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COPD EXACERBATIONS AND HOSPITAL ADMISSIONS –HOW CAN WE PREVENT
THEM?
Wisia Wedzicha
National Heart and Lung Institute,
Imperial College London, UK
Presenter Disclosures –Wisia Wedzicha
All disclosures prior to Jan 2015 – from Jan 2015, I am not accepting any honoraria from industry
Lecture Fees: Novartis, GSK, Boehringer, Pfizer, AstraZeneca
Advisory Boards: Novartis, Boehringer, Takeda, Pfizer, Astra Zeneca
Industry sponsored grants - Glaxo Smith Kline, Takeda, Johnson & Johnson, Vifor Pharma
• 3,000,000 estimated UK COPD patients (1,000,000
diagnosed)
• 24 million working days lost each year
• £800m direct healthcare costs – double the cost of
asthma
• COPD accounts for 10% of all hospital admissions
• 30% of COPD admissions readmitted within 3 months
• 10% of COPD patients die within 3 months of being
admitted
• In UK 25,000 – 30,000 deaths per year
• Associated co-morbidities
COPD - Statistics
Triggers of COPD Exacerbations
Wedzicha JA, Seemungal TA. Lancet 2007
Triggers
Bacteria Viruses Pollutants
EffectsInflamed COPD airway
Greater airway inflammation
Systemic inflammation Bronchoconstriction, edema, mucus
Expiratory flow limitation
Dynamic hyperinflationExacerbation symptoms
Cardiovascularcomorbidity
t
London December 5th 1952 London 2nd January 1954
0
10
20
30
40
O N D J F M A M J J A S
Y1
Y3
Y5
ALL EXACERBATIONS BY MONTH OF STUDY: Data from East London COPD
cohort
ECLIPSE ‒ Survival Curves Relatedto Prior Hospitalization History
Müllerova H et al. Chest 2015
Surv
ival (%
)
0 6 12 18 24
No COPD hospitalization, Year 1 (n=1,676)
COPD hospitalization, Year 1 (n=289)
Year 1 status N (censored) Year 2 survival (95% Cl)
No COPD Hosp 1,676 (1590) 94.9% (93.8%, 95.9%)
≥1 COPD Hosp 289 (247) 85.4% (81.4%, 89.6%)
95
90
85
80
75
100
Months observed
1.Adapted from Hurst JR, Vestbo J, Anzueto A, et al. N Engl J Med 2010;363:1128-38.
DISTRIBUTION OF EXACERBATIONS IN ECLIPSE
7%
22%18%
33% 33%
47%
GOLD Stage 2
(moderate)
GOLD Stage 3
(severe)
GOLD Stage 4
(very severe)
0
10
20
30
40
50
Pa
tie
nts
(%
)
39%
60
52%
62%
Hospitalized for exacerbation in Year 1
≥2 exacerbations in Year 1
≥1 exacerbation in Year 1
Disease severity
(2,138 patients in the ECLIPSE cohort study)
Strategies to prevent exacerbations
Pharmacological:
• Bronchodilators (LABA/LAMA)• Inhaled corticosteroids
• Combination of above• Dual bronchodilators • Macrolide Antibiotics
• Other antibiotics• Roflumilast (PDE4 inhibitor)
Non-pharmacological:
• Smoking cessation• Pollution control
• Pulmonary Rehabilitation • Vaccination
• Anti-viral agents• Noninvasive ventilation (NIV)
• Optimal therapy of acute event
Symptoms and COPD exacerbationsare closely related
Seemungal TA, et al. Am J Respir Crit Care Med 2000
70
60
50
40
30
20
10
−14 −9 −4 1 6 11 16 21 26 31
Exacerbations with increased dyspnea (%)
Days around onset of exacerbation
Symptom onset and early start of therapy
Wilkinson et al. Am J Respir Crit Care Med 2004
Patients who receive prompt therapy after symptom onset are likely to recover more rapidly than are patients whose treatment is delayed
24
18
12
6
0
0 7 14
Delay between onset and treatment (days)
Sym
pto
m r
eco
ve
ry t
ime
(d
ays)
p<0.001
Exacerbations ‒ Reported and Unreported
Seemungal TA et al. Am J Respir Crit Care Med 1998
50% not reported to
study team
(UNREPORTED
EXACERBATIONS)
Total Reported Unreported
Num
ber
of
exacerb
ations
RELATION BETWEEN EXACERBATION THERAPY AND HOSPITALISATION
P<0.04
Wilkinson et al AJRCCM 2004
ACTIVITY AND EXACERBATION REPORTINGAl Ahmari et al BMC Pum Med 2014
TELEHEALTH STUDY(EDINBURGH – TELESCOT)
Pinnock et al BMJ 2013
HRV load log 10pfu·mL-1
0.00.51.01.52.02.53.03.54.04.5
ExP Day 3 Day 7 Day 14Day 35
Sore throatNo sore throat
HRV load log 10pfu·mL-1
0.00.51.01.52.02.53.03.54.04.5
ExP Day 3 Day 7 Day 14Day 35
ColdNo cold
Time course of human rhinovirus load changes at COPD exacerbations
George SN, et al. Eur Respir J. 2014;44:87-96.
BACTERIA DETECTED AT EXACERBATION ONSET
NO BACTERIA DETECTED AT EXACERBATIONONSET
HRV load log
10pfu·mL-1
0.00.5
1.01.52.02.5
3.03.5
4.0
ExP Day 3 Day 7Day 14Day 35
BacteriaHRV
012
34
5
6
78
Bacterial load log
10cfu·mL-1
HRV load log
10pfu·mL-1
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
ExP Day 3 Day 7Day 14Day 35
BacteriaHRV
012
34
5
6
78
Bacterial load log
10cfu·mL-1
Relationship between viral and bacterial infection during exacerbation recovery
George SN, et al. Eur Respir J. 2014;44:87-96.
AMX 500/125 mg n/total (%)
PBO
n/total (%)p-value
Primary outcomes
Clinical cure at Days 9–11
Clinical success at Days 9–11
117/158 (74.1)
143/158 (90.5)
91/152 (59.9)
123/152 (80.9)
0.016
0.022
Secondary outcomes
Clinical cure at Day 20
Clinical success at Day 20
Days until next exacerbation, median (IQR)
Change of peak expiratory flow from basaland EOT visits, l/min, mean (SD)
129/158 (81.6)
143/158 (90.5)
233 (110–365)
52.8 (61.8)
103/152 (67.8)
122/152 (80.3)
160 (66–365)
38.5 (56.0)
0.006
0.015
0.015
0.039
AMX = amoxicillin/clavulanate; EOT = end of treatment
IQR = interquartile range; PBO = placebo
Summary of clinical efficacy results at end-of-treatment visit in the intention-to-treat population
Llor et al. Am J Respir Crit Care Med 2012
Kaplan-Meier survival analysis of exacerbation-free interval in patients with clinical success at Days 9 to 11
0 4000
1.0
Days after incusion
Pa
tie
nts
fre
e o
f e
xa
ce
rba
tio
n (
%)
0.8
0.4
0.2
300200100
0.6
Placebo
Amoxicillin/clavulanate 500/125 mg
Placebo-censored
Amoxicillin/clavulanate-censored
Treatment group
Llor et al. Am J Respir Crit Care Med 2012
Corticosteroid-treated group
(prednisolone 30 mg q.d.)
Placebo group
AdmissionDay 1 Day 2 Day 3 Day 4 Day 5Discharge–25
100
75
50
25
0
Time point of measurement
Oral steroids at COPD exacerbationdata from hospital admissions
Davies et al. Lancet 1999
Short-term vs conventionalsteroids: REDUCE trial
B
Proportion of patients without re-exacerbation
Proportion of patients alive
A
Leuppi et al. JAMA 2013
COMPARISON OF VILANTEROL/FLUTICASONE FUROATEVERSUS VILANTEROL ON EXACERBATIONS with
DIFFERENT COMBINATION DOSAGES
Dransfield et al Lancet Resp Med 2014
FORWARD STUDY – STRATIFICATION BY BLOODEOSINOPHIL COUNT
Siddiqui et al AJRCCM 2015 in press
INSPIRE ‒ Exacerbation Rates at 2 YearsFEV1 <50% Predicted
Exacerbation rates were similar with salmeterol/fluticasone propionate
and tiotropium in the INSPIRE study
Wedzicha JA et al. Am J Respir Crit Care Med 2008;177:19–26
Ra
te p
er
ye
ar
All exacerbations
2.0
1.5
1.0
0.5
0.0
p=ns
QVA149 Significantly Improved Mean Trough FEV1 vs Glycopyrronium and
Tiotropium Over 64 Weeks (Secondary Objective)
Wedzicha JA, et al. Lancet Respir Med 2013
*At all time points, p<0.0001 vs glycopyrronium and OL tiotropium
Data are least-squares mean ±±±± SE; OL = open label
1.10
OL tiotropium 18 µg q.d.
QVA149110/50 µg q.d.
Glycopyrronium 50 µg q.d.
1.05
1.00
0.95
0
**
**
* *
Baseline 4 12 26 38 52 64
Tro
ug
h F
EV
1 (l)
Time (weeks)
0.90
Glycopyrronium
50 µg q.d.
Rate of Moderate or Severe COPD Exacerbations
Wedzicha JA, et al. Lancet Respir Med 2013OL = open label
12% reduction, p=0.038 (primary endpoint)
10% reduction, p=0.096 (secondary endpoint)
OL tiotropium
18 µg q.d.
QVA149
110/50 µg q.d.
1.00
0.90
0.800
0.95
0.85
An
nu
al
rate
of
mo
de
rate
or
se
ve
re
CO
PD
ex
ac
erb
ati
on
s
QVA149 (ULTIBRO) significantly increased timeto first moderate or severe COPD exacerbation vs SFC(Salmeterol/Fluticasone)
SFC = salmeterol/fluticasone propionateZhong N, et al. Int J Chron Obstruct Pulmon Dis 2015
Hazard ratio, 0.65 (95% CI 0.44, 0.95)p=0.028
0 43 85 127
10
20
0
30
40
Pro
babili
ty o
f exacerb
ation (
%)
184
DaysPatients with exacerbation (%)QVA149 0 12 (3.3) 20 (5.5) 31 (8.6) 43 (12.1)SFC 0 24 (6.6) 38 (10.5) 48 (13.4) 67 (18.9)
QVA149 110/50 µg q.d. SFC 500/50 µg b.i.d.
NEJM 2014
Effect of Azithromycin on the airway immune response of COPD patients
Wenzel et al. NEJM 2012
Time to First Exacerbation (Days)
4003002001000
Cu
m S
urv
iva
l
1.0
0.8
0.6
0.4
0.2
0.0
MACROLIDES – TIME TO 1ST EXACERBATIONSeemungal et al AJRCCM 2008
ERYTHROMYCIN
PLACEBO
P=0.02
Symptom Duration is responsive to Therapy (Macrolide Study)
Seemungal et al. AJRCCM 2008
MACROLIDE (AZITHROMYCIN) STUDYPROPORTION OF PARTICIPANTS FREE OF ACUTE EXACERBATIONS OF COPD
Albert RK et al. N Engl J Med 2011;365:689-698.
EFFECT OF 3 MONTH THERAPY WITH ANTIBIOTICSON BACTERIAL RESISTANCE
Brill S et al Thorax 2015
Reduction of mortality with noninvasive ventilation in
acute hypercapnic respiratory failureBrochard et al NEJM 1995
P<0.05
P<0.02
Plant et al Lancet 2000
Bott et al Lancet 1993
Kings, Southampton, London Chest
Roberts CM et al Thorax 2011
Inpatient mortality – acute exacerbations of COPD
Data from National Audit
J Meecham Jones et al : Am J Respir Crit Care Med 1995
O2 + NPSV
100
p=0.03
p=0.007
O2 AloneRun-in
p=0.52
80
60
40
20
0
Mean
SG
RQ
Sco
re
Quality of Life – Randomised cross over study of
long-term non-invasive ventilation with oxygen for
Hypercapnic COPD
Lancet Resp Med 2014
Thorax 2014
ROFLUMILAST AND EXACERBATIONS(FEV1<50% predicted, Chronic bronchitis, exacerbation history)
Martinez F et al Lancet 2015
ROFLUMILAST AND SEVERE EXACERBATIONS
Martinez F et al Lancet 2015
Stablestate
Aortic Pulse Wave Velocity at Exacerbation
Patel AR et al. Am J Respir Crit Care Med 2013
12.5
Mean +
/–1S
E a
ort
ic p
uls
e w
ave v
elo
city (
m/s
)
0.0
9.5
10.0
10.5
11.0
11.5
12.0
Exacer-bation
Day 3 Day 7 Day 14 Day 35
Airway infection
No airway infection
Dransfield MT, et al. Thorax 2008;63(4):301–305
Quint JK, et al. BMJ 2013;347:f6650bb = beta blocker; MI = myocardial infarction
THERAPY OF BRONCHITIS
““““For those who can afford it a seasonable
change to one of the Mediterranean health
resorts, or to Rome or Egypt is highly to be
recommended…””””
Part 2, Chapter 1, Page 199
““““Next to avoiding a fatal issue, our efforts
must be directed to prevent the case going on
to chronic bronchitis, especially in those who
have had previous attacks””””
““““Catching colds is a far more important cause
of bronchitis than pneumonia…””””
Treatment of Exacerbations – from 1878!