copd the new epidemicclassification of severity of airflow limitation in copd* based on fev1 gold 1:...

COPDThe New Epidemic

Peter Lin MD CCFPDirector Primary Care InitiativesCanadian Heart Research Centre

Conflict Disclosure Information

Speaker: Dr. Peter Lin

Title of Talk: COPD – The New Epidemic

Financial Disclosure Company

Grants / Research Support None

Speakers Honorarium Astrazeneca, BMS, Takeda Boeringher Ingelheim, AbbottEli Lilly, Amgen, Mylan, Janssen Forest Laboratories, J&J, Merck, Novartis, Pfizer, Servier, Sanofi

Consulting Fees None

Patents None

Other None

Mitigating Potential Bias

• Only published data will be presented in this program and recommendations will be based on published Guidelines

Learning Objectives:

By the end of this workshop you will be able to:

1. Make appropriate diagnosis2. Understand appropriate testing3. Be able to incorporate guidelines into the

management of your patients4. Understand the role of new therapies for the

management of your patients

Percent Change in Age-Adjusted Death Rates, U.S., 1965 – 1998 (Proportion of 1965 Rate)

Air trapping

Mr. CO

• 76 year old man• Short of breath• Had Negative Cardiac workup• Smoker 40 pk years• Coughs most days – some sputum• Meds: • ARB, Statin, ASA, Vitamins

EXPOSURE TO RISK FACTORS

tobaccotobaccooccupationoccupation

indoor/outdoor pollutionindoor/outdoor pollution

SPIROMETRY: Required to establish diagnosis

SPIROMETRY: Required to establish diagnosis

Global Strategy for Diagnosis, Management and Prevention of COPD

Diagnosis of COPDGlobal Strategy for Diagnosis, Management and Prevention of COPD

Diagnosis of COPD

SYMPTOMS

chronic coughchronic coughshortness of breathshortness of breath

sputum sputum

© 2013 Global Initiative for Chronic Obstructive Lung Disease

Focus on Vital Capacity (VC)

12

Spirometry: Normal Trace Showing FEV1 and FVC

1 2 3 4 5 6

1

2

3

4

Volu

me,

lite

rs

Time, sec

FVC5

1

FEV1/FVC = 0.8


FVC = 5LFEV1 = 4L

Spirometry: Mr. COVo

lum

e, li

ters

Time, seconds

5

4

3

2

1

1 2 3 4 5 6

Normal

Obstructive< 0.70


FEV1/FVC = 0.56

FVC = 3.2L

FEV1 = 1.8L

Mr. CO

• Walking can’t keep up with his wife

Assessing Disability in COPDAssessing Disability in COPD

Mr. CO

• FEV1 is 70% predicted

Global Strategy for Diagnosis, Management and Prevention of COPDClassification of Severity of Airflow Limitation in COPD* based on FEV1

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


Global Strategy for Diagnosis, Management and Prevention of COPDClassification of Severity of Airflow Limitation in COPD* based on FEV1

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


Mr. CO FEV1 = 70%

Mr. CO

• 5 years he had 3 exacerbations

What is the impact of exacerbations on mortality?

50% of COPD patients are dead within 4 years of being admitted for first time with COPD1

1.Suissa S, Dell’Aniello S, Ernst P. Thorax. doi: 10.1136/thorax.jnl-2011-201518, 2.Soler-Cataluna JJ, et al. Thorax. 2005;60:925-931.

A= No Exacerbations

B= 1-2 Exacerbations

C= > 3 Exacerbations

Suissa S et al. Thorax 2012;67:957-963

Daily rates of death (per 10 000 per day) in the 90-day period after onset of severe chronic obstructive pulmonary disease exacerbation.

Suissa S et al. Thorax 2012;67:957-963

Copyright © BMJ Publishing Group Ltd & British Thoracic Society. All rights reserved.

LAMA vs Placebo for Exacerbation

Tashkin DP, et al. N Engl J Med. 2008;359:1543-1554.

Month

29863006

19961815

14861284

12231010

983776

838634

709545

610460

2621

TiotropiumPlacebo

No. at risk

0

20

40

60

80

0

Pro

bab

ility

of

exac

erb

atio

n (

%)

6 12 18 24 30 36 42 48

*p<0.001

*

Hazard ratio: 0.86CI: 0.81-0.91

250

200

150

100

50

0

Chan

ge from

baseline

in trou

gh FEV

1(m

L)

Week 4 Week 8 Week 12 Last visit

n=118

n=127

†

n=106 n=121

n=121n=121 n=129

* n=108* *

Formoterol (12 µg b.i.d.) + tiotropium (18 µg o.d.)

Tiotropium (18 µg o.d.)

Trough FEV1: Change from baseline

AM PMAM/PM average

Mean chan

ge in

symptom

score

0

‐0.2

‐0.4

‐0.6

‐0.8

‐1.0

‐1.2

‐1.4

‐1.6

Total COPD Symptom Score‡

*

**

LAMA vs LAMA + LABAFormoterol + Tiotropium

*p<0.05; †p<0.001 vs. tiotropium;‡ sum of scores for dyspnea (0 = none to 4 = severe), wheezing, cough, and chest ghtness (0 = none to 3 = very uncomfortable).Tashkin DP, et al.: COPD 2009; 6(1):17‐25.

TORCH – ICS vs LABA vs Combo

Calverley PMA et al. N Engl J Med 2007;356:775-789

0.4

0.3

0.2

0.1

0.00 15 30 45 60 75 90

Days since randomisation

Exac

erba

tions

/pat

ient

BUD/FORM + TIOPBO + TIO

62% reduction in rate of severe exacerbationRatio: 0.38 (95% CI: 0.25–0.57) P < 0.001

Poisson regression

LAMA vs LAMA + ICS + LABA

BUD/FORM=budesonide/formoterol (320/9 μg bid); PBO = placebo; TIO = tiotropium (18 μg od) Welte T, et al. Am J Respir Crit Care Med. 2009;180:741-750.

Global Strategy for Diagnosis, Management and Prevention of COPD

Combined Assessment of COPDGlobal Strategy for Diagnosis, Management and Prevention of COPD

Combined Assessment of COPD

> 2

1

0

(C) (D)

(A) (B)

mMRC 0-1CAT < 10

mMRC > 2CAT > 10

Symptoms© 2013 Global Initiative for Chronic Obstructive Lung Disease

SAMA prnor

SABA prn

LABA or

LAMA

ICS + LABAor

LAMA

ICS + LABAand/orLAMA

Exacerbations

4

3

2

1

GOLD FEV1<50% Predicted

Treatment of Stable COPD


BronchodilatorLAMA or LABA

2 BronchodilatorsLAMA + LABA

Bronchodilators + ICSLAMA + LABA + ICS

Pharmacotherapy Indicated for COPD in Canada§

B R O N C H O D I L A T O R SS H O R T ‐ A C T I N G B E T A 2 ‐ A G O N I S T S L O N G ‐ A C T I N G B E T A 2 ‐ A G O N I S T S

www.hc-sc.gc.ca accessed June 24, 2015

Budesonide/Formoterol (fumarate)

§ Chart not representative of all approved COPD medications Canada.

C O R T I C O S T E R I O D S / L O N G ‐ A C T I N G B E T A 2 ‐ A G O N I S T S

Tiotropium (bromide)/Olodaterol (hydrochloride)

Aclidinium (bromide)/Formoterol (fumarate)

DUAKLIR™Genuair 400/ 12

mcgINSPIOLTO™

Respimat 2.5/2.5 mcg

S H O R T ‐A C T I N G A N T I C H O L I N ER G I C S

Umeclidinium (bromide)

INCRUISEEllipta 62.5 mcg

L O N G ‐ A C T I N G A N T I C H O L I N E R G I C S

Umeclidinium (bromide)/Vilanterol (trifenatate)

Glycopyrronium (bromide)/Indacaterol (maleate)

Ipratropium (bromide)/Salbutamol (sulfate)

A N T I C H O L I N E R G I C S A N D L O N G ‐ A C T I N G B E T A 2 ‐ A G O N I S T S

COMBIVENTRespimat 20/100 mcg

34

Treatments for COPDAbbreviation Full name Examples Brand (Device)

ICS Inhaled corticosteroid

BudesonideFluticasone ProprionateFluticasone Furoate

Pulmicort (Turbuhaler)Flovent (Diskus)

(Ellipta)

LAMALAAC

Long-acting anticholinergic (also known as long-acting muscarinic antagonist)

TiotropiumGlycopyrroniumAclidinium BromideUmeclidinium

Spiriva (Respimat)Seebri (Breezhaler)Tudorza (Genuair)Incruse (Ellipta)

LABA Long-acting beta2 agonist

FormoterolSalmeterolIndacaterolVilanterolOlodaterol

Oxeze (Turbuhaler)Serevent (Diskus)Onbrez (Breezhaler)

(Ellipta)Striverdi (Respimat)

SABA Short-acting beta2 agonist

SalbutamolTerbutaline

Ventolin (Diskus)Bricanyl (Turbuhaler)

SAMA Short-acting antimuscarinic Ipratropium Atrovent

35





(Ellipta)

LAMALAAC












36





(Ellipta)

LAMALAAC












37





(Ellipta)

LAMALAAC












38





(Ellipta)

LAMALAAC












39





(Ellipta)

LAMALAAC












DeviceEfficacySafety

1 Adapted from : Newman SP, et al. Lung Deposition of fenoterol and flunisolide delivered using a novel device for inhaled medicine: Comparison of Respimat with conventional metered-dose inhalers with and without spacer devices. Chest1998;113: 957-963.

Adapted from asthmameds.ca

DPI (Diskus)

Breathe out until lungs are empty

Place the mouthpiece in mouth and close lips firmly around it Breathe in as “fast” & as “hard” as you can until lungs are full Hold breath for 10s Breathe out

Slide the lever away from you as far as it will go

Respimat

Turbuhaler

Devices

● Feedback on successful inhalation• Audible click when patient is inhaling sufficiently• Control window turns red when inhalation is

complete

Red & DoneGreen & Go

Tudorza® Genuair® Product Monograph, 2013

49





(Ellipta)

LAMALAAC













LAS39: Change from baseline FEV1 by timepoint over 24 hours at Day 1

*p<0.05 aclidinium vs tiotropium This study alone does not constitute a head-to-head study to support comparative claims of aclidinium vs tiotropium. Beier et al. COPD 2013

Aclidinium reduces COPD exacerbation (any severity) rates (24 weeks): ATTAIN

Healthcare ResourceUtilization criteria

EXACTcriteria

0.4

0.8

1.2

1.6

0.0

0.60

0.40

1.39

0.98

COPD

exacerbations

(/pt/year)

PlaceboAclidinium 400 µg BID

29%

33%

Jones et al. CHEST 2012

p<0.05

Reproduced with permission

p<0.05

Canadian RWE

In Canada, 5255 COPD patients were treated with an ICS/LABA before matching – 3969 (76%) patients in this cohort used FLU/SAL– 36% had exacerbations pre-index– More bud/form vs. flu/sal pats. had a first ICS/LABA initiated by a specialist (8% more)– Antibiotics were not evaluated as a definition of exacerbations – Patients were tracked for 1 year

In Canada, 5255 COPD patients were treated with an ICS/LABA before matching – 3969 (76%) patients in this cohort used FLU/SAL– 36% had exacerbations pre-index– More bud/form vs. flu/sal pats. had a first ICS/LABA initiated by a specialist (8% more)– Antibiotics were not evaluated as a definition of exacerbations – Patients were tracked for 1 year

Healthcare utilisation in the first year after initiating ICS/LABA therapy

Blais L et al. Clin Ther 2010; 32 (7): 1320

Courses of oral steroids/year 0.66 0.79 0.85 (0.72, 1.00)

ED visits/year 0.16 0.23 0.75 (0.58, 0.97)

Hospital admissions/year 0.11 0.21 0.61 (0.47, 0.81)

Addition of a tiotropium prescription/year 1.63 2.01 0.71 (0.57, 0.89)

A retrospective observational propensity-matched cohort study

These slides have been supplied, on request, by AstraZeneca Scientific Affairs.

For complete therapeutic and safety information please consult the SYMBICORT ® Product Monograph.

COPD Exacerbations

3.4

21

54

85

109

2.7

15

38

63

80

0.0 20.0 40.0 60.0 80.0 100.0 120.0 140.0 160.0

Emergencyvisits

Hospitalisations

Antibiotics

Oralsteroids

Allexacerbations

BUD/FORSAL/FLU

Rateratio(95%CI)

0.74(0.69,0.79)

0.74(0.68,0.81)

0.70(0.66,0.75)

0.71(0.65,0.78)

0.79(0.71,0.89)

Eventrateper100patient‐years

**

**

**

**

*

BUD/FOR (n=2734) or FLU/SAL (n=2734)

Adjusted yearly rates of healthcare utilisation events were compared using Poisson regression analysis. **P<0.0001; *P=0.0003 for difference. CI, confidence intervals; BUD/FOR, budesonide/formoterol; FLU/SAL, fluticasone/salmeterol

NNT = 3.4

NNT = 16

Larsson et al. J Intern Med 2013; DOI: 10.1111/joim.12067These slides have been supplied, on request, by AstraZeneca Scientific Affairs.


54





(Ellipta)

LAMALAAC





FormoterolSalmeterolIndacaterolVilanterol


(Ellipta)






Pneumonia Risk in COPD Patients (Stratified by ICS Type)

Singh S, Loke YJ. Curr Opin Pulm Med. 2010; 16: 118‐122.

Meta‐analysis of ICS use (studies 1‐3 yr duration)

Corticosteroid TypeFluticasone (16 studies)Budesonide (7 studies)Mometasone (1 study)

HR (95%CI)1.67 (1.47-1.89)*

1.19 (0.92-1.53) [ns]2.00 (0.83-4.81) [ns]

Corticosteroid Safer Corticosteroid Harmful0.20.1 1 5 100.5 2

Risk Ratio

*statistically significant increase with fluticasone p<0.0001[ns] = no statistically significant increase in risk detected

• The elderly and those with more severe disease and lower FEV1s are at the highest risk of pneumonia.

Cumulative Pneumonia Rate vs Time Post IndexFluticasone/salmeterol group

Any pneumoniaHospitalised pneumonia

Budesonide/formoterol groupAny pneumoniaHospitalised pneumonia

Cum

ulat

ive

pneu

mon

ia ra

te p

er 1

00 p

atie

nts

All pneumoniasRR 1.73 (1,57; 1.90) P<0.001 NNT 23

110

0

100908070605040302010

0 1 2 3 4 5 6 7 8 9Years

Hospitalised pneumoniasRR 1.74 (1,56; 1.94) P<0.001 NNT 34

Adjusted yearly pneumonia event rates compared using Poisson regression analysis. Janson et al. BMJ 2013;346:f3306 DOI: 10.1136/bmj.f3306



BacteriaFluticasone Fluticasone/GCS-receptor

Fluticasone/salmeterol

Mucosa/Lung tissue

1. Wedzicha JA et al. AJRCCM 20082. Calverley et al. Chest 2011;139:5053. Patterson C et al Respiratory Research 2012,13:404. Ek A et al Allergy (1999). 54: 691 5. Miller-Larsson et al. AJRCCM (2000). 162: 1456. Johnsson M et al Allergy (1995) 50:s11-147. Dalby C, et al. Respir Res (2009); 10:104

An Immunosuppressant / Infection hypothesis

ASL = Airway surface liquid

BudesonideBudesonide/GCS-receptor

ASL



Water solubility(μg/mL)

Dissolution time(human BAL fluid in vitro)

Flunisolide 140 <2 min

Triamcinoloneacetonide

21 n.d.

Budesonide 16 6 min

Beclomethasone 17-propionate

16 n.d.

Fluticasone 17-propionate

0.16 >8h

Beclomethasonedipropionate

0.13 >5h

Högger and Rohdewald, Rev Contemp Pharm 1998

Dissolution Time in Airway Fluid

n.d.= no data



Two major acid and alcohol metabolites are inactive Sentellas et al, 2010Alberti et al, 2010

Gavaldà et al. 2014

Safety: Hydrolysis of LAMAs

61

ICS + LABA – Advair (Diskus)

Abbreviation Full name Examples Brand




(Ellipta)

LAMALAAC







(Ellipta)





62

ICS + LABA – Symbicort (Turbuhaler)





(Ellipta)

LAMALAAC







(Ellipta)





63

ICS + LABA – Breo (Ellipta)





(Ellipta)

LAMALAAC







(Ellipta)





64

LAMA + LABA – Anoro (Ellipta)





(Ellipta)

LAMALAAC







(Ellipta)





65

LAMA + LABA – Ultibro (Breezhaler)





(Ellipta)

LAMALAAC







(Ellipta)





66

LAMA + LABA – Stiolto RespimatAbbreviation Full name Examples Brand




(Ellipta)

LAMALAAC












67

LAMA + LABA – Duaklir (Genuair)





(Ellipta)

LAMALAAC







(Ellipta)





68





(Ellipta)

LAMALAAC







(Ellipta)






Death

Disability

Never smoked or not susceptible to smoke

Smoked regularlyand susceptible toeffects of smoke

Stopped smoking at 45 (mild COPD)

Stopped smoking at 65 (severe COPD)

FEV

1(% of v

alue at a

ge 25)

Age (years) Fletcher C et al. Br Med J. 1977;1:1645–1648.

COPD Risk & Smoking Cessation1,5,7

Peter Lin MD CCFPDirector Primary Care InitiativesCanadian Heart Research CentreCOPD Maze

Keep COPD in DDx

Tools for Assessing Risk

Medications: Bronchodilators vs ICS

Step up: Single then dual then triple Rx

Decide based on: Device, Efficacy, Safety

Avoid Exacerbations

copd the new epidemicclassification of severity of airflow limitation in copd* based on fev1 gold 1:...

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