Use of Singulair in AsthmaAda Sum, MD

Case Presentation

9 yo boy presents to clinic to establish care

Hx of asthma and allergic rhinitis Current Rx: Flovent 44mcg 1 puff BID

and albuterol PRNMom asks if he can be switched to

SingulairROS:

Nocturnal cough causing awakening perhaps 1 every other week

Uses albuterol inhaler maybe 3/week

Brief Asthma Review

National Asthma Education and Prevention Program’s Expert Panel Report 3 published in 2007: Asthma severity: severity when initiating

therapy Asthma control: control to adjust therapy▪ Based on impairment and risk

Stepwise approach to managing long-term asthma Separated into ages 0-4, 5-11, & 12 and

up

Stepwise Approach

Inhaled corticosteroids is the preferred long-term control therapy for all ages

Evidence A: randomized controlled trials, rich body of data (NHLBI)

Components of control

Classification of asthma control (5-11 years of age)

Well-controlled

Not-well controlled

Very poorly controlled

Impairment Symptoms ≤2 days/week but not more than once on each day

>2 days/week or multiple times on ≤2 days/week

Throughout the day

Nighttime awakenings

≤1x/month ≥2x/month ≥2x/week

Interference with normal activity

None Some limitation Extremely limited

Short-acting beta2-agonist use for symptom control (not prevention of EIB)

≤2 days/week >2 days/week Several times per day

• FEV1 or peak flow• FEV1/FVC

• >80 percent predicted/personal best• >80 percent

• 60-80 percent predicted/personal best• 75-80 percent

• <60 percent predicted/personal best• <75 percent

Risk Exacerbations requiring oral corticosteroids

0-1/year ≥2/year

Consider severity and interval since last exacerbation

Reduction in lung growth

Evaluation requires long-term followup

Treatment-related adverse effects

Medication side effects can vary in intensity from none to very troublesom and worrisome.

Cysteinyl Leukotrienes

Eosinophils and mast cells produce cysteinyl leukotrienes (CysLT) Synthesized within minutes

CysLTs bind to receptors CysLT1 and CysLT2

CysLT1 receptor mediates: Induce smooth muscle

contraction and sustained bronchoconstriction▪ “slow reacting substance of

anaphylaxis” Mucus secretion Edema

CysLTs and Asthma

Asthmatics have higher baseline levels of CysLTs

Levels increase with exercise, exposure to allergens, and during exacerbations

Singulair (montelukast) and Accolate (zafirlukast): CysLT1 receptor

antagonists

Singulair

Chewable (30): $138.97Common side effects:

URI, fever, HA, pharyngitis, cough, abdominal pain, diarrhea, otitis media, flu, rhinorrhea, sinusitis, otitis

FDA warning: neuropsychiatric events Agitation, aggression, depression,

suicide, abnormal dreams, insomnia, hallucinations, irritability, tremor were reported in both kids and adults

Clinical Question

How does the addition of a leukotriene receptor antagonist to low-dose inhaled corticosteroids change the asthma control in children with poorly-controlled asthma, as compared to medium-dose inhaled corticosteroids?

Population: children with poorly-controlled asthma on low-dose inhaled corticosteroids

Intervention: leukotriene receptor antagonist + low-dose inhaled corticosteroids

Comparison: medium-dose inhaled corticosteroids

Outcome: change in asthma control

Search Efforts

Medline searchMeSH terms:

Asthma “Singulair” keyword = montelukast

leukotriene receptor antagonistsLimits:

Kids English Randomized controlled trials

Article Chosen

BADGER trial

Best Add-on Therapy Giving Effective Responses

Looking for differential response Three-way crossover design Based on composite of outcomes:▪ Asthma exacerbations▪ Asthma-control days▪ FEV1

Examined potential predictors: Race, age, genotype, baseline values

Study Design

Run-in Period

To determine whether asthma poorly-controlled on fluticasone 100 mcg BID

Daily diaryUncontrolled if during a 2-week

period, had >2 days/week of: Moderate or severe coughing Mild, moderate, or severe wheezing ≥2 puffs/day of rescue inhaler Peak flows <80% predicted

Crossover Trial

Randomized and double-blinded Placebo tablets Dummy disks

16 week periods: Flovent 250 mcg BID Advair (fluticasone 100 mcg +

salmeterol 50 mcg) BID Flovent 100 mcg BID + Singulair (5 or 10

mg) daily Initial 4 weeks considered active

washout

Asthma Action Plan

Customized written action planVisits every 4 weeksReceived albuterol inhalerStandardized course of prednisone

was initiated if predetermined clinical criteria met at the physician’s discretion

Outcome Measures

Based on composite of: Need for treatment with oral prednisone

for acute asthma exacerbation Number of asthma-control days FEV1

Treatment period ranked better if: Total prednisone during period 180mg

less Annualized asthma-control days 31 days

more Final FEV1 5% higher

Asthma-Control Day

Documented in diary No use of albuterol (other than

preexercise) No use of nonstudy asthma medication No day or night asthma symptoms No unscheduled visit to health care

provider for asthma No peak expiratory flow <80%

Proportion during the 12 weeks x 365 = annualized asthma-control days Adjusted for seasonal differences

Recruitment

March 2007 to July 2008Patients aged 6-17Childhood Asthma Research and

Education (CARE) Network Centers: National Jewish Health University of Wisconsin University of California San Diego Washington University School of Medicine Arizona Respiratory Center

480 enrolled

Inclusion Criteria

Mild to moderate asthmaAbility to perform reproducible

spirometryFEV1 ≥ 60% before bronchodilation Increase in FEV1 of at least 12% or

methacholine provocation causing a 20% fall

Nonsmoker

Patients

298 patients excluded during run-in period Compliance issues Asthma exacerbation Asthma symptoms controlled

182 underwent randomization157 patients completed the entire

study 90% adherence to study visits 96% adherence to paper diary 84% adherence to study tablets (electronic cap

monitor) 87% adherence to study inhalers (disk counter)

Patient Population

Age GroupCharacteristic 6-11 yr (n = 126) 12-17 yr (n = 56)

Age 9.1 ± 1.5 14.7 ± 1.7 Male 83 (66) 36 (64) Race Hispanic or Latino Non-Hispanic White Black Hispanic White

38 (30)54 (43)37 (29)28 (22)

22 (39)20 (36)12 (21)15 (27)

BMI 19.6 ± 4.5 23.3 ± 4.8 Age at asthma diagnosis 3.3 ± 2.2 4.7 ± 4.1 Eczema 69 (55) 24 (43) Eligibility Classification Step-up Step-neutral Step-down

35 (28)16 (13)75 (60)

14 (25)11 (20)31 (55)

PO steroids in past year 56 (44) 24 (45) Asthma Control Test (≤19) 20.5 ± 3.8 19.8 ± 3.4

Data

Null hypothesis: ≤25% of patients would have a

differential response If significant response (0.01 level),

then perform logistic regression to determine whether 4 preselected characteristics predicted differential responses

Differential response in 161/165 patients (98%)

Results

52% vs 34%, P=0.02

54% vs 32%, P=0.004

LABA on Top

LABA vs LTRA: relative probability 1.6 (CI 1.1-2.3, P=0.004)

LABA vs ICS: relative probability 1.7 (CI 1.2-2.4, P=0.002)

Preselected Predictors

P=0.009

Race (P=0.005)

Eczema (P=0.006)

Age (no difference)

Also no difference for genderA model with only the significant

predictors, correctly classified the ranks 68% of the time

Conclusion

Possible ceiling effect for ICS Addition of LABA more likely to provide better

asthma control But some children had best response to the other step-

up therapies Increasing ICS dosage is similar to addition of

LTRA

Study does NOT address long-term safety of LABAs Potential increased risk of severe exacerbations and

death Never to be used as monotherapy FDA label: discontinue LABA when possible

Validity

PROS

Adequate power Double blinded Randomized Kids Diverse population Decent adherence Individuals vs average

CONCERNS

No placebo or gold standard

Increased monitoring by participating in study

Medications donated Physician consulting

fees, lecture fees, grants by pharmaceutical companies

Answering Mom

Switch to Singulair? No!

Patient currently poorly controlled on low-dose ICS Needs step up in therapy

One of several options to discuss with Mom LABA, medium-dose ICS, or LTRA Other factors: race, history of eczema

Need to reassess control and follow-up

Application

The secret of the care of the patient is in caring for the patient.

-Francis Weld Peabody

References

Von Mutius, E and JM Drazen. “Choosing asthma step-up care.” N Eng J Med. 362(11): 1042-1043.

Lemanske, RF, et al. “Step-up therapy for children with uncontrolled asthma receiving inhaled steroids.” N Eng J Med. 362(11): 975-985, 2010.

National Asthma Education and Prevention Program. “Expert panel report 3 (ERP-3) summary report 2007: Guidelines for the diagnosis and management of asthma.” 2007. Accessed online: http://www.nhlbi.nih.gov/guidelines/asthma/asthsumm.pdf.

Weinberger, MM. “Use of LABAs in asthmatic children requires close monitoring.” AAP News. 31(9): 20, 2010.

Databases: Clinical Evidence, Dynamed, Medline, UpToDate.

Google images.