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Questions to ask:  Do you cough regularly?  Do you cough up phlegm regularly?  Do even simple chores make you short of breath?  Do you wheeze at night.

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Presentation on theme: "Questions to ask:  Do you cough regularly?  Do you cough up phlegm regularly?  Do even simple chores make you short of breath?  Do you wheeze at night."— Presentation transcript:

1 Questions to ask:  Do you cough regularly?  Do you cough up phlegm regularly?  Do even simple chores make you short of breath?  Do you wheeze at night or when you exert yourself?  Do you catch frequent colds that persist longer than most other individuals’ around you? Carry out spirometry testing Treatment goals:  Smoking cessation  Vaccination to prevent exacerbations  Regular physical activity  Bronchodilator therapy CTS: Clinical Assessment of COPD Adapted from Can Respir J January/February 2008;15(suppl A).

2 CTS: Potential Prevention Strategies for AECOPD  Smoking cessation  Vaccinations: Influenza (annually) Pneumococcal vaccine (every five to 10 years)  Self-management education  Regular therapy with ICS/LABA combination (for moderate to severe COPD with ≥1 AECOPD on average per year)  Oral corticosteroid therapy for AECOPD  Pulmonary rehabilitation Adapted from Can Respir J January/February 2008;15(suppl A).

3 II Mild Very severe V Smoking cessation/exercise/self-management/education PRN short-acting bronchodilator(s) Long-acting bronchodilator(s) Pulmonary rehabilitation Inhaled corticosteroids/LABA Oxygen Surgery Lung function impairment MRC dyspnea scale Early diagnosis (spirometry) + prevention Prevent/Rx AECOPD Follow-up End-of-life care CTS: Comprehensive Approach to COPD/AECOPD Management Adapted from Can Respir J January/February 2008;15(suppl A).

4 MildModerateSevere CTS: Recommendations for Optimal COPD Therapy Infrequent AECOPD (an average of <1 per year) Frequent AECOPD (≥1 per year) SABA prn persistent disability LAAC + SABA prn or LABA + SABD prn LAAC or LABA + SABA prn persistent disability LAAC + LABA + SABA prn persistent disability LAAC+ICS/LABA* +SABA prn LAAC + ICS/LABA + SABA prn persistent disability LAAC + ICS/LABA + SABA prn ± Theophylline Adapted from Can Respir J January/February 2008;15(suppl A). *Refers to the lower-dose ICS/LABA. Increasing Disability and Lung Function Impairment

5 Clinical Differences Between Asthma and COPD AsthmaCOPD Age of onsetUsually under 40 yearsUsually over 40 years Smoking historyNot casualUsually >10 pack-years Sputum productionInfrequentOften AllergiesOftenInfrequent Disease courseStable (with exacerbations)Progressive worsening (with exacerbations) SpirometryOften normalizesMay improve but never normalizes Clinical symptomsIntermittent and variablePersistent Adapted from Can Respir J January/February 2008;15(suppl A).

6 GradeDescription 1Not troubled by breathlessness except with strenuous exercise 2Troubled by shortness of breath when hurrying on the level or walking up a slight hill 3Walks slower than people of the same age on the level because of breathlessness or has to stop for breath when walking at own pace on the level 4Stops for breath after walking about 90 m or after a few minutes on the level 5Too breathless to leave the house or breathless when dressing or undressing Adapted from Can Respir J January/February 2008;15(suppl A). MRC Dyspnea Scale

7 COPD Is Projected to Be the Third Biggest Cause of Mortality by 2020 Adapted from Murray CJ, Lopez AD. Lancet 1997;349: Ischaemic heart disease Cardiovascular disease Lower respiratory infection Diarrheal disease Perinatal disorders COPD Tuberculosis Measles Road traffic accident Lung cancer Ischemic heart disease Cardiovascular disease COPD Lower respiratory infection Lung cancer Road traffic accident Tuberculosis Stomach cancer HIV Suicide 1 st 2 nd 3 rd 4 th 5 th 6 th 7 th 8 th 9 th 10 th

8 Inflammation Plays a Central Role in the Pathogenesis and Pathology of COPD Adapted from Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines, Available at Cigarette smoke (and other irritants) Inflammatory cells Inflammatory mediators Oxidative stress Proteases COPD pathology Obstructive bronchiolitis Mucus hypersecretion Alveolar wall destruction Genetic susceptibility Lung Inflammation

9 Amplification of Inflammation in COPD Adapted from Barnes PJ. Personal Communication Inflammation Normal smokers Non-smokers Mild COPD Severe COPD Exacerbation Bacteria Viruses  Inflammatory cells  Cytokines  Mediators  Proteases

10 Complementary Effect of ICS/LABA on COPD Inflammation Adapted from Bourbeau et al. Thorax 2007;Epub. SFC-FP=salmeterol/fluticasone DPI vs. fluticasone DPI SFC-P=salmeterol/fluticasone DPI vs. placebo; FP-P=fluticasone DPI vs. placebo CD8 + T-lymphocytes 20 0 –20 –40 –60 –80 –100 –120 –140 –160 Treatment difference (95% CI) (-96 to -9) ( to -53.0) (-90.9 to 1.6) Treatment difference (95% CI) (-57.8 to -0.9) (-61.1 to -2.3) (-32.5 to 27.8) –10 –20 –30 –40 –50 –60 –70 SFC-FPSFC-PFP-P Eosinophils –2 –4 –6 –8 –10 Treatment difference (95% CI) 0.87 (3.9 to 5.6) -3.1 (-8.0 to 1.8) (-9 to 1.1) CD68 + macrophagesNeutrophils –10 –20 –30 –40 Treatment difference (95% CI) (-35.4 to -10.2) (-17.6 to 8.5) (4.8 to 31.6) SFC-FPSFC-PFP-P

11 1. Donaldson et al. Thorax 2002;57: Donaldson et al. Eur Respir J 2003;22: Seemungal et al. Am J Respir Crit Care Med 1998;157: Groenewegen et al. Chest 2003;124: Soler-Cataluna et al. Thorax 2005;60: Exacerbations Drive Morbidity and Mortality COPD exacerbations lead to: Increased symptoms (breathlessness) 2 Increased risk of hospitalization 4 Increased risk of mortality 4,5 Decline in lung function 1 Worsening health status 3

12 Patients Under-report COPD Exacerbations 1. Seemungal et al. Am J Respir Crit Care Med 1998;157: Wilkinson et al. Am J Respir Crit Care Med 2004;169: Seemungal et al. 1 (n=184) 1 Wilkinson et al. 2 (n=1099) 2 Exacerbations (%) Reported exacerbations Unreported exacerbations 59.9

13 Pulmonary Function Testing: COPD

14 GOLD Guidelines Adapted from GOLD (December 2007).

15 What do COPD patients with a history of exacerbations want from their therapy? Adapted from Miravitlles et al. Respir Med 2007;101: Results from 1100 interviews in five EU countries and the USA Quicker symptom relief Patients (%) Fewer side effects 36 Lower costs of treatment 27 Better ability to cope with daily chores27 55 Longer intervals between flare-ups 40 Better doses 23

16 Frequent: >median 2.92 exacerbations/year Infrequent: ≤median 2.92 exacerbations/year FEV 1 : forced expiratory volume in 1 second Adapted from Donaldson et al. Thorax 2002;57: Frequent Exacerbations Lead to Declining Lung Function FEV 1 (l) Time (years) Frequent exacerbations Infrequent exacerbations

17 Increased Frequency of Exacerbations Increases the Risk of Mortality in COPD Adapted from Soler-Cataluna et al. Thorax 2005;60: Time (months) P< P< P= Survival probability 0 exacerbations 1–2 exacerbations ≥3 exacerbations

18 Prolonged Time to First Exacerbation P<0.05 Busesonide/formoterol (bud/form) vs. all other groups (log-rank test) Adapted from Calverley et al. Eur Respir J 2003;22: Time in study (days) Fraction of patients without an exacerbation during the study 96 days 154 days 254 days 178 days Formoterol Budesonide Placebo Budesonide/formoterol prolonged time to first exacerbation by 100 days vs. LABA alone Time in study (days) Fraction of patients without an exacerbation during the study 96 days 154 days 254 days 178 days Placebo Bud/form

19 IV: Very Severe III: Severe II: Moderate I: Mild Therapy at Each Stage of COPD  FEV 1 /FVC <70%  FEV 1 ≥80% predicted  FEV 1 /FVC <70%  50% ≤FEV 1 <80% predicted  FEV 1 /FVC <70%  30% ≤FEV 1 <50% predicted  FEV 1 /FVC < 70%  FEV 1 <30% predicted or FEV 1 <50% predicted plus chronic respiratory failure Add long-term oxygen if chronic respiratory failure Consider surgical treatments Add regular treatment with one or more long-acting bronchodilators (when needed); add rehabilitation Add inhaled glucocorticosteroids if repeated exacerbations Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed) Adapted from Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines, Available from FVC = forced vital capacity

20 Improvements in Health Status by ICS/LABA Combinations vs. Placebo *Measured by using the St. Georges Respiratory Questionnaire, a validated tool for measuring health status in COPD 1. Calverley et al. Eur Respir J 2003;22: Szafranski et al. Eur Respir J 2003;21: Calverley et al. Lancet 2003;361: Calverley et al. N Engl J Med 2007;356: –8 –7 –6 –5 –4 –3 –2 –1 0 ∆ Health status Clinically meaningful improvement Budesonide/ formoterol 1 Budesonide/ formoterol 2 Salmeterol/ fluticasone DPI 3 Salmeterol/ fluticasone DPI 4

21 Adapted from Soriano et al. Am J Respir Med 2003;2: ICS/LABA Improves Hospitalization-free Survival in a Cohort Study P<0.05 ICS/LABA vs. ICS or LABA Retrospective cohort analysis of COPD-related rehospitalization or death within one year of first hospitalization in 3636 COPD patients receiving ICS and/or LABA compared with 627 reference patients receiving SABA alone Risk of rehospitalization or death vs. reference patients (%) -41% -16% -10% –45 –40 –35 –30 –25 –20 –15 –10 –5 0 ICS/LABAICSLABA

22 ICS/LABA Improves Overall Survival in a Cohort Study Adapted from Mapel et al. Respir Med 2006;100: * Adjusted for age, gender, ICS treatment, LABA treatment, ICS plus LABA treatment, asthma diagnosis, measures of COPD severity at baseline, measures of asthma severity at baseline, hospitalization for respiratory illnesses, and both inpatient and outpatient Charlson–Deyo scores; n= Survival (days) Survival function estimate * Hazard ratio: 0.34* (95% CI, ) P< % lower relative risk for all-cause mortality LABA ICS SABA ICS/LABA

23 Improved Survival with Budesonide +/– Formoterol Compared to Bronchodilator Treatment Alone Adapted from Calverley et al. COPDV Time in study (days) Proportion of patients who died 400 Log-rank test: P= Cox regression: hazard ratio, 0.564; P= /917 34/917 Budesonide Non-budesonide

24 Budesonide/formoterol: Maintained Improvement in Lung Function vs. LABA Alone Calverley et al. Eur Respir J 2003;22: P<0.001 Budesonide/formoterol (bud/form) vs. placebo and budesonide P=0.002 Budesonide/formoterol vs. formoterol; P<0.001 formoterol vs. placebo Time from randomization (months) –0.5 Formoterol Budesonide Placebo Bud/form Mean FEV 1 (% of baseline)

25 *P<0.05 vs. placebo; P=0.015 budesonide/formoterol (bud/form) vs. formoterol Reduced Rate of Exacerbations Requiring Medical Intervention vs. LABA Alone Adapted from Calverley et al. Eur Respir J 2003;22:  Treating 100 patients with COPD (GOLD stage III–IV) with budesonide/formoterol instead of formoterol alone may prevent 47 exacerbations in one year –12% Number needed to treat Budesonide/ formoterol vs. formoterol 2.1 BudesonideFormoterol +3%+3% –30 –25 –20 –15 –10 –5 0 5 Rate of exacerbations/patient/year –24% * Bud/form

26 Lower Health Status Predicts Mortality Adapted from Gudmundsson et al. Respir Res 2006;7:109. SGRQ=St. George’s Respiratory Questionnaire Higher health status=SGRQ total score ≤60; lower health status=SGRQ total score > Survival (%) P= Observation time (days) Higher SGRQ total score (>60) Lower SGRQ total score (≤60)

27 Mortality Stratified by Median Baseline SGRQ Total Score Stratified by SGRQ total score, median 50-unit cut-off Adapted from Calverley et al. COPDV Time in study (days) Proportion of patients who died 400 SGRQ total score ≤50 SGRG total score >50 SGRQ total score >50 Budesonide Non-budesonide

28 Impact of Smoking Cessation Programmes on Mortality Adapted from Anthonisen et al. Ann Intern Med 2005;142:  All-cause 14.5-year survival from the Lung Health Study (LHS) Proportion of patients with no event 0 Time since LHS baseline (years) 15% Special intervention group Usual care group

29 Adapted from Sin et al. Am J Respir Crit Care Med 2001;164: ICS Improve Hospitalization-free Survival in a Cohort Study COPD hospitalization-free survival probability Time after discharge (months) % lower relative risk for all-cause mortality and repeat hospitalization Hazard ratio: 0.74 (95% CI, ) No ICS ICS 14

30 ISEEC Study: ICS Improve Survival Adapted from Sin et al. Thorax 2005;60: ISEEC=Inhaled Steroids Effects Evaluation in COPD * Stratified by individual trials and adjusted for age, gender, baseline post-bronchodilator FEV 1 (% predicted normal), baseline smoking status and body mass index; n= Follow-up (years) 1234 Survival probability Hazard ratio: 0.73 * (95% CI, ) P= % lower relative risk for All-cause mortality Placebo ICS

31 EUROSCOP Study Design  Primary end point: change over time in FEV 1  Patients: aged years, current smokers (smoking history of  ≥5 pack-years), FEV % predicted normal, FEV 1 /VC <70% *Patients who continued to smoke after two three-month smoking cessation programmes and were ≥75% compliant with the recommended treatment regimens were randomized. VC=vital capacity Adapted from Pauwels et al. N Engl J Med 1999;340: Randomization*Treatment 0 Run-in Budesonide 400 µg b.i.d. (n=634) Placebo (n=643) –6Month

32 TORCH: Further Evidence that ICS/LABA Can Reduce Mortality in COPD Month Adapted from: Vestbo et al. Eur Respir J 2004;24: Calverley et al. N Engl J Med 2007;356: Run-inRandomization 36 Treatment Salbutamol available as reliever medication to all patients Fluticasone DPI 500 µg b.i.d. Salmeterol DPI 50 µg b.i.d. Placebo – Follow-up Salmeterol/fluticasone DPI 50/500 µg b.i.d.  Primary end point: all-cause mortality over three years

33 TORCH: All-cause Mortality at Three Years Adapted from Calverley et al. N Engl J Med 2007;356: Vertical bars represent standard errors Placebo Salmeterol/ fluticasone DPI Time to death (weeks) Probability of death (%) HR 0.825, P= % risk reduction 2.6% absolute reduction Placebo (15.2% mortality rate) Salmeterol/fluticasone DPI (12.6% mortality rate) Number of patients alive:

34 Health Related QOL Over 3 Years - TORCH SAL/FP 500/50 SAL Placebo FP Improvement Week Adjusted mean change in SGRQ total score P<0.001 SAL/FP vs. SAL over 3 years P<0.001 SAL/FP vs. Placebo over 3 years P=0.017 SAL/FP vs. FP over 3 years Vertical bars represent standard errors Adapted from Calverley et al. N Engl J Med 2007;356:

35 Adjusted Mean Change FEV 1 (mL) Time (Weeks) P< SAL/FP vs. SAL and FP over 3 years SAL Placebo FP P< SAL/FP vs. Placebo over 3 years Adapted from Calverley et al. N Engl J Med 2007; 356: SAL/FP 500/50 Placebo SAL FP SAL/FP 500/50 Rate of decline (mL /yr) P-value vs. placebo <0.001 Improvements in Post Bronchodilator FEV 1 with SAL/FP 500/50 over 3 years - TORCH

36 Rationale for TORCH: ICS with LABA Probability of survival FP Reference (no ICS or LABA) SAL + FP Follow-up (months) Survival was significantly higher at year 3 in patients receiving SAL/FP than in the reference group Adapted from Soriano et al. Eur Respir J 2002;20(4): SAL SAL/FP=salmeterol/fluticasone


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