COPD. Salah Zeineldine, MD FACP Pulmonary & Critical Care Medicine American University of Beirut Lebanese Society of Family Medicine 2012

Transcription

1 COPD Salah Zeineldine, MD FACP Pulmonary & Critical Care Medicine American University of Beirut Lebanese Society of Family Medicine 2012

2 Attitude It is a disease on which a good deal of wholly, unmerited sympathy is frequently wasted. It is a disease of the gluttonous, bibulous, otiose and obese and represents a well-deserved nemesis for the unlovely indulgences From Middle and Old age Williams

3 Expanded Definition of COPD COPD is preventable, treatable, and characterized by airflow limitation that is not fully reversible Airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases Celli BR, et al. Eur Respir J. 2004;23: Pauwels RA, et al. Am J Respir Crit Care Med. 2001;163: GOLD guidelines 2006

4 Is COPD really a Problem?

5 Prevalence of COPD and Burden of Mortality

6 World s Top Ten Killers

7 World s Top Ten Killers

8 Age-adjusted Death Rate Proportion of 1965 rate % COPD % all other causes -62% CHD-Stroke 1998 Pawles and Rabe. Lancet 2004;364:

9 COPD Mortality by Gender, U.S., Number Deaths x Men Women Source: US Centers for Disease Control and Prevention, 2002

10 Burden of Lung Disease (BOLD) initiative Participants from 12 sites (n=9425) completed postbronchodilator spirometry testing plus questionnaires about respiratory symptoms, health status, and exposure to COPD risk factors. GOLD (stage I or higher disease) 11 4% to 26 1% Men > Women (prevalence varied greatly across sites) Buist et Al. Lancet 2007

11 Burden of Lung Disease (BOLD) initiative The prevalence of stage II or higher 10 1% overall 11 8% for men and 8 5% for women However, doctor diagnosis of COPD was reported by only 5.6% of participants Buist et Al. Lancet 2007

12 Burden of Lung Disease (BOLD) initiative Over 15% of COPD occurs in people who have never smoked. In low-income nations, exposure to indoor air pollution, such as the fumes from biomass fuels for cooking and heating, causes most COPD. The overall pooled adjusted odds ratio for stage II or higher COPD per 10-year age-increment was 1 94 this was much the same across sites and for women and men

13 The changing face of COPD: Prevalence in Young Adults Prevalence (%) Overall prevalence of COPD by GOLD stage in young adults (aged years) Stage 0 Stage 1 Stages 2 3 De Marco et al. Thorax 2004

14 Systemic Effect Of COPD COPD is now recognized as having both local lung and systemic effects. The mechanism of some systemic effects is not known, but is believed to be related to enhanced systemic inflammation and oxidative stress Serum biomarkers measured by protein microarray platforms have been identified in patients with COPD that relate to clinical phenotypes, such as extent of airflow limitation, 6MWD, exacerbation frequency, and BODE index

15 COPD and Co-Morbidities COPD patients are at increased risk for: Myocardial infarction, Angina (Atherosclerosis) Osteoporosis (regardless of seroid use) Respiratory infection Depression & Anxiety (40-90 vs 5% & 20 vs 3%) Diabetes Lung cancer

16 COPD and Co-Morbidities COPD has significant extrapulmonary (systemic) effects including: Weight loss Nutritional abnormalities Skeletal muscle dysfunction

17 Skeletal & Respiratory Muscles A reduction in the number of mitochondria in patients with COPD, which may contribute to the impaired oxidative capacity of the limb muscles in this setting. Mitochondrial dysfunction is particularly prominent in patients with COPD with a low body mass index, which may also contribute to the low muscle endurance. Skeletal muscle dysfunction influences outcome in patients with COPD. Quadriceps muscle strength predicts mortality in patients with moderate to severe COPD Gosker et al. Reduced mitochondrial density in the vastus lateralis muscle of patients with COPD. Eur Respir J 2007;30: Rabinovich et al. Mitochondrial dysfunction in COPD patients with low body mass index. Eur Respir J 2007;29: Swallow et al. Quadriceps strength predicts mortality in patients with moderate to severe chronic obstructive pulmonary disease. Thorax 2007;62:

18 Muscle strength vs FEV1 Kim HC, Mofarrahi M, Hussein SNA; International Journal of COPD 2008:3(4)

19 COPD Mortality Patients with COPD die mainly from extrapulmonary diseases, and COPD-related mortality is probably underestimated because identifying the precise cause of death is difficult in elderly patients with this disease, in whom cardiac arrhythmias, ischemia and chronic pulmonary heart disease (cor pulmonale) or pulmonary embolism, or both could be suspected. 25% of patients with COPD who were hospitalized for severe exacerbations were shown to have pulmonary embolisms

20 Mortality

21 Factors associated with increased Risk of Mortality Risk factors for COPD mortality include FEV 1 (<50% predicted and accelerated decline) 1 BMI 2 Dyspnea 3 Exercise capacity and functional status 4 BMI = body mass index FEV 1 = forced expiratory volume in one second 1. GOLD 2005; 2. Celli et al. NEJM Nishimura et al. Chest ZuWallack Mon Arch Chest Dis 2003

22 Factors associated with increased Risk of Mortality Risk factors for COPD mortality include: Health status 1 Exacerbations 2 Presence of comorbidities 3 1. Domingo-Salvany et al. AJRCCM Pietila et al. Sem Resp Infec Almagro et al. Chest 2002

23 The Clinical Course of COPD: Consequences of Exacerbations Reduced health-related quality of life Accelerated decline in FEV 1 Exacerbations Increased mortality with exacerbation hospitalizations Increased health resource utilization and direct costs

24 Repeated Exacerbations Slow SGRQ total score n=133 n=299 Recovery in Quality of Life n=133 n=280 n=116 n=233 n=115 n=221 6-month prospective study After one exacerbation treated with antibiotics Followed for 26 weeks n = patients remaining in the study at that time point With a further exacerbation 30 Presentation 4 weeks 12 weeks 26 weeks No new exacerbation Spencer S. et al. Thorax 2003;58:589

25 Repeated Exacerbations Reduce 1.0 the Probability of Survival - Prospective study, Cohort of 304 males - Exacerbations requiring hospital treatment during the year - Follow-up over 5 years Probability of surviving No exacerbation p< exacerbations p= exacerbations Time (months) Soler-Cataluña JJ et al. Thorax 2005;64:925-31

26 Prognosis B ody Mass Index Schols, Landbo O bstruction Anthonisen D yspnea BODE Nishimura E xercise Oga, Pinto-Plata

27 BODE Celli et al. NEJM, 2004

28 COPD HETEROGENEITY PT # 1 FEV1: 28 % MRC: 2/4 6MWD: 540 mt BMI: 30 BODE: FEV1 < 35% PT # 4 FEV1: 34% MRC: 4/4 6MWD: 154 m BMI: 24 BODE: 9 Cote et al.

29 Probability of Survival l Q Q 2 Q I II A Q B III #625 #611 #574 #521 #454 #322 #273 #159 # Months BODE #625 #611 #574 #521 #454 #322 #273 #159 # Months ATS Staging Celli et al NEJM 2004;350:1005

30 Pathophysiology of COPD: Airway Inflammation Neutrophils Monocytes Macrophages O 2 - TNF- Airway inflammation LTB-4 IL-8 CD8 + lymphocytes Protease/anti-protease imbalance Barnes et al. Eur Respir J 2003

31 Pathophysiology of COPD: airway inflammation Airway inflammation Increased numbers/ activation: - neutrophils - macrophages - CD8 + lymphocytes Elevated IL-8, TNF, LTB 4 Protease/anti-protease imbalance Mucosal oedema Sputum neutrophils (%) Sputum inflammatory cell levels p = COPD Healthy Rutgers et al. Thorax 2000

32 Inflammation is a key aspect of COPD and is present at all stages of the disease Airways with measurable cells (%) Airways with measurable cells (%) GOLD stage 0 GOLD stage 1 GOLD stages 2 and 3 GOLD stage 4 Neutrophils Macrophages CD8+ cells Adapted from Hogg JC et al. 4 The percentage of airways that contain inflammatory cells increases as COPD progresses (e.g. neutrophils, p<0.001; macrophages, p<0.001 and CD8 cells, p=0.038) 4

33 Pathophysiological features of COPD Bronchospasm Structural changes Mucociliary dysfunction Airway inflammation Airflow limitation Systemic component Declining lung function Symptoms Exacerbations Decreased exercise tolerance Deteriorating health status Increased morbidity Mortality

34 Available therapies for managing stable COPD Smoking cessation Bronchodilators agonists; anticholinergics Inhaled corticosteroids PDE4 Inhibitors Vaccines Pulmonary rehabilitation Long-term oxygen therapy LVRS

35 Objectives of COPD management: Relieve symptoms Improve exercise tolerance Improve health status Prevent and treat exacerbations Prevent and treat complications Reduce mortality Minimize side effects from treatment Prevent disease progression

36

37 Smoking Cessation Smoking cessation is the single most effective and cost effective intervention to reduce the risk of developing COPD and slow its progression.

38 Smoking Cessation

39 Inhaled Bronchodilators Inhaled bronchodilators are the foundation of pharmacotherapy for COPD because of their capacity to alleviate symptoms, decrease exacerbations of disease, and improve the quality of life. These drugs also improve airflow and hyperinflation thereby decreasing the work of breathing and improving exercise tolerance.

40 Inhaled Corticosteroids A post hoc analysis of the European Respiratory Society study on COPD (EUROSCOP) suggested that long-term inhaled corticosteroids (ICS) lowered the incidence of ischemic heart disease (3% vs. 5%) in patients with mild COPD This is supported by other retrospective database studies and by previous studies suggesting that ICS may reduce systemic inflammation in patients with COPD. Lofdahl et al Possible protection by inhaled budesonide against ischaemic cardiac events in mild COPD. Eur Respir J 2007;29: Huiart et al. Low-dose inhaled corticosteroids and the risk of acute myocardial infarction in COPD. Eur Respir J 2005;25: Sin et al. Do chronic inhaled steroids alone or in combination with a bronchodilator prolong life in chronic obstructive pulmonary disease patients? Curr Opin Pulm Med 2007;13: Fabbri et al. Complex chronic comorbidities of COPD. Eur Respir J 2008;31:204 21

41 Inhaled Corticosteroids The appropriate role of inhaled corticosteroids in COPD is controversial. Some studies have shown that inhaled corticosteroids do not substantially modify airway inflammation in COPD and may increase risk of pneumonia. Pauwels RA, Löfdahl C-G, Laitinen LA, et al. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. N Engl J Med 1999;340: Vestbo J, Sorensen T, Lange P, Brix A, Torre P, Viskum K. Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 1999;353: Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000;320: The Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med 2000;343:

42 We need to weigh up the balance of risks and benefits of prescribing ICS in COPD RISKS oral candidiasis hoarseness osteoporosis Possibly pneumonia BENEFITS exacerbations possibly better QoL

43 Long Term Oxygen Therapy Increases survival in appropriate patients [Evidence level A] May also improve: Hemodynamics Hematologic characteristics Exercise capacity Selection of Patients Stage III or IV COPD Hypoxemia while awake, at rest PaO2 55 mm Hg or less, or SpO2 88% or less Less severe hypoxemia if signs of end-organ dysfunction are present

44 Novel Therapies: Infliximab Anti-TNF antibody (Infliximab) did not show any benefit in patients with moderate to severe COPD on the Chronic Respiratory Questionnaire Score as a primary endpoint and on the secondary outcomes of prebronchodilator FEV1, 6MWD, transitional dyspnea index, and the rate of moderate to severe exacerbations. A higher incidence of pneumonia and cancers occurred in Infliximab-treated subjects, although this was not statistically significant Stephen et al American Journal of Respiratory and Critical Care Medicine Vol 175. pp , (2007)

45 Novel Therapies: Roflumilast In a randomized placebo controlled study of 1,513 patients (FEV1 41% predicted) the effects of 1-year treatment with the specific PDE4- inhibitor Roflumilast in severe COPD produced an improvement in lung function without changing exacerbation rate or health status. In patients with (Bronchitic) severe disease, Roflumilast reduced exacerbations. Calverley et al. American Journal of Respiratory and Critical Care Medicine Vol 175. pp

46 Statins and COPD Animal studies have shown protection against the development of smoke-induced emphysema. Statins may have both local lung and systemic anti-inflammatory and antioxidant effects. Statins have been shown to reduce cardiovascular mortality and may therefore protect against the increased cardiovascular risk that is known to occur in COPD.

47 Statins and COPD Statin treatment was associated with slower rates of decline in lung function in elderly subjects (FEV1 decline, 23.9 ml/yr vs10.9-ml/yr). These data are supported by further retrospective studies using large databases that have shown an apparent effect of statins on mortality in patients with COPD. Randomized clinical trials are warranted

48 Lung Volume Reduction Surgery It is an alternative for selected patients with severe inhomogeneous emphysema who remain symptomatic after optimal comprehensive medical therapy. LVRS improves FEV1 by close to 10%, with larger improvements in exercise tolerance, dyspnea, and health-related quality of life

49 Lung Volume Reduction Surgery the National Emphysema Treatment Trial found that the addition of LVRS to optimal medical therapy and rehabilitation led to an overall improvement in exercise tolerance and survival in a subgroup of patients with reduced exercise tolerance and predominantly upper-lobe emphysema National Emphysema Treatment Trial Research Group. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003;348:

50 Lung Volume Reduction Surgery The ideal candidate should have: FEV1 between 20% and 35% of predicted, DLCO > 20% of predicted, Hyperinflation, and limited comorbidities

51 Pharmacotherapy beyond SABA and SAMA ICS/LABA Fluticasone/Salmeterol Budesonide/Formoterol LAAC Tiotropium Aclidinium Ultra-LABA Indacaterol PDE-4 Inhibitor Roflumilast

52 2011 revision of Global Initiative for Chronic Obstructive Lung Disease The new goals and paradigm for the treatment of stable COPD

53 Introduction COPD assessment now includes assessment of risk of exacerbation, in combining symptomatic and spirometric and previous exacerbations during the last 12 months assessments Terminology changed from GOLD stage I, II, III, IV to GOLD grade A, B, C, D Patients grouped into 4 patient groups : A (less symptoms, low risk); B (more symptoms, low risk); C (less symptoms, high risk); D (more symptoms, high risk) Treatment options for each patient group now classified into first-choice, second-choice and alternate

54 Assessment of symptoms Patient questionnaire (2 options) COPD Assessment Test (CAT): An 8-item measure of health status impairment in COPD Breathlessness Measurement using the Modified British Medical Research Council (mmrc) Questionnaire

55 CAT Symptom Score I have no cough I have no phlegm My chest isn t tight Not breathless when walking uphill Not breathless with daily activities Confident leaving home I sleep well I have enough energy Total

56 mmrc: modified Medical Research Council breathlessness questionnaire * Dennis E.et al. Chronic Obstructive Pulmonary Disease: Consensus Recommendations for Early Diagnosis and Treatment. Journal of Family Practice, November, 2006.

57 Risk (GOLD classification of airflow limitation) Stable COPD: Combined assessment of symptoms + spirometry + exacerbation risk Report 2011, figure 2.3. Association between symptoms, spirometric classification and future risk of exacerbation (C) (A) mmrc 0 1 CAT < 10 Symptoms (mmrc or CAT score) (D) (B) mmrc > 2 CAT > 10 >2 1 0 Risk (Exacerbation history) *Patient is now in one of four categories: A: Less symptoms, low risk B: More symtoms, low risk C: Less symptoms, high risk D: More Symtoms, high risk *When identifying the Patient Group to which a patient belongs, if their level of risk is different between their GOLD grade and their exacerbation history assessment, choose the method indicating the highest risk

58 Treatments recommendations for stable COPD according to 2011 GOLD grades GOLD Grades FEV 1 /FVC < 0.70 Gold Stages Exacerbations previous year Symtom score mmrc CAT 1st choice* 2nd choice* A Low risk Less symptoms B Low risk More symptoms I: FEV1> 80% or II: 50% FEV 1 < 80% < 10 > 2 10 SAMA or SABA LAMA or LABA LAMA or LABA or SABA and SAMA LAMA and LABA C High risk Less symptoms D High risk More symptoms III: 30% FEV 1 < 50% IV: FEV 1 < 30% >2 0-1 < 10 LAMA and LABA > 2 10 ICS + LABA or LAMA ICS and LAMA or ICS + LABA and LAMA or ICS+LABA and PDE4-inh. or LAMA and LABA or LAMA and PDE4-inh.

59 Manage Stable COPD: Overall GOLD classification Patient First choice* Second choice* Alternative Choices* A SAMA prn or SABA prn LAMA or LABA or SABA and SAMA Theophylline B LAMA or LABA LAMA and LABA SABA and/or SAMA Theophylline C ICS + LABA or LAMA LAMA and LABA PDE4-inh. SABA and/or SAMA Theophylline D ICS + LABA or LAMA ICS and LAMA or ICS + LABA and LAMA or ICS+LABA and PDE4-inh. or LAMA and LABA or LAMA and PDE4-inh. Carbocysteine SABA and/or SAMA Theophylline

60 Barriers to Adherence with Prescribed Therapy in COPD Related to the therapy itself Related to the patient Related to us - the providers Make BJ, Respir Care 2003;48(12):

61 Barriers to Adherence with Prescribed Therapy in COPD Related to the treatment itself Purpose Duration Onset Expense Complexity

62

63

64 Improving COPD Management: The Easy Stuff & The Hard Stuff The Easy Stuff Prescribing drugs, O2, etc The Hard Stuff (for both clinician & pt) Smoking cessation Using inhaled medications & O2 optimally Pulmonary rehabilitation Navigating the health care system and the costs of treatment

65 What do these patients have in common? COPD & no spirometry!!! FEV1 = 562 ml (29%) FEV1 = 750 ml (31%) FEV1 = 640 ml (24%)

66 COPD Myth: Disease has no effective treatment. Reality: COPD responds to treatment. With good care the patients will get better. The prognosis has improved.

67 Summary COPD is a progressive and systemic disease COPD Pathophysiology is ongoingly being exposed Promising newer pharmacotherapy Changing treatment concepts and end-points

68 Thank you