Using Inhaled Corticosteroids as Needed for Asthma: giving patients relief or leaving them breathless?

Lindsay Thomas, Pharm.D. PGY2 Ambulatory Care Resident

Department of Pharmacotherapy and Pharmacy Services, University Health System Pharmacotherapy Division, the University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center, University of Texas San Antonio March 8th, 2019

Learning Objectives: 1. Describe the disease state, classification, and current guideline recommended management of

asthma2. Discuss adherence and complications associated with asthma3. Review the current literature regarding using inhaled corticosteroids as needed for management

of mild persistent asthma4. Summarize when using inhaled corticosteroids as needed is appropriate for mild persistent

asthma

Thomas 2

Assessment questions: 1. What is the American guideline recommended 1st line maintenance treatment for mild persistent

asthma? A. Inhaled corticosteroid B. Long-acting beta2 agonist C. Theophylline D. Leukotriene receptor antagonist

2. What estimated percent of patients with asthma are adherent to their maintenance inhaler

regimen? A. 5-10% B. 20-40% C. 20-60% D. 60-100%

3. True or False: Inhaled corticosteroids used as needed demonstrated similar control of symptoms and exacerbations to daily inhaled corticosteroids in the SYGMA trials.

A. True B. False

***To Obtain CE credit for attending this program please sign in. Attendees will be emailed a link to an electronic CE Evaluation Form. CE credit will be awarded upon completion of the electronic form. If you do not receive an email within 72 hours, please contact the CE Administrator at ana.franco-martinez@uhs-sa.com*** Faculty (Speaker) Disclosure: Lindsay Thomas has indicated she has no relevant financial relationships relative to the content of her presentation.

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Asthma is a chronic inflammatory disorder of the airways1-3

Common characteristics: episodic airflow limitation, bronchial hyperresponsiveness, underlying inflammation, and reversible airway obstruction

Symptoms: wheezing, breathlessness, cough, chest tightness Epidemiology in the United States4,5

Prevalence (2016): 26,515,000

Asthma related deaths (2016): 3,518 /year

Persons having > 1 asthma attack (2016): 12,426,000/year

Asthma related inpatient hospital discharges (2010): 439,435/year

Asthma related emergency department visits (2015): 1,700,000/year

Asthma related physician visits (2014): 11,000,000/year Pathophysiology1-3

Airway inflammation is a major factor in determining severity, cell/mediator pattern, and treatment response

Recurrent airflow limitation is caused by a variety of changes o Bronchoconstriction: can be induced by allergens, medications (e.g., aspirin, non-

steroidal anti-inflammatory drugs), exercise, cold air, irritants (e.g., chemicals, tobacco smoke)

o Airway edema o Airway hyperresponsiveness o Airway remodeling

Diagnosis1-3,6-8

Must determine presence of episodic airflow obstruction and airway hyperresponsiveness symptoms, at least partially reversible airflow obstruction, exclusion of other diagnosis

Tools used for diagnosis o Detailed medical history o Physical examination of upper respiratory tract, chest, and skin o Spirometry (Appendix A, Section a)5 o Patient Assessment Questionnaires (Appendix A, Section b)6-7

Classification (Appendix B)1-3

Four classes 1. Intermittent 2. Mild persistent

3. Moderate persistent 4. Severe persistent

Considers o Frequency of symptoms o Nighttime awakenings due to asthma symptoms o Use of short-acting beta2 agonist (SABA) o Interference with normal activity o Lung function o Exacerbation requiring systemic corticosteroids

Background

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Treatment1-3

Goals o Reduce impairment of daily activities

Prevent symptoms Maintain normal pulmonary function Maintain normal activity levels

o Reduce risk of exacerbation Minimize need of emergency department (ED) visits or hospitalizations Prevent progressive loss of lung function

Use the stepwise approach to determine medication therapy (Table 1) o Initial step is based on asthma classification (Figure 1, Appendix C) o Use stepwise approach to make medication adjustments

Assess asthma control (Appendix D)

Initial: every 2-6 weeks until controlled

Maintenance: every 1-6 months To step up

Address the following considerations: quality of life impairment, risk of exacerbation, adherence, environmental control, comorbid conditions

To step down, patient MUST be well-controlled for 3 months Figure 1: Stepwise approach to therapy

Source: figure 16. Summary report 2007. Guidelines for the diagnosis and management of asthma. NHLBI. 2007

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Table 1: Medication classes1-3, 9-45 Beta2 Agonists

Medications SABAs: albuterol, levalbuterol, terbutaline LABAs: formoterol (similar time of onset as short-acting), salmeterol, vilanterol

MOA agonize beta2 receptors which increases cAMP leading to relaxation of airway smooth muscle

AE tachycardia, QTc prolongation, hypokalemia, tremor, hyperglycemia

Place in therapy SABAs: rescue therapy LABAs: used in combination with ICS for long-term control of asthma

CANNOT be used as monotherapy in asthma

Inhaled Corticosteroids

Medications budesonide, fluticasone, beclomethasone, mometasone, ciclesonide

MOA block late-phase reaction to allergen, reduce airway hyperresponsiveness, inhibit inflammatory cell migration and activation

AE oral candidiasis, dysphonia, reflex cough, bronchospasm, and reduction in growth rate (children and adolescents)

Place in therapy long-term control of asthma for mild, moderate, or severe persistent asthma (monotherapy or in combination)

Anticholinergics

Medications short-acting: ipratropium long-acting: tiotropium

MOA inhibit muscarinic cholinergic receptors leading to bronchodilation

AE dry mouth, increase wheezing, blurred vision, decreased respiratory secretions

Place in therapy short-acting: moderate or severe asthma exacerbations in ED with SABA long-acting: tiotropium is FDA approved and currently recommended by GINA

Leukotrienes Receptor Antagonists

Medications montelukast, zafirlukast

MOA block the effects of leukotrienes leading to reduce inflammation

AE headache, dizziness, fatigue, skin rash, cough

Place in therapy alternative (NOT preferred) for long-term control of mild persistent asthma; use as adjunctive therapy with ICS

5-Lipoxygenase Inhibitor

Medications zileuton, zileuton CR

MOA inhibits production of leukotriene leading to reduce inflammation

AE elevated liver enzymes, hepatitis, hyperbilirubinemia

Place in therapy alternative for adults (less preferred than LTRAs)

Mast Cell Stabilizer

Medications cromolyn

MOA stabilize mast cells and eosinophil recruitment, interfere with chloride channel function

AE chest pain, edema, headache, irritability, skin rash, photosensitivity, diarrhea, nausea, abdominal pain, constipation, neutropenia

Place in therapy alternative (NOT preferred) for long-term control of mild persistent asthma

Methylxanthines

Medications theophylline

MOA non-selectively inhibits phosphodiesterase leading to bronchodilation

AE headache, nausea/vomiting, tachycardia, insomnia, hyperglycemia, hypokalemia, gastric upset, seizures

Place in therapy alternative (NOT preferred) for long-term control of mild persistent asthma; use as adjunctive therapy with ICS (NOT preferred)

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Immunomodulators

Medications benralizumab, mepolizumab, omalizumab, reslizumab

AE pain and bruising at injection site, anaphylaxis, malignant neoplasms

Place in therapy long-term control of moderate or severe persistent allergic asthma inadequately controlled with ICS

SABA: short-acting beta2 agonist; LABA: long-acting beta2 agonist; MOA: mechanism of action; AE: adverse effects; cAMP: cyclic adenosine monophosphate; ICS: inhaled corticosteroids; FDA: Food and Drug Administration; GINA: Global Initiative for Asthma; ED: emergency department; LTRA: leukotriene receptor antagonist; CR: controlled release

Adherence1-3,46

Estimated adherence to inhale corticosteroids (ICS) maintenance therapy in asthma: 22-63% o Risk factors for nonadherence: children and adolescents, African Americans, mild

asthma, low education level, and poor communication with healthcare providers

Implications: higher percentage of eosinophils in sputum, increased use of oral corticosteroids increased hospitalization, higher mortality rate

Complications1-3

Exacerbations (see Appendix F for risk factors)

Pneumonia

Respiratory failure

Death A 2013 Cochrane meta-analyses included 6 trials (n=1211) that evaluated ICS + SABA as needed (PRN) vs ICS maintenance therapy47

Rates of exacerbation: ICS + SABA PRN had similar to ICS maintenance therapy

Lung function, airway inflammation, asthma control, and reliever use: ICS maintenance therapy was superior to ICS + SABA PRN

Table 2. O’Byrne PM, et al. Inhaled combined budesonide-formoterol as needed in mild asthma (SYGMA 1). N Engl J Med. 2018;378:1865-1876

48

Objective To assess the long-term efficacy and safety of budesonide-formoterol PRN in mild persistent asthma

Methods

Design 52-week double-blind, randomized, parallel group, phase 3 trial involving patient > 12 years old with mild persistent asthma

Population Inclusion criteria Exclusion criteria

> 12 years old

Received asthma diagnosis > 6 months before enrollment

Needed GINA step 2 therapy > 30 days before visit 2

Worsening asthma within 30 days that required medication changes

Use of systemic steroids within 30 days

Use of any ß-blocking agents

Smoker with > 10 pack-year

History of life-threatening asthma

Intervention 3 groups 1. Terbutaline PRN: placebo BID + terbutaline (0.5 mg) PRN 2. Budesonide-formoterol PRN: placebo BID + budesonide-formoterol (200 mcg/6mcg)

PRN 3. Budesonide maintenance: budesonide (200 mcg) BID + terbutaline (0.5 mg) PRN

Literature Evaluating ICS as Needed in Asthma

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Primary outcomes

Determine superiority of budesonide-formoterol used as needed over terbutaline used as needed in terms of asthma symptom scores, nighttime awakenings, morning peak expiratory flow, additional use of inhaled or systemic glucocorticoids

Secondary outcomes

Determine noninferiority of budesonide-formoterol used as needed to budesonide maintenance therapy in terms of weeks of well-controlled asthma, comparing rates and time to the 1

st severe exacerbation, rates and time to 1

st moderate-to-severe

exacerbation, AQLQ, and ACQ-5

Safety (type, incidence, and severity of adverse events and by monitoring of vital signs)

Results

Baseline characteristics

n=3836

Characteristic Terbutaline PRN (n=1277)

Budesonide-formoterol PRN (n=1277)

Budesonide maintenance (n=1282)

Age—years +STD 40.0 +16.3 39.8 +16.9 39.0 +16.7

Female sex—n(%) 771 (60.4) 777 (60.8) 797 (62.2)

Time since asthma diagnosis—years (range)

6.3 (0.5-62.4) 6.5 (0.4-65.7) 6.3 (0.5-57.1)

ACQ-5 mean score +STD At trial entry

At baseline

1.52 +0.96 1.54 + 0.95

1.57 +0.97 1.61 +0.97

1.53 +0.97 1.55 +0.96

ACQ-5 score > 1.5—n/total n(%)

At trial entry At baseline

549/1160 (47.3) 602/1256 (47.9)

601/1174 (51.2) 649/1257 (51.6)

568/1177 (48.3) 596/1257 (47.4)

AQLQ score +STD 5.25 +0.99 5.20 +1.01 5.27 +1.01

FEV1— % of predicted value +STD

Before bronchodilator use After bronchodilator use

84.13 +14.08 95.27 +13.53

84.18 +12.24 95.86 +14.02

84.23 +13.91 95.67 +13.43

PEF > 80% predicted value in AM—n/total n(%)

362/1276 (28.4) 340/1277 (26.6) 376/1282 (29.3)

Bronchodilator reversibility—% +STD

14.4 +11.5 14.9 +11.3 14.6 +11.6

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Asthma control according to pretrial treatment

Uncontrolled with SABA alone—n(%)

Controlled with ICS or LTRA—n(%)

565 (44.2) 712 (55.8)

565 (44.2) 712 (55.8)

576 (44.9) 706 (55.1)

Severe exacerbation in previous 12 months—n(%)

256 (20.0) 257 (20.1) 241 (18.8)

Primary outcome

Mean percentage of electronically recorded weeks with well-controlled asthma per patient in budesonide-formoterol group vs. terbutaline group: 34.4% vs 31.1% of weeks; OR: 1.14; 95% CI: 1.00-1.30; p=0.046

Secondary outcome

Mean percentage of electronically recorded weeks with well-controlled asthma per patient in budesonide-formoterol PRN group vs. budesonide maintenance group: 34.4% vs 44.4% of weeks; OR: 0.64; 95% CI: 0.57-0.73

Rate of severe exacerbation budesonide-formoterol PRN group vs. terbutaline PRN group: 0.07 vs 0.20; RR: 0.36; 95% CI: 0.27-0.49

Rate of severe exacerbation budesonide-formoterol PRN group vs. budesonide maintenance group: 0.07 vs 0.09; RR: 0.83; 95% CI: 0.59-1.16

Time to 1st

exacerbation budesonide-formoterol PRN group vs. terbutaline PRN group: HR: 0.44, 95% CI:0.33-0.58

Time to 1st

exacerbation budesonide-formoterol PRN group vs. budesonide maintenance group: HR: 0.9; 95% CI: 0.65-1.24

Adverse events increased in terbutaline PRN group o Terbutaline PRN group—545 (42.7%) o Budesonide-formoterol PRN group—485 (38.0%) o Budesonide maintenance group—512 (39.9%)

Author’s Conclusion

Budesonide-formoterol PRN was superior to terbutaline PRN both for asthma symptom control and for reducing the risk of asthma exacerbations among patients with mild persistent asthma. Budesonide-formoterol PRN was inferior to budesonide maintenance therapy with asthma symptom control. However, budesonide-formoterol had similar reduction of exacerbation risk to budesonide maintenance therapy, at a substantially lower total glucocorticoid load and without the need to adhere to a BID maintenance therapy schedule.

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Reviewer’s Critique

Strengths: • Groups were similar • 52-week duration • Used electronic monitoring that required

real-time recording • Kept tract of ICS exposure • Adherence ~80%

Limitations: • Terbutaline PRN is not the guideline

recommended treatment for mild persistent asthma

• ICS PRN group included a fast-acting LABA • Adherence ~80%

Conclusion: • Budesonide-formoterol PRN superior to terbutaline PRN in controlling mild persistent asthma • Budesonide-formoterol PRN inferior to budesonide BID in controlling symptoms even though time to

1st

exacerbation was similar • Budesonide-formoterol PRN had less ICS and systemic steroid

GINA: Global Initiative for Asthma; BID: twice daily; PRN: as needed; AQLQ: Asthma Quality of Life Questionnaire; ACQ: Asthma Control Questionnaire; STD: standard deviation; FEV1: forced expiratory volume in 1 second; PEF: peak expiratory flow; CI: confidence interval; OR: odds ratio; RR: rate ratio; HR: hazard ratio; ICS: inhaled corticosteroid; SABA: short-acting beta2 agonist; LTRA: leukotriene receptor antagonist

Table 3. Bateman ED, et al. As-needed budesonide-formoterol versus maintenance budesonide in mild asthma (SYGMA 2). N Engl J Med. 2018;378:1877-1887

49

Objective To determine if budesonide–formoterol PRN is non-inferior to regular budesonide maintenance treatment in preventing severe exacerbations in patients with mild asthma

Methods

Design 52-week double-blind, randomized, parallel group, phase 3 trial involving patient > 12 years old with mild persistent asthma

Population Inclusion criteria Exclusion criteria

> 12 years old

Received asthma diagnosis > 6 months before enrollment

Needed GINA step 2 therapy > 30 days before visit

Asthma worsening that involved a change in treatment or use of glucocorticoids in previous 30 days

History of > 10 pack-years

History of life-threatening asthma

Intervention 2 groups 1. Budesonide-formoterol PRN: placebo BID + budesonide-formoterol (200 mcg/6mcg)

PRN 2. Budesonide maintenance: budesonide (200 mcg) BID + terbutaline (0.5 mg) PRN

Primary outcomes

Annualized rate of severe exacerbation in both groups

Secondary outcomes

Time to severe exacerbation

Use of inhaled and systemic glucocorticoids

FEV1 before bronchodilator use

Trial specific asthma-related discontinuation

Use of maintenance therapy and as-needed reliever therapy

The percentage of reliever-free days

ACQ-5 score, AQLQ score

Results

Baseline characteristics

N=4176

Characteristic Budesonide-formoterol PRN (n=2089)

Budesonide maintenance (n=2087)

Age—years Mean +STD

Range

41.3 +16.8 12-82

40.7 +17.1 12-83

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Female sex—n(%) 1208 (62.6) 1289 (61.8)

Current smoking—n(%) 53 (2.5) 54 (2.6)

Time since asthma diagnosis—years Median (range)

7.9 (0.5-62.4)

7.3 (0.4-71.2)

ACQ-5 mean score +STD 1.49 +0.89 1.53 +0.90

ACQ-5 score > 1.5—n/total n(%) 943/2043 (46.2) 1000/2037 (49.1)

FEV1— % of predicted value + STD Before bronchodilator use

After bronchodilator use

84.4 +13.9 96.3 +13.8

84.1 +13.9 96.0 +13.5

Bronchodilator reversibility—% +STD 15.1 +12.4 15.2 +13.0

Asthma control according to pretrial treatment

Uncontrolled with SABA alone—n(%) Controlled with ICS or LTRA—n(%)

956 (45.9) 1130 (54.1)

975 (46.7) 1112 (53.3)

Severe exacerbation in previous 12 months—n(%)

0 1

> 2

1630 (78.0) 365 (17.5) 94 (4.5)

1627 (78.0) 362 (17.3) 98 (4.7)

Primary outcome

Secondary outcome

Use of inhaled and systemic glucocorticoids

o Median daily dose in budesonide-formoterol group was 66 mcg and in budesonide maintenance group was 267 mcg (75% increase)

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Author’s Conclusion

In patients with mild asthma, budesonide–formoterol used as needed was noninferior to twice-daily budesonide with respect to the rate of severe asthma exacerbations during 52 weeks of treatment but was inferior in controlling symptoms. Patients in the budesonide–formoterol group had approximately one quarter of the inhaled glucocorticoid exposure of those in the budesonide maintenance group.

Reviewer’s Critique

Strengths: • Compared to guideline recommended

therapy • Similar baseline characteristics • Looked at steroid exposure (ICS and

systemic steroids)

Limitations: • Adherence ~64% in maintenance group • Did not assess markers of inflammation

Conclusion: • ICS maintenance therapy is better than ICS PRN • ICS PRN has lower corticosteroid exposure

GINA: Global Initiative for Asthma; BID: twice daily; PRN: as needed; AQLQ: Asthma Quality of Life Questionnaire; ACQ: Asthma Control Questionnaire; STD: standard deviation; FEV1: forced expiratory volume in 1 second; PEF: peak expiratory flow; CI: confidence interval; OR: odds ratio; RR: rate ratio; HR: hazard ratio; ICS: inhaled corticosteroid; SABA: short-acting beta2 agonist; LTRA: leukotriene receptor antagonist

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Table 4. Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomized, double-blind, placebo-controlled trial. Lancet. 2011;377:650-657

50

Objective To establish whether discontinuation of daily inhaled corticosteroids in children with well controlled, mild persistent asthma is associated with an increased risk of exacerbations, and whether or not the use of beclomethasone plus albuterol for relief, with or without concomitant use of daily beclomethasone, provides better protection against exacerbations than does a rescue strategy that uses albuterol alone.

Methods

Design A 44-week randomized, double-blind, four-treatment trial with a 2x2 factorial design

Population Inclusion criteria Exclusion criteria

Between 6 and 18 years old

Naive to controller treatment and had a history of 1-2 exacerbations in previous year

Treated for the previous 8 weeks with a monotherapy other than ICS

Their illness was controlled for previous 8 weeks on low-dose corticosteroids as monotherapy (< 160 mcg daily with beclomethasone equivalent)

Pre-bronchodilator FEV1 <60% of predicted at 1

st visit

Hospitalization due to asthma in previous year

Any asthma exacerbation in previous 3 months or > 2 in the previous year

History of life-threatening asthma exacerbations that required intubation or mechanical ventilation or resulted in a hypoxic seizure

Intervention 4 groups 1. Combined: beclomethasone BID + beclomethasone/albuterol PRN 2. Daily: beclomethasone BID + placebo/albuterol PRN 3. Rescue: placebo BID + beclomethasone/albuterol PRN 4. Placebo: placebo BID + placebo/albuterol PRN

Primary outcome

Time to first exacerbation that required treatment with prednisone

Secondary outcomes

FEV1, FENO, symptom diaries and control and quality of life questionnaires, linear growth

Results

Baseline characteristics

N=288

Characteristic Combined (n=71)

Daily (n=72) Rescue (n=71)

Placebo (n=74)

Age—years +STD 11.4 +3.1 10.8 +3.5 10.4 +2.8 10.4 +3.2

Sex (male)—n(%) 39 (55) 42 (58) 37 (52) 41 (55)

White—n(%) 50 (70) 51 (71) 57 (80) 59 (78)

Height—cm +STD 146.6 +17.4 141.9 +19.4 143.6 +18.4 140.6 +18.2

Weight—kg +STD 46.1 +22.9 44.1 +19.9 44.1 +19.1 42.3 +19.2

Age at asthma diagnosis—years +STD

4.5 +3.8 3.7 +2.7 4.1 +2.9 4.1 +3.1

Age at onset of asthma symptoms—years +STD

3.7 +3.4 2.7 +2.5 2.9 +2.6 3.1 +2.9

ICS use in previous year—n(%)

54 (76) 59 (82) 51 (72) 57 (77)

LTRA use in previous—n(%)

11 (16) 7 (10) 14 (20) 13 (18)

> 1 steroid course in last year—n(%)

19 (27) 19 (26) 24 (34) 21 (28)

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Pre-bronchodilator FEV1—% predicted

+STD FEV1/FVC—% +STD

101.5 +11.7 81.5 +7.3

100.1 +10.8 83.5 +6.4

101.4 +12.1 82.4 +6.1

100.4 +11.4 82.4 +6.3

Hospital visit in previous year—Mean +STD

0.3 +0.6 0.3 +0.8 0.2 +0.4 0.2 +0.5

Primary outcome

Probability of 1

st exacerbation by the end of the trial:

Combined: 31%

Daily: 28%

Rescue: 35%

Placebo: 49% Frequency of exacerbation

Placebo vs Daily: 49% vs. 28%, p=0.03

Placebo vs Combined: 49% vs. 31%, p=0.07

Placebo vs Rescue: 49% vs. 35%, p=0.07

Secondary outcome

Linear growth

Placebo and rescue: 1.1 cm more of growth than combined and daily (p<0.0001)

FEV1: no difference among groups in decline of FEV1 FENO: increase in the rescue and placebo groups vs daily and combined groups (p<0.0001)

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Author’s Conclusion

Children with mild persistent asthma should not be treated with rescue albuterol alone and the most effective treatment to prevent exacerbations is daily inhaled corticosteroids. Inhaled corticosteroids as rescue medication with albuterol might be an effective step-down strategy for children with well controlled, mild asthma because it is more effective at reducing exacerbations than is use of rescue albuterol alone. Use of daily inhaled corticosteroid treatment and related side-effects such as growth impairment can therefore be avoided.

Reviewer’s Critique

Strengths: • 4 different treatment arms • Evaluated linear growth • Children and adolescents only

Limitations: • Smaller study • Children and adolescents only • Deviated from original analysis plan due to

subadditive interactions

Conclusion: • ICS daily should be our first choice to reduce exacerbations in mild persistent asthma • ICS daily with PRN ICS + SABA demonstrated best control of asthma • If growth impairment or ICS exposure is a concern, ICS PRN could be considered

BID: twice daily; PRN: as needed; AQLQ: Asthma Quality of Life Questionnaire; ACQ: Asthma Control Questionnaire; STD: standard deviation; FEV1: forced expiratory volume in 1 second; FENO: fractional exhaled nitric oxide; FVC: forced vital capacity; CI: confidence interval; OR: odds ratio; RR: rate ratio; HR: hazard ratio; ICS: inhaled corticosteroid; SABA: short-acting beta2 agonist

When is using ICS PRN as monotherapy appropriate?

In mild persistent asthma, ICS maintenance therapy + SABA or ICS/SABA PRN should be 1st line

BUT, if the patient meets the following criteria, ICS PRN could be used o Asthma has been well-controlled for more than 3 months o Patient is non-adherent to ICS o Growth impairment is a concern

Take home points

1. Over 26 million Americans have asthma 2. The recommended treatment for mild persistent asthma is ICS maintenance therapy + SABA

PRN 3. All 3 trials demonstrated ICS maintenance therapy provided better control of symptoms than ICS

PRN

BUT, all 3 found similar rates of exacerbation between ICS maintenance therapy and ICS PRN

4. ICS PRN could be used in well-controlled mild persistent asthma in adolescents to limit ICS exposure and growth impairment

1. National Asthma Education and Prevention Program. Expert Panel Report 3. Guidelines for the diagnosis and management

of asthma. NHLBI. 2007 2. National Asthma Education and Prevention Program. Expert Panel Report 3. Summary report: guidelines for the diagnosis

and management of asthma. NHLBI. 2007 3. Global Initiative for Asthma (GINA). GINA report, global strategy for asthma management and prevention. 2018 4. Asthma: most recent asthma data. CDC. 2018. https://www.cdc.gov/asthma/most_recent_data.htm. Accessed January 4,

2019

Summary

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Inc; Oct 2016 34. Nelson HS, et al; SMART Study Group. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual

pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest. 2006;129(1):15-26 35. Peters SP, et al. Serious asthma events with budesonide plus formoterol vs. budesonide alone. N Engl J Med.

2016;375(9):850-860 36. Singulair (montelukast) [prescribing information]. Whitehouse Station, NJ: Merck and Co; December 2018. 37. Accolate [package insert]. Wilmington, DE: AstraZeneca; Nov 2013 38. Zyflo (zileuton) [prescribing information]. Cary, NC: Chiesi USA, Inc; May 2017 39. Zyflo CR (zileuton) [prescribing information]. Cary, NC: Chiesi USA, Inc; Dec 2018 40. Cromolyn Sodium (oral solution) [prescribing information]. Mason, OH: Prasco Laboratories; Dec 2011 41. Theophylline in 5% dextrose [package insert]. Bethlehem, PA: B. Braun Medial Inc; Jan 2016 42. Fasenra (benralizumab) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; Nov 2017 43. Nucala (mepolizumab) [product monograph]. Mississauga, Ontario, Canada: GlaxoSmithKline Inc; Jul 2018 44. Xolair (omalizumab) [product monograph]. Dorval, Quebec, Canada: Novartis Pharmaceuticals Canada Inc; Sep 2017 45. Cinqair (reslizumab) [prescribing information]. Frazer, PA: Teva Respiratory; Jan 2019 46. Barnes CB, et al. Asthma and adherence to inhaled corticosteroids: current status and future perspectives. Respiratory Care.

2015;60(3):455-468 47. Chauhan BF, et al. Intermittent versus daily inhaled corticosteroids for persistent asthma in children and adults. Cochrane

Database Syst Rev. 2013;(2):CD009611 48. O’Byrne PM, et al. Inhaled combined budesonide-formoterol as needed in mild asthma(SYGMA 1). N Engl J Med.

2018;378:1865-1876

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49. Bateman ED, et al. As-needed budesonide-formoterol versus maintenance budesonide in mild asthma (SYGMA 2). N Engl J Med. 2018;378:1877-1887

50. Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomized, double-blind, placebo-controlled trial. Lancet. 2011;377:650-657

A. Diagnosis tools

a. Spirometry: assesses severity of obstruction and reversibility of obstruction5 i. May be used in children > 5 years old

ii. The following are recommended before and after taking SABA for diagnosis: 1. Forced expiratory volume in 1 second (FEV1): volume of air a patient can

exhale forcefully in one second a. Reduced value: significant obstruction b. Can help determine reversibility

i. Increase of FEV1 by > 12% from baseline ii. Increase of predicted FEV1 by > 10% after inhalation of SABA

2. Forced expiratory volume in 6 seconds (FEV6) [only used in adults] a. Reduced value: restricted breathing

3. Forced vital capacity (FVC): largest volume of air a patient can exhale forcefully

a. Reduced value: restricted breathing 4. FEV1/FVC

a. Increased value: restricted breathing b. Reduced value: obstructed breathing

b. Patient Assessment Questionnaires6-7 i. Asthma Control Questionnaire (ACQ)6

1. 7 items: symptoms, rescue inhaler use, and FEV1% 2. 1-week recall 3. 7-point scale

a. 0: no impairment b. 6: maximum impairment for symptoms and rescue use

ii. Asthma Quality of Life Questionnaire (AQLQ)7 1. 4 domains: symptoms, activity limitation, emotional function, and

environmental exposure 2. 2- week recall 3. 7-point scale

a. 1: severely impaired b. 7: no impairment

Appendix

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B. Classifications1,2

Source: figure 14. Summary report 2007. Guidelines for the diagnosis and management of asthma. NHLBI. 2007

C. GINA Stepwise management for patients > 12 years old3

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D. Determining asthma control1,2

Source: figure 15. Summary report 2007. Guidelines for the diagnosis and management of asthma. NHLBI. 2007

E. Medications Table E-1: Asthma Inhalers Available in United States9-35

Name Components Dosing Type of Inhaler

Maintenance or Rescue

Short-Acting Beta2 Agonist (SABA)

ProAir ProAir RespiClick

Albuterol sulfate

2 puffs every 4-6 hours PRN wheezing or SOB

MDI DPI

Rescue

Proventil MDI

Ventolin MDI

Xopenex Levalbuterol 2 puffs every 4 to 6 hours PRN

MDI Rescue

Short-Acting Anti-Muscarinic Agents (SAMA)

Atrovent Ipratropium bromide 8 puffs every 20 minutes PRN

MDI Rescue*

Combivent Respimat Ipratropium bromide + albuterol sulfate

8 puffs every 20 minutes PRN

SMI Rescue*

Inhaled Corticosteroids (ICS)

Alvesco Ciclesonide BID MDI Maintenance

Arnuity Ellipta Fluticasone furoate QD DPI Maintenance

Asmanex Asmanex Twisthaler

Mometasone furoate BID QD or BID

MDI DPI

Maintenance

Flovent Flovent Diskus

Fluticasone propionate BID BID

MDI DPI

Maintenance

Pulmicort Flexhaler Budesonide BID DPI Maintenance

QVAR RediHaler Beclomethasone dipropionate

BID MDI Maintenance

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Long-Acting Beta2 Agonist (LABA)

Serevent Diskus Salmeterol xinafoate BID MDI Maintenance**

Long-Acting Anti-Muscarinic Agent (LAMA)

Spiriva Respimat Spiriva HandiHaler

Tiotropium bromide QD QD

SMI MDI

Maintenance

Combination: ICS + LABA

Advair Advair Diskus

Fluticasone propionate + salmeterol

BID BID

MDI DPI

Maintenance

Airduo RespiClick Fluticasone propionate + salmeterol

BID DPI Maintenance

Breo Ellipta Fluticasone furoate + vilanterol

QD DPI Maintenance

Dulera Mometasone furoate + formoterol fumarate

BID MDI Maintenance

Symbicort Turbuhaler Budesonide + formoterol fumarate

QD or BID DPI Maintenance

*Not recommended for rescue therapy outside the emergency room or urgent care settings; **Must be used with an ICS PRN: as needed; SOB: shortness of breath; MDI: metered-dose inhalers; DPI: dry powder inhaler; SMI: soft mist inhaler; QD: once daily; BID: twice daily

Table E-2: Low, Medium, and High doses of ICS inhalers for patients > 12 years old3,16-23

ICS Low Medium High

Beclomethasone dipropionate (HFA) 100-200 201-400 >400

Budesonide (DPI) 200-400 401-800 >800

Ciclesonide (MDI) 80-160 161-320 >320

Fluticasone furoate (DPI) 100 n/a 200

Fluticasone propionate (MDI, DPI) 100-250 251-500 >500

Mometasone furoate (MDI, DPI) 110-220 221-440 >440 MDI: metered-dose inhalers; DPI: dry powder inhaler

F. Exacerbation risk factors1-3

Severe airflow obstruction

Persistent airflow obstruction

> 2 ED visits or hospitalizations for asthma in last year

History of intubation or intensive care units admissions in last 5 years

Feeling in danger or frightened by asthma

Female

Nonwhite

Current tobacco smoker

Not using ICS

Depression

Increased stress

Socio economic factors

Attitudes and beliefs about medications