Reversibility: Redefining Airflow Reversibility: Redefining Airflow Obstruction in COPDObstruction in COPD

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Current Definition and Diagnosis of COPDCurrent Definition and Diagnosis of COPD

• AA preventable and treatable preventable and treatable disease disease

• Associated with significant Associated with significant extrapulmonary effectsextrapulmonary effects and and important important comorbid conditionscomorbid conditions

• Characterized by airflow limitation that isCharacterized by airflow limitation that is– Partially reversiblePartially reversible– Usually progressiveUsually progressive– Associated with anAssociated with an abnormal inflammatory response abnormal inflammatory response to noxious to noxious

particles or gasesparticles or gases

• Postbronchodilator FEVPostbronchodilator FEV11/FVC <0.7 used to help establish /FVC <0.7 used to help establish

diagnosisdiagnosis

Global Initiative for Chronic Obstructive Lung Disease. http://www.goldcopd.com/Guidelineitem.asp?l1=2&l2=1&intId=989. Accessed November 21, 2008.Global Initiative for Chronic Obstructive Lung Disease. http://www.goldcopd.com/Guidelineitem.asp?l1=2&l2=1&intId=989. Accessed November 21, 2008.

How is Reversibility of Airflow How is Reversibility of Airflow Obstruction Defined?Obstruction Defined?

• Defined by ATS/ERS Task Force on Lung Function Defined by ATS/ERS Task Force on Lung Function TestingTesting11

• Postbronchodilator FEVPostbronchodilator FEV11 and/or FVC ≥200 mL and 12% and/or FVC ≥200 mL and 12%

improvement over baseline is considered significant improvement over baseline is considered significant bronchodilationbronchodilation11

• GOLD COPD Guidelines have adopted this standardGOLD COPD Guidelines have adopted this standard22

1. 1. Pellegrino R, Viegi G, Brusasco V et a. Pellegrino R, Viegi G, Brusasco V et a. Eur Respir J. Eur Respir J. 2005;26:948–968.2005;26:948–968.2. 2. Global Initiative for Chronic Obstructive Lung Disease. http://www.goldcopd.org/guidelineitem.asp?l1=2&l2=1&intld=2003. Accessed November 21, 2008.Global Initiative for Chronic Obstructive Lung Disease. http://www.goldcopd.org/guidelineitem.asp?l1=2&l2=1&intld=2003. Accessed November 21, 2008.

Hyperinflation Is a Hallmark of COPDHyperinflation Is a Hallmark of COPD

• Increases FRC (EELV)Increases FRC (EELV)

• Decreases ICDecreases IC

• Increases volume at Increases volume at which tidal breathing which tidal breathing occursoccurs

• Worsens with exercise Worsens with exercise and reduces exercise and reduces exercise tolerance (dynamic tolerance (dynamic hyperinflation)hyperinflation)

Total Lung Capacity

TidalVentilation

HealthyPatients

PatientsWith COPD

Patients With COPD During Exercise

No Bronchodilator

With Bronchodilator

FRCFRC (EELV)(EELV)

IC = inspiratory capacity; FRC/EELV = functional residual capacity/end expiratory lung volume.IC = inspiratory capacity; FRC/EELV = functional residual capacity/end expiratory lung volume.

Adapted with permission from Sutherland ER et al. Adapted with permission from Sutherland ER et al. N Engl J MedN Engl J Med. 2004;350:2689-2697.. 2004;350:2689-2697.

ICIC

Airflow Obstruction Is a Airflow Obstruction Is a Central Feature of COPDCentral Feature of COPD1,21,2

Dyspnea Dyspnea Exercise Exercise

Tolerance Tolerance

Airflow Limitation, Air Trapping, Airflow Limitation, Air Trapping, Lung Hyperinflation, Mucus HypersecretionLung Hyperinflation, Mucus Hypersecretion

Decline in Decline in Lung FunctionLung Function

DeteriorationDeterioration in Health Statusin Health Status

Premature MortalityPremature Mortality

InactivityInactivity

Exacerbations Exacerbations

1. Global Initiative for Chronic Obstructive Lung Disease. http://www.goldcopd.org/guidelineitem.asp?l1=2&l2=1&intld=2003. Accessed November 21, 2008.1. Global Initiative for Chronic Obstructive Lung Disease. http://www.goldcopd.org/guidelineitem.asp?l1=2&l2=1&intld=2003. Accessed November 21, 2008.2. American Thoracic Society, European Respiratory Society. http://www.thoracic.org/sections/copd/. Accessed November 19, 2008.2. American Thoracic Society, European Respiratory Society. http://www.thoracic.org/sections/copd/. Accessed November 19, 2008.

Patients With COPD Ipratropium (anticholinergic)Patients With COPD Ipratropium (anticholinergic)

Patients With COPD Albuterol (βPatients With COPD Albuterol (β22-Agonist)-Agonist)

▲

Asthma and COPD Have Varying Degrees Asthma and COPD Have Varying Degrees of Bronchodilator Responsivenessof Bronchodilator Responsiveness

n=19.n=19.

Adapted with permission from Higgins BG Adapted with permission from Higgins BG et al.et al. Eur Resp JEur Resp J. 1991;4:415-420.. 1991;4:415-420.

Patients With Asthma Ipratropium (anticholinergic)Patients With Asthma Ipratropium (anticholinergic)

Patients With Asthma Albuterol (βPatients With Asthma Albuterol (β22-Agonist)-Agonist)

■

Cumulative Dose (µg)Cumulative Dose (µg)

0.80.8

0.70.7

0.60.6

0.50.5

0.40.4

0.30.3

0.20.2

0.10.1

00 1010 100100 10001000

Δ F

EV

Δ F

EV

11

■

■■

■

▲▲ ▲ ▲

COPD Previously Defined as “Irreversible” COPD Previously Defined as “Irreversible” Airway ObstructionAirway Obstruction

Note: Actual subset sizes were not proportional relative to the subset images.Note: Actual subset sizes were not proportional relative to the subset images.

Adapted from American Thoracic Society. Adapted from American Thoracic Society. Am J Respir Crit Care MedAm J Respir Crit Care Med. 1995;152(5 pt 2):S77-S121.. 1995;152(5 pt 2):S77-S121.

Chronic BronchitisChronic Bronchitis EmphysemaEmphysema

Airflow Airflow ObstructionObstruction

AsthmaAsthma

COPDCOPD(Irreversible)(Irreversible)

(Reversible)(Reversible)

Mean Reversibility ~4%

Baseline CharacteristicsBaseline Characteristics

Study GroupStudy Group

SIASIA(n=1961)(n=1961)

SIPSIP(n=1962)(n=1962)

UCUC(n=1964)(n=1964)

Mean (SD) age, yearsMean (SD) age, years 48.4 (6.8)48.4 (6.8) 48.6 (6.8)48.6 (6.8) 48.4 (6.9)48.4 (6.9)

Male, %Male, % 60.860.8 64.064.0 63.863.8

Mean (SD) pack-years of cigarette smokingMean (SD) pack-years of cigarette smoking 40.4 (19.7)40.4 (19.7) 40.4 (18.8)40.4 (18.8) 40.5 (18.9)40.5 (18.9)

Mean (SD) FEVMean (SD) FEV11 L (prebronchodilator) L (prebronchodilator) 2.62 (0.61)2.62 (0.61) 2.64 (0.59)2.64 (0.59) 2.65 (0.59)2.65 (0.59)

Mean (SD) FEVMean (SD) FEV11 L (postbronchodilator) L (postbronchodilator) 2.73 (0.64)2.73 (0.64) 2.75 (0.62)2.75 (0.62) 2.76 (0.62)2.76 (0.62)

Mean (SD) FEVMean (SD) FEV11, predicted %, predicted % 75.1 (8.8)75.1 (8.8) 75.2 (8.8)75.2 (8.8) 75.1 (8.8)75.1 (8.8)

Mean (SD) FEVMean (SD) FEV11/FVC, %/FVC, % 62.9 (5.6)62.9 (5.6) 63.0 (5.5)63.0 (5.5) 62.9 (5.5)62.9 (5.5)

Mean (SD) bronchodilator response (% of FEV1) 4.2 (5.2) 4.4 (5.1) 4.2 (5.1)

Patient Populations Included in COPDPatient Populations Included in COPDStudies Were Largely “Irreversible”Studies Were Largely “Irreversible”

n=5887.n=5887.

SIA=smoking intervention and inhaled bronchodilator ipratropium bromide.SIA=smoking intervention and inhaled bronchodilator ipratropium bromide.SIP = smoking intervention plus placebo.SIP = smoking intervention plus placebo.UC=usual care.UC=usual care.

Anthonisen NR et al. Anthonisen NR et al. JAMAJAMA. 1994;272:1497-1505.. 1994;272:1497-1505.

Lung Health Study Subject Demographics and Baseline CharacteristicsLung Health Study Subject Demographics and Baseline Characteristics

““Irreversible” Patients Can ChangeIrreversible” Patients Can ChangeTheir Reversibility Status Over TimeTheir Reversibility Status Over Time

Study Population: 660 Patients Meeting Both ERS and ATS Criteria for Study Population: 660 Patients Meeting Both ERS and ATS Criteria for Irreversible COPD, 40-75 Years of Age, Current or Ex-tobacco SmokersIrreversible COPD, 40-75 Years of Age, Current or Ex-tobacco Smokers

N = 660N = 660

Visit 0: 58%Visit 0: 58%

Visit 1: 62%Visit 1: 62%

Visit 2: 59%Visit 2: 59%

52% of Patients Changed Bronchodilator Responder Status 52% of Patients Changed Bronchodilator Responder Status Over a 2-month Period per ATS CriteriaOver a 2-month Period per ATS Criteria

Total % Not ReversibleTotal % Not Reversibleat Each Visitat Each Visit

Calverley PM et al. Calverley PM et al. ThoraxThorax. 2003;58:659-664.. 2003;58:659-664.

= Positive responders= Positive responders

= Negative responders= Negative responders

98

48 50

385

287

213 74

121

75 51

275

46

154

103

73% of Patients Show Reversibility to Short-acting Bronchodilators*73% of Patients Show Reversibility to Short-acting Bronchodilators*

27%27%

11%

(n=280)(n=280)

27%27%

35%35%

(n=217)(n=217)

(n=222)(n=222)

(n=91)

N=813.N=813.*Reversibility defined as ≥12% and >200 mL increase in FEV*Reversibility defined as ≥12% and >200 mL increase in FEV11..

Donohue J et al. Presented at the 1997 International Conference of the American Thoracic Society. San Francisco, CA; May 18-21, 1997. Donohue J et al. Presented at the 1997 International Conference of the American Thoracic Society. San Francisco, CA; May 18-21, 1997.

Reversibility Varies by PatientReversibility Varies by Patientand Bronchodilatorand Bronchodilator

BothBoth

NeitherNeither

Albuterol onlyAlbuterol only

Ipratropium onlyIpratropium only

A Recent Study Also Demonstrates A Recent Study Also Demonstrates Reversibility in Many Patients With COPDReversibility in Many Patients With COPD

Postbronchodilator FEVPostbronchodilator FEV11 measured after administration of 80 µg ipratropium and 400 µg albuterol. measured after administration of 80 µg ipratropium and 400 µg albuterol.

Adapted with permission from Tashkin DP et al. Adapted with permission from Tashkin DP et al. Eur Resp JEur Resp J. 2008;31:742-750.. 2008;31:742-750.

Change in FEVChange in FEV11 % %

1515

1010

55

00

Pat

ien

ts,

%P

atie

nts

, %

-30-30 -25-25 -20-20 -15-15 -10-10 -5-5 00 55 1010 1515 2020 2525 3030 3535 4040 4545 5050 5555 6060 6565 7070 7575 8080 8585 9090 9595 100100

Degree of ReversibilityDegree of Reversibility

~54% of Patients Met ATS Reversibility Criteria (≥12% + ≥200 mL)~54% of Patients Met ATS Reversibility Criteria (≥12% + ≥200 mL)

*65.6% showed a *65.6% showed a >>15% 15% increase in FEVincrease in FEV11

**

Bronchodilators Play an Important RoleBronchodilators Play an Important Rolein COPD Treatment Algorithmsin COPD Treatment Algorithms

ATS/ERS GuidelinesATS/ERS Guidelines

SA-BD = short-acting bronchodilator; LA-BD = long-acting bronchodilator;SA-BD = short-acting bronchodilator; LA-BD = long-acting bronchodilator; ICS = inhaled corticosteroid.ICS = inhaled corticosteroid.

Adapted from Celli B et al. Adapted from Celli B et al. Eur Respir JEur Respir J. 2004;23:932-946. . 2004;23:932-946.

Intermittent Sx Intermittent Sx (cough, wheeze, dyspnea)(cough, wheeze, dyspnea)

Persistent Sx Persistent Sx (dyspnea, pm awakenings)(dyspnea, pm awakenings)

SA-BDSA-BD p.r.n. p.r.n.

LA-BD/SA-BDLA-BD/SA-BD q.i.d. with rescue q.i.d. with rescue

Alternative class/combination (Alternative class/combination (LA-BDLA-BD/ICS)/ICS)

Add/substitute oral theophyllineAdd/substitute oral theophylline

Limited Benefit?Limited Benefit?

Limited Benefit? AE?Limited Benefit? AE?

YesYes

YesYes

Confirm DxConfirm Dxof COPDof COPD

Bronchodilatory Response Varies in COPDBronchodilatory Response Varies in COPDLong-acting Long-acting ββ22-agonist vs Long-acting Anticholinergic-agonist vs Long-acting Anticholinergic

AUC FEVAUC FEV11 0-2 hours; 0-2 hours;

Formoterol +114 mL vs tiotropium (Formoterol +114 mL vs tiotropium (PP=0.014)=0.014)

n=81.n=81.

Form = formoterol.Form = formoterol.Tio = tiotropium.Tio = tiotropium.

Richter K et al. Richter K et al. RespirationRespiration. 2006;73:414-419. . 2006;73:414-419.

1.31.3

1.41.4

1.51.5

1.61.6

1.71.7

1.81.8

00 6060 120120 180180 240240 300300 360360 420420 480480 540540 600600 660660 720720

Time (min)Time (min)

FE

VF

EV

11 (m

L)

(m

L)

Form 12 µg bidForm 12 µg bid Tio 18 µg qdTio 18 µg qd

n=80.n=80.

T = tiotropium; P = placebo; FRC = functional residual capacity.T = tiotropium; P = placebo; FRC = functional residual capacity.**PP<0.01.<0.01.

Celli B et al. Celli B et al. ChestChest. 2003;. 2003;124:1743-1748. 124:1743-1748.

Significant Improvements in Volume-based Significant Improvements in Volume-based Measurements After BronchodilatorMeasurements After Bronchodilator

-800-800

-600-600

-400-400

-200-200

00

200200

400400

600600

FVCFVC ICIC FRCFRC

Dif

fere

nce

(T

– P

) at

Day

28

(mL

)D

iffe

ren

ce (

T –

P)

at D

ay 2

8 (m

L)

FEVFEV11

****

FlowFlow VolumeVolume

PredosePredose PostdosePostdose

800800

** ****

**

**

**

Patients May Respond to Long-term Bronchodilator Patients May Respond to Long-term Bronchodilator Therapy, Regardless of Initial Reversibility StatusTherapy, Regardless of Initial Reversibility Status

n=921.n=921.

**PP<.001 vs placebo at all time points following drug administration.<.001 vs placebo at all time points following drug administration.

Tashkin D, Kesten S. Tashkin D, Kesten S. ChestChest. 2003;123:1441-1449.. 2003;123:1441-1449.

1.01.0

1.11.1

1.21.2

1.31.3

1.41.4

FE

VF

EV

11 (l

iter

s) (

lite

rs)

-60-60 -5-5 3030 6060 120120 180180

PlaceboPlacebo

TiotropiumTiotropium

Time (minutes)Time (minutes)

1.01.0

1.11.1

1.21.2

1.31.3

1.51.5

FE

VF

EV

11 (l

iter

s) (

lite

rs)

-60-60 -5-5 3030 6060 120120 180180

PlaceboPlacebo

TiotropiumTiotropium

Time (minutes)Time (minutes)

1.41.4

Day 1Day 1 Day 344Day 344

RespondersResponders Poor RespondersPoor Responders

**

**

Understanding Reversibility in COPDUnderstanding Reversibility in COPD

• Professional guidelines and clinical data demonstrate that Professional guidelines and clinical data demonstrate that airflow obstruction in COPD is at least partially reversibleairflow obstruction in COPD is at least partially reversible

• Studies show that bronchodilators can improve lung Studies show that bronchodilators can improve lung function in COPD patientsfunction in COPD patients

• Reversibility status may vary in response to different Reversibility status may vary in response to different bronchodilators, and may change over timebronchodilators, and may change over time

• Patients may respond to long-term bronchodilator therapy, Patients may respond to long-term bronchodilator therapy, regardless of short-term reversibility regardless of short-term reversibility