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The study was sponsored by PneumRx Inc, Mountain View, CA. The authors serve as advisors to the company and were reimbursed for study related travel expenses. None of the authors has a financial interest in the company. All authors had complete access to the data, reviewed and approved the manuscript. PneumRx was not involved in the draft of the manuscript, except the right to review the manuscript in its' final form regarding publication of proprietary information. No information was deleted.
Lung Volume Reduction Surgery (LVRS), which reduces hyperinflation by selective resection of severely damaged lung tissue, is an established palliative treatment for severe emphysema (Fishman). Lung volume reduction surgery can improve pulmonary function, walking distance and quality of life. Additionally, in a subset of patients LVRS has been shown to reduce mortality. Unfortunately, LVRS is also associated with high cost and substantial morbidity and mortality (Decamp and Decamp) and therefore, despite its demonstrated benefits, LVRS is uncommonly performed in the USA as per Medicare data.
Over the last decade, less invasive, bronchscopy based technologies have been developed with the goal to achieve the benefits of lung volume reduction in a less morbid way. One example is the development of one-way valves intended to be implanted in the airways that lead to the most damaged parenchyma (Hopkinson, 2007). The rationale behind this approach was to cause atelectasis in the affected region, thereby reducing its volume, as well as to restrict airflow into these damaged regions, resulting in a re-direction of airflow into less damaged regions of the lung where ventilation and perfusion are more normal. Success of some of these devices has been limited by collateral ventilation, which can bypass the device and reduce its effect (Add: Hopkinson NS, Toma TP, Hansell DM, Goldstraw P, Moxham J, Geddes DM, Polkey MI. Effect of bronchoscopic lung volume reduction on dynamic hyperinflation and
exercise in emphysema. Am J Respir Crit Care Med. 2005 Mar 1;171(5):453-60.) . A large clinical trial (ref FDA Panel) has shown one type of valve (Zephyr, Emphasys Medical, Redwood City, CA) to be most effective in a subset of patients with high heterogeneity and/or complete fissures where collateral flow would be expected to be minimal.
The current pilot study was undertaken to determine primarily the safety and secondarily the feasibility of bronchoscopic lung volume reduction using a lung volume reduction coil (LVRC) in patients with stage 3 or 4 emphysema (GOLD classification). Since the LVRC reduces lung volume by a simple mechanical means, its effect should be independent of the presence or absence of collateral flow.
Patient Selection Criteria
Patients with GOLD stage 3 or 4 were eligible to be enrolled into this pilot trial. Details of the inclusion and exclusion criteria are listed in table 1. Patients with homogenous as well as heterogeneous emphysema were eligible. Leading inclusion criteria were a post-bronchodilator FEV1 < 45% predicted, TLC > 100% predicted, and marked dyspnea with an mMRC score >2. Patients were excluded if they had giant bullae > 1/3 of lung volume, 6-minute walk distance < 140 m, or if they had previous lung volume reduction surgery or lung transplantation.
The study was approved by the Institutional Review Board and all patients signed an approved informed consent form.
Bronchial LVR Coil Implants and Procedure Description
The Lung Volume Reduction Coils (PneumRx, Inc., Mountain View, CA) are made from Nitinol wire that has been pre-formed to a shape that results in parenchymal compression after deployment (Figure 1). The device is made in a range of lengths to accommodate different sized airways.
The coils are implanted bronchoscopically using a proprietary delivery system. First, the airway in the selected segment is identified bronchoscopically and a low stiffness guidewire is advanced into the airway under fluoroscopic guidance. A catheter is passed over the guidewire and the length of the airway is measured using radio-opaque markers on the guidewire. The guidewire is then removed and a straightened LVRC is introduced into the distal end of the catheter with a grasper under fluoroscopic guidance. Next, the catheter is removed while the proximal end of the LVRC is held in place. As the catheter is pulled back the LVRC assumes its pre-formed shape, bending the airway and attached parenchyma with it. Finally, the LVRC is released from the grasper and the bronchoscope and grasper are removed. The coil is removed or repositioned by reversing the implantation process.
The basic bronchoscopic procedure was performed as per standard hospital practice. General anesthesia was induced and rigid bronchoscopy performed. The location of coil placement was determined as by the most severely affected lobe as visualized by CT scan. Three to six LVRCs were implanted through a flexible bronchoscope using the procedure described above. Following recovery from anesthesia patients stayed in the hospital for 3 days for observation.
All periprocedural and in- house events were charted. Patients were contacted by telephone 7 days after treatment and asked about their general health and adverse events using a list of specific questions. At 1 and 3 months post-treatment, patients returned to the clinic for follow-up visits, which included physical examination, spirometry, plethysmography, 6 minute walk test, modified MRC dyspnea questionnaire, and St. George's Respiratory Questionnaire. At the physician's discretion the patient could have a second LVRC treatment, with similar follow-up at 1 week, 1 month, and 3 months. Following the final 3-month visit patients were exited from the study.
The primary endpoint was safety and was measured by analysis of adverse events. Patients were actively queried at each telephone call and follow-up visit about adverse events that occurred between visits. Each adverse event was categorized by severity (mild, moderate, severe) and relatedness to device or procedure (probably related, possibly related, not related) by the treating physician.
Secondary endpoints included change from baseline in spirometry (FEV1, FVC), lung volumes (RV, RV/TLC), 6 minute walk test, mMRC dyspnea scale, and total SGRQ score. Spirometry, plethysmography, and 6 minute walk tests were administered in accordance with ERS standards.
This was a pilot study and was not powered to measure any statistical differences in endpoints. Descriptive statistics were used to summarize changes in quantitative variables.
Eleven patients were enrolled between January 2008 and March 2009. Of these, 10 received a second treatment. Implants for second treatments were placed in the contralateral lung in 6 patients and in the same lung as the first treatment in 4 patients. The time periods between the final follow up visit at 3 months after the first treatment and the retreatment ranged from 1 to 5 months. Summaries of demographics and baseline characteristics are presented in Tables 2 and 3. Due to the sequential treatments and operator discretion, all patients had a total follow up time of at least 7 up to 11 months.
The procedure was feasible and well tolerated in all patients. The average procedure time from introduction of the endoscope to removal of the scope was 40 + 15 minutes with a range of 20 - 75 minutes. The number of coils implanted per bronchoscopic session was 4.9 + 0.6, with a range of 3 - 6 coils (Table 4).
A total of 33 adverse events were reported in 11 patients (Table 5). Of these, 36% (12/33) were mild, 64% (21/33) were moderate and none were severe. Forty-two percent (14/33) of adverse events were deemed to be "not related" to the device or procedure and 58% (19/33) were "possibly related" to the device or procedure. None were deemed probably related to the device or procedure. Adverse events rated as possibly related to either the procedure or the device were dyspnea (10 events), cough (5 events), COPD exacerbation (3 events) and chest pain (1 event).
Changes in Effectiveness Measures
The effectiveness data are summarized in Table 6 below.
Emphysema continues to be an epidemic and medical treatment options, albeit plenty, continue to have limited efficacy, especially in end-stage disease. The search for additional modalities that afford symptom relief and eventually would confer a survival benefit is ongoing. Surgical lung volume reduction had raised hopes for many, especially since in a subgroup of patients morbidity can be reduced and a survival benefit over best medical management was demonstrated. Unfortunately the associated surgical morbidity and mortality has lead to poor acceptance in the medical community and amongst patients.
Endoscopic attempts at lung volume reduction have tried to duplicate the effects of lung volume reduction without incurring the surgical risks. Most reports involve the use of one- way valves with the goal of lobar airway occlusion and resulting lobar collapse (Wan, Yim Venuta). Unfortunately only a minority of patients experience atelectasis. It is speculated that the lack of response is probably due to collateral ventilation, which exists in many patients with emphysema (Cetti, Macklem, Higuchi, Hopkinson NS, Toma TP, Hansell DM, Goldstraw P, Moxham J, Geddes DM, Polkey MI. Effect of bronchoscopic lung volume reduction on dynamic hyperinflation and exercise in emphysema. Am J Respir Crit Care Med. 2005 Mar 1;171(5):453-60.).
The described LVRC approach would not be dependant on the lack of collateral ventilation for a positive effect and this pilot study demonstrates the feasibility and safety of the LVRC procedure, when applied to a group of patients with severe emphysema. There were no severe adverse events recorded during the 3 months following the last treatment. Adverse events that were observed were successfully treated with standard medical treatment.
Although this study was neither intended nor powered to analyze effectiveness some interesting trends have emerged. Although the mean changes over all patients in effectiveness endpoints were small, the group with predominantly heterogeneous disease appeared to show substantial improvements in pulmonary function, lung volumes, 6 minute walk tests and quality of life measures.
Subset analysis from the present study as well as the Emphasys pivotal study suggests that less invasive LVR procedures may be most effective in substantial subsets of patients with heterogeneous disease. Because the outcomes of these procedures may be related to the distribution of emphysematous damage within the lung, the development of patient selection tools, such as quantitative CT analysis, may be helpful to the development of new technologies for the less invasive treatment of emphysema (add: Revel MP, Faivre JB, Remy-Jardin M, Deken V, Duhamel A, Marquette CH, Tacelli N, Bakai AM, Remy J. Automated lobar quantification of emphysema in patients with severe COPD. Eur Radiol. 2008 Dec;18(12):2723-30.).
In summary, endoscopic lung volume reduction with coils seems well tolerated and feasible. Its effect should be independent of collateral ventilation and our study indicates that patients with heterogeneous emphysema may experience more pronounced benefits. Further studies addressing the efficacy, patient selection and safety of this device are warranted.