Add on therapy in asthma Local experience in context J Paul Dilworth, Nicola Marks, Lauren Geddes
Programme Omalizumab Evidence and assessment Local Experience Dysfunctional breathing The other effective add on!
Omalizumab Quiz Background Evidence Exercise Assessment NICE Summary
Quiz no cheating! Xolair therapy Decreases OCS dose by x% Decreases A&E visits by x% Anaphylaxis rate is x% Decision to treat is based mainly on previous OCS dose. True/false Clinical benefit correlates well with pre treatment IgE I feel x about the benefits of xolair therapy Very positive, positive, neutral, negative, very negative
Severe Asthma Costs in UK 6bn (direct and work related) 5% severe asthma skin prick positive to any common allergen 65-9% have an allergic basis (Holt 99) IgE binds to receptor on mast cells and basophils acute and chronic inflammation Xolair binds circulating IgE Reduces levels free serum IgE Prevents interaction between free IgE and mast cells/basophils Decreased degranulation and inflammatory mediator release
The obligatory cytokine slide Mast cell IgE Symptoms of allergic inflammation Acute IL-5, IL-3 GM-CSF Histamine Lipid mediators Enzymes Cytokines Chemokines Cough Chest tightness Wheeze Dyspnoea Chronic Eosinophil Recruitment, activation Basic proteins Enzymes Lipid mediators Cytokines Chemokines Bronchial hyperresponsiveness (BHR) Holt PG et al. Nature 1999
INNOVATE. 24. Severe persistent asthma (GINA step 4) RCT. 28/52 High dose ICS + LABA + frequent exacerbations 419 patients. 67% had A&E visit in last 12/12 Decrease severe exacerbation rate (.24v.48: p=.2; 26%) and emergency visits (.24v.43: p =.38; 44%) Improved QoL (AQLQ) and global evaluation scores
INNOVATE: Omalizumab Significantly Reduces.6 Severe Exacerbation Rate 5%.5 p=.2 Exacerbation rate.4.3.48.2.24.1 Omalizumab (n=29) Placebo (n=21) GINA definition (PEF/FEV 1 <6% personal best) Adapted from Humbert et al. Allergy 25; 6: 39-316
Britton. 212 Pooled data 4 UK centres. Real life effectiveness 2 years before v 16 weeks of treatment OCS decreased by 62.8%; 12.6 v 5.7mg Hospitalization -8.6%; 25.2 v 49 Bed days -92.6%; 546 v 46 ICU adm -95.2%; 21 v 1 A&E visits -82.1%; 26.3 v 47 GP visits -75.3% 587 v 145 Improved QoL (ACT and AQLQ)
Mean maintenance OCS dose (mg/day) Mean Maintenance OCS Dose 18 16 14 Mean Maintenance dose of OCS pre- and post-omalizumab treatment 54.8% Pre-OMB Post-OMB Post-OMB Pre-OMB Post-OMB 12 1 12.6 8 6 4 5.7 2 Pre-omalizumab (n=43) Post-omalizumab (n=43) The percentage of patients taking maintenance OCS was reduced from 67.4% (29/43) to 46.5% (2/43) after omalizumab initiation 1 Britton et al. European Respiratory Society Annual Congress 211 OCS-Oral Corticosteroid
Barnes N. 213. APEX (asthma patient experience). Non interventional 1 centre retrospective review of case notes real world Effect on oral corticosteroid (OCS) use. 12 months prior to xolair and 12 months after 136 patients OCS mean dose decreased by 34% (21.35 v 15.88) 49% stopped OCS Exacerbations per patient 3.67 to 1.73 (54%) A&E -7%;.46 v 1.52) Hospital adm -61%;.51 v 1.3)
Exacerbations 4.5 4 Asthma Exacerbations Pre- and Post-Omalizumab Initiation 54% p<.1 Post-OMB Pre-OMB Pre-OMB Post-OMB 3.5 3 3.67 2.5 2 1.5 1 1.7.5 Pre-omalizumab Post-omalizumab Adapted from Barnes et al. Journal of Asthma 213; 5 (5):529-536
Hospitalisations Mean Number of A&E Visits Hospitalisations and A&E Visits Pre- and Post-Omalizumab 1.8 61% 1.6 p<.1 Initiation 1.8 1.6 Pre-OMB 7% Post-OMB p<.1 1.4 1.4 1.52 1.2 1 1.3 1.2 1.8.8.6.6.4.2.51.4.2.46 Inpatient hospitalisation (n=136) A&E attendances (n=136) Adapted from Barnes et al. Journal of Asthma 213; 5 (5):529-536
Mansur 213 BTS poster 24 month response. 43 patients 87% reduction in unscheduled hospitalisations Discontinue OCS (82% v 42%) Reduction by 3 days missed school/work
Schumann. 211. XCLUSIVE 195 patients Germany. Real life FEV1 +13.7% Exacerbation rate -74.9% Days of absence -92.1% GETE excellent 78.8% RCT efficacy translates to clinical practice +++
Prediction of Response? Response unaffected by age or baseline serum IgE (Bousquet 24) GETE rating at week 16 predicts response at 32 weeks (Bousquet 211) i.e. supports current practice of identifying longer term clinical response at 16/52 High blood eosinophil count is a biomarker for clinical benefit (Busse 214)
Side effects Anaphylaxis USA.9% Canada.2% First 3 injections 2 hours Subsequent 3mins Common other local reaction, headache
Exercise What pre treatment conditions need to be met
NICE appraisal Adults and children over 6 Severe persistent confirmed allergic IgE mediated who need continuous or frequent (4 or more in 12 months) OCS Optimised standard therapy as a full trial of high dose ICS, LABA, leukotriene antagonist, theophylline, oral corticosteroids, smoking cessation Symptomatic, impaired lung function IgE <15IU/ml Maximum dose 6mg
Checklist Allergic Documented optimised therapy Exclusion other issues (e.g. hyperventilation, ANCA, ABPA) IgE QoL questionnaires and lung function Documented recent asthma history
Summary In both RCT and real life Decreased Exacerbation A&E and hospital stay OCS dose Symptoms Increased Asthma related QoL Lung function Frightened breathless patients feel dramatically better