Shaping a Dynamic Future in Respiratory Practice. #DFResp

Transcription

1 Shaping a Dynamic Future in Respiratory Practice #DFResp

2 Inhaled Therapy in COPD: Past, Present and Future Richard Russell Chest Physician West Hampshire Integrated Respiratory Service The views expressed in this presentation are those of the speaker and are not necessarily those of the meeting sponsors. This presentation may contain off-licence information. Please refer to the product SmPCs for the approved indication for use. UK/KOL/17/0008 Date of Preparation: February 2017

3 Disclosures: Who Boehringer Ingelheim GlaxoSmithKline Teva UK Limited AstraZeneca Pfizer Napp British Lung Foundation Editor at Int J COPD What Paid speaker Advisory boards Clinical trial investigator Travel support Support our patients! Increase our impact factor! I have no shares in pharmaceutical companies and do everything I can to hinder tobacco companies

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5 ICS therapies in COPD, the past Numerous studies have looked at ICS therapies to improve outcomes in COPD - ISOLDE 1 - TORCH 2 - INSPIRE 3 - FORWARD 4 - BUD/FORM 5 1. Burge PS, et al. BMJ 2000 (FP vs Pla) 2. Calverley PM, et al. N Engl J Med 2007 (FP/Sal vs FP vs Sal vs Pla) 3. Wedzicha JA, et al. Am J Respir Crit Care Med 2008 (FP vs Pla) 4. Wedzicha JA, et al. Respir Med 2014 (BDP/FF vs FF) 5. Calverley PM, et al. ERJ 2003 (BUD/FORM vs BUD vs FORM vs Pla)

6 ICS monotherapy is more effective than placebo in stable COPD (ICS monotherapy is NOT licenced in COPD) Lung function Significant improvement of lung function vs placebo Use of ICS for > 6 months did not have a major effect on the rate of decline in FEV 1 (mean benefit of 5.80 ml/year with ICS over placebo, 95% CI: to 11.88, n=2333) Exacerbations Mortality Health status Reduced exacerbation rates (mean difference of exacerbations/patient/ year, 95% CI: to -0.14, n=2586) Increased risk of reported pneumonia No significant effects on mortality (OR: 0.98, 95% CI: 0.83 to 1.16, n=8390) Slowing of the rate of decline in QoL (improvement in SGRQ of 1.22 units/year, 95% CI: to -0.60, n=2507) Conclusions from a Cochrane systematic review of 55 primary studies published up to and including 2011 (n=16,154) Yang IA, et al. Cochrane Database Syst Rev 2012

7 Burge PS, et al. BMJ 2000

8 Rate of exacerbations vs placebo (%) ICS significantly reduces the rate of exacerbations needing medical intervention Szafranski 1 Calverley 2 Budesonide Formoterol 5 Budesonide Formoterol +3% 0-2% %* % * -20 *p<0.05 vs placebo -20 *p<0.05 vs placebo Fewer future attacks 1. Szafranski W, et al. Eur Respir J Calverley PM, et al. Eur Respir J 2003

9 mean exacerbation rate per patient per year Mean exacerbation rate per patient per year The risk of acute exacerbations in the TRISTAN study There were no differences between the three active treatment groups 1.5 TRISTAN Mahler and Hanania studies no significant differences between groups 0.00 Seretide Fluticasone Salmeterol placebo Seretide Fluticasone Salmeterol Placebo 1. Calverley PM, et al. Lancet 2003

10 Probability of death (%) The TORCH study: All-cause mortality at 3 years Placebo SALM FP SALM/FP Vertical bars are standard errors Number alive Time to death (weeks) Calverley PM, et al. N Engl J Med 2007

11 Mean number of exacerbations/year The TORCH study: Rate of moderate and severe exacerbations over 3 years * 0.93* *p<0.001 vs placebo Placebo SALM FP Treatment Calverley PM, et al. N Engl J Med 2007

12 Long-term inhaled steroids in COPD Trial n Duration Severity Outcome Copenhagen City years Mild No effect EUROSCOP years Mild No effect ISOLDE years Moderate No effect Lung Health years Moderate No effect 1 o outcome = decline in FEV 1 over 3 years Cochrane Review: >16,000 COPD patients - No FEV 1 decline - No mortality Yang IM, et al. 2012

13 What are we doing now? The present

14 Adapted from Gartlehner GG, et al. Ann Fam Med. 2006;4: Adapted COPD, from chronic Singh S, obstructive Loke YK. J COPD. pulmonary 2010;5: disease Potential Side Effects of COPD Therapy: ICS COPD: What is on our wish list? Unmet needs of patients with COPD Cataracts More effective diagnosis and primary prevention Better symptom control Rhinitis Fewer exacerbations Slowing of disease progression Sore throat Better life expectancy Increased bruising Unmet needs of the medical community Adverse effects on Optimising bone density/fracture disease prevention Increased intraocular pressure/glaucoma Oral Candidiasis Upper respiratory infection Less systemic disease secondary to COPD and fewer comorbidities Improving symptom control Pneumonia Preventing exacerbations and decreasing their clinical impact Preventing disease progression Reducing disease-related mortality Identifying systemic effects and comorbidities 1. Calverley PMA. Br J Pharmacol. 2008;155(4):

15 Modified version of the Fletcher and Peto graph showing the decline in FEV 1. FEV 1, forced expiratory volume in 1 second. Fletcher C, Peto R. BMJ 1977; 1: FEV 1 decline: The traditional view

16 FEV 1 (% predicted) FEV 1 decline: What is really going on? 100 Δ 40mL/yr GOLD 1 (mild) 80 Δ L/yr GOLD 2 (moderate) Δ 56 59mL/yr GOLD 3 (severe) Δ <35mL/yr GOLD 4 (very severe) Time since drug administration (hours) More recent analyses concluded that, in contrast with earlier findings, FEV 1 decline was fastest in the early stages of COPD, particularly in GOLD 2 disease FEV 1, forced expiratory volume in 1 second. Tantucci C, Modina D. Int J Chron Obstruct Pulmon Dis 2012; 7:

17 Affecting disease progression UPLIFT (subgroup) TORCH (subgroup) Real GOLD II FEV1 loss 61ml/year UPLIFT GOLD II loss 49ml/year UPLIFT GOLD III 38ml/year

18 Jenkins et al, Respiratory Research 2009; 10:59 TORCH study: FEV 1 loss

19 UPLIFT: GOLD II analysis n Tio ml/yr n Con ml/yr diff (CI) p Decamer et al. Lancet ,9696;

20 Decamer et al. Lancet ,9696; How do patients feel?

21 Decamer et al. Lancet ,9696; UPLIFT: GOLD II exacerbations

22 Paradigm of COPD management is shifting Global Initiative for Chronic Obstructive Lung Disease. Revised Available at:

23 High levels of off-guidelines ICS use worldwide* USA Western Europe South America Other 28% 47% 41% 24% Patients at GOLD Stage II with no history of exacerbations in the past year who were receiving ICS at baseline on enrolment *Data from 11 studies in 44 countries with a total of 9482 patients Yawn D, et al. Am J Resp Crit Care Med 2012;185:A2944 (Abstract).

24 So what are we doing now? It seems almost random: Population database study n=24,957-17% no treatment - 24% ICS - 26% ICS/LABA - 23% ICS, LABA, LAMA - 2% LAMA alone Irrespective of GOLD stage or GOLD group (A-D) Price D, et al. Int J Chron Obstruct Pulmon Dis 2014;9:

25 NICE Clinical Guidance (2010) When the 2010 guideline was being written, the available evidence for LABA plus LAMA combination therapy was relatively limited. As the NICE guidelines are purely evidence-based, the recommendation for LABA plus LAMA therapy is restricted in the 2010 guideline. Adapted from NICE. COPD pathway updated Sept (last accessed November 2014)

26 Expiratory flow limitation has systemic effects in COPD COPD Exacerbations Expiratory flow limitations Air trapping/ hyperinflation Breathlessness Deconditioning HRQoL Inactivity Reduced exercise capacity Disability Progression: decline in lung function Mortality Ferro TJ. Clinical Pulmonary Medicine 2005;12(4 Suppl):S13-S15; Decramer M. Eur Respir Rev 2006;15(99): COPD, chronic obstructive pulmonary disease; HRQoL, health-related quality of life

27 Bronchodilation and its consequences Relaxation of ASM Not the same as increased radius from reduction in oedema/cells Change in the degree/location of EFL Reduced static hyperinflation (EELV) Delays onset of dyspnoea when exercising

28 Beta-agonists and muscarinic antagonists

29 Anticholinergics HENBANE Deadly Nightshade

30 LAMA

31 Change from baseline in FEV 1 (L) Duration of action of tiotropium FEV 1 time profile (0-12 hours), test day Time after dose administration (hours) Tiotropium Respimat 5µg (n=187) Tiotropium Respimat 10µg (n=179) Tiotropium HandiHaler 18µg (n=186) Placebo (n=181) Van Noord DE, et al. Respir Med 2009;103:22-29.

32 Twice daily LAMA therapy

33 Trough FEV 1 (L) Effects of aclidinium on FEV 1 : ACCLAIM COPD trial results 1.5 Aclidinium 200µg Placebo p<0.05 p<0.001 p<0.001 p< p<0.001 p<0.001 p<0.001 p< ACCLAIM/ COPD I ACCLAIM/ COPD II ACCLAIM/ COPD I ACCLAIM/ COPD II ACCLAIM/ COPD I ACCLAIM/ COPD II ACCLAIM/ COPD I Week 4 Week 12 Week 28 Week 52 ACCLAIM/ COPD II Jones PW, et al. Respir Res 2011;12:55

34 Percent with moderate or severe exacerbations Effects of aclidinium on FEV 1 : ACCLAIM COPD trial results 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% 26.60% Aclidinium ACCLAIM COPD I p= % Placebo 33.20% ACCLAIM COPD II p= % n=627 n=216 n=600 n=204 FEV 1, forced expiratory volume in 1 second Adapted from Jones PW, et al. Respir Res 2011;12:55

35 Long-term impact on health status Activity Tiotropium Control Symptoms Impact Troosters T, et al. Eur Respir J. 2010;36:65-73.

36 LABA

37 Formoterol has a significantly faster onset of action versus salmeterol (data presented after 28 days treatment) Cote C et al. Pulmonary Pharmacology & Therapeutics 2009; 22: 44 49

38 Trough FEV 1 (L) Indacaterol provided significant sustained improvement in trough FEV 1 over 26 weeks versus placebo and salmeterol Placebo Indacaterol 150µg o.d. Salmeterol 50µg b.i.d *** 1.42 *** 1.43 *** 1.39 *** 1.45 *** 1.36 *** ***p<0.001 vs placebo; p<0.001 vs salmeterol Data are LSM Day 2 Week 12 Week 26 Primary endpoint Kornmann et al. Eur Respir J 2011; Kornmann et al. ACCP 2009

39 Trough FEV 1 response, L FEV 1 AUC 0-3 response, L Olodaterol 5 and 10μg improve mean FEV 1 AUC 0-3h and trough FEV 1 responses over 48 weeks similarly Statistically significant at 12 weeks Studies.11/.12 Placebo Olodaterol 5µg Olodaterol 10µg Statistically significant at 24 weeks Studies.13/ Data on file. Studies ; ; Weeks Weeks Common baseline mean (standard error): Studies 11/12: (0.014); Studies 13/14: (0.011). Analysis with imputation (full analysis set). AUC0-3h, area under the plasma concentration time curve from 0 to 3 hours; FEV 1, forced expiratory volume in 1 second

40 LAMA/LABA

41 Short-acting 2-agonists versus anticholinergics D FEV 1 (%) Day 1 Day Ipratropium 36µg Salbutamol 200µg Both drugs combined Hours after test dose Combivent Study Group, Chest 1994; 105:1411

42 Dual bronchodilators for COPD Anoro Ellipta (VIL/UMEC) 55µg umeclidinium 22µg vilanterol One inhalation Once daily Spiolto Respimat 2.5µg tiotropium 2.5µg olodaterol Two inhalations Once daily Duaklir Genuair (ACL/FORM) 340µg aclidinium 12µg formoterol One inhalation Twice daily Ultibro Breezhaler 50µg glycopyrronium 110µg indacaterol One inhalation Once daily SPCs accessed at [Accessed Jan 2016]

43 FEV 1 (L) 24-hour FEV 1 profile after six weeks of treatment significant improvements in lung function versus monotherapy and placebo T+O FDC 5/5µg AUC 0-3h 338mL Trough 207mL* 24-hour FEV1 profile Time since drug administration (hours) *Difference between T+O FDC 5/5µg and placebo Tiotropium 2.5μg Tiotropium 5μg Placebo Olodaterol 5μg Tiotropium+olodaterol FDC 2.5/5μg Tiotropium+olodaterol FDC 5/5μg Beeh KM et al. Pulm Pharmacol Ther 2015; DOI /j.pupt )

44 Change from baseline in pre-morning dose lung function (trough FEV 1 ) at Week 24: pooled data ACL/FORM significantly improved lung function pre-morning dose compared with aclidinium or formoterol

45 VIL/UMEC 55/22mcg improves lung function compared with TIO Primary endpoint: Trough FEV 1 at day 169 ZEP11711 DB DB Maleki-Yazdi MR, Kaelin T, Richard N, Zvarich M, Church A. Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in COPD: results of a 24-week, randomized controlled trial. Respir Med. 2014;108(12): Decramer et al. Lancet Resp Med 2014 ; Vol 2 No. 6 pp

46 (L) VIVACITO: Adjusted mean IC, TLC, FRC and RV response (L) at 2:30 post-dose after six weeks treatment :30 hours after dosing Placebo Olo 5 Tio 2.5 Tio 5 T+O 2.5/5 T+O 5/5 IC * TLC * * * FRC * * RV FDC always superior over placebo. *Indicates additional superiority over at least one of the monotherapies. FDC, fixed-dose combination; FRC, functional residual capacity; IC, inspiratory capacity; L, litres; O/Olo, olodaterol; RV, residual volume; T/Tio, tiotropium; TLC, total lung capacity. 1. Beeh KM, et al. Pulm Pharmacol Ther 2015; May 6. pii: S (15) doi: /j.pupt

47 Rates of exacerbations at week 24: pooled data ACL/FORM was associated a statistically significant reduction of 29% in the rate of moderate or severe exacerbations AstraZeneca. Data on File: ABF/023/Jan15.

48 Probability of moderate/ severe exacerbation Exacerbations: Probability of moderate/severe exacerbations Tiotropium+olodaterol 2.5/5μg Tiotropium+olodaterol 5/5μg Tiotropium 2.5μg Olodaterol 5μg Tiotropium 5μg BI data on file. Studies /.6 combined dataset Test day Numbers at risk T+O 5/5 µg T+O 2.5/5 µg Tiotropium 5 µg Tiotropium 2.5 µg Olodaterol 5 µg

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50 FLAME is the first study to demonstrate superiority of indacaterol/glycopyrronium (Ultibro Breezhaler ) in exacerbation prevention versus SFC in COPD patients with 1 exacerbation in the preceding year Rate ratio (95% Cl) Superiority margin Non-inferiority margin Per-protocol set (Primary analysis) p=0.003 Modified intention-to-treat set (Supportive analysis) p< Favours IND/GLY Favours SFC Ultibro Breezhaler was non-inferior (primary endpoint) and superior to SFC for the rate of all (mild/moderate/severe) exacerbations over 52 weeks Wedzicha JA, et al. N Engl J Med 2016

51 Updated treatment algorithm in GOLD 2017

52 When should ICS be used in the management of COPD? The Future

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54 EVIDENCE UNCERTAINTY EVIDENCE UNCERTAINTY UNCERTAINTY EVIDENCE UNCERTAINTY UNCERTAINTY EVIDENCE UNCERTAINTY

55 When should we use ICS in COPD? My view Disclaimer the views represented are those of the speaker and his appraisal of current evidence; they are likely to be biased and may not be the TRUTH Personal expert opinion Richard Russell

56 Group C Further exacerbation(s) LAMA + LABA LAMA GOLD recommendations for COPD treatment LABA + ICS Consider roflumilast if FEV 1 <50% pred. and patient has chronic bronchitis LAMA Further exacerbation(s) Further exacerbation(s) LAMA + LABA + ICS LAMA + LABA Consider macrolide (in former smokers) Group D Persistent symptoms / further exacerbation(s) LABA + ICS Group A Continue, stop or try alternative class of bronchodilator LAMA + LABA Group B Evaluate effect Persistent symptoms A bronchodilator A long-acting bronchodilator (LABA or LAMA) Preferred treatment In patients with a major discrepancy between the perceived level of symptoms and severity of airflow limitation, further evaluation is warranted Global Initiative for Chronic Obstructive Lung Disease, all rights reserved. Use is by express license from the owner. From the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) Available from:

57 When should we use inhaled steroids in COPD? Consider use in GOLD groups C and D For patients with frequent exacerbations and poor lung function Do they help promote maximal bronchodilatation when added to LAMA/LABA? ICS can be withdrawn I make a positive decision to start ICS; it is NOT a default Personal expert opinion Richard Russell

58 Suissa S, et al. Thorax 2013 Pneumonia risk with ICS

59 Suissa S. Thorax Jun;68(6): doi: /thoraxjnl NNT and NNH for inhaled corticosteroids

60 Potential risks of ICS use Randomised controlled trial Observational study Systematic review Pneumonia Tuberculosis Bone fracture Skin thinning/easy bruising Cataract Diabetes No effect on fracture risk Oropharyngeal candidiasis Price D, et al. Prim Care Respir J 2013;22:92 100

61 New GOLD D: A treatable trait approach Several options are available if: Patient on LAMA/LABA Still exacerbating Poor lung function (<50%) 1. ICS: with eosinophils 2. Roflumilast: if chronic bronchitis and emphysema and BMI >23 3. Macrolide therapy: if not smoking (bronchiectasis, check microbiology) Role of therapeutic trial Non-eosinophilic Neutrophilic Personal expert opinion Richard Russell

62 The blood eosinophil count: reducing risk and ICS in COPD

63 Exacerbation rate INSPIRE 1 Blood eosinophils in COPD & ICS: reducing risk Randomised, double-blind, parallel-group, double-dummy study with either salmeterol/fluticasone propionate 50/500µg twice daily (n=658) or tiotropium bromide 18µg once daily (n=665) for 2 years Primary endpoint of health care utilisation exacerbation rate not different % diff p=0.006 SFC 50/500 Tio 18µg % diff p= n=263 n=287 n=371 n=348 EOS <2% EOS 2% 1. Wedzicha JA, et al. Am J Respir Crit Care Med Barnes N, et al. Am J Respir Crit Care Med 2015;191:A3975, poster 612

64 Blood eosinophils in COPD & ICS: reducing risk The effect of addition of fluticasone furoate (FF) to vilanterol (VI) HZC and HZC studies; safety and efficacy study 1 To determine if the combination of FF and VI is more protective than VI alone against COPD exacerbations; more AE, however, reanalysis by eos 2 42% diff 24% diff 32% diff 10% diff 1. Dransfield MT, et al. Lancet Respir Med Pascoe S, et al. Lancet Respir Med 2015

65 Blood eosinophils in COPD & ICS: reducing risk FORWARD Safety and efficacy of BDP/FORM vs FORM 1 Reduction in exacerbation rate in 3 rd and 4 th eosinophil quartile 2 1. Wedzicha JA, et al. Respir Med Siddiqui SH, et al. Am J Respir Crit Care Med 2015

66 Change from baseline pre-bronchodilator FEV 1 (ml) Blood eosinophils in COPD & ICS: reducing risk ISOLDE 1 Randomised, double-blind, parallel-group study with either fluticasone propionate 500µg twice daily (n=376) or placebo (n=375) for 3 years No difference in primary outcome of rate of FEV1 decline (ml/year), until analysed by Eos <2% 2% Difference=3.8mL/year p=0.616 Difference=37.7mL/year p= Treatment Placebo FP Burge PS, et al. BMJ Barnes N, et al. ATS 2015,p 613, AJRCCM 191, A Month

67 NEJM ICS (n=1243) ICS withdrawal (n=1242) Male, % Mean (SD) age, years 63.6 (8.6) 64.0 (8.4) Mean (SD) body mass index, kg/m (5.1) 25.2 (5.1) Current smoker, % Mean (SD) duration of COPD, years 7.8 (6.0) 8.0 (6.5) Lung function Mean (SD) post-dose screening FEV 1, L FEV 1 30 <50% (GOLD 3), n (%) FEV 1 <30% (GOLD 4), n (%) Mean (SD) baseline FEV 1, L* *After 6-week run-in on triple therapy 0.93 (0.29) 760 (61.1) 473 (38.1) 0.97 (0.36) 0.94 (0.30) 761 (61.3) 474 (38.2) 0.98 (0.36)

68 *p<0.05; **p<0.01. Watz et al., ATS 2016 Abstract 6944 Eosinophils and ICS

69 REAL-WORLD WISDOM sub-analysis: ICS withdrawal only EVIDENCE MONOTHERAPY COMBINATION WITHDRAWAL increased WISDOM the exacerbation subanalysis: rate in patients with the combination of raised eosinophil counts and frequent exacerbations HOME GUIDELINES SAFETY ALTERNATIVES ICS withdrawal only increased the exacerbation rate in patients with the combination of raised eosinophil counts and frequent exacerbations Patients, n Hazard ratio of exacerbations in patients with 300 or 400 cells/µl and <2 or 2 previous exacerbations HR 95% CI P-value Total 2441 Screening eosinophils , cells/µl < 2 exacerbations 2 exacerbations , , cells/µl < 2 exacerbations 2 exacerbations , , Favours ICS withdrawal Favours ICS Calverley PMA, et al. ERS 2016 oral presentation. Calverley PMA, et al. ERS 2016 oral presentation 63

70 WISDOM sub-analysis: Only a small subset of clearly identifiable patients may benefit from adding ICS to LAMA/LABA ICS may provide incremental benefit only in patients who meet 3 criteria 1. Severe/very severe COPD This is only 7% of the entire WISDOM study population 2. A history of 2 exacerbations/year 3. Blood eosinophil levels 300 cells/µl 1. Watz H, et al. Lancet Respir Med Calverley PMA, et al. ERS 2016 oral presentation

71 Differential treatment effect by blood eosinophil counts: anti IL-5Rα in eosinophilic COPD Change in FEV 1 (L) n= n=28 n=31 n=34 n=31 n=35 n= Blood eosinophil count (cell/µl) Brightling CE, et al. Lancet Respir Med 2014

72 Using the blood eosinophil count to guide ICS treatment in COPD The blood eosinophil count as a biomarker in COPD: - Relevant and valid Easily accessible Repeatable Identifies risk o Type and frequency of exacerbations o Mortality o Infection Personal expert opinion Richard Russell

73 Using the blood eosinophil count to guide ICS treatment in COPD The PBE: Predicts who can be taken off ICS (and who should not!) Predicts who should receive ICS - To reduce risk of exacerbation Predicts who will respond to new biological agents PBE, Percentage blood eosinophils Personal expert opinion Richard Russell

74 What about ACO? My view: - Truly try to diagnose asthma - Give steroids for a positive reason - Trial of treatment - Appropriate detailed testing Treatable trait approach will supersede labels Personal expert opinion Richard Russell

75 Choice is good Choice

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77 55-year-old man Ex-lorry driver Presented to GP with SOB Smoker 70 pack years GP worried by breathlessness and young age thus sent for specialist opinion

78 The CXR What is abnormal? A. Flat diaphragms B. Hyperlucency C. Consolidation D. Cardiomegaly Answers: 1. A,B,C,D 2. A,B 3. C 4. Normal CXR

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80 What will his spirometry show? 1. Fixed airway obstruction 2. Extra-thoracic obstruction 3. Restriction 4. Reversible airway obstruction

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83 Diagnosis Severe emphysema Gas trapping Reversible hyperinflation

84 What are the treatment options? 1. Inhaled corticosteroids 2. Inhaled LABA 3. LAMA 4. LABA/LAMA combination 5. ICS/LABA 6. Lung volume reduction surgery

85 Management Check A1AT Eosinophil count Assess for LTOT Pulmonary rehabilitation Maximise therapy LABA/LAMA Consider LVRS/bullectomy/single lung transplantation

86 Progress Low eosinophils: Commenced on tiotropium/olodaterol therapy Completed pulmonary rehabilitation Maximised exercise tolerance Now runs Marathons!

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88 How to treat COPD Diagnose early and stop smoking Bronchodilate to the maximum: - LAMA; LAMA/LABA Assess risk - Exacerbation - CVS Give inhaled steroids to the RIGHT patients (eos) Pulmonary rehabilitation for all

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