumilast
B) Pulmonary Rehab
C) Duel LAMA + LABA
D) Azithromycin
11
Treat The Patient!!!
• Improve Symptoms
• Prevent Progressive Loss of Lung Function
• Prevention of Acute Exacerbations
Hospitalized Severe AECOPD and Mortality:Severity of AECOPD
1- no AECOPD 2- AECOPD ED
N = 305 men with COPDx 5 years
Soler-Cataluna Thorax 2005
3- AECOPD Hosp4- AECOPD Readmit
12
Predictors of Acute Exacerbations of
COPD
Number of Exacerbations
≥2 vs. 0 1 vs. 0
Odds Ratio (95% CI) Odds Ratio (95% CI)
Exacerbation in Prior Year 5.7 (4.5-7.3) 2.2 (1.8-2.8)
FEV1 per 100ml decrease 1.1 (1.08-1.1) 1.1 (1.0-1.1)
SGRC (symptom score) per 4
points
1.1 (1.0-1.1) 1.1 (1.0 – 1.1)
GERD 2.1 (1.6-2.7) 1.6 (1.2-2.1)
WBC Count 1.1 (1-1.1) 1.1 (1.0-1.1)
Hurst NEJM 2010
Prevention of AECOPDRecommendations
• Influenza Vaccine (Grade 1B)
• Pulmonary Rehab (Grade 1C)
• Smoking Cessation (Grade 2C)
• Pneumococcal Vaccine (Grade 2C)
Criner et al. CHEST 147:894-942, 2015
Non-Pharmacologic Treatments/Vaccinations:
13
Pulmonary Rehab
Effects of interventions
Admission to hospital
Five studies involving 250 patients contributed data on admis-
sionsto hospital. Therewasasignificant reduction in theoddsof
hospital re-admission (OR 0.22; 95% CI 0.08 to 0.58; I2=51%)
(Behnke2000; Eaton 2009; Man 2004; Murphy 2005; Seymour
2010; Figure2) with aNNT of 4 (95% CI 3 to 8) Figure3. The
follow-up period for these studies ranged from 3 to 18 months,
with amean duration of 25 weeks. In onetrial (Eaton 2009) there
wasalargediscrepancy between theintention-to-treat and theper-
protocol analysisbecauseonly 19 (40%) patientsassigned to early
rehabilitation satisfied theapriori definition of adherence(atten-
danceat 75% of rehabilitation sessions). Repeatingthemeta-anal-
ysis using the per-protocol data of that trial did not change the
resultsof themeta-analysissignificantly (OR 0.19; 95% CI 0.09
to 0.39, fivestudies, N = 222) but did reduceheterogeneity (I2=
0%).
Figure 2. Forest plot of comparison: 1 Rehabilitation versus control, outcome: 1.1 Hospital admission (to
end of follow-up).
7Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Puhan Cochrane Database 2011
Pulmonary Rehab
Effects of interventions
Admission to hospital
Five studies involving 250 patients contributed data on admis-
sionsto hospital. Therewasasignificant reduction in theoddsof
hospital re-admission (OR 0.22; 95% CI 0.08 to 0.58; I2=51%)
(Behnke2000; Eaton 2009; Man 2004; Murphy 2005; Seymour
2010; Figure2) with aNNT of 4 (95% CI 3 to 8) Figure3. The
follow-up period for these studies ranged from 3 to 18 months,
with amean duration of 25 weeks. In onetrial (Eaton 2009) there
wasalargediscrepancy between theintention-to-treat and theper-
protocol analysisbecauseonly 19 (40%) patientsassigned to early
rehabilitation satisfied theapriori definition of adherence(atten-
danceat 75% of rehabilitation sessions). Repeatingthemeta-anal-
ysis using the per-protocol data of that trial did not change the
resultsof themeta-analysissignificantly (OR 0.19; 95% CI 0.09
to 0.39, fivestudies, N = 222) but did reduceheterogeneity (I2=
0%).
Figure 2. Forest plot of comparison: 1 Rehabilitation versus control, outcome: 1.1 Hospital admission (to
end of follow-up).
7Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Pulmonary
Rehab
Control Odds Ratio
Subject 124 126
Total Event 20 51 0.22 (0.08-
0.58)
Puhan Cochrane Database 2011
14
Pulmonary Rehab
Effects of interventions
Admission to hospital
Five studies involving 250 patients contributed data on admis-
sionsto hospital. Therewasasignificant reduction in theoddsof
hospital re-admission (OR 0.22; 95% CI 0.08 to 0.58; I2=51%)
(Behnke2000; Eaton 2009; Man 2004; Murphy 2005; Seymour
2010; Figure2) with aNNT of 4 (95% CI 3 to 8) Figure3. The
follow-up period for these studies ranged from 3 to 18 months,
with amean duration of 25 weeks. In onetrial (Eaton 2009) there
wasalargediscrepancy between theintention-to-treat and theper-
protocol analysisbecauseonly 19 (40%) patientsassigned to early
rehabilitation satisfied theapriori definition of adherence(atten-
danceat 75% of rehabilitation sessions). Repeatingthemeta-anal-
ysis using the per-protocol data of that trial did not change the
resultsof themeta-analysissignificantly (OR 0.19; 95% CI 0.09
to 0.39, fivestudies, N = 222) but did reduceheterogeneity (I2=
0%).
Figure 2. Forest plot of comparison: 1 Rehabilitation versus control, outcome: 1.1 Hospital admission (to
end of follow-up).
7Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Pulmonary
Rehab
Control Odds Ratio
Subject 124 126
Total Event 20 51 0.22 (0.08-
0.58)
Number Needed to Treat = 4!!!! CI 3-8Puhan Cochrane Database 2011
• LAMA vs PBO (Grade 1A)
• LABA vs PBO (Grade 1B)
• LAMA vs LABA (Grade 1C)
• COMBO Therapy vs MonoTherapy (Grade
1B,C)
Criner et al. CHEST 147:894-942, 2015GOLD 2019
Maintenance Inhaled Therapy:
Prevention of AECOPDRecommendations
15
A Word on ICS and COPD
• Modest Reduction in Exacerbation Rate
• Small (insignificant improvement in FEV1)
• Established Link to Pneumonia
• No Mortality Benefit
• Efficacy in COPD is very ControversialYang Cochrane 2012Caverly NEJM 2007Celli AJRCCM 2008
FLAME TRIAL
• LAMA + ICS = Good
• LABA + ICS = Good
16
FLAME TRIAL
• LAMA + ICS = Good
• LABA + ICS = Good
ICS risk of Pneumonia?
FLAME TRIAL
• LAMA + ICS = Good
• LABA + ICS = Good
• LABA + LAMA = ?
ICS risk of Pneumonia?
17
FLAME TRIAL
• LAMA + ICS = Good
• LABA + ICS = Good
• LABA + LAMA = ?
LABA (indacaterol) + LAMA (glycopyrronium) QDay
LABA (salmeterol) + ICS (fluticasone) BID
VS.
Wedzicha JA et al. N Engl J Med 2016;374:2222-2234
18
Wedzicha JA et al. N Engl J Med 2016;374:2222-2234
NNT = 9
Wedzicha JA et al. N Engl J Med 2016;374:2222-2234
Wedzicha JA et al. N Engl J Med 2016;374:2222-2234
19
• Macrolide (Grade 2A)
(Frequent AECOPD despite Tx)
• Systemic Corticosteroids (Grade 2B)
(For AECOPD – prevent next 30 days)
• Roflumilast (Grade 2A)
(Chr Bronchitis, ≥1 AECOPD in year)
Criner et al. CHEST 147:894-942, 2015
Oral Therapy:
Prevention of AECOPDRecommendations
NEJM 365:689-98, 2011
20
• NHLBI – COPD Clinical Research Network
• N = 1130
• Moderately-severe COPD
FEV1/FVC < 70%; FEV1 <80%
• “Exacerbation Prone”
• Primary Outcome: Time to first AECOPD
The MACRO Study(Azithromycin 250mg/day x 1 year)
NEJM 365:689-98, 2011
Rates of Acute Exacerbations of Chronic Obstructive Pulmonary Disease per Person-Year, According to Study Group.
Albert RK et al. NEJM 2011
Macrolides Decrease AECOPD
NNT=15
21
Ray WA et al. N Engl J Med 2012;366:1881-1890
Ray WA et al. NEJM 2012
Macrolides May Increase risk of
Cardiovascular Death
• Macrolides can prolong QT and QTc leading to
arrhythmias, including torsades de pointes
• Most arrhythmias with macrolides occur in patients
with underlying risk factors
• Incidence of arrhythmias in absence of additional
risk factors is very low, perhaps 1 in 100,000.
Mosholder, NEJM 2013
Am J Respir Crit Care Med2014; 189:1173-1180
22
“Macrolide-associated arrhythmias can be reduced by
not prescribing to patients with comorbidities of
concern…the majority of which can be discovered by:
• History
• ECG before initiating therapy
• ECG a short time after initiating therapy”
Am J Respir Crit Care Med2014; 189:1173-1180
Ray WA et al. N Engl J Med 2012;366:1881-1890
Roflumilast
• Oral Tablet
• 500 ug Once Daily
• Phosphodiesterase-4 Inhibitor
Martinez et al. Lancet 2015
• 1 year trial
• 40 years old, >20 pack years, +COPD
• FEV1% predicted<50%
• Symptoms of chronic bronchitis, +cough and sputum
• “Exacerbation Prone”
• ICS + LABA
23
Ray WA et al. N Engl J Med 2012;366:1881-1890
Roflumilast
Martinez et al. Lancet 2015
Ray WA et al. N Engl J Med 2012;366:1881-1890
Roflumilast
Martinez et al. Lancet 2015NNT=25 NNH=16
24
Summary of Treatments for COPD
Exacerbation Prevention
• Pulmonary Rehab (NNT=4)
• Duel Long Acting Bronchodilator Medications
over ICS + LABA (NNT=9)
• Azithromycin prevents COPD Exacerbations
(NNT=15)
– Potential Risk of Cardiac Arrhythmias
• Roflumilast offers some benefit in bronchitis
patients (NNT=25), (NNH=16)
Pulmonary Rehabilitation
• Benefits all levels of disease severity
• Reduces respiratory symptoms
• Reduces anxiety and depression
• Reduces medical and hospital usage
• Improves exercise performance
• Improves quality of life
• Is typically provided as outpatient
• Can be initiated as an inpatient until functional
ability has improved
2015 Cochrane Review, McCarthy
25
Update on the Management of Asthma
Definition of Asthma (Clinical)
• Epidemiological: Questionnaires
– Diagnosed with asthma by a physician and wheeze
in past 12 months
– Diagnosed with asthma by a physician and
currently taking asthma medications
• Clinical:
– Intermittent Airflow Obstruction + Symptoms
• + Bronchodilator Response (200ml +12%)
• + Methacholine Challenge test (PC 20 vs. Resistance)
26
Epidemiology
• 250-300 million people have asthma globally
• Asthma rates have been increasing in
low/middle income countries (caught up)
• Most of the morbidity/mortality from asthma
stems from the 5-10% with severe disease
Asthma Prevalence in USA 2001-10
CDC
27
EPR-3, NHLBI, 2011
* Off-label; data only with budesonide-formoterol (bud-form)
† Off-label; separate or combination ICS and SABA inhalers
PREFERRED
CONTROLLER
to prevent exacerbations
and control symptoms
Other controller options
Other reliever option
PREFERRED
RELIEVER
STEP 2
Daily low dose inhaled corticosteroid (ICS),
or as-needed low dose ICS-formoterol *
STEP 3
Low dose
ICS-LABA
STEP 4
Medium dose
ICS-LABA
Leukotriene receptor antagonist (LTRA), or
low dose ICS taken whenever SABA taken †
As-needed low dose ICS-formoterol *
As-needed short-acting β2 -agonist (SABA)
Medium dose
ICS, or low dose
ICS+LTRA #
High dose ICS, add-on
tiotropium, or add-on LTRA #
Add low dose
OCS, but
consider
side-effects
As-needed low dose ICS-formoterol ‡
Box 3-5A
Adults & adolescents 12+ years
Personalized asthma management:
Assess, Adjust, Review response
Asthma medication options:
Adjust treatment up and down for
individual patient needs
STEP 5
High dose
ICS-LABA
Refer for
phenotypic
assessment
± add-on
therapy,
e.g.tiotropium,
anti-IgE,
anti-IL5/5R,
anti-IL4R
Symptoms
Exacerbations
Side-effects
Lung function
Patient satisfaction
Confirmation of diagnosis if necessary
Symptom control & modifiable
risk factors (including lung function)
Comorbidities
Inhaler technique & adherence
Patient goals
Treatment of modifiable risk factors & comorbidities
Non-pharmacological strategies
Education & skills training
Asthma medications
1© Global Initiative for Asthma, www.ginasthma.org
STEP 1
As-needed
low dose
ICS-formoterol *
Low dose ICS
taken whenever
SABA is taken†
‡ Low-dose ICS-form is the reliever for patients prescribed bud-form or BDP-form maintenance and reliever therapy
# Consider adding HDM SLIT for sensitized patients withallergic rhinitis and FEV >70%predicted
* Off-label; data only with budesonide-formoterol (bud-form)
† Off-label; separate or combination ICS and SABA inhalers
PREFERRED
CONTROLLER
to prevent exacerbations
and control symptoms
Other controller options
Other reliever option
PREFERRED
RELIEVER
STEP 2
Daily low dose inhaled corticosteroid (ICS),
or as-needed low dose ICS-formoterol *
STEP 3
Low dose
ICS-LABA
STEP 4
Medium dose
ICS-LABA
Leukotriene receptor antagonist (LTRA), or
low dose ICS taken whenever SABA taken †
As-needed low dose ICS-formoterol *
As-needed short-acting β2 -agonist (SABA)
Medium dose
ICS, or low dose
ICS+LTRA #
High dose ICS, add-on
tiotropium, or add-on LTRA #
Add low dose
OCS, but
consider
side-effects
As-needed low dose ICS-formoterol ‡
Box 3-5A
Adults & adolescents 12+ years
Personalized asthma management:
Assess, Adjust, Review response
Asthma medication options:
Adjust treatment up and down for
individual patient needs
STEP 5
High dose
ICS-LABA
Refer for
phenotypic
assessment
± add-on
therapy,
e.g.tiotropium,
anti-IgE,
anti-IL5/5R,
anti-IL4R
Symptoms
Exacerbations
Side-effects
Lung function
Patient satisfaction
Confirmation of diagnosis if necessary
Symptom control & modifiable
risk factors (including lung function)
Comorbidities
Inhaler technique & adherence
Patient goals
Treatment of modifiable risk factors & comorbidities
Non-pharmacological strategies
Education & skills training
Asthma medications
1© Global Initiative for Asthma, www.ginasthma.org
STEP 1
As-needed
low dose
ICS-formoterol *
Low dose ICS
taken whenever
SABA is taken†
‡ Low-dose ICS-form is the reliever for patients prescribed bud-form or BDP-form maintenance and reliever therapy
# Consider adding HDM SLIT for sensitized patients withallergic rhinitis and FEV >70%predicted
* Off-label; data only with budesonide-formoterol (bud-form)
† Off-label; separate or combination ICS and SABA inhalers
PREFERRED
CONTROLLER
to prevent exacerbations
and control symptoms
Other controller options
Other reliever option
PREFERRED
RELIEVER
STEP 2
Daily low dose inhaled corticosteroid (ICS),
or as-needed low dose ICS-formoterol *
STEP 3
Low dose
ICS-LABA
STEP 4
Medium dose
ICS-LABA
Leukotriene receptor antagonist (LTRA), or
low dose ICS taken whenever SABA taken †
As-needed low dose ICS-formoterol *
As-needed short-acting β2 -agonist (SABA)
Medium dose
ICS, or low dose
ICS+LTRA #
High dose ICS, add-on
tiotropium, or add-on LTRA #
Add low dose
OCS, but
consider
side-effects
As-needed low dose ICS-formoterol ‡
Box 3-5A
Adults & adolescents 12+ years
Personalized asthma management:
Assess, Adjust, Review response
Asthma medication options:
Adjust treatment up and down for
individual patient needs
STEP 5
High dose
ICS-LABA
Refer for
phenotypic
assessment
± add-on
therapy,
e.g.tiotropium,
anti-IgE,
anti-IL5/5R,
anti-IL4R
Symptoms
Exacerbations
Side-effects
Lung function
Patient satisfaction
Confirmation of diagnosis if necessary
Symptom control & modifiable
risk factors (including lung function)
Comorbidities
Inhaler technique & adherence
Patient goals
Treatment of modifiable risk factors & comorbidities
Non-pharmacological strategies
Education & skills training
Asthma medications
1© Global Initiative for Asthma, www.ginasthma.org
STEP 1
As-needed
low dose
ICS-formoterol *
Low dose ICS
taken whenever
SABA is taken†
‡ Low-dose ICS-form is the reliever for patients prescribed bud-form or BDP-form maintenance and reliever therapy
# Consider adding HDM SLIT for sensitized patients withallergic rhinitis and FEV >70%predicted
28
Exacerbation ReductionSide Effects
- Pneumonia?- Thrush- Cost
ICS Formulations
• MDI: Metered Dose Inhalers
– Aerosol
– Theoretically achieves more distal
distribution (small airways), ciclesonide
– Flovent
• DPI: Dry Powder Inhalers
– No propellant
– Easier to use
– Less systemic absorption
29
ICS Toxicity
Placebo
Beclomethasone
Budesonide
Flunisolide
Fluticasone MDI
Triamcinolone
Fluticasone DPI
Martin AJRCCM 2002
30
Reducing ICS Toxicity
• Wash Mouth with water, GARGLE
• Spacer (MDI)
• Step down dosage
• Build Patient Trust
– PRN Dosage
Take Home
• ICS remain the mainstay therapy for
Asthma
• Improved appreciation of side effects
• Reassess and Step Down
32
Called patients“Do you have asthma”?
SpirometryPre/Post BD
PositiveAsthma Confirmed
Called patients“Do you have asthma”?
SpirometryPre/Post BD
Methacholine
PositiveAsthma Confirmed
PositiveAsthma Confirmed
33
Called patients“Do you have asthma”?
SpirometryPre/Post BD
Methacholine
Methacholine
Stop All Meds
PositiveAsthma Confirmed
PositiveAsthma Confirmed
PositiveAsthma Confirmed
Called patients“Do you have asthma”?
SpirometryPre/Post BD
Methacholine
Methacholine
Stop All Meds
PositiveAsthma Confirmed
PositiveAsthma Confirmed
MethacholineOr worse symptoms
12 Month Follow up
PositiveAsthma Confirmed
No Asthma
Positive Asthma Confirmed
34
What percentage of patients
had no asthma?
A) 0-10%
B) 10-20%
C) 30-40%
D) 40-50%
E) >50%
Black Box Warning
• Data from a large placebo-controlled U.S. study that
compared the safety of salmeterol or placebo added
to usual asthma therapy showed a small but
significant increase in asthma-related deaths in
patients receiving salmeterol (13 deaths out of
13,176 patients treated for 28 weeks) versus those
on placebo (3 of 13,179)".
35
Original Article
Serious Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone
NEJM 2016
Adolescent and adult patients >12 years
with persistent asthma were randomized to ICS (fluticasone) vs ICS + LABA (salmeterol) for 26 weeks
All patients had a history of a severe asthma exacerbation in the past year
Primary Safety End Point (Intention-to-Treat Population).
Stempel DA et al. N Engl J Med 2016;374:1822-1830
36
Summary of Safety End Points.
Stempel DA et al. N Engl J Med 2016;374:1822-1830
Haldar AJRCCM 2008
Asthma Phenotypes
38
Patients(%)
FEV1 Percent Change From Baseline
30
25
20
15
10
5
0<-30 -30 to
<-20-20 to<-10
-10 to<0
0 to<10
10 to<20
20 to<30
40 to<50
5030 to<40
Beclomethasone (n=246)
Montelukast (n=375)
Patients (≥15 Years) Not Controlled on PRN Beta-Agonists
FEV1: Distribution of Individual Patient Responses
Malmstrom et al.Ann Intern Med. 130:487-495, 1999
A Large Subgroup of Mild-to-Moderate Asthma
Is Persistently Noneosinophilic (NON Allergic)
• Asthma is a heterogeneous disease
• ~50% of asthmatics – poor response to steroids
• Eosinophilic airway inflammation not ubiquitous
McGrath et al (ACRN)
Am J Respir Crit Care Med 185:612–619, 2012
Sputum Eosinophil Percentage (No ICS)
39
Eosinophilia Predicts ICS Response
McGrath et al (ACRN)
Am J Respir Crit Care Med 185:612–619, 2012
• N=135, prednisone x ≥6 months, eosinophils >300
41
Type-2 Inhibitors for Severe Asthma
• Anti IgE Agents
– Omalizumab (Xolair)*
• Anti IL-5 Agents
– Mepolizumab (NUCALA)*
– Resilizumab (CINQAIR)*
– Benralizumab (FASENRA)*
• Anti IL-4/IL-13
– Dupilumab*
• Anti CRTH2
– Feviviprant* FDA Approved
Is There Really A
Difference Between
Asthma And COPD?
42
Pathophysiology in
COPD versus Asthma
Asthma• Inflammation
• Bronchial hyperresponsiveness
• Varying airway obstruction
COPD
• Loss of elastic recoil
• Changes in small airways
• “Inflammation”
• Fixed airway obstruction
Inflammation in
COPD versus Asthma
Calverley, Barnes. AJRCCM 2000; 161:341-344
COPD AsthmaPredominant Cells
Macrophages EosinophilsNeutrophils Activated Mast Cells
CD-8 T-Lymphocytes CD-4 T Lymphocytes
Predominant CytokinesInterleukin 8 Interleukin 4
Leukotriene B4 Interleukin 5Tumor Necrosis Factor alpha Interleukin 13
43
COPD Asthma Overlap
IN COPD
Postma DS, Rabe KF .N Engl J Med 2015; 373: 1241-1249
Asthma Summary
• ICS remain foundation of Asthma Management
– No more SABA alone, PRN ICS OK
• Optimize methods to reduce size effects
• LABAs are safe in asthma patients
• Not all Asthma is the Same
– “Th2-High” or Allergic Asthma responds to corticosteroids
– “Th2-Low” or Non-Allergic Asthma less responsive
• New Medications are here for Severe Allergic
Asthma