This document summarizes the National Emphysema Treatment Trial (NETT), a multicenter randomized controlled trial that compared lung volume reduction surgery (LVRS) to medical therapy alone in patients with severe emphysema. The trial found no difference in mortality between the two groups overall. However, LVRS was associated with improved exercise capacity. Subgroup analyses found possible survival benefits for non-high risk patients with upper lobe emphysema and low exercise capacity. The trial was criticized for its use of post-hoc subgroup analyses.

1. THE NATIONAL EMPHYSEMA TREATMENT
TRIAL
(NETT )
FIRAS ALJANADI
JOURNAL CLUB
RVH
16/09/2020

2. BACKGROUND
• HYPERINFLATION OF EMPHYSEMATOUS LUNG RESULTS IN:
 WORSENING EXERCISE TOLERANCE, SHORTNESS OF BREATH, WORSENING QOL, AND MORTALITY.
• LVRS/REDUCTION PNEUMOPLASTY /LUNG SHAVING/LUNG CONTOURING 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.
• WAS FIRST PROPOSED BY OTTO BRANTIGAN IN THE 1950’S :
 STAGED BILATERAL THORACOTOMIES WITH A CLAMP AND SEW METHOD OF VOLUME REDUCTION COUPLED WITH PARASYMPATHETIC
DENERVATION OF THE LUNG.
 REPORTED A 19% OP-MORTALITY IN 26 PATIENTS. THE PROCEDURE FELL OUT OF FAVOUR GIVEN THE HIGH MORTALITY AND
UNPREDICTABLE RESULTS
• JOEL COOPER LEARNED AND REVIVED OF LVRS IN THE EARLY 1990’S --- NEED FOR RCT AS:
 LUNG-VOLUME–REDUCTION SURGERY HAS BEEN PROPOSED AS A PALLIATIVE TREATMENT FOR SEVERE EMPHYSEMA
• EFFECTS ON MORTALITY, THE MAGNITUDE AND DURABILITY OF BENEFITS, AND CRITERIA FOR THE SELECTION OF PATIENTS HAVE
NOT BEEN ESTABLISHED
• 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 randomized trial
comparing lung-volume-
reduction surgery with
medical therapy for
severe emphysema
The New England Journal
of Medicine. 2003

4. 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?

5. DESIGN
• MULTICENTER, 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
• PRIMARY OUTCOMES:
• ALL-CAUSE MORTALITY
• IMPROVEMENT IN EXERCISE CAPACITY AT 24 MONTHS

6. 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)(8 KPA)
• PAO2 ON ROOM AIR: ≥45 MMHG (≥30 MMHG IN DENVER, CO)(6 KPA)
• 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

7. 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

8. 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
COUNSELLING ABOUT ISSUES INCLUDING SMOKING CESSATION

9. RESULTS
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)

11. Outcomes
Comparisons are LVRS vs. medical therapy. P-Y, person-year; RR, risk ratio.
• Primary Outcomes:MORTALITY AND MAXIMAL EXERCISE CAPACITY TWO YEARS AFTER RANDOMIZATION.
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:SECONDARY OUTCOMES INCLUDED THE DISTANCE WALKED IN SIX MINUTES, PULMONARY FUNCTION,
QUALITY OF LIFE, AND DEGREE OF DYSPNEA
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)

14. 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)

15. 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)

21. Criticisms
•Authors draw conclusions from post-hoc subgroup analyses.
•High rate of missing data, especially those in the medical arm.
•Costly intervention.
•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
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.
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

22. 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

23. FOLLOW UP
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 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.

24. Guidelines
Canadian Thoracic Society (2007):
•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):
•LVRS may improve symptoms, QOL, and possibly survival in highly-selected patients
(no rating given)

25. QUESTIONS
THANK YOU