NETT

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Fishman A, et al. "A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema". The New England Journal of Medicine. 2003. 348(21):2059-2073.
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Clinical Question

Among patients with severe, bilateral emphysema, does lung volume reduction surgery improve survival or level of function when compared to medical therapy alone?

Bottom Line

Lung volume reduction surgery in patients with severe bilateral emphysema does not improve survival but is associated with improved exercise tolerance when compared to medical therapy alone. A survival benefit may be present for low- and moderate-risk patients with upper lobe emphysema and low exercise capacity.

Major Points

Hyperinflation of emphysematous lung results in worsening exercise tolerance, shortness of breath, worsening QOL, and mortality.[1] Surgical resection of affected lung tissue is thought to allow expansion of less damaged lung. This restores more normal lung function with symptom improvement and a potential mortality benefit.[2] A small randomized trial of lung-volume-reduction surgery (LVRS) by Geddes et al. (2000) demonstrated that an improved functional outcome though no mortality benefit.[3] A large randomized trial was needed to further validate the intervention.

The pragmatic 2003 National Emphysema Treatment Trial (NETT) randomized 1,218 patients with severe emphysema who had participated in pulmonary rehabilitation to LVRS or medical therapy. With 2.4 years of follow-up, LVRS was associated with an improved exercise capacity but no mortality benefit when compared to medical therapy in the total population. A post-hoc subgroup analysis demonstrated a mortality benefit for non-high-surgical risk patients with upper lobe disease and lower baseline exercise tolerance. Furthermore, non-high-surgical risk patients with non-upper lobe disease and high exercise tolerance experienced an increased mortality rate. A 2006 follow-up publication by the NETT group reported persistence of these findings with 4.3 years of follow-up.[4]

This trial has been criticized for its use of the often maligned post-hoc subgroup analyses and the authors' resultant interpretation of the survival benefit.[5] These outcomes are, therefore, questionable as they do not meet the highest possible level of quality -- that of a prospective, randomized trial with predefined outcomes. No large randomized trial has been performed comparing these subgroups in a predefined manner.

There was much interest LVRS as a therapy for emphysema in the early 2000s. However, following the publication of NETT (and despite Medicare extending coverage for the procedure), it became unpopular in the late 2000s.[6]

Guidelines

Canadian Thoracic Society (2007):[7]

  • LVRS is potentially effective for those with advanced COPD who meet the inclusion and exclusion criteria of NETT (level 1A)

American Thoracic Society and European Respiratory Society COPD diagnosis and management (2004):[8]

  • LVRS may improve symptoms, QOL, and possibly survival in highly-selected patients (no rating given)

Design

  • Multicenter, open-label, randomized, controlled trial
  • N=1,218
    • LVRS (n=608)
    • Medical therapy (n=610)
  • Setting: 17 centers in the US
  • Enrollment: 1998-2002
  • Mean follow-up: 29.2 months
  • Analysis: Intention-to-treat
  • Primary outcomes:
    • All-cause mortality
    • Improvement in exercise capacity at 24 months

Population

Inclusion Criteria

  • Severe, bilateral emphysema with pre-rehabilitation PFTs as follows:
    • Post-bronchodilator TLC: ≥100%
    • Post-bronchodilator RV: ≥150%
    • FEV1: ≤45% (also ≥15% if age ≥70 years)
    • PaCO2 on room air: <60 mmHg (≤55 mmHg in Denver, CO)
    • PaO2 on room air: ≥45 mmHg (≥30 mmHg in Denver, CO)
  • Completion of a pulmonary rehabilitation program
  • Non-smoker for ≥4 months
  • Surgical clearance by a cardiologist if indicated, approval for surgery by CT surgeon, pulmonologist, and anesthesiologist after rehabilitation program

Exclusion Criteria

  • Post-rehabilitation, post-bronchodilator FEV1: ≤20% with either non-heterogeneous emphysema or CO diffusion ≤20% (added in 2001)
  • Diffuse emphysema non amenable to LVRS
  • Prior LVRS, sternotomy, or lobectomy
  • Pleural or interstitial disease precluding surgery
  • Bulla ≥1/3rd the volume of the containing lung
  • "clinically significant bronchiectasis" or "clinically significant" recurrent infections characterized by sputum
  • Pulmonary nodule requiring surgical intervention
  • LVEF <45% or MI in prior 6 months
  • BP ≥200/110 mmHg
  • Pulmonary hypertension
  • Unexplained weight loss in prior 90 days
  • Prednisone ≥20 mg/daily or equivalent corticosteroid
  • Exercise-related syncope
  • HR <50 BPM, frequent multifocal PVCs, sustained SVT, complex ventricular arrhythmia, or other cardiac condition precluding an exercise program
  • Life-shortening neoplasm or other systemic disease
  • 6MWT <140 meters

Baseline Characteristics

From the LVRS group.

  • Demographics: Age 67 years, non-Hispanic white 96%, non-Hispanic black 3%, female 42%
  • Emphysema distribution:
    • Upper lobe predominant: 63%
    • Non-upper lobe predominant: 37%
    • Heterogeneous: 54%
    • Homogeneous: 46%
  • PFTs: post-bronchodilator FEV1 26.8% of predicted, post-bronchodilator TLC 128%, post-bronchodilator residual volume 220%, CO diffusion 28.3%
  • Other respiratory data: Perfusion ratio 0.30 (radionucleotide perfusion ratio of upper to middle and lower lung fields), workload 38.7W, distance in 6MWT 1,216 ft,
  • Labs: PaO2 64.5 mmHg, PaCO2 43.3 mmHg
  • Questionnaires: St. George's Respiratory 52.5 (out of 100, lower is better QOL), Quality of Well-Being 0.58 (out 1, higher is better QOL), UCSD Shortness of Breath 61.6 (out of 120, lower is less SOB)

Interventions

  • Patients who had completed a medical evaluation and 6-10 weeks of pulmonary rehabilitation were randomized to one of two groups:
    • LVRS: Stapled wedge resection of 20-35% of diseased portions of each lung through a median sternotomy or VATS
    • Medical therapy: No surgery
  • Both groups were treated with appropriate medical therapy and counseling about issues including smoking cessation

Outcomes

Comparisons are LVRS vs. medical therapy. P-Y, person-year; RR, risk ratio.

Primary Outcomes

All-cause mortality
0.11/P-Y vs. 0.11/P-Y (RR 1.01; P=0.9)
Improvement in exercise capacity at 24 months
15% vs. 3% (OR 6.27; P<0.001)

Secondary Outcomes

All-cause mortality at 90 days
7.9% vs. 1.3% (P<0.001)
Improvement in QOL at 24 months
33% vs. 9% (OR 4.90; P<0.001)

Subgroup Analysis

High-risk surgical patients were excluded from subgroup analyses except where explicitly stated. High-risk was defined as FEV1 <20% and homogenous emphysema or CO diffusion <20%. All analyses are post-hoc.

All-cause mortality
High-risk: 0.33/P-Y v.s 0.18/P-Y (RR 1.82; P=0.06)
Non-high-risk: 0.09/P-Y vs. 0.10/P-Y (RR 0.89; P=0.31)
Upper lobe emphysema, low exercise capacity: 0.07/P-Y vs. 0.15/P-Y (RR 0.47; P=0.005)
Upper lobe emphysema, high exercise capacity: 0.07/P-Y vs. 0.07/P-Y (RR 0.98; P=0.70)
Non-upper lobe emphysema, low exercise capacity: 0.15/P-Y vs. 0.18/P-Y (RR 0.81; P=0.49)
Non-upper lobe emphysema, high exercise capacity: 0.10/P-Y vs. 0.05/P-Y (RR 2.06; P=0.02)
All-cause mortality at 90 days
High-risk: 28.6% vs. 0% (P<0.001)
Non-high-risk: 5.2% vs. 1.5% (P=0.001)
Upper lobe emphysema, low exercise capacity: 2.9% vs. 3.3% (P=1.00)
Upper lobe emphysema, high exercise capacity: 2.9% vs. 0.9% (P=0.17)
Non-upper lobe emphysema, low exercise capacity: 8.3% vs. 0% (P=0.02)
Non-upper lobe emphysema, high exercise capacity: 10.1% vs. 0.9% (P=0.003)
Improvement in exercise capacity at 24 months
High-risk: 7% vs. 2% (OR 3.48; P=0.37)
Non-high-risk: 16% vs. 3% (OR 6.78; P<0.001)
Upper lobe emphysema, low exercise capacity: 30% vs. 0% (OR cannot be calculated; P<0.001)
Upper lobe emphysema, high exercise capacity: 15% vs. 3% (OR 5.81; P=0.001)
Non-upper lobe emphysema, low exercise capacity: 12% vs. 7% (OR 1.77; P=0.50)
Non-upper lobe emphysema, high exercise capacity: 3% vs. 3% (OR 0.90; P=1.00)
Improvement in QOL at 24 months
High-risk: 10% vs. 0% (OR cannot be calculated; P=0.03)
Non-high-risk: 37% vs. 10% (OR 5.06; P<0.001)
Upper lobe emphysema, low exercise capacity: 48% vs. 10% (OR 8.38; P<0.001)
Upper lobe emphysema, high exercise capacity: 41% vs. 11% (OR 5.67; P<0.001)
Non-upper lobe emphysema, low exercise capacity: 37% vs. 7% (OR 7.35; P=0.001)
Non-upper lobe emphysema, high exercise capacity: 15% vs. 12% (OR 1.35; P=0.61)

Criticisms

  • Authors draw conclusions from post-hoc subgroup analyses.[5]
  • High rate of missing data, especially those in the medical arm.[9]
  • Costly intervention.[10]

Funding

NHLBI and other public sources.

Further Reading

  1. Criner GJ. "Alternatives to lung transplantation: Lung volume reduction for COPD." Clinics in Chest Medicine. 2011;32(2):379-397.
  2. Drazen JM and Epstein AM. "Editorial: Guidance concerning surgery for emphysema." The New England Journal of Medicine." 2003;348:2134-2136.
  3. Geddes D, et al. "Effect of lung-volume-redution surgery in patients with severe emphysema." The New England Journal of Medicine. 2000;343(4):239-245.
  4. Naunheim KS et al. "Long-term follow-up of patients receiving lung-volume-reduction surgery versus medical therapy for severe emphysema by the National Emphysema Treatment Trial research group." Annals of Thoracic Surgery. 2006;82(20):431-443.
  5. 5.0 5.1 Ware JH. "The National Emphysema Treatment Trial -- How strong is the evidence?" The New England Journal of Medicine. 2003;348:2055-2056.
  6. Kolata, G. "Medicare says it will pay, but patients say 'no thanks'." The New York Times. 2006-03-03. Accessed 2014-09-06.
  7. O'Donnell DE et al. "Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease - 2007 update." Canadian Respiratory Journal. 2007;14(Sup B):5B-32B.
  8. Multiple authors. "American Thoracic Society and European Respiratory Society: Standards for the diagnosis and management of patients with COPD." Thoracic.org, E-pub. 2004. Accessed 2013-08-11.
  9. Multiple authors. "Correspondence: Lung-Volume-Reduction Surgery." The New England Journal of Medicine. 2003;349:999-1000.
  10. NETT Group. "Cost effectiveness of lung-volume-reduction surgery for patients with severe emphysema." The New England Journal of Medicine. 2003;348:2092-2102.