Journal club low dose thephylline vs montelukast

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Journal club low dose thephylline vs montelukast

  1. 1. By SURASARIT KHAWLAOR 1
  2. 2. INTRODUCTION Disadvantage of theophylline  Side effect  Inconvenience of monitoring blood levels Advantage  Not expensive  Antiinflammatory & immunomodulatory effects Disadvantage of montelukast  More expensive Advantage  Not requiring titration  Not monitoring blood levels 2
  3. 3. INTRODUCTION Reason for this research Theophylline as add-on therapy to ICS shown oBenefit in oCons in Meta-analysis have questioned efficacy of LTRA in asthma therapy when added to ICS Not comparing effectiveness of these 2 oral agents 3
  4. 4. INTRODUCTION Objective To compare effectiveness of low-dose theophylline and montelukast for poorly controlled asthma patients focused on Primary outcome : asthma control by measuring rate of episodes of poor asthma control (EPACs) Secondary outcomes : ASUI, AQLQ, ACQ scores pre & post-BD spirometry 4
  5. 5. INTRODUCTION 5
  6. 6. INTRODUCTION 6 for patients with moderate asthma & persistent symptoms : low –dose inhaled budesonide with theophylline & high-dose inhaled budesonide produced similar benefits
  7. 7. INTRODUCTION 7
  8. 8. INTRODUCTION 8
  9. 9. INTRODUCTION 9 LTRA, but low-dose theophylline, conferred significant additive antiinflammatory effects to therapy with low-dose inhaled corticosteroid but not with medium-dose
  10. 10. PROTOCOL 10
  11. 11. PROTOCOL  Randomized, double-masked, placebo-controlled trial  Participants from 19 centers in American Lung Association Clinical Research center  Age >= 15 yrs., physician-diagnosed asthma  Prescribed daily asthma medication for >= 1 yr  FEV1 >= 50% of predicted values  Poor asthma control (by score >= 1.5 on ACQ) 11
  12. 12. PROTOCOL  Exclusion criteria Use oral corticosteroids, LTRA, theophylline within 4 wk preceding enrollment Current or former smokers with 20 pack-year or more smoking history Other significant illness 12
  13. 13. PROTOCOL  Primary outcome Measured by annualized rate of EPACs of following events Decrease of peak expiratory flow > 30% of personal best for >=2 consecutive days Use of bronchodilator rescue medication over baseline by > 4 metered-dose inhalations ( or 2 nebulizer treatments) in 1 day Oral corticosteroid treatment of asthma Unscheduled asthma health care visit to physician, emergency, hospital 13
  14. 14. PROTOCOL Objective (cont.) Secondary outcomes : ASUI, AQLQ, ACQ scores pre & post-BD spirometry 14
  15. 15. PROTOCOL 15 telephone 2 wk after Rz to assess compliance, S/E, asthma control adherence assessed by diary, plasma theophylline & montelukast at 1, 6 Mo
  16. 16. PROTOCOL 16
  17. 17. PROTOCOL 17
  18. 18. ASUI 18
  19. 19. ASUI 19
  20. 20. AQLQ 20
  21. 21. RESULTS 21
  22. 22. FLOWCHART 22
  23. 23. FLOWCHART 23
  24. 24. Baseline Characteristics 24
  25. 25. Baseline Characteristics 25
  26. 26. Adherence to therapy Self-report adherence 84% for theophylline 88% for montelukast & placebo Measured adherence by plasma drug concentration that exceeded lower limit Theophylline > 2mg/L (6.82.6 at 4 wks, 6.22.7 at 24 wks) montelukast > 5ng/ml (123163 at 4 wks,125157 at 24 wks) Termination : loss F/U, adverse events, withdrawal of consent, other 26
  27. 27. Adverse Events 27
  28. 28. EPACs28
  29. 29. PROTOCOL 29
  30. 30. EPACs  Subgroup analysis of adherence patients only Defined by detectable 24-wk drug concentration Not show significant improvement in EPACs for theophylline or montelukast compare with placebo group 30
  31. 31. Asthma Symptoms 31 not statistically different in either treatment group compared with placebo
  32. 32. Lung Function32
  33. 33. PROTOCOL 33
  34. 34. Lung Function  Overall prebronchodilator FEV1 was improved in both theophylline & montelukast group  Overall postbronchodilator FEV1 By theophylline was significant VS placebo By montelukast trends to be similar but smaller  Pre & postbronchodilator FVC were not significant improved 34
  35. 35. Lung Function 35
  36. 36. Influence of ICS Use36
  37. 37. PROTOCOL 37
  38. 38. Influence of ICS Use 38
  39. 39. DISCUSSION 39
  40. 40. DISCUSSION 1.Primary outcomes Use rate of EPACs because relevant to quality of life, cost medical care, goal of asthma care under current practice guideleines Neither theophylline nor montelukast had additional benefit in reducing EPACs, reducing asthma symptoms or improving quality of life compare with placebo 40
  41. 41. DISCUSSION 2.Secondary outcomes  Both theophylline & montelukast improved prebronchodilator spirometry, but only theophylline improved FEV1 after bronchodilator  theophylline augment bronchodilator effect (changes so small 0.08-0.09 L uncertain clinical importance 41
  42. 42. DISCUSSION 3.subgroup analysis  Theophylline reduced both event rates and symptoms in patients with asthma who were not using ICS 4.Adherence was good in all treatment group (by diary self-report at 4, 24 wks) but blood concentrations, at 24 wks, were absent 40% of both theophylline & montelukast group 5.Adverse effects were higher in theophylline group than in montelukast group 42
  43. 43. Researcher Comment • Theophylline has antiinflammatory properties including Inhibition of neutrophil migration Inhibition of neutrophil,lymphocyte,monocyte activation Production of antiinflammatory cytokine IL-10 Inhibition of inflammatory mediators 43
  44. 44. Researcher Comment • Low-dose theophylline reduce airway eosinophilia in patients with asthma, even in absence of bronchodilation response • Reduction in expired nitric oxide concentrations Lim S. et al. Am J Respir Crit care Med 2001; 164: 273-276 • Anti-inflammatory effects is activation of histone deacetylase o Histone deacetylase, component of pathway by which corticosteroids are believed to inhibit proinflammatory gene expression, and its activity is reduced in some patients with asthma, especially cigarette smokers Kazuhiro Ito et al. Am J Respir Crit Care Med 2002; 166: 392-396 44
  45. 45. Researcher Comment • Peripheral blood mononuclear cells were obtained from 24 asthmatic subjects  left in a resting state or stimulated with either mitogens (phytohemagglutinin, lipopolysaccharide) or antigen (tetanus, cat) ĉ or ŝ presence of theophylline (15 g/dL) • Supernatants were collected & evaluated for cytokine concentration by ELISA 45
  46. 46. Researcher Comment 46
  47. 47. Researcher Comment 47 1.theophylline did not inhibit production of allergenic cytokines (IL-4) 2.Statistically significant inhibition of IFN- synthesis was observed 3.Theophylline have anti-inflammatory effects on cytokine produced by mononuclear phagocytic cell
  48. 48. Researcher Comment 48PJ Barnes. Am J Respir Crit Care Med 2003; 167: 813-818
  49. 49. Researcher Comment  He hypothesized that pt. using ICS may benefit by addition of low-dose theophylline more than those not using He stratified participants by use of ICS  participants assigned to theophylline who not using ICS had both statistically & clinically significant in asthma control & symptoms  reason not clear But subgroup who not use ICS is so small need further investigation 49
  50. 50. Researcher Comment  ICS are generally considered to be mainstay of antiinflammatory controller treatment in asthma but theophylline ,although mild bronchodilator, is only marginal benefit in asthma symptom control for pts. with asthma already treated with ICS  Montelukast, like theophylline, no additional beneficial effect on asthma control as measured by lung function variability, - agonist use, health care use Subgroup of pts, not taking ICS at baseline  montelukast did not improve asthma control 50
  51. 51. Researcher Comment  Most guidelines recommend LABsA as add-on treatment when ICS do not provide adequate asthma control  But some studies raised questions about safety of LABA ,some have suggested low-dose theophylline may be alternative to LABAs when ICS alone do not adequately control asthma 1  However, no studies compared LABAs with low-dose theophylline until now 511 Martinez FD. N Engl J Med 2005;353: 2637-2639
  52. 52. Researcher Comment 52
  53. 53. Researcher Comment PRO : Shamsah Kazani, James H.,Ware & Jeffrey, M.Drazen 2 prospective randomzed studies that examined asthma-related mortality UK’s Serevent National Surveillance study (SNS) 12 death from 16,787 pts. (tx over 16 wks) compared with 2 death of 8,393 pts. In control group USA’s Salmeterol Multicenter Asthma Research Trial (SMART) 13 death in 13,176 pts. (tx 28 wks) compared with 3 death of 13,179 pts. In control group 53Shamsah KAZANI et al. PRO/CON debate. Respirology 2010: 15: 881-886 1.approximately 1 in 700 patient years of treatment 2.Both SMART & SNS were inadequately powered to study the safety of LABA when used in combination with ICS
  54. 54. Researcher Comment 54 Randomized trial to study the safety of LABA when combined with ICS GlaxoSmithKline claims that it is not feasible to study in randomized trial because of requiring approximately 700,000 subject per group The authors propose that 50,000 pts. With moderate or severe asthma should enrolled in randomized double-blind trial (half treated with ICS & other half treated with ICS plus LABA) Shamsah KAZANI et al. PRO/CON debate. Respirology 2010: 15: 881-886
  55. 55. Researcher Comment 55 CON : Malcolm R. Sears FDA meta-analysis involving 110 trials & 60,954 subjects (Leavenson M.) show RD (risk differences) for LABA VS non-LABA, ignoring ICS use ;RD was  0.40 (95% CI: 0.11–0.69) /1000 for asthma-related death  0.57 (95% CI: 0.01–1.12) for asthma-related death or intubation  2.57 (95% CI:0.90–4.23) for asthma-related hospitalization  all three end-points, 2.80 (95% CI: 1.11–4.49) Shamsah KAZANI et al. PRO/CON debate. Respirology 2010: 15: 881-886
  56. 56. Researcher Comment 56 CON (cont.) Stratified by ICS use  6 for patients receiving LABA without mandatory randomized ICS  RD was 3.63 (95% CI:1.51–5.75)  among patients receiving LABA with mandatory ICS  RD was non-significant (0.25: 95% CI: -1.69–2.18) per 1000 subjects From those data the author calculated sample size for receiving enough power on death (LABA plus ICS) about exceed 4 million subjects ! (mega-trial) Shamsah KAZANI et al. PRO/CON debate. Respirology 2010: 15: 881-886
  57. 57. Researcher Comment 57 CON (cont.) In contrast to the 1970s epidemic of deaths in NewZealand associated with SABA (fenoterol)  no epidemic of asthma deaths has occurred after introduction of LABA Sears MR, Taylor DR. Drug Saf. 1994; 11: 259–83 Shamsah KAZANI et al. PRO/CON debate. Respirology 2010: 15: 881-886
  58. 58. Researcher Comment 58 CON (cont.) Weatherall et al. reported no deaths among 22,600 asthmatics treated with salmeterol plus fluticasone in a single inhaler Weatheral M. et al. Thorax 2010; 65(1): 39-43 Sears and Radner reported no excess deaths among 14,346 asthmatics treated with formoterol plus budesonide in a single inhaler as maintenance and reliever therapy Sear MR, Radner F. Respir Med. 2009; 103: 1960-8 Shamsah KAZANI et al. PRO/CON debate. Respirology 2010: 15: 881-886 1.No adverse event signal coming from data in which LABA & ICS have been used in single inhaler 2.New appropriately designed study addressing mortality is neither required nor feasible
  59. 59. Researcher Comment  one previous trial has directly compared efficacy of theophylline with LTRA Dempsey and colleagues The added antiinflammatory effects of zafirlukast and theophylline, measured with either exhaled nitric oxide or methacholine reactivity were only present with low-dose but not with mediumdose ICS 59
  60. 60. THANK YOU FOR YOUR ATTENTION 60

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