1. Use of Singulair in Asthma Ada Sum, MD

2. 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 PRN Mom asks if he can be switched to Singulair ROS: Nocturnal cough causing awakening perhaps 1 every other week Uses albuterol inhaler maybe 3/week

3. 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

4. Stepwise Approach Inhaled corticosteroids is the preferred long-term control therapy for all ages Evidence A: randomized controlled trials, rich body of data (NHLBI)

7. 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

8. 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

9. Singulair Chewable (30): $138.97 Common 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

10. 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

11. Search Efforts Medline search MeSH terms: Asthma “Singulair” keyword = montelukastleukotriene receptor antagonists Limits: Kids English Randomized controlled trials

12. Article Chosen

13. 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

14. Study Design

15. Run-in Period To determine whether asthma poorly-controlled on fluticasone 100 mcg BID Daily diary Uncontrolled 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

16. 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

17. Asthma Action Plan Customized written action plan Visits every 4 weeks Received albuterol inhaler Standardized course of prednisone was initiated if predetermined clinical criteria met at the physician’s discretion

18. 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

19. 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

20. Recruitment March 2007 to July 2008 Patients aged 6-17 Childhood 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

21. Inclusion Criteria Mild to moderate asthma Ability to perform reproducible spirometry FEV1 ≥ 60% before bronchodilation Increase in FEV1 of at least 12% or methacholine provocation causing a 20% fall Nonsmoker

22. Patients 298 patients excluded during run-in period Compliance issues Asthma exacerbation Asthma symptoms controlled 182 underwent randomization 157 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)

23. Patient Population

24. 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%)

25. Results 54% vs 32%, P=0.004 52% vs 34%, P=0.02

26. LABA on Top LABA vs ICS: relative probability 1.7 (CI 1.2-2.4, P=0.002) LABA vs LTRA: relative probability 1.6 (CI 1.1-2.3, P=0.004)

27. Preselected Predictors P=0.009

28. Race (P=0.005)

29. Eczema (P=0.006)

30. Age (no difference) Also no difference for gender A model with only the significant predictors, correctly classified the ranks 68% of the time

31. 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

32. Validity pros concerns No placebo or gold standard Increased monitoring by participating in study Medications donated Physician consulting fees, lecture fees, grants by pharmaceutical companies Adequate power Double blinded Randomized Kids Diverse population Decent adherence Individuals vs average

33. 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

34. Application The secret of the care of the patient is in caring for the patient. -Francis Weld Peabody

35. 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.