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J Thorac Cardiovasc Surg 2007;133:65-73
© 2007 The American Association for Thoracic Surgery

General Thoracic Surgery

A multicenter trial of an intrabronchial valve for treatment of severe emphysema

^a Division of Cardiothoracic Surgery, the University of Washington, Seattle, Wash
^b Division of Thoracic Surgery, Cedars-Sinai Medical Center, Los Angeles, Calif
^c Division of Pulmonary Medicine, Washington University School of Medicine, St Louis, Mo
^d Division of Pulmonary Medicine, the University of Pennsylvania, Philadelphia, Pa
^e Division of Pulmonary Medicine, North Shore University Hospital, Manhasset, NY
^f Spiration, Inc, Redmond, Wash
^g Division of Pulmonary Medicine, Cleveland Clinic, Cleveland, Ohio.

Read at the Thirty-first Annual Meeting of the Western Thoracic Surgical Association, Victoria, British Columbia, Canada, June 22–25, 2005.

Received for publication October 18, 2005; revisions received May 30, 2006; accepted for publication June 7, 2006.

^_* Address for reprints: Douglas E. Wood, MD, University of Washington, Box 356310, 1959 NE Pacific, AA-115, Seattle, WA 98195-6310. (Email: dewood{at}u.washington.edu).

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion Appendix 1 References

 
OBJECTIVES: Minimally invasive endoscopic treatment of emphysema could provide palliation with less risk than lung volume reduction surgery and offer therapy to patients currently not considered for lung volume reduction surgery. The Intrabronchial Valve is used to block bronchial airflow in the most emphysematous areas of lung.

METHODS: Patients with severe chronic obstructive pulmonary disease and heterogeneous upper lobe–predominant emphysema were eligible. Patients underwent flexible bronchoscopic placement of valves into segmental or subsegmental airways in both upper lobes. Outcomes assessed over a minimum of 6 months of follow-up included the safety, feasibility, tolerance, and success of valve placement; health-related quality of life; exercise capacity; pulmonary function; and gas exchange.

RESULTS: Five centers treated 30 patients. Patient follow-up ranged from 1 to 12 months. A mean of 6.1 valves were placed per patient. Valves were positioned by means of flexible bronchoscopy in 99% of desired airways, and the procedure duration ranged from 15 to 125 minutes (mean, 65 minutes). Hospital discharge occurred within 2 days in 27 of 30 patients. There were no deaths or episodes of valve migration, tissue erosion, or significant bleeding. Eighty-three percent of patients had no adverse events judged probably or definitely related to the device. Patients experienced significant improvement in health-related quality of life, although the physiologic and exercise outcomes did not show statistically significant improvements.

CONCLUSIONS: These first multicenter results with the Intrabronchial Valve demonstrate significant improvements in health-related quality of life and acceptable safety, ease of use, and procedural complication rates. The valve might be a safer and less-invasive alternative to surgical therapy for patients with severe emphysema.

	Introduction

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Emphysema affects 2 to 3 million persons in the United States and is characterized by progressive deterioration in pulmonary function, with exercise limitation, disabling dyspnea, and an inexorable decrease in quality of life. Until recently, surgical palliation of the symptoms of emphysema was only used for the very small subset of patients with giant bullae. Lung transplantation was introduced as an option for patients with end-stage emphysema in the 1980s, but it is only offered to the most severely ill patients who have minimal comorbidity and younger age. The number of transplantations performed is further limited by a shortage of lung donors, with only approximately 400 patients with emphysema per year (0.013%) undergoing transplantation.¹ Lung volume reduction surgery (LVRS) was reintroduced in the early 1990s and has had its efficacy investigated more thoroughly than perhaps any other new surgical procedure. LVRS improves pulmonary function, exercise capacity, and quality of life in selected patients with severe chronic obstructive pulmonary disease (COPD) and emphysema, but it has demonstrated major limitations.² First, the benefit of LVRS is limited to narrow subsets of patients with certain patterns of emphysema and with minimal comorbidity.² Second, patients undergoing LVRS have significant risk of morbidity that can extend the period of convalescence before they can realize the desired clinical improvement or that might prevent benefit from LVRS at all.³

The goal for future developments in the treatment of advanced emphysema would be to provide similar benefit as LVRS, with less risk, shorter recovery, and decreased cost. Endobronchial occlusion with a plug or valve might be able to produce targeted areas of atelectasis and subsequent lung reduction with similar physiologic and functional outcomes to LVRS. Alternatively, valve occlusion of the airways might have effects that differ from LVRS, such as the ability to decrease dynamic hyperinflation, work of breathing, and dyspnea with exertion. The Intrabronchial Valve (IBV; Spiration, Inc, Redmond, Wash) is a novel implantable device designed as a one-way valve that is placed by means of flexible fiberoptic bronchoscopy. The IBV obstructs airflow into targeted bronchopulmonary segments and in unpublished animal model studies appears to allow drainage of distal air and mucus. This report describes the initial pilot human study results with the IBV to determine feasibility and safety data before proceeding to a larger pivotal clinical trial.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion Appendix 1 References

 
This prospective, open-enrollment, multicenter cohort study enrolled patients with heterogeneous, upper lobe–predominant emphysema, and severe COPD (Table E1). Patients excluded from the trial were those already accepted and listed for LVRS or lung transplantation, those defined as high risk within the National Emphysema Treatment Trial (NETT),⁴ those having a significant bronchospasm, or those with chronic bronchitis and heavy sputum production. Screening studies were similar to those used by the NETT,⁵ including baseline physiologic, radiologic, and quality-of-life testing. Patients were required to fulfill a pulmonary rehabilitation program or complete more than 140 m in a 6-minute walk test. The clinical protocol was reviewed and approved by each investigating site’s institutional review board and monitored by an oversight data safety monitoring board. All patients provided informed consent for the procedures, data collection, and participation in the clinical trial.

View larger version (80K): [in this window] [in a new window]   Figure E1. A, Intrabronchial Valve appearance and nomenclature. B, Intrabronchial Valve in an airway, as viewed with a flexible bronchoscope.

The IBV was deployed by means of flexible bronchoscopy with 2 different delivery systems. The direct-load system provided a loading kit that allowed the valve to be compressed and loaded retrograde into the 2-mm working channel of the bronchoscope (Figure E2, A). In the direct-load configuration the tip of the bronchoscope was inserted into the orifice to be occluded, and the tip of the scope was positioned at the desired depth of the valve anchors. The IBV deployment tool was used to advance the valve out of the working channel. When the anchor tips extruded and contacted the bronchial wall, the bronchoscope was withdrawn while continuing to deploy the valve until it was fully delivered out of the bronchoscope.

View larger version (101K): [in this window] [in a new window]   Figure E2. A, Direct-load delivery. The compressed valve is loaded into the distal end of the working channel in the flexible bronchoscope and extruded with a specialized catheter when the bronchoscope is seated in the targeted airway. B, Catheter-load delivery. The valve is constrained within a flexible delivery catheter that is deployed through the working channel of the flexible bronchoscope.

Valves were deployed in all planned segments or subsegments, followed by a final visual inspection. The patient was then extubated and managed on a surgical/medical inpatient floor for standard postanesthesia COPD management, which included the use of bronchodilators and supplemental oxygen. Patients had a chest radiograph taken immediately after the procedure and each day of inpatient hospitalization. Prophylactic antibiotics and perioperative steroids were used at the discretion of the investigating physician. For the first 19 procedures, the protocol required hospitalization and observation for a minimum of 2 postprocedure days. Because patients typically had no obvious need for hospitalization on the second day after the procedure, the protocol-required stay in the hospital was decreased to a minimum of 1 postprocedure day.

Patients were asked to keep a symptom and medical history diary. The patients were evaluated at 1 to 2 weeks after discharge from the hospital with a history, physical examination, chest radiograph, and resting oxyhemoglobin saturation measurement. At 1 month after valve placement, patients had another follow-up visit and testing. The patients then underwent a second bronchoscopy procedure after either topical anesthesia with conscious sedation or general anesthesia was obtained. The implanted valves were inspected for evidence of tissue erosion, migration, and appropriate seal of the membrane against the airway wall and to assess for signs of complications, including purulence or granulation tissue. During this bronchoscopy, valves could be removed, removed and replaced, or added, as determined by the investigator. If new valves were inserted, the patient underwent general anesthesia, hospitalization, and follow-up similar to the initial procedure.

Patients returned for follow-up evaluation by the investigators at 3-, 6-, and 12-month intervals. Chest radiographs were analyzed at each visit to document the stability of the valve position. The investigators assessed intervening adverse clinical changes for their seriousness and any possible relationship to the device.

A panel of experts, investigators, and Spiration, Inc, personnel determined a priori adverse event definitions. A clinical events committee adjudicated all adverse events for severity and relationship to the device. The primary end point of the pilot study was safety, as measured by the incidence of migration, erosion, and/or infection related to the device. Other safety measures included pneumothorax requiring a chest tube for more than 7 days, hospital length of stay beyond that required by the protocol, additional procedures required because of adverse events, COPD exacerbations, persistent cough, bronchitis or pneumonia, respiratory failure, hemoptysis requiring intervention, and death.

Three variables were identified prospectively as pilot study measures for efficacy: an increase in posttreatment forced expiratory volume in 1 second (FEV₁) of 15% or greater, an increase of 6-minute walk distance of 15% or greater, or an improvement in the St George’s Respiratory Questionnaire (SGRQ) total score of more than 4 points. These thresholds for minimal clinically important differences were based on published literature.^6-8 Other measures of efficacy included decrease in oxygen supplementation requirements, improvement in Medical Outcome Study Short-Form Health Survey (SF-36) scores, and improvement in the modified Medical Research Council dyspnea score. Dyspnea and general health-related quality of life were assessed with questionnaires that were provided onsite or through the mail. All questionnaires were completed during periods of clinical stability.

Descriptive data are expressed as means ± standard deviation, medians, and 95% confidence intervals. Categoric data are expressed as counts and proportions. Mean scores before and after valve placements were compared by using the Wilcoxon signed-rank test. A P value of less than .05 was considered statistically significant, and comparisons for multiple tests were not used. Spiration, Inc, assisted in data collection and collation and provided an independent consultant for statistical analysis.

	Results

Top Abstract Introduction Materials and Methods Results Discussion Appendix 1 References

 
Thirty patients were treated at 5 clinical centers from January through July 2004 (Table 1). Patients had severe to very severe airflow obstruction, with air trapping, thoracic hyperinflation, and a reduced diffusing capacity of lung for carbon monoxide value. All patients had bilateral upper lobe treatment. The average initial procedure time was 65 ± 33 minutes (range, 15-125 minutes). The average time for the last 8 procedures (with the modified catheter) was 41 minutes. There were 184 valves in place at completion of the initial procedure and 194 valves after the completion of the 1-month bronchoscopy, for an average of 6.5 ± 1.6 valves (range, 5-10 valves) per patient. The airways treated were 166 (73%) segmental airways and 62 (27%) subsegmental airways. When 1 valve treated 2 segmental airways, it was counted as 2 segments treated. The 7-mm valves were used in 69% of the instances, with 6 mm at 27% and 5 mm at 4%, and only one 4-mm valve was placed. Successful valve placement was accomplished in all but 2 of the attempted sites (99%) at the first procedure, and all desired sites were treated after the second procedure. The 2 locations not initially treated were the anterior subsegments of the upper lobes of each lung, where the angle did not allow scope entry for direct-load placement. The 1-month bronchoscopy resulted in revisions in 17 patients with removal of 8 valves, replacement with 16 valves, and placement of 15 additional valves in new segments or subsegments. Reasons for valve revisions at 1 month were visual judgment that valves were angulated or too distal in an airway, resulting in incomplete contact between the membrane and an airway wall. Sometimes 1 segmental valve was removed and replaced with 2 subsegmental valves. In most cases valves were added for additional treatment.

Twenty-eight patients have been followed for at least 6 months after valve placement. Data are currently available on 6 patients at 12 months. Because the protocol and IBV design allows removal, 7 patients (48 valves) underwent late valve removal within the study period. Reasons for late valve removal were LVRS (2 patients) at 7 and 9 months, pneumonia in the area of valves (2 patients) at 9 and 12 months, and nonresponders who requested removal (3 patients) at 3, 5, and 8 months. Only 1 valve in a patient electing LVRS was not removed (1/48 [2%] valves) because of inadequate visualization and difficult access. Several more valves were difficult to visualize because of hyperplastic tissue, but these were removed with the aid of fluoroscopy.

On the basis of the judgment of the investigator and adjudication by the clinical events committee, no adverse events were definitely attributed to the valves. There were 6 events in 5 (17%) patients judged probably related and 20 events in 12 (40%) patients judged possibly related to the device. Fifty events were judged definitely not or probably not related. There were no unanticipated serious adverse events. Two patients experienced 5 anticipated serious adverse events, 3 events in the patient described above and pneumonia and a COPD exacerbation (at 22 and 53 days) that each required hospitalization in another patient. Specifically, valve erosion, migration, severe hemoptysis, and death did not occur. Device-, procedure-, or anesthesia-related events did occur in up to 9% of the procedures (Table 2). The most frequent event was cardiovascular, with a combination of arrhythmias, hypotension, or hypertension. Table 2 shows the occurrence of events on the procedure day and until discharge (periprocedure), after discharge and before 30 days, and from 30 days to 6 months after the initial procedure.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion Appendix 1 References

Within 3 to 4 years after the reintroduction of LVRS, several investigators proposed a variety of bronchoscopic techniques to treat patients with emphysema and COPD.^16-22 Some of the pilot studies of segmental airway obstruction with 1-way endobronchial valves have been able to show improvement in FEV₁, exercise capacity, or quality of life, although the patient numbers are small, and the results are variable. Endobronchial valve placement has been well tolerated, with complications of pneumothorax in 15% to 25% and few reports of bronchospasm or obstructive pneumonia. Reported in-hospital length of stay for the pilot endobronchial valve studies has been 6 to 10 days.^19-22

The IBV was designed as a 1-way valve to limit airflow into the distal bronchopulmonary segments in an effort to achieve lung volume reduction, reduction of dynamic hyperinflation, and other physiologic changes, with subsequent improved functioning, lessened dyspnea, and improved quality of life. The valve has been successfully removed in animal studies at periods ranging from a few days to 12 months.²³ This design benefit is important for initial safety and possible efficacy, allowing valves to be removed and repositioned for optimal effect and allowing valve removal for any early valve-related complications.

This pilot clinical trial is, to date, the largest published experience with bronchoscopic approaches to emphysema and the first with results beyond 3 months. Valve implantation was technically straightforward, with short procedure times even across multiple bronchoscopists and multiple clinical centers. In this initial clinical experience placement of valves was successful in all desired segments and subsegments. Valves were able to be easily adjusted, removed, or replaced at the initial and follow-up procedures. Although intended as permanent implants, valves were able to be removed up to 12 months after implantation. Early and late reversibility of the procedure has not been previously addressed in the endobronchial lung reduction literature but has important implications in the event of adverse events related to the valve or an elective decision to remove the valves if there is an absence of clinical benefit.

This clinical trial had a protocol-driven hospital stay of 2 postprocedure days and, later, 1 postprocedure day. Most patients were hospitalized only because of protocol requirements, with a median hospital stay of 3 days (90%), comparing favorably with earlier series with hospital stays 2 to 3 times as long. There were very few hospital or 30-day complications and no serious late valve-related complications, confirming a very high safety profile. Specifically, there were no instances of pneumothorax, obstructive pneumonia, intractable cough, or valve dislodgement in the first 6 months. Our clinical experience suggests that endobronchial treatment of emphysema with the valve can likely be performed as an outpatient procedure in the future because of the high degree of procedure safety and good patient tolerance. This is important from a public health and cost-effectiveness perspective. Surgical lung volume reduction, even in the most select subgroup with low exercise tolerance after rehabilitation and heterogeneous upper lobe disease, has an estimated cost of approximately $100,000 per quality-adjusted life-year, with much of this cost a result of the initial hospitalization.²⁴

The current trial was not designed to establish effectiveness, although data were collected to provide guidance for the design of a larger randomized pivotal trial. In this study valve placement did not produce significant changes in FEV₁, lung volume, alveolar gas exchange, or exercise capacity. In contrast, significant improvements were found in disease-specific quality of life, as measured by the SGRQ. One possible explanation is that these patients achieved a placebo effect as a benefit of having an intervention in a clinical trial. However, placebo effects on the SGRQ within a pharmacology trial showed an improvement of only 4 points,²⁵ and experts have suggested that placebo effects diminish over time. The mean improvement at 1 month in this series was greater than 8 points, and this was sustained at 6 months, which is suggestive of a true treatment effect not captured by the common spirometry, lung volume, alveolar gas exchange, or exercise measures.

Although the original goal of endobronchial therapies has been to mimic surgical lung reduction by promoting atelectasis in treated segments, the achievement of this goal has been sporadic in previous reports and was noted only a few times in this study (data not shown). Although atelectasis is achieved in animal studies, this appears harder to achieve in the setting of collateral ventilation in patients with end-stage emphysema. There are several possible mechanisms of action that might explain the improvement of patients in our series. Valve placement in the more severe segments might help to redirect ventilation to better-perfused segments and improve ventilation-perfusion matching and symptoms without seeing an obvious spirometric or lung volume effect. The other mechanism of improvement can be seen only with exercise because of a possible treatment effect on dynamic hyperinflation.²⁶ During exercise, increased respiratory rate can lead to increased air trapping, particularly in areas with worse emphysema and high compliance, ultimately increasing lung volumes and worsening exercise tolerance and dyspnea. Endobronchial occlusion might help to mitigate dynamic hyperinflation during exercise and improve symptoms without showing improvements in resting pulmonary function.

The patient’s primary motives for seeking palliative therapies for end-stage emphysema are to improve symptoms, functioning, and health-related quality of life.²⁷ This study showed overall improvement in disease-specific quality of life, whereas only a subset of patients showed improvement in lung function or exercise capacity. In addition to seeing improvements in health-related quality of life, investigators wish to see improvement in more objective measures, such as FEV₁ and exercise capacity, which might or might not function as surrogates for quality of life.²⁷ Two recent randomized controlled trials of LVRS have focused on a quality-of-life end point as a primary outcome.^10,11 Targeted endobronchial occlusion of upper lobe segments in patients with emphysema can be achieved with very high success and low morbidity and might provide palliation of symptoms for some patients. Endobronchial therapies for emphysema can create treatment options for patients not currently considered candidates for LVRS and might offer less morbidity and more acceptability for LVRS candidates. Further studies need to concentrate on quality of life as the fundamental end point and try to establish the important mechanisms of improvement.

	Appendix 1

Top Abstract Introduction Materials and Methods Results Discussion Appendix 1 References

 
Spiration research group: Cedars-Sinai Medical Center, Los Angeles, Calif: R. McKenna, W. Houck, D. Kusuanco; Cleveland Clinic Foundation, Cleveland, Ohio: A. Mehta, T. Gildea, S. Murthy, Y. Meli; North Shore University Hospital–Long Island Jewish Health System, Manhasset, NY: D. Ost, A. Talwar, E. Figueredo; University of Pennsylvania Medical Center, Philadelphia, Pa: D. Sterman, A. Musani, M. Machuzak, A. Haas, B. Finkel; University of Washington Medical Center, Seattle, Wash: D. Wood, M. Mulligan, K. Seymour.

Data Safety Monitoring Board: Gordon Snider (Chairman), Bartolome Celli, Jamie Stoller, and Satoshi Furukawa.

Clinical Events Committee: Roger D. Yusen (Chairman), Matthew Brenner, and Stephen D. Cassivi.

	Acknowledgments

 
We thank Yi-Jing Duh, PhD, for statistical computations; Bill Sirokman for data compilation; and Vickii Wyttenbach for manuscript preparation assistance.

	Footnotes

 
The members of the Spiration research group are listed in Appendix 1.

This clinical trial was sponsored and funded by Spiration, Inc, Redmond, Wash, the manufacturer of the intrabronchial valve tested. Xavier Gonzalez and Steven Springmeyer are Spiration employees and report stock ownership in Spiration. Atul Mehta reports lecture fees from Alveolus. Daniel Sterman reports consulting fees from Spiration and Alveolus. Douglas Wood reports consulting fees and grant support from Spiration. Roger Yusen reports consulting fees from Spiration.

	References

Top Abstract Introduction Materials and Methods Results Discussion Appendix 1 References

 

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