Lynn M. Keenan, MD, FACP, FCCP Lynn M. Keenan, MD, FACP, FCCP Pulmonary/Critical Care Medicine...

Lynn M. Keenan, MD, FACP, FCCPPulmonary/Critical Care Medicine

Northwest Hospital and Medical CenterWAPA

January 2013

Overview of COPD

Disclosures

Speakers Bureau Boehringer Ingelheim I hate tobacco abuse I am a old SNL and Seinfeld Fan If you were here last year, I updated my jokes I miss “The Closer”, doesn’t everyone?

Clinical Course of COPD

Air TrappingExpiratory Flow Limitation

Breathlessness

Inactivity

Poor Health-Related Quality of Life

Hyperinflation

Deconditioning

COPD

Disability Disease progression Death

Reduced Exercise Capacity

COPD

Exacerbations

Adapted from Decramer M. Eur Respir Rev. 2006;15:51-57.

COPD Definition and Epidemiology

GOLD: Global Initiative for Chronic Obstructive Lung Disease

Goals: awareness, decrease mortality and morbidity

Improve prevention and management Systemic consequences: persistent systemic

inflammatory state leads to: Decreased fat-free mass, impaired systemic muscle

function, anemia, osteoporosis, depression, pulmonary hypertension, cor pulmonale


Largest disease burden >age 40: 9-10 % adults, greater in men Affects 10% general population and 50%

heavy smokers > 80% pts. Under diagnosed survey 8,215 pts. 16 million people with 110,000 deaths 2010 3rd leading cause of death 2011 3% mortality for hospital admission 50% mortality for ICU admission within 2 years

• High BODE index• Multiple severe exacerbations• CVD • Decreased FEV1

• Dyspnea• Hyperinflation (IC/TLC ≤ 25%)• Pulmonary hypertension• Impaired Exercise Performance• Depression• Low BMI

Predictors of COPD Mortality

2 Million, Severe Disease*

10 Million

12+ Million at risk

and unidentified

SUBCLINICAL COPD

Clinical COPD – Tip of the Iceberg

Adapted from Mannino DM, et al. MMWR Morb Mortal Wkly Rep. 2002;51(SS06):1-16.

Airflow Limitation Starts Before Symptoms are Evident


Women >er mortality poorer prognosis with BMI of 25 and lower BODE

index Faster decline in FEV1 has a modest increased

risk of death and time to COPD related hospitalization

Severe COPD: increased mortality with more advanced age, lower BMI, oxygen supplementation, greater hyperinflation, also patients at increased risk lung cancer, atherosclerosis, and osteoporosis

Presence of chronic cough/sputum identifies a subgroup with higher risk of developing COPD, independent of smoking habits

Question 1: Who is your average COPD patient?

The Marlboro man55 year old working woman85 yo man with ASCAD, and prostate

cancer80 yo retired Army thoracic surgeon

Who does COPD Affect? Aunt Ann and my Dad.

Really?

My Aunt Carrie

Seriously?

It even looks like a fungus


Risk Factors: cigarette smoking, Marijuana, alpha-1-antitrypsin deficiency, heavy occupational dusts, biomass fuels and chemical fumes, environmental tobacco smoke, lung growth (viral, fetal exposure)

Caused by interaction of noxious inhaled agents and host factors increasing neutrophils and macrophages

Toxic gases generate cytokines and chemokines control migration of inflammatory immune cells, leading to compromised repair of lung structure and function, increased apoptosis of endothelial and epithelial cells

* Years after 2000 include adults aged ≥ 25y only

COPD Mortality

0

10000

20000

30000

40000

50000

60000

70000

1975 1980 1985 1990 1995 2000 2005 2010

Male

Female

Year

An

nu

al U

S D

eath

s

Mannino DM, et al. MMWR Morb Mortal Wkly Rep. 2002;51(SS-6):1-16.Brown DW, et al. MMWR Weekly. 2008;57(45):1229-1232

COPD Immunology Small airways: inflammatory cell infiltrate,

remodeling thickens the airway and increases resistance to flow

Prominent inflammatory infiltrates in the alveolar walls, destruction of alveoli, and enlargement of air spaces

Inflammation mediated by T-cells persists after smoking cessation

Cigarette use increased oxidative stress

24

Tamagawa E et al. Chest. 2006;130:1631-1633.

Lung Inflammation and Vascular DiseaseEffects of Lung Inflammation on Blood Vessels

Normal Lungs and Lungs With COPD

Manifestations of COPD

• Emphysema: pathologic diagnosis

• Hyperinflation

• Mucus hypersecretion (chronic bronchitis)

• Frequent exacerbations

• Severe hypoxemia

• Low BMI

• Skeletal muscle dysfunction

Papaioannou AI, et al. Respir Med. 2009;103:650-660. Celli BR. Proc Am Thorac Soc. 2006;3:461-465.

Increased Risk for Cardiovascular Disease in COPD

MI = myocardial infarction, CHF = congestive heart failure, CVD = cardiovascular disease; All between-group differences P < 0.05 – adjusted for CV risk

Curkendall SM, et al. Ann Epidemiol. 2006;16:63-70.

21.1

11.2

5.6

31.3

9.6

70.4

22.8

11.7

6.43.2

9 7.9

54

11.2

0

10

20

30

40

50

60

70

80

Arrhythmia Angina Acute MI CHF Stroke Other CVD CVDHospitalization

Per

cen

t of

Subj

ects

COPD (N = 11,493)Controls (N = 22,986)

• Retrospective study of Canadian databases• Subjects age ≥ 40 years • Diagnosed with COPD during 1997–2000 • Received ≥ 2 Rx for dilators w/i 6 months

The Risk of Osteoporosis in Caucasians With Obstructive Airways Disease

Sin DD, et al. Am J Med. 2003;114:10-14.

P = 0.005 for trends

1.93.9

6.8

11

7.610.3

20.9

33

0

5

10

15

20

25

30

35

None Mild Moderate Severe

Severity of Airflow Obstruction

Per

cen

t of

Su

bje

cts

wit

h

Ost

eop

oros

is

Men

Women

Severe Obstructive Airway Disease Is Associated With Greater Risk of Fracture

de Vries F, et al. Eur Respir J. 2005;25:879-884.

0.2 0.5 1 2.0 5.0

Hip fracture

Osteoporotic fracture

Vertebral fracture

*Adjusted in patients with severe COPD for general risk factors, smoking status, duration of enrollment, and exposure to bronchodilators

ICS - No

ICS - Yes

ICS - No

ICS - Yes

ICS - No

ICS - Yes

Odds Ratio*

Skeletal Muscle Dysfunction in COPD

Low muscle mass Poor capillarity Low muscle oxidative

enzyme activity Low fraction of type I fibers Muscle inflammation Corticosteroid myopathy Low levels of anabolic

hormones Vasoregulatory abnormalities

Lactate Increase During Exercise

Maltais F, et al. Am J Respir Crit Care Med. 1996;153:288-293.

VO2 (L/min)

Testosterone

IGF-1

Insulinresistance

Negative energy balance

Hypoxemia

Steroidtreatment

Muscle protein breakdown

Muscle wastingand cachexia

Inflammation

Mechanisms of Muscle Wasting and Cachexia in COPD

Balasubramanian VP, Varkey B. Curr Opin Pulm Med. 2006;12:106-112.

Pro

por

tion

Su

rviv

ing

Months of Follow-up

BMI (kg/m2)■ > 29● 24-29✴ 20-24▼ < 20

Low BMI Predicts Increased Mortality

• Cox proportional hazards model • Low BMI was an independent predictor of increased mortality (P < 0.001)• After stratification into BMI quintiles, the mortality risk was clearly

increased below 25 kg/m2

Schols AM, et al. Am J Respir Crit Care Med. 1998;157(6 Pt 1):1791-1797.

Prevalence of Depression in COPD

Overlap between symptoms of depression and COPD (fatigue, sleep, appetite)1

Prevalence: 20%–60%1,2

Impact3

– Decreased functional performance– Lower QOL scores

Inadequate recognition and treatment1

1. Kunik ME, et al. Chest. 2005;127:1205-1211.2. Norwood R. Curr Opin Pulm Med. 2006;12:113-117.3. Felker B, et al. Gen Hosp Psych. 2001;23:56-61.

Prognostic Impact of Pulmonary Hypertension

Oswald-Mammosser M, et al. Chest. 1995;107:1193-1198.

– – – mean PAP ≥ 25 mmHg–––– mean PAP < 25 mmHg

mean PAP > 18 mmHgmean PAP 18 mmHg

PAP: pulmonary artery pressure

Years w/o Hospitalization for Exacerbation

Kap

lan

-Mei

er E

stim

ates

Survival time, months

Su

rviv

al R

ate

The Majority of Patients with COPD Are Among Working Age Population

Employees With COPD Incurred >4 Times Higher Total Mean Healthcare Costs

Patients with COPD often have Multiple Comorbid Conditions

Comorbid Conditions in Patients with COPD Are More Likely to be Treated Than COPD

Mortality Associated With COPD

COPD Management

Prevent disease and progression Relieve symptoms Improve exercise tolerance Improve health status Prevent and treat complications Treat exacerbations Reduce mortality

The COPD Population Screener (COPD-PS)

1. During the past 4 weeks, how much of the time did you feel short of breath?

2. Do you ever cough up any “stuff”, such as mucus or phlegm?

4. Have you smoked at least 100 cigarettes in your ENTIRE LIFE?

Yes

A little of the time

Some of the time

Most of the time

All of the time

None of the time

0 1 2 20

Only with occasional

colds or chest infections

Yes, a few days a month

Yes, most days a week

No, never Yes, every day

0 1 1 20

Disagree Unsure Agree Strongly agree

Strongly disagree

0 0 10 2

5. How old are you?

Don’t knowNo

0 2 0

Age 35 to 49 Age 50 to 59 Age 60 to 69 Age 70 +

1 2 20Martinez FJ, et al. COPD. 2008;5:85-95.

3. Please select the answer that best describes you in the past 12 months, I do less than I used to because of my breathing problems.

Screening for COPD with Spirometry?

Lin K, et al. Ann Intern Med. 2008;148(7):535-543.

Current status Underrecognized

Spirometry screening

Overdiagnosis (other causes of symptoms)

Symptom screening

Overdiagnosis (asymptomatic

healthy)

1. Symptoms

2. Spirometry Appropriate diagnosis

Global Strategy for Diagnosis, Management and Prevention of COPD

Diagnosis and Assessment: Key Points

A clinical diagnosis of COPD should be considered in any patient who has dyspnea, chronic cough or sputum production, and/or a history of exposure to risk factors for the disease.

Spirometry is required to make the diagnosis; the presence of a post-bronchodilator FEV1/FVC < 0.70 confirms the presence of persistent airflow limitation and thus of COPD.

Need a Quality Test

Spirometry: Obstructive DiseaseVolu

me,

liters

Time, seconds

5

4

3

2

1

1 2 3 4 5 6

FEV1 = 1.8L

FVC = 3.2L

FEV1/FVC = 0.56

Normal

Obstructive

Spirograms and Flow Volume Curves

A- RestrictiveB- NormalC- Obstructive

Flow volume loops:Normal vs. COPD

:

Normal Flow volume loop vs. COPD

MILD COPD

Severe COPD


Classification of Severity of Airflow Limitation in COPD*

In patients with FEV1/FVC < 0.70:

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

Assess symptoms Assess degree of airflow limitation

using spirometry Assess risk of exacerbations

Assess comorbidities

Use history of exacerbations and spirometry. Two exacerbations or more within the last year

or an FEV1 < 50 % of predicted value are indicators of high risk


Assessment of COPD


Assess Risk of Exacerbations

To assess risk of exacerbations use history of exacerbations and spirometry: Two or more exacerbations within the last year or an FEV1

< 50 % of predicted value are indicators of high risk.


Combined Assessment of COPD

Assess symptoms Assess degree of airflow limitation using spirometry Assess risk of exacerbations

Combine these assessments for the purpose of improving management of COPD



Ris

k

(GO

LD

Cla

ssif

icat

ion

of A

irfl

ow L

imit

atio

n)

Ris

k

(Exa

cerb

atio

n hi

stor

y)

> 2

1

0

(C) (D)

(A) (B)

mMRC 0-1CAT < 10

4

3

2

1

mMRC > 2CAT > 10

Symptoms(mMRC or CAT score)



(C) (D)

(A) (B)

mMRC 0-1

CAT < 10

mMRC > 2CAT > 10


If mMRC 0-1 or CAT < 10: Less Symptoms (A or C)

If mMRC > 2 or CAT > 10: More Symptoms (B or D)

Assess symptoms first


Combined Assessment of COPDR

isk

(G

OL

D C

lass

ific

atio

n of

Air

flow

Lim

itat

ion

)

Ris

k

(Exa

cerb

atio

n hi

stor

y)

> 2

1

0

(C) (D)

(A) (B)

mMRC 0-1CAT < 10

4

3

2

1

mMRC > 2CAT > 10


If GOLD 1 or 2 and only 0 or 1 exacerbations per

year: Low Risk (A or B)

If GOLD 3 or 4 or two ormore exacerbations per

year: High Risk (C or D)

Assess risk of exacerbations next



Ris

k

(GO

LD

Cla

ssif

icat

ion

of A

irfl

ow L

imit

atio

n)

Ris

k

(Exa

cerb

atio

n hi

stor

y)

> 2

1

0

(C) (D)

(A) (B)

mMRC 0-1CAT < 10

4

3

2

1

mMRC > 2CAT > 10


Patient is now in one offour categories:

A: Les symptoms, low risk

B: More symtoms, low risk

C: Less symptoms, high risk

D: More Symtoms, high risk

Use combined assessment

Patient Characteristic Spirometric Classification

Exacerbations per year

mMRC CAT

ALow Risk

Less SymptomsGOLD 1-2 ≤ 1 0-1 < 10

BLow Risk

More SymptomsGOLD 1-2 ≤ 1 > 2 ≥ 10

CHigh Risk

Less SymptomsGOLD 3-4 > 2 0-1 < 10

DHigh Risk

More SymptomsGOLD 3-4 > 2 > 2

≥ 10



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

COPD Risk: exacerbations, hospitalization, death

CAT Scores: impact and management

< 10: low impact: smoking cessation, annual influenza vaccination, reduce exacerbation risk, therapy by clinical assessment

10-20: medium impact: add review maintenance therapy, refer pulmonary rehab, minimize exacerbation, review aggravating factors: smoking

CAT Scores: impact and management

21-30:high impact: pt has significant room for improvement, consider referral to specialist, additional pharmacologic treatments

>30: very high impact: same as high impact

Exacerbations Can Increase Healthcare Burden Associated With COPD

• Exacerbations of COPD can have negative impacts on patient lung function, health-related quality of life, and socioeconomic costs• Lung function declined more rapidly in patients with frequent exacerbations

• Direct medical costs for exacerbations associated with COPD remain at approximately $18 billion per year

1) The Global Initiative for Chronic Obstructive Lung Disease. GOLD Report—Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Updated 2009.; 2) Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57(10):847-852. ; 3)Anzueto A, Sethi S, Martinez FJ. Exacerbations of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2007;4(7):554-564.

Communication Is Essential to Monitoring Exacerbations

Management of Exacerbations Associated With COPD

The Global Initiative for Chronic Obstructive Lung Disease. GOLD Report—Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Updated 2009.

Impact of COPD

The BODE Index

0 1 2 3

FEV1 (% predicted) 65 50-64 36-49 35

Distance walked in 6 min. (M) 350 250-349 150-249 149

MMRC dyspnea scale 0-1 2 3 4

BMI > 21 21

Variable Points on BODE Index

Celli BR, et al. N Engl J Med. 2004;350:1005-1012.

BODE = body mass index, obstruction, dyspnea, and exercise capacity; MMRC = Modified Medical Research Council

Survival in COPDFEV1 Stage BODE

Months

1.0

0.8

0.6

0.4

0.2

0.00 4 8 12 16 20 24 28 32 36 40 44 48 52 0 4 8 12 16 20 24 28 32 36 40 44 48 52

Stage I (> 50%) predicted

Stage II (36-50%) predicted

Stage III ( 35%) predicted

Quartile 1 (BODE 0-2)

Quartile 2 (BODE 3-4)

Quartile 3 (BODE 5-6)Quartile 4 (BODE 7-10)

Pro

babi

lity

of

Surv

ival

P < 0.001 P < 0.001

Celli BR, et al. N Engl J Med. 2004;350:1005-1012.

COPD DIFFERENTIAL

Asthma Congestive heart failure Bronchiectasis Verklempt

More Than 50% of Patients With COPD Were Misdiagnosed With Asthma

Tinkelman DG, Price DB, Nordyke RJ, Halbert RJ. Misdiagnosis of COPD and asthma in primary care patients 40 years of age and over. J Asthma. 2006;43(1):75-80.

Differential Diagnosis: COPD and Asthma

COPD Management

Ongoing monitoring and assessment Progressive disease Follow up spirometry Monitor pharmacotherapy: therapeutics,

adherence, technique, effectiveness of controlling symptoms

Monitor exacerbation: frequency and severity

Question 2: If a patient stops smoking the lung function improves

True False Maybe a little

Smoking Cessation Can Slow COPD Onset and Progression

Question 3: What 4 interventions improve survival in severe COPD?

1. Exercise, oxygen, beta agonists, nutrition

2. Exercise, oxygen, anticholinergics, nutrition

3. Exercise, oxygen, quitting smoking, inhalers

4. Exercise, oxygen, quitting smoking, nutrition

Comprehensive Approach for COPD Management

• Counseling• Nicotine replacement

– Gum

– Inhaler

– Nasal spray

– Transdermal patch

– Sublingual tablet

– Lozenge

Acidic Beverages (coffee)

• Bupropion• Varenicline

First Line Smoking Cessation Treatments

GOLD Guidelines 2008. http://www.goldcopd.com/Guidelineitem.asp?l1=2&l2=1&intId=2003. Accessed September 2010.

Carbon Monoxide-Confirmed 4-Week Continuous Quit Rates Weeks 9–12

OR = 3.85*

OR = 1.93*

OR = 3.85*

OR = 1.90*

100

44.0 43.9

29.829.5

17.617.7

0

20

40

60

Study I Study II

Res

pon

se R

ate

(%)

Varenicline Bupropion Placebo

N = 352 N = 329 N = 344 N = 344 N = 342 N = 341

OR = odds ratio

*P < 0.001

Gonzales D, et al. JAMA. 2006;296:47-55. Jorenby DE, et al. JAMA. 2006;296:56-63.

Smoking Cessation with Varenicline

Tx Period

Tashkin DP, et al. Chest. 2010 Sep 23. [Epub ahead of print]

1o Endpoint

Adverse Event Varenicline0.5 mg BID

n = 129

Varenicline1 mg BIDn = 821

Placebon = 805

Nausea 16% 30% 10%

Insomnia* 19% 18% 13%

Abnormal Dreams

9% 13% 5%

Constipation 5% 8% 3%

Flatulence 9% 6% 3%

Vomiting 1% 5% 2%

Varenicline: Most Common Adverse EventsFrom 12-week Fixed-Dose, Placebo-Controlled Studies

* Includes Preferred Terms: Insomnia/Initial insomnia/Middle insomnia/Early morning awakening*

Varenicline package insert. Available at: www.pfizer.com/files/products/uspi_chantix.pdf. Accessed September 2010.

• Psychiatric symptoms

– Changes in behavior

– Agitation

– Depressed mood

– Suicidal ideation

– Suicidal behavior• “Advise patients and caregivers that the patient should

stop taking CHANTIX (varenicline) and contact a health care provider immediately if agitation, depressed mood, or changes in behavior that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior.”

Varenicline Warning

Varenicline package insert. http://www.pfizer.com/files/products/uspi_chantix.pdf. Accessed September 2010.

Nicotine Nasal Spray with Nicotine Patch for Smoking Cessation

Percentage (number) of participants abstinent from smoking at follow up

• 237 smokers followed for 6 years• Combination of a 5 month nicotine patch + nicotine nasal spray is

more effective for smoking cessation than the patch alone

Blondal T, et al. BMJ. 1999;318:285-288.

• At every encounter, ask patient if he/she is still smoking, and chart response

• At every encounter, give strong advice to quit smoking• Measure expired CO (> 10 ppm) • Perform/order spirometry, use spirometry results and ‘lung age’

as leverage to advise smoking cessation• Ask patient if they are ready to quit and their history of attempts• Negotiate/impose a target ‘Quit Day’, have staff follow up that

day– Schedule follow-up appointments

• Refer patient to a behavioral support program or telephone quit line

• Prescribe pharmacological support as appropriate– NRT, bupropion SR, varenicline

Tips to Help Patients Quit Smoking

Adapted from Tashkin DP, and Murray RP. Respir Med. 2009;103:963-974.

Short acting bronchodilators: B2 adrenergic agonist: albuterol, levalbuterolAnticholinergic agent: ipratropiumCombination: albuterol/ipratropium

Long acting bronchodilatorsB2 adrenergic agonists: salmeterol, formoterol,

aformoterol , IndacaterolAnticholinergic: tiotropium bromide, Aclidinium

Inhaled corticosteroids: fluticasone, budesonide, beclomethasone, mometasone

Combinations: fluticasone-salmeterol, budesonide-formoterol, mometasone-fomoterol

Methylxanthines: theophyllinePDE4 Inhibitor: RoflumilastAntibiotics: Azithromycin

Rescue vs Maintenance Medication in Moderate COPD

COPD Management: PharmacologicTheophylline

Theophylline: Thoracic Park Smooth muscle relaxation Fall in trapped gas volume Pulmonary vascular dilator Level 6-10 Studies: 110 patients 100mg bid over 1 year,

favorable, decreased exacerbations, decreased clinic visits, increased FEV1

42 Theophylline and 43 placebo

COPD Management:Pharmacologic

Theophylline May act as nonselective phosphodiesterase inhibitors Significance is disputed Clearance of the drug decreases with age All studies were performed with slow release

preparations There is evidence to show greater improvement in

FEV1 when added to salmeterol than salmeterol alone

Toxicity: arrythmias, nausea, vomiting, seizure, GERD, plus multiple drug interactions

PDE4 Inhibitor RoflumilastStudy Design

Anti-inflammatory action Previously shown to improve lung function but not

exacerbations Assess exacerbations in carefully selected patients Patients: confirmed COPD

Severe airflow limitation (FEV1/FVC ≤ 70%) Bronchitic symptoms History of exacerbations Current or former smokers (≥ 20 pack-year

history) > 40 years old

2 parallel identical studies

Calverley PM, et al. Lancet. 2009;374(9691):685-694.

PDE4 Inhibitor Roflumilast 4 week run-in with placebo Randomization (Study M2-124 n = 1525; M2-125 n = 1571)

Roflumilast 500 mcg qd Placebo

52 weeks of treatment Permitted co-medications

LABA SABA Continuing short- or long-acting anticholinergics

Forbidden co-medications Inhaled CS New long-acting anticholinergics

1o endpoints Change in pre-bronchodilator FEV1

Rate of COPD exacerbations NO NOT GIVE IN COMBINATION with Theophylline


PDE4 Inhibitor RoflumilastResults


M2-124 M2-125 Pooled

Rof Pbo Δ P Rof Pbo Δ P Rof Pbo Δ P

Δ pre-dilator FEV1 (mL) 46 8 39 0.0003 33 -25 58 < 0.0001 40 -9 48 < 0.0001

RR RR RR

Mean exac rate (per pt*yr)

1.08 1.27 0.85 0.028 1.21 1.49 0.82 0.004 1.14 1.37 1.37 0.0003

• Study confirms efficacy in selected patients with COPD

• No roflumilast effect on mortality or CRP levels

• Diarrhea, nausea, weight loss more common with roflumilast

COPD Management: PharmacologicBeta Agonists

Sympathomimetics: Albuterol, Salbutamol, Levalbuterol, Salmeterol, Formoterol, Indacaterol

B2: bronchial smooth muscle: small and medium airways, stimulate beta2 adrenergic receptors

Improve mucocilliary clearance Increased response in combination therapy Cardiovascular effects, hypokalemia,

tachyphylaxis, lactic acidosis and respiratory failure

Dose: technique, spacer

COPD Management: PharmacologicBeta Agonists

SABA: takes effect in 15-20 minutes and lasts 4 hours

LABA: Salmeterol: takes effect in 4 hours and lasts 12

hours Fomoterol: takes effect in 1 hour and lasts

12hours Indacaterol: takes effect in 1 hout and lasts 24

hours All significantly improve lung volumes, dyspnea,

health related quality of life, and exacerbation rate Aformoterol nebulized lasts 12 hours

COPD Management: Pharmacologic Anticholinergics Muscarinic receptors Airway smooth muscle: M3 Chronic bronchitis and emphysema 2x -4x

increased cholinergic tone Atropine 1920’s, Ipratropium bromide 1980’s,

Tiotropium 2004- proximal bronchiole and bronchi, Aclidinium 2012

Expiratory Airflow Limitation Leads to Air Trapping

Airflow Limitation Leads to Air Trapping and Hyperinflation

Hyperinflation

COPD Management: Pharmacologic

Ipratropium Dosing: 4 puffs Q6 hours Combivent 1990’s: Albuterol + Ipratropium

FEV1 increased 31-33% over baseline Fewer exacerbations

Tiotropium Bromide- once daily long acting bronchodilator

Long acting antimuscarinic agent, M3 receptors, effect one hour and lasts 24 hours


Minimal side effects: dry mouth, exacerbation glaucoma and constipation

Very safe Poorly absorbed

Donahue et al:Indacaterol vs. Tiotropium

Evaluated Indacaterol vs. placebo and placebo and Tiotropium over 26 weeks

1,683 patients, Moderate to severe COPD, Indacaterol 150 mcg or 300 mcg

SGRQ, FEV1, and exacerbations post dose trough FEV1 increased 180 ml with

Indacaterol and 140 ml with Tiotropium SGRQ improved but not statistically

significant, no improvement in decreased exacerbations

UPLIFT Trial

Time to first exacerbation: Tiotropium 16.5 months vs placebo 12.5 months

14% reduction in # exacerbations Tiotropium Mortality not statically significant 14.4% vs

16.3%

Clinical Course of COPD

Air TrappingExpiratory Flow Limitation

Breathlessness

Inactivity

Poor Health-Related Quality of Life

Hyperinflation

Deconditioning

COPD

Disability Disease progression Death

Reduced Exercise Capacity

COPD

Exacerbations

Adapted from Decramer M. Eur Respir Rev. 2006;15:51-57.

Question 5: what happens to your end expiratory lung volume with exercise?

A- increasesB- decreases

Totallung

capacity

Tidal volume

Inspiratory reservevolume

Expiratory reservevolume

Residual volume

Inspiratory capacity

Vital capacity

Functional residual capacity

Lung Volume Terminology

FRC

TV

IC

RV

Normal

Rest

Static and Dynamic Lung Volumes in COPD

Exercise

Rest

COPD

Exercise

Lung Volume Response to Exercise

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

0 5 10 15

Lung

vol

ume

(L)

Exercise time (minutes)

EELV

TLC

VT

IRV

Placebo

IC (1.92 L)

Operating Lung Volumes & Exercise Endurance Maltais et al

EELV

TLC

VT

IRV

IC (1.78 L)

Tiotropium

Management: Aclidinium bromide

Long term management of COPD, chronic bronchitis, emphysema

LAMA, twice a day, muscarinic receptor M3 receptors

Management: Aclidinium Bromide

Potential side effects: narrow angle glaucoma, urinary retention, cough, hypersensitivity to milk protein

Peak FEV1 improvements: 200mcg 235 ml and 400mcg 264ml

Trough FEV1 improvements: 200 mg 44 ml and 400mcg 109 ml

Sustained over 52 weeks


Steroids: acute exacerbation of COPD favorable results and substantial benefits

Improvement in wheezing, air flow Improvement in abnormal mucus Trial for 2-3 weeks Demonstrate 20-30% improvement FEV1 Response to oral steroids poor predictor

respond to inhaled steroids


Four large studies regular treatment with inhaled glucocorticosteroids appropriate for symptomatic COPD patients FEV1< 50% predicted

Treatment reduce frequency of exacerbations and improve health status

Benefit 25-50% of patients: improvement 6 minute walk

TRIPLE THERAPY

Welte et al.:Efficacy and Tolerability of Budesonide/Formoterol Added to Tiotropium in Patients with Chronic Obstructive Pulmonary Disease

To assess the efficacy and tolerability of budesonide/formoterol added to tiotropium in patients eligible for inhaled corticosteroid/long-acting β2-agonist combination therapy.

Triple Therapy

Over the treatment period, budesonide/formoterol plus tiotropium significantly increased predose FEV1 by 6% (65 ml) and postdose by 11% (123 and 131 ml at 5 and 60 min postdose, respectively) versus tiotropium alone (both P < 0.001). The number of severe exacerbations decreased by 62%. Both treatments were well tolerated.

FEV1 With Triple Combination Therapy

1. Aaron SD, et al. Ann Intern Med. 2007;146(8):545-555. 2. Welte T, et al. Am J Respir Crit Care Med. 2009;180(8):741-750.

● BUD/FORM + TIO

■ PBO + TIO

Tio +/- Fluc/Sal1 Tio +/- Bud/Form2

Exacerbations With Triple Combination Therapy

Tiotropium (n = 156)

Tiotropium + Salmeterol(n = 148)

Tiotropium + Salmeterol + Fluticasone

(n = 145)

% Pts with ≥ 1 exacerbations

62.8 % 64.8% 60.0%

Total Exacerbations 222 226 188

Exacerbations with Hospitalization

Incidence rate ratio compared with tiotropium + placebo (95% CI)

49 38

0.83(0.54 to 1.27)

26

0.53(0.33 to 0.86)

Aaron SD, et al. Ann Int Med. 2007;146(8):545-555.

COPD Management: Pharmacologic Side effects : well recognized with steroids Inhaled steroids: oral thrush, hoarseness,

bruising Increased pneumonia with

fluticasone/salmeterol (TORCH trial) Triamcinolone increased risk of bone fracture Budesonide least absorbed, no effect on

bone mineral density Fluticosone/salmeterol;

mometasone/formoterol; budesonide/formoterol

COPD Management: Pharmacologic Vaccines: influenza reduce the serious

illness and death in COPD by 50% Pneumococcal vaccine: 65 and older,

younger patients with COPD FEV1< 40%, reduction pneumonia

Alpha-1-antitrypsin augmentation therapy Smoking cessation: Varenicline, nicotine

acetycholine receptor agonist Mucolytics: controvertial, some evidence in

pts not on inhaled steroids N-acetylcyseine or carbocysteine may reduce exacerbations

Management

Azithromycin: macrolide antibiotics have immunomodulatory and anti-bacterial properties

1142 COPD patients: randomized placebo to Azithromycin 250 mg daily

Azithromycin increased time to first exacerbation from 174 days to 266 days

37% decrease exacerbation rate

Effects best in patients with more moderate GOLD II disease and former smokers

Increased hearing decrement 25% vs 20% 1 yr, no guidance for long term efficacy or

potential adverse effects of resistance Patients with tachycardia and prolonged QT

excluded

Management: Azithromycin

COPD mortality is increasing Exacerbations are an important risk factor for

mortality Treatment with current drugs and combinations can

reduce exacerbations Currently available drugs alone and in combination

have been shown to have beneficial impacts on lung function and patient-centered outcomes in COPD and are useful in managing COPD.

No pharmacologic agent has thus far been shown to modify the persistence or progression of the underlying inflammatory/profibrotic/elastolytic pathology in COPD

Implications of Recent Trial Results

COPD Management: Oxygen

1895: commercially produced liquid air 1920: hypoxia and right heart failure 1956: improves exercise capacity 1967: low flow O2 1968: improvement function in patients

receiving ambulatory O2 1970: long term home O2 increase survival 1980: O2 conserving device


Mortality reduced in patients with RA PaO2 < 56 mmHg or O2 saturation < 88%

RA PaO2 < 60 mmHg with erythrocytosis, mental dysfunction, CHF, or cor pulmonale

Need therapy for 18-24 hours


Improves quality of life, decreased hospitalization, improved psychomotor performance

Decreases pulmonary artery pressure

Improved COPD Survival on LTOT

Güell Rous R. Int J Chron Obstruct Pulmon Dis. 2008;3(2):231-237. Nocturnal Oxygen Therapy Trial Group. Ann Intern Med. 1980;93:391-398.Medical Research Council Working Party. Lancet 1981;1:681-686.

COPD Management: Pulmonary Rehab

Reduces symptoms, improve quality of life, increased physical and emotional participation in life activities

Covers non pulmonary issues Respiratory muscles abnormal: inactivity,

systemic inflammation, malnutrition, increased work of breathing, impaired oxygen delivery, co morbid states, electrolyte imbalance, and drugs


Involve several health professionals Comprehensive exercise training Nutrition counseling Education

Efficacy of Pulmonary Rehabilitation

0

50

100

150

200

250

Baseline 6 wks 1 yr

Griffiths TL, et al. Lancet. 2000;355:362-368.

02468

101214161820

Baseline 6 wks 1 yr

Control Rehabilitation

Walking DistanceDyspnea

•Patients participated in 3 half day sessions per week for 6 weeks in a multidisciplinary rehabilitation program including smoking cessation, occupational, physical, breathing, and diet sessions

•Physical therapy included 30 min sessions in-office as well as home sessions

–Treadmills, cycling, circuit training

P = 0.000

P = 0.017P = 0.000

P = 0.002


80 patients at LLUMC reduction from 19 to 6 days of hospitalization

Less time in hospital, fewer ER and office visits, return to work, increased ADL’s, more self care, decreased extended care and home care

Improved dyspnea and cough

COPD Management: Nutrition

Nutritional Supplements Have Not Increased Weight of Patients

Study

DeLetter 1991

Knowles 1988

Otte 1989

Rogers 1992

Schols 1995

Schols 1995a

Steiner 2003

Weekes 2004

18

13

13

15

39

33

25

30

N

17

12

15

12

25

38

35

25

N

Nutritional supplementation versus placebo or usual diet

Adapted from Ferreira IM, et al. Cochrane Database Syst Rev. 2009;(2):CD000998.

Standardized Mean Difference (Random)

9.2

7.2

8.1

7.8

12.9

13.9

12.6

11.9

Weight %95% CI

Total 214 205 100.0Test for overall effect Z = 1.25 P = 0.21

-4.0 -2.0 4.02.00Control better Supplement better

LVRS: resection of functionless areas of emphysematous lung to improve mechanics

FEV1< 20% and either homogenous emphysema or DLCO < 20% high risk for death or unlikely to benefit

Increases exercise capacity not confer survival advantage

COPD Management: Surgery

Yield advantage for patients both predominantly upper lobe emphysema and low baseline exercise capacity

Range of FEV1 improvement 250-350 ml Improved 6 minute walk $140,000 per quality-adjusted life year Resection of large bullae > 1/3 hemithorax Lung transplant

COPD Management: Surgery


Manage Stable COPD: Non-pharmacologic

Patient Essential Recommended Depending on local guidelines

ASmoking cessation (can include pharmacologic

treatment)Physical activity

Flu vaccinationPneumococcal

vaccination

B, C, D

Smoking cessation (can include pharmacologic

treatment)Pulmonary rehabilitation

Physical activityFlu vaccinationPneumococcal

vaccination


Manage Stable COPD: Pharmacologic Therapy(Medications in each box are mentioned in alphabetical order, and therefore not necessarily in order of preference.)

Patient First choice Second choice Alternative Choices

ASAMA prn

or SABA prn

LAMA or

LABA or

SABA and SAMA

Theophylline

BLAMA

or LABA

LAMA and LABA SABA and/or SAMATheophylline

C

ICS + LABAor

LAMA LAMA and LABAPDE4-inh.

SABA and/or SAMATheophylline

D

ICS + LABAor

LAMA

ICS and LAMA orICS + LABA and LAMA or

ICS+LABA and PDE4-inh. orLAMA and LABA or

LAMA and PDE4-inh.

CarbocysteineSABA and/or SAMA

Theophylline

Exa

cerb

atio

ns p

er y

ear

> 2

1

0

mMRC 0-1CAT < 10

GOLD 4

mMRC > 2CAT > 10

GOLD 3

GOLD 2

GOLD 1

SAMA prnor

SABA prn

LABA or

LAMA

ICS + LABAor

LAMA


Manage Stable COPD: Pharmacologic TherapyFIRST CHOICE

A B

DCICS + LABA

or LAMA

> 2

1

0

mMRC 0-1CAT < 10

GOLD 4

mMRC > 2CAT > 10

GOLD 3

GOLD 2

GOLD 1

LAMA or LABA or

SABA and SAMA

LAMA and LABA ICS and LAMA orICS + LABA and LAMA or

ICS + LABA and PDE4-inh orLAMA and LABA orLAMA and PDE4-inh.

LAMA and LABA


Manage Stable COPD: Pharmacologic TherapySECOND CHOICE

A

DC

B

Exa

cerb

atio

ns p

er y

ear

> 2

1

0

mMRC 0-1CAT < 10

GOLD 4

mMRC > 2CAT > 10

GOLD 3

GOLD 2

GOLD 1 Theophylline

PDE4-inh.SABA and/or

SAMATheophylline

CarbocysteineSABA and/or SAMA

Theophylline

SABA and/or SAMATheophylline


Manage Stable COPD: Pharmacologic TherapyALTERNATIVE CHOICES

A

DC

B

Exa

cerb

atio

ns p

er y

ear

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Bibliogrpahy

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