Keywords: bronchoscopy; emphysema; lung volume reduction

Transcription

1 Endoscopic Lung Volume Reduction An American Perspective Hans J. Lee 1 *, Samira Shojaee 2 *, and Daniel H. Sterman 3 1 Interventional Pulmonology, Pulmonary Disease, and Critical Care Medicine, The Johns Hopkins Hospital, Baltimore, Maryland; 2 Interventional Pulmonology, Pulmonary Disease, and Critical Care Medicine, Virginia Commonwealth University, Richmond, Virginia; and 3 Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania Abstract There are limited therapies for severe emphysema. Bronchoscopic treatments of emphysema were introduced to achieve the beneficial physiological changes seen in surgical lung volume reduction; however, at the present time these treatments are mostly aimed at improving quality of life and functional status in patients with emphysema. At this time, none of these minimally invasive approaches have been approved in the United States for treatment of emphysema; however, several novel interventions have demonstrated potential in early-phase clinical trials. We performed a systematic evaluation of the relevant medical literature and present herein an evidence-based review of bronchoscopic treatments for emphysema, with a focus on the current status of this technology in the United States as compared with Europe. Keywords: bronchoscopy; emphysema; lung volume reduction (Received in original form June 7, 2013; accepted in final form October 26, 2013 ) *Contributed equally as co primary authors. Correspondence and requests for reprints should be addressed to Hans J. Lee, M.D., Assistant Professor of Medicine, Interventional Pulmonology, Pulmonary Disease, and Critical Care Medicine, The Johns Hopkins Hospital, 1800 Orleans Street, Sheikh Zayed Tower, 7125L, Baltimore, MD hlee171@jhmi.edu Ann Am Thorac Soc Vol 10, No 6, pp , Dec 2013 Copyright 2013 by the American Thoracic Society DOI: /AnnalsATS FR Internet address: Chronic obstructive pulmonary disease (COPD) affects nearly 10% of the world s population and is the fourth leading cause of death in the United States (1). In addition, advanced COPD causes physical impairment, reduced quality of life, and increased health care use. As the FEV 1 falls below 30% of, the 3-year median survival is less than 50% (2). Although there may be effective medical treatments for mild/moderate COPD, severe COPD has fewer effective treatment options. Supplemental oxygen, bronchodilator therapy, inhaled corticosteroids, pulmonary rehabilitation, lung transplantation, and lung volume reduction surgery (LVRS) are among these options for advanced COPD. Lung transplantation and LVRS are highly invasive and benefit only a small select patient population, with a minimal impact on overall survival. Less invasive bronchoscopic treatments for advanced COPD, most notably for the emphysema variant, are currently in clinical development. At this time none of these endoscopic approaches have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of emphysema; however, several newer techniques have demonstrated potential benefits in pulmonary function, exercise capacity, and health-related quality of life (HRQL) in small early-phase clinical trials. Bronchoscopic treatments for emphysema (BTE) can be divided into interventions targeting heterogeneous emphysema and those designed for homogenous disease. Computed tomography (CT) scan imaging and scoring is used to measure for emphysema heterogeneity. The lungs are graded according to the percentage area showing changes (low attenuation, lung destruction, and vascular disruption) suggestive of emphysema and scored accordingly. Collateral channels are frequently seen between lobes in emphysematous lungs (3). This may explain the close association between the level of homogeneity and the degree of collateral ventilation. The goal in treating either group of patients with emphysema is to reduce the adverse physiological effects of the disease on lung function. These include: (1) increased airway resistance, (2) decreased elastic recoil, and (3) hyperinflation. The clinical goals are the improvement of lung function, increase in exercise capacity, and amelioration of quality of life. LVRS or reduction pneumoplasty was first reported in 1957 by Dr. Otto Brantigan, a thoracic surgeon from the University of Maryland (4). This procedure Perspectives 667

2 as described had significant limitations, including persistent air leaks from suture lines, that prevented this procedure from widespread acceptance by the medical community. This operation was reintroduced and refined by Dr. Joel Cooper at Barnes University Hospital/ Washington University in St. Louis in the 1990s and spurred the National Institutes of Health to launch a multicenter, randomized clinical trial of LVRS versus standard medical therapy the National Emphysema Treatment Trial (NETT) (5). The NETT showed a survival benefit with LVRS for a subset of patients with advanced emphysema who had heterogeneous, upper lobe predominant disease and low baseline exercise capacity. In addition, LVRS improved exercise capacity by more than 10 W in 15% of patients in the surgery group as compared with 3% of patients in the medical therapy group (P, 0.001). The major disadvantages for LVRS are its selective benefit, attendant morbidity, and increased early mortality in patients with FEV 1 or diffusing capacity of carbon monoxide (DL CO ), 20% of values or in the presence of a homogeneous pattern of emphysema (6). Nonetheless, despite the benefits of LVRS seen in selected subsets, there have been relatively few referrals of patients with emphysema for LVRS since the publication of the NETT results in the New England Journal of Medicine, in part because of the significant morbidity and mortality of the procedure (7, 8). In the wake of the NETT study, multiple clinical trials of endoscopic lung volume reduction were initiated. Most of the current BTE attempt to achieve the beneficial physiological changes seen in LVRS. Methods The systematic review was performed according to the published recommendations and checklist of the Preferred Reporting Items for Systematic Reviews and Metaanalyses (PRISMA) statement (9). Searches were conducted on MEDLINE (inception to Sept 2012) and Cochrane Review (inception to Sept 2012). The following key terms were used bronchoscopic lung volume reduction or bronchoscopy emphysema treatment or bronchoscopy valves or bronchoscopy coils or bronchoscopy glue or bronchoscopy vapor. All searches were limited to humans and prospective trials. Case reports and series (n, 20), early reports with the same subjects in a larger trial, and non-english publications were excluded. Two independent reviewers (H.J.L. and S.S.) performed the literature search and reviewed all the studies that fit the inclusion criteria, independently. The following variables were extracted from each study: publication year, treatment device, number of patients in each arm, inclusion criteria, unilateral or bilateral treatment, duration of study, outcomes such as FEV 1, 6-minute-walk distance (6MWD), St George s respiratory questionnaire (SGRQ), HRQL scores, exacerbations, treatment failure, death, and complications. To review the summery of U.S. studies and reported complications in each device category, see Tables 1 3. Bronchial Valves The most commonly studied devices for BTE are bronchial valves designed to prevent inspired air from entering targeted airways but allow for exit of trapped air from distal airways and lung parenchyma. There are two commercially produced bronchoscopic endobronchial one-way valves (EBOV) that have been developed and studied in emphysematous lobes, which in many cases are the upper lobes (10) (Figure 2). The EBOV promote unidirectional flow of gas out of the lobe with secretions and the blockage of inspiratory gas flow. Initially, the planned physiological mechanism was to produce LVRS and cause lobar atelectasis by decreasing air flow to treated lobes. However, the early-phase studies demonstrated clinical benefit in some patients without lobar or segmental atelectasis (10 12). These studies hypothesized that the benefits may stem from several effects, including: reduction in dynamic hyperinflation, interlobar collateral ventilation, improvement in V/Q relationship, and redirection of ventilation to more functional lung units (13, 14). Both of the EBOV that have been studied in clinical trials were designed to be removable, offering a valuable advantage over other bronchoscopic approaches for emphysema treatment that irreversibly alter airways and/or lung parenchyma. Spiration IBV The Spiration IBV is an umbrella-shaped valve with a nitinol frame consisting of anchors, struts, and a thin polyurethane membrane surrounding the struts, which acts as a barrier to air flow. The IBV valves are available in different sizes (5, 6, 7 mm) to fit variably sized airway segments. The diameters of the target airways are measured with a calibrated, dedicated balloon catheter (Olympus America, Center Valley, PA). After measurement, the valve is deployed through a specially designed delivery catheter via the working channel (.2.5 mm) of the flexible bronchoscope. Valve placement is performed under general anesthesia or deep sedation to reduce cough and respiratory movement. The IBV valve was designed with a central rod for potential removal with standard flexible bronchoscopic forceps. One of the initial IBV valve pilot studies for the treatment of severe emphysema was an open-label trial targeting 91 patients with severe, bilateral heterogeneous disease with an upper lobe predominance (15). Six hundred nine bronchial valves were placed bilaterally in upper lobes, and a median of six IBV valves (range, 3 11) were used per lung. The study s initial goal was complete bilateral lobe treatment, but a significant number of pneumothoraces (up to 29%) were seen with complete lobar exclusion, particularly with treatment of the entire left upper lobe. As a result of these early adverse events, the goal of the study was changed to near-complete bilateral upper lobe exclusion with sparing of the lingula on the left and one segment or subsegment in the right upper lobe. The results of the IBV pilot study were notable for a sustained benefit in HRQL measures that was evidenced by an improvement in SGRQ results at Months 3, 6, and 12 post valve placement. There were, however, no statistically significant increases in FEV 1, lung volumes by plethysmography, or 6MWD. The most common adverse effects of valve placement were: pneumothorax (12.1%), bronchospasm (2.2%), and pneumonia (6.6%). In this study there were a total of 44 valves removed in 16 patients; the longest valve removal occurred at Day 358. Sixteen patients with post obstructive pneumonia had IBV valves removed without complications. A total of 45.4% of the pneumothoraces occurred when all segments in the left upper lobe were treated. Only 17 patients had complete left upper lobe treatment, and 5 patient among this group developed pneumothorax, a 29% 668 AnnalsATS Volume 10 Number 6 December 2013

3 Table 1. Summary of U.S. results Author/ Device Year Subjects Study Duration Homogeneity Primary Endpoints Results Springmeyer et al. (18)*/IBV Criner et al. (32)*/BioLVR hydrogel mo Heterogeneous upper lung bilateral treatment mo Heterogeneous upper lobe Lung function, walk distance, and improvement in HRQL as measured by the SGRQ Efficacy endpoints: change from baseline in pulmonary function test, dyspnea score, 6MWD. Safety endpoints; incidence of various medical complications by BioLVR hydrogel Sciurba et al. (24) /Zephyr mo Heterogeneous Efficacy endpoints: percent changes in FEV 1 and 6MWD. Safety endpoints: rate of a composite of 6 major complications of Zephyr EBVs Sterman et al. (15) /IBV mo Heterogeneous upper lung Shah et al. (40)*/airway bypass Safety, evaluated as the rate of observed migration, erosion, or infection associated with the IBV valve during the first 3 months after placement mo Homogeneous.12% Improvement in FVC and >1 point decrease in the mmrc dyspnea score with use of EASE Snell et al. (35)*/BTVA mo Heterogeneous unilateral upper lung Herth et al. (36)*/BTVA yr Heterogeneous unilateral upper lung Using BTVA for improvement in SGRQ. Safety, adverse events Improvement in FEV 1, SGRQ, 6MWD, mmrc dyspnea score, and hyperinflation with unilateral BTVA. Safety. Clinically meaningful improvement in SGRQ. There were no changes in total lung volume. BioLVR improved both physiology and functional outcomes up at 6 months with an acceptable safety profile. Improvement was greater and more durable with 20 ml per site dosing than 10 ml per site dosing. Modest improvement in FEV 1, exercise tolerance, and symptoms. More frequent exacerbations of COPD, pneumonia, and hemoptysis. Highly significant HRQL improvement and acceptable safety was noted. There was a proportional shift, a redirection of inspired volume to the untreated lobes. No sustainable benefit was regarding efficacy with EASE. BTVA resulted in clinically relevant improvements in lung function, SGRQ, and 6MWD. Most serious adverse events were respiratory in origin, exacerbations being the most common. Unilateral lobar BTVA improved lung function and health outcomes in 1 yr, but were more pronounced at 6 mo compared with 12 mo Definition of abbreviations: 6MWD = 6-minute-walk distance; BTVA = Bronchoscopic Thermal Vapor Ablation; COPD = chronic obstructive pulmonary disease; EASE = Exhale Airway Stent for Emphysema; EBV = endobronchial valve; HRQL = health-related quality of life; mmrc = modified Medical Research Council; SGRQ = St. George s Respiratory Questionnaire. *International studies including the United States. U.S. studies. Perspectives 669

4 Table 2. Summary of inclusion criteria Author/Device FEV 1 DL CO Resting Pa CO2 Resting Pa O2 Imaging Miscellaneous Springmeyer et al. (18)*/IBV 45% or less of Criner et al. (32)*/BioLVR hydrogel 45% or less of 20% or less of 20% or less of,60 mm Hg.45 mm Hg CT scan evidence of bilateral emphysema N/A N/A Upper lobe predominant emphysema on HRCT Sciurba et al. (24) /Zephyr 15 45% N/A,50 mm Hg.45 mm Hg Heterogeneous emphysema on CT scan Sterman et al. (15) /IBV 45% or less of Shah et al. (40)*/airway bypass 50% or less of or FEV 1, 1L 20% or less of.15% of,60 mm Hg.45 mm Hg CT scan evidence of bilateral emphysema N/A.45 mm Hg Homogeneous emphysema on CT scan Snell et al. (35)*/BTVA 15 45% N/A,55 mm Hg.45 mm Hg Upper lobe predominant emphysema on HRCT Herth et al. (36)*/BTVA 15 45%.20% N/A N/A Upper lobe predominant emphysema on HRCT Nonsmoker for 4 mo before initial interview, post-bronchodilator TLC.100%, RV. 150%, BMI < 31 (men) or < 32 (women).40 years old, TLC. 110%, and RV. 150%, nonsmoker since 4 mo before initial interview Age of yr, post-bronchodilator TLC. 100%, RV. 150%, BMI < 31 (men) or < 32 (women), post-rehabilitation 6MWD of at least 140 m Nonsmoker for 4 mo before initial interview, post-bronchodilator TLC.100%, RV. 150%, BMI < 31 (men) or < 32 (women).20 pack-year smoking history, dyspnea. 2 on mmrc scale, RV/TLC > 0.65, RV. 180%, FEV 1 /FVC, 70% Age yr, nonsmoker for 4 mo, post-bronchodilator TLC. 100%, RV. 150%, mmrc dyspnea score > 2 TLC. 100%, RV. 150%, 6MWD > 140 m Definition of abbreviations: 6MWD = 6-minute-walk distance; BMI = body mass index; BTVA = Bronchoscopic Thermal Vapor Ablation; CT = computed tomography; DL CO = diffusing capacity of carbon monoxide; HRCT = high-resolution CT; mmrc = modified Medical Research Council; N/A = not available; RV = residual volume. *International studies including the United States. U.S. studies. 670 AnnalsATS Volume 10 Number 6 December 2013

5 Table 3. Summary of complications Death Valve Migration or Expectoration Hemoptysis Pneumothorax Pulmonary Infections and/or Antibiotics Author Device Subjects COPD Exacerbation Springmeyer et al. (18)* IBV Criner er al. (32)* BioLVR hydrogel Sciurba et al. (24) Zephyr Sterman et al. (15) IBV Shah et al. (40)* Airway bypass Snell et al. (35)* BTVA Herth et al. (36)* BTVA Definition of abbreviations: BTVA = Bronchoscopic Thermal Vapor Ablation; COPD = chronic obstructive pulmonary disease. *International studies including the United States. U.S. studies. incidence. These pneumothoraces were believed to be related to rapid, complete lobar atelectasis with resultant rupture of the pleural surface related to tension from preexistent pleural adhesions. Interestingly, after amendment of the pilot study protocol specifying that the lingula was to be left untreated, a marked reduction in the number of pneumothoraces was seen (12.1%). Another study by Wood and colleagues (16) included 30 patients and showed no deaths or episodes of valve migration, tissue erosion, or significant bleeding and no instances of pneumothorax. A total of 83% of patients had no adverse events judged probably or definitely related to the device. Patients experienced significant improvement in HRQL, although the physiologic and exercise outcomes did not show statistically significant improvements. Although plethysmographic lung volumes were not significantly decreased, quantitative chest CT scans showed a diminution in the end-inspiratory volume of the treated upper lobes compared with the untreated lower lobes, albeit without producing an overall decrease in total lung volume (17). Although subjects who had radiographic atelectasis had the greatest clinical benefit from IBV valve treatment, there was a cohort that demonstrated clinical improvements in the absence of atelectasis. A potential physiological mechanism to explain the clinical benefit of IBV valve placement in the absence of lobar atelectasis is the shift in lobar volume seen on quantitative CT imaging from poorly perfused treated upper lobes to better perfused untreated lower lobes (10 12). This redirection of ventilation to the lower lobes combined with perfusion changes could potentially lead to improved V/Q matching. Intriguingly, in the pilot study, the CT interlobular volume changes also correlated significantly with improvements in HRQL (18). A prospective, double-blind, randomized, sham-controlled multicenter clinical trial to evaluate the safety and effectiveness of the IBV valve system for the treatment of severe emphysema has been completed and presented in only abstract form and national society meetings (19). Two hundred seventy-seven patients were enrolled, with 142 randomized to treatment and 135 to control group. The treatment group had bilateral upper lobes treated with partial occlusion of segmental airways. The control group had airway measurements but no valves. Both groups were blinded to treatment allocation and evaluated and followed up for a 6-month study period. The primary endpoint was the difference in responder rate in treatment and control group defined as both quality of life and lobar volume change. There were no differences between groups in lobar volumes at baseline, as determined by quantitative CT imaging. The upper lobes (UL) were nearly as large as the non-ul (UL: valve treatment [T], L; sham control [C], L; and non- UL: T, L; C, L). After valve treatment the UL were % and % smaller at 3 and 6 months. The non-ul volumes were % and % larger at 3 and 6 months, showing a significant decrease in volume in treated regions and increase in untreated regions of the lung in patients who received the valves. The bronchial valve achieved the primary endpoint of improved quality of life (evaluated by SGRQ), but the responder rate was too low to be acceptable. The preliminary results of the study showed that no procedure-related serious adverse events were noted in the control group, and only 2% pneumothorax was noted in the treatment group. Conscious sedation was used in only 4% of the cases but was associated with 19% of the serious adverse events. The FDA has, however, approved the IBV valve system under a humanitarian device exemption for the control of prolonged air leaks of the following: lobectomy, segmentectomy, and LVRS. This approval of the IBV valve system is based on results from 58 patients enrolled in a U.S. Investigational Device Exemption (IDE) study for the treatment of emphysema and four patients treated with the IBV valve system for prolonged air leaks under IDE compassionate use exemptions (20). The IBV valve has not been approved for treatment of emphysema in the United States and awaits the results of a new pivotal clinical trial of BTE with the goal of complete, unilateral lobar exclusion. The IBV valve system has received the CE mark (Conformité Européene, mandatory conformity marking for products sold in the European economic area) and is available for commercial use in selected countries in the European Union (EU). A new phase 3 prospective, randomized, controlled multicenter clinical Perspectives 671

6 trial to evaluate the safety and effectiveness of the IBV valve system for the treatment of severe emphysema is currently underway in North America. The key difference between this new study and prior IBV studies is total lobar occlusion rather than sparing the lingula and having partial lobar occlusion. A reason for changing the protocol may be due to the results of a European study by Eberhardt and colleagues demonstrating improved efficacy and a lower pneumothorax rate with unilateral complete lobar occlusion of the most diseased lobe by imaging compared with partial bilateral occlusion at 90 days (21). Pulmonary function, 6MWD, and quality of life were significantly improved in the complete unilateral lobar occlusion group at 90 days compared with the bilateral, incomplete treatment cohort. Zephyr Valve The Zephyr valve (PulmonX Inc., Palo Alto, CA) is another endobronchial valve (EBV) that has been studied in both pilot and pivotal human clinical trials. The Zephyr EBV device is a duck-billed silicone one-way valve that opens at low pressure within a self-expandable stent. It contains a flexible retainer, which expands to anchor the device in the airway and create an airtight seal against the bronchial wall to prevent air from leaking around the device. The entire device is coated in medical-grade silicone, to prevent tissue growth through the nitinol retainer. Although the design of the EBV is quite different from the IBV, its function is similar in that air entry into the targeted lobes is diminished, while trapped gas and secretions are able to escape during exhalation. The Zephyr EBV device is deployed through a delivery catheter, which is inserted through the working channel of the flexible bronchoscope. Initial pilot studies of the Zephyr EBV device were conducted in the United States and other countries from 2005 to 2011 and showed safety of valve placement and evidence for improved pulmonary function and exercise tolerance (22, 23). This led to the pivotal randomized controlled trial of the Zephyr EBV device, the Bronchial Valve for Emphysema Treatment (VENT) trial (24). The U.S. and European cohorts of this trial were reported and published separately. Three hundred twenty-one patients were enrolled across multiple centers in the United States from December 2004 through April The U.S. VENT trial data demonstrated a modest but statistically significant improvement in both primary endpoints: mean FEV 1 (60 ml, 6.8%) and median 6MWD (19.1 m, 5.8%). There were, however, two deaths in the treatment group as well as an increased rate of COPD exacerbations (17, 7.9%) and hospitalizations (1, 1.1%) in the treatment group. At 12 months, the rate of complications composite was 10.3% in the EBV group versus 4.6% in the control group (P = 0.17). Despite the fact that the trial reached its primary endpoints, in 2008 the FDA denied approval for the Zephyr valve to be used in the treatment of emphysema. A premarket application was submitted to the FDA advisory panel in December 2008 noting the VENT pivotal trial results. FDA approval was denied, as the FDA noted that more than 19% of subjects did not meet inclusion criteria, mostly with respect to pulmonary function parameters and pulmonary rehabilitation. Also, loss to follow-up and missing data occurred in more than 35% of patients. Although statistically significant changes were achieved in SGRQ score, modified Medical Research Council (mmrc) dyspnea score, and cycle ergometry at 6 months (secondary effectiveness endpoints), the effects on these three metrics decreased at 12 months and did not achieve statistical significance. The FDA argued that the two coprimary endpoints achieved statistical significance in the treatment group at 6 months; however, the clinical significance level of 15% was not achieved for either coprimary endpoint. Regarding safety and major medical complications, they noted that the major medical complication was more than five times higher in the Zephyr EBV treatment group than the control group at 6 months and more than two times higher at 12 months. The differences in survival or the composite progression to death, LVRS, or lung transplantation were not statistically significant (25). There were important lessons learned from the VENT trial, particularly from the analysis of specific patient subsets. The presence of a complete interlobar fissure on CT scan was an independent predictor of treatment response. The European cohort of the VENT trial by Herth and colleagues had similar results as the U.S. cohort (26, 27). A unique analysis, which was not included in the U.S. cohort, was the evaluation of completeness of lobar occlusion achieved on follow-up CT scans. The presence of an incomplete fissure theoretically allows for interlobar collateral ventilation. This is especially important in advanced emphysema, because when airway resistance exceeds collateral resistance, air may preferentially flow through collateral pathways (28). The overall results of the European cohort showed that in patients with fissure completeness and satisfactory valve placement (complete occlusion), the results were more impressive: the target lobe volume decreased by a mean of ml, and FEV 1 increased by as much as 26%. Therefore, occluding a single lobe with one-way valves may fail to cause lung volume reduction because of collateral ventilation (27). The Chartis system (PulmonX) is a catheter-mediated device to quantitatively measure interlobar collateral ventilation. The catheter is inserted via the working channel of a flexible bronchoscope and has a balloon at the distal end to occlude the selected segment. The catheter has a oneway valve that closes on inspiration and measures relative flow through the catheter during inspiration/expiration. Although there are no large studies using this instrument before valve placement, the Chartis system can be used to select the patients who would derive the most benefit from endoscopic lung volume reduction. In a prospective study by Eberhardt and colleagues, 17 patients were enrolled; the lobes targeted for endoscopic lung volume reduction were blocked via the Chartis catheter system, and pressure and flow were assessed (29). In 14 patients, pressure and flow measurement was performed without any complications, and no adverse events were reported. The resistance measurements directly correlated with the chest X-ray atelectasis result made after placement of the commercially available EBV used for the endobronchial lung volume reduction procedure. This study showed that measurement of airway pressures and flows in various lobes were safely and successfully achieved. The Chartis system is currently approved for clinical use in Europe but is not available in the United States for clinical practice. The FDA has approved a request for an IDE to commence a U.S. multicenter pivotal clinical trial using the Chartis system with EBV device. PulmonX may intend to use the trial results to support a subsequent premarket application for the Zephyr EBV. 672 AnnalsATS Volume 10 Number 6 December 2013

7 The primary endpoint will be reaching threshold of sustained improvement of 15% or greater in FEV 1. In the United States at the present time, presence of complete or incomplete interlobar fissure is evaluated by assessing sagittal and coronal CT isotropic reconstruction by manual or automated computerized schemes. Biologic Lung Volume Reduction Another approach to bronchoscopic treatment of emphysema is the use of biological agents, which are biocompatible and biodegradable substances. Agents such as blood patches and fibrin plugs have been used in the past with various results for emphysema (30, 31). The advantages of the biological agents are that they would not have the associated complications of a foreign body (i.e., valves or stents) and may function well despite collateral ventilation. Biologic Lung Volume Reduction System Biologic lung volume reduction (BioLVR) is a novel endobronchial therapy that reduces lung volume by administration of a fibrinogen biopharmaceutical suspension and thrombin solution, which polymerize to a hydrogel in situ as they come in contact with each other. For this reason, endoscopic introduction of these agents into the bronchi takes place separately to polymerize to a hydrogel at the desired site. These agents are introduced through a catheter via the working channel of the bronchoscope. The hydrogel initiates a localized inflammatory reaction that causes atelectasis by occlusion, remodeling, and reducing volume over a 4- to 6-week period. An open-label multicenter phase 2 trial by Criner and colleagues compared two different doses of the hydrogel (32). The study results were summarized from three phase 2 trials conducted between February 2007 and August All trials were open-labeled, nonrandomized, and noncontrolled. The first trial, performed at a single site (Israel), evaluated low-dose (LD) therapy in eight patients. The second trial (at five sites) performed concurrently in the United States, evaluated LD therapy in 20 patients. The third trial (at eight sites) was initiated after completion of enrollment in the LD studies and evaluated high-dose (HD) therapy in 22 U.S. patients. Patients included in this study had upper lung predominant emphysema and were organized into two treatment groups. The LD group included 28 patients treated with 10 ml per subsegment of BioLVR hydrogel at eight sites, four in each lung. Fourteen LD patients received treatment during two sessions separated by 6 to 12 weeks, and 14 received treatment during a single session. The HD group included 22 patients treated with 20 ml per subsegment of BioLVR hydrogel at eight sites, four in each lung. Ten HD patients received treatment during two sessions separated by 6 to 12 weeks, and 12 received treatment during a single session. The combined results of these trials showed a larger improvement with the higher dose (20 ml), in which there was an improved FEV 1 (16.6%, P = 0.002) and residual volume (RV) reduction (29.0%, P = 0.006) compared with those who received lower dose (10 ml) at baseline. There were no deaths reported in the series. There was a common adverse effect in 20 of 22 subjects in the HD group: fever, leukocytosis, and/or malaise. COPD exacerbation was seen in 11 of 50 subjects, with the majority in the HD group. The majority of COPD exacerbations occurred within the first few days of treatment and were believed to be directly related to the procedure. Similar results to those of Criner and colleagues (32) were found when using HD BioLVR (20 ml per site) at subsegments compared with LD (10 ml per site) for homogenous emphysema with respect to safety and effectiveness (33, 34). This study was also a summary of two different phase 2 studies in seven centers from the United States and one center in Israel (HD, 17 patients; LD, 8 patients) (33). Patients had homogeneous disease that was determined by chest CT scans and were observed at 3 and 6 months. A significant reduction in gas trapping was noted in the HD group at 3 months, which was not seen in the LD group. After 6 months, FEV 1, FVC, RV/TLC, dyspnea scores, and SGRQ total domain scores remained better with HD when compared with LD therapy. Although one can hypothesize that increased inflammatory response and cytokine release could contribute to COPD exacerbation in the HD group, the overall procedural rate of COPD exacerbations observed with BioLVR was similar to that reported with other BTE procedures. The AeriSeal System The popularity of BioLVR has largely been replaced by the AeriSeal system. As opposed to BioLVR hydrogel system, the AeriSeal system is synthetic and does not use human blood products, so there is no risk of transmissible infections (34). Also, the preclinical responses after AeriSeal system treatment were more durable as compared with BioLVR. The AeriSeal system (AerisTheraputics, Woburn, MA) uses a biologic hydrogel foam. Similar to the BioLVR, the Aeriseal system uses a hydrogel, but in a synthetic, nonbiologic foam construct. The hydrogel foam is a biodegradable substance instilled in the upper lobes causing atelectasis, inflammation, scarring, and shrinkage of the bronchi and subsequent lung parenchyma. The procedure requires an initial instillation (through the bronchoscope working channel) of a primer agent to deactivate native surfactant followed by a washout solution. This phase of the treatment induces atelectasis by deactivating surfactant. A dual-lumen catheter is then inserted into the working channel of the bronchoscope. Two agents (fibrinogen and thrombin) are instilled through the catheter to form a hydrogel foam, which will cause scarring and lung reduction through inflammation. A nonrandomized open-label multicenter phase 1 trial was conducted in Europe using the AeriSeal system in examining fissure integrity in upper lobe predominant emphysema (35). Fissure status, lung volumes, tissue density, and disease heterogeneity were assessed radiographically in 28 patients with upper lobe predominant disease, as fissure integrity has been a potential explanation for decreased efficacy in EBV treatments. There was a statistically significant improvement in the entire cohort in: FEV 1 (0.18 L, 19.1%), RV (20.51 L, 29.3%), 6MWD (30.9 m), and SGRQ (211.6 units). When comparing the complete and incomplete fissure groups, there was no significant difference in terms of their overall improvement in lung function or measured outcomes. Complications were not reported in this trial. A pivotal trial, study of the AeriSeal System for Hyperinflation Reduction in Emphysema (ASPIRE), was recently terminated for financial reasons in the United States. This multicenter trial attempted to enroll 300 patients in 30 centers around the Perspectives 673

8 United States as well as 9 centers internationally. The purpose of this study was to demonstrate the safety and efficacy of AeriSeal System treatment for advanced upper lobe predominant heterogeneous emphysema. Patients were to be treated with the AeriSeal System in two subsegments in the upper lobes of each lung (four subsegments total); 20 ml of foam sealant will be injected via catheter into each subsegment selected for treatment. Inclusion criteria are: age 40 years or older, advanced upper lobe predominant emphysema confirmed by CT scan, 6MWD greater than or equal to 150 m post pulmonary rehabilitation, FEV 1 less than 50%, FEV 1 /FVC ratio less than 70%, TLC greater than 100%, RV greater than 150%, DL CO greater than or equal to 20% and less than or equal to 60%, oxygen saturation measured by pulse oximetry greater than or equal to 90% on less than or equal to 4 L/min supplemental O 2,Pa CO2 less than 65, and smoking history of greater than or equal to 20 pack-years with abstinence for 16 weeks. Bronchoscopic Thermal Vapor Ablation System Bronchoscopic Thermal Vapor Ablation (BTVA) (Uptake Medical, Seattle, WA) uses heated water to produce thermal injury leading to an initial localized inflammatory response followed by permanent fibrosis and atelectasis. However, results of a canine study suggested that ischemia related to the thermal injury and reduced local/ downstream perfusion produces LVR by this method (34). The method involves introduction of a disposable bronchoscopic catheter with an occlusion balloon into a segmental bronchus. The balloon creates a seal while the catheter delivers a predetermined heated water vapor dose to emphysematous target lobes (Figure 2). A nonrandomized trial was conducted in 44 patients for unilateral treatment with BTVA, targeting upper lobe predominant emphysema (35). Entry criteria included: age 40 to 75 years, FEV 1 15 to 45%, previous pulmonary rehabilitation, and a heterogeneity index (tissue/air ratio of lower lobe/upper lobe) from high-resolution CT (HRCT) greater than 1.2. At the end of 6 months, all patients had radiographic lung volume reduction and improvement in mean FEV 1 (141 ml, 17%), RV reduction (2406 ml, 8%), 6MWD (46.5 m), BODE index (1.48 units), and SGRQ (214 units) (36). An additional follow-up was reported using the same study cohorts at 12 months, which showed a continued improved mean FEV 1 (FEV 1, 86 ml; 10%), as well as a baseline decrease in RV (2303 ml, 6%), 6MWD (63.7 m), BODE index (1.25 units), and SGRQ (211 units) when compared with baseline, although decreased from 6 months. The study was conducted internationally in Europe (seven sites, 18 patients), Australia (two sites, 16 patients), and the United States (four sites, 10 patients). HRCT data showed stability of lobar volume reduction in the treated lobe between 6 and 12 months. There were a total of 39 serious adverse events in 23 patients, with COPD exacerbation being the most common and two deaths unrelated to the study procedure. Currently, there are no ongoing or registered trials on bronchoscopic thermal vapor ablation in the United States. Airway Modification Airway Bypass. The airway bypass procedure was developed in large part to address the challenges of endoscopic treatment of homogenous emphysema. Choong and colleagues showed in a human ex vivo model in 2003 at Washington University of St. Louis that by creating artificial communications through bronchial walls into the parenchyma of explanted lungs (airway bypass), there is a decrease in the amount of gas trapping and an increased rate and volume of air expelled during forced expirations (37). Lung mechanics were measured before and after performance of the airway bypass procedure, which involved placement of three or four stent-supported fenestrations in 10 emphysematous lungs removed at transplantation surgery (Figure 2). Explanted VC increased by 1.30 L or 132% (range, %). Maximal expiratory flows and volumes increased, and flow resistance decreased. The results showed that airway bypass improves the mechanics of breathing in severely emphysematous lungs in vitro. In human clinical trials of airway bypass, anatomic fenestrations were created between the bronchial tree and lung parenchyma to improve decompression of hyperinflated lung (38). Small drug-eluting stents (5.3-mm outer diameter, 2-mm length, 3.3-mm inner diameter) were placed across the airway wall into the emphysematous lung parenchyma after fenestrating the segmental/subsegmental airway wall with a needle and balloon dilation. The stainless steel stents were coated with paclitaxel-covered silicone to inhibit granulation and fibrotic tissue from obstructing patency of the fenestrations. The fenestrated passages take advantage of the collateral ventilation seen in emphysema by increasing gas flow from hyperinflated lung parenchyma directly into the main airway during exhalation, reducing hyperinflation. CT images were initially reviewed to identify targeted locations for fenestration and stent placement in the most diseased lobes. Under deep sedation, a flexible bronchoscope was advanced to the targeted segmental or subsegmental bronchi of each lobe. A Doppler probe was passed through the working channel to identify peribronchial blood vessels. After probing the targeted area with the Doppler probe to ensure a nonvascular site, the probe was removed, and a dilating needle was used to puncture the bronchial wall, creating the initial fenestration. This was followed by balloon dilation and stent insertion to maintain patency. Prior versions of this procedure used radiofrequency ablation to create the airway passage rather than a needle (39). The major reason for change was potential thermal injury to surrounding structures by radiofrequency ablation. The Exhale Airway Stent for Emphysema (EASE) trial was a multicenter, randomized, double-blinded, and sham bronchoscopy controlled pivotal study (40). Three hundred fifteen patients were included in the study, with 208 assigned to the airway bypass group and 107 assigned to sham control group. The coprimary endpoints were a 12% or greater improvement in FVC and greater than or equal to a 1-point decrease in the mmrc dyspnea score. The targeted treatment population was patients with severe homogeneous emphysema with a residual volume greater than 180%. The study results demonstrated an initial improvement in lung function and HRQL measures; however, the benefits were not sustained with repeated assessments at 6 months and 12 months. A subset analysis examining the role of stent occlusion by tissue density (masked stent) as opposed to patent clear stents (unmasked stent) was performed, which showed no significant 674 AnnalsATS Volume 10 Number 6 December 2013

9 differences in its endpoints and did not explain the final EASE trial result. However, there was a trend toward preserved reduction in RV, if the stent was free of tissue density. The EASE trial showed safety and transient improvement, but no sustainable benefit was recorded with airway bypass in patients with severe homogeneous emphysema. It is noteworthy that at 6 months post procedure, analysis of the patients with available CT scans showed significant stent loss, likely due to expectoration, and also partial or complete occlusion of remaining stents with mucus or granulation tissue. As of now, there is no long-term proven benefit of this procedure, and the possible future use will require improvements in stent or procedural design, such that benefits achieved are durable. RePneu Lung Volume Reduction Coil. The RePneu Lung Volume Reduction Coil (LVRC) (PneumRx, Mountain View, CA) is a nitinol self-actuating coil designed to engender lung volume reduction by implanting nitinol coils in to the lungs to compress damaged tissue (lung volume reduction) and restore elastic recoil to the healthier lung tissue in emphysema (Figure 2). The coils are available in different lengths to accommodate varioussized airways. Under bronchoscopy and fluoroscopy, a guidewire is inserted into the desired airway to select the length of the coil. This is followed by introduction of a catheter loaded with straightened coil over the guidewire. On coil deployment, the straightened coil then conforms to its predetermined shape (Figure 1). By deploying the coil, bends in the airway from the deployed coil result in compression of adjacent lung tissue, creating local lung volume reduction in addition to restoring elastic recoil of the healthier lung compartments. The coils may potentially be adjusted or removed at the time of the procedure. To our knowledge, there are no published reports of long-term coil removal. A single-center open-label pilot study in Germany using the LVRC was conducted in heterogeneous emphysema (41). Twentyeight LVRC procedures were performed in 16 patients (baseline FEV 1, 28% ). Four patients had treatment in one lung, and 12 patients had treatment in both lungs. A median of 10 (range, 5 12) coils were placed per lung. The results of this pilot study showed a statistically significant improvement at 6-month follow-up assessment in SGRQ (214.9 points, P, 0.005). There was also a clinically meaningful improvement in 9 of 14 patients in: FEV 1 (>12%), RV (>10% reduction), and 6MWD (>48 m). The RV reduction also correlated with improvements in SGRQ. COPD exacerbation was the most common adverse effect, but none of the subjects required intensive care unit admission or noninvasive ventilation. Patients experiencing COPD flares returned to baseline after 1 month. There was only one pneumothorax reported in the trial, which was treated and resolved with a chest tube for less than 48 hours. The U.S. pivotal clinical trial, Lung Volume Reduction Coil for Treatment in Patients with Emphysema (RENEW) Study, has started enrollment in the United States. This is a multicenter, randomized phase 3 trial. Primary outcome measures of the study are mean change from baseline at 12 months in the 6MWD comparing test and control groups. Secondary outcome measure is SGRQ. Secondary endpoints include change in FEV 1, SGRQ, and 6MWD responder analysis (>25 m). The inclusion criteria include subjects with a residual volume of greater than or equal to 225%, post-bronchodilator FEV 1 less than or equal to 45%, and CT scan with bilateral emphysema, which have been reviewed by a core radiology lab for suitability for coil treatment. In this study, the treatment group undergoes two bronchoscopic sessions under general or moderate sedation with coil placement. The control group receives standard medical treatment as the treatment group, except they do not undergo any bronchoscopies for coil placement during the investigational device exemption study and do not receive prophylactic antibiotics or steroids before and after treatment, nor Figure 1. Results of literature search. Perspectives 675

10 Figure 2. Images of devices for bronchoscopic lung volume reduction. (Top left) Zephyr Valve; (top middle) IBV valve; (top right) airway bypass exhale stent; (bottom left) InterVapor; (bottom middle) RePneu Coil; (bottom right) AeriSeal. do these subjects receive chest X-rays in connection with the treatment visits. However, the frequency of visits to the study doctor or designee is similar to the treatment group. Discussion The NETT trial showed a survival benefit for patients with severe emphysema who had LVRS with heterogeneous, upper lobe predominant disease and low baseline exercise capacity. A study by Tschernko and colleagues (42) showed that in the NETT trial ventilatory mechanics improved immediately after LVR, probably by decompression of lung tissue and relief of thoracic distension. They further concluded that an improvement in diaphragmatic function 3 and 6 months postoperatively also contributes to improved respiratory function after LVR. Although lung volume reduction can be performed in selected patients with acceptable mortality, the incidence of major cardiopulmonary morbidity remains high, thus making BTE an attractive treatment. Several unique endoscopic procedures attempt to induce minimally invasive lung volume reduction in patients with severe and very severe emphysema. However, none have been approved for U.S. clinical practice, and they remain investigational. Early studies had shown a potential benefit but had disappointing results in terms of sustained benefit and safety. This should not be discouraging, as there are a record number of pivotal trials being conducted in the United States ready to capitalize on lessons learned from earlier experiences (Table 4). Our systematic review of the BTE literature revealed the limited data, which in itself is heterogeneous. The heterogeneous inclusion criteria, study durations, and endpoints make a comparative conclusion unrealistic. The only commonality was the inability to significantly improve homogenous emphysema presumably from collateral ventilation and failure to improve local V/Q. The current and future studies continue to be quite different in their evaluations and will most likely make future systematic review and metaanalysis difficult, if not impossible. The current message is that none of these devices have been successful in significantly improving emphysema, despite their favorable pilot results. The CE marking indicates a product s compliance with EU legislation and enables the free movement of products within the European market. Several of the BTE described in this review have already obtained a CE mark and are already in European practice (i.e., IBV, Zephyr, RePneu, AeriSeal, and InterVapor system). FDA approval is normally several months and, in some cases, years behind the CE mark or potentially never achieved (43). In 2012, the FDA issued a report examining medical devices that were approved by 676 AnnalsATS Volume 10 Number 6 December 2013

11 Table 4. Ongoing and future multicenter U.S. studies Trial Device Primary Endpoint Inclusion Criteria Status Lung Volume Reduction Coil for Treatment in Patients with Emphysema (RENEW) study Study of the AeriSeal System for HyPerInflation Reduction in Emphysema (ASPIRE) Evaluation of the IBV Valve for Emphysema to Improve Lung Function (EMPROVE) Lung Function Improvement after Bronchoscopic Lung Volume Reduction with PulmonX Endobronchial Valves used in Treatment of Emphysema (LIBERATE STUDY) RePneu AeriSeal IBV Zephyr Charitis Mean absolute 6MWD change from baseline at 12 mo Change in FEV 1 over 12 mo Change in FEV 1 over 6mo Change in FEV 1 over 12 mo Age > 35 yr Post-bronchodilator FEV 1, 45% Subject has TLC. 100% RV > 225% Subject has marked dyspnea > 2 on mmrc scale of 0 4 Smoking cessation for at least 8 wk prior Smoking abstinence for 16 wk Age > 40 yr Upper lobe predominant emphysema FEV 1, 50% and FEV 1 /FVC ratio, 70% TLC. 100% RV. 150% DL CO > 20% and < 60% Blood gases and oxygen saturation showing both: Sp O2 > 90% on < 4 L/min supplemental O 2 and Pa CO2, 65 torr 6MWD > 140 m Cessation from cigarette smoking for 4 mo Pulmonary function testing: FEV 1 < 45%, RV > 150%, TLC > 100% Clinical and radiological evidence of emphysema Currently nonsmoking Stable on current medication FEV 1 between 15% and 45% Recruiting patients Terminated Recruiting patients Not yet recruiting Definition of abbreviations: 6MWD = 6-minute walk-distance; DL CO = diffusing capacity of carbon monoxide; mmrc = modified Medical Research Council; N/A = not available; RV = residual volume; Sp O2 = oxygen saturation measured by pulse oximetry. the EU CE mark but had not received U.S. FDA approval (44). Most of the devices included in the FDA report were eventually withdrawn in the EU market, mainly after the ineffectiveness and risks were realized as a result of studies conducted in the United States for FDA approval. Because there currently is no approved substantially equivalent device in the United States, the FDA requires proofofreasonableassuranceofsafetyand efficacy of these new devices. A future pathway may be possible for a 510K (premarket notification) pathway after the first predicate device has successfully passed the FDA approval process. In contrast, the CE mark needs to show that the device performs in a manner consistent with the manufacturer s intended use and not clinically significant efficacy (45). In addition, review and approval of devices in the EU is conducted by private for-profit third parties, notified bodies, chosen and hired by the manufacturer (44). There is no oversight by a central government authority in most EU countries. Approval by a notified body in any country authorizes marketing throughout the EU. There is also no central collection of information on device side effects, and those that are reported to the manufacturer and notified body after approval are generally not disclosed to the public (46). These key differences require pivotaltrialstobemorerigorousand potentially costly for devices such as those used for emphysema. Thus, there should becautionwhenevaluatingdevicestudies that have not met the standards of the U.S. FDA. The disappointing results from the VENT trial may hold valuable lessons for future device testing, better patient selection, and/or device design. The FDA has now approved a request for a new IDE to commence another pivotal clinical trial for the Zephyr Endobronchial Valve in conjunction with the Chartis system to screen for collateral ventilation. The redesigned trial may potentially show an improvement in reaching their 12-month efficacy and safety by better patient selection. Another example of refinement is the Spiration IBV; Eberhardt and colleagues showed an improved efficacy and safety with unilateral complete lobar occlusion compared with bilateral partial occlusion (21). Based on their own experiences, Spiration is also relaunching their trial, using complete lobar occlusion rather than partial lobar occlusion, which was used in their initial pivotal trial. Newer design devices attempt to show their benefit by potentially overcoming collateral ventilation. An early attempt of this was the Airway bypass procedure, which unfortunately had disappointing results in the EASE trial. But newer devices have been developed and will have their Perspectives 677