update on copd & asthma disclosures - ucsf · pdf file2 to review copd • copd is a...

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Update on COPD & Asthma

Michael C. Peters, M.D. MASDivision of Pulmonary & Critical Care Medicine

Cardiovascular Research InstituteUniversity of California San Francisco

UCSF Primary Care MedicineSan Francisco, CAJune 24, 2016

Disclosures

• No Pharma Disclosures

• NHLBI - Asthma Clinical Research Network

• NHLBI – Severe Asthma Research Program

Update on the Management of COPD

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To review COPD• COPD is a leading cause of death worldwide, and

mortality is increasing

• Exacerbations are the major complication of COPD•Associated with increased loss of lung function•And Mortality

• There are effective strategies for decreasing exacerbations

• COPD = Inflammatory Disease

• O2 therapy

• Pharmacologic Therapy: - More than symptoms -- Decreasing exacerbations- Change natural history?

•Pulmonary Rehab: reduces symptoms, depression, health care utilization; improves Q of L, exercise

COPD

• Smoking Cessation modifies natural history(lung function, mortality)

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Question #1: Which of the following is NOT true?A. COPD mortality has plateauedB. Hospitalization for exacerbation

predicts mortalityC. Most exacerbations are caused by

infectionD. There are effective strategies for

decreasing exacerbations

C O PD m

o r ta l i t

y h as p l

a t . ..

H o sp i t a

l i z at i o n

f o r e x a

c e . ..

M os t e

x a ce r b

a t i on s a

r e .. .

T h er e a

r e ef f e c

t i v e s t r

a t e. . .

74%

4%17%

4%

Percent Change in Age-Adjusted Death Rates (US, 1965–1998)

Proportion of 1965 Rate

0.00.51.01.5

2.02.53.0

1965 – 1998 1965 – 1998 1965 – 1998 1965 – 1998 1965 – 1998–59% –64% –35% +163% –7%

CHD Stroke Other CVD COPD All othercauses

Hey Doc, Do I Have COPD????

Simel and RennieEvidence-based Clinical DiagnosisMcGraw Hill, 2008

•CHRONIC Obstructive Pulmonary Disease• NEED SPIROMETRY: FEV1/FVC < 0.70

Hey Doc, Do I Have COPD????

Simel and RennieEvidence-based Clinical DiagnosisMcGraw Hill, 2008

•CHRONIC Obstructive Pulmonary Disease• NEED SPIROMETRY: FEV1/FVC < 0.70

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Respiratory Symptoms Smokers with Normal Pulmonary Function

Woodruff PG et al. N Engl J Med 2016;374:1811-1821

Symptom Scores

Prevalence of Symptoms and Risk of Respiratory Exacerbations

Woodruff PG et al. N Engl J Med 2016;374:1811-1821

Anthonisen et alJAMA 272:1497-505, 1994

• No benefit of screening adults with no symptoms

• No evidence that treating asymptomatic individuals prevents future symptoms, or reduces the subsequent decline in lung function.

Qaseen, Ann Int Med 155:179-91, 2011USPTF JAMA 2016

• Other: – Proteases/inflammation– Repetitive bacterial/viral infections – Genetics, especially α1-antitrypsin deficiency

NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease. April 2001; (Updated 2003).American Thoracic Society Statement Statement. Am J Respir Crit Care Med. 1995;152(suppl 5):S77-S120.

Risk Factors for COPD

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Give it to me Straight. Is it BAD?

GOLD Guidelines 2007

GOLD 1: (Mild COPD) FEV1 > 80% predictedFEV1/FVC < 0.70

GOLD 2: (Moderate COPD) FEV1 50-80% predictedGOLD 3: (Severe COPD) FEV1 30-50% predictedGOLD 4: (Very Severe COPD) FEV1 <30% predicted

GOLD 2007N = 2164 stable COPDN = 337 “Healthy Smokers”N = 245 Never Smokers

Characterized Extensively at:Baseline3, 6, 12, 18, 24, 30, 36 months

Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points

(ECLIPSE)Eur Respir J 2008; 31:869-73

2007 Gold Guidelines Not Good EnoughRespir Res 2010; 11:122

Agusti Respir Res 2010; 11:122Symptom Scores

Respir Res 2010; 11:122

Agusti Respir Res 2010; 11:122

2007 Gold Guidelines Not Good Enough

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COPD Assessment: A New ModelRisk

GOLD

Clas

sifica

tion

of A

irflow

Lim

itatio

n

(C) (D)

(B)(A)

4

3

2

1

≥2 or

1

0

Risk

Exace

rbatio

n Hist

ory

mMRC 0-1CAT < 10 mMRC ≥ 2

CAT ≥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 <10B Low Risk, More Symptoms GOLD 1-2 ≤1 ≥2 ≥10C High Risk, Less Symptoms GOLD 3-4 ≥2 0-1 <10D High Risk, More Symptoms GOLD 3-4 ≥2 ≥2 ≥10


≥1 leading to hospital admission(no hospital admission)

Risk

GOLD

Clas

sifica

tion

of A

irflow

Lim

itatio

n

(C) (D)

(B)(A)

4

3

2

1

≥2 or

1

0

Risk

Exace

rbatio

n Hist

ory

mMRC 0-1CAT < 10 mMRC ≥ 2

CAT ≥10Symptoms(mMRC or CAT score)

When assessing risk, choose the highest risk according to GOLD grade or exacerbation history


≥1 leading to hospital admission(no hospital admission)

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

Question #2:Which of the Following Is the Best

Predictor of a Future Acute Exacerbations of COPD?

A. SpirometryB. SymptomsC. Smoking StatusD. Socio-Economic StatusE. Prior Exacerbation History

S p i ro m

e t ry

S y mp t o

m sS m

o k i ng S t

a t us

S o ci o - E

c o no m

i c St a t u

s

P r i or E x

a c er b a

t i o n H i s

t o ry

4% 8%

83%

0%4%

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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

Acute Exacerbations of COPD• Some patients seldom exacerbate• Some patients exacerbate frequently• Best predictor of ≥2 AECOPD/year

(“Frequent Exacerbator”) = previous frequent exacerbations

• Spirometry does not correlate well with clinical features of disease

• “Frequent Exacerbator” is a stable phenotype

COPD Exacerbations

• “Exacerbations are to COPD what myocardial infarctions are to coronary artery disease”

• “They are the acute, often trajectory-changing, and sometimes deadly manifestations of a chronic disease”

- Gerard J Criner, MDTemple University School of Medicine

Philadelphia, PA, USA

COPD Exacerbations (AECOPD): The Major Complication of COPD

• Characterized by episodic increases in dyspnea, sputum production and cough

• 16 million office visits/year• 500,000 hospitalizations/year• 110,000 deaths/year• $18 billion in direct health care costs

Mannino et al. MMWR Surveill Summ 2002; 51:1-16NHLBI: http://www.nhlbi.gov/resources/docs/02_chtbk.pdf

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Question #3:Which of the Following DOES NOT

Reduce Acute Exacerbations of COPD?A. Inhaled CorticosteroidsB. Long Acting Beta AgonistC. Long Acting Muscarinic

AgonistsD. AzithromycinE. EMR training

I n ha l e d

C or t i c

o s te r o

i d s

L o ng A

c t i ng B e

t a Ag o n

i s t

L o ng A

c t i ng M

u s ca r i n

i c . ..

A z i th r o

m yc i n

E MR t r

a i n in g

0%7%

60%

33%

0%

Prevention of AECOPDAmerican College of Chest Physicians & Canadian

Thoracic Society Guideline• PICO (population, intervention, comparator,

outcome)• Literature Search

• Quality Assessment (AGREE II, DART)

• Grading Evidence (GRADEpro)• Recommendations (CHEST)

Criner et al. CHEST 147:894-942, 2015

Prevention of AECOPDRecommendations

• Influenza Vaccine (Grade 1B)• Pulmonary Rehab (Grade 1C)• Smoking Cessation (Grade 2C)• Pneumococcal Vaccine (Grade 2C)

Mod-severe-very severe; recent AECOPD<4 weeks

Criner et al. CHEST 147:894-942, 2015

Non-Pharmacologic Treatments/Vaccinations:• 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, 2015

Maintenance Inhaled Therapy:


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• 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)

• Do not use statins for AECOPD (Grade 1B)Criner et al. CHEST 147:894-942, 2015

Oral Therapy:


NEJM 365:689-98, 2011

• 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

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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

“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

Side Effects, GIDiarrheaWeight Loss

Nausea

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N Engl J Med. 2014 Jun 5;370(23):2201-10 Wedzicha JA et al. N Engl J Med 2016;374:2222-2234

Wedzicha JA et al. N Engl J Med 2016;374:2222-2234

Rate Ratio

Wedzicha JA et al. N Engl J Med 2016;374:2222-2234

Time ToFirst Exacerbation

Effect of Corticosteroids on Treatment Failure Rates after AE COPD

Niewoehner et al., NEJM 340:1941, 1999

2 week = Solumedrol 125mg q6hr x 3d, Prednisone 60mg qd x 4d, 40mg qd x 4d,20mg qd x 4d

8 week = additional 10mg qd x 5 week, then 5 mg qd x 1 week

Rat

e o

f Tr

eatm

ent

Fai

lure

(%

)

Month

0 1 2 3 4 5 6

60

50

40

20

0

10

308 week

2 week

Placebo

12

Leuppi et alJAMA 2013; 309:2223-2231

• Prednisone, 40 mg/day x 5 daysvs

• Prednisone, 40 mg/day x 14 days

Time to Reexacerbation of COPD

(Intention-to-treat) (Per-Protocol)

Leuppi et al.JAMA 2013;309(21):2223-2231

Summary

• Azithromycin prevents COPD Exacerbations– Potential Risk of Cardiac Arrhythmias

• Roflumilast offers some benefit in bronchitis patients

• 5 days of corticosteroids is the appropriate time frame

• No indication for statins in preventing AECOPD

• Duel Bronchodilators Over ICS

Goals of TreatmentFor Primary Care Physicians

• Improve Symptoms• Prevent Progressive Loss of Lung Function

• Prevention of Acute Exacerbations

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Effect of Smoking Cessation on FEV1

JAMA 272:1497,1994.

Sustained Quitters2.9

2.8

2.7

2.6

2.5

2.4

Continuing Smokers

Follow-up in years

1 2 3 4 5Screen 2

.

Po

st B

ron

chd

ilato

r F

EV

1(l

iter

s)

Effects of a Smoking Cessation Intervention on 14.5-year Mortality

Anthonisen et alAnn Intern Med 2005; 142:233-239

P=0.03

Smoking Cessation

Usual Care

Celli et alAm J Respir Crit Care Med 178:332-38, 2008

Therapy Reduces Lung Decline(TORCH)

Placebo

Salmeterol + Fluticasone

Tashkin et alNEJM 359:1543-54, 2008

Tiotropium Reduces Lung Decline

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Downward Spiral In FunctionAssociated With COPD

Disease

DyspneaInactivity

Deconditioning

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

Update on the Management of Asthma

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Definition of Asthma• Obstruction that is reversible either spontaneously or with treatment; [NAEPP-EPR, 1991]

• Chronic inflammatory disorder (MCs, Eos, Tcells, Macs, PMNs, Epi); variable obstruction; [NAEPP-EPR2, 1997]

• Variable symptoms, obstruction, BHR; inflammation; interaction [NAEPP-EPR3, 2007]

Definition of Asthma• Chronic inflammatory disorder; many different cells; BHR; variable/reversible symptoms and obstruction; phenotypes? [GINA, 2011]

• Heterogeneous; Chronic airway inflammation; variable/reversible symptoms and obstruction;•Different phenotypes or clusters [GINA, 2014]

EPR-3, NHLBI, 2011 Haldar AJRCCM 2008

Asthma Phenotypes

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Fahy, NRI, 2015

Not all asthma is the same!!(Heterogeneity)(Phenotypes)

Question #4 - Asthma

A. TrueB. False

Inhaled Corticosteroids are effective (at some dose) in all asthmatics.

True or False?

T ru e

F al s e

88%

12%

17

Patients(%)

FEV1 Percent Change From Baseline

302520151050

<-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

Eosinophils

Charcot-Leyden Crystals

A Large Subgroup of Mild-to-Moderate AsthmaIs Persistently Noneosinophilic

• Asthma is a heterogeneous disease

• Prior ACRN data (n=995; 2.7 SI; ≥2% eos):• ~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)

TH2 Genes Overexpressed in Asthma

Woodruff et alAm J Respir CCM 180:388, 2009

Th2High

Th2High Th2

High

Th2Low

Th2Low Th2

Low

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Th2 Status Predicts Corticosteroid Response

Woodruff et alAm J Respir CCM 180:388, 2009

• N=135, prednisone x ≥6 months, eosinophils >300

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A Large Subgroup of Mild-to-Moderate AsthmaIs Persistently Noneosinophilic

• Asthma is a heterogeneous disease

• Prior ACRN data (n=995; 2.7 SI; ≥2% eos):• ~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)

Steroids in Eosinophil Negative Asthma (SIENA)

1. Does the response to ICS differ between subjects who are persistently EOS– and

those who are EOS+?

Co-Primary Research Questions:

2. Does the response to LMA differ between subjects who are persistently EOS– and

those who are EOS+?

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Interim HxLimited PESpiro w/IPB MRSIPeriostineNOEosinophilsGenetics BloodDiary ReviewReview Elig & ComplianceQuestionnaires

EOS-

EOS+

Run-in

Wk 0 3SI SI

SIENA: Schematic

3-month treatment;1st mo censored



ConsentH&PSpiro w/Alb MR(Mch)CBC, IgEImmunoCAPSIPeriostineNOEosinophilsPregnancy testQuestionnaires

LMA + Int ICS LMA + Int ICS LMA + Int ICS

PBO + Int ICS PBO + Int ICS PBO + Int ICS

PBO + Int ICS PBO + Int ICS PBO + Int ICS

LMA + Int ICS LMA + Int ICS LMA + Int ICS

Phone Visit 18 30 4224 36

Phone Visit

Phone Visit

Phone Visit

Phone Visit

Interim HxLimited PESpiroDiary ReviewQuestionnaires



6

RandomizeInterim HxLimited PESpiro(SI)(Periostin)(eNO)Diary ReviewQuestionnaires

12Phone Visit

Phone Visit



Interim HxPESpiroDiary ReviewQuestionnairesPregnancy test

Alb MR = Albuterol Maximum Reversibility SI = Sputum InductionIPB MR = Ipratropium Maximum Reversibility ICS = Inhaled CorticosteroidMch = Methacholine PC20 LMA = Long-acting Muscarinic Antagonist

ICS + Int ICS ICS + Int ICS ICS + Int ICS

ICS + Int ICS ICS + Int ICS ICS + Int ICS

Single-blind Placebo

(SI)

Phone VisitV 1 2 3 4 5 6 7 8 9

(See Appendix A for list of Questionnaires)

N = 384Alternative Treatment?

Tiotropium Step-Up for Uncontrolled Asthma

Peters et al.N Engl J Med 363:18, 2010

Eur Respir J; 43:343-73, 2014

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Eur Respir J; 43:343-73, 2014

Recommendations:• In adults with severe asthma – use sputum eos in experienced centers

• In severe allergic asthma – therapeutic trial of omalizumab

• Do not use methotrexate for asthma• Do not use azithromycin for asthma

Eur Respir J; 43:343-73, 2014

Recommendations:• Use anti-fungals for ABPA• Do not use anti-fungals without ABPA• Consider bronchial thermoplasty only as part of a study

NAEPP GUIDELINES“If there is a clear and positive response for at least 3 months, a careful step down in therapy should be attempted to identify the lowest dose required to maintain control. (Evidence D)””””

Evidence D = Panel Consensus Judgment

Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007.National Asthma Education and Prevention Program.J Allergy Clin Immunol. 2007 Nov;120(5 Suppl):S94-138.

GINA GUIDELINES“Controller treatment may be stopped if the patient’s asthma remains controlled on the lowest dose of controller and no recurrence of symptoms occurs for 1 year (Evidence D)””””

Global strategy for asthma management and prevention: GINA executive summary.Eur Respir J. 2008 Jan;31(1):143-78.

Evidence D = Panel Consensus Judgment

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Is There Really A Difference

Between Asthma And COPD?

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 inCOPD versus Asthma

Calverley, Barnes. AJRCCM 2000; 161:341-344

COPD AsthmaPredominant Cells

Macrophages EosinophilsNeutrophils Activated Mast Cells

CD-8 T-Lymphocytes CD-4 T LymphocytesPredominant Cytokines

Interleukin 8 Interleukin 4Leukotriene B4 Interleukin 5

Tumor Necrosis Factor alpha Interleukin 13

COPD Asthma OverlapIN COPD

Postma DS, Rabe KF .N Engl J Med 2015; 373: 1241-1249

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Asthma Summary

• Asthma not a single disease but a heterogeneous group of diseases

• Patients respond differently to medications based upon underlying “endotype/phenotype”

• “Th2-High” or Allergic Asthma responds to corticosteroids

• Treatments for “Th2-Low” or Non-Allergic Asthma remain unclear

update on copd & asthma disclosures - ucsf · pdf file2 to review copd • copd is a...

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