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Asthma Management – The One Size Fits all Approach Asthma Management – The One Size Fits all Approach Great for Socks…not for patients!Great for Socks…not for patients!

Asthma Management – The One Size Asthma Management – The One Size Fits all Approach Fits all Approach

Great for Socks…not for patients!Great for Socks…not for patients!Anne K. Ellis, MD MSc FRCPCAnne K. Ellis, MD MSc FRCPCAssociate Professor and ChairAssociate Professor and ChairDivision of Allergy & ImmunologyDepartment of Medicine, Queen’s Universityellisa@kgh.kari.netTwitter: @DrAnneEllis

Date: Sept 22nd, 2015

Time: 12:15h

Disclosures

Facilitator’s Name: Dr. Anne K. Ellis

Grants/research support: Circassia Ltd/Adiga Life SciencesGlaxoSmithKlineNovartisSunPharma Advanced Research CorporationMerck

Speaker’s bureau/honoraria:

Merck, Pfizer, AstraZeneca, Novartis

Consulting fees: ALK Abello, Ora Inc.

Advisory Boards: Merck, Novartis

Objectives

By the end of this learning session, the attendee will be able to: Describe differences in performance characteristic of

the various asthma controller therapies Develop a patient focused approach to asthma

management Learn where to access educational resources for

patients

Introduction - Asthma

Chronic inflammatory lung disorder characterized by: reversible airflow obstruction airway hyperresponsiveness

Presents symptomatically with dyspnea, wheeze and sensation of chest tightness

Barnes PJ. Clin Exp Allergy 1996;26:738-745.

Diagnosis of Asthma

Confirmed when compatible symptom pattern is accompanied by objective measures of variable airflow obstruction

Spirometry: >12% improvement in FEV1 15 mins after SABA OR >20% improvement after 10-14 days of oral prednisone OR >20% spontaneous variability

Serial PEF >20% change after bronchodilation or over time

Methacholine challenge 20% reduction in FEV1 with provocative concentration of

methacholine

Boulet L, et al. CMAJ 1999;161(11 Suppl):S1-61, Kaplan AG. CMAJ 2009;181:E210-20

FEV1: forced expiratory volume in 1 second, SABA: short-acting bronchodilator

Asthma – Phenotypes

Eosinophilic Bronchitis Steroid-responsive Typically atopic

Neutrophilic bronchitis Less steroid-responsive Smoking, viral illness, others

Non-inflammatory Obesity, others

Allergic Asthma

Allergen contact with airway mucosa in a sensitized individual results in rhinitis, conjunctivitis, and asthmatic responses

Immediate allergic response maximal 15 to 30 min after allergen challenge, resolves in 1 to 3 hours

~50% of subjects develop a late-phase allergic response persistent, less reversible decrease in pulmonary

function maximal in 6-12h and partially resolves within 24h

Late Phase Asthmatic Response

The Prevalence of Asthma in Canada:1.Has increased steadily over the past 20 years2.Is one of the highest in the world3.Affects a large portion of the pediatric population4.Affects nearly 3 million people in Canada5.All of the above

Polling Question:Epidemiology of Asthma in Canada

Statistics Canada. Available at: Statistics Canada. Available at: www40.statcan.ca. www40.statcan.ca. Asthma Society of Canada. Available at: Asthma Society of Canada. Available at: www.asthma.cawww.asthma.ca..

Epidemiology of Asthma in Canada

Prevalence increased over past 20 years among adults until 2001 and remains one of the highest in the world 1979: 2.3% 1988: 4.9% 1994: 6.1% 2001: 8.4% 2009: 8.4%

At least 12% of children have asthmaStatistics Canada. Available at: www40.statcan.ca.

Asthma Society of Canada. Available at: www.asthma.ca.

Asthma Triggers

Allergens Dust mites, mold spores, animal dander,

cockroaches, pollen, indoor and outdoor pollutants, irritants (smoke, perfumes, cleaning agents)

Pharmacologic agents (ASA, beta-blockers) Physical triggers (exercise, cold air) Physiologic factors

Stress, GERD, viral and bacterial URI, rhinitis

Lung Function Declines with Frequency of Asthma Exacerbations

Bai T. Bai T. Eur Respir J 2007;30:452-456Eur Respir J 2007;30:452-456

P<0.05P<0.05

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InfrequenInfrequentt

ExacerbationsExacerbationsFrequentFrequent

Factors Leading to Inadequate Asthma Control

Wrong diagnosis or confounding illness Incorrect choice of inhaler or poor technique Concurrent smoking Concomitant rhinitis Individual variation in treatment response Undertreatment Unintentional or intentional nonadherence

Haughney J, et al. Respir Med 2008;102:1681-1693Haughney J, et al. Respir Med 2008;102:1681-1693

Goals of Asthma Management

Achieve and maintain control of symptoms Prevent asthma exacerbations Maintain optimal pulmonary function Maintain normal activity levels (+ exercise) Avoid adverse effects from asthma medications Prevent the development of irreversible airflow

obstruction Prevent asthma mortality

GINA: Global Strategy for Asthma Management and Prevention, 2009GINA: Global Strategy for Asthma Management and Prevention, 2009 1717

What are the drugs?What are the devices?

Asthma Medications

1919

Treatment Effects Most common AEsRelievers

Short-acting beta-2 agonists

• Use on-demand only at min. dose and frequency

• Tremor, palpitations, restlessness, headache, muscle cramps, nervousness

ControllersInhaled corticosteroids • For persistent asthma

• Not intended as rescue med.

• May take 1-2 weeks to see benefits

• Local: Oral candidiasis, dysphonia, reflex cough and bronchospasm

• Systemic: bone density, poor growth, adrenal gland suppression, bruising, blood sugar

Leukotriene receptor antagonists

• Alternative for persistent asthma and as add-on to ICS

• Headaches, stomach pain, and cough

Anti-IgE MAb • For moderate to severe asthma with frequent need for oral CS

• Headache, malaise, anaphylaxis

LemièreLemière et al. Can Respir J 200 et al. Can Respir J 2004;11 Suppl A:9A-18A4;11 Suppl A:9A-18AIrwin R. Chest 2006;130(1 Suppl):41S-53SIrwin R. Chest 2006;130(1 Suppl):41S-53S

Asthma Medications (cont’d)

Treatment Effects Most common AEsAdd-on therapies

Long-acting beta-2-agonists

• Improves asthma control in older children and adults

• Only to be used as an add-on when asthma not controlled with ICS

• Not to be used as monotherapy

• Tachycardia, palpitation, irritability, insomnia, muscle cramps, tremor

LemièreLemière et al. Can Respir J 200 et al. Can Respir J 2004;11 Suppl A:9A-18A4;11 Suppl A:9A-18A

http://asthma.ca/inhalertraining.php

Canadian Thoracic Society Asthma Management Continuum

LABA = long-acting beta agonistLougheed MD, et al. Can Respir J 2010; 17(1):15-24.

<6 yr of age < 100 mcg/day <6 yr of age < 100 mcg/day

Asthma Management - Details

Allergen and Irritant Avoidance Avoidance of other triggers (e.g. cold air,

influenza vaccine, NSAIDs in sensitive px’s) Education, education, education Assessment of Control at each patient visit

I judge patient’s asthma control by:1.Need for fast-acting beta-agonist2.Physical activity3.Night time symptoms4.Exacerbations5.Absence from work or school

Polling Question:Indicators of Asthma Control

Statistics Canada. Available at: Statistics Canada. Available at: www40.statcan.ca. www40.statcan.ca. Asthma Society of Canada. Available at: Asthma Society of Canada. Available at: www.asthma.cawww.asthma.ca..

Indicators of Asthma Control

Characteristic Frequency or Value

Daytime symptoms < 4 days/week

Night-time symptoms < 1 night/week

Physical activity Normal

Exacerbations Mild, infrequent

Absence from work or school due to asthma None

Need for a fast-acting beta-agonist < 4 doses/week

FEV1 or PEF ≥ 90% personal best

PEF diurnal variation† < 10% to 15%

FEV1 = forced expiratory volume in 1 second; PEF = peak expiratory flow.†Diurnal variation is calculated as the highest PEF minus the lowest divided by the highest PEF multiplied by 100 for morning and night (determined over a 2-week period).

Lougheed MD, et al. Can Respir J 2010; 17(1):15-24.

Educate Patients That This Level of Asthma Control is Generally Achievable

Actual and Perceived Asthma Control in Canada: TRAC Study

100

Pat

ient

s (%

)

Actual(based on CACG)

53%

80

60

40

20

60

47%

3%

97%12%

88%

10%

90%

Patients Generalpractitioners

Specialists

Perceptions

CACG = Canadian Asthma Consensus Guidelines.FitzGerald JM, et al. Can Respir J 2006; 13(5):253-9.

Not controlledControlled

Why Don’t Patients Take Asthma Medications as Prescribed?

Most do not want to take daily medications when they feel well and have no asthma symptoms

Many believe they know when they need to take their asthma medications

Most use SABAs because these work quickly Many do not know or believe that poor

current asthma control results in future risks

SABA = short-acting beta agonist.SABA = short-acting beta agonist.

Short Acting Beta-Agonists (SABA)

Onset of action 5 to 15min, duration ~4 hr Salbutamol (Ventolin®)

MDI (100 mcg) Diskus (200 mcg)

Terburtaline (Bricanyl®) Turbuhaler (500 mcg)

Long Acting Beta-Agonists (LABA)

Black Box warning against monotherapy Only for 12 yr of age and up Salmeterol (Serevent®)

Maximal dose 100 mcg/day Onset of action ~ 1 hr MDI – 25 mcg; Diskus – 50 mcg

Formoterol (Oxeeze®) Maximal dose 48 mcg/day Onset of action ~ 15 min Turbuhaler – 6 mcg

Inhaled CorticosteroidsGeneric Name Formulation Doses

Beclomethasone (QVAR®)*** Inhalation aerosol (MDI) 50 mcg100 mcg

Fluticasone (Flovent®) Dry powder for inhalation (Diskus**) ¥

¥Contains lactose/milk protein

Inhalation aerosol (MDI)*

50 mcg100mcg250 mcg500 mcg

50 mcg125 mcg250 mcg

Budesonide (Pulmicort®)*** Dry powder for inhalation (Turbuhaler)

100 mcg200 mcg

Ciclesonide (Alvesco®)*** Inhalation aerosol (MDI) 100 mcg200mcg

Mometasone (Asmanex®)§ Dry powder for inhalation (Twisthaler)**

200 mcg400 mcg

***6 yoa and up***6 yoa and up § 12 yoa and up§ 12 yoa and up**4 yoa and up**4 yoa and up*12 mo and up*12 mo and up

Available ICS + LABA Single-inhaler Combinations

Advair® Product Monograph. GlaxoSmithKline Inc., July 2010.Symbicort® Product Monograph. AstraZeneca Canada Inc., December 2010.ZenhaleTM Product Monograph. Merck Canada Inc., January 2011.

Combination Formulation Doses

Fluticasone + salmeterol (Advair®)

Dry powder for inhalation(Diskus¥)

¥Contains lactose/milk protein

Inhalation aerosol (MDI)

100 mcg/50 mcg 250 mcg/50 mcg 500 mcg/50 mcg

50 mcg/25 mcg125 mcg/25 mcg250 mcg/25 mcg

Budesonide + formoterol (Symbicort®)

Dry powder for inhalation(Turbuhaler)

100 mcg/6 mcg200 mcg/6 mcg

Mometasone + formoterol (Zenhale®)

Inhalation aerosol (MDI) 50 mcg/5 mcg100 mcg/5 mcg200 mcg/5 mcg

Use of Asthma Inhalers/Meds

PRN SABA alone Fixed dose ICS (and/or LTRA); PRN SABA Fixed dose ICS/LABA (± LTRA); PRN SABA

At times of acute exacerbation, double or quadruple ICS dose or introduce oral CS

Single inhaler Maintenance and Rescue Therapy (SMART) – Fixed dose ICS/LABA and PRN ICS/LABA* * Only effective if the LABA is formoterol due to onset

of action differences * Only Health Canada approved for Symbicort®

ICS Safety: Key Pharmacokinetic and Pharmacodynamic PropertiesICS Oral bio-

availability (%)

Receptor binding affinity

Protein binding (%)

Beclomethasone 15 53/1,345a 87

Budesonide 11 935 88

Fluticasone < 1 1,800 90

Mometasone < 1 2,200 98-99

Ciclesonide < 1 12b/1,212c 99

Key characteristics:↑ receptor binding/potency↑ lipophilicity↑ plasma protein binding↑ metabolism↓ bioavailablity↓ systemic exposure

↑ therapeutic index

Rossi GA, et al. Pulm Pharmacol Ther 2007; 20(1):23-35.Bousquet J. Int J Clin Pract 2009; 63(5):806-19.

a Relative receptor affinity for 17-beclomethasone monopropionate.b Ciclesonide.c Desisobutyryl-ciclesonide

Corticosteroid Trade name

Daily ICS dose, mcg^Adult (>12 years old)

Low Medium HighBeclomethasone dipropionate HFA QVAR† ≤250 251-500 >500

Budesonide* Pulmicort Turbuhaler‡ ≤400 401-800 >800Ciclesonide* Alvesco§ ≤200 201-400 >400Fluticasone Flovent MDI and spacer; Flovent Diskus¶ ≤250 251-500 >500Mometasone Asmanex Twisthaler** 200 400 >400

Adapted from Lougheed MD, et al. Can Respir J. 2012;19:127-64.

^Comparative clinical significance has not been established

What is Low Dose ICS?

LABA Differences: Onset of Bronchodilation

**pp ≤ 0.016 vs. fluticasone + salmeterol. ≤ 0.016 vs. fluticasone + salmeterol.Bernstein DI, et al. Allergy Asthma Clin Immunol 2010; 6 (Suppl 2):33.Bernstein DI, et al. Allergy Asthma Clin Immunol 2010; 6 (Suppl 2):33.

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Mometasone + formoterol 200/10 mcg bidMometasone + formoterol 200/10 mcg bid

Fluticasone + salmeterol 250/50 mcg bidFluticasone + salmeterol 250/50 mcg bid

Specific for CysLTR1 CysLT2 is present in the lung but appears to

be confined to blood vessels Available agents: Singulair® = montelukast

4mg, 5mg and 10mg tablets, dosing is OD Accolate® = zafirlukast

20mg BID

Leukotriene Receptor Antagonists (LTRA’s)

Montelukast is approved for use in children 1 year of age and older for asthma and 2 years of age and older for allergic rhinitis Pregnancy category B

Zafirlukast approved for children 12 y and older Pregnancy category B

Leukotriene Receptor Antagonists (LTRA’s)

Personalized Asthma Treatment

Assess patient preference and ability to use device(s) **

Patients fearful of ICS, evaluate steroid alternatives for maintenance, such as LTRAs; ensure Aerochamber in use

Ask patient about desire for rapid onset, and select the ICS/LABA accordingly

Choose ICS with lowest bioavailability and associated with lowest risk of adverse effects but that also produces desired efficacy outcomes

Patient Compliance to ICS Therapy Can Prevent Asthma Deaths

Suissa S, et al. N Engl J Med 2000; 343(5):332-6.Suissa S, et al. N Engl J Med 2000; 343(5):332-6.

Fitted rate ratio for death from asthma as a function Fitted rate ratio for death from asthma as a function of the number of canisters of ICS used during year of the number of canisters of ICS used during year

before index date.before index date.

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Number of canisters of ICS per yearNumber of canisters of ICS per year3311 44 55 12129988 1010 111166 7700 22

Non-adherence to Asthma Therapy

Intentional Motivation Beliefs/preferences Perceptual barriers

Non-intentional Capacity and resources Practical barriers

Barriers to assessing adherence: Patient and physician may prefer to avoid the subject Lack of clear, easy methods for addressing barriers to

adherence Perception that little can be done?

Horne R, et al. Chest 2006;130:65SHorne R, et al. Chest 2006;130:65S--72S72S 4040

Strategies to Improve Adherence

Focus on patient education Ensure language at appropriate level Write it down Consider referral to an asthma educator

Encourage self-monitoring Use a written asthma action plan Monitor adherence to medication regimen and

proper inhaler techniques Combination therapy may improve complianceNational Heart, Lung, and Blood Institute National Asthma Education and Prevention Program Expert Panel. National Heart, Lung, and Blood Institute National Asthma Education and Prevention Program Expert Panel.

Guidelines for the Diagnosis and Management of Asthma Full Report 2007Guidelines for the Diagnosis and Management of Asthma Full Report 2007Stoloff SW, et al. J Allergy Clin Immunol 2004;113:245-251Stoloff SW, et al. J Allergy Clin Immunol 2004;113:245-251

4141

Asthma Education Centres

A link to this resource has been posted as a hand out in your control panel that you can download.

Unique Considerations

Pediatrics Allergic Asthma

Pediatric Considerations

Diagnostic challenge before age 5 Atopy risk factor for persistence of childhood wheeze Lower ICS doses usually sufficient Aerochambers not optional – discussion of benefits

can improve adherence Adherence to oral/non-steroidal therapy often higher

but must assess patient response Spirometry generally becomes reliable around age 8

to 10 to provide objective assessment of disease

Unique considerations – Allergic Population

Allergic rhinitis and asthma often co-exist Treating rhinitis improves asthma outcomes Remember to treat with INCS as well LTRA’s indicated for both, as is omalizumab and

immunotherapy Dual targets one medication:

LTRAs Allergen specific immunotherapy Omalizumab

Biologic Therapy

Omalizumab (Xolair®) Monoclonal antibody against IgE molecule Indicated for moderate to severe allergic

asthma Shown to decrease hospitalizations, ER visits,

and requirements for oral corticosteroids Typically given under specialist supervision

(injection, risk of anaphylaxis)

Allergen immunotherapy

Reached its 100th anniversary (Noon, 1911) Currently, subcutaneous immunotherapy (SCIT),

a.k.a ‘allergy shots’ established as effective in the treatment of IgE-mediated reactions to: Hymenoptera venom Allergic rhinitis Allergic asthma

What is immunotherapy?

Decrease allergen sensitivity via gradual administration of increasing doses of allergen extracts

Advances over last 25 yrs include improved quality of extracts, better understanding of underlying immune mechanisms

Modifies immune response from an allergic, inflammatory pattern to a more protective, less damaging response

IT and allergen avoidance are the only treatments that modify the natural history of allergic disease, inducing remission and/or long-term cure

Efficacy in Asthma

Confirmed in 3 meta-analyses of RCTs of specific immunotherapy for patients with allergic asthma

Most recent included 75 trials involving over 3500 patients 33 dust mite 20 pollen 10 animal 2 mould 6 multiple aeroallergens

Abramson et al. Cochrane Database System Rev 2009Abramson et al. Cochrane Database System Rev 2009

Efficacy

Standardized Mean Difference in symptoms scores were best for dust mite and all pollens; overall SMD -0.72 (95% CI -0.99 to -0.44)

If studies reported better, same, worse: Overall NNT = 4 to prevent one asthma deterioration Pollen NNT = 3

NNT = 5 to prevent one increase in medication requirements; NNT = 4 to prevent worsening of BHR

Established aspects

Effective doses of allergen extract: Ragweed Timothy Birch D. pteronyssinus D. farinae Cat dander Dog dander

Duration: After 5 years of SCIT,

benefit generally persists

If after 1-2 years at an appropriate maintenance dose, and no benefit noted, can discontinue Rx

Safety of Immunotherapy

Local, systemic, and even fatal reactions are a recognized complication of SCIT

Large local reactions not predictive of future systemic reactions (SRs)

Incidence of SRs a function of: Patient sensitivity Dose Modifications to extract

Systemic reactions to SCIT occur in 0.9 – 3.3% of injections with traditional schedules

Rush protocols, up to 38% Nelson. J Allergy Clin Immunol 2007Nelson. J Allergy Clin Immunol 2007

Additional Agents/On the Horizon

Ipatropium bromide (Atrovent®) 500 ug q4h PRN

Tiotropium bromide (Spiriva®) 18 mg QAM

Mepolizumab (Mepo®) Monoclonal anti-IL-5 antibody

Other biologics?

Summary

Asthma is a chronic disease–control inflammation to prevent symptoms

Avoidance of triggers with ongoing education essential components of asthma management

Review device technique/adherence whenever possible

Uncontrolled asthma and severe exacerbations accelerate decline in lung function

Unique considerations in allergic populations United airways; Disease modifying therapy

Questions?

ellisa@queensu.ca or ellisa@kgh.kari.net Twitter: @DrAnneEllis