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Journal club low dose thephylline vs montelukast






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    Journal club low dose thephylline vs montelukast Journal club low dose thephylline vs montelukast Presentation Transcript

    • INTRODUCTION Disadvantage of Disadvantage of theophylline montelukast Side effect  More expensive Inconvenience of monitoring blood levels Advantage Advantage  Not requiring Not expensive titration Antiinflammatory  Not monitoring & blood levels
    • 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
    • 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
    • INTRODUCTIONfor patients with moderateasthma & persistent symptoms: low –dose inhaledbudesonide with theophylline &high-dose inhaled budesonideproduced similar benefits
    • INTRODUCTION LTRA, but low-dose theophylline, conferred significant additive antiinflammatory effects to therapy with low-dose inhaled corticosteroid but not with
    • 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
    • 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
    • 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
    • PROTOCOLObjective (cont.) Secondary outcomes : ASUI, AQLQ, ACQ scores pre & post-BD spirometry
    • PROTOCOL adherence telephone 2 assessed by diary,wk after Rz to plasma theophylline assess & montelukast at 1, compliance, 6 MoS/E, asthma control
    • ASUI
    • ASUI
    • AQLQ
    • Baseline Characteristics
    • Baseline Characteristics
    • 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
    • Adverse Events
    • EPACs
    • 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
    • Asthma Symptoms not statistically different in either treatment group compared with placebo
    • Lung Function
    • 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
    • Lung Function
    • Influence of ICS Use
    • Influence of ICS Use
    • DISCUSSION1.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
    • DISCUSSION2.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
    • DISCUSSION3.subgroup analysis  Theophylline reduced both event rates and symptoms in patients with asthma who were not using ICS4.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
    • Researcher Comment• Theophylline has antiinflammatory properties including Inhibition of neutrophil migration Inhibition of neutrophil,lymphocyte,monocy te activation
    • 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
    • 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
    • Researcher Comment
    • Researcher Comment1.theophylline did not inhibit production of allergenic cytokines (IL-4)2.Statistically significant inhibition of IFN- synthesis was observed3.Theophylline have anti-inflammatory effects on cytokine produced by mononuclear phagocytic cell
    • Researcher Comment PJ Barnes. Am J Respir Crit Care Med 2003; 167: 813-818
    • 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
    • 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,
    • 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 FD. N Engl J Med 2005;353: 2637-2639 Martinez studies compared 1
    • Researcher Comment
    • Researcher Comment 1.approximately 1 in 700PRO : Shamsah years of James patient Kazani, H.,Ware &treatment Jeffrey, 2.Both SMART & SNS M.Drazen were inadequately 2 prospective randomzed studies that powered to study the examined asthma-related mortality safety of LABA when UK’s Serevent National Surveillance used in combination study (SNS) ICS with 12 death from 16,787 pts. (tx over 16 wks) compared with 2 death of 8,393 pts. In control group Shamsah Salmeterol Multicenter Asthma USA’s KAZANI et al. PRO/CON debate. Respirology 2010: 15: 881-886
    • Researcher Comment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
    • Researcher Comment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
    • Researcher Comment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
    • Researcher Comment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
    • 1.No adverse event Researcher Comment signal coming from data in whichCON (cont.) LABA & ICS have been used in Weatherall et al. reported no deaths among single inhaler 22,600 asthmatics treated with salmeterol plus 2.New fluticasone in a single inhaler appropriatelyM. et al. Thorax 2010; 65(1): 39-43 Weatheral designed Sears and Radner reported no excess deaths study addressing among 14,346 asthmatics treated with formoterol plus budesonide in a singleis mortality inhaler as maintenance and reliever required neither therapy nor feasible F. Respir Med. 2009; 103: 1960-8 Sear MR, Radner Shamsah KAZANI et al. PRO/CON debate. Respirology 2010: 15: 881-886
    • 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