IP Fellows Reading List

https://www.ncbi.nlm.nih.gov/pubmed/20860505

Landmark Article (Zephyr)

Reference: Sciurba FC, Ernst A, Herth FJ, et al. A randomized study of endobronchial valves for advanced emphysema. N Engl J Med. 2010;363(13):1233-44.

Background: This was the first large multicenter study evaluating endobronchial valve (EBV) use for lung volume reduction. It enrolled 321 patients and followed them over 1 year.

PICO:

Populations:

• Age 40-75, 15% < FEV1 < 45%, TLC > 100%, RV > 150%, DLCO ≥ 20%, BMI ≤ 31.1 (men), BMI ≤ 32.3 (women), PaCO2 < 50 mmHg, PaO2 > 45 mmHg, 6 MWD ≥140 meters

Intervention:

• Endobronchial valve placement

Comparison:

• Standard of care

Outcome:

• No significant change in FEV1, 6MWD, SGRQ, cycle ergometer, or Oxygen use
• Increased death, chronic obstructive pulmonary disease (COPD) exacerbations, pneumonias, hemoptysis, and pneumothorax
• More improvement when there was increased heterogeneity of the target lobe relative to the ipsilateral lobes
• Subgroup with intact fissure
• Clinically significant improvement of FEV1 and 6MWD

Take Home: Although this was an initial failure, the subgroup analysis revealed that lack of collateral ventilation was necessary to achieve lobar collapse and symptomatic/physiologic improvement. This principle was foundational for all subsequent studies.

Complete unilateral vs partial bilateral endoscopic lung volume reduction in patients with bilateral lung emphysema

https://www.ncbi.nlm.nih.gov/pubmed/22459779

Landmark Article (Spiration)

Reference: Eberhardt R, Gompelmann D, Schuhmann M, et al. Complete unilateral vs partial bilateral endoscopic lung volume reduction in patients with bilateral lung emphysema. Chest. 2012;142(4):900-908.

Background: This was the first study to compare outcomes of bronchoscopic lung volume reduction targeting unilateral complete occlusion or bilateral incomplete occlusion over 3 months. Only 22 patients were enrolled at this single center study, but this laid the ground work for all future studies.

PICO:

Populations:

• FEV1 < 40%, RV > 150%, TLC > 100%, 6MWD > 150 meters, PaCO2 < 55 mmHg

Intervention:

• Unilateral endobronchial valve placement with complete lobar occlusion

Comparison:

• Bilateral endobronchial valve placement with incomplete lobar occlusion

Outcome:

• The unilateral complete occlusion arm demonstrated statistically and clinically significant improvement of: FEV1, RV, SGRQ, and 6MWD

Take Home: This was the first study to demonstrate unilateral complete occlusion of a lung lobe is superior to bilateral incomplete occlusion. This demonstrated a meaningful improvement of symptoms and lung function.

 Expert statement: pneumothorax associated with endoscopic valve therapy for emphysema–potential mechanisms, treatment algorithm, and case examples

https://www.ncbi.nlm.nih.gov/pubmed/24777292

Review

Reference: Valipour A, Slebos DJ, De oliveira HG, et al. Expert statement: pneumothorax associated with endoscopic valve therapy for emphysema–potential mechanisms, treatment algorithm, and case examples. Respiration. 2014;87(6):513-21.

Summary: A review of performing bronchoscopic lung volume reduction with one-way valves including cases, how to perform, and treatment algorithms. One of the highlights includes an algorithm for treating and managing pneumothoraces after valve placement.

 Bronchoscopic Lung Volume Reduction with Endobronchial Zephyr Valves for Severe Emphysema: A Systematic Review and Meta-Analysis

https://www.ncbi.nlm.nih.gov/pubmed/31117102

Review (Zephyr)

Reference: Labarca G, Uribe JP, Pacheco C, et al. Bronchoscopic Lung Volume Reduction with Endobronchial Zephyr Valves for Severe Emphysema: A Systematic Review and Meta-Analysis. Respiration. 2019;98(3):268-278.

Summary: This is a meta-analysis of clinical trials utilizing Zephyr valves for bronchoscopic lung volume reduction evaluating patient population, outcomes, and adverse events.

 Efficacy of the Spiration Valve System in Patients with Severe Heterogeneous Emphysema: A Systematic Review and Meta-Analysis

https://www.ncbi.nlm.nih.gov/pubmed/31760389

Review (Spiration)

Reference: Majid A, Labarca G, Uribe JP, et al. Efficacy of the Spiration Valve System in Patients with Severe Heterogeneous Emphysema: A Systematic Review and Meta-Analysis. Respiration. 2020;99(1):62-72.

Summary: This is a meta-analysis of clinical trials utilizing Spiration valves for bronchoscopic lung volume reduction evaluating patient population, outcomes, and adverse events.

 Endoscopic Lung Volume Reduction: An Expert Panel Recommendation – Update 2019

https://www.ncbi.nlm.nih.gov/pubmed/30836374

Review

Reference: Herth FJF, Slebos DJ, Criner GJ, Valipour A, Sciurba F, Shah PL. Endoscopic Lung Volume Reduction: An Expert Panel Recommendation – Update 2019. Respiration. 2019;97(6):548-557.

Summary: Expert panel and review on performing bronchoscopic lung volume reduction, 2019 version.

 Bronchoscopic lung volume reduction with endobronchial valves for patients with heterogeneous emphysema and intact interlobar fissures (the BeLieVeR-HIFi study): a randomised controlled trial

https://www.ncbi.nlm.nih.gov/pubmed/26116485

Clinical Trial (Zephyr)

Reference: Davey C, Zoumot Z, Jordan S, et al. Bronchoscopic lung volume reduction with endobronchial valves for patients with heterogeneous emphysema and intact interlobar fissures (the BeLieVeR-HIFi study): a randomised controlled trial. Lancet. 2015;386(9998):1066-73.

Background: This was one of the first large studies to follow the VENT study, and it evaluated 3-month outcomes when EBV were place in patients with intact fissures along with use of the Chartis system. This was one of the first studies to utilize the Chartis system, a physiologic measure of collateral ventilation. This was a 50 patient single center, double blind, randomized control trial evaluating patients with heterogeneous emphysema

PICO:

Populations:

• FEV1 < 50%, TLC > 100%, RV > 150%, 6MWD < 450 meters
• No collateral ventilation

Intervention:

• Endobronchial valve placement

Comparison:

• Standard of care
• Sham bronchoscopy and sham valve placement

Outcome:

• Improved FEV1 and CAT score

Take Home: This was one of the first pilot studies that demonstrated a strong signal for valve use in hyperinflated lungs with intact fissures. This confirmed the subgroup findings from the VENT study. This study was also the first large study using valves that utilized the Chartis system. All subsequent Zephyr/PulmonX studies utilized it as well.

Endobronchial Valves for Emphysema without Interlobar Collateral Ventilation

https://www.ncbi.nlm.nih.gov/pubmed/26650153

One-Year Follow-Up after Endobronchial Valve Treatment in Patients with Emphysema without Collateral Ventilation Treated in the STELVIO Trial

https://www.ncbi.nlm.nih.gov/pubmed/27974713

Clinical Trial (Zephyr)

Reference: STELVIO

• Klooster K, Ten hacken NH, Hartman JE, Kerstjens HA, Van rikxoort EM, Slebos DJ. Endobronchial Valves for Emphysema without Interlobar Collateral Ventilation. N Engl J Med. 2015;373(24):2325-35.
• Klooster K, Hartman JE, Ten hacken NH, Slebos DJ. One-Year Follow-Up after Endobronchial Valve Treatment in Patients with Emphysema without Collateral Ventilation Treated in the STELVIO Trial. Respiration. 2017;93(2):112-121.

Background: STELVIO was a follow up to BeLieVer-HIFi. It is unique in that 50% of enrolled of patients had homogeneous emphysema (homogeneous ipsilateral lobe delta emphysema score < 15%; heterogeneous ipsilateral lobe delta emphysema score > 15%). There were also a few patients with alpha-1-antitrypsin deficiency enrolled in both experimental and control arms. This was a single center randomized control trial with planned crossover of the control arm following the initial 6-month study. An initial 68 patients were enrolled and then randomized to either experimental or control arms. The patients were followed for 1 full year after the initial procedure and this was published as a separate paper.

PICO:

Populations:

• Age > 35, FEV1 < 60%, TLC > 100%, RV > 150%
• No collateral ventilation

Intervention:

• Endobronchial valve placement

Comparison:

• Standard of care with planned cross over at the end of the study

Outcome:

• Clinical and statistically significant improvement of: FEV1, FVC, 6MWD
• Increased rate of pneumothorax, pneumonia, COPD exacerbation, and death
• No pneumothoraces after the first 6 months
• Greater improvement of FEV1, FVC, and SGRQ in heterogeneous emphysema, but a similar improvement of 6MWD in both heterogeneous and homogeneous emphysema
• Improvements persisted at 1 year follow up with a slight decline

Take Home: This was the first study to demonstrate viability at 6 months and then 1 year with persistent improvement after bronchoscopic lung volume reduction with valves in heterogeneous and homogeneous emphysema.

Endobronchial Valve Therapy in Patients with Homogeneous Emphysema. Results from the IMPACT Study

https://www.ncbi.nlm.nih.gov/pubmed/27580428

Clinical Trial (Zephyr)

Reference: Valipour A, Slebos DJ, Herth F, et al. Endobronchial Valve Therapy in Patients with Homogeneous Emphysema. Results from the IMPACT Study. Am J Respir Crit Care Med. 2016;194(9):1073-1082.

Background: This was the first study to evaluate the use of EBVs in homogeneous emphysema. 93 patients were enrolled with 43 in the experimental arm and 50 in the control arm. This was a 3-month evaluation with the primary endpoint being improvement in FEV1

PICO:

Populations:

• Age > 40, 15% ≤ FEV1 ≤ 45%, TLC > 100%, RV ≥ 200%, 6MWD ≥ 150 meters
• < 20% perfusion difference between the left and right hemithorax
• Homogeneous emphysema, <15% difference in emphysema scores between the target and ipsilateral lobes
• No collateral ventilation

Intervention:

• Endobronchial valve placemen

Comparison:

• Standard of care

Outcome:

• Clinically and statistically significant improvement of FEV1 and 6MWD
• Zero deaths in the experimental arm and 1 death in the control arm
• In the experimental arm, increased risk of COPD exacerbation (16% vs 12%) and pneumothorax (26% vs 0%)

Take Home: Homogeneous emphysema can be successfully treated with EBVs. This, along with the STELVIO study, demonstrate a patient population that can be treated outside of the surgical lung volume reduction cohort of only heterogeneous apical predominant emphysema from NETT.

A Multicenter Randomized Controlled Trial of Zephyr Endobronchial Valve Treatment in Heterogeneous Emphysema (TRANSFORM)

https://www.ncbi.nlm.nih.gov/pubmed/28885054

Clinical Trial (Zephyr)

Reference: Kemp SV, Slebos DJ, Kirk A, et al. A Multicenter Randomized Controlled Trial of Zephyr Endobronchial Valve Treatment in Heterogeneous Emphysema (TRANSFORM). Am J Respir Crit Care Med. 2017;196(12):1535-1543.

Background: This was the first multicenter randomized control trial after the lessons learned from the previous studies. 97 patients were enrolled across 17 sites in Europe. 65 were enrolled in the experimental arm and 32 were enrolled in the standard of care arm. This study followed outcomes over 6 months.

PICO:

Populations:

• Age ≥ 40, 15% ≤ FEV1 ≤ 45%, TLC > 100%, RV ≥ 180%, 150 meters ≤6MWD ≤ 450 meters
• Heterogeneous emphysema ≥ 10% difference between the target and ipsilateral lobes
• No collateral ventilation

Intervention:

• Endobronchial valve placement

Comparison:

• Standard of care

Outcome:

• Clinically and statistically significant improvement of FEV1, 6MWD, and SGRQ
• The experimental arm had a 23% pneumothorax rate and 1.5% death rate compared to 0% for both in the control arm

Take Home: This was one of the first multicenter trials demonstrating a significant signal for symptom and respiratory function improvement with EBV placement. This led to the LIBERATE study.

A Multicenter Randomized Controlled Trial of Zephyr Endobronchial Valve Treatment in Heterogeneous Emphysema (LIBERATE)

https://www.ncbi.nlm.nih.gov/pubmed/29787288

Clinical Trial (Zephyr)

Reference: Criner GJ, Sue R, Wright S, et al. A Multicenter Randomized Controlled Trial of Zephyr Endobronchial Valve Treatment in Heterogeneous Emphysema (LIBERATE). Am J Respir Crit Care Med. 2018;198(9):1151-1164.

Background: This is the largest randomized multicenter trial demonstrating efficacy of the Zephyr valve system in COPD. This study was powered for a primary outcome of 15% improvement in FEV1 over 1 year. 190 subjects were randomized in a 2:1 fashion, 128 in the experimental and 62 in the standard of care across 24 sites

PICO:

Populations:

• Age 40-75, 15% < FEV1 < 45%, TLC > 100%, RV > 175%, DLCO > 20%, 100m < 6MWD < 450m, BMI < 35, PaCO2 < 50 (Denver < 55), PaO2 > 45 (Denver > 30)
• Target lobe emphysema score > 50% (-910 Hounsfield Units)
• Heterogeneous emphysema (delta of > 15% between the target and ipsilateral lobes)
• Emphysema score < 75% in all ipsilateral lobes

Intervention:

• Endobronchial valve placement

Comparison:

• Standard of care

Outcome:

• Statistical and clinically significant improvement of FEV1, 6MWD, and SGRQ
• 33% (intervention) vs. 0% rate of pneumothorax over one year
• 4% (intervention) vs 1.6% rate of death
• 30% (intervention) vs 35% COPD exacerbation rate

Take Home: In the correct patient population, Zephyr valves can be beneficial; however, there is a non-insignificant risk morbidity and mortality.

Improving Lung Function in Severe Heterogenous Emphysema with the Spiration Valve System (EMPROVE). A Multicenter, Open-Label Randomized Controlled Clinical Trial

https://www.ncbi.nlm.nih.gov/pubmed/31365298

Clinical Trial (Spiration) 

Reference: Criner GJ, Delage A, Voelker K, et al. Improving Lung Function in Severe Heterogenous Emphysema with the Spiration® Valve System (EMPROVE): A Multicenter, Open-Label, Randomized, Controlled Trial. Am J Respir Crit Care Med. 2019

Background: This is the largest randomized multicenter trial demonstrating efficacy of the Spiration valve system in COPD. This study was powered for a primary outcome of 15% improvement in FEV1, and it builds on smaller previous studies. Prior studies had shorter term follow up and/or did require an intact lobar fissure. 174 subjects were enrolled across 41 sites. They were then randomized in a 2:1 fashion with 113 in the experimental arm and 59 in the control arm

PICO:

Populations:

• Age > 40, FEV1 < 45%, TLC > 100%, RV > 150%, 6MWD > 140 meters, PCO2 < 50 mmHg, PO2 > 45 mmHg, BMI > 15
• Target lobe Emphysema score > 40% (-920 Hounsfield Units)
• Emphysema heterogeneity (delta of > 10% between the target and ipsilateral lobes)

Intervention:

• Endobronchial valve placement

Comparison:

• Standard of care

Outcome:

• Statistically and clinically significant improvement of FEV1 over 1 year
• Statistically and clinically significant improvement of SGRQ
• No significant improvement of 6MWD
• 12.4% (intervention) vs. 0% rate of pneumothorax over one year
• 1% (intervention) vs 0% rate of death
• 30% (intervention) vs 19% COPD exacerbation rate

Take Home: In the correct patient population, Spiration valves can be beneficial; however, there is a non-insignificant risk of morbidity including pneumothoraces. There is not a significant improvement in 6MWD, unlike in the LIBERATE study. However, there is a lower rate of pneumothoraces compared to the LIBERATE study.

One- to four-year follow-up of endobronchial lung volume reduction in alpha-1-antitrypsin deficiency patients: a case series