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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

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

Nathaniel Marchetti, DO

Temple University

Philadelphia, PA



Nett productivity
NETT Productivity and

  • >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


Nett design
NETT Design and

  • 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


Nett design1
NETT Design and

  • 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


Nett design2
NETT Design and

  • 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


Outcomes
Outcomes and

  • 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


Survival
Survival and

Surgical 90-day mortality = 7.9%

Medical 90-day mortality = 1.3%

NETT Research Group NEJM, 2003


Survival1
Survival and

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


Survival excluding high risk
Survival excluding high risk and

Surgical 30-day mortality = 2.2%

Medical 30-day mortality = 0.2%

NETT Research Group NEJM, 2003


Survival2
Survival and

UL and low exercise = YES

UL and high exercise = NO

NETT Research Group NEJM, 2003


Survival3
Survival and

Non-UL and low exercise = NO

Non-UL and high exercise = NO

NETT Research Group NEJM, 2003


Exercise performance all patients
Exercise performance all patients and

NETT Research Group NEJM, 2003


Durability of lvrs
Durability of LVRS and

High risk patients excluded

Naunheim et al, Ann Thorac Surg 2006


Durability of lvrs1
Durability of LVRS and

UL/Low Exercise

UL/high Exercise

Naunheim et al, Ann Thorac Surg 2006


Durability of exercise
Durability of Exercise and

UL/Low

UL/High

Naunheim et al, Ann Thorac Surg 2006


Quality of life durability
Quality of Life Durability and

MCID for SGRQ is -4 but a priori was -8 for NETT

Naunheim et al, Ann Thorac Surg 2006


P a o 2 following lvrs
P and aO2 Following LVRS

Snyder et al, AJRCCM 2008


O 2 needs following lvrs
O and 2 needs following LVRS

Snyder et al, AJRCCM 2008


Lvrs enhances co 2 elimination during exercise
LVRS Enhances CO and 2 Elimination During Exercise

Sub-study CPET with a-line (n=47)

Criner et al, Chest 2009


Lvrs improves f v t index
LVRS Improves f/V and T Index

Criner et al, Chest 2009


Lvrs reduces exacerbations
LVRS Reduces Exacerbations and

Surgical 0.27 exacerbations/patient-year

Medical 0.37 exacerbations/patient-year

30% reduction (13-48%, p=0.0005)

Washko et al, AJRCCM 2008


Most important lessons from nett
Most important lessons from NETT? and

  • LVRS works!!

  • Interventions to improve survival

    • Smoking cessation

    • Oxygen

    • LVRS

  • LVRS improves

    • Oxygenation and oxygen requirements

    • Favorable alters breathing patterns

    • Reduces exacerbations


Who should not get surgery
Who should not get surgery? and

NETT Research Group NEJM, 2001


Who should not have lvrs
Who should not have LVRS? and

Criner et al, PATS 2008


Durability of non ul high exercise
Durability of non-UL/high exercise and

Naunheim et al, Ann Thorac Surg 2006


Who should not have lvrs1
Who should not have LVRS? and

Criner et al, PATS 2008


1 antitrypsin deficiency
α and -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



Lvrs and air leaks
LVRS and Air Leaks and

  • 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


Duration
Duration and

Median 7 days

DeCamp et al, Ann Thorac Surg 2006


Consequence of air leak
Consequence of air leak and

  • 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


Risk factors
Risk Factors and

  • 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


Video assisted thorascopy vats vs median sternotomy ms
Video Assisted Thorascopy (VATS) vs Median Sternotomy (MS) and

  • 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


Vats vs ms
VATS vs MS and

  • 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


Costs of vats compared to ms
Costs of VATS Compared to MS and

  • VATS = MS for outcomes and complications

  • Shorter hospital stay with VATS

    • Less expensive

McKenna et al, J Thorac Cardiovasc Surg, 2004



Small airway disease in emphysema

Thickened Epithelium and

Inflammation

Subepithelial

Fibrosis

Small Airway Disease in Emphysema?

Smooth

Muscle

Hypertrophy


Nature of small airway obstruction in copd
Nature of Small Airway Obstruction in COPD and

  • 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


Luminal occlusion
Luminal Occlusion and

Hogg et al, NEJM 2004


Fev 1 falls as lumen occludes
FEV and 1 falls as lumen occludes

r = -0.505, p=0.001

Hogg et al, NEJM 2004


Fev 1 falls as the airway thickens
FEV and 1 falls as the airway thickens

r = -0.687, p<0.001

Hogg et al, NEJM 2004



Significance of small airway disease in emphysema
Significance of Small Airway Disease in Emphysema and

  • 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


Decreased survival with luminal occlusion
Decreased Survival with Luminal Occlusion and

OR 3.28, 1.55-6.92; p=0.002

Hogg et al, AJRCCM 2007


Effect of ics or oral steroids
Effect of ICS or Oral Steroids and

  • 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



Predictors of mortality in severe emphysema
Predictors of mortality in severe emphysema and

  • 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


Mortality in medical arm nett
Mortality in Medical Arm NETT and

Martinez et al, AJRCCM 2006


Bode in multivariate model
BODE in multivariate model and

Martinez et al, AJRCCM 2006


Not predictive
Not predictive and

  • FEV1 alone (i.e. not in BODE)

  • Total % of emphysema on CT scan

  • DLCOwas weak in multivariate

  • PaO2 was not predictive while O2 use was

    • Oxygen increases mortality or epimarker of disease severity?

    • LOTT

Martinez et al, AJRCCM 2006


Mbode change in copd predicts mortality
mBODE Change in COPD Predicts Mortality and

  • BODE change in medical and surgical arms NETT

  • Divided group into BODE classes

    • Decrease by 1

    • No change

    • Increase by 1

    • Data missing

  • Used to predict death

Martinez et al, AJRCCM 2008


Changes in mbode
Changes in mBODE and

Martinez et al, AJRCCM 2008


Mbode change in surgical cohort and mortality
mBODE Change in Surgical Cohort and Mortality and

P<0.01

Martinez et al, AJRCCM 2008


Hr for change in mbode
HR for Change in mBODE and

P<0.01

Martinez et al, AJRCCM 2008


Genetic epidemiology of copd copdgene study design
Genetic Epidemiology of COPD (COPDGene) Study Design and

  • Multi-center (21) observational study

  • Designed to identify genetic factors associated with COPD

    • Genome-wide association study (GWAS) analysis to be done

  • Will permit identification of radiographic and clinical phenotypes to be identified

Regan et al, COPD 2011


Copdgene study population
COPDGene Study Population and

  • 10,000 subjects enrolled with 2/3 non-Hispanic whites and 1/3 African American

  • Enrollment goals were met early

  • Inclusion criteria

    • Self identified as non-Hispanic white or African American

    • Age 45-80 with 10 pack-years smoking history

Regan et al, COPD 2011


Copdgene study population1
COPDGene Study Population and

  • Exclusion criteria

    • Pregnancy due to CT imaging

    • Other lung disease except asthma

    • Prior LVRS or lobectomy

    • Active cancer

    • Suspected lung cancer

    • Metal in the chest

    • Recent AECOPD requiring therapy

    • Recent eye surgery

    • 1st or 2nd degree relative already in study

    • History of chest radiation therapy

Regan et al, COPD 2011


Data collected
Data Collected and

  • Blood for genetic and biomarker analysis

  • Inspiratory and expiratory HRCT scans with sub-millimeter thickness

  • Pre and post bronchodilator spirometry

  • ATS respiratory questionnaire

  • medical history, medications

  • St George’s respiratory questionnaire

  • BMI, blood pressure, oxygen saturation

  • Six minute walk test

Regan et al, COPD 2011


Analysis
Analysis and

  • HRCT phenotyping

    • Emphysema quantification

    • Gas trapping

    • Airway wall thickness

  • GWAS: look for genes associated with following:

    • COPD status defined by GOLD criteria

    • FEV1% as a continuous variable

    • HRCT parameters listed above

Regan et al, COPD 2011



Gold undefined subjects
GOLD Undefined Subjects and

  • Data from 1st 2,500 subjects

  • 9% of current or ex-smokers with

    • Low FEV1 but preserved FEV1/FVC ratio

  • GOLD-U has been described previously

    • Stable pattern

    • Associated with increased mortality

    • Associated with significant symptoms

  • COPDGene provided largest database with both clinical and radiographic data

Wan et al, AJRCCM 2011



Gold u comparison
GOLD-U Comparison and

GOLD-U

Controls

COPD

Wan et al, AJRCCM 2011


Gold u predictors
GOLD-U Predictors and

Wan et al, AJRCCM 2011


Significance of gold u
Significance of GOLD-U and

  • Represents significant # of smokers/ex-smokers

  • Clinical course largely unknown

    • ?progression

  • Are these changes related to obesity alone?

    • BMI contributes but changes in FEV1 are > than previously reported

    • No reduction in FRC compared to smoking controls


Early onset copd differences of race and sex
Early Onset COPD: Differences of Race and Sex and

  • First 2,500 subjects only

  • Early onset definition:

    • Age <55

    • FEV1/FVC < 0.7

    • FEV1 <50% predicted

  • Comparator group

    • Age >64

    • FEV1/FVC < 0.7

    • FEV1 <50% predicted

Foreman et al, AJRCCM 2011


Demographic clinical differences
Demographic & Clinical Differences and

Foreman et al, AJRCCM 2011


Multivariate analysis
Multivariate Analysis and

Foreman et al, AJRCCM 2011


Significance of findings
Significance of Findings and

  • Early onset COPD is rare

  • African Americans and women disproportionately affected

  • Smoked less

  • Maternal history of COPD is important

  • Genetic follow up studies pending

Foreman et al, AJRCCM 2011


Racial differences in quality of life in copdgene
Racial Differences in Quality of Life in COPDGene and

African Americans smoked less, were younger but had the same lung function

Han et al, Chest 2011


St george respiratory questionnaire
St George Respiratory Questionnaire and

African Americans had worse SGRQ scores (higher)

Han et al, Chest 2011


Multivariate analysis1
Multivariate Analysis and

  • After adjustment for age, sex, pack-years smoking, education level, MMRC dyspnea, 6MWD, and current smoking status no difference in quality of life in those without exacerbations

  • African Americans with history of prior exacerbation (1.887 for every exacerbation, p = 0.006)

Han et al, Chest 2011


Family history as a risk for copd
Family History as a Risk for COPD and

COPD >GOLD II

Hersch et al, Chest 2011


Multivariate analysis2
Multivariate analysis and

  • Controlling for demographics, parental history of smoking, parental history of COPD, childhood ETS

    • Parental history of COPD OR 1.73 (1.36-2.2), p = <0.001

    • Paternal history COPD 1.66 (1.24-2.22), p = 0.006

    • Maternal history COPD 1.51 (1.10-2.09), p = 0.011

Hersch et al, Chest 2011



Chronic bronchitc phenotype
Chronic Bronchitc Phenotype and

Kim et al, Chest 2011


Chronic bronchitics and aecopd
Chronic Bronchitics and AECOPD and

Kim et al, Chest 2011



Frequent vs non frequent exacerbators
Frequent vs non-frequent exacerbators and

Han et al, Thorax 2011


Effect of airway wall thickness and emphysema on exacerbations
Effect of Airway Wall Thickness and % Emphysema on Exacerbations

Han et al, Thorax 2011


Multivariate analysis3
Multivariate Analysis Exacerbations

Han et al, Thorax 2011


Smoking related ild on hrct
Smoking Related ILD on HRCT Exacerbations

  • Ground glass or reticular abnormalities

  • Diffuse centrilobular nodules

  • Non-emphysematous cysts

  • Honeycombing

  • Traction bronchiectasis

Washko et al, NEJM 2011


Ila vs no ila
ILA vs No ILA Exacerbations

Washko et al, NEJM 2011


Multivariate analysis4
Multivariate Analysis Exacerbations

Adjusted for age, sex, BMI, smoking, COPD (except for COPD model)

Washko et al, NEJM 2011


Ila and lower 6mwd
ILA and lower 6MWD Exacerbations

Doyle et al, AJRCCM in press


Genetics
Genetics Exacerbations

  • Three genetic loci identified as being associated with COPD susceptibility

    • 4q24

    • 6p21

    • 5q33

  • Low BMI associated with COPD

    • Pts from Eclipse, Norway-Bergen cohort, NETT and COPDGene

    • Found an association of low BMI in SNP at FTO gene

      • FTO gene has been associated with obesity

Castaldi et al, AJRCMB 2011

Wan et al, AJRCMB 2011


Summary
Summary Exacerbations

  • NETT

    • Most of analysis is done

    • LVRS improves survival, exercise performance, QOL

    • Small airway disease is important even in emphysematous phenotype

    • Use of BODE to track response to therapy

  • COPDGene

    • Most of analysis not yet done

      • Genetics

    • Definition of phenotypes which may lead to better directed Rx

      • Radiographic

      • Chronic bronchitis

    • Smoking related diseases other than COPD exist

      • GOLD U

      • Interstitial changes on CT


Conclusion
Conclusion Exacerbations

  • Large multi-centered studies in COPD are feasible and lead to important findings

    • NETT

    • COPDGene

    • ECLIPSE

    • TORCH

  • Continued co-operation amongst investigators will lead to new advances in COPD


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