1. FIFTH CONGRESS OF THE MACEDONIAN RESPIRATORY SOCIETY
Ohrid, 26-29.September,2012
Realistic and possible abilities in prevention
of COPD exacerbation
Dejan Žujović
Municipal Institute for Lung Diseases and Tuberculosis
Belgrade

2. Disclosure
Speaker fees from: GSK, Pfizer, Takeda-Nycomed,
Merck, AstraZeneca, Boehringer Ingelheim, Sanofi
Aventis, MSD.
I have no, real or perceived, conflicts of
interest that relate to this presentation.

3. Effect of acute exacerbations of COPD
(AECOPD) versus myocardial infarction
(MI) on survival
Mortality at 12 months following hospitalization for an exacerbation of
COPD is between 20% and 40%. This is much worse than the mortality
observed following hospital admission with an acute MI, whether or not
patients received acute reperfusion therapy
Halpin D. Mortality in COPD: Inevitable or Preventable? Insights from the Cardiovascular Arena. COPD: Journal of Chronic Obstructive Pulmonary Disease, 2008;5:187–200

4. Proper treatment of AECOPD
as prevention of future
exacerbations?

5. AECOPD - High readmission rates
2011, St. George’s Hospital
N=577
218 episodes with >1 admission
47% readmissions within 30 days
Nearly half of the patients were
readmitted within 30 days

6. Quality of Care in Hospitalized COPD
Patients
Retrospective cohort study of 360 US
hospitals involving 69,820 patients
hospitalized for AECOPD
66% received all recommended Rx
– O2, bronchodilatators, CS, antibiotics
45% received non-recommended Rx
33% received “ideal” care
Lindenaurer PK, et al. Ann Intern Med. 2006;144:894-903.

7. Antibiotic treatment is associated with
reduced risk of a subsequent AECOPD: an
historical population based cohort study
Roede BM et al. Thorax. 2008;63:968-973.

8. Outcomes With Antibiotic Therapy in
Patients Hospitalized With Exacerbations:
Retrospective Cohort Study
Early Antibiotics No/Late Antibiotics
14
P<0.001
12
10 P<0.001
8
6
4
P<0.001
2
0
In-hospital Mortality Treatment Failure Readmission Within
30 Days for COPD
N= 84 621 patients
Rothberg MB, et al. JAMA.2010; 303(20); 2035-2042

9. Optimizing antibiotic selection in
treating COPD exacerbations
N=572
5 days moxifloxacin PO 400mg od
vs.
7 days amoxicillin PO 500mg tds or clarithromycin PO 500mg bd or cefuroxime-axetil PO 250mg bd
Life-table analysis of time to the first composite event (treatment failure, and/or new exacerbation and/or
any further antibiotic treatment) stratified according to the time of the last exacerbation prior to
randomisation.
AECB > 6 months AECB ≤ 6 months
Moxifloxacin Moxifloxacin
Comparator Comparator
P=0.01
Siddiqi A, Sethi S. Int J Chron Obstruct Pulmon Dis. 2008 March; 3(1): 31–44.

10. Analysis of hospitalizations for COPD
exacerbation: opportunities for improving
care
 All patients hospitalized with acute exacerbation of COPD
between January 2005 and December 2006 at 5 New York City
hospitals
 1285 unique patients with 1653 hospitalizations
 systemic steroids (85%), bronchodilators (94%) and antibiotics
(80%)
On discharge, only 46.0% were prescribed
maintenance bronchodilators and 24% were not
prescribed any inhaled therapy
Yip NH, et al. COPD. 2010 Apr;7(2):85-92.

11. Strategies aimed at preventing
exacerbations
Proven efficacy Questioned efficacy
Smoking cessation Theophyllines
LABAs: salmeterol, formoterol Prophylactic antibiotic in selected
patients
Tiotropium
Immunomodulators
Combination therapy: LABA/ICS
Mucolytic agents
Anti-influenza vaccine
Antioxidants
Antipneumococcal vaccine#
Rehabilitation
Physical exercise
Self-management plans #: efficacy demonstrated in prevention of pneumonia but not in the
prevention of exacerbations
LVRS in selected patients
Miravitlles M. Prevention of exacerbations of COPD with pharmacotherapy. Eur Respir Rev. 2010.19;116:119-126

12. Characteristics of patients with
AECOPD treated in our department
Demonstration of use Written instructions in
Smoking
of inhalation therapy case of exacerbation
12%
31% Current smoker 28%
Ex-smoker 37% No No
Never smoker 63% Yes Yes
57%
72%
Demonstrated Influenza vaccination
breathing exercises last year
28%
42% No No
Yes Yes
58% 72%
126 patients with AECOPD
Zujovic D, Unpublished Data. 2012

13. The Effects of Smoking Cessation on the
Risk of COPD Exacerbations
N= 23 971
Ex-smokers had a significantly reduced risk of COPD exacerbation after
adjusting for age, comorbidity, markers of COPD severity and socio-economic
status (adjusted HR 0.78, 95% CI 0.75–0.87)
Au DH et al. The Effects of Smoking Cessation on the Risk of Chronic Obstructive Pulmonary Disease Exacerbations. J Gen Intern Med. 2009 April; 24(4): 457–463.

14. Prevalence of smoking cessation
pharmacotherapy in hospitalized smokers
with acute myocardial infarction
risk reduction (RR) in reinfarction of 32%
all-cause mortality of 36%
benefit that may exceed standard pharmacotherapy for secondary prevention
N= 1 631
Only 14% (222/1,631) of AMI patients who smoked were
prescribed smoking cessation medication at discharge.
Katz DA et al. Prevalence and correlates of smoking cessation pharmacotherapy in hospitalized smokers with acute myocardial infarction. American Heart Journal. 2011. 162;1:74-80.

15. Potential Quality Gaps in Pharmacological
Treatment for Smoking Cessation Following
Hospitalization for Acute COPD
Exacerbation
Use of medications for tobacco dependence is uncommon in a
high−risk population of smokers following hospitalization for
AECOPD
18% of patients who smoked were prescribed smoking
cessation medication at 30 days post discharge
N= 684
McBurnie et al. Am J Respir Crit Care Med. 179;2009:A2157

16. Tobacco treatment in patients with COPD
25
Complete abstinence rate at 12 months
20
15
10
5
0
None Placebo NRT patch NRT gum NRT NRT Bupropion Varenicline
inhaler lozenge
Wu J, Sin DD. Improved patient outcome with smoking cessation: when is it too late? International Journal of COPD. 2011.6: 259–267
Strassmann R et al. Smoking cessation interventions in COPD: a network meta-analysis of randomized trials. ERJ. 2009.34(3):634-640

17. Influenza vaccine and AECOPD
significant reduction in the total number of exacerbations per vaccinated subject compared with
those who received placebo
Annually for all patients with COPD (SOR: A) GOLD,2011
Poole P, Chacko EE, Wood-Baker R, Cates CJ. Influenza vaccine for patients with chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2006, Issue 1.

18. Influenza and Pneumococcal Vaccine:
An Additive Effect?
1
0,9
The proportion of COPD patients free from
0,8
inf. acute exacerbation
0,7
0,6
0,5
0,4
0,3 Pneumococcal Vaccine + Influenza Vaccine
0,2 Influenza Vaccine
0,1 P=0.037 N=167
0
1 51 101 151 201 251 301 351 401 451 501 551 601 651 701
Time (days)
Furumoto A et al. Additive effect of pneumococcal vaccine and influenza vaccine on acute exacerbation in patients with chronic lung disease. Vaccine 2008; 26:4284-4289.

19. Low influenza vaccine uptake in COPD
80 Influenza vaccine uptake in COPD
70
% COPD patients
60
50
40
30
20
10
0
Vozoris NT. AoRM 2009

20. Low coverage rates of PPV23 vaccine
Cumulative doses distributed per 10 000 persons
UK 2123
Germany 1607
Ireland 1488
Spain 1280
Belgium 1220
Greece 922
Sweden 901
Iceland 721
Italy 677 Countries recommending pneumococcal
vaccination for all elderly people and those
Austria 652 considered „at risk‟ of pneumococcal infection
Norway 587 Countries recommending pneumococcal
vaccination only for those considered „at risk‟ of
Switzerland 333 pneumococcal infection
Finland 218
France 583
Portugal 452
Denmark 271
Netherlan… 49
In most European countries coverage rates is 20 - 30%.
Fedson DS et al. Pneumococcal Polysaccharide Vaccination for Adults. Expert Rev Vaccines. 2011;10(8):1143-1167.

21. Pulmonary rehabilitation following
exacerbations of COPD
Pulmonary rehabilitation should be made available to all
appropriate people with COPD including those who have
had a recent hospitalisation for an acute exacerbation.
NICE guideline, 2010
Reduction of hospital admissions
NNT=4
Puhan Maet al. Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2011, Issue 10.

22. Pulmonary Rehabilitation Should Be
Prescribed in the Same Way Medications
Are Prescribed
“There is no drug that has beneficial effects on as many
clinical variables as pulmonary rehabilitation;
there is no drug with effects that are as long-lasting (up
to 18 months) as those of pulmonary rehabilitation;
and there is no drug with an research and development
investment as low as the costs of the most sophisticated
pulmonary rehabilitation program.”
Alba Ramírez-Sarmiento
Arch Bronconeumol. 2008;44(3):119-21

23. What is reality?
1%
Only 1.2% of the more than 750 000
Canadians suffering from COPD have
access to PR programs
Brooks D et al. Can Respir J. 2007;14(2):87-92.
615 patients with COPD, 139 GPs
5% Pulmonary rehabilitation was prescribed
to 5% of all patients and less than 1/3 of
patients exercised regularly.
Jochmann A et al. Swiss Med Wkly. 2010
Of the 69,820 patients hospitalized for
6% acute exacerbations of COPD, 6% had
chest physiotherapy Lindenauer PK et al. Ann Intern Med. 2006

24. Adherence in COPD: effects on
survival and exacerbations
rate ratio: 0.56; 95% CI: 0.48–0.65; p < 0.001
0.4
admission rates/patient-year
0.35
Nonadherent
0.3
Adherent
0.25
0.2
0.15
0.1
0.05
0
Salmeterol Fluticasone SFC Placebo
44% reduction in admissions rate
N=6112
T=3 year
Good adherence= adherence >80%
Vestbo J, Anderson JA, Calverley PMA et al. Adherence to inhaled therapy, mortality and hospital admission in COPD. Thorax. 2009. 64:939–943

25. Adherence in COPD: effects on
survival and exacerbations
hazard ratio [HR]: 0.40; 95% CI: 0.35–0.46; p < 0.001
35
Nonadherent
30
Adherent
3-year mortality rate
25
20
%
15
10
5
0
Salmeterol Fluticasone SFC Placebo
60% mortality risk reduction
N=6112
T=3 year
Good adherence= adherence >80%
Vestbo J, Anderson JA, Calverley PMA et al. Adherence to inhaled therapy, mortality and hospital admission in COPD. Thorax. 2009. 64:939–943

26. What is reality?
(N>1500) Physicians’ knowledge of inhaler devices and
inhalation techniques remains poor (~14.5%) Spain
Plaza V et al. J Aerosol Med Pulm Drug Deliv. 2012;25(1):16-22
60% nonadherent
85% use their inhaler ineffectively
Restrepo RD et al. Medication adherence issues in patients treated for COPD. Int J Chron Obstruct Pulmon Dis. 2008; 3(3): 371–384.

27. COPD Exacerbation

28. Self-Management Education:
Reduces Hospitalization

29. Benefits of COPD Self Management Education

31. Creating a Community COPD Action Plan?

32. Active prevention of AECOPD?
Patients need personalized education and
encouragement to use treatment properly and
act on symptoms early

33. Comorbidity and risk for exacerbations
Independent effect of depression on COPD
exacerbations and hospitalizations.
* * *
2
Adjusted incidence ratio
1.5
HADS ≤ 7
1 HADS 8-10
HADS ≥ 11
0.5
0
Exacerbation Exacerbation Hospitalisation
(self reported) (event)
HADS: Hospital Anxiety and Depression Scale
Xu W et al. AJRCCM 2008; 178:913-20

34. Proportion of patients with
pathological cognitive deficit when fit
for discharge post-exacerbation
Cognitive Age-matched COPD COPD
p value
Domain Controls -Stable -Exacerbation
Visual Memory 0.003
13% 32% 55%
DR
Verbal Memory <0.001
10% 24% 57%
IR
Trail Making 7% 40% 53% <0.001
Verbal Fluency 7% 10% 41% <0.001
Working
10% 18% 50% 0.001
Memory
Processing
3% 24% 50% <0.001
Speed
Visuo-Spatial 0% 30% 52% <0.001
Dodd JW et al. Submitted

35. Pharmacologic treatments for COPD:
a mixed-treatment comparison meta-
analysis
43 RCT
odds of having an exacerbation
LABA TIO ICS LABA
N= 31 020 +
TROP ICS
IUM
-16% -15%
-24%
-31%
Baker WL, Baker EL, Coleman CI. Pharmacologic treatments for chronic obstructive pulmonary disease: a mixed-treatment comparison meta-analysis. Pharmacotherapy. 2009 Aug;29(8):891-905.

36. Relative Risk of Exacerbations in
COPD Patients Treated With LABA
21% reduction (95% CI, 10%-31%) in COPD
exacerbation rates
Sin DD et al. JAMA. 2003;290(17):2301-2312.

37. Tiotropium versus Salmeterol for the
Prevention of Exacerbations of COPD
N= 7376
FEV1 49% RR 0.89 Tiotropium
12 months
annual rate of exacerbations
P=0.002 Salmeterol
RR 0.93
P=0.048
RR 0.73
P<0.001
all exacerbations moderate exacerbations severe exacerbations
Vogelmeier C et al. Tiotropium versus Salmeterol for the Prevention of Exacerbations of COPD. N Engl J Med 2011;364:1093-1103.

38. LABA/ICS reduces the rate of
exacerbations requiring medical
intervention vs. LABA alone
N=1022
5 +3% FEV1 36%
12 months
0
exacerbations/patient/year
3
Number needed to treat
–5
2.1
Rate of
–10 2
–12%
–15
1
–20
–25 –24% 0
Bud/Form vs. formoterol
*
–30
Bud/Form Budesonide Formoterol
NNT=2.1
*P < 0.05 vs. placebo;
P = 0.015 Bud/Form vs. formoterol
Calverley et al. Eur Respir J 2003;22:912-9.

39. The prevention of COPD exacerbations
by salmeterol/fluticasone propionate or
tiotropium bromide (INSPIRE Trial)
2
1.8
N=1323
annual exacerbation rate
1.6
p = 0.656 FEV1 39%
24 months
1.4
1.2
1,28 1,32
1
0.8
0.6
0.4
0.2
0
Salmeterol/Fluticasone Tiotropium
Wedzicha JA, Calverley PM, Seemungal TA, et al. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. (INSPIRE Trial) Am J Respir Crit Care Med
2008; 177:19-26.

40. Optimal Therapy of COPD To Prevent
Exacerbations and Improve Quality of
Life (OPTIMAL) study
p = n.s.
100
N=449
90 FEV1 40%
% patients with exacerbation
12 months
80
70 62.8 64.8 60.0
60
(1 year )
50
40
30
20
10
0
Tiotropium (N=156) Tiotropium + Salmeterol (N=148) Tiotropium +
Salmeterol/Fluticasone (N=145)
Aaron SD, Vandemheen KL, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007;146:545-555.

41. Efficacy and Tolerability of
Budesonide/Formoterol Added to Tiotropium
in Patients with COPD
Rate of severe exacerbations reduced by 62%
0.4
Budesonide/formoterol + tiotropium N= 660
FEV1 38%
Exacerbations/patient
Placebo + tiotropium 12 weeks
0.3 Cox-proportional hazards: rate ratio 0.38 (95% CI 0.25, 0.57, p<0.001)
0.2
0.1
0.0
0 15 30 45 60 75 90
Days since randomisation
Welte T et al. Efficacy and Tolerability of Budesonide/Formoterol Added to Tiotropium in Patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2009; 180: 741–750

42. The impact of triple therapy on mortality
and exacerbations in COPD
retrospective cohort study
1857 patients LABA/ICS+Tio vs. 996 patients LABA/ICS
Mean follow-up 4.65 years
Short PM et al. CHEST. 2012;141(1):81-86

43. Roflumilast reduced exacerbations
when added to bronchodilators

44. Roflumilast reduced exacerbation rate
when added to ICS
M2-111 and M2-112 pooled post hoc analysis of sub-group with chronic bronchitis
+/- ICS
Rennard SI, Calverley PMA, Goehring UM, et al. Respiratory Research 2011; 12: 18. ICS = Inhaled corticosteroids

45. Effects of roflumilast in highly
symptomatic COPD patients
N=743
395 patients mMRC≥ 2
Tio18 mcg + roflumilast500mcg OD vs. Tio18mcg + placebo OD
24 weeks
0.45 Δ= -23.2% Δ= -45.5%
Rate ratio=0.768 Rate ratio=0.545
0.4 95%Cl 0.515,1.146 95%Cl 0.311,0.955
Annual rate of mod/severe
exacerbation per patient
0.35
p=0.196 p=0.0338
0.3
0.25
Placebo + Tio
0.2
Roflumilast + Tio
0.15
0.1
0.05
0
Total population mMRC ≥ 2 subgroup
Tio= Tiotropium
mMRC= Modified Medical Research Council Dyspnea Scale
Fabbri LM, et al. Effects of roflumilast in highly symptomatic COPD patients [abstract]. In: European Respiratory Society's 22nd Annual Congress; 2012 Sept 1-5; Vienna, Austria: ERS; 2012. Abstract P742.

47. Morbidity and mortality benefits with
statin use in COPD
Dobler CC et al. BMC Pulmonary Medicine 2009, 9:32

48. STATCOPE Study – Phase II
 The STATCOPE study is funded by
the National Heart Lung & Blood
Institute and is being conducted to
determine if an FDA approved
statin drug called simvastatin might
reduce swelling in the lungs in
patients with COPD.
 If it is found that this statin drug
reduces lung inflammation, there is
a possibility that the statin drug
could also limit the number or the
severity of flare-ups, called
exacerbations, in patients with
COPD.

49. Effect of β blockers in treatment of
COPD
Retrospective
cohort study
N=5977
4.35 years follow-up
Adjusted hazard ratios for hospital admissions due to respiratory disease among patients with
COPD in reference to the control group (who received only inhaled therapy with short acting β
agonists or antimuscarinics).
Short PM et al. BMJ 2011;342:bmj.d2549

50. Effect of β blockers in treatment of
COPD
β blockers may reduce mortality and
COPD exacerbations when added to
established inhaled stepwise therapy for
COPD, independently of overt
cardiovascular disease and cardiac
drugs, and without adverse effects on
pulmonary function.
Short PM et al. BMJ 2011;342:bmj.d2549

51. TOO COMPLICATED?

52. Realistic and possible abilities in
prevention of COPD exacerbation
Dejan Žujović
Municipal Institute for Lung Diseases and Tuberculosis
Belgrade