update on copd & asthma guidelines

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

















0%).


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

14

Pulmonary Rehab

















0%).


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 3-8Puhan 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:


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



ICS risk of Pneumonia?

FLAME TRIAL



• LABA + LAMA = ?

ICS risk of Pneumonia?

17

FLAME TRIAL



• 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


NNT = 9



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:


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

http://www.nhlbi.nih.gov/index.htm

http://www.nih.gov/

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


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


Roflumilast

Martinez et al. Lancet 2015


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



PREFERRED

CONTROLLER





PREFERRED

RELIEVER

STEP 2



STEP 3

Low dose

ICS-LABA

STEP 4

Medium dose

ICS-LABA





Medium dose

ICS, or low dose

ICS+LTRA #



Add low dose

OCS, but

consider

side-effects


Box 3-5A







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





Comorbidities


Patient goals




Asthma medications


STEP 1

As-needed

low dose

ICS-formoterol *

Low dose ICS

taken whenever

SABA is taken†





PREFERRED

CONTROLLER





PREFERRED

RELIEVER

STEP 2



STEP 3

Low dose

ICS-LABA

STEP 4

Medium dose

ICS-LABA





Medium dose

ICS, or low dose

ICS+LTRA #



Add low dose

OCS, but

consider

side-effects


Box 3-5A







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





Comorbidities


Patient goals




Asthma medications


STEP 1

As-needed

low dose

ICS-formoterol *

Low dose ICS

taken whenever

SABA is taken†



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

31

JAMA 2017

Called patients“Do you have asthma”?

32


SpirometryPre/Post BD

PositiveAsthma Confirmed



Methacholine



33



Methacholine

Methacholine

Stop All Meds






Methacholine

Methacholine

Stop All Meds



MethacholineOr worse symptoms

12 Month Follow up


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

37

Not all asthma is the same!!

(Heterogeneity)

(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

update on copd & asthma guidelines

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