This policy was created with a search of the MEDLINE database through September 2010. The literature identified in this search is as follows:
Treatment of air leaks
No randomized controlled trials or comparative observational studies were identified. Only case report data are available on the IBV Valve System (Spiration). Data on four patients with prolonged air leaks was submitted to the FDA as part of the HDE process. In all four patients, there was an immediate decrease or complete resolution of the air leak after valve placement. Valves were removed without complication in three of the four cases; the fourth patient had not yet had valves removed at the time data were submitted.
The largest case series, published in 2009, reported on 40 patients treated at 17 sites in the United States and Europe; six of the patients had been included in previously published case reports. Zephyr (Emphasys, now Pulmonx) endobronchial valves were used. Data were abstracted retrospectively from medical records. No specific eligibility criteria were reported and patients did not need to demonstrate that they were refractory to other treatments. All patients in the series had prolonged pulmonary air leak (mean duration of 119 days, median of 20 days). Twenty-five patients had continuous air leaks, 14 had expiratory air leaks and one was unidentified. The most common co-morbidities were cancer and COPD. Prior to the procedure, 39 of the 40 patients had at least one chest tube. Five patients had other treatments e.g., blood patch before valve placement. The mean number of valves placed per patient was 2.9 (standard deviation [SD] =1.9) overall. After valve placement, 19 patients (47.5%) had complete resolution of acute air leak, 18 (45%) had a reduction in air leak, 2 (5%) had no change and data were not available for one patient. The mean time from valve placement to chest tube removal was 21 days and the median time was 7.5 days (data from 2 patients were not available). Eight patients had the valves removed after the air leak ceased; in 32 patients, the clinician chose to leave the valves in place. Six patients experienced adverse effects 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 was highly variable, ranging from 5 to 1109 days. At last follow-up, 16 patients were reported to have died; none of the deaths were attributed to the valve or valve implantation procedure.
Treatment of emphysema
The published literature consists of one randomized controlled trial (RCT) and several prior case series. The RCT, called the Endobronchial Valve for Emphysema Palliation Trial (VENT), was published by Sciurba and colleagues in 2010. It was industry-funded and data were collected at 31 centers in the United States. Key eligibility criteria were: diagnosis of heterogenous emphysema, FEV1 of 15-45% of the predicted value, total lung capacity of more than 100% of the predicted value, residual volume of more than 150% of the predicted value and post-rehabilitation 6-minute walk distance of at least 140 meters. A total of 321 patients were randomly assigned on a 2:1 basis to receive Zephyr endobronchial valves (n=220) or standard medical care (n=101). Prior to randomization, all patients received 6-8 weeks of pulmonary rehabilitation and medical management was optimized at the discretion of the treating physician using guidelines from the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The mean number of valves placed in the endometrial valve group was 3.8 per patient (range 1 to 9). The primary effectiveness outcomes were percent change from baseline to six months in the FEV1 and distance on the 6-minute walk test. A total of 42 of 220 (19.1%) in the endobronchial valve group and 28 of 101 (27.7%) had missing data for the primary efficacy outcomes. Of the 70 patients with missing data, six had died, four were too ill to participate and 60 dropped out or did not have follow-up within the specified time window. The data analysis was intention to treat and missing data were imputed.
Among the secondary outcomes reported at the 6-month follow-up, quality of life was measured using the St. George’s Respiratory Questionnaire (SGRQ) which ranges from 0 to 100 with a higher score indicating a worse quality of life. At 6 months, the SGRQ score decreased -2.8 points (95% confidence interval [CI] =-4.7 to -1.0) in the endobronchial valve group and increased 0.6 points (-1.8 to 3.0) in the control group. The between-group difference was -3.4 (95% CI=-6.7 to 0.2) which was statistically significant (p=0.04) but was less than the four points generally considered to represent a clinically meaningful difference. According to body plethysmography, the mean change in total lung volume at six months was -1.2 (SD=10.6) in the endobronchial valve group and -0.4% (SD=13) in the control group; this difference was not statistically significant, p=0.41. Similarly, changes between groups in residual volume and inspiratory capacity were not statistically significant.
The primary safety variable was a composite measure consisting of six major complications (death, empyema, massive hemoptysis, pneumonia distal to valves, pneumothorax or air leak of more than seven days’ duration or ventilator-dependent respiratory failure for more than 24 hours). The rate by six months was 6.1% in the endobronchial group and 1.2% in the control group. The between-group difference was 4.9% (95% CI=1.0 to 8.8) which was not statistically different (p=0.08) and fell within the pre-specified safety criteria. The adverse events to six months included six deaths (2.8%) in the endobronchial valve group and no deaths in the control group (p=0.19). Between three and twelve months, 25 of 214 (11.7%) patients in the endometrial valve group followed over this time experienced COPD exacerbations; 22 of these events resulted in hospitalization. Over the same time period, 8 of 87 (9.2%) patients in the control group had COPD exacerbations all of which resulted in hospitalization. The difference in number of exacerbations was not statistically significant. For hemoptysis (other than massive), between three and twelve months there were thirteen (6.1%) cases in the endobronchial valve group and none in the control group (p=0.02). Among the 214 patients who received valves and were followed to twelve months, there were six cases (2.8%) of valve expectoration, aspiration or migration and nine cases (4.2%) of bronchial granulation tissue. Valves were removed in 31 (14%) patients after 1 to 377 days; removal was based on investigators’ discretion; there was no specific protocol.
A limitation of the study was lack of blinding, which could have affected performance on the primary efficacy outcomes, e.g., it may have affected clinicians’ coaching of patients and/or the degree of effort exerted by patients. About 28% of the data were missing on the primary efficacy outcomes; most of this was due to lack of compliance rather than death or illness. Although there was a pre-specified plan for handling missing data, with this degree of missing data findings might not accurately represent outcomes in the population. In addition, there may have been insufficient power to detect meaningful differences for secondary outcomes, including safety outcomes. Even in the primary outcomes, there tended to be wide confidence intervals indicating an insufficiently large sample size. Moreover, some between-group differences, though statistically significant, may not be clinically significant e.g., a 6.8% absolute change from baseline in FEV1. An editorial accompanying publication of the trial noted that the rate of complications such as COPD, were higher in the endobronchial valve group, albeit not statistically different. The editorial additionally criticized the study for not standardizing medical treatment for the control group, and for possibly providing suboptimal medical therapy for both groups. For example, only 57% of patients received recommended bronchodilators at the beginning of the study and that the medical therapy was not standardized.
An earlier uncontrolled study, published in 2006, reported on 98 patients from nine centers in seven countries (not including the United States) who received endobronchial valves for severe emphysema. Data were obtained from a prospectively-collected multicenter registry. Patients had symptomatic emphysema and shortness of breath on daily activities despite optimized medical therapy; most were candidates for lung volume reduction surgery at the participating centers. A mean of four (SD=1.6) valves were placed per patient (range of 1 to 8 valves). On average, there was statistically significant improvement in change from baseline to the 90-day follow-up in efficacy variables. For example, the mean absolute change in FEV1 was 0.06 liters (L) (SD=0.21) and the mean absolute change in the six minute walk test was 36.9 (SD=90) meters. The p-values for change from baseline were 0.007 and <0.001, respectively. Among the 98 patients, there were eight serious complications including one death and 30 patients had other complications including 17 exacerbations of COPD and five pneumonias in untreated lobes.
The only available data on endobronchial valves for treating air leaks are uncontrolled trials with small numbers of heterogenous patients. Data on the FDA-approved endobronchial valve device is particularly limited. A single unblinded RCT on endobronchial valves for the off-label treatment of patients with advanced emphysema provides insufficient evidence that the technology improves the net health outcome. In this trial, there were marginal benefits that may not be clinically meaningful and the adverse events experienced by patients who received endobronchial valves raise concerns about the safety of the treatment. Therefore, endobronchial valve placement for treatment of prolonged air leaks or emphysema is considered experimental, investigational and unproven.
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