Acute Care of COPD: Gaps in our knowledgeRobert A. Wise, M.D.

May 20, 2010

Outline of talk

• Importance of COPD exacerbations• Current treatments• Areas for improvement• Significant knowledge gaps• Strategies for improving care

Importance of COPD exacerbations

20%-24%

5%-10%

22%-32%

13%-33%

Hospital mortality

Hospital mortality

Relapse (repeat ER visit)

Treatment failure rate

In hospitalized patients

In ER patients

In ICU patients

In outpatients

Outcome of Exacerbations – Room for Improvement

• Seneff et al. JAMA. 1995; 274:1852-1857; Murata et al. Ann Emerg Med. 1991;20:125-129; Adams et al. Chest. 2000;117:1345-1352.

Exacerbations Affect Quality of Life

Seemungal TA, et al. Am J Respir Crit Care Med. 2000;161:1608–1613.

* P<0.05 versus lower exacerbation rate

49 5164

34

6272

79

48

0102030405060708090

100

Total SymptomsActivities

Activities Impacts

SGR

Q S

core

0-2 Exacerbations 3-8 Exacerbations

*

**

*

Baseline Rate of Change in SGRQ (control group)and Exacerbation Frequency During the UPLIFT Trial

0

0.5

1

1.5

2

2.5

Rat

e of

cha

nge

in S

GR

Q to

tal s

core

(uni

ts/y

r)

0 >0 to 1 >1 to 2 >2

SGRQ, St George’s Respiratory Questionnaire

Exacerbation Rate (per patient-year)

High Mortality Following Emergency Department Visit for COPD Exacerbation

Kim S, et al. COPD. 2006;3:75-81.

5%9% 11%

16%

23%

32%

39%

0%5%

10%15%20%25%30%35%40%45%

30 Days 60 Days 90 Days 180Days

1 Year 2 Years 3 Years

Time Following Visit

Perc

ent M

orta

lity

7

Effects of Repeated Exacerbations on Survival

Time (months)

0.0

0.2

0.4

0.6

0.8

1.0

0 10 20 30 40 50 60

Pro

babi

lity

of s

urvi

ving

p<0.001

p=0.07

3-4 exacerbations

1-2 exacerbations

No exacerbationProspective study

Cohort of 304 males

Exacerbations requiringhospital treatmentduring the year

Follow-up over 5 years

Soler-Cataluña JJ et al. Thorax 2005;64:925-31

2010 projected Health Care Costs for COPD

Hospital Care, $13.2

Physican Fees, $5.5

Prescriptions, $5.8

Home Health Care, $1.3

Long-term Care, $3.7

Hospital Care Physican Fees PrescriptionsHome Health Care Long-term Care

.

Cost in BillionsTotal = $29.5

Recurrence of Exacerbations

• 27% of first exacerbations associated with second exacerbation in 8 weeks

• 34% of 1,221 hospitalized patients in UK readmitted within 3 months (range 5-65%)

C M Roberts et al.Thorax 2002;57:137–141Hurst et al. Am J Respir Crit Care Med 2009; 179:369

Effects of Repeated Exacerbations on Recovery of QoL

•6-month prospective study

•After one exacerbation treated with antibiotics

•Followed for 26 weeks.

•31% had recurrent exacerbation

•N =Patients remaining in the study at that time point

No new exacerbation

With a further exacerbation

N=133

SGR

Q to

tal s

core

N=133

N=221N=233

N=280

N=116N=115

N=299

30

40

50

60

Presentation 4 weeks 12 weeks 26 weeks

• Spencer S. et al. Thorax 2003;58:589

Recurrent admissions after hospital discharge –the critical issue for COPD in 2010

• 10% of patients account for 70% of costs• Medicare reimbursement schedule makes

hospitals interested• High mortality in frequent exacerbators• Wide range of readmissions at hospitals (5-65%)• Event rate high enough to study easily• Outcome measure easy to count• We can probably do something about it

Triple therapy – Fewer hospitalizations

Tiotropium (n=156)

Tiotropium + Salmeterol

(n=148)

Tiotropium + Salmeterol + Fluticasone

(n=145)% Pts with 1 or

more exacerbation(s)

62.8 % 64.8% 60.0%

Total Exacerbations 222 226 188

Exacerbations with Hosp

49 38 26*

Aaron et. al. Ann Int Med. 2007

Checklist for Acute Coronary Syndrome Discharge

ASA ACE / ARBBeta-blockerStatinRehabilitation / Exercise prescriptionSmoking cessation treatment / adjunctsHypertension treated

Checklist for AE-COPD Discharge

Has he got a way to get home?

Checklist for AE-COPD Discharge

ICS / LABALAMAInhaler instruction with actual devicesOxygen instructionSteroid taper instruction and monitoringRehabilitation / Exercise prescriptionSelf-management care planFollow-up care planDrug affordability

Need for economic analyses?

Cost-Utility Analyses - TORCH• Salmeterol-Fluticasone $33,865 / QALY• Salmeterol alone $20,792 / QALY• Fluticasone – null

• Salmeterol-Fluticasone $52,046 / QALY• Salmeterol alone $56,519 / QALY

• Salmeterol-Fluticasone $43,600 / QALY• Salmeterol alone $197,000 / QALY

Earnshaw et al. Cost-effectiveness of fluticasone propionate/salmeterol (500/50 microg) in the treatment of COPD. Respir Med. 2009 Jan;103(1):12-21.Oba Y.et al. Cost-effectiveness of salmeterol, fluticasone, and combination therapy for COPD. Am J Manag Care. 2009;15:226-32Briggs A et al. Is treatment with ICS and LABA cost-effective for COPD? Multinational economic analysis of the TORCH study. Eur Respir J. 2010;35:532-9

Etiology of Exacerbations of COPD

• Obaji A, Sethi S. Drugs and Aging. 2001;18:1-11

e.g., air pollution. climate change, noncompliance,etc.

Bacteria

Bacteria and virus

Virus

Non-infectious

Immunization

• Influenza vaccination• Pneumococcal vaccination

Pneumococcal Vaccine Dec-March

0.59 0.53

1

1.68

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

I+/P- I+/P+ I-/P- I-/P+Vaccination status

Rel

ativ

e R

isk

of D

eath

P = Pneumococcal vaccineI = Influenza vaccinen = 177,120

Adjusted for age, gender,Co-morbidities

**

*

Schembri S. et al. Influenza but not pneumococcal vaccination protects against all-cause mortality in patients with COPD. Thorax. 2009;64:567-72.

Pneumococcal Vaccine Apr-Nov

0.980.88

1

1.29

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

I+/P- I+/P+ I-/P- I-/P+Vaccination status

Rel

ativ

e R

isk

of D

eath

P = Pneumococcal vaccineI = Influenza vaccinen = 177,120

Adjusted for age, gender,Co-morbidities

*

Schembri S. et al. Influenza but not pneumococcal vaccination protects against all-cause mortality in patients with COPD. Thorax. 2009;64:567-72.

Key questions

• Is it harmful to give pneumococcal vaccine?

• Is it beneficial to give influenza vaccine for hospitalized COPD patients on steroids?

Helium-Oxygen Mixtures

• Improves exercise tolerance and dynamic hyperinflation in COPD

• Does not improve bronchodilator response as carrier for nebulizer

• Question: Can Heliox by inhalation or by NIPPV prevent intubation or improve outcomes compared with NIPPV alone?

Rodrigo G, Pollack C, Rodrigo C, Rowe B. Heliox for treatment of exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2002;(2):CD003571.

Heliox and PPV reduces work of breathing during COPD exacerbations

Jaber S, et al. Noninvasive ventilation with helium-oxygen in acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;161:1191-200

Heliox and PPV decrease PaCO2 during COPD exacerbations

Jaber S, et al. Noninvasive ventilation with helium-oxygen in acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;161:1191-200

Self – Management / Case ManagementCan’t hurt, can it?

Self Management – Cochrane Systematic Review

• … because of heterogeneity in interventions, study populations, follow-up time, and outcome measures, data are still insufficient to formulate clear recommendations regarding the form and contents of self-management education programmes in COPD. There is an evident need for more large RCTs with a long-term follow-up, before more conclusions can be drawn.

Effing et al. Self-Management education for patients with COPD. Cochrane Review 2007 4:CD002990

Care Management in COPD

N = 743 ptsUsual Care vs Disease Management•1.5 hr education•Action plan for self treatment•Monthly f/u calls from case manager•Results: All cause hospitalizations decreased 28%

Rice KL, Disease Management Program for Chronic Obstructive Pulmonary Disease: A Randomized Controlled Trial. Am J Respir Crit Care Med. 2010 Jan 21. Epub.

Mucolytics

• Meta-analysis of 28 trials with 7,042 pts.– 21% reduction in exacerbation rate– 44% reduction in days of disability– 1.93 OR of remaining exacerbation free– Possibly increased benefit in patients NOT on

ICS

Poole P, Black PN. Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Reviews 2010, CD001287.

Carbocysteine – PEACE Trial

Zheng JP. . Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study. Lancet. 2008;371::2013-8

•Carbocysteine - 1.01 exac/yr

•Placebo – 1.35 exac/yr

•P = 0.004

•No effect for 3 months

•No interaction with ICS, smoking status

Corticosteroids for COPD exacerbation in hospital

Niewoehner DE, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. VA Study Group. N Engl J Med. 1999;340:1941-7

Hospital daysDecreased from9.7 to 8.5 in steroid group

Oral steroids after ER visit for COPD

Aaron SD, et al.. Outpatient oral prednisone after emergency treatment of chronic obstructive pulmonary disease. N Engl J Med. 2003;348:2618-25

Steroid Resistance in COPD

• Induced by oxidative / nitrosative stress on HDAC2

• Reduced by theophylline, anti-oxidant treatments

• Can adjuvants be used to augment corticosteroid efficacy?

Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ. Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med. 2004 6;200:689-95

Etiology of Exacerbations of COPD

Obaji A, Sethi S. Drugs and Aging. 2001;18:1-11

e.g., air pollution. climate change, noncompliance,etc.

Bacteria

Bacteria and virus

Virus

Non-infectious

Inhalation during swallowing in COPD

0%

2%

4%

6%

8%

10%

12%

14%

Cookie Pudding

COPD Control

O.R. = 4.4, p < 0.002 O.R. = 1.23, p = 0.44

Gross RD et al. The coordination of breathing and swallowing in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;179:559-65

Can we prevent exacerbations with aspiration precautions,

swallowing training, or dietary modification?

Etiology of Exacerbations of COPD

• Obaji A, Sethi S. Drugs and Aging. 2001;18:1-11

e.g., air pollution. climate change, noncompliance,etc.

Bacteria

Bacteria and virus

Virus

Non-infectious

Antibiotics

Zpak is a simple prescription to write because it comes in a self-explanatory packet.--- Indiana School of Optometry

Erythromcycin decreases frequency, severity and time to first exacerbation

Seemungal TA, et al. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. 2008;178:1139-47

•N = 109 pts

•Erythromycin 250mg bid

•36% reduction in exacerbations

Clinical trial of doxycycline in COPD flares treated with corticosteroids

• No difference in 30 day outcomes• Improved efficacy at day 10

Daniels JM, et. al.. Antibiotics in addition to systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;181:150-7

Impaired macrophage clearance of bacteria in COPD reversed with sulforaphane

0

50

100

150

200

250

Vehicle Sulforaphane

% In

ocul

ated

CFU

s P1P2P3P4P5P6P7P8P9 0

50

100

150

200

250

Vehicle Sulforaphane%

Inoc

ulat

ed C

FUs P6

P7P8P9P10P11P12P13P14

PA NTHI

*

*

Courtesy of C. Harvey, S. Biswal

Key Messages

• Recurrent hospital admissions are a major lever point for improving COPD care

• The future probably lies with real-world studies of combined therapies

• Both administrative and pharmacological strategies need to be explored conjointly

Thank you!