PERSPECTIVES. Endoscopic Lung Volume Reduction A European Perspective. Abstract. Daniela Gompelmann 1, Ralf Eberhardt 1, and Felix J. F.

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1 Endoscopic Lung Volume Reduction A European Perspective Daniela Gompelmann 1, Ralf Eberhardt 1, and Felix J. F. Herth 1 1 Department of Pneumology and Respiratory Care Medicine, Thoraxklinik at University of Heidelberg, Heidelberg, Germany; Translational Lung Research Center, Member of the German Center for Lung Research, Heidelberg, Germany Abstract Endoscopic lung volume reduction (ELVR) offers a novel therapeutic approach for patients with severe pulmonary emphysema. In Europe, several types of ELVR are available. The choice of ELVR technique depends both on the distribution of emphysema and the presence or absence of interlobar collateral ventilation (CV). For this reason, accurate patient selection is crucial. Bronchial valve implantation is the technique that has been most widely studied and represents an effective treatment option for patients with severe heterogeneous upper- or lower-lobe predominant emphysema. Lobar occlusion and low interlobar CV are predictive factors for positive outcomes. Lung volume reduction coil implantation is an effective option for patients with upper- and lower-lobe predominant emphysema, and the efficacy is not influenced by CV; however, the technique should be regarded as mainly irreversible. Polymeric lung volume reduction relies on irreversible scarring and fibrosis and is especially effective in patients with chronic obstructive pulmonary disease classified as Global Initiative for Chronic Obstructive Lung Disease stage III; it also offers benefits to patients with upper-lobe predominant emphysema and those with homogeneous emphysema. Like polymeric lung volume reduction, bronchoscopic thermal vapor ablation is also not influenced by CV and represents a good option for patients with upper-lobe predominant emphysema. Exhale airway stents for emphysema airway bypass appeared to be a promising technique but proved ineffective in randomized clinical trials, likely in part due to long-term occlusion of the drug-eluting stents. Although European physicians are able to choose from a host of approved bronchoscopic interventions for emphysema, future studies for techniques in use are needed to further clarify patient selection criteria. Keywords: chronic obstructive pulmonary disease; endoscopic lung volume reduction; bronchoscopy (Received in original form January 10, 2013; accepted in final form July 8, 2013 ) Correspondence and requests for reprints should be addressed to Daniela Gompelmann, M.D., Pneumology and Critical Care Medicine, Thoraxklinik Heidelberg, Amalienstrasse 5, Heidelberg, Germany. daniela.gompelmann@thoraxklinik-heidelberg.de Ann Am Thorac Soc Vol 10, No 6, pp , Dec 2013 Copyright 2013 by the American Thoracic Society DOI: /AnnalsATS FR Internet address: Over the past decade, endoscopic lung volume reduction (ELVR) has emerged as a new treatment modality for patients with severe emphysema. Since the first description of bronchial valve implantation in 2003, the knowledge of indications and methods for successful valve treatment has increased significantly, and other therapeutic modalities, such as lung volume reduction coil (LVRC) implantation, polymeric lung volume reduction (PLVR), and bronchoscopic thermal vapor ablation (BTVA), have also been developed. The concept of ELVR has its roots in lung volume reduction surgery (LVRS), initially developed by Brantigan and colleagues (1) in the 1950s and reintroduced by Cooper and colleagues (2) in the 1990s. In LVRS, the physiological goal is reduction of hyperinflation leading to optimized diaphragmatic function and improved expiratory flow (3). The most comprehensive clinical trial of LVRS was the National Emphysema Treatment Trial (NETT), which enrolled 1,218 patients with severe emphysema. Of those, 608 patients were randomized to LVRS and 610 patients were randomized to medical therapy. After LVRS, patients experienced improvements of pulmonary function, health-related quality of life, and exercise capacity that were stable over 24 months. Fifteen percent of the patients who underwent surgery had an improvement by more than 10 W on cycle ergometry compared with 3% of patients in the medical-therapy group. However, surgical intervention particularly in patients with non upperlobe predominant emphysema and high baseline exercise capacity was associated with increased morbidity and mortality, stimulating the search for other approaches with comparable physiological benefits to the patient and less attendant risk. As Perspectives 657

2 a minimally invasive alternative treatment modality for advanced emphysema, ELVR has developed rapidly in recent years, particularly in Europe. Clinical trials studying various techniques of ELVR were initiated in the United States and Europe in the first decade of the 21st century. The most important trials are listed in Table 1. Several randomized controlled trials were conducted in the United States, but none of the ELVR interventions studied has been approved by the U.S. Food and Drug Administration. For this reason, ELVR remains investigational in the United States. By contrast, all currently available techniques of ELVR have been approved in Europe and are now available commercially to patients in some countries after achievement of CE mark status. Depending on the situation in individual European nations, some of the techniques are reimbursed by health insurance. The current approximate costs of the different techniques are as follows: bronchial valves, V1,500 per device; LVRC, V1,000 per device; and a PLVR or BTVA procedure (including planning), V6,000 to V8,000. As mentioned, precise patient selection is crucial for the most beneficial outcome after ELVR. Techniques vary by type of device used, degree of reversibility, dependency on intact interlobar fissures, and degrees of safety and toxicity. However, all these methods of ELVR are only worth considering in patients with advanced emphysema (i.e., pulmonary function tests showing an FEV 1 of,45% predicted and a residual volume [RV]. 150% predicted; see Figure 5). Figure 1. Endobronchial valve (EBV; Zephyr; Pulmonx, Inc., Palo Alto, CA). In general, two different kinds of valves have been studied for ELVR. The first valves available for clinical evaluation were the endobronchial valves (EBV; Zephyr; Pulmonx, Inc., Palo Alto, CA) (Figure 1) followed by the intrabronchial valves (IBV; Spiration; Olympus, Tokyo, Japan) (Figure 2). Both valves have similar mechanisms of action but different structures. The EBV has a design similar to a bronchial stent, with a self-expanding, membrane-covered retainer that provides stability and prevents dislocation. The IBV is an umbrella-shaped, one-way valve incorporating a nitinol skeleton consisting of five distal anchors holding the valve in place and six proximal struts covered by a polymer membrane. There are two different sizes of EBV (4 mm in diameter [in two different lengths] and 5.5 mm in diameter) available and three sizes of IBV (5 mm, 6 mm, and 7 mm in diameter). Both the EBV and the IBV act as oneway valves. During expiration, the valves allow the air to exit the targeted area while preventing air from entering the Bronchial Valve Implantation One-way bronchial valve implantation represents the blocking ELVR technique with which there has been the greatest clinical experience worldwide. Since publication of the first studies related to valve implantation in patients with severe emphysema in 2003 (4, 5), several clinical trials have been performed leading to expanded knowledge and expertise with this technology. The identification of predictive factors for improved clinical outcomes has advanced this minimally invasive approach. Figure 2. Intrabronchial valve (IBV; Spiration; Olympus, Tokyo, Japan). 658 AnnalsATS Volume 10 Number 6 December 2013

3 lung compartment during inspiration. Ideally, a reduction of hyperinflation of the most destroyed emphysematous lung parenchyma can be achieved, leading to reduction in target lung volume. Both valves allow mucus to be expelled to prevent postobstructive infectious complications. Technically, the implantation techniques for both types of valves in the airways of the most emphysematous lung are relatively straightforward. After measurement of the airway diameter, the appropriate valves are placed by using a special flexible delivery catheter that can be inserted through a 2.0-mm or larger working channel of a standard bronchoscope. The simple placement of valves takes approximately 10 to 30 minutes. Since the first pilot studies by Toma and colleagues (4) and Snell and colleagues in 2003 (5) describing bronchial valve implantation for emphysema, other studies (6, 7) were performed confirming the safety and feasibility of valve placement and demonstrating encouraging outcomes. The first randomized trial was the Endobronchial Valve for Emphysema Palliation Trial (VENT). The U.S. data from this trial were published in The New England Journal of Medicine by Sciurba and colleagues in 2010 (8). In the VENT, 321 patients with advanced emphysema were randomly assigned to standard medical care (n = 101) or lobar EBV implantation (n = 220). Six months after intervention, the EBV group (n = 214) demonstrated an increase in FEV 1 of 4.3% compared with a decrease of 2.5% in those who received only standard medical care and also exhibited similar benefits in 6-minute walk distance (6MWD). Overall, there was a mean between-group difference of 6.8% in the FEV 1 and of 5.8% in the 6MWD. At 12 months follow-up, the overall rate of the complications was 10.3% in the EBV group versus 4.6% in the control group, but this difference was not statistically significant. The most frequent adverse events included chronic obstructive pulmonary disease (COPD) exacerbations, pneumonia distal to the valves, hemoptysis, and pneumothorax. Similar results could be observed in data from the European cohort of VENT (Euro-VENT), which were published in 2012 (9). In the Euro-VENT, 111 of the 171 patients who were enrolled and randomly assigned were treated with EBV; the remaining 60 control patients received only standard medical care. Efficacy measures revealed a significant improvement of FEV 1, cycle ergometry, and St. Georges Respiratory Questionnaire (SGRQ) measurements at 6 months in the EBV group compared with control subjects. Furthermore, the results of the Euro-VENT provided an impressive demonstration of the influence of fissure integrity and lobar occlusion on outcome. Patients with a complete interlobar fissure and a complete occlusion of the targeted lobe by the EBV experienced a target lobe volume reduction of %, supporting the results of the U.S. study. In comparison to the U.S. cohort, however, the European data showed that a high heterogeneity score is not a prerequisite for the success of valve therapy: a low emphysema heterogeneity score in the European cohort did not reduce the success in patients with complete interlobar fissure and successful lobar occlusion. In summary, VENT (8) and Euro- VENT (9) demonstrated statistically significant but only modestly clinically relevant improvement of clinical outcome measures in patients with advanced emphysema. However, as noted, subanalysis of these trials revealed that patients who had a complete interlobar fissure (defined as.90% completeness of the fissure between the target and adjacent lobes on at least one axis in the thin-slice high-resolution computed tomography [HRCT]) experienced marked improvement in a variety of clinical outcome measures after valve placement. Therefore, a complete interlobar fissure was hypothesized to be a surrogate for low collateral ventilation (CV) and has emerged in European clinical practice as a reliable predictive factor for superior outcome after valve placement, whereas an incomplete fissure was associated with high interlobar CV and therefore responsible for valve failure. Besides the computed tomography (CT) fissure analysis, in Europe there is another method available to provide an estimate of the CV before valve treatment: the Chartis Pulmonary Assessment System (Pulmonx Inc., Redwood City, CA). The Chartis device is used to bronchoscopically quantify the resistance of airflow through collateral airways by temporarily occluding a lung compartment and measuring the air pressure and flow from the sealed compartment. This measurement allows classifying the patient as CV-negative in case of low or absent CV or as CV-positive in case of high CV. In a double-blind safety and feasibility study of the Chartis system, 25 patients with advanced emphysema underwent CV measurement followed by a complete occlusion of the targeted lobe by the EBV (10). The final analysis of this study included 20 patients and revealed an accuracy of the Chartis System of 90% in correctly predicting the development of atelectasis. In a subsequent multicenter trial (11), 80 patients underwent Chartis assessment with subsequent ELVR by EBV. In that trial, the accuracy of the CV assessment in correctly predicting the target lobe volume reduction was found to be 75%. Therefore, both CT fissure analysis and implementation of the Chartis system appear to optimize patient selection for valve treatment. The results of one retrospective analysis confirmed that the two techniques are comparable and that both offer an efficient method for predicting target lobe volume reduction with valve treatment (12). When the Chartis system was used to predict target lobe volume reduction, 74% of patients responded as predicted; when CT fissure analysis was used, 77% responded as predicted. The highest predictive value was achieved in patients in whom both measurements were in agreement that is, when both the Chartis system and CV fissure measurements offered the same results. Low CV is a crucial factor if the aim is to achieve an atelectasis of the most destroyed lobe. Another important prerequisite to achieve atelectasis is a complete lobar exclusion specifically, an occlusion of all the airways of the targeted lobes by bronchial valves placed in lobar, segmental, or subsegmental bronchi. It is known, however, that the induction of lobar atelectasis is associated with increased risk of pneumothorax, which is believed to be secondary to parenchymal rupture in the adjacent untreated lung lobe in the setting of rapid volume reduction in the treated lobe. Although the induction of a pneumothorax seems to be associated with substantial improvement of efficacy measures due to target lobar volume reduction (13), pneumothorax also presents an adverse event requiring thoracostomy tube insertion in many cases. To avoid this complication, a strategy of intentional incomplete lobar occlusion was proposed, allowing for reduction of dynamic Perspectives 659

4 hyperinflation and redistribution of air from diseased areas of the lung to healthier regions but with lower risk of complications. In the first U.S. clinical trials involving implantation of IBV, a bilateral, incomplete lobar occlusion strategy was evaluated (14 17). These pilot studies demonstrated a significant improvement of health-related quality-of-life measurements, a decrease in volume in the treatedlobe,andanincreaseinvolumeinthe nontreated lobe. However, the pilot studies of incomplete lobar occlusion with the IBV revealed no significant improvements in spirometry, plethysmographic lung volumes, or exercise capacity. One German trial published in 2012 compared the incomplete treatment approach (incomplete closure of two contralateral lobes) to the complete treatment approach (complete occlusion of one lobe by valves with the goal of an atelectasis) (18). The aim of the incomplete approach was a redirection of the air from the diseased compartments of the lung to healthier portions. Eleven patients with advanced upper- or lower-lobe predominant emphysema underwent unilateral complete occlusion of one targeted lobe, and another 11 patients were treated bilaterally by an incomplete lobar occlusion. Results of this randomized trial showed that only patients treated by unilateral complete occlusion experienced significant improvement in clinical outcome measures. Furthermore, atelectasis was observed on radiologic studies in 7 out of the 11 patients treated with complete unilateral lobar occlusion but in none of the patients treated with bilateral incomplete lobar exclusion. As for adverse events, pneumothorax developed in one patient in the unilateral complete ELVR group, and two cases of respiratory failure occurred in the bilateral ELVR group. These results revealed that the complete ELVR is superior to the incomplete bilateral occlusion, and only a complete occlusion of the targeted lobe with subsequent atelectasis led to true volume reduction associated with significant clinical benefit. Similar results were obtained in the Euro- VENT, wherein lobar occlusion was revealed as another predictive characteristic associated with a greater effect after EBV placement (9). In addition, this study showed that not only may bilateral incomplete treatment not improve lung function but also it may worsen gas exchange in some patients. Although the previously reported trials confirmed an improvement of symptoms in patients with advanced emphysema, another crucial issue is whether valve treatment influences the survival of patients with emphysema. A study by Hopkinson and colleagues in 2011 evaluated the survival of 19 patients treated with EBV (19). In 5 of the 19 patients, radiological atelectasis occurred. During a 6-year clinical followup, 8 of 14 patients who did not experience an atelectasis after valve placement died, whereas the 5 patients with evidence of an atelectasis still were alive at the end of the follow-up period. Similar results were reported in a 2012 study by Venuta and colleagues, which compared the survival of 40 patients who underwent ELVR with complete versus incomplete fissure (20). This retrospective analysis revealed a visible complete interlobar fissure on HRCT in 37.5% of these patients. Follow-up results suggested that a complete fissure in valve therapy was associated with a survival benefit. From another perspective, device implantation can be considered as a temporary approach that may assist in predicting candidacy for LVRS. One case series reported on six patients who developed atelectasis after valve placement associated with marked improvement in clinical parameters (21); however, the effect was not sustainable, and atelectasis diminished over time. Ultimately, these patients were referred for lobectomy for LVRS. Three months after the surgical procedure, these same patients showed significant improvements in FEV 1, RV, 6MWD, and modified Medical Research Council (MRC) scale measurements. These results suggest that a prior successful valve treatment optimizes patient selection for LVRS. However, it should be remembered that patients with high CV who are therefore unlikely to benefit from valve treatment might nonetheless be good candidates for LVRS. Valve treatment appears to be positioned to become a disease-modifying and potentially survival-enhancing therapy in patients with advanced emphysema. Although valve therapy can be targeted based on outcome predictors, patient selection criteria need to be revised. The question of whether a fissure completeness of 90 to 100% is necessary to achieve a good outcome must be clarified. Besides visual assessment of fissure integrity, automatic computerassisted analysis could provide more precise evaluation of integrity. In the United States, two controlled clinical trials of valve placement after fissure analysis have been begun; perhaps the results of these trials will help to refine patient selection criteria. In summary, bronchial valve treatment presents an effective treatment option for patients with severe heterogeneous upperor lower-lobe predominant emphysema (22). Lobar occlusion and low interlobar CV are predictive factors for an excellent clinical benefit. In addition to influencing clinical symptoms, studies have also demonstrated encouraging results in survival benefits among patients who underwent valve procedures and who experienced subsequent atelectasis. LVRC Implantation One technique that is not based on blocking the airways is the implantation of LVRC (PneumRx, Inc., Mountain View, CA) (Figure 3). Composed of nitinol wire, the coils are preformed in a shape designed to cause parenchymal compression after deployment. By implantation of up to 10 coils in the targeted lung lobe, volume reduction can be achieved, leading to improvement in respiratory mechanics. Coil implantation is performed by using a dedicated delivery system under fluoroscopic guidance. First, a guide wire is inserted into the targeted airway to measure the airway size and determine the length of the coil that is needed. Coils are available in three different sizes. Afterward, a catheter is advanced over the guide wire, which is then extracted. The coils are inserted in an extended form into the catheter by using a grasper. By pulling the catheter back, the coil assumes its original coiled shape and is deployed when released from the forceps. In the clinical pilot study conducted in Germany, 11 patients with heterogeneous or homogeneous emphysema were treated by implantation of three to six coils (23). There were 33 mild or moderate adverse events, including dyspnea, cough, COPD exacerbation, or chest pain, but no serious adverse events were observed. Although the mean changes in effectiveness endpoints were small, the group with predominantly heterogeneous disease appeared to show substantial improvements in pulmonary function, lung volumes, 6MWD, and quality-of-life measures. Due to these 660 AnnalsATS Volume 10 Number 6 December 2013

5 Until now, our knowledge about coil implantation is based on only a few published trials. But it is likely that the coils will be of great significance, particularly in patients with lower-lobe predominant emphysema and high CV in whom coils are currently the only therapeutic option. However, positive outcome predictors need to be identified, especially because this technique is only partially reversible. One of the goals of the RENEW Pivotal Trial, which has already begun in Europe and the United States, is to improve patient selection for LVRC treatment. Polymeric Lung Volume Reduction Figure 3. Chest X-ray after implantation of lung volume reduction coils (PneumRx, Inc., Mountain View, CA) in the left upper lobe (courtesy of C. P. Heussel). encouraging results, particularly in patients with heterogeneous disease, a further prospective cohort pilot study using LVRC only in patients with heterogeneous emphysema distribution was initiated (24). Sixteen patients were treated with a median of 10 LVRC in one or two procedures, resulting in a significant improvement of pulmonary function tests, exercise capacity measured by 6MWD, and health-related quality of life measured by SGRQ. Mild hemoptysis, transient chest pain, COPD exacerbation, pneumonia, and one pneumothorax were documented as adverse events. In a recent report, the 12-month summary data of two feasibility trials involving 85 patients with upper- or lowerlobe emphysema treated bilaterally with LVRC therapy showed sustained statistical improvements in RV, 6MWD, and SGRQ (25). The results of the first randomized, controlled study of LVRC implantation in patients with advanced emphysema the RePneu Endobronchial Coils for the Treatment of Severe Emphysema with Hyperinflation (RESET) Trial were published in 2013 (26). In this study from the United Kingdom, 23 patients with advanced emphysema were randomized to coil placement, and 24 patients were randomized to best medical care. Twentyone out of the 23 patients in the treatment group underwent bilateral coil implantation, and two patients had unilateral treatment. At 90 days after intervention, there were significantly greater improvements in SGRQ, 6MWD, FEV 1,andRVinthe LVRC group than in the control group. However, serious adverse events were observed more frequently in the treatment group, including pneumothoraces, exacerbations of COPD, and lower respiratory tract infections. The advantage of LVRC compared with valve placement is that the success of the procedure is independent from the presence or absence of interlobar CV. A retrospective analysis demonstrated that patients in whom an incomplete fissure could be observed experienced similar efficacy results compared with the entire study population (27). Thus, this approach can be used in a greater number of patients. However, the treatment with coils is a partially irreversible therapy, thus presenting a disadvantage compared with reversible valve implantation. In addition, LVRC have been shown to be an effective treatment modality in patients with upper- and lowerlobe predominant emphysema (28). PLVR, also called ELS (emphysematous lung sealant) (Aeris Therapeutics, Inc., Woburn, MA), is another nonblocking technique. This technique consists of the administration of synthetic hydrogel foam sealant (AeriSeal; Aeris Therapeutics, Inc.) into the most emphysematous, destroyed areas of the lung (Figure 4). The main mechanism of action of this hydrogel foam sealant is based on an inflammatory reaction that induces scarring and formation of fibrotic tissue, resulting in lung volume reduction. The resultant volume reduction is increased by the absorption of the air from the hydrogel foam. The process of remodeling takes several weeks, so that the maximum effect is apparent 8 to 12 weeks after the intervention. The endoscopic treatment is a simple technique that can be performed under general anesthesia or sedation by using a flexible bronchoscope. AeriSeal consists of 4.5-ml synthetic polymer (chemically modified) polyvinyl alcohol and 0.5-ml cross-linker (29) and is administered through a special catheter that can be introduced through the working channel of a conventional flexible bronchoscope. The AeriSeal is injected into targeted subsegments over a few seconds, followed by injection of 30 ml of air, leading to a peripheral distribution of the hydrogel foam. To achieve local polymerization, the bronchoscope is kept in wedge position for approximately 1 minute. Afterward, the bronchoscope can be repositioned at the next subsegmental treatment site. PLVR is similar to an older technology studied for ELVR called biological lung Perspectives 661

6 Figure 4. Hydrogel foam within the airways after polymeric lung volume reduction (Aeris Therapeutics, Inc., Woburn, MA). volume reduction (BLVR) (30 32), which differs only in the reagent used to induce the inflammatory response. Although BLVR used a biological hydrogel foam involving animal and human products, PLVR uses a synthetic hydrogel foam. PLVR s use of synthetic foam offers two distinct advantages over BLVR: the foam is easier to produce, and it eliminates the risks associated with the use of animal- or human-derived substances. The first study related to BLVR was a U.S. safety trial by Reilly and colleagues in 2007, in which the authors reported the outcome of six patients with heterogeneous upper-lobe predominant emphysema (30). The patients were subdivided into two groups: The first group of patients received BLVR on two subsegments, and the second group of patients was treated in four subsegments. No serious adverse events were observed during a 3-month follow-up. Efficacy data demonstrated significant increases in FVC in two of the six patients and a decrease in RV in five of the six patients. In addition, an increase in the 6MWD was demonstrated in five of the six patients. Overall, patients in the second group experienced a better clinical outcome than patients in the first group, suggesting a dose response pattern. These results spurred a dose-ranging study involving 50 patients with severe upper-lobe predominant emphysema (31). This openlabel multicenter Phase IIa study confirmed that the clinical benefit was greater in patients treated with 20 ml per target site compared with patients receiving 10 ml per target site. A more recent clinical trial of BLVR involved patients with homogeneous emphysema distribution (32). Analysis of efficacy measures noted a significant reduction of hyperinflation in patients treated by BLVR using 20 ml hydrogel foam per treatment site at eight subsegments. After completion of these Phase II studies, BLVR was replaced by PLVR for further clinical trials as a result of the safety concerns outlined above. The first published study describing PLVR was by Herth and colleagues in 2011 (33). In this multicenter study, 25 patients underwent PLVR in up to six treatment sites. Fourteen out of the 25 patients had COPD GOLD (Global Initiative for Chronic Obstructive Pulmonary Disease) stage III disease; the other 11 patients had COPD GOLD stage IV. At the 6-month follow-up available for 21 of 25 patients, 43% of the patients exceeded the minimal clinically important difference of DFEV 1 of 15% or more, and 55% of the patients achieved the minimal clinically important difference of DFVC of 15% or more. Furthermore, 38% of the patients experienced an improvement of more than 50 m in the 6MWD. Overall, the clinical benefits were better among COPD GOLD stage III patients than among COPD GOLD stage IV patients. The most common adverse event was a flu-like reaction that started 8 to 24 hours after instillation. Clinical symptoms such as dyspnea, fever, and chest pain as well as increased inflammatory markers and radiographic infiltrates occurred but were mostly self-limited. In addition, COPD exacerbation and pneumonia were observed after PLVR. A recently published study confirmed the efficacy of PLVR in 10 patients with upper-lobe predominant emphysema and demonstrated that PLVR using AeriSeal also represented an effective treatment modality in patients with homogeneous emphysema, although the physiological and clinical benefits were not equivalent to those seen in patients with upper-lobe predominant disease (34). As PLVR belongs to the group of nonblocking interventions, it s likely that this technology will not be influenced by CV. This hypothesis was confirmed by an analysis of the impact of interlobar fissure integrity on the clinical outcome measures of three clinical trials using AeriSeal treatment in patients with severe upperlobe predominant emphysema. Subjective and objective measurements were similar between the patients with incomplete fissures and the patients with complete fissures in the preinterventional CT scan, demonstrating that fissure integrity has minimal impact on PLVR efficacy (35). In summary, PLVR represents an effective nonblocking treatment for patients with advanced emphysema, particularly for patients with COPD GOLD stage III. PLVR offers clinical benefits in patients with upper-lobe predominant emphysema and is an effective treatment modality in patients with homogeneous emphysema. By inducing an irreversible fibrosis, PLVR results in lung volume reduction independent of CV. Bronchoscopic Thermal Vapor Ablation In addition to PLVR, there is another nonblocking ELVR technology whose mechanism of action is based on initiation of a localized intraparenchymal inflammatory response: BTVA (Uptake Medical Corporation, Seattle, WA). BTVA uses heated water vapor delivered to emphysematous lung parenchyma within 662 AnnalsATS Volume 10 Number 6 December 2013

7 Figure 5. Current algorithm of endoscopic lung volume reduction in practice in the Thoraxklinik Heidelberg in CV = collateral ventilation; HI = heterogeneity index; RV = residual volume. *Within clinical trials. a targeted region. The vapor induces an inflammatory reaction with subsequent fibrosis, resulting in lung volume reduction within 8 to 12 weeks. Before the procedure, the vapor dose per lung mass is defined by the application time and the treatment sites within the target lobe and is determined by the InterVapor Personalized Procedure Program. A disposable catheter is used for delivery of the 1258C-heated water vapor from the vapor generator (InterVapor System); the catheter is advanced via the working channel of a flexible bronchoscope into the targeted area. A balloon at the tip of this dedicated catheter is inflated for occlusion of the lung compartment, and the predetermined dose of vapor is delivered over 3 to 10 seconds. The balloon is then deflated and inserted into the next treatment site. In 2009, the results of a BTVA safety and feasibility trial conducted in Australia were published. Eleven patients with advanced upper-lobe predominant emphysema underwent unilateral BTVA using a vapor dose of 5 cal/g of lung tissue (36). All patients tolerated the intervention very well. During follow-up, five serious adverse events, including pneumonia, COPD exacerbations, and/or tachycardia, were observed in five patients. All serious adverse events resolved without sequelae. Efficacy data indicated an improvement of healthrelated quality-of-life measured by MRC dyspnea score and SGRQ. Therefore, Perspectives 663

8 Table 1. Overview of the most important endoscopic lung volume reduction trials Trial Patients n Technique FU (mo) DFEV 1 (%) D6MWT (m) DErgometry DSGRQ (points) DMMRC DTLVR (%) Sciurba and colleagues, 2010; VENT Herth and colleagues, 2012; Euro-VENT Herth and colleagues, 2012; Chartis study Eberhardt and colleagues, 2012; complete unilateral vs. partial bilateral Slebos and colleagues, 2012; bronchoscopic lung volume reduction coil treatment Shah and colleagues, 2013; RESET Herth and colleagues, 2011; treatment with AeriSeal Kramer and colleagues, 2012; bilateral endoscopic sealant lung volume reduction therapy Snell and colleagues, 2012; bronchoscopic thermal vapor ablation therapy All 214 EBV implantation W 23 20,1 All 111 EBV implantation W Subgroup complete fissure, lobar occlusion W CV negative 51 EBV implantation CV positive Complete 11 IBV implantation unilateral occlusion Partial bilateral occlusion All 16 Coil implantation All 23 Coil implantation All 21 PLVR using AeriSeal All 20 PLVR using AeriSeal All 44 BTVA Definition of abbreviations: 6MWT = 6-minute walk test; BTVA = bronchoscopic thermal vapor ablation; CV = collateral ventilation; FU = follow-up; MMRC = modified research council; PLVR = polymeric lung volume reduction; SGRQ = St. George s Respiratory Questionnaire; TLVR = target lung volume reduction. The results were rounded up. although this trial confirmed feasibility of BTVA with an acceptable safety profile, only a modest efficacy was observed. In a retrospective analysis, a heterogeneity index (HI), defined as the tissue-to-air ratio of lower lobe to upper lobe, was identified as a patient selection criterion to improve outcomes after BTVA (37). Patients with an HI greater than 1.2 experienced a greater improvement compared with those with an HI less than 1.2 Based on results of a preclinical animal study that showed dose-dependent volume reduction, a subsequent clinical trial using a higher vapor dose (10 cal/g) was performed in Europe and Australia to determine if efficacy would be increased without a concomitant worsening in safety profile (38). In this open-label, single-arm, multicenter trial, 44 patients with severe upper-lobe predominant emphysema were treated by unilateral BTVA in a single procedural setting. At 6-month follow-up, the lobar volume measured by HRCT was reduced by 48% and was associated with statistically significant improvements in pulmonary function tests, 6MWD, and health-related quality-of-life measures. In this study, BTVA showed a mean FEV 1 improvement of ml (P, 0.001) and mean RV reduction of ml (P, 0.001). Significant improvements were also observed in 6MWD ( m) and in SGRQ ( ) (P, for both). The most common adverse events were lower respiratory tract infections. Patients experienced a flu-like reaction with fever, cough, sputum, dyspnea, and hemoptysis that peaked within the first 2 to 4 weeks and gradually resolved within 8 to 12 weeks of BTVA. A subanalysis showed that patients who experienced a lower respiratory tract event associated with clinically relevant symptoms and an increase of laboratory inflammatory markers had greater improvements than patients without events in the first 30 days after BTVA (39). Therefore, it appeared that the localized inflammatory response proved crucial for the desired lobar volume reduction effect. As with PLVR, BTVA results also were independent of CV. In fact, patients with incomplete interlobar fissures and thus high CV had positive outcomes after the intervention (40). In conclusion, BTVA is an effective treatment for patients with upper-lobe predominant emphysema independent of CV. After initial localized inflammatory reaction, scarring and fibrosis lead to desired lobar volume reduction associated with clinical benefit. Both PLVR and BTVA are mainly performed in patients with upper-lobe predominant emphysema and high CV. At the moment, HI is the only predictor for success in BTVA; for PLVR, no reliable predictors are available. Therefore, there are no clear recommendations to indicate which of these approaches is preferred in any given patient. In the future, the main focus will be the evaluation of patient selection criteria for these two techniques. As both therapeutic approaches are based on an irreversible induction of an inflammatory process, 664 AnnalsATS Volume 10 Number 6 December 2013

9 patient selection is an extremely important issue. The balance between safety and efficacy are challenges that will be evaluated in ongoing trials in Europe. Exhale Airway Stents for Emphysema Exhale airway stents (Broncus Technologies, Mountain View, CA) were developed primarily for those patients with diffuse homogeneous emphysema. However, in randomized clinical trials, no sustainable benefit could be demonstrated with this technology for airway bypass (41); therefore, it is no longer performed in patients with emphysema in Europe. In contrast to the other techniques, particularly bronchial valve implantation, Exhale airway stents took advantage of the effect of CV to achieve lung volume reduction in patients with homogeneous emphysema. Extraanatomic airway bypasses were created by using a dedicated Doppler probe to exclude vessels, followed by bronchial wall puncture and dilation of a passageway using a transbronchial balloon dilation needle. After confirming an avascular location via the Doppler probe, the Exhale paclitaxel-eluting stents were positioned into the passageways, creating the airway bypass and allowing trapped gas to exit from hyperinflated emphysematous lung zones (41). In a multicenter, multinational, randomized, double-blind, sham-controlled clinical trial, 208 patients with homogeneous emphysema were treated with Exhale airway stents, and 107 patients underwent sham bronchoscopy without further intervention (41). Within 24 hours after the procedure, patients who underwent airway bypass experienced significant improvements in lung function parameters such as FEV 1 ( %, P, 0.001) and RV ( %, P = 0.017). However, these improvements returned to baseline within the course of 6 months in the majority of patients. Potential explanations for this transitory beneficial effect include stent occlusion by granulation tissue (despite drug elution) and airway stent loss. Regarding adverse events, one periprocedural death occurred in a patient in the airway bypass arm due to a ruptured aortic aneurysm. Another patient experienced major hemoptysis that could be controlled bronchoscopically. Other side effects were COPD exacerbation, pneumothorax, and pulmonary infection. Airway bypass with Exhale stents was a good approach to the reduction of lung volume in patients with advanced homogeneous emphysema. This technique relied on the presence of intra- and interlobar CV to facilitate decompression of hyperinflated emphysematous lungs by newly created extraanatomic airway bypasses. However, the initial benefits seen did not persist beyond 6 months because of issues with the device as delineated above; as a result, this procedure is currently not performed in Europe, and the technique is no longer available worldwide. 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