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Utilising real-world evidence to achieve precision medicine in COPD

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Plenary speech from Alan Kaplan at REG 2016 Summit

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Utilising real-world evidence to achieve precision medicine in COPD

  1. 1. 19/04/2016 1 Precision medicine: tailoring COPD management to specific patient needs, phenotypespat e t eeds, p e otypes Alan Kaplan MD CCFP(EM) FCFP Chairperson Family Physician Airways Group of Canada Conflicts: Advisory Board or speakers bureau for  Astra Zeneca, Boehringer Ingelheim, Novartis, Takeda,  Merck Frosst, Pfizer, Purdue 1 Objectives • Review current guidelines for COPD pharmacotherapy • Review how to tailor our pharmacotherapy to those who  will best benefit from them – Personalized care vs guideline care oror – How to use guidelines in the patient in front of you • Discuss how to fix it when therapy is perhaps..not as  optimized as it could be! 2 I am not going to talk about • Making an early diagnosis • Smoking cessation • Pulmonary Rehabilitation • Oxygen therapy • End of life therapy in COPD • Multimorbitidity 3 Nice overview to make you consider the individual patient in front of you 4
  2. 2. 19/04/2016 2 TREATABLE TRAITS (can coexist) IMP RE C DIAGNOSTIC CRITERIA TREATMENT MAIN EXPECTE D BENEFIT First choice Efficacy Second choice* Airflow limitation +++ +++ FEV1/FVC < 0.7 (or LLN) S Airway smooth muscle contraction ++ +++ BD Reversibility, PEF variability, positive PC20 Maintenance: LABA and/or LAMA Rescue: SABA or SAMA +++ ICS Bronchial Thermoplastya S Loss of elastic recoil (Emphysema ) +++ ++ CT, DLCO, compliance Smoking cessation + LVRS, Lung transplantation, a1anti-trypsin replacement if deficient. Valves, coils S,P Airway mucosal oedema ++ + CT. Spirometry-induced bronchoconstriction. ICS ++ OCS. Anti-IL5, IL13, IL4 E Eosinophilic airway +++ +++ Sputum eos, blood eos, ICS +++ OCS, LTRA, Anti-IgE, Anti- E Table 1. Pulmonary treatable traits of airway diseases 5 Eosinophilic airway inflammation (EAI) Sputum eos, blood eos, FENO, (periostin) ICS OCS, LTRA, Anti IgE, Anti IL5, IL13, IL4 E Chronic bronchitis ++ +++ Cough and sputum 3 months x 2 yrs. (no EAI) Smoking cessation + Carbocysteine, macrolides, roflumilast E Airway bacterial colonization* ++ ++ Sputum culture, quantitative PCR Antibiotics ++ Long-term low dose macrolides, vaccination E/S Bronchiectasis* ++ ++ CT Drainage + Macrolides, Nebulized Antibiotics, Surgery, Vaccination E/S Cough reflex hyper- sensitivity ++ +++ Capsaicin challenge, cough counts, cough questionnaire. Speech and language treatment (63) + Gabapentin (62) . S Pre-capillary pulmonary hypertension* ++ ++ Doppler echocardiography, BNP Right-heart catheterization LTOT ++ NIV Lung transplantation S,E,P Chronic respiratory failure* Arterial hypoxemia +++ +++ PaO2<55 mmHg LTOT ++ P Arterial hypercapnia +++ +++ PaCO2>45 mmHg + NIV Agusti A et al. 2015 TREATABLE TRAITS (can coexist) IMP RE C DIAGNOSTIC CRITERIA TREATMENT MAIN EXPECT ED BENEFIT First choice Efficacy Second choice* Deconditioning + + CPET, 6MWD Exercise, rehabilitation + S,P Obesity + +++ BMI Diet, Physical activity + Medication, Bariatric surgery S,P Cachexia + +++ BMI Diet, Physical activity + S, E OSAS + ++ Questionnaires, PSG CPAP + Weight loss. Mandibular advancement splint S,P Cardiovascular disease ++ +++ EKG, Doppler Echocardiography, BNP ACE inhibitors, diuretics, b-Blockers ++ Surgery S,E,P GERD (64) + ++ GI endoscopy pH PPI, H2 antagonist + Surgery S Table 2. Extra-pulmonary treatable traits of airways diseases 6 GERD (64) GI endoscopy, pH monitoring PPI, H2 antagonist Surgery S Upper airway diseases rhino- sinusitis + ++ History and examination, imaging Topical steroids ++ LTRA, antihistamines, surgery S, E Upper airway diseases Inducible laryngeal obstruction (vocal cord dysfunction) ++ + Fibreoptic laryngoscopy, flow- volume curve, dynamic CT neck Speech pathology therapy (63) ++ Laryngeal botulinum toxin Psychology/psychiatry S Psychiatric disorders: depression ++ ++ Questionnaires, psychologist/liaison psychiatrist assessment CBT, pharmacotherapy ++ S Psychiatric disorders Anxiety: Anxiety/other behavioural aspects including breathing ++ ++ Questionnaires, psychologist/liaison psychiatrist assessment Anxiety management, breathing retraining + Anxiolytic/antidepressant medication, CBT, Psychotherapy S Agusti A et al. 2015 7 8
  3. 3. 19/04/2016 3 Let’s deal with two scenarios 1) The patient with recurrent exacerbations 2) The returning patient on therapy 9 Case 1 • 67 year old woman with established COPD • No longer golfing due to dyspnea • On LABA/LAMA plus SABA for breakthrough • FEV1 40% • CAT score 15 • Says, ‘I am doing fine’ • Averages two exacerbations yearly, admitted last year once • You have done all the other little things: CV protection, osteoporosis screening, mood is ok, weight is stable, referred for pulmonary rehabilitation • Is she fine? • How do you decide? 10 What are your options (for exacerbation prevention)? • Add ICS to LABA/LAMA • Change to ICS/LABA plus LAMA • Add Roflumilast to LABA/LAMA f CS/• Add Roflumilast to LAMA plus ICS/LABA 11 Based on combined assessment of airflow limitation, symptoms and exacerbation risk Exacerb cationof ation (FEV1 < 30% predicted) (30% ≤ FEV1 < 50% predicted) GOLD Group C ICS + LABA, or LAMA ICS + LABA +/or LAMA Recommended first choice GOLD Group D ≥2 or ≥1 leading to hospital admission GOLD Grade 4 LAMA + LABA or LAMA + PDE-4i or LABA + PDE-4i ICS + LABA + LAMA or ICS + LABA + PDE-4i or LAMA + LABA or LAMA + PDE-4i Alternative choice Pharmacologic management of COPD GOLD 2015 GOLD Grade 3 12 Risk bationhistory Risk GOLDclassific airflowlimit (50% ≤ FEV1 < 80% predicted) (FEV1 ≥ 80% predicted) LAMA or LABASAMA or SABA p.r.n. GOLD Group A GOLD Group B 1 (not leading to hospital admission) Symptoms CAT ≥10CAT <10 mMRC 01 mMRC ≥2 Breathlessness LAMA or LABA or SABA + SAMA LAMA + LABA GOLD 2015 CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; HRQoL, health-related quality of life; ICS, inhaled corticosteroids; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; mMRC, modified Medical Research Council; PDE-4i, phosphodiesterase type 4 inhibitor; SABA, short-acting β2-agonist; SAMA, short-acting muscarinic antagonist GOLD Grade 2 GOLD Grade 1
  4. 4. 19/04/2016 4 CTS/CHEST Guidelines: AECOPD EVEN EASIER, RIGHT? 2014 CHEST-CTS Guideline: Prevention of Acute Exacerbation of Chronic Obstructive Pulmonary Di COPD Exacerbations: Effects of ICS   (ISOLDE ‐ stratified by FEV1) 2.64 1.86 1.722.0 2.5 3.0 * * Placebo r year) Fluticasone 1.24 1.41 1.24 0.0 0.5 1.0 1.5 Burge et al. Br Med J. 2000; 320:1297-1303. FEV1 (litres) Exacerbations (pe 1.25 ‐ 1.54 >1.54<1.25 14 Impact of ICS on survival without re‐ hospitalisation • Alberta • 6,740 patients • Aged > 65 yrs ICS 29% ehospitalisation 1.0 0.9 0 8 Inhaled steroids Sin DD & Tu JV, AJRCCM 2001; 164: 580-584 • ICS group: 29% relative risk reduction for all-cause mortality and 24% for re-hospitalisation Survivalwithoutre Time from discharge (months) 0.8 0.7 0.6 No inhaled steroids 0 2 4 6 8 10 12 15 TORCH: LABA/ICS Significantly Reduced Rate of  Exacerbations Over 3 Years exacerbations/year 1.13 0.97* 0.93* 0.85*†‡ SALM/FP 25% reduction in exacerbations vs. placebo 0.8 1 1.2 LABA: Long-acting beta2-agonist ; ICS: inhaled corticosteroid SALM: salmeterol; FP: fluticasone propionate SALM/FP: salmeterol/fluticasone propionate *P < 0.001 vs. placebo †P =0.002 vs. SALM ‡P = 0.024 vs. FP Meannumberofe 0 0.2 0.4 0.6 Placebo SALM FP SALM/FP Treatment Adapted from Calverley PM, et al. N Engl J Med. 2007;356:775-789. 16
  5. 5. 19/04/2016 5 0.4 0.3 0.2 erbations/patient TIO + budesonide/formoterol 320/9 µg BID TIO + placebo CLIMB: ICS/LABA + Tiotropium Reduced Severe Exacerbations at 3 Months A reduction in rate of exacerbation by 62% 17 0.1 0.0 0 15 30 45 60 75 90 Days since randomisation Exac Ratio: 0.38 (95% CI: 0.25–0.57) P < 0.001* *Poisson regression adjusted for overdispersionSevere exacerbations were defined as worsening of COPD leading to treatment with systemic steroids (oral or parenteral) and/or hospitalization/emergency room visits. Welte T, et al. Am J Respir Crit Care Med 2009; doi:10.1164/rccm.200904-0492OC. Goal: prevent exacerbations Goal: decrease symptoms Bronchodilate!!! Cough and Sputum: One of the Susceptible Phenotypes for COPD Exacerbators * * p<0.0001 erbationsPerYear 19 Percentwith≥2Exac Burgel P-R, et al. Chest. 2009;135:975-982. How about Roflumilast Proportion of Patients with a Moderate or Severe Exacerbation sal or tio + placebo sal or tio + roflumilast 500 µg 20 16 12 acerbation (%) 16 1111 18 Exacerbation rates were based on a Poisson regression model; Risk ratios (RiR) were based on a log binomial regression model Fabbri LM, et al. Lancet. 2009 Aug 29;374(9691):695-703. n = 83/467 n = 51/466 n = 58/372 n = 42/371 RiR = 0.60 (95% CI 0.43, 0.82) p = 0.0015 RiR = 0.73 (95% CI 0.51, 1.05) p = 0.0867 Salmeterol study Tiotropium study 12 8 4 0 n=83/467 n=51/466 n=58/372 n=42/371 Patients with an exa 1111
  6. 6. 19/04/2016 6 0.60 1.0 REACT – reduction in rate of severe exacerbations (i.e. events leading to hospitalization and/or death) Adding Roflumilast to triple therapy ∆ = -24.3% Rate ratio = 0.757 CI: 0.601, 0.952 p=0.018 All patients Patients with a prior hospitalization Patients without a prior hospitalization ∆ = -34.9% Rate ratio = 0.651 CI: 0.477, 0.887 p=0.007 ∆ = -7.6% Rate ratio = 0.924 CI: 0.669, 1.278 p=0.634 cerbationsper eryear 0.32 0.18 0.24 0.39 0.17 0 0.5 N=319      N=322 N=647     N=647 Analysis of rate of severe exacerbations per patient per year using a negative binomial regression model, ITT Martinez FJ, et al. Presented at ERS 2015; OA482 Martinez FJ, et al. Lancet 2015;385:857-66. Placebo + LABA/ICS Roflumilast + LABA/ICS N=966 N=969 NNT = 12.5 NNT = 4.8 NNT = 100.0 Meanrateofexac patientpe Roflumilast: Incidence of AEs ( 2.5%)* Adverse Event AURA/HERMES 1 year HELIOS 6 months Roflumilast (n=1547) Placebo (n=1545) Tiotropium + Roflumilast (n=374) Tiotropium + Placebo (n=369) COPD 10% 13% 16% 19% Weight loss 10% 3% 6% <1% Diarrhea 8% 3% 9% <1% Nasopharyngiti s 6% 6% 6% 5% Nausea 4% 2% 3% 1% Bronchitis 4% 4% 2% 3% Headache 3% 2% 2% 0% Back pain 3% 2% 2% 1% *Independent of investigator causality assessments Calverley PM, et al. Lancet. 2009 Aug 29; 374(9691):685-94. Fabbri LM, et al. Lancet. 2009 Aug 29;374(9691):695-703. So, where are we? • Tailor our therapy to our patient • Bronchodilate aggressively to improve functionality • Anti-inflammatory to help prevent exacerbations • Reassess over time • But what is the real life situation? • In Canada/ most of the world, there are a large number of patients with COPD currently on ICS! 23 ICS use in COPD (Real life data in Canada) Reza Maleki-Yazdi M. et al. ATS 2015, P551 024
  7. 7. 19/04/2016 7 So, where are we? • Tailor our therapy to our patient • Bronchodilate aggressively to improve functionality • Anti-inflammatory to help prevent exacerbations • Reassess over time • But what is the real life situation? • In Canada/ most of the world, there are a large number of patients with COPD currently on ICS! • Do ICS decrease COPD mortality?? 25 TORCH: All‐Cause Mortality at 3 Years 18 16 14 12 10 ofdeath(%) SALM/FP 17.5% reduction in mortality vs placebo (p=0.052) No significant difference of mortality with ICS SALM = salmeterol FP = fluticasone propionate SALM/FP = salmeterol/fluticasone propionate 8 6 4 2 0 Time to death (weeks) Probabilityo 0 12 24 36 48 60 72 84 96 108 120 132 144 156 Vertical bars are standard errors SALM SALM/FP FP Placebo Adapted from Calverley PMA, et al. N Engl J Med. 2007;356. 26 Case 2 • A different patient with COPD • FEV1 45% • No exacerbations needing steroids in five years • Couple of antibiotics for Sinusitis, did not move into their chest • CAT score: 18 • On triple therapy: ICS/LABA and LAMA • Does this patient need their ICS? • Can you stop it? • If so, how to stop it? 28
  8. 8. 19/04/2016 8 Side effects of ICS in COPD  and type of evidence  Randomised controlled trial Observational study Systematic review Pneumonia X X X Tuberculosis X Bone fracture (no effect on fracture risk) X X fracture risk) Skin thinning/ easy bruising X Cataract X Diabetes X Oropharyngeal candidiasis X X X Price D. Prim Care Respir J 2013; 22: 92-100. 29 Risk of Diabetes1 Risk of Bone Fracture2 3.5 3.0 2.5 atio 2 Loke YK et al Thorax 2011;66(8):699-708 31 Meta-analysis of studies including 17,513 patients with COPD 2.0 1.5 1.0 0.5 0 250 500 750 10001250 1500 17502000 Daily dose in fluticasone equivalents (mcg) Rate Ra 1. Suissa S, et al.: Am J Med 2010; 123(11):1001‐6.  Several recent studies with varying populations/design have compared bronchodilator therapy with LABA/ICS OPTIMO – in patients with moderate COPD (FEV1 >50% predicted) and <2 exacerbations, currently maintained on ICS for past year, ICS withdrawal was not associated with increased exacerbations, difference in lung function or CAT (Rossi, et. al. Resp Res 2014; 6 month “real-world” study of ICS withdrawal - decision to maintain or withdraw ICS at discretion of clinician) INSTEAD – in patients with moderate COPD (FEV1 40-80% predicted) and no recent exacerbations, maintained on SFC for > 3 months, indacaterol was NI on lung function (t h FEV1 9 l) d id f i d b ti(trough FEV1 = -9 ml) and no evidence of increased exacerbations (Rossi, et. al. ERJ 2014; 26 week randomized, parallel, DB study of withdrawal of ICS from SFC 500/50 to Indacaterol 150 µg) ILLUMINATE - in patients with moderate COPD (FEV1 40-80% predicted) and no recent exacerbations, QVA (LABA/LAMA) improved lung function (FEV1AUC0-12 138ml, p<0.001) and TDI vs LABA/ICS (Vogelmeier, et. al. Lancet Resp Med 2012, 26 week randomized, parallel, DB study of QVA149 vs SFC 500/50) LANTERN- in symptomatic patients with moderate to severe COPD (FEV1 30-80) and 0-1 exacerbations on SFC changed to QVA (LABA/LAMA) showed improved lung function (FEV1 AUC0-4h 122 mL; p<0.001) and decreased exacerbations (HR 0.65 p .028) (Zhong et al. Int J COPD 2015. A randomized control study of QVA 149 vs SFC)32
  9. 9. 19/04/2016 9 Wisdom Estimated probability of moderate or severe COPD exacerbation 0.6 0.4 tedprobability 0.3 0.5 Hazard ratio, 1.06 (95% CI, 0.94–1.19) P=0.35 by Wald’s chi-squared test 1243 1242 1059 1090 927 965 827 825 763 740 646 646 694 688 615 607 581 570 14 19 No. at risk ICS ICS withdrawal 0.2 0.0 0 6 12 18 24 30 36 42 48 54 ICS ICS withdrawal Estima Time to events (weeks) 0.1 Magnussen H et al. N Engl J Med DOI 10.1056/NEJMoal407154 -20 0 0 6 12 18 52 SE)change FEV1(mL) Week ICS 38 mL 100 µg BID 0 µg (placebo)250 µg BID Mean change from baseline in lung function: FEV1 ICS withdrawal -80 -60 -40 Adjustedmean(S frombaselinein **p<0.01; ***p<0.0001 vs ICS; restricted maximum likelihood repeated measures model; baseline values 970 mL for ICS, 981 mL for ICS withdrawal ICS ICS withdrawal *** ** 1223 1218 1135 1135 1114 1092 1077 1058 970 935 n ICS withdrawal ICS 43 mL Magnussen H et al. N Engl J Med DOI 10.1056/NEJMoal407154 Time to first severe and any severity on- treatment COPD exacerbation 0.975 1.202 1.482 Time to first severe COPD exacerbation 36 Hazard ratio Time to first COPD exacerbation (any severity) On-treatment exacerbations assessed; hazard ratio from Cox proportional hazards model adjusted for baseline FEV1 Favours ICSFavours withdrawal Magnussen H et al. N Engl J Med DOI 10.1056/NEJMoal407154
  10. 10. 19/04/2016 10 So, definitely not with patients with Asthma-COPD Overlap Syndrome (ACOS) • Older patients (≥45 years) with chronic airflow limitation • Bronchodilator response (>12%, >400 mL) but not fully reversiblebut not fully reversible • Family or personal history of asthma, atopy or allergic rhinitis • Asthmatic with smoking history or biomass exposure Dr. Don Sin. 16th Annual Respiratory Medicine Update, 8 February 2014. Papaiwannou A, et al. J Thoracic Dis 2014;6(S1):S146-S151. FLAME: QVA149 vs.SFC in terms of rate of all COPD exacerbations (mild/moderate/severe) for 52 weeks • moderate to very severe COPD (GOLD 2011), • a smoking history of ≥10 pack-years, • one or more 1 COPD exacerbation requiring systemic corticosteroids and/or antibiotics in the previous 12 months.38 Initial results: press release 39 Does it depend on the eosinophil?
  11. 11. 19/04/2016 11 Changes in post- bronchodilator FEV1 in patients with or without sputum eosinophilia EV1(L) 0.10 *,# 0.15 *,# With sputum eosinophilia Without sputum eosinophilia SputumSputum eosinophiliaeosinophilia and responseand response toto budesonidebudesonide in COPD:in COPD: ICSICS worksworks in COPDin COPD withwith sputumsputum eosinophiliaeosinophilia Leigh et al. ERJ 2006;27:964-971 ∆Post-BDFE -0.05 0.05 0.00 PrednisoneBudesonidePlacebo *p<0.05 within group (sputum eosinophilia) vs placebo #p<0.05 between groups If blood eosinophils predict response to ICS, what is the appropriate cutoff? 42 Do eosinophils predict response to ICS beyond exacerbations? Chiesi data: 43 | QVA Update | Robert Fogel | Canada Advisory Board, Sep 26, 2015 |Business Use Only | Material ID Code:
  12. 12. 19/04/2016 12 Taking patients off ICS in COPD 45 Risk of recurrent pneumonia rises with current ICS use,  not linked to past ICS use 46 Eurich DT et al. Clin Infect Dis. 2013; 57 (8): 1138-1144 Discontinuation of ICS reduced the risk of pneumonia associated with long-term ICS use Risk of pneumonia following ICS withdrawal Retrospective analysis using the Quebec health insurance databases for COPD patients discontinued from ICS during 1990-2005 (n=103,386). COPD=chronic obstructive pulmonary disease; ICS=inhaled corticosteroid. Suissa S et al. Chest. 2015;148(5):1177-1183.
  13. 13. 19/04/2016 13 Are they eligible for ICS withdrawal? If no reason they should stay on ICS... PREDICTIVE ACCURACY OF PREDICTING ≥ 2 EXACERBATIONS IN OUTCOME YEAR Daryl Freeman GP Mundesley North Norfolk,  Clinical Director East of England SCN  (respiratory). IMPACT study REG sponsored Odds ratios for ≥ 2 exacerbations from logistic regression in patients with CAT score available (n=3,713) total population n=3,713 Odds Ratio (95% CI) P-value Baseline number of exacerbations 1.79 (1.68-1.92) <10-10 19% of patients had ≥ 2 exacerbations FEV1 % predicted per 10% lower 1.06 (1.01-1.12) 0.02 Female gender 1.32 (1.10-1.58) 0.003 Asthma record ever 1.19 (1.00-1.43) 0.052 Nasal polyps ever 2.02 (1.24-3.29) 0.005 Eosinophilia (≥ 0.5 x 10-9 ) in non-smokers 1.42 (1.03-1.97) 0.03 CAT score per 10 units higher 1.26 (1.14-1.40) 1 x 10--5
  14. 14. 19/04/2016 14 There may be other factors we can use • To predict exacerbations • To predict response to ICS • To predict response to stopping ICS o New REG study being done on those with COPD whoy g have stopped ICS and outcomes o -unfortunately, numbers are small in GPRD currently. What does a personalized COPD assessment look like? • Symptoms: CAT, MRC, CCQ • Are they at risk of attack? – Previous exacerbations, chronic bronchitis, lung function, GERD • Lung function • Still smoking? • Is there Asthma there? Allergy, rhinitis hx? • Comorbidities: GERD, Depression, Osteoporosis, Anxiety • Adherence – Refill prescription rates • Inhaler technique • Pulmonary Rehabilitation • Biomarkers: eosinophils (blood and sputum), FENO? • Biologics..coming? • Self management plan • Pathway to further treatments: oxygen, LVRT, transplant.EOL care! 54 Thank you for any thoughts you have about this study! www fpagc comwww.fpagc.com for4kids@gmail.com

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