Transcript Asthma Management Update: What*s new and what*s changed?

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:
• 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.
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.
Asthma Management Update:
What’s new and what’s changed?
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.
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.
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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
Asthma
COPD
FEV1*
Normal/Reduced
Normal/Reduced
FEV1/FVC*
Normal/Reduced
Reduced
* Post-bronchodilator
Pre-bronchodilator FEV1/FVC often normal in Asthma
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
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
FVC: Forced vital capacity (Liters)
Pre: Pre-Bronchodilator:
% Pred: Percent of Predicted Normal
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)
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Asthma Action Plan
Flovent 250
micrograms1p
uff 2xday
Ventolin 1-2
puffs 4xday as
needed
Flovent 250
micrograms
2 puffs 2xday
Ventolin 1-2
puffs 4xday as
needed
What’s new with inhaled corticosteroids (ICS)
in asthma management.
Efficacy and Safety of MFDPI Compared to Placebo in Patients
Previously Dependent on Twice-Daily ICS
3-Month DBPC Phase
Day −28
Day 1
MFDPI 200 mcg once daily PM
(n = 78)
MFDPI 400 mcg once daily PM
(1 x 400 mcg/inhalation) (n = 80)
ICS Reduction Period
MFDPI 400 mcg once daily PM
(2 x 200 mcg/inhalation) (n = 78)
MFDPI 200 mcg twice daily
(n = 81)
(N = 400 patients)
DBPC = double-blind, placebo-controlled; ICS = inhaled
glucocorticosteroids.
Placebo
(n = 83)
Follow-up visits: Weeks 1, 2, 4, 7, 12
D’Urzo A et al. Curr Med Res Opin. 2005;21:1281–1289.
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Week 12
MFDPI Significantly Improved FEV1 vs Placebo in Patients
Previously Dependent on Twice-Daily ICS
28-day
dose-reduction phase
of prior therapy
0.6
b
Mean Change in FEV1 From
Baseline (L)
Randomization
b
a
12
Endpoint
b
0.5
b
a
0.4
0.3
0.2
0.1
0.0
Baseline
1
2
4
7
Weeks of Study
Placebo (n = 83)
MFDPI 200 mcg qd PM (n = 78)
MFDPI 400 mcg qd PM, 1 x 400 μg /inhalation (n = 80)
MFDPI 200 mcg bid (n = 81)
MFDPI 400 mcg qd PM, 2 x 200 μg/inhalation (n = 78)
For all MFDPI treatment groups aP ≤ 0.001 versus placebo. bP < 0.05 versus placebo.
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.
MFDPI Significantly Improved AM and PM Asthma
Symptom Scores
% Change
From Baseline
to Endpoint in
Total
Symptom
Scorea
Placebo (n = 83)
MFDPI 200 mcg once daily PM (n = 78)
MFDPI 200 mcg twice daily (n = 80)
MFDPI 400 mcg once daily (1 x 400/inhalation) PM (n = 80)
MFDPI 400 mcg once daily (2 x 200/inhalation) PM (n = 78)
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.
D’Urzo A et al. Curr Med Res Opin. 2005;21:1281–1289.
MFDPI Reduced Number of Nocturnal Awakenings Compared
With Placebo
Mean %
Change at
Endpoint in
Nighttime
Awakenings/
Day
Placebo (n = 83)
MFDPI 200 mcg once daily PM (n = 78)
MFDPI 200 mcg twice daily (n = 80)
MFDPI 400 mcg once daily (1 x 400/inhalation) PM (n = 80)
MFDPI 400 mcg once daily (2 x 200/inhalation) PM (n = 78)
• 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.
31
D’Urzo A et al. Curr Med Res Opin. 2005;21:1281–1289.
D’Urzo A et al. Curr Med Res Opin. 2005;21:1281–1289.
How to safely use long-acting B2-agonists
and the biologic agent Omalizumab.
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.
34
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
Arch Intern Med. Published online August 27, 2012. doi:10.1001/archinternmed.2012.3250
Arch Intern Med. Published online August 27, 2012. doi:10.1001/archinternmed.2012.3250
Arch Intern Med. Published online August 27, 2012. doi:10.1001/archinternmed.2012.3250
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.
30
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
• 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
Almost 40% patients with severe asthma* remain
inadequately controlled despite optimized treatment with
salmeterol/fluticasone combination therapy
Patients (%)
n=568
Well controlled at 1 year
Inadequately controlled at 1 year
80
60
40
20
0
Salmeterol/fluticasone
*>500–1,000 µg beclometasone dipropionate (BDP)
or equivalent at baseline
24
Salmeterol/fluticasone
plus course of oral
corticosteroids (OCS)
The most severe group of patients have the highest
incidence of hospitalization and emergency visits
Patients (%)
25
17
Mild (n=219)
Moderate (n=2,285)
Severe (n=2,285)
20
15
10
5
0
Emergency department visit
Hospitalization
Dolan CM, et al. Ann Allergy Asthma Immunol 2004
33
Prevalence of asthma is related to the level of serum IgE
40
Asthma (odds ratio)*
n=2,657
20
10
5.0
2.5
1.0
0.32
*Logarithmic scale
1
3.2 10
32 100
Serum IgE (IU/mL)*
320 1,000 3,200
Burrows B, et al. N Engl J Med 1989
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The anti-inflammatory role of
omalizumab
in allergic respiratory disease
Omalizumab mechanism of action
in IgE-mediated asthma
B lymphocyte
Allergic
mediators
-switch
50
Reduces
Allergic
mediator
release inflammation:
eosinophils and
lymphocytes
Plasma cell
Release
of IgE
Perennial
aeroallergens
Omalizumab
Binds to free IgE,
reducing
cell-bound IgE
Asthma exacerbation
Reduces
high-affinity
receptors
Mast cells
Basophils
Reduces asthma
exacerbations and
symptoms
62
Omalizumab significantly reduces severe
exacerbations and emergency visits
Severe exacerbation rate
0.6
0.6
0.5
Total emergency visit rate
0.5
∆ –50.0%
p=0.002
0.4
0.4
∆ –43.9%
p=0.038
0.3
0.3
0.2
0.2
0.1
0.1
0
0
Omalizumab
(n=209)
Placebo
(n=210)
Omalizumab
(n=209)
Placebo
(n=210)
Humbert M, et al. Allergy 2005
73
Omalizumab significantly reduces
exacerbations irrespective of OCS use
Annualized exacerbation rate
OCS
Non-OCS
4
4
3
∆ –34.9%
p=0.001
3
2
2
1
1
0
0
Omalizumab
(n=271)
Control
(n=173)
∆ –29.4%
p<0.001
Omalizumab
(n=1,454)
Control
(n=899)
Wenzel S, et al. Chest 2007
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 question
Methotrexate 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 prevention
2. Possible reduction in maintenance therapy
3. Improved quality of life
Overview of omalizumab
general 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
81
• 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
Issues and controversies around
asthma management in Primary Care
78%
72%
8%
11% 0%
6%
3%
8919%
0%
3%
8%
0%
0%
Overdiagnosis of asthma in obese and nonobese adults
Aaron 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 an
era 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 V
ERJ 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 V
ERJ 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.
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
Clinical Implications for Primary Care
• 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.
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 Glucocorticoids
in Childhood on Adult Height
N Engl J Med 2012;367:904-12.
DOI: 10.1056/NEJMoa1203229
Effect of Inhaled Glucocorticoids
in Childhood on Adult Height
N Engl J Med 2012;367:904-12.
DOI: 10.1056/NEJMoa1203229
Asthma Management Update: What’s
new and what’s changed?
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.