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Managing COPD --- Recent Advance 蔡熒煌 長庚醫院胸腔暨重症科 長庚大學呼吸照護學系 Revised 2006 Definition of COPD • Chronic Obstructive Pulmonary Disease (COPD) is a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients. • Its pulmonary component is characterized by airflow limitation that is not fully reversible. • The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases. COPD: Linking Structure with Function Driving pressure (parenchyma) Resistance (small airways) Airflow = limitation The Nature of Small-Airway Obstruction in Chronic Obstructive Pulmonary Disease GOLD stage 4 GOLD GOLD stage 3 stage 2 GOLD stages 0 and 1 0.25 V:SA (mm) 0.20 0.15 0.10 0.05 0.00 0 20 40 60 FEV1 Hogg JC et al., NEJM 2004;350:2645-2653 80 100 120 Mechanisms of Uneven Ventilation in COPD • Unequal lung compliances and airway resistances of lung units leads to a wide distribution of RC-constants • Asynchronously emptying results in a changing gas concentration at the mouth • Contributes to air trapping Clinical Course of COPD: Disease Progression COPD Expiratory Flow Limitation Air Trapping Hyperinflation Exacerbations Breathlessness Deconditioning Inactivity Reduced Exercise Capacity Poor Health-Related Quality of Life Disability Disease progression Death age 40-50 50-55 55-60 60-70 Five leading causes of death by the year 2020 Ischaemic heart disease Cerebrovascular disease COPD Lower respiratory infections Trachea, bronchus and lung cancers 0 2,000 4,000 6,000 8,000 10,000 12,000 Of the six leading causes of death in the United States, only COPD has been increasing steadily since 1970. Source: Jemal A. et al. JAMA 2005 Percent Change in Age-Adjusted Death Rates, U.S., 1965-1998 Proportion of 1965 Rate 3.0 3.0 2.5 2.5 Coronary Heart Disease Stroke Other CVD COPD All Other Causes –59% –64% –35% +163% –7% 2.0 2.0 1.5 1.5 1.0 1.0 0.5 0.5 0.0 0 1965 - 1998 1965 - 1998 1965 - 1998 1965 - 1998 1965 - 1998 Number Deaths x 1000 COPD Mortality by Gender, U.S., 1980-2000 70 60 Men 50 40 Women 30 20 10 0 1980 1985 1990 1995 2000 22 Mortality rate per 100,000 20 22.2 ICD-9 A323: ICD-9 490 Bronchitis, not specified as acute or chronic 491 Chronic bronchitis 492 Emphysema 493 Asthma ICD-9 490-493, 496 18 16.4 16 15.8 14 15.1 ICD-9 496 12 10 7.1 8 6 4 2 ICD-9 490-493 ( A 323 ) ICD-9 496 Chronic airways obstruction, not elsewhere classified 0.6 19811982 1984 1986 1988 1990 1992 1994 1996 1998 Trend of Mortality of Chronic Airway Obstruction - Related Diseases in 21 Years in Taiwan 2000 慢阻肺病患門診就醫狀況 4,000,000 3,500,000 3,000,000 2,500,000 2,000,000 1,500,000 1,000,000 500,000 0 1998 1999 2000 2001 2002 2003 2004 2005 門診人數COPD 就醫人次COPD 醫療費用COPD 慢阻肺病患住院治療 250,000 200,000 150,000 100,000 50,000 0 1998 1999 住院人數COPD 2000 2001 2002 住院人次COPD 2003 2004 2005 住院費用COPD(萬) Medical Cost --- COPD vs. Asthma 2,500,000 2,000,000 1,500,000 1,000,000 500,000 0 1998 1999 2000 COPD OPD COPD Admission 2001 2002 2003 2004 2005 Asthma OPD Asthma Admission Data from BNHI Taiwan : * 1,000 NT Medical Cost and COPD Severity • There is a striking direct relationship between the severity of COPD and the cost of care, and the distribution of costs changes as the disease progresses. • The hospitalization and ambulatory oxygen costs soar as COPD severity increases Key Indicators for Considering a COPD Diagnosis •Consider COPD and perform spirometry if any of these indicators are present in an individual over age 40. These indicators are not diagnostic by themselves, but the presence of multiple key indicators increases the probability of a diagnosis of COPD. Spirometry is needed to establish a diagnosis of COPD. Key Indicators for Considering a COPD Diagnosis • Dyspnea that is: – – – – Progressive (worsens over time). Usually worse with exercise. Persistent (present every day). Described by the patient as an “increased effort to breathe,” “heaviness,” “air hunger,” or “gasping.” • Chronic cough: May be intermittent and may be unproductive. • Chronic sputum production: Any pattern of chronic sputum production may indicate COPD. • • History of exposure to risk factors: – Tobacco smoke (including popular local preparations). – Occupational dusts and chemicals. – Smoke from home cooking and heating fuel. Risk Factors for COPD Nutrition Infections Socio-economic status Aging Populations Diagnosis of COPD EXPOSURE TO RISK FACTORS SYMPTOMS cough tobacco sputum occupation indoor/outdoor pollution dyspnea SPIROMETRY Airway Patency is Fundamental • Spirometry is the gold standard for the diagnosis and assessment of COPD • Measuring post-bronchodilator FEV1 is essential for the classification of severity of COPD Spirometry Diagnosis of COPD in practice (II) For the diagnosis and assessment of COPD, spirometry is the gold standard Healthcare workers involved in the diagnosis and management of COPD patients should have access to spirometry Spirometry should be undertaken whenever respiratory problems are suspected GOLD workshop report 2001 Spirometer Spirometry: Normal and COPD FEV1 (l) 5 FVC Normal FEV1 FVC 4 3 COPD FEV1 2 1 FEV1 FVC FEV1/FVC Normal 4.15 5.2 80% COPD 2.35 3.9 60% 0 0 1 2 3 4 Time (S) Adapted from GOLD workshop report 2001 5 6 Diagnosis of COPD • Existing COPD prevalence data show remarkable variation due to differences in survey methods, diagnostic criteria, and analytic approaches • Survey methods can include: – Self-report of a doctor diagnosis of COPD or equivalent condition – Spirometry with or without a bronchodilator – Questionnaires that ask about the presence of respiratory symptoms COPD is Under-appreciated and Under-diagnosed Example from Japan: NICE Survey of COPD prevalence NICE study population was comprised of 2343 Japanese subjects aged ≥ 40 years. Carried out in several regions of Japan using standardized methods COPD Prevalence Rate (adjusted)* in Population 40 years 10.00% 8.5%** 8.00% 6.00% 4.00% 2.00% 0.3% 0.00% Study MHW Survey 5.3 vs 0.2M COPD patients in Japan ≥40 years *Adjusted for age, sex, cluster **8.5-10.9% depending on criteria Fukuchi et al. Respirology 2004;9:458-65 COPD Prevalence Survey (NICE) in Japan 9% Had prior diagnosis Undiagnosed Diagnosed Did not have prior diagnosis: 91% Fukuchi et al. Respirology 2004;9:458-65 Prevalence of GOLD Stage 1+ COPD1, Guangzhou, China MEN 15.3% 1 FEV WOMEN 7.6% 1/FVC<0.70, post BD • The Latin American Project for the Investigation of Obstructive Lung Disease (PLATINO) examined the prevalence of post-bronchodilator airflow limitation (Stage I: Mild COPD and higher) among persons over age 40 in five major Latin American cities each in a different country – Brazil, Chile, Mexico, Uruguay, and Venezuela 四十歲以 上成年人 抽煙或吸 入污染接 觸者 Is it Inevitably All Downhill ? How we can change the clinical course of COPD? Therapy at Each Stage of COPD I: Mild II: Moderate III: Severe IV: Very Severe FEV1/FVC < 70% • FEV1/FVC < 70% • FEV1/FVC < 70% • FEV1 > 80% predicted • 50% < FEV1 < 80% predicted • FEV1 < 30% predicted • FEV1/FVC < 70% or FEV < 50% 1 predicted plus • 30% < FEV1 < chronic 50% predicted respiratory failure Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed) Add regular treatment with one or more long-acting bronchodilators (when needed); Add rehabilitation Add inhaled glucocorticosteroids if repeated exacerbations Add long term oxygen if chronic respiratory failure. Consider surgical treatments The Fletcher-Curve Smoking Cessation Slows Lung Function Decline in Mild COPD: The Lung Health Study at 11 Years Sustained quitters Intermittent quitters Continuous smokers 2.9 2.8 2.7 2.6 2.5 2.4 2.3 2.2 2.1 2.0 0 1 2 3 4 5 6 7 8 9 10 Anthonisen NR et al. Am J Respir Crit Care Med. 2002:166:675-9. Calverley PMA and Walker P. Lancet 2003;362:1053-1061 11 Smoking Cessation Slows Lung Function Decline in Mild COPD: The Lung Health Study at 11 Years Anthonisen NR et al. Am J Respir Crit Care Med. 2002:166:675-9. Calverley PMA and Walker P. Lancet 2003;362:1053-1061 Rate of Death per 1000 Person-Years Effect of Smoking Cessation on Cause of Mortality 3.5 Special Intervention Usual Care 3.0 2.5 2.0 1.5 1.0 0.5 0 CHD CVD Lung Cancer Other Respiratory Other Cancer Disease Cause of Death Unknown Anthonisen et al. Ann Intern Med. 2005;142:233-239 Bronchodilators in Stable COPD • Bronchodilator medications are central to symptom management in COPD. • Inhaled therapy is preferred. • The choice between Beta2-agonist, anticholinergic, theophylline or combination therapy depends on availability and individual response in terms of symptoms relief and side effects. Inhalation Medication • Short acting beta-2 agonist (SABA) – Rescue use • • • • Long acting beta-2 agonist (LABA) Long acting anticholinergic agent Steroid Combination of steroid and LABA 吸入劑型藥物之吸入道具 Metered-Dose Inhalers (MDI) Nebulizer Dry Powder Inhalers (DPI) Change from Baseline in Trough FEV1 Over 1 Year (Versus Ipratropium) 200 Δ Trough FEV1 (mL) Tiotropium (n=329) 150 100 50 ΔT-I= 160 mL 0 -50 Ipratropium (n=161) -100 8 50 92 182 273 364 Test day P<0.0001 at all timepoints Vincken W et al. Eur Respir J (2002) Mean FEV1 Over 6 Months in Combined Salmeterol Trials Day 1 Day 169 Tiotropium (n=386) 1.35 1.30 ΔT-S= 70 mL† FEV1 (L) 1.25 Salmeterol (n=388) 1.20 1.15 ΔT-P= 210 mL* 1.10 Placebo (n=362) 1.05 1.00 0.95 -60 -10 30 60 120 180 Time after administration (minutes) *P<0.0001; †P<0.001 Brusasco V et al. Thorax (2003) 2003 Canadian COPD Guidelines ISOLDE: Lack of effect of ICS on FEV1 decline 373 372 1.50 Start of Double-Blind Treatment 298 269 246 1.40 235 216 FEV1 (L) 288 241 222 Randomization and Start of Oral Steroid Trial 1.30 168 194 174 141 FP MDI 500 mcg b.i.d. (n=376) Placebo b.i.d. (n=375) 1.20 -3 0 3 12 24 Time (months) 36 Burge et al. BMJ. 2000; 320:1297-1303. Effects of Inhaled Steroids: Long Term Placebo-Controlled Studies Efficacy Variables Primary: FEV1 Secondary: Symptoms Exacerb. Q of L MD visits Bronchial responsive-ness ISOLDE EUROSCOPE Copenhagen Lung Health Study No effect No effect No effect No effect NR 25% less NR NR NR NR NR No effect No effect NR NR ~dyspnea NR No effect MD visits NR NR NR Reduced NR = not reported Exacerbations Drive Morbidity and Mortality A downward spiral COPD exacerbations lead to: Decline in lung function1 Increased symptoms (breathlessness)2 Worsening quality of life3 Increased risk of hospitalisation4 1. 2. 3. 4. 5. Donaldson et al. Thorax 2002;57(10):847–52 Donaldson et al. ERJ 2003;22:931–936 Seemungal et al. Am J Respir Crit Care Med 1998;157:1418–1422 Groenewegen et al. Chest 2003;124(2):459–67 Soler-Cataluna, et al. Thorax 2005;60:925-931 Increased risk of mortality4,5 The clinical course of COPD: consequences of exacerbations COPD Expiratory flow limitation Air trapping Hyperinflation Reduced health-related Exacerbations quality of life Increased mortality with exacerbation hospitalizations Breathlessness Deconditioning Exacerbations Inactivity Reduced exercise capacity Accelerated decline in FEV1 Poor health-related quality of Disability Disease progression Increased health life resource utilization and direct costs Death Natural History of COPD Lung Function Never smoked Exacerbation Smoker Exacerbation Exacerbation Time (Years) Fletcher C. Br Med J. 1977;1:1645-1648 Severe exacerbations and mortality in COPD COPD (N=304, FEV1=46% pred.) 5 yrs Exacerbations vs. Mortality (N=116) No exacerb. (N=163) 1-2 exacerb. requiring hospital admission (N=60) 3 exacerb. (N=36) JJ Soler-Cataluna et al., Thorax 60:925, 2005 Prognosis after Exacerbations No exacerbations p < 0.0002 p < 0.0001 2 exacerbations p = 0.069 3 exacerbations 304 men with COPD classified according to number of exacerbations in first year Soler-Cataluña et al. Thorax 2005;60:925 Moderate (n= 54) Maintenance medications Severe (n= 54) 11,012 10,385 13,276 Very Severe (n= 54) 16,277 Non-ICU hospitalization 42,117 73,876 3,193 ICU management 51,578 102,876 1,178 Emergency visits 5,366 6,748 Comparison of annual direct medical cost in different Severity of COPD patients (Chiang CH. VGH-Taipei, 2003) Acute Exacerbation Prevention • • • • ICS LABA Anti cholinergic Combination 2003 Canadian COPD Guidelines Inhaled Corticosteroids Regular use of high dose inhaled corticosteroids alone should only be considered when patients with moderate to severe COPD have recurrence of acute exacerbations. The only evidence of a significant effect with inhaled corticosteroids is in reducing the rate of exacerbation (Alsaeedi 2002). (Level of Evidence: 1 A) Can Respir J 2003; 10(Suppl A): 11A-33A. Relative Risk of Exacerbations in COPD Patients Treated With ICS: A Meta-analysis Reference Favors ICS Favors Placebo Vestbo et al. 1999 Bourbeau et al. 1998 Burge et al. 2000 Lung Health Study, 2000 Weir et al. 1999 Paggiaro et al. 1998 Overall relative risk = 0.70 95% CI = 0.58 to 0.84 Overall 0 0.5 1.0 1.5 2.0 Relative Risk Alsaeedi et al. Am J Med. 2002;113:59-65 2.5 3.0 Relative Risk of Exacerbations in COPD Patients Treated With LABA: A Meta-analysis Reference Favors LABA Favors Placebo Wadbo et al. 2002 Van Noord et al. 2000 Chapman et al. 2002 Rossi et al. 2002 Dahl et al. 2001 Aalbers al. 2002 Overall relative risk = 0.79 95% CI = 0.69 to 0.90 Overall 0 0.5 1.0 1.5 2.0 Relative Risk Sin et al JAMA 2003;290: 2301–2312 2.5 3.0 Salmeterol/fluticasone in COPD Moderate/severe exacerbations Placebo 1.0 SALM 50µg bd Exacerbation rate FP 500µg bd SALM/FP 50/500µg bd * * #* 0.5 0 * p<0.002 vs placebo # p=0.059 vs SALM Moderate/severe exacerbations requiring OCS Baseline: FEV1 <50% predicted Calverley et al. Lancet 2003;361:449-456 Budesonide/formoterol (Bud/Form) in COPD Rate of severe exacerbations Calverley Szafranski Rate of severe Bud/Form BudesonideFormoterol exacerbations vs placebo (%) Bud/Form BudesonideFormoterol 5 0 0 –10 –10 –20 –20 *p<0.05 vs placebo * *p<0.05 vs placebo p=0.043 Symbicort vs formoterol –30 * –30 W Szafranksi et al., ERJ 2003;21:74- p=0.015 Symbicort vs formoterol PM Calverley et al., ERJ ICS and LABAs improve symptoms and lung function via different mechanisms Inhaled corticosteroids reduce LABAs inhibit Inflammation Structural changes Airway constriction Increased neutrophils and CD8+ lymphocytes Alveolar destruction Smooth muscle contraction Elevated IL–8, TNF Glandular hypertrophy Protease/antiprotease imbalance Collagen deposition Airway fibrosis Symptoms FEV1 Exacerbations Increased cholinergic tone Loss of elastic recoil Sensory nerve activation Veterans Administration – Exacerbation Trial Exacerbations/patient-year 19% reduction 1.2 Exacerbation days/patient-year 20 21% reduction 15 0.8 10 P<0.001 P=0.003 0.4 5 1.05 0.85 0 16.0 12.6 Placebo Tiotropium 0 Placebo Tiotropium Niewoehner et al. Ann Intern Med. 2005;143:317 Risk of a New Exacerbation 0.4 20 % Probability of Exacerbation 0.3 0.2 Placebo group Tiotropium group P=0.028 0.1 0.0 0 30 60 90 120 Study 788 Days 743 Patients at risk, n Tiotropium group 838 Placebo 832 772 Niewoehner et al. Ann Intern Med. 2005;143:317 709 150 690 663 180 658 619 514 454 Effect of Current Drugs on Exacerbation Frequency of COPD Szafranski Brusasco TRISTAN Szafranski TRISTAN Brusasco Percentage change (versus placebo) 10 0 -10 -2 -20 -17 -20 -30 -40 -50 Formoterol Salmeterol Salmeterol -24 -25 -28 Formoterol/ Salmeterol/ Tiotropium budesonide Fluticasone COPD: Defining the Clinical Course and Implications of Therapeutic Interventions • Changing the Clinical Course – Prevent the PFT decline • Smoking cessation • pharmacotherapy • Pulmonary rehabilitation – Prevent of exacerbations – Impact on survive • Systemic co morbidity COPD and Systemic Disorders • COPD involves several systemic features, particularly in severe disease, • Increased concentrations of inflammatory mediators, including TNF-, IL-6, and oxygen-derived free radicals, may mediate some of these systemic effects. • There is an increase in the risk of cardiovascular diseases, which is correlated with an increase in C-reactive protein (CRP)21. COPD and Systemic Disorders • Data from the Netherlands show that up to 25% of the population 65 years and older suffer from two comorbid conditions and up to 17% have three. • COPD and lung cancer. Whether this association is due to common risk factors (e.g., smoking), involvement of susceptibility genes, or impaired clearance of carcinogens is not clear. COPD and Co-Morbidities • COPD patients are at increased risk: • Myocardial infarction, angina • Osteoporosis • Respiratory infection • Depression • Diabetes • COPD and lung cancer GOLD: COPD Pharmacotherapy New 0: At Risk I. Mild II. Moderate III. Severe IV. Very severe Characteristics •Chronic symptoms •Exposures to risk factors •Normal spirometry •FEV1/FVC<70% •FEV1>80% •With or without symptoms •FEV1/FVC<70% •50%>FEV1<80% •With or without symptoms •FEV1/FVC<70% •30%>FEV1<50% •With or without symptoms •FEV1/FVC<70% •FEV1<30% or presence of chronic respiratory failure or right heart failure Avoidance of risk factor(s); influenza vaccination Add short-acting bronchodilator when needed Add regular treatment with one or more long-acting bronchodilators Add rehabilitation Add inhaled glucocorticosteroids if repeated exacerbations Add long-term oxygen if chronic respiratory failure Consider surgical treatments NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease. April 2001 (Updated 2003). "Mild" COPD – causes of death [%] 50 25 % – 39 % 40 30 20 10 0 COPD cardiovascular Lung carcinoma other EUROSCOP (n = 18/1277) LUNG HEALTH (n = 149/5887) Postma et al. (n = 22/81) (n = number of deaths/total number) R. A. Pauwels et al., NEJM 1999; 340:1948–1953.; N. R. Anthonisen et al., JAMA 1994; 272:1497–1505; D. S. Postma et al., ARRD 1986; 134:276–280. COPD and systemic inflammation Meta-analysis COPD studies (n=14) Markers of systemic inflammation CRP WQ Gan et al., Thorax 59:574, 2004 COPD and myocardial infarction Potential role of systemic inflammation 8 NHANES III survey (n=6,629) spirometr y CRP Cardiac infarction injury score DD Sin & SFP Man, Circulation 107:1514, 2003 6 *FEV1/FVC < 0.70, FEV1 < 50 % pred. 4 2 0 High CRP severe High obstruct. CRP+sever * e obstruct.* COPD and systemic inflammation Influence of fluticasone on CRP COPD (n=41, FEV1=55% pred.) DD Sin et al., AJRCCM 170:760, 2004 ICS >> placebo FP 500µg b.i.d FP 500µg b.i.d. FP 1000µg b.i.d. CRP Pred. 30 mg/d COPD and systemic inflammation ICS>> RCT Influence of fluticasone on CRP FP 500µg b.i.d. -4 -2 0 2 18 4 6 8 10 12 14 16 weeks Placeb o -20 Change in CRP from randomization [%] FP 1000µg b.i.d. FP -40 -60 -80 Pred. DD Sin et al., AJRCCM 170:760, 2004 Budesonide protects against cardio-ischaemic events in mild - moderate COPD [EUROSCOP] COPD patients 35 [n] Placebo 30 Budesonide 400 µg bid (n=634) Placebo (n=643) 3 years 25 20 15 10 5 Cardio-ischaemic events Löfdahl et al., ERS 2005 Budesonide ICS and mortality in COPD Pooled analysis of 7 trials (N=5085) DD Sin et al., Thorax 60:992, 2005 6,000 patients randomized: placebo, F, F/S and S for 3 years Outcome = mortality Primary Analysis --all-cause mortality at 3 years Probability of death (%) 18 16 14 -17.5% 12 10 8 NNT = 39 6 4 2 0 Placebo 0 12 24 Vertical bars are standard errors 36 SFC 48 60 72 84 96 108 120 132 144 156 Time to death (weeks) Cause of Death on Treatment (adjudicated by CEC) 7.0 Placebo SFC Deaths (%) 6.0 5.0 4.0 3.0 2.0 1.0 0.0 Cardiovascular Pulmonary Cancer Other Unknown age 40-50 50-55 55-60 60-70 age 40-50 50-55 55-60 60-70 COPD Comorbidities Comorbid heterogeneity Common cause Heart failure Lung cancer Complicating Pneumonia Coincidential Diabetes mellitus Arthritis hip/knee Depression 84 PATIENT – DISEASE ANOMALY • • • • • • • • COPD – The Disease Airflow obstruction Function decline Continuous treatment Lifestyle Regular follow-up ‘Management plan’ Compliance Effects, safety treatment • • • • • • • • Patient with COPD Social isolation Unhealthy environment Poverty Poor self-efficacy Multiple health problems Disruptive life conditions Trust & support Safety line 85 What do we mean by ‘changing the course of the disease’? Photos courtesy David Halpin MD