Episodic vs. Continuous Use of Inhaled Steroids in Preschool Wheezing Children Leonard B. Bacharier, MD

Transcription

1 Episodic vs. Cotiuous Use of Ihaled Steroids i Preschool Wheezig Childre Leoard B. Bacharier, MD Robert C. Struk Edowed Chair for Lug ad Respiratory Research Professor of Pediatrics & Medicie Cliical Director, Divisio of Allergy, Immuology, & Pulmoary Medicie Uit Leader Patiet Orieted Research Uit

2 Disclosures Employmet Washigto Uiversity Fiacial Iterests Cosultat: DBV, Merck, Novartis, Teva, Regeero/Saofi, Vectura, Circassia Hooraria/Speakers Bureau: GSK, Teva AstraZeeca, Novartis, Boehriger Igelheim Research Support: Vectura, Saofi/Regeero Research Iterests NIH NHLBI, NIAID Orgaizatioal Iterests Gifts AAAAI Aual Meetig Plaig Committee ABAI Director JACI Associate Editor GINA Sciece Committee Nothig to Disclose Other Iterests Nothig to Disclose

3 Learig Objective Examie the potetial roles of cotiuous ad itermittet ICS therapy i the maagemet of recurret wheezig i preschool childre

4 Stepwise Approach Pharmacotherapy (childre 5 years) STEP 4 PREFERRED CONTROLLER CHOICE STEP 1 STEP 2 Daily low dose ICS STEP 3 Double low dose ICS Cotiue cotroller & refer for specialist assessmet Other cotroller optios Leukotriee receptor atagoist (LTRA) Itermittet ICS Low dose ICS + LTRA Add LTRA Ic. ICS frequecy Add itermitt ICS RELIEVER As-eeded short-actig beta 2 -agoist (all childre) CONSIDER THIS STEP FOR CHILDREN WITH: Ifrequet viral wheezig ad o or few iterval symptoms Symptom patter cosistet with asthma ad asthma symptoms ot well-cotrolled, or 3 exacerbatios per year Symptom patter ot cosistet with asthma but wheezig episodes occur frequetly, e.g. every 6 8 weeks. Give diagostic trial for 3 moths. Asthma diagosis, ad ot well-cotrolled o low dose ICS Not wellcotrolled o double ICS First check diagosis, ihaler skills, adherece, exposures

5 Case 3 yr old with atopic dermatitis ad 4 episodes/yr of wheezig, 2-3 severe eough to require oral corticosteroids Episodes separated by log periods without ay asthma-related symptoms At high risk for persistet asthma (positive asthma predictive idex) recurret wheeze ad atopic dermatitis

6 Modified Asthma Predictive Idex (mapi) Idetifies High Risk Childre Ages 2-3 Years 4 wheezig episodes i the past year (at least oe must be MD diagosed) PLUS Oe major criterio ØParet with MD asthma ØMD atopic dermatitis ØAeroallerge sesitivity OR Two mior criteria ØFood sesitivity ØPeripheral eosiophilia (³4%) ØWheezig ot related to ifectio Modified from Castro-Rodriguez JA et al. Am J Respir Crit Care Med 2000;162:1403-6

7 Daily ICS Therapy NAEPP/EPR3 ad GINA Recommeded First Lie Therapy Efficacy Heterogeeity i respose Growth effects

8 PEAK Outcomes Screeig/ Eligibility Ru-i Treatmet FP 88mcg BID or Placebo Observatio 1 moth Years 1 & 2 Year 3 Treatmet Phase: Exacerbatios (57.4/100 child-yrs vs 89.4/100 child-yrs) Supplemetal medicatios (ICS ad LTRA) = brochodilator use ad uscheduled visits ~2 days/moth Observatio Phase: = Exacerbatios = Supplemetal medicatios (ICS ad LTRA) = Brochodilator use ad uscheduled visits EFD: No cough or wheeze, uscheduled cliic, urget care, ED or hospital visits; o use of asthma medicatios Guilbert, NEJM 2006

9 Meta-aalysis of 23 studies (3592 subjects) 1-23mo with wheezig or asthma for 6mo ICS therapy associated with sigificatly fewer exacerbatios requirig oral corticosteroids (18 vs 32.1%, RR 0.59, , p=0.0001)), NNT=7 (95% CI 6-9) (PEAK) Effect greater i those with asthma rather tha wheezig (RR 0.65 ( ) for wheeze vs 0.50 ( ) for asthma; Iteractive test RR 0.76 ( ), p=0.04 Castro-Rodriguez JA et al. Pediatr 2009;123:e519-e525

10 Stratifyig Variable PEAK - Heterogeeity of ICS Respose Withi the mapi+ Populatio ICS Mea (95% CI) Percetage of Episode-Free Days Placebo Mea (95% CI) Differece (95% CI) P-value (ICS vs Placebo) Male 93 (92, 95) 86 (83, 89) 7.3 (3.9, 11.1) Female 92 (89, 94) 92 (89, 94) 0.1 (-3.4, 3.5) 0.9 Caucasia 93 (91, 95) 84 (80, 88) 9.1 (4.8, 13.9) No-Caucasia 92 (89, 94) 93 (91, 94) -1.0 (-3.9, 1.7) 0.6 Ru-I EFD <80% 92 (90, 94) 84 (79, 87) 8.6 (4.2, 13.2) Ru-I EFD 80% 93 (91, 95) 93 (91, 95) 0.0 (-2.5, 2.5) 0.9 ED/Hospitalizatio History 95 (93, 96) 87 (83, 90) 7.7 (3.9, No ED/Hospitalizatio History 90 (87, 92) 91 (89, 93) -1.1 (-4.4, 2.1) Positive Aeroallerge Ski Test 93 (91, 94) 86 (83, 89) 6.5 (3.2, 10.0) Negative Aeroallerge Ski Test 93 (90, 95) 92 (89, 94) 0.9 (-2.5, 4.4) 0.6 Bacharier LB et al. J Allergy Cli Immuol 2009:123:

11 Stratifyig Variable PEAK - Heterogeeity of ICS Respose Withi the mapi+ Populatio ICS Mea (95% CI) Number of Predisoloe Bursts Placebo Mea (95% CI) Relative Rate (95% CI) P-value (ICS vs Placebo) Male 1.1 (0.9, 1.4) 1.8 (1.5, 2.2) 0.6 (0.5, 0.8) Female 1.6 (1.2, 1.9) 1.4 (1.1, 1.7) 1.2 (0.8, 1.6) 0.4 Caucasia 1.4 (1.1, 1.7) 2.2 (1.9, 2.7) 0.6 (0.5, 0.8) No-Caucasia 1.3 (1.0, 1.6) 1.1 (0.9, 1.4) 1.2 (0.8, 1.7) 0.3 ED/Hospitalizatio History 1.2 (0.98, 1.6) 2.3 (1.9, 2.8) 0.5 (0.4, 0.7) < No ED/Hospitalizatio History 1.4 (1.1, 1.8) 1.1 (0.8, 1.3) 1.3 (0.97, 1.8) Positive Aeroallerge Ski Test 1.3 (1.0, 1.5) 2.1 (1.7, 2.4) 0.6 (0.5, 0.8) Negative Aeroallerge Ski Test 1.4 (1.1, 1.8) 1.2 (0.9, 1.5) 1.2 (0.8, 1.7) 0.4 Bacharier LB et al. J Allergy Cli Immuol 2009:123:

12 Liear Growth Not Differet Two Years After Treatmet Discotiuatio Treatmet Observatio + p<0.05 Guilbert, J Allergy Cli Immuol 128(5):

13 Liear Growth Differet i Youger Ad Lighter Childre Treatmet Observatio 2 years old ad 15kg at erollmet 2 years old ad < 15kg at erollmet + p<0.05 Guilbert, J Allergy Cli Immuol 128(5):

14 Liear Growth Not Differet i Older Childre Treatmet Observatio 3 years old ad 15kg at erollmet + p< years old ad < 15kg at erollmet Guilbert, J Allergy Cli Immuol 128(5):

15 Coudrum with Daily ICS Use Most effective ad guidelie preferred cotroller for persistet pediatric asthma as it improves dayto-day asthma cotrol ad prevets exacerbatios However, despite daily ICS, exacerbatios occur yearly i about 30% of childre with mild ad 40% of childre with mild-moderate asthma i trials Suboptimal real-world adherece: Log-term adherece with daily ICS is cosistetly low: 30-50% i geeral pediatric practice Fear/axiety of usig too much medicatio Growth effects small but may be permaet

16 Alterative Regimes to Daily ICS Use Itermittet ICS: Admiisterig ICS wheever specific evets occur & for prespecified duratio Rescue ICS: Admiisterig ICS wheever asthma symptoms appear as eeded (pr) with beta-agoists till symptoms resolve

17 Alterative Regimes to Daily ICS Use Itermittet ICS: Admiisterig ICS wheever specific evets occur & for prespecified duratio Rescue ICS: Admiisterig ICS wheever asthma symptoms appear as eeded (pr) with beta-agoists till symptoms resolve

18 Is Itermittet ICS a Alterative Strategy i Preschool-aged Childre?

19 Episodic Use of a ICS or LTRA i Preschool Childre with Moderate-to-Severe Itermittet Wheezig Radomized, double-blid placebo-cotrolled trial 238 childre moths old with recurret moderatesevere wheezig i the cotext of a URI Primary outcome: proportio of episode free days over 1 year At first sig of RTI symptoms x 7 days Budesoide 1 mg bid + Placebo LTRA + b-agoist Ru i Radomizatio Motelukast 4 mg daily + Placebo ICS + b-agoist Placebo LTRA + Placebo ICS + b-agoist Bacharier LB et al. J Allergy Cli Immuol 2008; 122:

20 Episodic Use of a ICS or LTRA i Preschool Childre with Moderate-to-Severe Itermittet Wheezig No differece i proportio of episode free days (EFDs) or i oral corticosteroid use % of EFDs (95% CI) # OCS courses (95% CI) Budesoide 76% (70% to 81%) 0.7 ( ) Motelukast 73% (66% to 79%) 1.0 ( ) Covetioal Therapy 74% (65% to 81%) 0.9 ( ) No growth effects of itermittet ICS Bacharier LB et al. J Allergy Cli Immuol 2008; 122:

21 Improvemet i Symptoms Relative to Covetioal Therapy i mapi+ Childre Percet Chage i Area Uder the Curve (Relative to Covetioal Therapy) POSITIVE Asthma Predictive Idex Motelukast Budesoide * P<0.05 vs Cov Therapy, ** P<0.01 vs Cov Therapy * Wheezig Score * ** Trouble Breathig Score ** * Iterferece with Activity Negative Asthma Predictive Idex: No sigificat effect of treatmet o ay symptom measure Bacharier LB et al. J Allergy Cli Immuol 2008; 122:

22 Preemptive Use of High-Dose Fluticasoe for Virus-Iduced Wheezig i Youg Childre 129 childre 1-6 yrs of age with 3 wheezig episodes (lifetime) seemigly triggered by URIs No itercurret symptoms 1 course of oral corticosteroids i past 6 moths (or 2 i past 12 mo) Exclusio of childre with suspected allergic rhiitis or allergic sesitizatio to aeroallerge(s) Triple-blid placebo-cotrolled trial At 1 st sig of URI, parets bega study drug (fluticasoe 750mcg BID or placebo) util 48 hrs with o symptoms of cough or wheeze + albuterol as eeded Primary outcome: group rate of oral corticosteroid use Ducharme FM et al. NEJM 2009;360:339-53

23 Preemptive Use of High-Dose Fluticasoe for Virus-Iduced Wheezig i Youg Childre Outcome FP Group Placebo Group # URTI URTI requirig oral steroids OR for FP Group 43 (8%) 93 (18%) 0.49 (0.3, 0.83) No differece i proportio of URTI associated with wheezig, cough, dyspea, or hospitalizatio FP associated with shorter duratio of albuterol use FP group had sigificatly smaller icreases i height (6.23cm vs 6.56 cm) ad weight (1.53kg vs 2.17kg) No differeces i basal cortisol level, boe mieral desity, or adverse evets Ducharme FM et al. NEJM 2009;360:339-53

24 Which is Superior? Daily Low Dose ICS Therapy OR Episodic High Dose ICS Therapy i Preschool Childre with Recurret Severe Episodes of Wheezig ad Positive APIs

25 Maiteace vs. Itermittet Ihaled Steroids I Wheezig Toddlers (MIST) Zeiger RSet al. Lacet 2011;377:650-7 NEJM 2011;365:

26 MIST - Iclusio Criteria (N=278) moths Number of wheezig episodes i the prior year: 4 or 3 with at least 3 moths of asthma cotroller therapy Positive modified Asthma Predictive Idex 1 severe exacerbatio requirig systemic corticosteroids, urget uscheduled, emerget visit or hospitalizatio i prior year Zeiger RS et al. NEJM 2011;365:

27 MIST - Exclusio Criteria History i the prior year: >6 courses of oral corticosteroids or >2 hospitalizatios for wheezig Course durig 2-week ru-i o placebo respule ightly ad albuterol pr Persistet symptomatic asthma Albuterol use o average 3 days per week or 2 ights with awakeigs due to symptoms Iadequate adherece <75% of days adheret to diary completio ad placebo ebulizatio Zeiger RS et al. NEJM 2011;365:

28 MIST Protocol - Overview Ru-i: 2 wks Placebo respule ightly + albuterol PRN Radomized Treatmet Group Daily low-dose budesoide Itermittet high-dose budesoide Treatmet Phase: 52 Weeks Nightly EXCEPT Durig Respiratory Tract Illesses 0.5 mg PM Placebo PM Durig Respiratory Tract Illesses ONLY for 7 days Placebo AM 0.5 mg PM 1.0 mg AM 1.0 mg PM Zeiger RS et al. NEJM 2011;365:

29 % of Patiets Primary Outcome - Frequecy of Exacerbatios A. Itermittet Daily p-value = 0.6 (Rate 0.95/perso yr) (Rate 0.97/perso yr) Number of Predisoloe Courses Zeiger RS et al. NEJM 2011;365:

30 MIST Secodary Outcomes No differece i: Time to 1 st exacerbatio # of RTIs % of RTIs requirig oral steroids (25%) Severity of symptoms durig RTI Symptom free days (78%) Health care utilizatio Growth Itermittet group used less budesoide durig trial (150mg vs 46mg) Zeiger RS et al. NEJM 2011;365:

31 MIST Coclusios Recommed for +mapi childre mo with a exacerbatio i the past year, 3 days/week of albuterol ad <2 ights with awakeigs/2 weeks Itermittet 7-day treatmet with high-dose budesoide started early durig predefied respiratory-tract illesses sice this regime may be preferable to daily low-dose budesoide give its ü similar efficacy ü less frequet use ü lower ICS exposure Zeiger RS et al. NEJM 2011;365:

32 Alterative Regimes to Daily ICS Use Itermittet ICS: Admiisterig ICS wheever specific evets occur & for prespecified duratio Rescue ICS: Admiisterig ICS wheever asthma symptoms appear as eeded (pr) with beta-agoists till symptoms resolve

33 Regular vs PRN ICS Treatmet i Childre with Persistet Symptoms Double-blid placebo cotrolled trial (N=276) 1-4yrs with 3 episode of wheeze i past 6 moths Cough, wheeze &/or shortess of breath o 7 days of 14 day ru-i period Stratified by asthma risk factors (eczema, 1 st degree relative with asthma, eosiophilia >4%) 12 week placebo-cotrolled treatmet period Regular BDP BDP 400mcg BID + albuterol 2.5mg PRN PRN Combiatio Group BDP 800mcg + albuterol 2.5mg PRN PRN Albuterol Group Albuterol 2.5mg PRN Outcome measures Primary: Percetage of symptom-free days (ot icludig reliever use) Secodary: Symptom scores, octural symptoms, medicatio use, exacerbatios (umber ad time to 1 st exacerbatio) Papi A et al. Allergy 2009;64:

34 Regular vs PRN ICS Treatmet i Childre with Persistet Symptoms PRN Albuterol % Symptom-Free Days P= Regular BDP 64.9 PRN Combiatio Proportio without exacerbatio 23 exacerbatios occurred 14 treated with OCS Prologed time to 1 st exacerbatio i regular BDP group compared to PRN albuterol group (p=0.03) ad PRN combiatio group (p=0.03) Time to 1 st course of oral corticosteroids loger i regular BDP compared to PRN albuterol (p=0.01), but ot differet from PRN combiatio Papi A et al. Allergy 2009;64:

35 Regular vs PRN ICS Treatmet i Childre with Persistet Symptoms Coclusios Regular treatmet with ICS is the most effective therapy (regardless of the presece or absece of asthma risk factors) Rescue use of a fixed combiatio of a SABA ad ICS could be a alterative to PRN SABA use aloe Papi A et al. Allergy 2009;64:

36 Idividualized Therapy For Asthma i Toddlers (INFANT) 300 childre mo ecessitatig treatmet with Step 2 cotroller Ru-I (2-8 weeks) Placebo or Active Therapy Daily ICS Placebo LTRA As eeded placebo ICS Placebo ICS Daily LTRA As eeded placebo ICS Placebo ICS Placebo LTRA As eeded active ICS 16 weeks 16 weeks 16 weeks Blood ad urie sample collectio for predictor aalyses Ihaled fluticasoe (44 mcg/actuatio) 2 ihalatios twice daily Oral motelukast (4 mg) oce daily HS As-eeded albuterol plus ihaled fluticasoe (44 mcg/actuatio) 2 ihalatios for every 2 ihalatios albuterol Fitzpatrick AM et al. J Allergy Cli Immuol 2016:138;

37 Which Step 2 Asthma Therapy is BEST for the Greatest Number of Childre? A. p < Hierarchical composite variable of time to exacerbatios ad umber of asthma cotrol days Probability of best respose Differetial respose betwee at least two treatmets was observed i 74% (170 of 230) of childre who provided usable data for aalysis B. Asthma Cotrol Days (%) No-differetial respoders N = 60 Differetial respoders N = 170 Probability of best respose highest for daily ICS No-differetial respoders had idicators of less disease severity C. Cumulative exacerbatio probability No-differetial respoders N = 60 Differetial respoders N = 170 Fitzpatrick AM et al. J Allergy Cli Immuol 2016:138;

38 A. Probability of best respose C. Probability of best respose Not aeroallerge sesitized (N = 130) Female (N = 87) Aeroallerge sesitized (N = 100) Male (N = 143) p = p = B. Probability of best respose D. Probability of best respose No exacerbatio i 12 moths (N = 57) Blood eosiophils <300/μL (N = 113) 1 exacerbatio i 12 moths (N = 173) p = Blood eosiophils 300/μL (N = 92) p = Are there baselie characteristics that predict which treatmet will produce the best respose (for the greatest umber of childre)? E. Not sesitized ad eosiophils <300/μL (N = 87) Not sesitized ad eosiophils 300/μL (N = 28) Sesitized ad eosiophils <300/μL (N = 26) Sesitized ad eosiophils 300/μL (N = 64) Probability of best respose p = Fitzpatrick AM et al. J Allergy Cli Immuol 2016:138;

39 A. No-differetial respoders (N = 60) Not aeroallerge sesitized (N = 91) Aeroallerge sesitized (N = 79) B. No-differetial respoders (N = 60) Blood eosiophils <300/μL (N = 82) Blood eosiophils 300/μL (N = 71) Cumulative exacerbatio probability Cumulative exacerbatio probability C. Cumulative exacerbatio probability Nodifferetial respoders (N = 60) Not sesitized ad eosiophils <300/μL (N = 61) Not sesitized ad eosiophils 300/μL (N = 19) Sesitized ad Sesitized ad eosiophils eosiophils <300/μL (N = 21) 300/μL (N = 52) Fitzpatrick AM et al. J Allergy Cli Immuol 2016:138;

40 Itermittet ICS i Preschool Childre Reduces Risk of Severe Exacerbatio Ducharme FM et al. Lacet 2014;383:

41 We searched MEDLINE (1946-2/25/15), EMBASE (1947-2/25/15), ad CENTRAL Studies were icluded based o Desig (radomized cotrolled trials) Populatio (childre <6 years with asthma or recurret wheeze) Itervetio/compariso (daily ICS/placebo, itermittet ICS/placebo, daily ICS/itermittet ICS, ICS/motelukast) Outcome (wheezig exacerbatios requirig systemic steroids) Kaiser SV et al. Pediatr 2016;137(6);e

42 Kaiser SV et al. Pediatr 2016;137(6);e

43 Daily ICS Reduce Exacerbatios Kaiser SV et al. Pediatr 2016;137(6);e

44 Daily ICS versus Itermittet ICS Kaiser SV et al. Pediatr 2016;137(6);e

45 Daily ICS versus Daily Motelukast Itermittet ICS versus Itermittet Motelukast Kaiser SV et al. Pediatr 2016;137(6);e

46 Results: Subgroup Aalyses Most studies of daily ICS focused o childre with persistet asthma (8 of 15), ad most studies of itermittet ICS focused o childre with itermittet or viral-triggered wheezig (5 of 6) Subgroup aalysis of childre with persistet asthma showed reduced exacerbatios with daily ICS compared to placebo (8 studies, N=2505, RR 0.56, 95% CI , NNT=11) ad daily ICS compared to motelukast (1 study, N=202, RR 0.59, 95% CI ) Kaiser SV et al. Pediatr 2016;137(6);e

47 Itermittet ICS Reduce Exacerbatios Meta-aalysis of RCTs i childre 6 yrs with asthma or recurret wheeze Subgroup aalysis of childre with itermittet asthma or viraltriggered wheezig showed reduced exacerbatios with preemptive high-dose itermittet ICS compared to placebo (5 studies, N=422, RR 0.65, 95% CI , NNT=6) Kaiser SV et al. Pediatr 2016;137(6);e

48 Coclusios There is strog evidece to support daily ICS for prevetig severe exacerbatios i preschool childre with recurret wheeze, specifically i childre with persistet asthma For preschool childre with itermittet asthma or viraltriggered wheezig, there is strog evidece to support itermittet ICS for prevetig severe exacerbatios With either treatmet strategy, we recommed frequet reassessmet of wheezig symptoms/patter, close moitorig of growth, ad active titratio to the lowest ICS dose that is effective More studies are eeded that directly compare these strategies Kaiser SV et al. Pediatr 2016;137(6);e

49 Caveats to Alterative No-Daily ICS Use Remember the efficacy ad preferred positio of daily ICS is based o a multitude of welldesiged radomized trials over the etire asthma spectrum Alterative strategies of ICS use are based o a growig umber of studies over the past few years However, cosistet demostratio of populatios with preschool childre with mild asthma who do ot appear to beefit with daily ICS over itermittet ICS

50 Summary for No-Daily ICS Use i Preschool Childre Pheotype to cosider use: üpreschoolers with frequet wheeze, prior year exacerbatio, ad positive asthma predictive idex ü Parets willig ad capable of followig Actio Pla Pheotypes to ot cosider use: Persistet ucotrolled asthma More moderate to severe disease