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!