State of the art pearls for managing asthma in primary Care Anthony D. D’Urzo MD, MSc, BPHE, CCFP, CFPC Associate Professor University of Toronto, Department

State of the art pearls for managing asthma in primary Care

Anthony D. D’Urzo MD, MSc, BPHE, CCFP, CFPC

Associate Professor

University of Toronto,

Department of Family and Community Medicine (DFCM),

Chair, Primary Care Respiratory Alliance of Canada (PCRC)

Faculty/Presenter Disclosure

• Faculty: Dr. Anthony D’Urzo

• Relationships with commercial interests:

• Dr D’Urzo has received research, consulting and lecturing fees from GlaxoSmithkline, Sepracor, Schering Plough, Altana, Methapharma, AstraZeneca, ONO pharma, Merck Canada, Forest Laboratories, Novartis Canada/USA, Boehringer Ingelheim (Canada) Ltd, Pfizer Canada, SkyePharma, , and KOS Pharmaceuticals.

Disclosure of Commercial Support• This program has not received financial support from any entity.• This program has not received in-kind support from any entity

• Potential for conflict(s) of interest: • Dr D’Urzo has received research, consulting and lecturing fees from

GlaxoSmithkline, Sepracor, Schering Plough, Altana, Methapharma, AstraZeneca, ONO pharma, Merck Canada, Forest Laboratories, Novartis Canada/USA, Boehringer Ingelheim (Canada) Ltd, Pfizer Canada, SkyePharma, , and KOS Pharmaceuticals.

Mitigating Potential Bias

•The material presented has been peer reviewed and in many cases represents data included in National and International management Guidelines.

Asthma Management Update: What’s new and what’s changed?

Objectives

1) Review current guidelines and new practical approaches that facilitate objective diagnosis of asthma. 2) Discuss what’s new with inhaled corticosteroids (ICS) in asthma management. 3) Learn how to safely use long-acting B2- agonists and biologic agents. 4) Review issues and controversies around asthma management in primary care.


Review of current guidelines and new practical

approaches that facilitate objective diagnosis of asthma.

Key Message

D’Urzo AD et al, Can Fam Physician 2011;57:1148-52.

12

Differentiating Asthma from COPD

• First Line Therapy• Asthma - Inhaled glucocorticosteroids

• COPD - Inhaled bronchodilator therapy – long - acting for maintenance: ↓

hyperinflation - ↑ inspiratory capacity

IMPORTANT• Long-acting-β2-agonist monotherapy

contraindicated in ASTHMA- large scale safety studies commissioned by the FDA are ongoing.

Spirometric Diagnosis of Asthma and COPD

• FEV1 Asthma• FVC• FEV1/FVC COPD

*COPD = Chronic Obstructive Pulmonary Disease

FEV1 / FVC

• Pure obstruction = ↓ FEV1/FVC but FVC normal: often normal in Asthma

• Restriction = Normal FEV1/FVC but both FEV1 and FVC reduced

• Combined obstruction/restriction/hyperinflation = ↓ FEV1/FVC plus ↓ FVC

Reversibility of Airflow Obstruction

• COPD– FEV1 may improve 12% and 200 mL with

bronchodilator– FEV1/FVC remains below 0.70 or LLN with

bronchodilation

Spirometric overlap between Asthma and COPD

* Post-bronchodilatorPre-bronchodilator FEV1/FVC often normal in Asthma

Asthma COPD

FEV1* Normal/Reduced Normal/Reduced

FEV1/FVC* Normal/Reduced Reduced

Spirometric Overlap between Asthma and COPD

• Changes in Post-bronchodilator FEV1 are not useful for differentiating asthma from COPD

• A NORMAL FEV1/FVC (> 0.70 or LLN) rules out a spirometric diagnosis of COPD

18

FVC: Forced vital capacity (Liters)Pre: Pre-Bronchodilator:% Pred: Percent of Predicted Normal

PRE POST % Change

Best % Pred Best % Pred

FVC 3.54 89 3.86 97 9

FEV1 1.65 50 1.94 59 18

FEV1/FVC 46.7 50.3

PRE POST % Change

Best % Pred Best % Pred

FVC 3.39 98 3.52 101 4

FEV1 2.17 73 2.74 92 26

FEV1/FVC 63.9 77.8

FEV1: Forced Expiratory Volume in 1 second (Liters)Post: Post-Bronchodilator: % Change: Percent Change = (FEV1 post) – (FEV1 pre)

_______________________________________________________

(FEV1 pre)

Asthma Action Plan

Flovent 250 micrograms1puff 2xdayVentolin 1-2 puffs 4xday as needed

Flovent 250 micrograms 2 puffs 2xdayVentolin 1-2 puffs 4xday as needed Go to the

Emergency Dept -

What’s new with inhaled corticosteroids (ICS) in asthma management.

28

Screening

Day −28

Baselin

e

Week 12Day 1

Follow-up visits: Weeks 1, 2, 4, 7, 12

(N = 400 patients)

Efficacy and Safety of MFDPI Compared to Placebo in Patients Previously Dependent on Twice-Daily ICS

3-Month DBPC Phase

DBPC = double-blind, placebo-controlled; ICS = inhaledglucocorticosteroids.

D’Urzo A et al. Curr Med Res Opin. 2005;21:1281–1289.

Placebo(n = 83)

MFDPI 400 mcg once daily PM

(2 x 200 mcg/inhalation) (n = 78)

MFDPI 200 mcg once daily PM(n = 78)

MFDPI 200 mcg twice daily

(n = 81)

MFDPI 400 mcg once daily PM (1 x 400 mcg/inhalation) (n = 80)

ICS Reduction Period

0.6

0.4

0.3

0.1Mea

n Ch

ange

in F

EV1

From

Bas

elin

e (L

)

Weeks of Study

Endpoint1 2 4 7 12

0.0

0.2

0.5Randomization

Baseline

a

a

b

b

b

b

MFDPI Significantly Improved FEV1 vs Placebo in Patients Previously Dependent on Twice-Daily ICS

Prior to randomization, patients completed an ICS reduction period lasting up to 4 weeks, to confirm ICS dependency. The ICS reduction period was initiated by decreasing ICS dose by 50% at screening visit. At baseline, patients were randomized to MFDPI treatment or placebo. FEV1 = forced expiratory volume in 1 second; ICS = inhaled glucocorticosteroids.

Adapted from D’Urzo A et al. Curr Med Res Opin. 2005;21:1281–1289.

For all MFDPI treatment groups aP ≤ 0.001 versus placebo. bP < 0.05 versus placebo.

Placebo (n = 83)

MFDPI 200 mcg qd PM (n = 78)

MFDPI 200 mcg bid (n = 81)

MFDPI 400 mcg qd PM, 1 x 400 μg /inhalation (n = 80)

MFDPI 400 mcg qd PM, 2 x 200 μg/inhalation (n = 78)

28-day dose-reduction phase

of prior therapy

MFDPI Significantly Improved AM and PM Asthma Symptom Scores

aTotal symptom scores are the sum of the 3 individual symptoms: wheezing, coughing, and difficulty breathing.For AM symptoms, % change from baseline to endpoint for MFDPI 400 mcg once daily PM (2x200/inhalation) = -51.6%; % change from baseline to endpoint for MFDPI 200 mcg twice daily = -51.6%. For PM symptoms, % change from baseline to endpoint for MFDPI 400 mcg once daily PM (2x200/inhalation) = -47.3%; % change from baseline to endpoint for MFDPI 200 mcg twice daily = -39.5%; data not shown.


% Change From Baseline to Endpoint in

Total Symptom

Scorea

MFDPI 200 mcg once daily PM (n = 78)

MFDPI 400 mcg once daily (1 x 400/inhalation) PM (n = 80)

Placebo (n = 83)


MFDPI 200 mcg twice daily (n = 80)

MFDPI Reduced Number of Nocturnal Awakenings Compared With Placebo

• Once-daily evening dose of MFDPI 400 mcg (combined 1 x 400 and 2 x 200/inhalation groups) significantly reduced nighttime awakenings from 12 per month to 2 per month.

31D’Urzo A et al. Curr Med Res Opin. 2005;21:1281–1289.

Mean % Change at

Endpoint in Nighttime

Awakenings/Day

MFDPI 200 mcg once daily PM (n = 78)


Placebo (n = 83)


MFDPI 200 mcg twice daily (n = 80)


How to safely use long-acting B2-agonists and the biologic agent Omalizumab.

34

Differentiating Asthma from COPD

• First Line Therapy• Asthma - Inhaled glucocorticosteroids

• COPD - Inhaled bronchodilator therapy – long - acting for maintenance: ↓

hyperinflation - ↑ inspiratory capacity

IMPORTANT• Long-acting-β2-agonist monotherapy

contraindicated in ASTHMA- large scale safety studies commissioned by the FDA are ongoing.

Arch Intern Med. Published online August 27, 2012. doi:10.1001/archinternmed.2012.3250

Long-Acting 2-Agonist Step-off in Patients With Controlled Asthma, Systematic Review With Meta-analysis Jan L. Brozek, MD, PhD; Monica Kraft, MD; Jerry A. Krishnan, MD, PhD; Michelle M. Cloutier, MD; Stephen C. Lazarus, MD; James T. Li, MD, PhD; Nancy Santesso, RD, MLIS; Robert C. Strunk, MD; Thomas B. Casale, MD



Identifying the Patient with Severe Uncontrolled Asthma in Primary Care: The role of Biologic therapy

Severe, difficult to control Asthma

• Patients, who despite receiving regular aggressive maintenance therapy, including bursts of oral corticosteroids, often report disabling symptoms which may require urgent care in the hospital setting.

Uncontrolled severe asthma

• The most severe group of patients have the greatest– incidence of hospitalization and emergency visits– risk of fatal asthma attacks

• Those who are poorly controlled with severe asthma use three times more resources than those who are well controlled

• The GINA 2006 guidelines recommend a step-wise approach to therapy until control is achieved

• Patients who remain inadequately controlled despite best available therapy have had limited therapeutic options – remain at high risk of hospitalization and mortality– are greatly restricted in their daily activities

• A clear unmet need exists for an effective and safe treatment for inadequately controlled severe persistent asthma

30

• Complications of Systemic/Inhaled Steroids– Suppression of HPA axis = ↓ cortisol-adrenal

insufficiency, blunted response to stress such as infection, trauma → severe illness

– Osteoporosis– ↓ growth in children– Muscle weakness

Long Term Sequelae of Steroid Use in Asthma

Almost 40% patients with severe asthma* remain inadequately controlled despite optimized treatment with

salmeterol/fluticasone combination therapy

*>500–1,000 µg beclometasone dipropionate (BDP) or equivalent at baseline

Patients (%)

Well controlled at 1 yearInadequately controlled at 1 year

0

20

40

60

80

Salmeterol/fluticasoneSalmeterol/fluticasone

plus course of oral corticosteroids (OCS)

Bateman ED, et al. Am J Respir Crit Care Med 2004

n=568

24

The most severe group of patients have the highest incidence of hospitalization and emergency visits

Hospitalization

Patients (%)

Emergency department visit

Moderate (n=2,285)Severe (n=2,285)

Mild (n=219)

25

20

15

10

5

0

Dolan CM, et al. Ann Allergy Asthma Immunol 2004

17

Prevalence of asthma is related to the level of serum IgE

Serum IgE (IU/mL)*

Ast

hma

(odd

s ra

tio)*

n=2,657

0.32 1 3.2 10 32 100 320 1,000 3,200

1.0

2.5

5.0

10

20

40

Burrows B, et al. N Engl J Med 1989*Logarithmic scale

33

The anti-inflammatory role of omalizumab in allergic respiratory disease

41

Asthma exacerbation

Omalizumab mechanism of actionin IgE-mediated asthma

PerennialaeroallergensOmalizumab

Binds to free IgE, reducing

cell-bound IgE

Reduces high-affinity receptors

Reducesmediator release

Reduces asthma exacerbations and

symptoms

Plasma cell

B lymphocyte

-switchAllergic

mediators

Release of IgE

Mast cellsBasophils

Allergicinflammation:

eosinophils and lymphocytes

50

Omalizumab significantly reduces severe exacerbations and emergency visits

Omalizumab(n=209)

Placebo(n=210)

0.6

0.5

0.4

0.3

0.2

0.1

0

∆ –50.0%

p=0.002

Omalizumab(n=209)

Placebo(n=210)

0.6

0.5

0.4

0.3

0.2

0.1

0

∆ –43.9%

p=0.038

Severe exacerbation rate Total emergency visit rate

Humbert M, et al. Allergy 2005

62

Omalizumab significantly reduces exacerbations irrespective of OCS use

Omalizumab(n=271)

Control(n=173)

4

3

2

1

0

∆ –34.9%

p=0.001

Omalizumab(n=1,454)

Control(n=899)

∆ –29.4%

p<0.001

OCS Non-OCS

Wenzel S, et al. Chest 2007

4

3

2

1

0

Annualized exacerbation rate

73

Other Therapies for Severe Asthma??

None are currently considered a well-established therapy that can be recommended at this time. Often tested in an era when higher-dose inhaled corticosteroid therapy with or without long-acting β2-agonists was not available, their relevance currently is in questionMethotrexate is an example: when given for arthritis, need of ICS goes down…

Chapman K, Mcivor A,Asthma that is unresponsive to usual care CMAJ January 12, 2010 vol. 182 no. 1

Omalizumab: Dosing and Administration

• Omalizumab is administered subcutaneously– Once- or twice-monthly dosing

• Dose and dosing frequency is based on serum total IgE level measured before the start of treatment and body weight– No more than 150mg is injected at a single site– Doses > 150mg are to be divided among more than 1

injection site– Dosage adjustments may be made based on changes in

body weight– Repeat IgE levels cannot be used to adjust dose as total

levels which measure both the omalizumab:IgE complex and free IgE are elevated

Xolair Product Monograph.

What expectations should the clinician(s) have regarding Omalizumab therapy?

1. Exacerbation prevention2. Possible reduction in maintenance therapy3. Improved quality of life

Overview of omalizumabgeneral safety profile

• Large safety database of more than 7,500 patients (>5,000 treated with omalizumab)– majority with allergic asthma

• Frequencies of adverse events were similar between omalizumab and control groups, even in severe patients

• No trend or cluster of adverse events

• Majority of adverse events were mild-to-moderate and of short duration

• Anaphylaxis 0,2 %

• Injection site reactions was similar to placebo– omalizumab: 45%; placebo: 43%

Corren J, et al. Clin Exp Allergy 2009

Summary

• Pooled data from seven controlled studies clearly demonstrate that add-on omalizumab significantly reduces the rate of– clinically significant asthma exacerbations– emergency visits

• Omalizumab is efficacious irrespective of OCS or leukotriene modifier use

• Omalizumab significantly improves QoL

• Significantly more patients achieved either complete control or a marked improvement in control of asthma symptoms

• Omalizumab should be considered as add-on treatment for patients who continue to suffer with inadequately controlled asthma despite the use of high-dose ICS and LABAs

81

Issues and controversies around asthma management in Primary Care

72%

8% 11% 0% 6% 3%

78%

0% 3% 8%

8919%

0% 0%

Overdiagnosis of asthma in obese and nonobese adultsAaron SD et al, CMAJ 2008;179(11):1121-31

The diagnosis of asthma was confirmed in 346 of the participants:

54 (16%) by means of postbronchodilator spirometry

(least 15% and at least 200 mL) AND

249 (72%) by means of the bronchial challenge test, 8 (2%) on the basis of exacerbation of asthma symptoms during the tapering off of medications, and 35 (10%) through adjudication

Improvement in FEV1 of ≥ 15% and ≥ 200 mL after bronchodilator, [no. (%)], was 24 (9.1) in obese and 29 (10.6) in nonobese patients at baseline.

D’Urzo AD et al, Can Fam Physician 2011;57:1148-52.

Luks VP, Vandemheen KL, Aaron SD. Confirmation of asthma in anera of over diagnosis. Eur Respir J 2010; 36: 255–260.

At Visit 1, 54 out of 499 (10.8%) patients were diagnosed with asthma using simple pre- and post-bronchodilator spirometry.

At visit 2, methacholine challenge testing (MCT) resulted in a confirmation rate of 274 out of 444 (61.7%) patients and an exclusion rate of 121 out of 444 (27.3%) patients.

In order to identify the most simple and practical approach to asthma diagnosis confirmation in this

population, a methacholine challenge test (MCT) should have been performed at visit 1. It is possible that some, if not most, of the spirometrically confirmed cases (visit 1) would also be

confirmed with MCT.

This issue is relevant because it would provide practical information about which test should be ordered first in the real world; the results of the study by LUKS et al suggest that MCT may be the

option of choice among this population.

Aaron SD and Luks VERJ 2010, 37(1): 223 (1)

A. D’Urzo has correctly identified from our data [1] that bronchialchallenge testing seems to be a more sensitive test to confirm asthma compared to pre- and post-bronchodilator

spirometry.

Our results were similar to those of GOLDSTEIN et al. [2] who demonstrated that bronchial challenge testing with

methacholine has far greater sensitivity to diagnose asthma compared with post-bronchodilator spirometry.

Despite these findings, pre- and post-bronchodilator spirometry should probably be the first-line test to diagnose or confirm asthma

for several reasons.

2) Goldstein MF et al. Chest. 2001 Apr;119(4):1001-10.

3) D’Urzo AD et al, WONCA Europe 2012

Aaron SD and Luks VERJ 2010, 37(1): 223

- bronchial challenge test poses a risk to the patient that could be avoided if that patient is able to have asthma diagnosed, or confirmed, with post-bronchodilator spirometry.

- the risk may be more theoretical than evidence-based

- to date there are no reported deaths from methacholine challenge testing [1] and there are studies demonstrating that it is quite safe, even in patients with severe obstruction [2].

1) Crapo RO et al, Am J Respir Crit Care Med 2000; 161: 309–329. 2) Martin RJ et al, Chest 1997; 112: 53–56.

Practical Considerations

Data from the studies of Aaron (1) and colleagues and Lusuardi and colleagues (2) reveal a challenge to the attempted establishment of a diagnosis of asthma with spirometry in populations with a high probability of normal lung function at the time of testing.

1) Aaron SD et al, CMAJ 2008;179(11):1121-31 2) Lusuardi M. et al, CHEST 2006; 129:844–852

• The available publications reviewed suggest that MCT has far greater sensitivity for asthma diagnosis (among primary care patients) compared to Bronchodilator Reversibility (BDR) using simple spirometry.

• In fact, most asthma patients in primary care present with normal baseline spirometry on initial testing; few studies describe practical strategies for spirometric asthma diagnosis and management when initial spirometric testing is normal.

Clinical Implications for Primary Care

The concept of current control and future risk

Conclusions: Current control predicts future risk of instability and exacerbations.

-Budesonide/formoterol maintenance and reliever therapy reduces exacerbations versus

comparators and achieves at least similar control.

J Allergy Clin Immunol 2010;125:600-8.

Effect of Inhaled Glucocorticoidsin Childhood on Adult Height

N Engl J Med 2012;367:904-12.DOI: 10.1056/NEJMoa1203229

Effect of Inhaled Glucocorticoidsin Childhood on Adult Height

N Engl J Med 2012;367:904-12.DOI: 10.1056/NEJMoa1203229


Conclusions:- The revised Canadian asthma management guidelines provide relevant up-

dates on issues related to current control and future risk.- Inhaled momeatosne fuorate (Asmanex) represents a welcome addition to the

inhaled corticosteroid class.- The appropriate and safe use of LABAs in asthma management continues to

evolve.- Differentiating asthma from COPD represents an important clinical challenge in

primary care.- Omalizumab (Xolair) should be considered in severe asthma- the family

physician may play an important collaborative role in identifying and managing these patients.

- The role of simple spirometry for asthma diagnosis in primary continues to generate considerable discussion among primary and specialty care physicians.

Documents

State of the art pearls for managing asthma in primary Care Anthony D. D’Urzo MD, MSc, BPHE, CCFP, CFPC Associate Professor University of Toronto, Department