Giftedness: Understanding Everyday Neurobiology for Self-Knowledge
Utilising real-world evidence to achieve precision medicine in COPD
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. 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. 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 01 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
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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. 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. 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. 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. 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. 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. 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. 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. 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. 19/04/2016
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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. 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