Use of Singulair in asthma

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Use of Singulair in asthma

  1. 1. Use of Singulair in Asthma<br />Ada Sum, MD<br />
  2. 2. Case Presentation<br />9 yo boy presents to clinic to establish care<br />Hx of asthma and allergic rhinitis<br />Current Rx: Flovent 44mcg 1 puff BID and albuterol PRN<br />Mom asks if he can be switched to Singulair<br />ROS:<br />Nocturnal cough causing awakening perhaps 1 every other week<br />Uses albuterol inhaler maybe 3/week<br />
  3. 3. Brief Asthma Review<br />National Asthma Education and Prevention Program’s Expert Panel Report 3 published in 2007:<br />Asthma severity: severity when initiating therapy<br />Asthma control: control to adjust therapy<br />Based on impairment and risk<br />Stepwise approach to managing long-term asthma<br />Separated into ages 0-4, 5-11, & 12 and up<br />
  4. 4. Stepwise Approach<br />Inhaled corticosteroids is the preferred long-term control therapy for all ages<br />Evidence A: randomized controlled trials, rich body of data (NHLBI)<br />
  5. 5.
  6. 6.
  7. 7. Cysteinyl Leukotrienes<br />Eosinophils and mast cells produce cysteinyl leukotrienes (CysLT)<br />Synthesized within minutes<br />CysLTs bind to receptors CysLT1 and CysLT2<br />CysLT1 receptor mediates:<br />Induce smooth muscle contraction and sustained bronchoconstriction<br />“slow reacting substance of anaphylaxis”<br />Mucus secretion<br />Edema<br />
  8. 8. CysLTs and Asthma<br />Asthmatics have higher baseline levels of CysLTs<br />Levels increase with exercise, exposure to allergens, and during exacerbations<br />Singulair (montelukast) and Accolate (zafirlukast):<br />CysLT1 receptor antagonists<br />
  9. 9. Singulair<br />Chewable (30): $138.97<br />Common side effects:<br />URI, fever, HA, pharyngitis, cough, abdominal pain, diarrhea, otitis media, flu, rhinorrhea, sinusitis, otitis<br />FDA warning: neuropsychiatric events<br />Agitation, aggression, depression, suicide, abnormal dreams, insomnia, hallucinations, irritability, tremor were reported in both kids and adults<br />
  10. 10. Clinical Question<br />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?<br />Population: children with poorly-controlled asthma on low-dose inhaled corticosteroids<br />Intervention: leukotriene receptor antagonist + low-dose inhaled corticosteroids<br />Comparison: medium-dose inhaled corticosteroids<br />Outcome: change in asthma control<br />
  11. 11. Search Efforts<br />Medline search<br />MeSH terms:<br />Asthma<br />“Singulair” keyword = montelukastleukotriene receptor antagonists<br />Limits:<br />Kids<br />English<br />Randomized controlled trials<br />
  12. 12. Article Chosen<br />
  13. 13. BADGER trial<br />Best Add-on Therapy Giving Effective Responses<br />Looking for differential response<br />Three-way crossover design<br />Based on composite of outcomes:<br />Asthma exacerbations<br />Asthma-control days<br />FEV1<br />Examined potential predictors:<br />Race, age, genotype, baseline values<br />
  14. 14. Study Design<br />
  15. 15. Run-in Period<br />To determine whether asthma poorly-controlled on fluticasone 100 mcg BID<br />Daily diary<br />Uncontrolled if during a 2-week period, had >2 days/week of:<br />Moderate or severe coughing<br />Mild, moderate, or severe wheezing<br />≥2 puffs/day of rescue inhaler<br />Peak flows <80% predicted<br />
  16. 16. Crossover Trial<br />Randomized and double-blinded<br />Placebo tablets<br />Dummy disks<br />16 week periods:<br />Flovent 250 mcg BID<br />Advair (fluticasone 100 mcg + salmeterol 50 mcg) BID<br />Flovent 100 mcg BID + Singulair (5 or 10 mg) daily <br />Initial 4 weeks considered active washout<br />
  17. 17. Asthma Action Plan<br />Customized written action plan<br />Visits every 4 weeks<br />Received albuterol inhaler<br />Standardized course of prednisone was initiated if predetermined clinical criteria met at the physician’s discretion<br />
  18. 18. Outcome Measures<br />Based on composite of:<br />Need for treatment with oral prednisone for acute asthma exacerbation<br />Number of asthma-control days<br />FEV1<br />Treatment period ranked better if:<br />Total prednisone during period 180mg less<br />Annualized asthma-control days 31 days more<br />Final FEV1 5% higher<br />
  19. 19. Asthma-Control Day<br />Documented in diary<br />No use of albuterol (other than preexercise)<br />No use of nonstudy asthma medication<br />No day or night asthma symptoms<br />No unscheduled visit to health care provider for asthma<br />No peak expiratory flow <80%<br />Proportion during the 12 weeks x 365 = annualized asthma-control days <br />Adjusted for seasonal differences<br />
  20. 20. Recruitment<br />March 2007 to July 2008<br />Patients aged 6-17<br />Childhood Asthma Research and Education (CARE) Network Centers:<br />National Jewish Health<br />University of Wisconsin<br />University of California San Diego<br />Washington University School of Medicine<br />Arizona Respiratory Center<br />480 enrolled<br />
  21. 21. Inclusion Criteria<br />Mild to moderate asthma<br />Ability to perform reproducible spirometry<br />FEV1 ≥ 60% before bronchodilation<br />Increase in FEV1 of at least 12% or methacholine provocation causing a 20% fall<br />Nonsmoker <br />
  22. 22. Patients<br />298 patients excluded during run-in period<br />Compliance issues<br />Asthma exacerbation<br />Asthma symptoms controlled<br />182 underwent randomization<br />157 patients completed the entire study<br />90% adherence to study visits<br />96% adherence to paper diary<br />84% adherence to study tablets (electronic cap monitor)<br />87% adherence to study inhalers (disk counter)<br />
  23. 23. Patient Population<br />
  24. 24. Data<br />Null hypothesis:<br />≤25% of patients would have a differential response<br />If significant response (0.01 level), then perform logistic regression to determine whether 4 preselected characteristics predicted differential responses<br />Differential response in 161/165 patients (98%)<br />
  25. 25. Results<br />54% vs 32%, P=0.004<br />52% vs 34%, P=0.02<br />
  26. 26. LABA on Top<br />LABA vs ICS: relative probability 1.7 (CI 1.2-2.4, P=0.002)<br />LABA vs LTRA: relative probability 1.6 (CI 1.1-2.3, P=0.004)<br />
  27. 27. Preselected Predictors<br />P=0.009<br />
  28. 28. Race (P=0.005)<br />
  29. 29. Eczema (P=0.006)<br />
  30. 30. Age (no difference)<br />Also no difference for gender<br />A model with only the significant predictors, correctly classified the ranks 68% of the time<br />
  31. 31. Conclusion<br />Possible ceiling effect for ICS<br />Addition of LABA more likely to provide better asthma control<br />But some children had best response to the other step-up therapies<br />Increasing ICS dosage is similar to addition of LTRA<br />Study does NOT address long-term safety of LABAs<br />Potential increased risk of severe exacerbations and death<br />Never to be used as monotherapy<br />FDA label: discontinue LABA when possible<br />
  32. 32. Validity<br />pros<br />concerns<br />No placebo or gold standard<br />Increased monitoring by participating in study<br />Medications donated<br />Physician consulting fees, lecture fees, grants by pharmaceutical companies<br />Adequate power<br />Double blinded<br />Randomized<br />Kids<br />Diverse population<br />Decent adherence<br />Individuals vs average<br />
  33. 33. Answering Mom<br />Switch to Singulair?<br />No!<br />Patient currently poorly controlled on low-dose ICS<br />Needs step up in therapy<br />One of several options to discuss with Mom<br />LABA, medium-dose ICS, or LTRA<br />Other factors: race, history of eczema<br />Need to reassess control and follow-up<br />
  34. 34. Application<br />The secret of the care of the patient is in caring for the patient.<br /> -Francis Weld Peabody<br />
  35. 35. References<br />Von Mutius, E and JM Drazen. “Choosing asthma step-up care.” N Eng J Med. 362(11): 1042-1043.<br />Lemanske, RF, et al. “Step-up therapy for children with uncontrolled asthma receiving inhaled steroids.” N Eng J Med. 362(11): 975-985, 2010.<br />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.<br />Weinberger, MM. “Use of LABAs in asthmatic children requires close monitoring.” AAP News. 31(9): 20, 2010.<br />Databases: Clinical Evidence, Dynamed, Medline, UpToDate.<br />Google images.<br />

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