Background

Pulmonary Air Leaks

Proper lung functioning depends on the separation between the air-containing parts of the lung and the small vacuum-containing space around the lung called the pleural space. When air leaks into the pleural space, the lung is unable to inflate, resulting in hypoventilation and hypoxemia; this condition is known as a pneumothorax. A pneumothorax can result from trauma, high airway pressures induced during mechanical ventilation, lung surgery, and rupture of lung blebs or bullae, which may be congenital or a result of chronic obstructive pulmonary disease (COPD).

Emphysema

Emphysema, a form of COPD, is a progressive, debilitating disease characterized by irreversible destruction of alveolar tissue. This destruction results in reduced elastic recoil, progressive hyperinflation and gas trapping with patients experiencing chronic dyspnea, limited exercise tolerance and poor health related quality of life. In emphysematous COPD, diseased portions of the lung ventilate poorly, cause air trapping, and hyperinflate, compressing relatively normal lung tissue. The patterns and degree of emphysema heterogeneity (i.e., the extent and distribution of air space enlargements) can be measured using computed tomography (CT) density as an indicator for tissue destruction. The most diseased portions of lung can then potentially be targeted for lung volume reduction procedures. In homogeneous emphysema, there is minor or no regional difference in disease within or between lobes of the lung.

The Global Initiative for Chronic Obstructive Lung Disease, or GOLD, system is commonly used to categorize patients with emphysema according to severity.^1, Stages of airflow limitation are based on the FEV1, or the amount of air a person can force out in 1 second after taking a deep breath. Patients with an FEV1 of less than 50% of their predicted value are considered to have severe airflow limitation. Patients are also grouped in the GOLD system according to categories of risk of having an exacerbation, These groups are based on number and type of exacerbations per year and self-reported symptoms such as breathlessness.

Table 1: Classification of severity of airflow obstruction

Stages of Airflow Limitation	Severity Grouping
GOLD 1 (mild): FEV1≥ 80% predicted GOLD 2 (moderate): 50% ≤FEV1 <80% predicted GOLD 3 (severe): 30% ≤FEV1 <50% predicted GOLD 4 (very severe): FEV1 <30% predicted	Group A: low risk 0-1 exacerbation per year, not requiring hospitalization, fewer symptoms Group B: low risk 0-1 exacerbation per year, not requiring hospitalization, more symptoms Group C: high risk ≥2 exacerbations per year, or one or more requiring hospitalization, fewer symptoms Group D: high risk ≥2 exacerbations per year, or one or more requiring hospitalization, more symptoms

Bronchial Valves

Bronchial valves are synthetic devices deployed with bronchoscopy into ventilatory airways of the lung to control airflow. During inhalation, the valve is closed, preventing air flow into the diseased area of the lung. The valve opens during exhalation to allow air to escape from the diseased area of the lung.They have been investigated for use in patients who have prolonged bronchopleural air leaks and in patients with lobar hyperinflation from severe or advanced emphysema.

When used to treat persistent air leaks from the lung into the pleural space, the bronchial valve theoretically permits less air flow across the diseased portion of the lung during inhalation, aiding in air leak closure. The valve may be placed, and subsequently removed, by bronchoscopy.

The use of bronchial valves to treat emphysema is based on the improvement observed in patients who have undergone lung volume reduction surgery. Lung volume reduction surgery involves excision of peripheral emphysematous lung tissue, generally from the upper lobes. The precise mechanism of clinical improvement for patients undergoing lung volume reduction has not been firmly established. However, it is believed that elastic recoil and diaphragmatic function are improved by reducing the volume of the diseased lung. Currently, and at the time the clinical trials were designed, very few lung volume reduction procedures were performed. The procedure is designed to relieve dyspnea and improve functional lung capacity and quality of life; it is not curative. Medical management remains the most common treatment for a majority of patients with severe emphysema.

In early trials of bronchial valves for treatment of emphysema, absence of collateral ventilation (pathways that bypass the normal bronchial airways) was associated with better outcomes, presumably because patients with collateral ventilation did not develop lobar atelectasis (collapse). In subsequent trials, patients were selected for absence of collateral ventilation, and it is current practice for patients to be assessed for the presence of collateral ventilation prior to undergoing the procedure. Collateral ventilation is measured by the Chartis System, which requires bronchoscopy, or as a surrogate, CT scanning to assess the completeness of fissures. After 45 days post-procedure, residual volume can provide information on whether lung volume reduction has been achieved successfully.

Regulatory Status

In October 2008, the Spiration® IBV Valve System (Spiration) was approved by the U.S. Food and Drug Administration (FDA) through the humanitarian device exemption (H060002) process for use in controlling prolonged air leaks of the lung or significant air leaks that are likely to become prolonged air leaks following lobectomy, segmentectomy, or lung volume reduction surgery. An air leak present on postoperative day 7 is considered prolonged unless present only during forced exhalation or cough. An air leak present on day 5 should be considered for treatment if it is: (1) continuous, (2) present during the normal inhalation phase of inspiration, or (3) present on normal expiration and accompanied by subcutaneous emphysema or respiratory compromise. Use of the Intrabronchial Valve System is limited to 6 weeks per prolonged air leak. FDA product code: OAZ.

Two bronchial valve systems are FDA approved for treatment of patients with severe emphysema. In June 2018, FDA granted the Zephyr Valve system breakthrough device status with expedited approval for the bronchoscopic treatment of adult patients with hyperinflation associated with severe emphysema in regions of the lung that have little to no collateral ventilation. In December 2018, FDA approved the Spiration Valve System for adult patients with shortness of breath and hyperinflation associated with severe emphysema in regions of the lung that have evidence of low collateral ventilation. FDA product code: NJK.

Table 2. Bronchial Valve Systems Approved by FDA

Device	Indication	Manufacturer	Location	Date Approved	HDE/PMA No.
IBV® Valve System	To control prolonged air leaks of the lung, or significant air leaks that are likely to become prolonged air leaks, following lobectomy, segmentectomy, or lung volume reduction surgery	Spiration, Inc	Redmond, WA	10/24/08	H060002
Spiration® Valve System	For adult patients with shortness of breath and hyperinflation associated with severe emphysema in regions of the lung that have evidence of low collateral ventilation	Spiration, Inc	Redmond, WA	12/03/18	P180007
Zephyr® Endobronchial Valve System	For the bronchoscopic treatment of adult patients with hyperinflation associated with severe emphysema in regions of the lung that have little to no collateral ventilation	Pulmonx Corporation	Redwood City, CA	06/29/18	P180002

FDA: Food and Drug Administration, HDE: human device exemption; PMA: premarket approval application.

Related Policies

• Lung Volume Reduction Surgery for Severe Emphysema (Policy #032 in the Surgery Section)

• Treatment of prolonged air leaks, and
• Treatment for members with chronic obstructive pulmonary disease or emphysema.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.
To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Treatment of Pulmonary Air Leaks
Clinical Context and Therapy Purpose

The purpose of placing bronchial valves in patients who have pulmonary air leaks is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does placement of bronchial valves improve the net health outcome in patients with pulmonary air leaks?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals with pulmonary air leaks.

Interventions

The therapy being considered is the placement of bronchial valves. A bronchial valve is a device that permits one-way air movement. During inhalation, the valve is closed, preventing air flow into the diseased area of the lung. The valve opens during exhalation to allow air to escape from the diseased area of the lung. When used to treat persistent air leak from the lung into the pleural space, the bronchial valve theoretically permits less air flow across the diseased portion of the lung during inhalation, aiding in air leak closure. The valve may be placed, and subsequently removed, by bronchoscopy.

Comparators

The following practices are currently being used:

• Inserting a chest tube (tube thoracostomy) and employing a water seal or one-way valve to evacuate air collected in the pleural space and prevent it from reaccumulating;
• Lowering airway pressures by adjusting the mechanical ventilator;
• Using autologous blood patches; and
• Performing a thoracotomy with mechanical or chemical pleurodesis.

The general outcomes of interest, in addition to overall survival, are a reduction in symptoms (eg, pneumothorax) and improvements in functional outcomes. Placement of bronchial valves requires an inpatient surgical procedure. Bronchial valves can be utilized for up to six weeks to effect resolution of a persistent pulmonary leak.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

No RCTs or comparative observational studies were identified. Only case series and case reports are available.

In the largest case series, Travaline et al (2009) reported on 40 patients treated at 17 sites in the United States and Europe.^2, The Zephyr Endobronchial Valve (EBV) was used. All patients in the series had prolonged pulmonary air leak (mean duration, 119 days; median, 20 days). The most common comorbidities were cancer and chronic obstructive pulmonary disease (COPD). After valve placement, 19 (47.5%) patients had complete resolution of acute air leak, 18 (45%) had a reduction in air leak, 2 (5%) had no change, and no data were available for 1 patient. The mean time from valve placement to chest tube removal was 21 days (median time, 7.5 days). Six patients experienced adverse events related to valve placement, including valve expectoration, moderate oxygen desaturation, initial malpositioning of a valve, pneumonia, and Staphylococcus aureus colonization. The length of follow-up varied, ranging from 5 to 1109 days. At last follow-up, 16 patients had died, though none of the deaths was attributed to the valve or the implantation procedure.

Firlinger (2013) et al studied 13 patients with persistent, continuous air leak (ie, having an intrathoracic chest tube for >7 days despite conservative and/or surgical therapy) in Austria.^3, Spiration valves were used in 9 patients and Zephyr valves in 4 patients. Ten (77%) of 13 patients were considered responders, defined as successful chest tube removal without need for further intervention. The Spiration IBV (intrabronchial valve) was used in six of ten responders and all three nonresponders.

Gillespie et al (2011) reported on a case series of 7 patients with pulmonary air leaks treated with Spiration IBV.^4, The median duration of air leaks in the 7 patients before valve placement was 4 weeks (range, 2 weeks to 5 months). One patient had a second valve implanted due to an additional air leak. Complete air leak cessation occurred in 6 of 8 procedures after a mean duration of 5.2 days. The other 2 procedures resulted in a reduction of air leak. There were no operative or postoperative complications attributed to the bronchial valves. The valves were removed in 5 of the 7 patients at a mean of 37 days after placement (range, 14-55 days). Valves were not removed from a patient who entered hospice care or the patient who underwent 2 procedures because the patient declined removal.

The Humanitarian Device Exemption approval of the IBV Valve required post-approval study (PAS). The study was a prospective observational study to collect safety information about the IBV Valve System for the treatment of prolonged air leak. Eligible subjects were into the study on the day of valve treatment. The subjects were monitored after treatment until discharge from the hospital (a minimum of 1 night stay after the procedure). After discharge, the subjects were seen by the investigator for assessment of air leak status as clinically indicated. Valves were to be removed after the air leak is resolved. If the air leak was not resolved, the valves were to be removed no longer than 6 weeks after device placement and other options were to be considered. A summary of the FDA PAS is provided in Table 3.

Table 3. Summary of IBV Valve PAS

Study	Countries	Sites	Dates	Participants	SAE Effect Findings Air Leak Resolution
H060002 / PAS001 Prospective Cohort Study	US	11	2009-2014	39 post IBV valve placement for prolonged air leak	21	32/39 per protocol follow-up 2/32: no response 30/32: positive response)11/30: complete resolution 19/30: improvement

Source: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma_pas.cfm?c_id=249&t_id=367937
IBV: Intrabronchial valve; PAS: Post-Approval Study; SAE: serious adverse event.

¹ AE: One systolic arrest secondary to hypercapnia resolved prior to IBV placement and one mucus impaction of a bronchial valve

Data on the Spiration IBV are limited to reports of the first patients submitted to the Food and Drug Administration for the Humanitarian Device Exemption for use for prolonged air leaks as well as the results of the post-approval study completed in 2014. Other reports are small series of heterogeneous patients. There are no comparative data with alternatives. This evidence is inadequate to determine the impact of this technology on the net health outcome.

Treatment of Severe or Advanced Emphysema
Clinical Context and Therapy Purpose

The purpose of placing bronchial valves in patients who have severe or advanced emphysema is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does placement of bronchial valves improve the net health outcome in patients with severe or advanced emphysema?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals with severe/advanced emphysema who remain symptomatic despite optimal medical management.

Emphysema, a form of Chronic Obstructive Pulmonary Disease (COPD), is a progressive, debilitating disease characterized by irreversible destruction of alveolar tissue. This destruction results in reduced elastic recoil, progressive hyperinflation and gas trapping with patients experiencing chronic dyspnea, limited exercise tolerance and poor health related quality of life.

Bronchial valves would be considered for patients at GOLD stage 3 or 4 (severe or very severe).

Interventions

The therapy being considered is the placement of bronchial valves. Bronchial valves are synthetic devices deployed with a flexible bronchoscope into the airways of the lung. The devices use a one-way valve to achieve an atelectasis (collapse) of the lobe, allowing air to escape while blocking airflow into the treated lobe. Valves are designed to prevent air inflow during inspiration but to allow air and mucus to exit during expiration. This is intended to result in a reduction in lung volume and hyperinflation in the targeted area. Endobronchial valve insertion is done with the patient under sedation or general anesthesia. Several valves may be needed. Bronchial valves can be removed or replaced using bronchoscopy.

Comparators

Alternatives for the treatment of severe emphysema include medical management, lung volume reduction surgery, and lung transplantation.

GOLD (2020) lists the following components of optimal medical management for severe emphysema:^1,

• Smoking cessation
• Individualized pharmacological therapy
• Assessment of inhaler technique
• Pulmonary rehabilitation (exercise training, health education, breathing techniques)
• Influenza and pneumococcal vaccinations
• Oxygen therapy
• Palliative approaches to symptom control (treat dyspnea, support nutrition, address panic, anxiety, depression, fatigue)

The general outcomes of interest, in addition to overall survival, are a reduction in symptoms, functional outcomes, quality of life, and treatment-related morbidity.

Relevant health outcomes include COPD exacerbations, mortality, and adverse events (e.g., pneumothorax, pneumonia, and respiratory failure). Efficacy outcomes include measures of lung function, physical function, and quality of life (Table 4).

Improvement in lung function after use of bronchial valves as part of multimodality pulmonary care should be assessed at 6 months after insertion.

Table 4. Efficacy Outcome Measures

Measure	Description	Clinically Meaningful Difference
FEV1	Volume of air a person can force out in one second after taking a deep breath. Not an objective of COPD management, but frequently used by regulatory authorities to interpret treatment efficacy in COPD trials Used to categorize severity of airflow limitation	15% improvement 100-140 mL increase
SGRQ	Measures quality of life in patients with emphysema Scores range from 0 to 100, with higher scores indicating a worse quality of life.	4-point decrease (improvement)
6-Minute Walk Test	Distance a person can walk in 6 minutes Measures physical function Healthy subjects can walk 400-700 meters	Increase of 25-30 meters

COPD: chronic obstructive pulmonary disease; FEV1: forced expiratory volume in 1 second; SGRQ: St. George Respiratory Questionnaire;

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

Seven RCTs have evaluated the Zephyr valve in patients with severe emphysema (Table 5). Only one trial (BELIEVER) used a sham procedure as a comparator; the rest were open label and compared the Zephyr valve to standard medical care, typically optimal medical care as described in the GOLD guidelines. The VENT trial included patients with collateral ventilation, but subgroup analyses of patients with collateral ventilation were reported. The IMPACT (A Multicentre, Prospective, Randomized, Controlled, One-way Crossover Investigation of Endobronchial Valve (EBV) Therapy vs. Standard of Care (SoC) in Homogeneous Emphysema) trial included patients with homogeneous emphysema distribution and the other trials were limited to those with heterogeneous emphysema. The BELIEVER trial was limited in that it only had a 3-month follow up duration. The other trials followed patients for 6 or 12 months. A post hoc analysis of the two earliest trials (Endobronchial Valve for Emphysema Palliation Trial (VENT) EU 2012 and VENT US 2010) showed better response rates in participants who had intact fissures. As a result, the newer trials altered their inclusion criteria to only select participants with intact fissures, thereby lowering the chance of selecting participants who had collateral ventilation, which resulted in better functional outcomes.^5,

The trials showed statistically and clinically significant improvements in FEV1 (Table 6). Both response and mean change were significantly higher in the valve group in all the trials that measured this. This was consistent and clinically meaningful, but there was some imprecision, with wide confidence intervals in some of the trials. On the SGRQ, there was no significant in the sham controlled study, while the open label trials consistently showed a better outcome in the valve group.

The incidence of COPD exacerbations requiring hospitalization reported in the trials are shown in Table 7. In the immediate post-procedure period, more patients who received the intervention experienced a COPD exacerbation. However, at later time points the incidence was lower among patients who received the valve. For example, in the LIBERATE (Lung Function Improvement After Bronchoscopic Lung Volume Reduction With Pulmonx Endobronchial Valves Used in Treatment of Emphysema) trial, the mean difference up to 45 days was 3.0% (95% CI -4.1% to 10.1%), compared to 7.69% (95% CI -5.99% to 21.38%) from day 46 up to 12 months.

Mortality and adverse event results are detailed in Table 8. The number of deaths was low and studies were not powered to detect a difference in events between groups.The most common serious adverse event was pneumothorax, which occurred in up to 27% of patients.

Table 5. Summary of Key RCT Characteristics- Zephyr Valve

Trial	Countries	Sites	Dates	Participants	Interventions		Duration
LIBERATE, Criner et al (2018)6, NCT01796392 7,	US and other	31	2013- 2016	Heterogeneous emphysema and little to no collateral ventilation	Zephyr valve(n=128)	Standard care (n=62)	12 months
TRANSFORM, Kemp et al (2017)8, NCT02022683	Europe	17	2014- 2016	Heterogeneous emphysema and no collateral ventilation	Zephyr valve(n=65)	Standard care(n=32)	6 months
IMPACT, Valipour et al (2016)9, NCT02025205	Austria, Germany, Netherlands	15	2014- 2016	Homogenous emphysema and no collateral ventilation	Zephyr valve(n=43)	Standard care(n=50)	3 months
STELVIO, Klooster et al (2015)10, NTR2876 (Netherlands)	Netherlands	1	NR	Severe emphysema and no collateral ventilation	Zephyr valve(n=34)	Standard care(n=34)	6 months
BELIEVER HI-FI, Davey et al (2015)11,ISRCTN04761234	England	1	2012- 2013	Heterogeneous emphysema and intact interlobar fissures	Zephyr valve (n=25)	Sham procedure(n=25)	3 months
VENT EUROPE, Herth et al (2012)12,NCT00129584.	Multiple European	23	2005- 2009	Severe heterogenous emphysema	Zephyr valve(n=111, 44 with complete fissure)	Standard care (n=60, 19 with complete fissure)	12 months
VENT US, Sciurba et al (2010)13,NCT00129584	US	31	2004- 2006	Severe heterogenous emphysema	Zephyr valve (n=220)	Standard care (n=101)	6 months

NCT: National Clinical Trial; NR: Not reported; n:sample size; RCT: randomized controlled trial

Table 5. RCTs of the Zephyr Valve- Efficacy Results

Study	FEV1 Responders (>15% Increase from Baseline1)	FEV1- Mean Change	SGRQ Responders (>4-point decrease from baseline)	SGRQ- Mean Change	6-MInute Walk Distance-  Responders (>25 meters increase from baseline)	6-MInute Walk Distance- mean change, meters
LIBERATE (2018)
Number analyzed	190	190	190	190	190	190
Zephyr valve	47.7%	17.2%	56.2%		41.8%
Standard care	16.8%	-0.8%	30.2%		19.6%
Difference (95% CI)	31.5% (18.9%-44.1%)	17.96% (9.84% to 26.09%)	25.6% (11.3% to 39.9%)	-7.05 (-11.84 to -2.27)	22.8% (9.8% to 35.9%)	39.31 (14.64 to 63.98)
p-value	<.001	<.001	NR	.004	NR	<.002
TRANSFORM (2017)
Total N	97	97	97	97	97	97
Zephyr valve	56.3%		61.7%		52.4%	36.2
Standard care	3.2%		34.4%		12.9%	-42.5
Difference (95% CI)	53.1% (NR)	0.23 L (95% CI 0.14 to 0.32)	27.3% (NR)	-6.5 (-12.4 to -0.6)	39.5% (NR)	78.7 (46.3 to 111.0)
P-value	<.001	<. 001	.042	.031	.001	<.001
IMPACT (2016)
Total N	93	93	85			90
Zephyr valve	34.9%	0.10	56.8%		50.0%	22.6 (66.6)
Standard care	4.0%	-0.02	25.0%		14.0%	-17.3 (52.8)
Difference (95% CI)	30.9% (NR)	0.12 (0.06 to 0.18)	31.8% (NR)	-9.64 ( -14.09 to -5.20)	36.0% (NR)	40.0 (15.0 to 65.0)
P-value	<.0001	<.0001	.003	<.0001	.0002	.002
STELVIO (2015)
Total N	68	NR	68	NR	68	68
Zephyr valve	59.0%	NR	79%	NR	59%	60 (35 to 85)
Standard care	24.0%	NR	33%	NR	6%	-14 (-25 to -3)
Difference (95% CI)	35.0% (NR)	NR	46% (NR)	NR	49% (NR)	74 (47 to 100)
P-value	0.001	NR	NR	NR	<.001	.001
BELIEVER HI-FI (2015)
Total N	43	43	43	43	NR	43
Zephyr valve	47%	24.8%	58%		NR	Median, IQR: 25 (7 to 64)
Sham	4%	3.9%	46%		NR	Median, IQR: 3 (-14 to 20)
Difference (95% CI)	43.2% (19.4% to 67.0%)	20.9% (4.3% to 37.5%);	12.1% (-17.8% to 41.9%)	-9.64 (-14.09 to -5.20)	NR	NR
p-value	.0022	.033	NR	.36	NR	.0119
VENT Europe
Total N	NR	63	NR	63	NR	63
Zephyr valve	NR	15%	NR	-6.0	NR	13%
Standard care	NR	-2%	NR	3.0	NR	10%
Difference (95% CI)	NR	17% (NR)	NR	3.0 (NR)	NR	3% (NR)
p-value	NR	.04	NR	.09	NR	.80
VENT US2
Total N	321	NR	321	NR	321	NR
Zephyr valve	23.5%	NR	23.5%	NR	25.3%	NR
Standard care	10.7%	NR	10.7%	NR	17.8%	NR
Difference (95% CI)	6.8 (NR)	NR	12.8%	NR	7.5% (NR)	NR
p-value	.02	NR	.02	NR	.25	NR

¹Responder definition was >10% in STELVIO and >12% in TRANSFORM
AE: adverse events; CI: confidence interval; FEV1: forced expiratory volume in 1 second; IQR: interquartile range; MRC: Medical Research Council; N: sample size; NR: not reported; RCT: randomized controlled trial; SD: standard deviation. SGRQ: St. George Respiratory Questionnaire.

Table 7. COPD Exacerbations in RCTs of the Zephyr Valve

Study	Time Point	Zephyr vs Control
LIBERATE	0 - 46 days	7.8% vs 4.8% Difference 3.0% (95% CI -4.1% to 10.1%)
	> 46 days to 12 mos	23.0% vs 30.6% Difference 7.69% (95% CI -5.99% to 21.38%)
TRANSFORM	0 - 30 days	4.6% vs 0%
	> 30 days to 6 mos	4.6% vs 6.3%
IMPACT	0 days to 3 mos	16.3% vs 12.0%
STELVIO	0 days to 6 mos	12% vs 6%; P =.67
BELIEVER	0 days to 3 mos	20.0% vs 12.0%; P =.70
VENT EU	0 days to 3 mos	11.7% vs. 10.0%; P =.80
	> 3 mos to 12 mos	Data NR (NS)
VENT US	0 to 90 days	7.9% vs. 1.1%; P =.03
	0 days to 12 mos	NR

CI: confidence interval; COPD: chronic obstructive pulmonary disease; NR: not reported; RCT: randomized controlled trial.

Table 8. Mortality and Serious Adverse Events in RCTs of the Zephyr Valve

Study	Time Point	Mortality(Zephyr vs Control)	Serious Adverse Events(Zephyr vs Control)
LIBERATE	0-46 days	3.1% vs 0% Difference 3.1% (95% CI 0.11% to 6.1%)	39.8% vs 4.8%
	>46 days to 12 mos	0.8% vs 1.6%	38.5% vs 50.0%
TRANSFORM	0-30 days	4.6% vs 0%	44.6% vs 0%
	>30 days to 6 mos	4.6% vs 6.3%	20.0% vs 9.3%
IMPACT	0 days to 3 mos	1 vs 0	44.2% vs 12.0%
STELVIO	0 days to 6 mos	1 vs 0	67.6% vs 14.7%
BELIEVER	0 days to 3 mos	2 vs 0	% patients NR
VENT EU	0 days to 3 mos	NR	% patients NR
	>3 mos to 12 mos	4.5% vs 5.2%	% patients NR
VENT US	0 to 90 days	1% vs 0%	4.2% vs 0%
	0 days to 12 mos	3.7% vs 3.5%	10.3% vs 4.6%

CI: confidence interval; RCT: randomized controlled trial.

Tables 9 and 10 summarize the design and conduct limitations of the Zephyr valve RCTs. Because they included patients with collateral ventilation, the VENT trials are no longer representative of the intended use of the device. BELIEVER and IMPACT are limited by their 3-month followup duration. A major limitation in most of the trials was a lack of blinding, which could have influenced performance on measures of lung function, exercise tolerance (e.g., it might have affected clinicians' coaching of patients and/or the degree of effort exerted by patients), and patient-reported measures of symptoms and quality of life. Most studies were too small to detect detect differences between groups on important health outcomes such as mortality and COPD exacerbations.

Table 9. RCTs of the Zephyr Valve- Study Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
LIBERATE
TRANSFORM				6.Used >12% in FEV for response
IMPACT					1,2 three months only
STELVIO				6. Used >10% for FEV1 response
BELIEVER HI-FI					1,2 three months only
VENT Europe	4. included patients with collateral ventilation
VENT US	4. included patients with collateral ventilation				.

The evidence limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Study	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
LIBERATE		1, 2 not blinded
TRANSFORM		1, 2 not blinded
IMPACT		1, 2 not blinded
STELVIO		1, 2 not blinded		6.Not ITT for some outcomes		3. confidence intervals not reported for some outcomes
BELIEVER HI-FI
VENT Europe		1, 2 not blinded			3 smaller than the a priori estimate	3. confidence intervals not reported for some outcomes
VENT US		1, 2 not blinded

^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Several recent systematic reviews with meta-analyses have assessed the use of the Zephyr valve system for patients with severe emphysema.^5,14,15,16, Authors of all of these reviews came to similar conclusions: In patients with severe emphysema and low collateral ventilation, RCTs provide evidence of clinically meaningful benefit for bronchial valves compared to standard medical management on short-term (up to 12 months) measures of lung function, exercise tolerance, and quality of life, but these benefits should be measured against the greater risk of serious adverse events compared to usual care. Limitations of the evidence noted by review authors included a lack of comparisons to lung volume reduction surgery and significant heterogeneity for some analyses.

A comprehensive systematic review and meta analysis of the Zephyr valve system in patients with severe emphysema was conducted by La Barca et al (2019) (Table 11).^16, The remainder of this section focuses on this review. La Barca et al included all 7 RCTs of the Zephyr valve, but excluded from quantitative meta-analyses the 2 RCTs that included patients with collateral ventilation (VENT EU and VENT US). Two independent reviewers assessed the risk of bias of the included studies, and the quality of the overall body of evidence was ranked using the GRADE approach. Prespecified efficacy outcomes were change in FEV1, change in SGRQ; change in 6-minute walk test distance, and change in residual volume. The safely analysis included assessment of all-cause mortality and pneumothorax. The reviewers also conducted subgroup analyses based on length of follow-up (3 months vs 6 months or longer), heterogeneous vs homogeneous emphysema distribution, and study comparator (standard of care vs sham valve).

Results are summarized in Table 12. Meta-analyses found statistically and clinically significant improvements with the Zephyr valve in FEV1, residual volume, 6-minute walk distance, and SGRQ, but with increased risk of adverse events. The certainty of evidence was rated high only for SGRQ and risk of pneumothorax. Certainty of the evidence for the other efficacy outcomes was downgraded due to risk of bias from lack of blinding, heterogeneity between studies, and non-primary outcomes. Certainty of the evidence was rated low for overall mortality because it was not a primary outcome and the estimate had wide confidence intervals.

Table 11. Systematic Review and Meta-Analysis of the Zephyr Valve-Characteristics

Study	Search end date	RCTs	Participants	N (Range)	Duration
LaBarca et al (2020)16,	Oct 2018	7 (5 included in meta-analyses; excluded studies in patients with collateral ventilation)	Adult patients (mean age range 59.7 to 65.3 years); mostly COPD stage IV; without collateral ventilation measured by the Chartis system; optimal medical management according to GOLD recommendations;	498 (50-190)	3 months to 12 months

COPD: chronic obstructive pulmonary disease; GOLD: Global Initiative for Chronic Obstructive Lung Disease; N: sample size; RCT: randomized controlled trial.

Table 12. Meta-analysis of RCTs of the Zephyr Valve- Results^16,

Outcome	Pooled Result (95% CI)	Certainty of the Evidence (reasons for downgrading)
Change in Residual Volume, mL (mean difference)	-0.53 (-0.75, -0.32)	Not assessed
Change in FEV1, mL (mean difference)	17.36 (9.28, 25.45)	Moderate (risk of bias due to lack of blinding)
Change in 6-min walk distance, meters (mean difference)	49.75 (28.75, 70.75)	Low (high heterogeneity between studies despite subgroup analysis, non-primary outcome)
Change in SGRQ score (mean difference)	-8.42 (-10.86, -5.97)	High
Pneumothorax (relative risk)	6.32 (3.74, 10.67)	High
Overall Mortality (relative risk)	1.26 (0.50, 3.15)	Low (non-primary outcome, wide confidence interval)

CI: confidence interval; FEV1: forced expiratory volume in 1 second.; RCT: randomized controlled trial; SGRQ: St. George Respiratory Questionnaire.

Several other systematic reviews with meta-analyses have assessed the use of the Zephyr valve system for patients with severe emphysema.^5,14,15, Authors of all of these reviews came to similar conclusions: In patients with severe emphysema and low collateral ventilation, RCTs provide evidence of clinically meaningful benefit for bronchial valves compared to standard medical management on short-term measures of lung function, exercise tolerance, and quality of life, but these benefits should be measured against the greater risk of serious adverse events compared to usual care. Limitations of the evidence noted by review authors included a lack of comparisons to lung volume reduction surgery and significant heterogeneity for some analyses.

Spiration Valve
Review of Evidence
Randomized Controlled Trials

Three RCTs of the Spiration valve in patients with emphysema have been published.^17,18,19, One used a sham control and two were open-label.Tables 13-16 summarize the characteristics and results of these trials.

EMPROVE (A Prospective, Randomized, Controlled Multicenter Clinical Study to Evaluate the Safety and Effectiveness of the Spiration® Valve System for the Single Lobe Treatment of Severe Emphysema) was an open-label trial of 172 patients with severe emphysema and no collateral ventilation. Trial results were published in a peer-reviewed journal in 2019;^19,results were previously available as part of the Spiration PMA application.^20, Patients who received the Spiration valve had improvements in lung function and quality of life compared to usual care, but there was no significant difference between groups in exercise capacity. Thoracic serious adverse events, the primary safety outcome, were more frequent in the Spiration group (31.0% vs 11.9%), primarily due to a 12.4% incidence of serous pneumothorax. The REACH (The Spiration Valve System for the Treatment of Severe Emphysema) trial found improvements in FEV1, 6MWT, and SGRQ, The sham-controlled IBV Valve (A Prospective, Randomized, Controlled Multicenter Clinical Trial to Evaluate the Safety and Effectiveness of the IBV® Valve System for the Treatment of Severe Emphysema) trial showed statistically significant results favoring the Spiration valve, but confidence intervals were wide and the study authors concluded that the trial did not obtain clinically meaningful results.^17,.

Table 13. Summary of Key RCT Characteristics-Spiration Valve

Trial	Countries	Sites	Dates	Participants	Interventions		Duration
					Active	Comparator
EMPROVE 19,20,IDE #G 120192.	US and Canada	31	2013-2017	Severe emphysema without collateral ventilation	Spiration valve(n=113)	Standard care(n=59)	12 months
REACH, Li et al (2018) 18,NCT01989182	China	12	2013-2017	Severe emphysema and intact interlobular fissures	Spiration valve(n=72)	Standard care(n=35)	6 months
IBV Valve, Wood et al (2014)17,NCT00475007	US	36	2007-2017	Emphysema, airflow obstruction,hyperinflation, and severe dyspnea	Spiration valve (n=142)	Sham procedure (n=135)	6 months

IDE: Investigational Device Exemption; NCT: National Clinical Trial; NR: Not reported; n:sample size; RCT: randomized controlled trial;

Table 14. RCTs of the Spiration Valve- Efficacy Results

Study	FEV1 Responders (>15% Increase from Baseline1)	FEV1 Mean Change, liters	SGRQ Responders (>4-point decrease from baseline)	SGRQ Score Mean Change	6-MInute Walk Distance- Responders (>25 meters increase from baseline)	6-MInute Walk Distance- Mean change, meters
EMPROVE19,20,
Total N	156	156	136	136	150	150
Spiration valve	36.8%	NR	50.5%	-5,8	32.4%	NR
Standard care	10.0%	NR	22.0%	3.7	22.9%	NR
Difference (95% CI)	25.7% (12.7% to 38.7%)	0.101 (0.060 to 0.141)	28.6% (12.4% to 44.8%)	-9.5 (-14.4 to -4.7)	9.4% (-5.5% to 24.4%)	Difference 6.9 (-14.2 to 28.2)
p-value	NR	NR	NR	NR	NR	NR
REACH 18,
Total N	NR	NR	NR	NR	NR	NR
Spiration valve	48%	0.09 (95% CI 0.16 to 0.05)	NR	-8.39 (95% CI -12.69 to -4.08)	NR	20.82 (95% CI -0.58, 42.22)
Standard Care	13%	-0.24 (95% CI -0.14, -0.07)	NR	2.11 (95% CI -3.87, 8.08)	NR	-15.58 (95% CI -40.12, 8.96)
Difference (95% CI)	35% (NR)	NR	NR	NR	NR	NR
p-value	.001	.001	NR	.007	NR	NR
IBV Valve17,
Total N	NR	250	254	277	NR	NR
Spiration valve	NR	-0.07 (SD 0.17)	32.2%	2.15 (16.36)	NR	-24.02
Sham	NR	0.00 (SD 0.16)	39.8%	-1.41 (11.26)	NR	-3.0
Difference	NR	(-0.11, -0.02)	7.6% (-4.15% to 19.39%)	(0.04, 7.07)	NR	-21.02 (-38.84 to -2.44)
p-value	NR	NR	NR	NR	NR	NR

CI: confidence interval; FEV1: forced expiratory volume in 1 second; MRC: Medical Research Council; N: sample size; NR: not reported; RCT: randomized controlled trial; SGRQ: St. George Respiratory Questionnaire;

Table 15. COPD Exacerbations in RCTs of the Spiration Valve

Study	Time Point	Spiration vs Control
EMPROVE	0--6 months	16.8% vs 10.2%Difference 6.6% (95% CI -5.1% to 16.0%)
	>6-12 months	13.6% vs 8.5%Difference 5.1% (95% CI -7.4% to 14.2%)
REACH	0-6 months	19.7% vs 24.2%
IBV Valve	0-6 months	4.9% vs 1.5%Difference 3.4% (95% CI -0.5, 7.9%)

CI: confidence interval; COPD: chronic obstructive pulmonary disease; RCT: randomized controlled trial.

Table 16. Mortality and Serious Adverse Events in RCTs of the Spiration Valve

Study	Time Point	Mortality Spiration vs Control	Serious Adverse EventsSpiration vs Control
EMPROVE	0--6 months	5.3% vs 1.7%Difference 3.6% (95% CI -1.7% to 8.9%)	31.0% vs 11.8%19.1% (95% CI 5.9% to 29.7%)
	>6-12 months	3.9% vs 6.4%	21.4% vs 10.6%10.7% (95% CI 3.0% to 21.2%)
REACH	0-6 months	0% vs 3.0%	44.3% vs 24.2%
IBV Valve	0-6 months	4.2% vs 0.7%Difference 3.5% (95% CI 0.2%, 7.5%)	14.1% vs 3.7%10.4% (95% CI 4.0% to 17.1%)

CI: confidence interval; RCT: randomized controlled trial.

Tables 17 and 18 summarize the design and conduct limitations of the Spiration valve RCTs. A major limitation was a lack of blinding, which could have influenced performance on measures of lung function, exercise tolerance (e.g., it might have affected clinicians' coaching of patients and/or the degree of effort exerted by patients), and patient-reported measures of symptoms and quality of life.

Table 17. RCTs of the Spiration Valve- Study Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
EMPROVE
REACH
IBV Valve

The evidence limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Study	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
EMPROVE		1, 2 not blinded
REACH		1, 2 not blinded
IBV Valve

^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

In patients with severe emphysema and low collateral ventilation, RCTs provide evidence of clinically meaningful benefit for bronchial valves compared to standard medical management on measures of lung function, exercise tolerance, and quality of life. However, confidence in these results is low due to study limitations including a lack of blinding and wide confidence intervals around estimates of effect. Across studies, there was an increased risk of serious procedure-related adverse events compared to usual care, including pneumothorax (occurring in up to 27% of patients).

Summary of Evidence

For individuals who have pulmonary air leaks who receive bronchial valves, the evidence includes the case series and a prospective cohort observational study related to the Humanitarian Device Exemption for the Spiration IBV Valve device. Relevant outcomes are overall survival, symptoms, functional outcomes, quality of life, and treatment-related morbidity. Other reports are small series of heterogeneous patients. There are no comparative data with alternatives. This evidence is inadequate to determine the impact of this technology on the net health outcome. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have severe or advanced emphysema who receive bronchial valves, the evidence includes RCTs and systematic reviews. Relevant outcomes are overall survival, symptoms, functional outcomes, quality of life, and treatment-related morbidity. In patients with severe emphysema and low collateral ventilation, RCTs provide evidence of clinically meaningful benefit for bronchial valves compared to standard medical management on measures of lung function, exercise tolerance, and quality of life. However, confidence in these results is low due to study limitations including a lack of blinding and wide confidence intervals around estimates of effect. Across studies, there was an increased risk of serious procedure-related adverse events compared to usual care, including pneumothorax occurring in up to 27% of patients. The potential benefits of the procedure do not outweigh the demonstrated harms. The evidence is insufficient to determine that the technology improves the net health outcome.

SUPPLEMENTAL INFORMATION
Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 1 physician specialty society and 3 academic medical centers while this policy was under review in 2011. Input generally agreed that use of bronchial valves is investigational for treating emphysema. Regarding the use of bronchial valves for treating prolonged air leaks, reviewers acknowledged that only limited case series are available. Of the 4 reviewers, 1 supported the investigational indication, 2 supported the compassionate use of valves for treating prolonged air leaks and the fourth thought that treatment of prolonged air leaks might be reasonable but had concerns about potential complications.

Practice Guidelines and Position Statements
Global Initiative for Chronic Obstructive Lung Disease (GOLD)

The GOLD (2020) publication makes the following statements on lung volume reduction interventions:^1,

• "In selected patients with heterogeneous or homogeneous emphysema and significant hyperinflation refractory to optimized medical care, surgical or bronchoscopic modes of lung volume reduction (e.g., endobronchial one-way valves, lung coils, or thermal ablation) may be considered."
• In select patients with advanced emphysema, bronchoscopic interventions reduce end-expiratory lung volume and improve exercise tolerance, quality of life and lung function at 6-12 months following treatment (Evidence Level A for endobronchial valves: well-designed RCTs with consistent findings in the intended population without any important limitations).

In December 2017, NICE issued the following recommendations on endobronchial valve insertion to reduce lung volume in emphysema:^21,

1.1 Current evidence on the safety and efficacy of endobronchial valve insertion to reduce lung volume in emphysema is adequate in quantity and quality to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit.
1.2 Patient selection should be done by a multidisciplinary team experienced in managing emphysema, which should typically include a chest physician, a radiologist, a thoracic surgeon and a respiratory nurse.
1.3 Patients selected for treatment should have had pulmonary rehabilitation.
1.4 The procedure should only be done to occlude volumes of the lung where there is no collateral ventilation, by clinicians with specific training in doing the procedure.

Offer a respiratory review to assess whether a lung volume reduction procedure is a possibility for people with COPD when they complete pulmonary rehabilitation and at other subsequent reviews, if all of the following apply:

• they have severe COPD, with FEV1 less than 50% and breathlessness that affects their quality of life despite optimal medical treatment
• they do not smoke
• they can complete a 6‑minute walk distance of at least 140 m (if limited by breathlessness).

• hyperinflation, assessed by lung function testing with body plethysmography and
• emphysema on unenhanced CT chest scan and
• optimised treatment for other comorbidities.

Not applicable.

Ongoing and Unpublished Clinical Trials

Some ongoing trials that might influence this policy are listed in Table 19.

Table 19. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT02382614a	Safety and Effectiveness of the Spiration Valve System (SVS) in Air Leaks (VAST)	200	Dec 2019 (suspended; interim analysis and potential modification)
NCT01796392a	Lung Function Improvement After Bronchoscopic Lung Volume Reduction With Pulmonx Endobronchial Valves Used in Treatment of Emphysema (LIBERATE)	183	Feb 2023
NCT01812447a	A Prospective, Randomized, Controlled Multicenter Clinical Study to Evaluate the Safety and Effectiveness of the Spiration® Valve System for the Single Lobe Treatment of Severe Emphysema (EMPROVE)	172	May 2022
NCT04186546a	Zephyr Valve Registry (ZEVR)	150	Dec 2024

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Bronchial Valves
Endobronchial Valves
Emphysema, Endobronchial Valve
Endobronchial Valve, Emphysema
IBV Valve System
Zephyr Endobronchial Valve

References:
1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). 2020 Global Strategy for Prevention, Diagnosis, and Management of COPD. https://goldcopd.org/gold-reports/. Accessed June 8, 2020.

2. Travaline JM, McKenna RJ, Jr., De Giacomo T, et al. Treatment of persistent pulmonary air leaks using endobronchial valves. Chest. Aug 2009;136(2):355-360. PMID 19349382

3. Firlinger I, Stubenberger E, Muller MR, et al. Endoscopic one-way valve implantation in patients with prolonged air leak and the use of digital air leak monitoring. Ann Thorac Surg. Apr 2013;95(4):1243-1249. PMID 23434254

4. Gillespie CT, Sterman DH, Cerfolio RJ, et al. Endobronchial valve treatment for prolonged air leaks of the lung: a case series. Ann Thorac Surg. Jan 2011;91(1):270-273. PMID 21172529

5. van Agteren JE, Hnin K, Grosser D, et al. Bronchoscopic lung volume reduction procedures for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. Feb 23 2017;2:CD012158. PMID 28230230

6. Criner, G, 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 May 23;198(9). PMID 29787288

7. Dransfield MT, Garner JL, Bhatt SP, et al. Effect of Zephyr Endobronchial Valves on Dyspnea, Activity Levels and Quality of Life at One Year. Ann Am Thorac Soc. Mar 30 2020. PMID 32223724

8. Kemp, S, Slebos, D, 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 Sep 9;196(12). PMID 28885054

9. Valipour, A, Slebos, D, Herth, F, et al. Endobronchial Valve Therapy in Patients with Homogeneous Emphysema. Results from the IMPACT Study.. Am. J. Respir. Crit. Care Med., 2016 Nov 1;194(9). PMID 27580428

10. Klooster, K, ten Hacken, N, Hartman, J, et al. Endobronchial Valves for Emphysema without Interlobar Collateral Ventilation.. N. Engl. J. Med., 2015 Dec 10;373(24). PMID 26650153

11. 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. Sep 12 2015;386(9998):1066-1073. PMID 26116485

12. Herth FJ, Noppen M, Valipour A, et al. Efficacy predictors of lung volume reduction with Zephyr valves in a European cohort. Eur Respir J. Jun 2012;39(6):1334-1342. PMID 22282552

13. Sciurba FC, Ernst A, Herth FJ, et al. A randomized study of endobronchial valves for advanced emphysema. N Engl J Med. Sep 23 2010;363(13):1233-1244. PMID 20860505

14. National Institute for Health and Care Excellence. Chronic obstructive pulmonary disease in over 16s: Diagnosis and management. Available at: https://www.nice.org.uk/guidance/ng115/chapter/Recommendations#managing-stable-copd. Accessed May 29, 2020

15. van Geffen, W, Slebos, D, Herth, F, et al. Surgical and endoscopic interventions that reduce lung volume for emphysema: a systemic review and meta-analysis.. Lancet Respir Med, 2019 Feb 13;7(4). PMID 30744937

16. 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. NA 2019; 98(3): 268-278. PMID 31117102

17. Wood DE, Nader DA, Springmeyer SC, et al. The IBV Valve trial: a multicenter, randomized, double-blind trial of endobronchial therapy for severe emphysema. J Bronchology Interv Pulmonol. Oct 2014;21(4):288-297. PMID 25321447

18. Li, S, Wang, G, Wang, C, et al. The REACH Trial: A Randomized Controlled Trial Assessing the Safety and Effectiveness of the Spiration Valve System in the Treatment of Severe Emphysema.. Respiration, 2018 Dec 17;1-12:1-12. PMID 30554211

19. 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 Clinical Trial. Am J Respir Crit Care Med. Dec 01 2019; 200(11): 1354-1362. PMID 31365298

20. U.S. Food & Drug Administration. Spiration Valve System. Summary of Safety and Effectiveness Data. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf18/P180007B.pdf. Accessed June 8, 2020.

21. National Institute for Health and Care Excellence. Endobronchial valve insertion to reduce lung volume in emphysema. Available at: https://www.nice.org.uk/guidance/IPG600/chapter/1-Recommendations. Accessed May 29, 2020.

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