[PDF] - Disclosures No Pharma Disclosures NHLBI - Asthma Clinical Research PDF Document

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Update on COPD & Asthma

Michael C. Peters, M.D. MAS Division of Pulmonary & Critical Care Medicine Cardiovascular Research Institute University of California San Francisco

UCSF Primary Care Medicine San Francisco, CA May 26, 2017

Disclosures

No Pharma Disclosures
NHLBI - Asthma Clinical Research Network
NHLBI – Severe Asthma Research Program

Update on the Management of COPD

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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

Rate of Deaths per 100,000 in the USA 2005-2011

Heart Disease Cancer COPD/Chronic respiratory

Rate Year

2005 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%)

MEN

Lung 72,120 (26%) Breast 40,450 (14%) Colorectal 23,170 (8%) Pancreas 20,330 (7%) Ovary 14,240 (5%)

WOMEN

American Cancer Society 2016

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Simel and Rennie Evidence-based Clinical Diagnosis McGraw Hill, 2008

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

Simel and Rennie Evidence-based Clinical Diagnosis McGraw Hill, 2008

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

Original Article

Clinical Significance of Symptoms in Smokers with Preserved Pulmonary Function

N Engl J Med Volume 374(19):1811-1821 May 12, 2016

Observational study 2734 current and former smokers and controls who never smoked Examined whether current or former smokers with preserved lung function had symptoms or suffered COPD exacerbations

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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 al JAMA 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, 2011 USPTF JAMA 2016

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5 GOLD Criteria

Risk GOLD Classification of Airflow Limitation

(C) (D) (B) (A)

4 3 2 1 ≥2 or 1

Risk Exacerbation History

mMRC 0-1 CAT < 10 mMRC ≥ 2 CAT ≥10 Symptoms (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 2015

≥1 leading to hospital admission (no hospital admission)

Risk GOLD Classification of Airflow Limitation

(C) (D) (B) (A)

4 3 2 1 ≥2 or 1

Risk Exacerbation History

mMRC 0-1 CAT < 10 mMRC ≥ 2 CAT ≥10 Symptoms (mMRC or CAT score) When assessing risk, choose the highest risk according to GOLD grade or exacerbation history

GOLD Guidelines 2015

≥1 leading to hospital admission (no hospital admission)

Take HOME

Treat the patient

– Symptoms – Exacerbations

Spirometry assists with diagnosis
Lung Cancer Screening

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Treat The Patient!!!

Improve Symptoms
Prevent Progressive Loss of Lung Function
Prevention of Acute Exacerbations

What treatment is the most effective for preventing COPD exacerbations?

A) Roflumilast B) Pulmonary Rehab C) Duel LAMA + LABA D) Azithromycin Treat The Patient!!!

Improve Symptoms
Prevent Progressive Loss of Lung Function
Prevention of Acute Exacerbations

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7 Hospitalized Severe AECOPD and Mortality: Severity of AECOPD

1- no AECOPD 2- AECOPD ED N = 305 men with COPD x 5 years Soler-Cataluna Thorax 2005 3- AECOPD Hosp 4- AECOPD Readmit

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 AECOPD

American College of Chest Physicians & Canadian Thoracic Society Guideline

PICO (population, intervention, comparator,
utcome)
Literature Search
Quality Assessment (AGREE II, DART)
Grading Evidence (GRADEpro)
Recommendations (CHEST)

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

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Prevention of AECOPD

Recommendations

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:

Pulmonary Rehab

Figure 2. Forest plot of comparison: 1 Rehabilitation versus control, outcome: 1.1 Hospital admission (to end of follow-up).

Puhan Cochrane Database 2011

Pulmonary Rehab

Figure 2. Forest plot of comparison: 1 Rehabilitation versus control, outcome: 1.1 Hospital admission (to end of follow-up).

Pulmonary Rehab Control Odds Ratio Subject 124 126 Total Event 20 51 0.22 (0.08- 0.58)

Puhan Cochrane Database 2011

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Pulmonary Rehab

Figure 2. Forest plot of comparison: 1 Rehabilitation versus control, outcome: 1.1 Hospital admission (to end of follow-up).

Pulmonary Rehab Control Odds Ratio Subject 124 126 Total Event 20 51 0.22 (0.08- 0.58)

Number Needed to Treat = 4!!!! CI 3-8

Puhan 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, 2015

Maintenance Inhaled Therapy:

Prevention of AECOPD

Recommendations

FLAME TRIAL

LAMA + ICS = Good
LABA + ICS = Good

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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?

FLAME TRIAL

LAMA + ICS = Good
LABA + ICS = Good
LABA + LAMA = ?

LABA (indacaterol) + LAMA (glycopyrronium) QDay LABA (salmeterol) + ICS (fluticasone) BID

VS.

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

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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:

Prevention of AECOPD

Recommendations

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

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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

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 Med 2014; 189:1173-1180

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“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 Med 2014; 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

Ray WA et al. N Engl J Med 2012;366:1881-1890

Roflumilast

Martinez et al. Lancet 2015

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Ray WA et al. N Engl J Med 2012;366:1881-1890

Roflumilast

Martinez et al. Lancet 2015

NNT=25 NNH=16

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

Rate of Treatment Failure (%) Month

1 2 3 4 5 6 60 50 40 20 10 30

8 week 2 week Placebo Leuppi et al JAMA 2013; 309:2223-2231

Prednisone, 40 mg/day x 5 days

vs

Prednisone, 40 mg/day x 14 days

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Time to Reexacerbation of COPD

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

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

Summary

Pulmonary Rehab (NNT=4)
Duel Long Acting Bronchodilator Medications
ver 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)

5 days of corticosteroids is the appropriate

time frame

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

Therapy Reduces Lung Decline (TORCH)

Placebo Salmeterol + Fluticasone

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Tashkin et al NEJM 359:1543-54, 2008

Tiotropium Reduces Lung Decline

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

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

bstruction; phenotypes? [GINA, 2011]
Heterogeneous; Chronic airway inflammation;

variable/reversible symptoms and obstruction;

Different phenotypes or clusters [GINA, 2014]

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

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Asthma Prevalence in USA 2001-10 Causes of Asthma

Hygiene Hypothesis
Exposure to Antibiotics

– Microbiome

Genetics
Obesity
Environmental Influences

– Dogs/Cats – Medications

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Asthma

JAMA 2017 Called patients “Do you have asthma”?

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Called patients “Do you have asthma”? Spirometry Pre/Post BD Positive Asthma Confirmed Called patients “Do you have asthma”? Spirometry Pre/Post BD Methacholine Positive Asthma Confirmed Positive Asthma Confirmed Called patients “Do you have asthma”? Spirometry Pre/Post BD Methacholine Methacholine Stop All Meds Positive Asthma Confirmed Positive Asthma Confirmed Positive Asthma Confirmed

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Called patients “Do you have asthma”? Spirometry Pre/Post BD Methacholine Methacholine Stop All Meds Positive Asthma Confirmed Positive Asthma Confirmed Methacholine Or worse symptoms 12 Month Follow up Positive Asthma Confirmed No Asthma Positive Asthma Confirmed

What percentage of patients had no asthma?

A) 0-10% B) 10-20% C) 30-40% D) 40-50% E) >50%

Aging and Asthma

Years Lost Disability Years Lost Life

Global Asthma Report 2014

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Obesity and Asthma

Obesity is an important risk factor for the development of asthma

CDC National Asthma Control Program 2010

Percentage of adults with asthma who are obese

EPR-3, NHLBI, 2011

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

n placebo (3 of 13,179)".

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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

Summary of Safety End Points.

Stempel DA et al. N Engl J Med 2016;374:1822-1830

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Haldar AJRCCM 2008

Asthma Phenotypes

Fahy, NRI, 2015

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

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Patients (%) FEV1 Percent Change From Baseline

30 25 20 15 10 5 <-30

30 to

<-20

20 to

<-10

10 to

<0 0 to <10 10 to <20 20 to <30 40 to <50 50 30 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)

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TH2 Genes Overexpressed in Asthma

Woodruff et al Am J Respir CCM 180:388, 2009 Th2 High Th2 High Th2 High Th2 Low Th2 Low Th2 Low

Th2 Status Predicts Corticosteroid Response

Woodruff et al Am J Respir CCM 180:388, 2009

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

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Type-2 Inhibitors for Severe Asthma

Anti IL-5 Agents

– Mepolizumab (NUCALA)* – Resilizumab (CINQAIR)*

Anti IL-13 Agents

– Lebrikizumab

Anti IL-4/IL-13

– Dupilumab

Anti TSLP

– AMG 157

* FDA Approved

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)

Alternative Treatment?

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Tiotropium Step-Up for Uncontrolled Asthma

Peters et al. N Engl J Med 363:18, 2010 Eur Respir J; 43:343-73, 2014 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
malizumab: Mepolizumab?
Do not use methotrexate for asthma
Do not use azithromycin for asthma

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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

ccurs 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
bstruction

COPD

Loss of elastic

recoil

Changes in small

airways

“Inflammation”
Fixed airway
bstruction

Inflammation in COPD versus Asthma

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

COPD Asthma Predominant Cells Macrophages Eosinophils Neutrophils Activated Mast Cells CD-8 T-Lymphocytes CD-4 T Lymphocytes Predominant Cytokines Interleukin 8 Interleukin 4 Leukotriene B4 Interleukin 5 Tumor Necrosis Factor alpha Interleukin 13

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COPD Asthma Overlap IN COPD

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

Asthma Summary

The “Cause” of asthma remains unknown, but is

unlikely to be fully explained by genetics

Many patients with asthma diagnosis may not have

asthma

LABA are safe to use in asthma patients
Patients respond differently to medications based

upon underlying “endotype/phenotype”

“Th2-High” or Allergic Asthma responds to

corticosteroids

New Medications are on the way for Severe Allergic