Morbidity of copd symptoms

The Morbidity of COPD Symptoms

Learning Objectives

• Appreciate the current epidemiology and gaps in the management of COPD in Canada

• Recognize why diagnosing and treating COPD is important for physicians and their patients

• Differentiate the clinical characteristics and diagnostic criteria for COPD and asthma

• Discuss current management strategies for patients with COPD, contrasting the roles of bronchodilators and anti-inflammatory agents in current guidelines

Case Study

Mr. A.C. is a 61-year-old real-estate agent who has recently undergone angioplasty.

Until 6 months ago, you saw him infrequently in your practice, perhaps because you usually tried to discuss smoking cessation with him.

Following an ER visit for chest pain he was managed by the cardiologists and underwent successful and uneventful angioplasty.

Case Study (cont’d)

• Mr. A.C. is trying to make lifestyle changes recommended to him, including participation in a cardiac rehab program

• During his rehab, he frequently feels breathless, earlier than others in the group

• He finds the incline on the treadmill difficult

• He has no history of lung disease but has cut down his smoking to one cigarette at bedtime 4 months ago and has a 35 pack-year smoking history

The Evolving Epidemiology of COPD in Canada

Growing Burden of COPD

Jemal A, et al. JAMA. 2005 Sept. 14; 294(10):1255-9.

Trends in age-standardized death rates for the 6 leading causes of death in the United States,

1970-2002

COPD: The Leading Cause of Hospital Admissions Today

*An ambulatory care sensitive condition is a condition that is normally manageable on an outpatient basis. Data are for the Canadian population, excluding Quebec . Canadian Institute for Health Information. Health Indicators 2008. Ottawa: CIHI; 2008.

18,000

16,000

14,000

12,000

10,000

8,000

6,000

4,000

2,000

0 COPD Angina Asthma Heart Failure Diabetes Epilepsy

Ambulatory Care Sensitive Condition*

Nu

mb

er

of

Pat

ien

ts

Single Hospitalization

1 Repeat Hospitalization

2 or More Repeat Hospitalizations

COPD is Underdiagnosed: Screening Spirometry in Primary Practice

*Criteria for COPD: FEV1/FVC < 0.70 Hill K, et al. CMAJ. 2010 Apr. 20;182(7):673-8.

Patients >40 years + 20 pack-year history of smoking visiting a primary care physician for any reason

(n=1,003)

Screening for COPD

Patients not meeting criteria for COPD*

(n=795; 79.3%)

Patients meeting criteria for COPD*

(n=208; 20.7%)

Previous diagnosis of COPD (n=67; 32.7%)

No previous diagnosis of COPD (n=141; 67.3%)

Deterioration in Lung Function versus Symptoms in COPD

Sutherland EM, et al. N Engl J Med 2004 Jun 24;350(26):2689-87.

100

50

20

Severe

Mild

Sym

pto

ms

FEV

1 (

% o

f p

red

icte

d)

Axis of Progression

Lung function normal

Asymptomatic

Lung function reduced

Why is pursuing the diagnosis of COPD important for Mr. A.C.?

Relationship Between FEV1, Smoking Status and CV Mortality

Young RP, et al. Eur Respir J. 2007 Oct;30(4):616-22.

Od

ds

Rat

io f

or

CV

mo

rtal

ity

8

6

4

2

0 <65 65-79 80-100 >100

Current smoker

Ex-smoker

Never-smoker

FEV1 % pred

Prediction of Death Within 5 years by GOLD Categories and Presence of Comorbid Disease

*Diabetes, hypertension or CV disease Mannino DM, et al. Eur Respir J. 2008 Oct;32(4):962-9.

100

10

1

GOLD 3/4

GOLD 2

GOLD 1

R GOLD 0

Normal

# of comorbidities*

Two

One

None

Three

Haz

ard

rat

io

Comorbidities of COPD

Cardiovascular disease is a major comorbidity in COPD and probably both the most frequent and most important disease co-existing with COPD.

Other major comorbidities:

– Osteoporosis

– Depression

– Lung cancer (most frequent cause of death in mild COPD)

Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2011.

often underdiagnosed and associated with poor health status and prognosis

Case Study (cont’d)

The rehab clinic placed him on salbutamol as needed and asked for him to follow up with his GP.

How would you proceed with Mr. A.C’s assessment?

Spirometry

Mr. A.C.: Spirometry Results Parameter Pred. value Observed pre % Pred.

Observed post

% pred. % change

FVC (L) 5.64 5.23 93 5.77 102 10.3

FEV1 (L) 4.57 2.92 64 3.01 66 3.2

FEV1/FVC (%) 81 56 69 52 64 -6.4

FEF25-75 (L/S) 11.27 5.52 49 5.70 51 3.3

FEF50 (L/S) 5.64 2.02 36 1.73 31 -14.3

FEF75 (L/S) 2.82 0.75 27 0.59 21 -21.2

VE (L/min) 173 -- -- -- -- --

Raw insp. (cmH2O/l/s) 0.68 1.71 256

Are these results more compatible with asthma or COPD?

Spirometry Results = Asthma

Spirometry Ref Pre Meas Pre % Ref Post Meas Post % Ref Post % Chg

FVC Liters 3.81 3.45 90 3.78 99 10

FEV1 Liters 3.27 2.34 72 2.90 89 24

FEV1/FVC % 86 68 79 77 89 13

FEF25-75% L/sec 3.83 1.44 38 2.40 63 67

FEF50% L/sec 4.11 1.93 47 3.33 81 73

FEF75% L/sec 1.91 0.57 30 0.98 51 73

PEF L/sec 6.55 6.08 93 7.57 116 25

PIF L/sec 3.63 4.53 25

PULMONARY FUNCTION ANALYSIS

An acceptable effort was provided.

There is evidence of slight airflow limitation that improved with acute bronchodilator.

This study is similar to those seen in patients with asthma.

Distinguishing Asthma from COPD

Adapted from O’Donnell DE, et al.:Can Respir J. 2007 Sep;14 Suppl B:5B-32B.

Asthma COPD

Age of onset Usually <50 years Usually >35 years

Smoking history Not causal (but people with asthma sometimes smoke)

Usually >10 pack-years

Sputum production Infrequent unless poorly controlled

Often in exacerbation-prone chronic bronchitis, infrequent in emphysema

Allergies Often in early onset but less often in late onset

1/3 of the general population

Disease course Stable (with exacerbations) Progressive worsening (with exacerbations)

Spirometry More likely to normalize with treatment

May improve but never becomes normal

Clinical symptoms Intermittent and variable Persistent and variable

Response to therapy

Responds well to therapy, especially corticosteroids

Does not respond as well to therapy

His post bronchodilator spirometry FEV1 66%

FVC 102%

FEV1/FVC 0.52

He is using his salbutamol 3-5 times a day.

Case Study (cont’d)

How would you proceed?

Evaluating COPD Severity

Classification of COPD By Impairment of Lung Function*

Stage Spirometry (post bronchodilator)

FEV1 FEV1/FVC

Mild ≥80% predicted <0.7

Moderate 50-79% predicted <0.7

Severe 30-49% predicted <0.7

Very severe <30% predicted <0.7

*In keeping with current GOLD criteria O'Donnell DE, et al. Can Respir J. 2008 Jan-Feb;15 Suppl A:1A-8A.

MRC Dyspnea Scale and CTS COPD Classification

Fletcher CM, et al. Br Med J. 1959 Aug 29;1:257-66. O’Donnell DE, et al. Can Respir J. 2003 May-Jun;10 Suppl A:11A-33A.

none

severe

Mild

Moderate

Severe

Grade 1 Breathless with strenuous exercise

Grade 2 Short of breath when hurrying on the level or walking up a slight hill

Grade 3 Walks slower than people of the same age on the level or stops for breath while walking at own pace on the level

Grade 4 Stops for breath after walking 100 yards

Grade 5 Too breathless to leave the house or breathless when dressing or undressing

Lung Function and Symptoms: Both Are Tied to Outcomes

Survival by ATS Stage (based on FEV1)

Survival by Level of Dyspnea

Nishimura K, et al. Chest. 2002 May; 121(5):1434-40.

100

80

60

40

20

0

0 10 20 30 40 50 60 70

Stage I (n=42)

Stage II (n=59)

Stage III (n=82)

p = 0.08

Months of Follow-Up

Cu

mu

lati

ve P

erce

nt

Surv

ival

(%

) 100

80

60

40

20

0

0 10 20 30 40 50 60 70

Grade II (n=67)

Grade III (n=87)

Grade IV (n=26) p < 0.001

Months of Follow-Up

Grade V (n=3)

Scoring range 0-40

Mr. A.C.'s CAT score = 18

Mr. A.C.: CAT Score I never cough I cough all the time 0 1 2 3 4 5 1

I have no phlegm (mucus) in my chest at all

My chest is completely full of phlegm (mucus)

0 1 2 3 4 5 0

My chest does not feel tight at all

My chest feels very tight 0 1 2 3 4 5 3

When I walk up a hill or one flight of stairs I am not breathless

When I walk up a hill or on flight of stairs I am very breathless

0 1 2 3 4 5 3

I am not limited doing any activities at home

I am very limited doing activities at home

0 1 2 3 4 5 4

I am confident leaving my home despite my lung condition

I am not at all confident leaving my home because of my lung condition

0 1 2 3 4 5 3

I sleep soundly I don’t sleep soundly because of my lung condition

0 1 2 3 4 5 1

I have lots of energy I have no energy at all 0 1 2 3 4 5 3

How would you treat Mr. A.C.?

Benefits of Smoking Cessation

Smoking Cessation and FEV1

Adapted from Fletcher C, et al. Br Med J. 1977 Jun;1(6077):1645-8.

0

20

40

60

80

100

20 30 40 50 60 70 80 90

FEV

1 (

%)

Age (Years)

Death

Disability

Symptoms Quit age 45

age 55

Why do we use bronchodilators as first-line therapy?

Ventilation (L/min)

Vo

lum

e (

%p

red

TLC

)

0 20 40 60 80

140

120

100

80

60

40

20

0

Normal (n=25)

RV

IRV IC

0 20 40 60 80

140

120

100

80

60

40

20

0

COPD (n=105)

IC VT

Dynamic Lung Hyperinflation

O'Donnell DE, et al. Am J Respir Crit Care Med. 2001 Sep 1;164(5):770-7.

LAACs and LABAs Available in Canada

Mode of action Individual agents

Long-acting anticholinergic (LAAC) Also known as long-acting muscarinic antagonist (LAMA)

Tiotropium Glycopyrronium Bromide

Long-acting beta2-agonist (LABA)

Formoterol

Salmeterol

Indacaterol

Long-Acting Anticholinergics (LAACs)

Also known as long-acting antimuscarinics (LAMAs)

Tiotropium vs. Ipratropium: 3-month FEV1 Response

Van Noord JA, et al. Thorax. 2000 Apr;55(4):289-94.

Time after Administration (minutes)

FEV

1 (

L)

Day 1 Day 8 Day 92

1.5

1.4

1.3

1.2

1.1

-60 -5 30 60 120 180 240 300 360

Tiotropium 18 mcg o.d. (n=182)

Ipratropium 40 mcg q.i.d. (n=93)

FEV1 from 5 Minutes to 4 Hours Post-dose on Day 1

Glycopyrronium bromide provided significant early bronchodilation following the first dose, and was significantly more effective than OL tiotropium 18 µg o.d.

Kerwin E, et al. Eur Respir J. 2012 Nov;40(5):1106-14; Novartis, data on file.

p<0.01 for glycopyrronium bromide versus tiotropium at all timepoints 5 min to 4 h

FEV

1 (

L)

Time post-dose (h)

Placebo Tiotropium Glycopyrronium bromide 1.8

1.6

1.4

1.2 1 2 3

1.7

1.5

1.3

4 0

Time to First Moderate or Severe COPD Exacerbation Glycopyrronium bromide 50 µg o.d. significantly prolonged the time to first exacerbation versus placebo (HR 0.66, p=0.001), comparable with OL tiotropium 18 µg o.d. (HR 0.61, p=0.001 vs. placebo)

Pat

ien

ts e

xace

rbat

ion

fre

e (

%)

Time to first exacerbation (weeks) Number at Risk Glycopyrronium bromide 495 451 426 394 370 360 341 335 318 310 296 282 239 Placebo 229 202 188 168 159 153 142 137 129 129 122 116 98 Tiotropium 245 222 209 200 190 184 176 169 166 163 157 155 129

100

90

80

70

60

50

40

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

Treatment:

Glycopyrronium bromide 50 μg o.d.

Placebo

OL Tiotropium 18 μg o.d.

HR = hazard ratio Kerwin E, et al. Eur Respir J. 2012 Nov;40(5):1106-14.

Safety of anticholinergics

The key findings were that inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD.

Cardiovascular Events

Placebo Tiotropium Rate Ratio† (95 % CI)

n Rate‡ n Rate‡

UPLIFT

Composite endpoint 246 2.89 208 2.25 0.78 (0.65, 0.94)

Fatal composite 124 1.42 98 1.04 0.73 (0.56, 0.95)

†rate ratio tio vs. placebo; ‡per 100 person-years of time at risk to tiotropium or placebo *SOC cardiac (fatal), SOC vascular (fatal), MI (fatal+nonfatal), stroke (fatal+nonfatal), sudden death, sudden cardiac death 1. Singh S, et al. JAMA. 2008 Sep 24;300(12):1439-50. 2. Tashkin DP, et al. N Engl J Med. 2008 Oct 9;359(15):1543-54.

Composite Endpoint* Used by Singh et al1, applied to UPLIFT2

Adverse Events (n, %) in ≥3% of Any Treatment Group

Glycopyrronium

bromide

50 µg o.d.

N=525

Placebo

N=268

OL Tiotropium

18 µg o.d.

N=267

Any adverse event 402 (76.6) 205 (76.5) 198 (74.2)

COPD worsening 191 (36.4) 116 (43.3) 90 (33.7)

Upper respiratory tract infection 57 (10.9) 33 (12.3) 30 (11.2)

Nasopharyngitis 47 (9.0) 15 (5.6) 21 (7.9)

Sinusitis 28 (5.3) 14 (5.2) 10 (3.7)

Upper respiratory tract infection bacterial 28 (5.3) 28 (10.4) 21 (7.9)

Headache 25 (4.8) 14 (5.2) 12 (4.5)

Hypertension 21 (4.0) 12 (4.5) 14 (5.2)

Urinary tract infection 14 (2.7) 8 (3.0) 16 (6.0)

COPD worsening: includes chronic obstructive pulmonary disease (COPD) exacerbation. Kerwin E, et al. Eur Respir J. 2012 Nov;40(5):1106-14.

Twice-daily Long-acting Beta2 agonists (LABAs)

Salmeterol vs. Ipratropium vs. Placebo in COPD: Spirometric Impact

Mahler DA, et al. Chest. 1999 Apr; 115(4):957-65.

Time (hours) -0.1

0.0

0.1

0.2

0.3

0.4

0.5

1 2 3 4 5 6 7 8 9 10 11 12 13 Ch

ange

fro

m b

ase

line

in F

EV1

(L)

Day 84

Salmeterol Ipratropium Placebo

Once-Daily LABAs

Mean Change in FEV1 on Day 1 of Indacaterol Treatment

Data are unadjusted means. Adapted from: Novartis Pharmaceuticals Inc. Onbrez* Breezhaler* Product Monograph. Date of Revision: October 24, 2012. Novartis Pharmaceuticals Inc. Data on file (Study B2355).

0

50

100

150

200

250

0 1 2 3 4

FEV

1 m

ean

ch

ange

fro

m b

ase

line

(m

L)

Time post dose (hours)

Indacaterol 75 µg (N=150) Placebo (N=155)

5 mins post-dose

Sustained Bronchodilation Over 24 Hours: Indacaterol vs. Placebo

Adapted from: Novartis Pharmaceuticals Inc. Onbrez* Breezhaler* Product Monograph. Date of Revision: October 24, 2012. Novartis Pharmaceuticals Inc. Data on file (Study B2355).

Rapid onset within 5 minutes

Time (hours)

FEV

1 (

L)

1.30

1.35

1.40

1.45

1.50

1.55

1.60

0 4 8 12 16 20 24 1.20

1.25

Indacaterol 75 µg o.d. Placebo

Improvement in FEV1 vs. placebo at every time point, measured by 24-hour spirometry

Recommended Next Step for Mr. A.C.

• It has been 6 months since you have seen him

• He has been taking a once daily LAMA + Salbutamol prn

• Mr. A.C. has not had an exacerbation of his COPD

• He states that he is still an MRC 3 dyspnea and has been needing a breakthrough salbutamol a few times a week

How would you proceed?

Rehabilitation Is A Powerful Tool For Improving QOL In COPD

SGRQ = St George’s Respiratory Questionnaire 1. Donohue JF, et al. Chest. 2002 Jul;122(1):47-55. 2. Calverley P, et al. Lancet. 2003 Feb 8;361(9356):449-56.

3. Vincken W, et al. Eur Respir J. 2002 Feb;19(2):209-16. 4. Griffiths TL, et al. Lancet. 2000 Jan 29;355(9201):362-8.

Ch

ange

s in

to

tal S

GR

Q s

core

-5

-4

-3

-2

-1

0

-6

-7

-8

Salmeterol1

Salmeterol/ fluticasone2 Tiotropium3 Rehabilitation4

6 months

1 year

1 year

6 weeks

1 year

-3.5

-4.5

-3.8

-7.1

-3.4

Clinical significance threshold

Imp

rove

me

nt

Combining Bronchodilators in Mild to Moderate COPD

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

Tiotropium (18 µg o.d.)

Trough FEV1: Change from baseline Total COPD Symptom Score‡

Dual Bronchodilation with Formoterol + Tiotropium

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

Me

an c

han

ge in

sym

pto

m s

core

*

* *

AM PM AM/PM average

0

-0.2

-0.4

-0.6

-0.8

-1.0

-1.2

-1.4

-1.6

Ch

ange

fro

m b

ase

line

in

tro

ugh

FEV

1 (

mL)

n=118

n=127

†

n=106 n=121

n=121 n=121 n=129

* n=108

* *

Week 4 Week 8 Week 12 Last visit

250

200

150

100

50

0

LABA/LAMA Provides Better Improvements in Lung Function at 6 Weeks Than LABA/ICS

*p<0.05 between groups at each time point Rabe KF, et al. Chest. 2008 Aug;134(2):255-62.

Time after drug administration (hours)

Tiotropium 18 μg o.d. + formoterol 12 μg b.i.d.

Salmeterol 50 μg b.i.d. + fluticasone propionate 500 μg b.i.d.

FEV

1 (

L)

1.8

1.7

1.6

1.5

1.4

1.3 0 1 2 3 4 5 6 7 8 9 10 11 12

Is there any reason not to use ICS therapy at this point in his management?

Lack of Benefit with LABA/ICS vs. LABA Alone in Stable COPD: Meta-analysis

Rodrigo GJ, et al. Chest. 2009 Oct;136(4):1029-38.

LABAs/ICS LABAs Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI

1.1.1 All-cause mortality

Calverley (16) 2 358 3 372 1.1% 0.69 (0.12, 4.12)

Calverley (17) 5 254 14 255 5.3% 0.36 (0.13, 0.98)

Calverley (23) 193 1533 205 1521 78.4% 0.93 (0.78, 1.12)

Ferguson (25) 6 394 3 388 1.2% 1.97 (0.50, 7.82)

Kardos (24) 7 507 9 487 3.5% 0.75 (0.28, 1.99)

Safranski (20) 6 208 6 201 2.3% 0.97 (0.32, 2.95)

SCO100250 (29) 4 394 6 403 2.3% 0.68 (0.19, 2.40)

SCO100470 (30) 3 518 3 532 1.1% 1.03 (0.21, 5.07)

SCO40041 (28) 5 92 7 94 2.6% 0.73 (0.24, 2.22)

Tashkin (26) 7 845 1 284 0.6% 2.35 (0.29, 19.04)

Wouters (21) 2 189 4 184 1.5% 0.49 (0.09, 2.63)

Subtotal (95% CI) 5292 4721 100.0% 0.90 (0.76, 1.06)

Total events 240 261

Heterogeneity: Chi2 = 6.52, df = 10 (P = 0.77), I2 = 0%

Test for overall effect Z = 1.27 (P = 0.20)

Bone Density vs. Dose and Duration of ICS Therapy

Hanania NA, et al.: J Allergy Clin Immunol 1995; 96(5 Pt 1):571-9.

0 4 -2.5

2.0

2.0

2.0

-2.5

-2.5

0

0

4

4 Dose x Duration/BMI

Dose x Duration/BMI

Dose x Duration/BMI

r=-0.53 p=0.01

r=-0.58 p=0.005

r=-0.33 p=0.08

Lumbar Spine

Femoral Neck

Ward’s Triangle

Z score Z score

Z score

"More" Combination Therapies

* p<0.05 Casaburi R, et al. Chest. 2005 Mar;127(3):809-17.

* *

32% 42%

End

ura

nce

Tim

e (

min

s)

Weeks on Treatment

Control

Tiotropium

24

20

12

16

8 0 2 4 6 8 10 12 14 16 18 20 22 24

Rehabilitation

What If. . .

Mr. A.C. has had a URTI and a worsening of his COPD

He has ended up in the walk-in clinic and was sent home on antibiotics and prednisone for one week

He comes back to you for follow up…

Should you change therapy?

Patients Who Exacerbate Frequently Account for a Small but Important Portion of the Overall COPD Population

27%

16% 11% Hurst JR, et al. N Engl J Med. 2010 Sept 16;363(12):1128-38.

GOLD: Combined Assessment of COPD

Ris

k

(GO

LD C

lass

ific

atio

n o

f A

irfl

ow

Lim

itat

ion

)

Ris

k

(Exa

cerb

atio

n h

isto

ry)

mMRC 0-1 CAT < 10

> 2

1

0

4

3

2

1

mMRC > 2 CAT > 10

Symptoms (mMRC or CAT score)

GOLD assessment

variables are similar

to 2007 Cdn.

Recommendations:

Lung function

impairment

Symptoms

(C) (D)

(A) (B)

Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2011.

Summary COPD is a lethal disease that has a profound impact on patient outcome as well as on the health care system.

Patients at risk for COPD need to be diagnosed with spirometry.

In the medical management of COPD, long-acting bronchodilators, even in mild or moderate disease are clinically beneficial.

Introduction of an ICS (and only in combination with a LABA) should be done appropriately and in the right patient population.

Patient Factors in COPD Management

Adapted from Cramer JA, et al. Can Respir J. 2007 Jan-Feb;14(1):25-9.

12-month Persistence with Inhaled Medications: Canadian Data

% continuing for 12 months

0 20 30 40 50 10 60

Ipratropium (Atrovent®)

8%

Ipratropium/salbutamol (Combivent®)

12%

Formoterol (Oxeze®)

16%

Salmeterol (Serevent)®

18%

Formoterol-budesonide (Symbicort®)

25%

Salmeterol/fluticasone (Advair)®

32%

Tiotropium (Spiriva®)

53%

Four times daily

Twice daily

Once daily

Does the device make a difference?

COPD Treatment Options

Tiotropium Glycopyrronium

bromide Salmeterol / Fluticasone

Formoterol Salmeterol Indacaterol Formoterol/ Budesonide

Mode of Action

LAAC/ LAMA

LAAC LABA + ICS

(FDC) LABA LABA LABA

LABA + ICS (FDC)

Devices

Handihaler (18 µg/

inhalation)

Breezhaler (50 µg /

inhalation)

Diskus DPI (50/250 µg

and 50/500 µg / inhalation)

Aerosol MDI (25/50,

25/125 or 25/250 µg / inhalation)

Aerolizer (12 µg / capsule)

Turbuhaler DPI (6 & 12 µg /

inhalation)

Diskus DPI (50 µg /

inhalation)

Diskhaler Disk DPI (50 µg /

inhalation)

Breezhaler (75 µg /

inhalation)

Turbuhaler DPI (110/6 or

200/6 μg / inhalation)

Breezhaler®

0

20

40

60

80

100

120

0 2 4 6 8 10

Inspiratory effort (kPa)

Flo

w r

ate

(L/

min

)

kPa1/2 L-1 min

Breezhaler® 2.2 x 10-2

Diskus®/Accuhaler® 2.7 × 10-2

Turbuhaler® 3.4 × 10-2

HandiHaler® 5.1 × 10-2

Increasing Resistance

Flow Rates with Various Inhalers Used for COPD Medications

Diskus® and Accuhaler® are registered trademarks of GlaxoSmithKline; Turbuhaler® is a registered trademark of AstraZeneca; HandiHaler® is a registered trademark of Boehringer Ingelheim; Breezhaler® is a registered trademark of Novartis. Singh D, et al. Am J Respir Crit Care Med. 2010;181:A4419 (+ additional material from poster).

Diskus® / Accuhaler®

Turbuhaler®

HandiHaler®

Patient Education: There is Help!

Certified Respiratory Educators (CREs) perform a critical role in improving the lives of Canadians living with respiratory illness.

They assists with adherence, they deal with patient fears and review inhaler techniques.

These highly professional, knowledgeable and skilled CREs support the disease management approach: education

evaluation

reinforcement

Education takes time!

“To be effective, education must be supported by a physician and provided by trained educators.”

Dr. Ken Chapman President

Canadian Network for Respiratory Care

Learn more at the Canadian Network for Respiratory Care website at http://cnrchome.net

Summary • COPD prevalence is increasing in Canada but

underdiagnosis is common

• Modern COPD algorithms are driven by symptoms plus future risk as determined by lung function and exacerbation history

• For the non-exacerbation-prone COPD with mild-to-moderate obstruction, use long acting bronchodilators; given once daily improves adherence.

• For exacerbation-prone patients, triple therapy is recommended

Back-up Information

Additional supporting information for use at the facilitators' discretion

What If?

Mr. A.C. has had two more worsenings of his COPD over the next 9 months?

He has ended up in walk in clinic and was sent home on antibiotics and prednisone for one week.

He comes back to you for follow up…

Should you change therapy?

Mortality Increases with Frequency of AECOPD

Soler-Cataluña JJ, et al. Thorax. 2005 Nov;60(11):925-31.

Time (months)

0

Pro

bab

ility

of

surv

ivin

g 0 AEs

1-2 AEs

>3 AEs

0.0 10 20 30 40 50 60

0.2

0.4

0.6

0.8

1.0

p<0.0001

p=0.069

p<0.0002

Is triple therapy effective?

OPTIMAL Study Design

Aaron SD, et al. Ann Intern Med. 2007 Apr 17;146(8):545-55.

Tiotropium qd + Salmeterol MDI 2 puffs bid n=148 R Tiotropium + Placebo

Run-in

Visit:

Month:

1 2 3 4 5 6

-0.5 0 1 4 8 12

Tiotropium qd + Placebo MDI 2 puffs bid n=156

Tiotropium qd + Salmeterol/Fluticasone 50/250 MDI 2 puffs bid n=145

OPTIMAL Study: Primary Outcome – Proportion of Patients with Exacerbations

Aaron SD, et al. Ann Intern Med. 2007 Apr 17;146(8):545-55.

60

64.8

62.8

0 20 40 60 80

Tiotropium + fluticasone/salmeterol(n=145)

Tiotropium + salmeterol (n=148)

Tiotropium + placebo (n=156)

% of patients

OPTIMAL Study: Secondary Outcome Variable – COPD Hospitalizations

p = 0.01

Aaron SD, et al. Ann Intern Med. 2007 Apr 17;146(8):545-55.

26

38

49

0 10 20 30 40 50 60

Tiotropium + fluticasone/salmeterol(n=145)

Tiotropium + salmeterol (n=148)

Tiotropium + placebo (n=156)

Number of patients

What is the impact of oral PDE4 inhibitors (roflumilast)?

Proportion of Patients with a Moderate or Severe Exacerbation

Exacerbation rates were based on a Poisson regression model. Risk ratios (RiR) were based on a log binomial regression model. Fabbri LM, et al. Lancet. 2009 Aug 29;374(9691):695-703.

sal or tio + placebo sal or tio + roflumilast 500 µg

n = 83/467 n = 51/466 n = 58/372 n = 42/371

RiR = 0.60 (95% CI 0.43, 0.82)

p = 0.0015

RiR = 0.73 (95% CI 0.51, 1.05)

p = 0.0867

Salmeterol study Tiotropium study

20

16

12

8

4

0 n=83/467 n=51/466 n=58/372 n=42/371 P

atie

nts

wit

h a

n e

xace

rbat

ion

(%

)

16

11 11

18

Roflumilast: Incidence of AEs ( 2.5%)*

Adverse Event

AURA/HERMES 1 year

HELIOS 6 months

Roflumilast (n=1547)

Placebo (n=1545)

Tiotropium + Roflumilast

(n=374)

Tiotropium + Placebo (n=369)

COPD 10% 13% 16% 19%

Weight loss 10% 3% 6% <1%

Diarrhea 8% 3% 9% <1%

Nasopharyngitis 6% 6% 6% 5%

Nausea 4% 2% 3% 1%

Bronchitis 4% 4% 2% 3%

Headache 3% 2% 2% 0%

Back pain 3% 2% 2% 1%

*Independent of investigator causality assessments Calverley PM, et al. Lancet. 2009 Aug 29; 374(9691):685-94. Fabbri LM, et al. Lancet. 2009 Aug 29;374(9691):695-703.

Risk of ICS

Lack of Benefit with ICS on FEV1 Decline in COPD: Meta-analyses

1. Highland KB, et al. Ann Intern Med. 2003 Jun 17;138(12):969-73. 2. Sutherland ER, et al. Thorax. 2003 Nov;58(11):937-41.

Authors Difference between ICS and placebo groups (95% CI)

Highland et al. (2003)1 5.0 mL / year (-1.2 to 11.2)

Sutherland et al. (2003)2 7.7 mL / year (1.3 to 14.2)

Inhaled Corticosteroids and the Risk of Cataracts - Dose Response

Data are for posterior, subcapsular cataracts Cumming RG, et al.: N Engl J Med 1997; 337(1):8-14.

3.1

2.1

1.3

0 0.5 1 1.5 2 2.5 3 3.5

Puffs/Wk

Prevalence ratio

> 28

15-28

14 or less

p < 0.001

Increased Risk of Pneumonia with ICS vs. Placebo in COPD: Meta-analysis

Subgroup # of events / # of patients

Odds Ratio 95% CI ICS No ICS

ICS vs. placebo 285 / 3881 180 / 3633 1.51 1.08 – 2.10

ICS + LABA vs. LABA 356 / 4754 217 / 4728 1.72 1.28 – 2.30

Total 641 / 8635 397 / 8361 1.60 1.33 – 1.92

Singh S, et al.: Arch Intern Med 2009; 169(3):219-29.

Increased Risk of New-onset Diabetes with Increasing ICS Dose

Suissa S, et al. Am J Med. 2010 Nov;123(11):1001-6.

3.5

3.0

2.5

2.0

1.5

1.0

0.5 0 250 500 750 1000 1250 1500 1750 2000

Daily dose in fluticasone equivalents (mcg)

Rat

e R

atio

Patient Preference

Inhaler Regimens: Patient Preferences

Venables TL, et al. Br J Clin Res. 1996;7:15-32.

61% 12%

27% Once Daily

Twice Daily

No Preference

Breezhaler® vs. Handihaler®: Comfort, Simplicity & Confidence

Breezhaler® is a registered trademark of Novartis. HandiHaler® is a registered trademark of Boehringer Ingelheim. *p<0.05, ***p=0.001 between the two inhalers Patient preference scores with respect to comfort, simplicity and confidence in use measured on a 10-point scale from 1 = not at all to 10 = extremely Chapman K, et al. Int J Chron Obstruct Pulmon Dis. 2011;6:353-63.

***

* *

9.2

9.0

8.8

8.6

8.4

8.2

8.0

7.8

7.6

7.4 How comfortable

is it to inhale through the inhaler?

Overall, how simple is it to use

the inhaler?

How confident are you that you have taken the medication successfully?

Breezhaler® Handihaler®

Me

an s

core

± S

E

Receptor Selectivity: Glycopyrronium Bromide versus Tiotropium

Equilibrium affinity: Glycopyrronium bromide has greater M3 versus M2 receptor binding selectivity than tiotropium (5-fold vs. 2-fold)

pKi M2 pKi M3

Selectivity (ratio)

Tiotropium 10.050.05 10.370.

04 2

Glycopyrronium bromide

8.700.04 9.470.0

2 5

t½ at M2

(min)

t½ at M3

(min) Kinetic selectivity

(ratio)

Tiotropium 10.8 46.2 4.3

Glycopyrronium bromide

1.1 9.9 9.0

Novartis, data on file.

Kinetic selectivity: Glycopyrronium bromide shows faster dissociation from M2 versus M3 receptor than tiotropium (9-fold vs. 4-fold) Clinical Implications a) faster time of onset

b) ? Increased cardiac safety

M3

:M2

se

lect

ivit

y ra

tio

*

*Ratio of occupancy versus time over 24 hours

14 12 10

0

8 6 4 2

Glycopyrronium bromide

Tiotropium

4.4

12.9

Sample: Plan of Action

Tools and Resources

Where can I learn more on the subject of spirometry in primary care?

http://www.respiratoryguidelines.ca/2013-cts-slide-kit-spirometry-in-primaary-care