Slideshow Transcript

1. Slide 1: 8th Pulmonary Medicine Update February 6, 2008 Denver Health COPD State-of-the-Art Richard K. Albert, M.D. Chief of Medicine Denver Health Professor of Medicine University of Colorado Adjunct Professor of Engineering and Computer Science University of Denver
2. Slide 2: COPD Citations Denver Health 2500 2000 Citationas (N) 1500 1000 500 0 1986 1990 1994 1998 2002 2006 Year
3. Slide 3: Objectives Denver Health Definition Epidemiology Phenotyping Genetics Pathophysiology Acute Exacerbations Treatment
4. Slide 4: Changes in Definition Denver Health of COPD ATS/ERS Guidelines  COPD has systemic consequences - Systemic inflammation - Weight loss - Skeletal muscles - Cardiac disease and death (Huiart, Chest 2005) > 5648 receiving “1st Rx for COPD” > HF most common cause of hospitalization > More hospitalizations for CV disease than COPD > CVD more common cause of death than COPD
5. Slide 5: COPD Epidemiology Denver Health Prevalence: 12.4 - 24 million in US Morbidity:  2004: 461,000 hospitalizations (4th most common)  1.5 million ED visits Mortality:  120,000 deaths in 2001 (6th most common - 3rd by 2020)  1 death/4 min (14 during this lecture)  Only cause of death in top 10 that is  Cost:  $6.5 billion
6. Slide 6: COPD Epidemiology: Denver Health Gender Discrepancy in Mortality  Mortality for women on O2 Machado, AJRCCM 2006
7. Slide 7: COPD Phenotyping Denver Health Correlates with Does Not Correlate FEV1 with FEV1  Health status  Emphysema  Resource utilization  Hyperinflation  AECOPD  BMI  Mortality  Peripheral muscle fxn  Small airway wall thickness  Dyspnea - Inflammatory cell infiltration  Exercise tolerance - Smooth muscle - Subepithelial fibrosis
8. Slide 8: COPD Phenotyping Denver Health (courtesy John Riley, B & W) FEV1: 105% FEV1: 95% FEV1: 40% DLCO: 50% DLCO: 70% DLCO: 70%
9. Slide 9: COPD Phenotyping: Predictors of Mortality Denver Health (Multivariate Analysis) 609 pts, NETT, medical Rx Predictor Hazard Ratio % Upper lobe emphysema 1.80 Age > 70 1.72 RV (% predicted) 1.56 Perfusion ratio 1.53 Modified BODE 1.48 Maximum work 1.48 O2 use 1.40 Hemoglobin < 13.4 1.38 DLCO < 22 1.36 Martinez, AJRCCM 2006
10. Slide 10: COPD Phenotyping: Denver Health CRP Predicts Hospitalization and Prognosis Hospitalization Death Dahl, AJRCCM 2006
11. Slide 11: COPD Phenotyping: Denver Health BNP Predicts PHT and Prognosis 176 pts “scheduled for RH cath” BNP Predicts PHT predicts BNP predicts PHT survival survival 85% sensitivity 88% specificity (5% with Ppa > 40 torr) Leuchte, AJRCCM 2006
12. Slide 12: COPD Genetics Denver Health Candidate Gene Abns  SERPINA 1 (-1-AT)  MMP-9 (C-1562 SNP  promotor activity)  ADAM-33 (adhesion, signaling, proteolysis)  Elastin (Gly  Asp in terminal exon)  Secretory PLA2, Group IID  CCL1 SNP ( AECOPD x 2 yr)
13. Slide 13: COPD Pathophysiology: Denver Health Chronic Inflammation Tissue Airspace Cells (x 1012) Control COPD Control COPD PMNs (x 1012) 24 ± 8 140 ± 29* 20 ± 5 300 ± 50* Alv Macs (x 1012) 5±2 71 ± 19* 270 ± 80* 4000 ± 400* Eos (x 108) 25 ± 8 220 ± 50* 3 ± 1* 8 ± 1* CD4+ (x 1012) 45 ± 10 330 ± 58* 58 ± 30* 750 ± 89* CD8+ (x 1012) 31 ± 6 250 ± 51* 40 ± 17* 1400 ± 590* No smoking for mean of 9 yrs Retamales, AJRCCM 1997
14. Slide 14: COPD Pathophysiology Inflammatory Model: Denver Health New Ideas Cigarette Smoke Irritants  PDE4-dependent (Martorana, 2005)  Blocked by simvistatin (Lee, 2005)  Dust-induced (Al-SiO4, kaolin) (Giron, 2005)  Related to adenosine receptor affinity/density (Varani, 2006) Oxidative stress Inflammatory Neutrophil elastase cells (apoptosis) Metalloproteinases  LTB4 (Santus, 2005)  COHb CD8+ (Yasuda, T cells Peribronchial fibrosis Loss of alveolar units 2005) Genetics (?) Lack of SP-D  Starvation Latent  RSV in 33%, (Coxson, 2004) Viruses   FEV1 decline  TGFSmad 2,3  Collagen domain (Wilkinson, 2006) (Kingma, 2006)  IL-1Lappalainen, 2005)
15. Slide 15: COPD Pathophysiology: Vascular Apoptosis Model Denver Health New Ideas Cigarette Smoke Klotho gene Cocaine Vascular cell Vasoconstriction death  Anti-endothelial Proteinases, Abs (immune) VEGF (Taraseviciene-Stewart, 2005)  Vasculitis Loss of alveolar units (Hunt, 2006) (apopotosis)
16. Slide 16: COPD Physiology: Denver Health Respiratory Muscles Functional diaphragm impairment  Loss of myosin heavy chains   ubiquitin-conjugated proteins ( protein degredation) (Ottenheijm, AJRCCM 2006) Myosin-Actin Sarcomere Caspace-3 E-3 Ligases Myosin (Astrigin-1) (MURF-1) Myosin-Ubiquitin 26S Proteosomes Degradation
17. Slide 17: COPD Physiology: Respiratory Muscles Denver Health Functional diaphragm impairment  Dysfunctional contractile proteins - Ca++ sensitivity - Alternative titin gene splicing (Moore, 2006) Question  ”Disease” vs epiphenomenon (?)
18. Slide 18: COPD Physiology Gas Trapping  PInspmax Denver Health TLC Resp Muscles  Weak? Lung Volume  Dysfunctional? Respiratory Muscle Weakness (? fatigue) RV -100 0 PInspmax
19. Slide 19: COPD Physiology: Denver Health Skeletal Muscles in COPD  Muscle mass  Skeletal muscle weakness assoc’d with: -  exercise capacity -  HRQOL -  mortality  No benefit of nutritional support or testosterone   cytokines (TNF-NF-B) -  protein synthesis -  protein degredation -  muscle regeneration
20. Slide 20: AECOPD: Denver Health Dynamic Hyperinflation 22 COPD pts Hospitalized for AECOPD Stevenson, AJRCCM 2005
21. Slide 21: AECOPD: Denver Health Biomarkers 90 pts, stable/exacerbation, most on ICS Abx and/or systemic steroids “Severity” by sxs and PEF CRP IL-6 MPIF-1 PARC ACRP-30 s-ICAM-1 Amphiregulin BDNF -NGF ENA-78 Eotaxin-2 Erb-B2 Fibrinectin IFN- IL-1 IL-1RA IL-2RIL-8 IL-12 p40 IL-15 IL-17 IP-10 ITAC MCP-1 MIP-1 MMP-9 MPO Prolactin RANTES L-selectin TGF- TIMP-1 TNF- TNFR1 TNFR2 VEGF Hurst, 2006
22. Slide 22: AECOPD: Denver Health Biomarkers Purpose?  Dx AECOPD  Assess severity  Dx other problem  Pathobiology  Etiology Hurst, 2006
23. Slide 23: AECOPD: Denver Health Left Heart Dysfunction Abroug, AJRCCM 2006  148 consecutive pts with AECOPD - 55 (37%) on mechanical ventilation  All got ECHO, BNP, Troponins  Excluded pneumonia, PE, CPA, inotropes ARF, nonechogenic  LVF and RVF diagnosed by 4 MDs - Definite, Possible, Unlikely - Clinical data (not BNP or Troponins)
24. Slide 24: AECOPD: Denver Health Left Heart Dysfunction 75 (51%) with LV dysfunction  17 (23%) systolic dysfunction  48 (64%) diastolic dysfunction  10 (13%) both 41 (31%) 20 BNP > 1000 82 (14%) 94% Sensitive (55%) 77% Specific (Abroug, AJRCCM 2006)
25. Slide 25: AECOPD: Denver Health Pulmonary Embolism Spiral CT & US  211 consecutive pts with “unexplained” AECOPD - Not requiring mechanical ventilation - No acute bronchitis, pneumonia, PTX - Disparity between CXR and ABGs  49/197 (25%) positive for PE - 43 by CT (19 of whom had + US) - 6 by US  Associations: - Previous PE, malignancy, 5 torr  PaCO2 (Tillie-Leblond, 2006)
26. Slide 26: COPD Rx: Denver Health Steroid Resistance Limited effect of steroids in stable disease  Cells, cytokines, proteases in BAL  Histology of biopsies  IL-8, TNF suppression  AM cytokine production Oxidative/nitrative stress inhibits HDAC fxn
27. Slide 27: Mechanisms of Transcription Denver Health Regulation Histone octamer H3 H4 H3 H3 H4 H4 H2AH3 H2B H2A Lysine H2A H2A H2B
28. Slide 28: Mechanisms of Transcription Denver Health Regulation Histone acetyltransferases (HAT) (Co-activators: CBP, p300, PCAF) HAT HDAC Histone deacetylases (HDAC) (Co-repressors: NuRD, Sin3, Co-REST)
29. Slide 29: Histone Acetyltransferases Denver Health IL-1 TNF IIB2 IB2 CS ROS NF-B GR CS NF-B Cell wall CBP (HAT activity) Nucleus HDAC ROS
30. Slide 30: Histone Acetylation Denver Health in COPD Ito, NEJM 2005
31. Slide 31: COPD Rx Denver Health What Endpoint?  FEV1   FEV1 over time  Mortality  QOL  AECOPD
32. Slide 32: COPD Rx: Denver Health GOLD Guidelines
33. Slide 33: COPD Rx: Denver Health Long-Acting Bronchodilators GOLD Guidelines  Regular treatment with long-acting bronchodilators is more effective and convenient than treatment with short-acting agents  Regular use of a long-acting bronchodilator… improves health status  Treatment with a long-acting bronchodilator reduces the rate of AECOPD
34. Slide 34: COPD Rx: Denver Health Do LABAs  AECOPD? (Sin, JAMA 2003)
35. Slide 35: COPD Rx: Does Tiotropium  AECOPD? Denver Health (Sin, JAMA 2003)
36. Slide 36: COPD Rx: Denver Health ICS GOLD Guidelines  Regular treatment with ICS is appropriate for symptomatic patients with COPD with an FEV1 < 50% predicted (stages III and IV) and repeated AECOPD (e.g., 3/3 yr) (Evidence A).  This treatment has been shown to reduce AECOPD and thus improve health status (Evidence A)  Withdrawal from treatment can lead to AECOPD in some patients.
37. Slide 37: COPD Rx: Do ICS  AECOPD? Denver Health Sin, JAMA 2003
38. Slide 38: Effect of Rx on AECOPD Denver Health (Suissa, AJRCCM 2006) Methods of Analysis  Unweighted (individual pt data) (Bad) - AEs for each pt/time of f/u for each pt - Each pt contributes equally regardless of f/u time - Exaggerates Rx effect  Weighted (pooled data) (Better) - Total AE for all pts/total time of f/u for all pts - Weights each pt’s AE rate by their f/u time - Produces correct and best estimate (i.e., maximum likelihood estimate) of AE rate (not biased by short f/u)
39. Slide 39: Effect of Rx on AECOPD Denver Health (Suissa, AJRCCM 2006) Analysis of weighted data  Assume Poisson distribution for AEs (Bad) - AEs can occur repeatedly, randomly, independently - Ignores that some pts may have frequent AEs and some may have none  Estimate variability and use “overdispersion parameter” (Better) - p value and CI based on within- and between- subject variability
40. Slide 40: COPD Rx: Denver Health Quality of the Data Cited supporting references  Many used unweighted analyses  None used an overdispersion parameter  Some analyzed adjusted data  One  QOL just exceeded “clinically significant”  (e.g., 5 vs 4)  Many included Pharma employees as authors with analyses performed in-house  Some actually reported NO beneficial effects
41. Slide 41: Gold Sponsors Denver Health
42. Slide 42: COPD Rx: Denver Health Do ICS  AECOPD? Berge (+ Glaxo), BMJ 2000 (ISOLDE)  ICS, LABA, ICS + LABA, placebo  Analyzed by Glaxo  Reported median exacerbation rate  # AEs/# Rx days extrapolated to #/yr  Unweighted analysis (overestimates effect)
43. Slide 43: COPD Rx: Denver Health Do ICS  AECOPD? Van der Valk, AJRCCM 2003  Routine Rx + ICS x 4 M, continue ICS vs P  Primary outcome measures - First and second AE - Rapid recurrent AEs - HRQL  21% crossovers  1.3  1.5 vs 1.3  1.6 AEs/yr - 48% had no AEs  Time to first AE different (“adjusted for smoking status”)
44. Slide 44: COPD Rx: Denver Health Does Tiotropium  AECOPD? Niewoehner, AIM 2005  1829 pts (Mod-Severe)  Tiotropium vs usual Rx AECOPD (1 yr):  Tiotropium: 28%  Placebo: 32%  P < 0.05 “These treatment effects were small to modest, and their overall clinical importance must be weighed against other considerations, including cost”
45. Slide 45: COPD Rx: Denver Health Do ICS  AECOPD? Szafranski, ERJ 2003 (126)  ICS, LABA, ICS + LABA, placebo  Poisson regression, dispersion adjustment  Corresponding author @ Astra-Zeneca Rx P value ICS + LABA vs Placebo 0.035 ICS + LABA vs ICS NS ICS + LABA vs LABA 0.043 ICS vs Placebo NS LABA vs Placebo NS  No correction for multiple comparisons (P < 0.016)
46. Slide 46: COPD Rx: Denver Health Do ICS  Mortality? TORCH study (NEJM 2007)  6100 pts, FEV1 ~ 1.2 L (44%) - Salmeterol - Salmeterol/fluticasone - Fluticasone - Placebo  Endpoints: - Death (Primary) - Frequency of AECOPD - QOL (SGRQ) - Lung function Calverley, 2007
47. Slide 47: COPD Rx: Denver Health Do ICS  Mortality? 3-yr mortality:  Placebo: 15.2%  Combination: 12.6%  17.5% relative   P = 0.052 LaVecchia & Fabbri  Salmeterol vs not  13 vs 15.6% (P = 0.004)  Fluticasone vs not  14.3 vs 14.3% (P = 0.99) Calverley, 2007
48. Slide 48: COPD Rx: Denver Health Do ICS  Mortality? 3-yr COPD mortality:  Placebo: 6.0%  Combination: 4.7%  21.7% relative   P = 0.11  Fluticasone: 6.9%  Combination: 4.7%  31.8% relative   P = 0.008  LABA vs Combo: NS Calverley,NEJM 2007
49. Slide 49: COPD Rx: Denver Health Do ICS  Mortality? FEV1 (ml) SGRQ (units) Calverley, NEJM 2007
50. Slide 50: COPD Rx: Denver Health Do ICS  Mortality? Problems:  40% drop out in placebo group (P < 0.05)  All pts had indications for Rx  Pts with more severe disease might not have enrolled  Pneumonia - Placebo: 12.3% - Combination: 19.6% (P < 0.001) - Ernst, AJRCCM 2007: RR 1.70 (1.63-1.77) Rabe, NEJM 2007
51. Slide 51: COPD Rx: Denver Health Do ICS  Mortality?  “All trials are a gamble, and the TORCH investigators came close to winning, but did not win”  “LABA was a winner, ICS was a clear loser”  Combination Rx better - Health status - Use of oral steroids - AECOPD -  in FEV1  Combination Rx: severe disease &/or AECOPD (same as GOLD recommendations)  More pneumonia in combination Rx Rabe, NEJM 2007
52. Slide 52: COPD Rx: Denver Health Novel Therapies PDE4 inhibitors  PDE4 degrades cAMP - Modulates inflammation - Bronchodilator?   FEV1, QOL, ? AECOPD vs placebo - Roflumilast (Rabe, 2005) - Cilomilast (Rennard, 2006) Infliximab (anti-TNF)  No benefit (N = 14) (van der Vaart, 2005)
53. Slide 53: Summary Denver Health Definition Epidemiology Phenotyping Genetics Pathophysiology Acute Exacerbations Treatment
54. Slide 54: Smoking Addiction Denver Health