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1
EmphysemaEmphysemaThe Future of ManagementThe Future of Management
Daniel A. Nader, D.O., FCCPCenter for Respiratory MedicineOklahoma State University
2
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
3
4
5
Chronic Airflow ObstructionChronic Airflow Obstruction
ASTHMA
CHRONIC BRONCHITIS EMPHYSEMA
airflowobstruction
COPD
6
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
7
lobal Initiative for Chronic
bstructive
ung
isease
lobal Initiative for Chronic
bstructive
ung
isease
G
OLD
G
OLD
8
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
9
10
Before Emphysema
NormalLung Sizeand Shape
Right lung
Diaphragm with normal curvature
11
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
12
13
14
15
16
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
17
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
18
Emphysema and LVRS
• Perioperative mortality 17%• Overall 90 day mortality 5.5%• Perioperative morbidity 59%• Prolonged Mechanical Ventilation
8%• Pneumonia 18%• Reintubation 2%
19
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
20
Bronchial ApproachesBronchial Approaches
• Plugs or Blockers (too much pneumonia)
• Sealants and biologics• Decompression with spiracles• Bronchial Valves
• Spiration® IBV® Valve (umbrella valve)
21
22
23
IBVIBV®® Valve Valve (Spiration Inc., Redmond, WA)
CAUTION - Investigational Device. Limited by FederalLaw to Investigational Use.
24
IBVIBV®® Valve Delivery Valve Delivery
Catheter with IBV® Valve
Utilizes Flexible Bronchoscope
25
IBV® Valve Deployment and Function
26
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
27
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
28
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
29
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
30
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
31
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
32
QOL is Outcome QOL is Outcome Most Important to PatientMost Important to Patient
Quality of Life
Dyspnea
Oxygen Use Daily Activities
33
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
34
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
35
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
36
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
37
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
38
Treatment Results in Redirected VolumeTreatment Results in Redirected Volume
Redirect volume from upper lobes to
healthier lower lobes
39
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
40
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
41
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
42
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
43
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
44
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
45
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)
46
Study Team – Institution Name
• Principal Investigator – Daniel Nader, D.O. – Tel: 584-5336– Email: [email protected]
• Study Coordinator – Diana Tameny– Tel: 918-584-5336– Email: [email protected]
47
Patient InformationPatient Information
• Spiration® website – www.spiration.com
• Contact study coordinator for patient information materials
• Dr. Daniel Nader, 918-584-5336
48
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
49
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
50
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
51
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
52
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
53
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
54
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
55
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
56
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.
57
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
58
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)
59
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
60
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
61
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
62
63
QUESTIONS ????