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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
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
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)
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: -0.28 to 11.88, n=2333) Exacerbations Mortality Health status Reduced exacerbation rates (mean difference of -0.26 exacerbations/patient/ year, 95% CI: -0.37 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: -1.83 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
Burge PS, et al. BMJ 2000
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% 0-5 -5-10 -10-15 -15%* -15-12% * -20 *p<0.05 vs placebo -20 *p<0.05 vs placebo -25-25 -30-30 Fewer future attacks 1. Szafranski W, et al. Eur Respir J 2003 2. Calverley PM, et al. Eur Respir J 2003
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 1 1.0 1 0.5 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
Probability of death (%) The TORCH study: All-cause mortality at 3 years 18 16 14 12 10 8 6 4 2 Placebo SALM FP SALM/FP Vertical bars are standard errors Number alive 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 1524 1533 1521 1534 1464 1487 1481 1487 Time to death (weeks) 1399 1426 1417 1409 1293 1339 1316 1288 Calverley PM, et al. N Engl J Med 2007
Mean number of exacerbations/year The TORCH study: Rate of moderate and severe exacerbations over 3 years 1.2 1.13 1.0 0.97* 0.93* *p<0.001 vs placebo 0.8 0.6 0.4 0.2 0.0 Placebo SALM FP Treatment Calverley PM, et al. N Engl J Med 2007
Long-term inhaled steroids in COPD Trial n Duration Severity Outcome Copenhagen City 290 3 years Mild No effect EUROSCOP 1277 3 years Mild No effect ISOLDE 751 3 years Moderate No effect Lung Health 2 1116 3.5 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
What are we doing now? The present
Adapted from Gartlehner GG, et al. Ann Fam Med. 2006;4:243-262. Adapted COPD, from chronic Singh S, obstructive Loke YK. J COPD. pulmonary 2010;5:189-195. 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):487-493.
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: 1645 1648. FEV 1 decline: The traditional view
FEV 1 (% predicted) FEV 1 decline: What is really going on? 100 Δ 40mL/yr GOLD 1 (mild) 80 Δ 47 79 L/yr GOLD 2 (moderate) 50 30 0 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: 95 99.
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
Jenkins et al, Respiratory Research 2009; 10:59 TORCH study: FEV 1 loss
UPLIFT: GOLD II analysis n Tio ml/yr n Con ml/yr diff (CI) p Decamer et al. Lancet 2009 374,9696;1171-1178
Decamer et al. Lancet 2009 374,9696;1171-1178 How do patients feel?
Decamer et al. Lancet 2009 374,9696;1171-1178 UPLIFT: GOLD II exacerbations
Paradigm of COPD management is shifting Global Initiative for Chronic Obstructive Lung Disease. Revised 2015. Available at: http://www.goldcopd.org/.
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).
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;9:889 904.
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 2013. http://pathways.nice.org.uk/pathways/chronic-obstructive-pulmonary-disease#path=view%3a/pathways/chronic-obstructive-pulmonarydisease/inhaled-therapy-in-copd.xml&content=view-index (last accessed November 2014)
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):51-57. COPD, chronic obstructive pulmonary disease; HRQoL, health-related quality of life
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
Beta-agonists and muscarinic antagonists