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EmphysemaEmphysemaThe Future of ManagementThe Future of Management

Daniel A. Nader, D.O., FCCPCenter for Respiratory MedicineOklahoma State University

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Chronic Obstructive Pulmonary Disease Chronic Obstructive Pulmonary Disease (COPD) (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 ObstructionChronic Airflow Obstruction

ASTHMA

CHRONIC BRONCHITIS EMPHYSEMA

airflowobstruction

COPD

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Current COPD Treatment OverviewCurrent COPD Treatment Overview

AsthmaAsthma - Controlled with drug therapy

Chronic BronchitisChronic Bronchitis - Controlled with drug therapy

EmphysemaEmphysema - Inadequate therapies

Medical treatments: Bronchodilators Oxygen Therapy

Surgical treatments: Lung Volume Reduction Surgery Lung Transplantation

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lobal Initiative for Chronic

bstructive

ung

isease

lobal Initiative for Chronic

bstructive

ung

isease

G

OLD

G

OLD

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Therapy at Each Stage of COPDTherapy at Each Stage of COPD

• FEV1/FVC < 70%

• FEV1 > 80% predicted

• FEV1/FVC < 70%

• 50% < FEV1 < 80% predicted

• FEV1/FVC < 70%

• 30% < FEV1 < 50% predicted

• FEV1/FVC < 70%

• FEV1 < 30% predicted

or FEV1 < 50% predicted plus chronic respiratory failure

Add regular treatment with one or more long-acting bronchodilators (when needed); Add rehabilitation

Add inhaled glucocorticosteroids if repeated exacerbations

Active reduction of risk factor(s); influenza vaccinationAdd short-acting bronchodilator (when needed)

Add long term oxygen if chronic respiratory failure. Consider surgical treatments

II: Moderate III: Severe

IV: Very Severe

I: Mild

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Before Emphysema

NormalLung Sizeand Shape

Right lung

Diaphragm with normal curvature

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The Disease: EmphysemaThe 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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EmphysemaEmphysema

Size and Shapewith Emphysema

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

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Emphysema and LVRSEmphysema and LVRS

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

Staples lines

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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?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 ApproachesBronchial Approaches

• Plugs or Blockers (too much pneumonia)

• Sealants and biologics• Decompression with spiracles• Bronchial Valves

• Spiration® IBV® Valve (umbrella valve)

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IBVIBV®® Valve Valve (Spiration Inc., Redmond, WA)

CAUTION - Investigational Device. Limited by FederalLaw to Investigational Use.

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IBVIBV®® Valve Delivery Valve Delivery

Catheter with IBV® Valve

Utilizes Flexible Bronchoscope

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IBV® Valve Deployment and Function

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U.S. Pilot - Subject EnrollmentU.S. Pilot - Subject EnrollmentSite Total

U Penn 19

Cleveland Clinic 17

U Washington 16

Indiana U 11

Cedars Sinai 8

LIJ - Northshore 4

U Virginia 4

Ohio State 4

Duke 4

U Alabama - Birm 2

Columbia 2

Total 91

609 Valves Deployed in 91 Subjects

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Pilot Study Patient SelectionPilot 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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Selection for Bronchial Valve TherapySelection for Bronchial Valve Therapy

• FEV1/FVC < 70%

• FEV1 > 80% predicted

• FEV1/FVC < 70%

• 50% < FEV1 < 80% predicted

• FEV1/FVC < 70%

• 30% < FEV1 < 50% predicted

• FEV1/FVC < 70%

• FEV1 < 30% predicted

or FEV1 < 50% predicted plus chronic respiratory failure

Add regular treatment with one or more long-acting bronchodilators (when needed); Add rehabilitation

Add inhaled glucocorticosteroids if repeated exacerbations

Active reduction of risk factor(s); influenza vaccinationAdd short-acting bronchodilator (when needed)

Add long term oxygen if chronic respiratory failure. Consider surgical treatments

II: Moderate III: Severe

IV: Very Severe

I: Mild

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Baseline CharacteristicsBaseline 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 CharacteristicsBaseline 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 ResultsSummary 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 QOL is Outcome Most Important to PatientMost Important to Patient

Quality of Life

Dyspnea

Oxygen Use Daily Activities

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SGRQ – US Pilot Study SGRQ – US Pilot Study (91 subjects treated)(91 subjects treated)

1 Month 3 months 6 Months 12 Months

U.S. Pilot Studies

% responders 51% 53% 55% 63%

Mean change (from baseline) (5.2) (5.1) (7.9) (9.0)P value 0.0004 0.0107 0.0003 0.0005

-4 unit change is threshold for being clinically meaningful

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SGRQ - Study ComparisonSGRQ - Study Comparison

00

-3.2

-3.1-3.5

-3.0

-5.3 -4.5-5.3-5.7

-3.9

-2.5-3.0

-10.4

-11.3

-9.0

-7.9

-5.1-5.2

-12

-10

-8

-6

-4

-2

0

0 1 2 3 4 5 6 7 8 9 10 11 12

Time Point (month)

Me

an

ch

an

ge

in S

GR

Q T

ota

l

Tiotropium (Casaburi et al) Tiotropium (Vincken et al)

Budesonide/formoterol (Szafranski et al) Budesonide/formoterol (Calverley et al)

LVRS (NETT) IBV™ Valve Pilot Data

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SGRQ Responder Rate SGRQ Responder Rate ComparisonsComparisons

Spiriva®

1

(tiotroprium)

IBV®2 Valve

LVRS3

SGRQ total(% with improvement of ≥4 units)

49% 55% 60%

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: 217–2242 IBV® Valve US Pilot Study, 91 subjects, 6 month results3 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; 348:2059-73

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Results over Time91 US Patients (mean SD)

Baseline 1 mo 3 mo 6 mo

TLC(liter,

plethy)

7.6 1.4n=90

7.5 1.5n=83

7.7 1.5n=79

7.6 1.4n=65

RV(liter)

4.7 1.1n=90

4.8 1.1n=83

5.0 1.2n=79

4.9 1.2n=65

6 MWDFeet

1108 313*n=91

1102 323n=80

1112 334n=76

1155 345*n=64

*6 month mean change: 26 ± 197 feet, p = 0.18

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How Does the Valve Work?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 VolumeTreatment Results in Redirected Volume

Redirect volume from upper lobes to

healthier lower lobes

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UL Volume Change at3 Months

50%

60%

70%

80%

90%

100%

110%

120%

Baseline UL (% of Baseline)

UL

Vol

ume

(% o

f Bas

elin

e U

L V

olum

e)

27/33 (82%) patients had a UL volume decrease

NUL Volume Change at 3 Months

90%

95%

100%

105%

110%

115%

120%

125%

130%

135%

140%

Baseline NUL (% of Baseline)

NU

L V

olu

me

(%

of

Bas

elin

e N

UL

Vo

lum

e)

28/33 (85%) patients had a NUL volume increase

Individual Paired DataIndividual Paired Data

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UL Volume Change at6 Months

50%

60%

70%

80%

90%

100%

110%

120%

Baseline UL (% of Baseline)

UL

Vol

ume

(% o

f Bas

elin

e U

L Vo

lum

e)

13/15 (87%) patients had a UL volume decrease

NUL Volume Change at 6 Months

90%

95%

100%

105%

110%

115%

120%

125%

130%

135%

Baseline NUL (% of Baseline)

NU

L V

olum

e (%

of B

asel

ine

NU

L V

olum

e)

14/15 (93%) patients had a NUL volume increase

Individual Paired DataIndividual Paired Data

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Average Change in Upper Lobe (UL) and Non-Upper Lobe (NUL) Volume

-30.0%

-20.0%

-10.0%

0.0%

10.0%

20.0%

30.0%

N=34 N=34 N=16

1 Month 3 Month 6 Month

Ave

rag

e C

han

ge

(% o

f B

asel

ine)

UL Volume

NUL Volume

Lung volumes by Quantitative CT (with Harvey Coxson and Nester Müller- Vancouver General Hospital)

Mean Proportional Volume Changes at Mean Proportional Volume Changes at Treatment IntervalsTreatment Intervals

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Example of Valve Effects on Lung VolumesExample of Valve Effects on Lung Volumes Reflects lobar volume changes: –16% UL, + 15% NUL

But no significant change in total lung volume: -1.8%

Emphysema Density Mask: < -950 HU (19.1 mL/g)

Before 3 Months After

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Conclusion and ImplicationsConclusion and Implications of Lung Volume by QCT Data 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 IBVRemoval of IBV®® Valves 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 <30 minute procedure

• Has been performed up to 18 months after treatment

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IBVIBV® ® Valve TrialValve 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 < 45% of pred)

• Lung volumes with severe hyperinflation (TLC > 125% and RV > 150% by plethy)

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Study Team – Institution Name

• Principal Investigator – Daniel Nader, D.O. – Tel: 584-5336– Email: daniel.nader@okstate.edu

• Study Coordinator – Diana Tameny– Tel: 918-584-5336– Email: diana.tameny@okstate.edu

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Patient InformationPatient Information

• Spiration® website – www.spiration.com

• Contact study coordinator for patient information materials

• Dr. Daniel Nader, 918-584-5336

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IBVIBV® ® Valve Trial Study DesignValve 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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IBVIBV® ® Valve Trial Study Design (cont.)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 The Following are Examples of Patient Symptoms and the Patient Symptoms and the

Responses to Valve TherapyResponses to Valve Therapy

Results from the Spiration® Pilot Study

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IBVIBV® ® Pilot Study and SGRQ Pilot Study and SGRQ Impact on Doing Household ChoresImpact 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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IBVIBV®® Pilot Study and SGRQ Pilot Study and SGRQImpact on Taking Bath or Shower Impact 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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IBVIBV®® Pilot Study and SGRQ Pilot Study and SGRQImpact on Walking in HouseImpact 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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IBVIBV®® Pilot Study and SGRQ Pilot Study and SGRQImpact on TalkingImpact 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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IBVIBV®® Pilot Study and SGRQ Pilot Study and SGRQImpact on Feeling in ControlImpact 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?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 IBVLVRS and IBV®® Valve Comparisons Valve Comparisonsfor Mortality and Major Morbidity (%)for 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.

LVRS (CMS)

LVRS NETT

n = 608

IBV®

Valven = 91

IBV®

Valven = 33

Evaluable*

Death, 90 day 14.4 7.9 3.3 0Air leak > 7 days

50 47.5 2.2 0

Major pulmonary†

Pneumothorax Pneumonia

29.8“100”18.2

3.313.24.4

000

Major cardiac† 20.0 3.3 0

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Evaluable Pilot Data SubgroupEvaluable Pilot Data Subgroup• Risk Factors for Complications in Pilot Trial

– Added treatment of the lingular segment of LUL n = 17

– Age > 74 +9– Age > 70 and DLCO < 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?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

withLower 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 ????