Emphysema The Future of Management

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EmphysemaThe Future of Management

• Daniel A. Nader, D.O., FCCP
• Center for Respiratory Medicine
• Oklahoma State University

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Chronic Obstructive Pulmonary Disease
(COPD)

• 16 million Americans diagnosed with COPD
• 3 million Americans with emphysema
• 4th leading cause of death in the U.S.
• Consumes 30 billion annually in the U.S.
• 13 million physician office visits
• 1.5 million emergency room visits
• 700,000 hospitalizations
• Global disease 5th leading cause of mortality

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Chronic Airflow Obstruction
ASTHMA
airflow obstruction
COPD
CHRONIC BRONCHITIS
EMPHYSEMA
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Current COPD Treatment Overview

• Asthma - Controlled with drug therapy
• Chronic Bronchitis - Controlled with drug
  therapy
• Emphysema - Inadequate therapies
• Medical treatments
• Bronchodilators
• Oxygen Therapy
• Surgical treatments
• Lung Volume Reduction Surgery
• Lung Transplantation

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lobal Initiative for Chronicbstructiveungisease
G OLD
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IV Very Severe
III Severe
II Moderate
I Mild
Add regular treatment with one or more
long-acting bronchodilators (when needed) Add
rehabilitation
Add inhaled glucocorticosteroids if repeated
exacerbations
Add long term oxygen if chronic respiratory
failure. Consider surgical treatments
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Before Emphysema
Normal Lung Size and Shape
Right lung
Diaphragm with normal curvature
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The Disease Emphysema

• Loss of lung tissue, particularly the alveolar
  septa
• Enlargement of alveolar airspaces with loss of
  elastic recoil of the lung
• Lung and thorax hyperinflation
• Compression of adjacent lung tissue
• Dynamic hyperinflation with more airway
  compression
• Dysfunction of chest cage mechanics and diaphragm
• Overload or dysfunction of respiratory and
  skeletal muscles

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Emphysema

• Pink areas depict the worst areas of emphysema.
• This depicts heterogeneous disease with the
  worst disease in the apices of the lobes

Size and Shape with Emphysema
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Emphysema and LVRS
Staples lines

• 1/3 of lung volume is resected
• The reduced thorax has improved mechanics
• The reduced lung has better elastic recoil
• Improved respiratory muscle function

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Emphysema and LVRS

• Perioperative mortality 17
• Overall 90 day mortality 5.5
• Perioperative morbidity 59
• Prolonged Mechanical Ventilation 8
• Pneumonia 18
• Reintubation 2

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Treatment without Surgery?

• How can emphysema be treated without surgery?
• Many more patients
  may benefit from a minimally
  invasive procedure because
• Co-morbidities exclude many of the most
  severely affected
  patients
• Minimally invasive procedure may allow earlier
  and staged therapeutic intervention

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Bronchial Approaches

• Plugs or Blockers (too much pneumonia)
• Sealants and biologics
• Decompression with spiracles
• Bronchial Valves
• Spiration IBV Valve (umbrella valve)

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IBV Valve (Spiration Inc., Redmond, WA)
CAUTION - Investigational Device. Limited by
Federal Law to Investigational Use.
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IBV Valve Delivery
Utilizes Flexible Bronchoscope
Catheter with IBV Valve
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IBV Valve Deployment and Function
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U.S. Pilot - Subject Enrollment
609 Valves Deployed in 91 Subjects
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Pilot Study Patient Selection

• Severe emphysema, predominantly upper lobe
• Similar to NETT selection criteria for LVRS but
  without high-risk group
• Less stringent exclusion criteria than NETT
• Able to tolerate bronchoscopy
• No active infection
• Not on lung transplant or LVRS list
• Pulmonary rehabilitation not required

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IV Very Severe
III Severe
II Moderate
I Mild
Add regular treatment with one or more
long-acting bronchodilators (when needed) Add
rehabilitation
Add inhaled glucocorticosteroids if repeated
exacerbations
Add long term oxygen if chronic respiratory
failure. Consider surgical treatments
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Baseline Characteristics

• Age 64.9 8 years
• 56 male, 44 female
• SGRQ Total 57 13
• SF-36 PF 28 17
• SF-36 PCS 33 6

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Baseline Characteristics

• FEV1 post bronchodilator (L) 0.87 0.25 or 31
• FVC post bronchodilator (L) 2.74 0.81 or 74
• TLC (L) plethysmography 7.57 1.42 or 129
• RV (L) plethysmography 4.74 1.06 or 221
• DLCO (mL/mmHg/min) 9.54 3.45 or 39
• PO2 room air (mmHg) 68 9
• PCO2 (mmHg) 40 5
• 6 MWT (Feet) 1108 313
• Cycle ergometry (Watts) 41 23

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Summary Results

• Selected patients with bilateral upper lobe
  predominant emphysema and treated both upper
  lobes
• A total of 609 valves were placed in 91 patients
• A mean of 6.7 (median 6) valves per patient were
  placed
• Procedure averaged 59 minutes
• Valves were positioned in 9.7 of desired
  airways, in which 75 were segmental and 25
  subsegmental
• Length of hospital stay mean was 2.5 days, median
  1 day
• No migration, no erosion, no expectoration and no
  unanticipated adverse events

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QOL is Outcome Most Important to Patient

Dyspnea
Quality of Life
Oxygen Use
Daily Activities
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SGRQ US Pilot Study (91 subjects treated)
-4 unit change is threshold for being clinically
meaningful
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SGRQ - Study Comparison
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• SGRQ Responder Rate
• Comparisons

1 Casaburi R, Mahler DA, Jones PW, et al. A
long-term evaluation of once-daily inhaled
tiotropium in chronic obstructive pulmonary
disease. Eur Respir J 2002 19 217224 2 IBV
Valve US Pilot Study, 91 subjects, 6 month
results 3 Non-high risk subjects at 6 months,
Supplement to National Emphysema Treatment Trial
Research Group. A randomized trial comparing
lung-volume-reduction surgery with medical
therapy for severe emphysema. N Engl J Med, 2003
3482059-73
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Results over Time91 US Patients (mean ? SD)
6 month mean change 26 197 feet, p 0.18
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How Does the Valve Work?

• Redirects inspired air to better lung tissue
• Treated upper lobes are 10 smaller but overall
  lung volume unchanged
• Change in lobar lung volumes correlate with what
  the patients report as a SGRQ change (p 0.004)
• This was found with quantitative HRCT methodology

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Treatment Results in Redirected Volume
Redirect volume from upper lobes to healthier
lower lobes
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Individual Paired Data
28/33 (85) patients had a NUL volume increase
27/33 (82) patients had a UL volume decrease
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Individual Paired Data
14/15 (93) patients had a NUL volume increase
13/15 (87) patients had a UL volume decrease
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Mean Proportional Volume Changes at Treatment
Intervals
Lung volumes by Quantitative CT (with Harvey
Coxson and Nester Müller- Vancouver General
Hospital)
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Example of Valve Effects on Lung Volumes
Reflects lobar volume changes 16 UL, 15
NUL But no significant change in total lung
volume -1.8
Before
3 Months After
Emphysema Density Mask lt -950 HU (19.1 mL/g)
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Conclusion and Implications of Lung Volume by
QCT Data

• The effect of IBV Valve treatment is to redirect
  air and blood volume from the treated lobes to
  the untreated lobes
• A 300 ml air volume shift (10 of treated lobe)
  likely indicates 40-55 of each breath is
  redirected to healthier tissue
• Lobar volume change as measured by CT correlates
  with what the patients report as a SGRQ change
• Traditional PFT and exercise studies are
  insensitive to the regional effects of IBV Valve
  treatment

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Removal of IBV Valves

• A removal rod was a design feature
• Removal potential adds a safety factor to enhance
  treatment of complications
• Valves have mostly been removed electively in
  non-responders
• Typically lt30 minute procedure
• Has been performed up to 18 months after
  treatment

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IBV Valve Trial

• Randomized trial commenced June 2007
• Patients with COPD/Emphysema and dyspnea on
  exertion
• CT scan with upper-lobe predominant emphysema
• Spirometry with severe airflow obstruction (FEV1
  lt 45 of pred)
• Lung volumes with severe hyperinflation (TLC gt
  125 and RV gt 150 by plethy)

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Study Team Institution Name

• Principal Investigator Daniel Nader, D.O.
• Tel [phone]
• Email daniel.nader_at_okstate.edu
• Study Coordinator Diana Tameny
• Tel [phone]
• Email diana.tameny_at_okstate.edu

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Patient Information

• Spiration website www.spiration.com
• Contact study coordinator for patient information
  materials
• Dr. Daniel Nader, 918-584-5336

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IBV Valve Trial Study Design

• Randomized, sham controlled
• Treatment group bronchoscopy with valves
• Control group bronchoscopy without valves
• Blinded
• Subjects, investigators and personnel who perform
  subject follow-up will be blinded to treatment
• Control Group - Continued Access protocol
• If completed testing and all follow-up visits -
  eligible to be re-evaluated to receive valve
  treatment after completing 6 month visit

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IBV Valve Trial Study Design (cont.)

• 6-week run-in period with best medical management
  prior to baseline testing
• Follow-up at 1, 3, and 6 months
• Primary endpoints at 6 months
• Safety - composite of serious AE
• Effectiveness- responder analysis of SGRQ
  Quantitative CT
• Annual contact for 5 years
• Study Size 200 to 500 subjects at up to 40
  sites

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The Following are Examples of Patient Symptoms
and the Responses to Valve Therapy

• Results from the Spiration Pilot Study

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IBV Pilot Study and SGRQ Impact on Doing
Household Chores

• At start of study
• 23 of 74 said their disease prevents them from
  doing household chores

• At 6 months
• 15 of the 23 now can do household chores

All patients with data at 6 months after treatment
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IBV Pilot Study and SGRQImpact on Taking Bath
or Shower

• At start of study
• 29 of 74 said their disease makes it difficult to
  take a bath or shower

• At 6 months
• 13 of the 29 no longer have difficulty taking a
  bath or shower

All patients with data at 6 months after treatment
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IBV Pilot Study and SGRQImpact on Walking in
House

• At start of study
• 42 of 72 said that walking in their house makes
  them short of breath

• At 6 months
• 17 of the 42 no longer are short of breath when
  walking in their house

All patients with data at 6 months after treatment
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IBV Pilot Study and SGRQImpact on Talking

• At start of study
• 38 of 72 said that talking makes them short of
  breath

• At 6 months
• 15 of the 38 no longer are short of breath when
  talking

All patients with data at 6 months after treatment
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IBV Pilot Study and SGRQImpact on Feeling in
Control

• At start of study
• 52 of 73 said they do not feel in
  control of their respiratory problem

• At 6 months
• 26 of the 52 now feel like they are
  in control

All patients with data at 6 months after treatment
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What were the Complications?

• Procedure- most common was temporary bronchospasm
• Valve- most common was pneumothorax associated
  with lobar atelectasis
• Randomized Trial the complications are predicted
  to be less than 2 with the protocol revisions
  for improved safety.

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LVRS and IBV Valve Comparisonsfor Mortality and
Major Morbidity ()
Subset of pilot study who are evaluable based on
pivotal trial inclusion criteria and treatment
algorithm 30 day interval- Naunheim, JTCVS, Jan
2006, n 511.
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Evaluable Pilot Data Subgroup

• Risk Factors for Complications in Pilot Trial
• Added treatment of the lingular segment of LUL
  n 17
• Age gt 74 9
• Age gt 70 and DLCO lt 20 1
• TLC 125 of predicted 27
• Did not meet incl/excl criteria 4
• Total is 58
• Evaluable subgroup data for predicting Pivotal
  Trial complications is 33 subjects (91-58)

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What is Upper Lobe Predominant?

• Classification of the distribution of emphysema
  with HRCT by choosing one of four categories
• Upper lobe predominant - included
• Non-upper lobe excludes patients and is those
  with
• Lower lobe predominant
• Diffuse
• Superior segments of lower lobes
• Method used for NETT primary results
• Direct comparison within a single study

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Alpha-1-Antitrypsin Deficiency

• ATS/ERS recommendation for testing
• COPD
• Early onset emphysema
• Family history
• Dyspnea and cough occurring in multiple family
  members
• Liver disease of unknown cause

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AAT Testing

• Bronchiectasis of unknown cause
• Asthmatic without reversibility
• Unexplained panniculitis and antiproteinase-3
  vasculitis
• Confirmation of absent alpha-1-anstitrypsin peak
  on serum protein electrophoresis

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QUESTIONS ????