Description
Bronchial valves are synthetic devices deployed with bronchoscopy into ventilatory airways of the lung to control airflow. They have been investigated for use in patients who have prolonged bronchopleural air leaks and as an alternative to lung volume reduction surgery in patients with lobar hyperinflation from severe or advanced emphysema.

For individuals who have pulmonary air leaks who receive bronchial valves, the evidence includes case series. Relevant outcomes are overall survival, symptoms, functional outcomes, quality of life, and treatment-related morbidity. The only available data on bronchial valves for treating persistent air leaks are uncontrolled trials with small numbers of heterogeneous patients. Data on the Spiration IBV device (the only device approved by the U.S. Food and Drug Administration) are particularly limited. These valves were successfully placed in 40 patients in a multicenter case series and other series. These case series do not provide any comparative evidence with alternatives. 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 7 randomized controlled trials and a systematic review of these trials. Relevant outcomes are overall survival, symptoms, functional outcomes, quality of life, and treatment-related morbidity. Of the 7 randomized controlled trials, 5 did not use a U.S. Food and Drug Administration-approved valve. For the U.S. Food and Drug Administration-approved Spiration IBV, there was no improvement in quality of life or exercise capacity in the combined results. Although some outcomes of the larger trials were statistically significant for bronchial valve treatment, the magnitude of the difference was generally of uncertain clinical significance. Moreover, the numerous adverse events experienced by patients who received bronchial valves in these trials raise concerns about treatment safety. Overall, it is not possible to determine whether there is a clinically meaningful benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

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):GOLD 4 (very severe): FEV1 <30% predicted 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
70171 Lung Volume Reduction Surgery for Severe Emphysema

Policy
Bronchial valves are investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY in all situations including, but not limited to:

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

Policy Guidelines
Please see the Codes table for details.

Benefit Application
BlueCard/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all U.S. Food and Drug Administration (FDA)-approved devices may not be considered investigational, and thus these devices may be assessed only on the basis of their medical necessity.

Rationale 
This evidence review was created in November 2010 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through April 15, 2022.

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 1 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 (RCT) 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 evidence review 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 review.

Populations
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.

Outcomes
The general outcomes of interest, in addition to overall survival, are a reduction in symptoms (e.g., pneumothorax) and improvements in functional outcomes. Placement of bronchial valves requires an inpatient surgical procedure. Bronchial valves can be utilized for up to 6 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.

Review of Evidence
Case Series
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.⁵ 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 the 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 et al. (2013) studied 13 patients with persistent, continuous air leak (i.e., having an intrathoracic chest tube for > 7 days despite conservative and/or surgical therapy) in Austria.⁶ 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 6 of 10 responders and all 3 nonresponders.

Gillespie et al. (2011) reported on a case series of 7 patients with pulmonary air leaks treated with Spiration IBV.⁷ 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 to 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 a post-approval study (PAS). The PAS was a prospective observational study to collect safety information about the IBV Valve System for the treatment of prolonged air leak. Eligible subjects were enrolled 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 was 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 U.S. Food and Drug Administration (FDA) PAS is provided in Table 3.

Table 3. Summary of IBV Valve PAS

Study	Countries	Sites	Dates	Participants	SAEs	Findings Regarding Air Leak Resolution
H060002/PAS001 Prospective Cohort Study	U.S.	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.
¹AE: One systolic arrest secondary to hypercapnia resolved prior to IBV placement and one mucus impaction of a bronchial valve

Section Summary: Treatment of Pulmonary Air Leaks
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 PAS 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 with little or no collateral ventilation between target and ipsilateral lobe is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does placement of bronchial valves improve the net health outcome in patients with severe or advanced emphysema with little or no collateral ventilation between target and ipsilateral lobe?

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

Populations
The relevant population of interest is individuals with severe/advanced emphysema with little or no collateral ventilation between target and ipsilateral lobe who remain symptomatic despite optimal medical management.

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.

Bronchial valves would be considered for patients at Global Initiative for Chronic Obstructive Lung Disease (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 lists the following components of optimal medical management for severe emphysema:⁴

• 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, and fatigue)

Outcomes
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 1 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 to 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 to 700 meters	Increase of 25 to 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.

Review of Evidence
Zephyr Valve
Randomized Controlled Trials
Seven RCTs have evaluated the Zephyr valve in patients with severe emphysema (Table 5). Only a single 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. In IMPACT, participants in the standard of care arm were crossed over to the Zephyr valve arm if eligible after completing 6 months of follow-up. Eberhardt et al. (2021) reported randomized results up to 6 months and single-arm results at 12 months.⁸

A post hoc analysis of the 2 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.⁹

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 outcome. This was consistent and clinically meaningful, but there was some imprecision, with wide confidence intervals in some of the trials. On the St. George Respiratory Questionnaire (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 is 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% confidence interval [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)10,11 NCT01796392	U.S. and other	31	2013 – 2016	Heterogeneous emphysema and little to no collateral ventilation 91.6% White, 5.8% Black, 2.6% other race 46.8% male	Zephyr valve (n = 128)	Standard care (n = 62)	12 months
TRANSFORM, Kemp et al. (2017)12 NCT02022683	Europe	17	2014 – 2016	Heterogeneous emphysema and no collateral ventilation Race and ethnicity not reported 59.8% male	Zephyr valve (n = 65)	Standard care (n = 32)	6 months
IMPACT, Valipour et al. (2016)13 Eberhardt et al. (2021)8 NCT02025205	Austria, Germany, Netherlands	15	2014 – 2016	Homogenous emphysema and no collateral ventilation Race and ethnicity not reported 38.7% male	Zephyr valve (n = 43)	Standard care (n=50)	6 months
STELVIO, Klooster et al. (2015)14 NTR2876 (Netherlands)	Netherlands	1	NR	Severe emphysema and no collateral ventilation Race not reported 32.4% male	Zephyr valve (n = 34)	Standard care (n = 34)	6 months
BELIEVER HI-FI, Davey et al. (2015)15 ISRCTN04761234	England	1	2012 – 2013	Heterogeneous emphysema and intact interlobar fissures Race and ethnicity not reported 62.0% male	Zephyr valve (n = 25)	Sham procedure (n = 25)	3 months
VENT EUROPE, Herth et al. (2012)16 NCT00129584	Multiple European	23	2005 – 2009	Severe heterogenous emphysema 99.4% White 71.9% male	Zephyr valve (n = 111, 44 with complete fissure)	Standard care (n = 60, 19 with complete fissure)	12 months
VENT US, Sciurba et al. (2010)17 NCT00129584	U.S.	31	2004 – 2006	Severe heterogenous emphysema 97.2% White 82.4% male	Zephyr valve (n=220)	Standard care (n=101)	6 months

NCT: National Clinical Trial; NR: Not reported; RCT: randomized controlled trial.

Table 6. RCTs of the Zephyr Valve- Efficacy Results

Study (Publication Date)	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% to 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 ( 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 and 2021)
Total N	93	93	84	84	92	92
Zephyr valve	30.2%	11.54%	63.9%	-6.84	45.2%	21.3
Standard care	10.0%	-4.73%	31.3%	0.63	22.0%	-7.1
Difference (95% CI)	20.2% (NR)	16.3% (NR)	32.8% (NR)	-7.51 (NR)	23.2% (NR)	28.3 (NR)
P-value	.014	< .0001	.003	< .0001	.018	.016
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

Study (Publication Date)	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% to 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 ( 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 and 2021)
Total N	93	93	84	84	92	92
Zephyr valve	30.2%	11.54%	63.9%	-6.84	45.2%	21.3
Standard care	10.0%	-4.73%	31.3%	0.63	22.0%	-7.1
Difference (95% CI)	20.2% (NR)	16.3% (NR)	32.8% (NR)	-7.51 (NR)	23.2% (NR)	28.3 (NR)
P-value	.014	< .0001	.003	< .0001	.018	.016
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 IMPACT and TRANSFORM. 
CI: confidence interval; FEV1: forced expiratory volume in 1 second; IQR: interquartile range; NR: not reported; RCT: randomized 
controlled trial; SGRQ: St. George Respiratory Questionnaire. 

Table 7. COPD Exacerbations in RCTs of the Zephyr Valve

Study	Time Point	Zephyr vs Control
LIBERATE	0 days to 46 days	7.8% vs. 4.8% Difference 3.0% (95% CI -4.1% to 10.1%)
	> 46 days to 12 months	23.0% vs. 30.6% Difference 7.69% (95% CI -5.99% to 21.38%)
TRANSFORM	0 days to 30 days	4.6% vs. 0%
	> 30 days to 6 months	4.6% vs. 6.3%
IMPACT	0 days to 30 days	14.0% vs. 1.0% p = .046
	31 days to 6 months	18.6% vs. 20.0%; p = 1.00
STELVIO	0 days to 6 months	12% vs. 6%; p = .67
BELIEVER	0 days to 3 months	20.0% vs. 12.0%; p = .70
VENT EU	0 days to 3 months	11.7% vs. 10.0%; p = .80
	> 3 months to 12 months	Data NR (NS)
VENT US	0 days to 90 days	7.9% vs. 1.1%; p = .03
	3 months to 12 months	10.3% vs. 9.2%; p = .84

CI: confidence interval; COPD: chronic obstructive pulmonary disease; NR: not reported; NS: nonsignificant; 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 days to 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 months	0.8% vs. 1.6%	38.5% vs. 50.0%
TRANSFORM	0 days to 30 days	1.5% vs. 0%	38.5% vs. 3.1%
	> 30 days to 6 months	0% vs. 0%	15.4% vs. 9.4%
IMPACT	0 days to 30 days	0 vs. 0	44.2% vs. 1.0%; p < .001
	31 days to 6 months	0 vs. 2 (4.0%)	34.9% vs. 26.0%; p = .269
STELVIO	0 days to 6 months	1 vs. 0	67.6% vs. 14.7%
BELIEVER	0 days to 3 months	2 vs. 0	% patients NR
VENT EU	0 days to 3 months	1 (0.9%) vs. 1 (1.7%); p = 1.00	% patients NR
	> 3 months to 12 months	5 (4.5%) vs. 3 (5.0%)	% patients NR
	0 days to 12 months	6 (5%) vs. 4 (7%)	% patients NR
VENT US	0 to 90 days	2 (0.9%) vs. 0 (0%)	4.2% vs. 0%
	3 months to 12 months	6 (2.8%) vs. 3 (3.4%); p = .72	6.1% vs. 4.6%
	0 days to 6 months	6 (2.8%) vs. 0 (0%); p = .19	6.1% vs. 1.2%; p = .08
	0 days to 12 months	3.7% vs. 3.5%; p = .88	10.3% vs. 4.6%; p = .17

CI: confidence interval; NR: not reported; 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 is limited by its 3-month follow-up 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 differences between groups on important health outcomes such as mortality and COPD exacerbations. Five of 7 trials were conducted outside of the U.S. Three of 7 trials did not report race or ethnicity data on participants. In the 3 trials that reported race, 91.7% to 99.4% of participants were White. Therefore it is uncertain if their results would be generalizable to the U.S. population.

Table 9. RCTs of the Zephyr Valve- Relevance Limitations

tudy	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
LIBERATE
TRANSFORM	4. unable to determine; race of participants not reported			6. Used > 12% in FEV for response
IMPACT	4. unable to determine; race of participants not reported
STELVIO	4. unable to determine; race of participants not reported			6. Used > 10% for FEV1 response
BELIEVER HI-FI	4. unable to determine; race of participants not reported				1,2 three months only
VENT Europe	3. included patients with collateral ventilation; 4. 97.2% white
VENT US	3. included patients with collateral ventilation; 4. 99.4% White				.

           .
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. Study population is unclear; 3. Study population not representative of intended use; 
4. Enrolled populations do not reflect relevant diversity; 5. Other.
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.

Table 10. RCTs of the Zephyr Valve- Study Design and Conduct Limitations

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

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

Systematic Reviews
Multiple systematic reviews with meta-analyses have assessed the use of the Zephyr valve system for patients with severe emphysema.9,18,19,20 
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.

A recent and relevant good methodological quality meta-analysis was conducted by LaBarca et al. in 2019.²⁰ The remainder of this section focuses on this review. La Barca et al. (2019) 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 safety 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 versus 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 an 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, 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)20	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 to 190)	3 to 12 months

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

Table 12. Meta-analysis of RCTs of the Zephyr Valve- Results20,

Outcome	Pooled Result (95% CI)	Heterogeneity	Certainty of the Evidence (reasons for downgrading)
Change in Residual Volume, mL (mean difference)	–0.57 (–0.76 to –0.39)	I2 = 37%; p =.18	Not assessed
Change in FEV1, mL (mean difference)	20.74% (15.68 to 25.79)	I2 = 25%; p =.25	Moderate (risk of bias regarding blinding of participants and personnel in most studies )
Change in 6-min walk distance, meters (mean difference)	53.10 (34.72 to 71.49)	I2 = 54%; p = .07	Low (high heterogeneity between studies despite subgroup analysis, non-primary outcome) Note: An erratum published in 2021 with corrected data found heterogeneity was no longer significant for this outcome, but the Certainty of Evidence rating was not changed
Change in SGRQ score (mean difference)	-8.42 (-10.86 to -5.97)	I2 = 6%; p = .37	High
Pneumothorax (relative risk)	6.32 (3.74 to 10.67)	I2 = 25%; p = .25	High
Overall Mortality (relative risk)	1.26 (0.50 to 3.15)	I2 = 25%; p = .25	Low (non-primary outcome, wide CI)

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

Spiration Valve
Randomized Controlled Trials
Three RCTs of the Spiration valve in patients with emphysema have been published.21,22,23, One used a sham control and 2 were open-label. 
Tables 13 to 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;²³ results were previously available as part of the Spiration Premarket Approval (PMA) application.24, 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, 6-minute walk test, 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.21,.

Table 13. Summary of Key RCT Characteristics-Spiration Valve

Trial	Countries	Sites	Dates	Participants	Interventions		Duration
					Active	Comparator
EMPROVE 23,24 IDE #G 120192.	U.S. and Canada	31	2013 – 2017	Severe emphysema without collateral ventilation Race not reported 53.5% male	Spiration valve (n = 113)	Standard care (n = 59)	12 months
REACH, Li et al. (2018) 22 NCT01989182	China	12	2013 – 2017	Severe emphysema and intact interlobular fissures 100% Asian 99% male	Spiration valve (n = 72)	Standard care (n = 35)	6 months
IBV Valve, Wood et al. (2014)21 NCT00475007	U.S.	36	2007 – 2017	Emphysema, airflow obstruction, hyperinflation, and severe dyspnea Race not reported 57% male	Spiration valve (n = 142)	Sham procedure (n = 135)	6 months

IDE: Investigational Device Exemption; NCT: National Clinical Trial; NR: Not reported; 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
EMPROVE23,24
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 22
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 Valve21
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; 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 to 6 months	16.8% vs. 10.2% Difference 6.6% (95% CI -5.1% to 16.0%)
	> 6 to 12 months	13.6% vs. 8.5% Difference 5.1% (95% CI -7.4% to 14.2%)
REACH	0 to 6 months	19.7% vs. 24.2%
IBV Valve	0 to 6 months	4.9% vs. 1.5% Difference 3.4% (95% CI -0.5 to 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 Events Spiration vs Control
EMPROVE	0 to 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 to 12 months	3.9% vs. 6.4%	21.4% vs. 10.6%; 10.7% (95% CI 3.0% to 21.2%)
REACH	0 to 6 months	0% vs. 3.0%	44.3% vs. 24.2%
IBV Valve	0 to 6 months	4.2% vs. 0.7%; Difference 3.5% (95% CI 0.2% to 7.5%)	14.1% vs. 3.7%; 10.4% (95% CI 4.0% to 17.1%)

CI: confidence interval; RCT: randomized controlled trial.

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

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
EMPROVE	4. unable to determine; race of participants not reported
REACH	4. 100% male
IBV Valve	4. unable to determine; race of participants not reported

           
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. Study population is unclear; 3. Study population not representative of intended use; 
4. Enrolled populations do not reflect relevant diversity; 5. Other.
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.

Table 18. RCTs of the Spiration Valve- Study Design and Conduct Limitations

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

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

Prospective Cohort Study
Hartman et al. (2021) conducted a prospective cohort study to investigate patient satisfaction and patient-specific treatment goals among individuals who received bronchial valves for treatment of severe emphysema at 1 hospital in The Netherlands.²⁵ Patient satisfaction was measured by a questionnaire administered 1 year after valve placement. Patient-specific goals were measured using the Dutch patient-specific complaint (PSC) questionnaire. In this questionnaire, patients reported their 3 most personally desired post-treatment goals and used a numeric rating scale (0 to 10) to score the level of disability per goal before and 1 year after treatment. Lung function, exercise capacity, dyspnea severity, and quality of life were also measured before treatment and at 1-year follow-up. Of 134 patients who underwent bronchial valve placement prior to Jan. 1, 2019, 109 (81.3%) completed the patient-satisfaction questionnaire, 88 (65.7%) completed the PSC questionnaire at baseline and follow-up, and 94 (70.1%) returned to the hospital for a follow-up visit at 1 year. Reasons for loss to follow-up in 40 patients were bronchial valve removed (16 patients), died (n = 5), comorbidity (n = 5), revision at that time (n=3), lung volume reduction surgery (LVRS) or lung transplant (n = 2), and other (n = 9). The PSC-questionnaire score significantly improved 1 year after bronchial valve treatment, from 23.7 to 17.1 points (mean decrease of 6.5 points; p = .001) and an improvement in the PSC-questionnaire sum score was significantly associated with a larger improvement in FEV1, residual volume, exercise capacity, dyspnea severity, and quality of life. Seventy-five percent of the patients who completed the questionnaire were satisfied or very satisfied with the treatment and 11% were unsatisfied or very unsatisfied. Just over half of the questionnaire respondents (52.6%) were satisfied or very satisfied with the reduction in their symptoms after treatment, and 24.9% were unsatisfied or very unsatisfied. For the question of whether the treatment satisfied their expectations (range 1 to 5), the mean score was 3.29 (standard deviation 1.43). Most of those who completed the questionnaire (91.4%) would recommend the treatment to other patients.

This study was limited by its uncontrolled design and relatively high loss to follow-up (29.9%), but it provides information on outcomes important to patients that could be used to guide future research.

Section Summary: Severe or Advanced Emphysema
In patients with severe or advanced emphysema with little or no collateral ventilation between target and ipsilateral lobe, RCTs provide evidence of a 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). A prospective cohort study provides information on outcomes important to patients, but confidence in its findings is limited by the study's uncontrolled design and high loss to follow-up (29.9%).

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 that the technology results in an improvement in the net health outcome.

For individuals who have severe or advanced emphysema with little or no collateral ventilation between target and ipsilateral lobe who receive bronchial valves, the evidence includes a prospective cohort study with patient-reported outcomes, 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. In a prospective cohort study of patient-reported outcomes 1 year following treatment, 74.8% were satisfied with the treatment and 10.9% were unsatisfied, 52.6% were satisfied with the reduction in their symptoms after treatment and 24.9% were unsatisfied, and 91.4% said they would recommend the treatment to other patients. Confidence in these findings is limited by the study's uncontrolled design and high loss to follow-up (29.9%). The potential benefits of the procedure do not outweigh the demonstrated harms. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

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.

2011 Input
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
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

Global Initiative for Chronic Obstructive Lung Disease (GOLD)
The GOLD publication makes the following statements on lung volume reduction interventions:⁴

• "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 to 12 months following treatment (Evidence Level A for endobronchial valves: well-designed RCTs with consistent findings in the intended population without any important limitations).

National Institute for Health and Care Excellence (NICE)
In December 2017, NICE issued the following recommendations on endobronchial valve insertion to reduce lung volume in emphysema:²⁶

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.

NICE guidance on the diagnosis and management of COPD (2018) included the following recommendations on lung volume reduction procedures:¹⁸

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).

At the respiratory review, refer the person with COPD to a lung volume reduction multidisciplinary team to assess whether lung volume reduction surgery or endobronchial valves are suitable if they have:

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

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some ongoing and unpublished trials that might influence this review are listed in Table 19.

Table 19. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT01796392a	Lung Function Improvement After Bronchoscopic Lung Volume Reduction With Pulmonx Endobronchial Valves Used in Treatment of Emphysema (LIBERATE)	183	Feb 2023 (post approval study, 5-year extension)
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 (planned longer-term follow-up, 5 and 2 years for the treatment and control groups, respectively)
NCT04186546a	Zephyr Valve Registry (ZEVR)	150	Dec 2024
NCT04302272a	The Spiration Valve System (SVS) Post-Market Registry Study for Severe Emphysema	150	Apr 2028
Unpublished
NCT02382614	Safety and Effectiveness of the Spiration Valve System (SVS) in Air Leaks (VAST)	200	Dec 2021 (suspended; interim analysis and potential modification)
NCT04161235a	Post-Market Clinical Evaluation of the Zephyr Valve 5.5-LP EBV for Bronchoscopic Lung Volume Reduction (BLVR) Procedures	2	Jun 2021

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

References  

1. Centers for Disease Control and Prevention. Chronic Obstructive Pulmonary Disease (COPD). Data and Statistics. 2021. https://www.cdc.gov/copd/data.html. Accessed April 21, 2022.
2. Xu JQ, Murphy SL, Kochanek KD, Arias E. Mortality in the United States, 2018. NCHS Data Brief, Number 355. Hyattsville, MD: National Center for Health Statistics; 2020. https://www.cdc.gov/nchs/data/databriefs/db355-h.pdf. Accessed April 21, 2022.
3. Zarrabian B, Mirsaeidi M. A Trend Analysis of Chronic Obstructive Pulmonary Disease Mortality in the United States by Race and Sex. Ann Am Thorac Soc. Jul 2021; 18(7): 1138-1146. PMID 33347376
4. Global Initiative for Chronic Obstructive Lung Disease (GOLD). 2022 Global Strategy for Prevention, Diagnosis, and Management of COPD. https://goldcopd.org/gold-reports/. Accessed April 19, 2022.
5. Travaline JM, McKenna RJ, De Giacomo T, et al. Treatment of persistent pulmonary air leaks using endobronchial valves. Chest. Aug 2009; 136(2): 355-360. PMID 19349382
6. 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): 1243-9. PMID 23434254
7. 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): 270-3. PMID 21172529
8. Eberhardt R, Slebos DJ, Herth FJF, et al. Endobronchial Valve (Zephyr) Treatment in Homogeneous Emphysema: One-Year Results from the IMPACT Randomized Clinical Trial. Respiration. NA 2021; 100(12): 1174-1185. PMID 34350884
9. 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
10. 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. Nov 01 2018; 198(9): 1151-1164. PMID 29787288
11. Dransfield MT, Garner JL, Bhatt SP, et al. Effect of Zephyr Endobronchial Valves on Dyspnea, Activity Levels, and Quality of Life at One Year. Results from a Randomized Clinical Trial. Ann Am Thorac Soc. Jul 2020; 17(7): 829-838. PMID 32223724
12. 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. Dec 15 2017; 196(12): 1535-1543. PMID 28885054
13. 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. Nov 01 2016; 194(9): 1073-1082. PMID 27580428
14. Klooster K, ten Hacken NH, Hartman JE, et al. Endobronchial Valves for Emphysema without Interlobar Collateral Ventilation. N Engl J Med. Dec 10 2015; 373(24): 2325-35. PMID 26650153
15. 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): 1066-73. PMID 26116485
16. 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): 1334-42. PMID 22282552
17. 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): 1233-44. PMID 20860505
18. 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 April 19, 2022
19. van Geffen WH, Slebos DJ, Herth FJ, et al. Surgical and endoscopic interventions that reduce lung volume for emphysema: a systemic review and meta-analysis. Lancet Respir Med. Apr 2019; 7(4): 313-324. PMID 30744937
20. 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
21. 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): 288-97. PMID 25321447
22. Li S, Wang G, Wang C, et al. The REACH Trial: A Randomized Controlled Trial Assessing the Safety and Effectiveness of the Spiration(R) Valve System in the Treatment of Severe Emphysema. Respiration. 2019; 97(5): 416-427. PMID 30554211
23. 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
24. 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 April 19, 2022.
25. Hartman JE, Klooster K, Ten Hacken NHT, et al. Patient Satisfaction and Attainment of Patient-Specific Goals after Endobronchial Valve Treatment. Ann Am Thorac Soc. Jan 2021; 18(1): 68-74. PMID 32881586
26. 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 April 19, 2022.

Coding Section

Codes	Number	Description
CPT	31647	Bronchoscopy, rigid or flexible, including fluoroscopic guidance, when performed; with balloon occlusion, when performed, assessment of air leak, airway sizing, and insertion of bronchial valve(s), initial lobe
	31651	; with balloon occlusion, when performed, assessment of air leak, airway sizing, and insertion of bronchial valve(s), each additional lobe (List separately in addition to code for primary procedure[s])
	31648	; with removal of bronchial valve(s), initial lobe
	31649	; with removal of bronchial valve(s), each additional lobe (List separately in addition to code for primary procedure)
ICD-10-CM
	J43.0-J43.9	Emphysema code range
	J44.0-J44.9	code range (used for emphysema with chronic obstructive bronchitis)
ICD-10-PCS		ICD-10-PCS codes are only used for inpatient services.
	0BH38GZ, 0BH48GZ, 0BH58GZ, 0BH68GZ, 0BH78GZ, 0BH88GZ, 0BH98GZ, 0BHB8GZ	Surgical, respiratory system, insertion, via natural or artificial opening endoscopic, endobronchial valve; codes specific to type of bronchus and left or right
Type of Service	Surgery
Place of Service	Inpatient, outpatient

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.  

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2014 Forward     

08/24/2022	Annual review, no change to policy intent. Updating policy to change the word patient to individual. Updating rationale and references.
08/10/2021	Annual review, no change to policy intent. Updating rationale and references.
08/07/2020	Annual review, no change to policy intent. Updating background, regulatory status, guidelines, coding, rationale and references.
08/01/2019	Annual review, no change to policy intent. Updating background, regulatory status, rationale and references.
08/16/2018	Annual review, no change to policy intent. Updating background and rationale.
08/29/2017	Annual review, removing "endo" from the title and policy verbiage, "Bronchial Valves" will be the verbiage used. Also updating background, description, rationale and references.
08/11/2016	Annual review, no change to policy intent. Updating background, description, rationale and references.
08/19/2015	Annual review, no change to policy intent, but policy verbiage reworded for clarity to include: "Endobronchial valves are considered investigational in all situations including, but not limited to....". Updated background, description, guidelines, rationale and references. Added coding.
08/04/2014	Annual review. Updated rationale and references. No change to policy intent.