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Lessons from great trials for the pulmonologist: the NETT and COPDgene

Lessons from great trials for the pulmonologist: the NETT and COPDgene. Nathaniel Marchetti, DO Temple University Philadelphia, PA. The National Emphysema Treatment Trial (NETT). NETT Productivity. >75 peer reviewed publications using NETT data Who should and should not have LVRS?

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Lessons from great trials for the pulmonologist: the NETT and COPDgene

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  1. Lessons from great trials for the pulmonologist: the NETT and COPDgene Nathaniel Marchetti, DO Temple University Philadelphia, PA

  2. The National Emphysema Treatment Trial (NETT)

  3. NETT Productivity • >75 peer reviewed publications using NETT data • Who should and should not have LVRS? • What did we learn about emphysema? • Pathobiology of emphysema • Genetics • Role of hyperinflation • Hemodynamics in advanced emphysema • Measurements of lung function in severe empysema • Racial differences in severe emphysema • Mortality in emphysema • Medical therapy in severe emphysema • Oxygen use in severe emphysema Criner et al, AJRCCM, 2011

  4. NETT Design • 17 clinical centers • Randomized 1,218 patients to medical therapy or medical therapy plus LVRS • Screened 3,777 • Pulmonary function • FEV1 15% to 45% • TLC >105% • RV > 150% • No significant cardiac disease or pulmonary HTN • No other pulmonary diseases present • Bilateral emphysema amenable to LVRS • Upper lobe predominant • Diffuse NETT Research Group Chest, 1999

  5. NETT Design • Pulmonary rehab • 16-20 sessions pre-randomization • 10 sessions post-randomization • Long term maintenance • Aggressive bronchodilator therapy • Surgical therapy • Bilateral stapled resection of 25-30% of lung • Median sternotomy at 8 centers • VATS at 3 centers • 6 centers randomized to MS vs VATS NETT Research Group Chest, 1999

  6. NETT Design • Anesthesia • Intra-operative care standardized • Median sternotomy patient has epidural catheters • Extubation within 2 hours • Physical therapy started on 1st post-op day NETT Research Group Chest, 1999

  7. Outcomes • Primary • Survival • 10 W improvement on CPET • Secondary • Quality of life • Cost effectiveness • Pulmonary function • CT scans and nuclear perfusion scans • Oxygen requirement • 6 minute walk distance • Cardiovascular measures (echo) NETT Research Group Chest, 1999

  8. Survival Surgical 90-day mortality = 7.9% Medical 90-day mortality = 1.3% NETT Research Group NEJM, 2003

  9. Survival High risk group FEV1< 20% predicted + Either DLCO< 20% or homogeneous emphysema Surgical 30-day mortality = 16% Medical 30-day mortality = 0% NETT Research Group NEJM, 2003

  10. Survival excluding high risk Surgical 30-day mortality = 2.2% Medical 30-day mortality = 0.2% NETT Research Group NEJM, 2003

  11. Survival UL and low exercise = YES UL and high exercise = NO NETT Research Group NEJM, 2003

  12. Survival Non-UL and low exercise = NO Non-UL and high exercise = NO NETT Research Group NEJM, 2003

  13. Exercise performance all patients NETT Research Group NEJM, 2003

  14. Durability of LVRS High risk patients excluded Naunheim et al, Ann Thorac Surg 2006

  15. Durability of LVRS UL/Low Exercise UL/high Exercise Naunheim et al, Ann Thorac Surg 2006

  16. Durability of Exercise UL/Low UL/High Naunheim et al, Ann Thorac Surg 2006

  17. Quality of Life Durability MCID for SGRQ is -4 but a priori was -8 for NETT Naunheim et al, Ann Thorac Surg 2006

  18. PaO2 Following LVRS Snyder et al, AJRCCM 2008

  19. O2 needs following LVRS Snyder et al, AJRCCM 2008

  20. LVRS Enhances CO2 Elimination During Exercise Sub-study CPET with a-line (n=47) Criner et al, Chest 2009

  21. LVRS Improves f/VT Index Criner et al, Chest 2009

  22. LVRS Reduces Exacerbations Surgical 0.27 exacerbations/patient-year Medical 0.37 exacerbations/patient-year 30% reduction (13-48%, p=0.0005) Washko et al, AJRCCM 2008

  23. Most important lessons from NETT? • LVRS works!! • Interventions to improve survival • Smoking cessation • Oxygen • LVRS • LVRS improves • Oxygenation and oxygen requirements • Favorable alters breathing patterns • Reduces exacerbations

  24. Who should not get surgery? NETT Research Group NEJM, 2001

  25. Who should not have LVRS? Criner et al, PATS 2008

  26. Durability of non-UL/high exercise Naunheim et al, Ann Thorac Surg 2006

  27. Who should not have LVRS? Criner et al, PATS 2008

  28. α-1 Antitrypsin Deficiency • 16 patients had severe deficiency (<80 mg/dL) • 10 randomized to surgery • 7 had upper lobe predominant emphysema • Compared to the 6 that had medical Rx • LVRS mortality was higher (20% vs 0%) • Compared to normal α-1 AT levels • Less improvement in exercise • Less improvement in FEV1 response Stoller et al, Ann Thorac Surg 2007

  29. What did NETT teach us about surgical techniques?

  30. LVRS and Air Leaks • 580/608 patients had surgery • Air leak data available on 552 • 90% had air leak in first 30 days • Presence of air leak not effected by • Surgical approach (VATS vs MS) • Use of any buttressing agent (fibrin glue, etc) • Stapler brand • Intraoperative procedures • Pleurodesis • Tenting DeCamp et al, Ann Thorac Surg 2006

  31. Duration Median 7 days DeCamp et al, Ann Thorac Surg 2006

  32. Consequence of air leak • No difference in mortality • Longer hospital stay (11.8+6.5 vs 7.6+4.4 d, p=0.0005) • Increased pneumonia (20% vs 7.4%) • Increased ICU admission (9.3% vs 1.9%) DeCamp et al, Ann Thorac Surg 2006

  33. Risk Factors • Increased risk and duration • Lower diffusion capacity (p=0.06) • Upper lobe disease (p=0.04) • Presence of moderate to severe adhesions (p=0.007) • Increased Duration • Caucasian race (p<0.0001) • Use of inhaled steroid (p=0.004) • Lower FEV1 (p=0.0003) DeCamp et al, Ann Thorac Surg 2006

  34. Video Assisted Thorascopy (VATS) vs Median Sternotomy (MS) • 8 centers used MS • 3 used VATS • 6 randomized to either • Total patients: 359 MS vs 152 VATS • Randomized patients: 77 MS vs 71 VATS McKenna et al, J Thorac Cardiovasc Surg, 2004

  35. VATS vs MS • 30 day mortality • 2.8% MS vs 2.0% VATS (p = 0.76) • 90 day mortality • 5.9% MS vs 4.6% (p = 0.67) • No mortality difference for randomized patients • Intra-operative hypoxemia more common in VATS (0.8% vs 5.3%) • No difference in days with air leak • Median hospital LOS of 10 d in MS vs 9 in VATS (p=0.01) • Randomized patients: 15d for MS vs 9d for VATS (p<0.001) McKenna et al, J Thorac Cardiovasc Surg, 2004

  36. Costs of VATS Compared to MS • VATS = MS for outcomes and complications • Shorter hospital stay with VATS • Less expensive McKenna et al, J Thorac Cardiovasc Surg, 2004

  37. Pathologic Lessons

  38. Thickened Epithelium Inflammation Subepithelial Fibrosis Small Airway Disease in Emphysema? Smooth Muscle Hypertrophy

  39. Nature of Small Airway Obstruction in COPD • 159 patients across all GOLD stages • 59 GOLD III/IV patients from NETT • 100 GOLD 0–III patients • Measure small airway (<2mm) luminal content and the amount of inflammation in airway • Correlated luminal occlusion and airway edema with FEV1 Hogg et al, NEJM 2004

  40. Luminal Occlusion Hogg et al, NEJM 2004

  41. FEV1 falls as lumen occludes r = -0.505, p=0.001 Hogg et al, NEJM 2004

  42. FEV1 falls as the airway thickens r = -0.687, p<0.001 Hogg et al, NEJM 2004

  43. More inflammatory cells with increasing GOLD stage Hogg et al, NEJM 2004

  44. Significance of Small Airway Disease in Emphysema • Airway thickening is possibly tissue remodeling • Decreased mucociliary clearance leading to obstruction • Increased lymphoid follicles possibly secondary to: • Repeated infection • Bacterial colonization • Persistent inflammation may explain the decline in lung function even after smoking cessation • All NETT subject non-smokers >6 months Hogg et al, NEJM 2004

  45. Decreased Survival with Luminal Occlusion OR 3.28, 1.55-6.92; p=0.002 Hogg et al, AJRCCM 2007

  46. Effect of ICS or Oral Steroids • No effect on airway thickness or luminal occlusion • Less airway associated lymphoid follicles for those on oral steroids • Represents decreased adaptive immunity • Could this explain increased pneumonia? r = -0.505, p=0.001 Hogg et al, AJRCCM 2007

  47. Mortality and Emphysema

  48. Predictors of mortality in severe emphysema • 609 patients in the medical arm of NETT • Well characterized • Severe disease with high mortality • High quality long term follow up Martinez et al, AJRCCM 2006

  49. Mortality in Medical Arm NETT Martinez et al, AJRCCM 2006

  50. BODE in multivariate model Martinez et al, AJRCCM 2006

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