Design of the Endobronchial Valve for Emphysema Palliation Trial (VENT): a non-surgical method of lung volume reduction
- Charlie Strange†1Email author,
- Felix JF Herth†2,
- Kevin L Kovitz†3,
- Geoffrey McLennan†4,
- Armin Ernst†5,
- Jonathan Goldin†6,
- Marc Noppen†7,
- Gerard J Criner†8,
- Frank C Sciurba†9 and
- the VENT Study Group10
© Strange et al; licensee BioMed Central Ltd. 2007
Received: 07 December 2006
Accepted: 03 July 2007
Published: 03 July 2007
Lung volume reduction surgery is effective at improving lung function, quality of life, and mortality in carefully selected individuals with advanced emphysema. Recently, less invasive bronchoscopic approaches have been designed to utilize these principles while avoiding the associated perioperative risks. The Endobronchial Valve for Emphysema PalliatioN Trial (VENT) posits that occlusion of a single pulmonary lobe through bronchoscopically placed Zephyr® endobronchial valves will effect significant improvements in lung function and exercise tolerance with an acceptable risk profile in advanced emphysema.
The trial design posted on Clinical trials.gov, on August 10, 2005 proposed an enrollment of 270 subjects. Inclusion criteria included: diagnosis of emphysema with forced expiratory volume in one second (FEV1) < 45% of predicted, hyperinflation (total lung capacity measured by body plethysmography > 100%; residual volume > 150% predicted), and heterogeneous emphysema defined using a quantitative chest computed tomography algorithm. Following standardized pulmonary rehabilitation, patients were randomized 2:1 to receive unilateral lobar placement of endobronchial valves plus optimal medical management or optimal medical management alone. The co-primary endpoint was the mean percent change in FEV1 and six minute walk distance at 180 days. Secondary end-points included mean percent change in St. George's Respiratory Questionnaire score and the mean absolute changes in the maximal work load measured by cycle ergometry, dyspnea (mMRC) score, and total oxygen use per day. Per patient response rates in clinically significant improvement/maintenance of FEV1 and six minute walk distance and technical success rates of valve placement were recorded. Apriori response predictors based on quantitative CT and lung physiology were defined.
If endobronchial valves improve FEV1 and health status with an acceptable safety profile in advanced emphysema, they would offer a novel intervention for this progressive and debilitating disease.
In this paper we describe the design of the Endobronchial Valve for Emphysema Palliation Trial (VENT). The primary objective of this study is to evaluate patients with heterogeneous emphysema treated with optimal medical management including pulmonary rehabilitation with or without implantation of the Emphasys (Emphasys Medical, Inc., Redwood City, CA) Endobronchial Valve (EBV).
Emphysema affects approximately 1.8% of the global population. The disease is characterized by the gradual, irreversible breakdown of tissue and loss of elastic recoil within the lungs, leading to a reduction in expiratory airflow. As this disease progresses, the diseased, hyper-inflated regions of the lung continue to expand, imposing on the effective volume for more viable lung tissue to expand. As a result of these abnormalities in lung mechanics producing static and dynamic hyperinflation, patients exhibit a progressive increase in dyspnea, and reductions in exercise tolerance and quality of life.
Standard medical treatments for emphysema, which include smoking cessation, bronchodilators, pulmonary rehabilitation programs, and long-term home oxygen therapy, are aimed at providing improved exercise capacity and quality of life.
Surgical treatments for emphysema include single or double lung transplantation, lung volume reduction surgery (LVRS), and bulla resection. Transplantation is greatly limited by the small number of available donor organs and may not prolong survival. Lung volume reduction surgery, where the most diseased and hyper-inflated lung tissue is surgically resected, has been shown to offer relief to some subsets of patients with advanced emphysema when other treatment options have failed [2–6]. The National Emphysema Treatment Trial (NETT) randomized 1,218 patients with advanced emphysema to either bilateral LVRS or standard medical therapy. In NETT, patients with bilateral, predominantly upper-lobe disease demonstrated sustained improvements in lung function, exercise tolerance and quality of life as compared to medical therapy alone. Moreover in the subgroup with upper lobe disease and low exercise performance post rehabilitation, a greater than 50% reduction in two year mortality following LVRS was demonstrated. Bulla resection is reserved for symptomatic emphysema patients presenting with a giant bulla which occupies more than 50% of the volume of a hemithorax.
The paradoxical effect of improving lung function by removing substantial amounts of diseased lung tissue suggests that breathlessness due to emphysema is a function of mechanical inefficiencies imposed by marked elevations in end-expiratory lung volume. Researchers have speculated that less invasive bronchoscopic approaches can utilize these principles of isolating and deflating the diseased, hyper-inflated regions to improve lung function and symptoms while avoiding the risks associated with LVRS.
Rationale for VENT
Non-controlled pilot studies using similar or earlier generation devices have been reported, showing improvement in lung function in short term follow-up evaluations (1–3 months after EBV implantation). Reported complication rates were favorable with respect to LVRS although pneumothorax incidence was 6.1% at 90 days.
VENT is the first prospective, randomized, multi-center trial to study endobronchial valves. The primary objective of VENT is to assess the safety and efficacy of EBV implantation combined with pulmonary rehabilitation, compared to optimal medical management with pulmonary rehabilitation, in patients with heterogeneous emphysema. Additionally, the study is intended to identify patient characteristics or other procedural covariates that may affect the outcome of EBV placement and to shed further light on EBV mechanisms of improvement.
VENT is a two-arm, randomized, controlled, multi-center trial designed to study the safety and efficacy of the EBV implantation procedure, and the ability of the EBV to produce sustained improvement of symptoms in emphysema. The study sample size was a minimum of 270 subjects with heterogeneous emphysema, with randomization at a ratio of 2 to 1 (i.e., two patients were randomized to the study device treatment arm for every one randomized to the control group).
Given the similarity in intended treatment effect between LVRS and EBV implantation, combined with a goal of allowing easy comparisons between the results of the NETT and VENT, the VENT design largely followed that of the NETT. The inclusion/exclusion criteria were similar and both studies required pulmonary rehabilitation prior to randomization in order to maximize function prior to intervention. Both studies allowed treatment of the upper or lower lobes based on CT analysis; however, the NETT required bilateral (left and right lung) treatment whereas VENT treatments were unilateral only. Patient randomization in VENT was stratified per the subgroups identified in the NETT according to lung treatment region (upper versus lower) and post rehabilitation pre-treatment exercise capacity (low versus high).
In addition, the VENT study design conformed to the consensus recommendations of an independent panel of physician specialists convened by the U.S. Food and Drug Administration in February of 2003 to provide study design input for emerging bronchoscopic treatments for emphysema. Questions considered at the panel included appropriate control groups, safety assessment, appropriate outcome metrics, and length of follow up.
A double-blinded sham controlled study design was considered for VENT, but was determined to be unsuitable for a number of reasons. Since the implants are radiopaque, it would be difficult to maintain the blind. Post-procedure chest x-rays are mandated by the protocol and are often clinically indicated along with CT scans during the management of the patient during the follow up period. For example, COPD exacerbations, a frequent occurrence in patients of this severity, are often seen with radiographs in the local emergency room. Maintaining the blind from emergency room physicians and radiologists would be problematic. Bronchoscopy during the follow up period would also un-mask the treatment arm. A patient may cough up a valve after implantation, thereby breaking the blind. Additionally, treatment decisions may differ based on the presence of an implant, forcing primary caregivers to unblind study subjects for evaluation and management of adverse events. Even if sham bronchoscopies were performed, patient recall of bronchoscopy procedures during moderate sedation is present in many cases. A sham procedure becomes less important as more objective effort-independent lung function parameters are included in the comparative analysis (e.g., residual volume measurements). Lastly, performing an unnecessary sham bronchoscopic implant in control patients with no chance of benefit, given their fragile health status, was considered to carry unacceptable risk.
A Clinical Events Committee (CEC) consisting of two pulmonologists and two thoracic surgeons adjudicates all reported complications. The CEC characterizes the severity of each reported event (mild, moderate, severe) and determines whether the event is related to the endobronchial valve or procedure (not related, remote possibility, possible, probable, unknown). Adjudicated complications are summarized and presented to an independent Data and Safety Monitoring Board (DSMB) consisting of two pulmonologists, two thoracic surgeons, and a biostatistician. The DSMB establishes pre-defined safety stopping rules and meets regularly to determine whether the study safety profile warrants continuation of the study.
Primary outcome measures
The co-primary effectiveness endpoints are the mean percent change in both forced expiratory volume in one second (FEV1) and distance traveled in the six minute walk test (6 MWT) in the treatment group (EBV implantation) as compared to the control group (optimal medical management) at 180 days after randomization. The primary safety endpoint is a comparison of major complications between the two groups over the initial follow-up period of 180 days. Additionally, patients will be followed for up to 3 years post randomization for long term safety assessment.
Secondary outcome measures
Co-primary efficacy endpoints
Mean % change in FEV1 and 6 MWT in the treatment group as compared to control group at 180 days post randomization.
Primary safety endpoint
Major Complications Composite at 180 days post randomization.
Secondary efficacy endpoints
Mean absolute change in:
- St. George's Respiratory Questionnaire
- Maximal work load as measured by cycle ergometry
- Daily oxygen requirement
Secondary safety endpoints
Complications (type, timing, and severity, including Kaplan-Meier survival analysis)
Device-related adverse events during procedure hospitalization
Device-related adverse events post discharge
Study sites were encouraged to advertise for local recruitment, and web-links to study information were provided to relevant organizations (e.g.: the American Lung Association and the National Emphysema Foundation). Additionally, enrolling physicians were given written study information and a slide presentation for referring physicians in their area.
Patients identified as potential participants were provided detailed explanations of the study and were asked for informed consent prior to initial screening. The patient consent form was approved by the Institutional Review Board (IRB) of all study sites, and failure to provide informed consent rendered the patient ineligible for the study.
Screening assessments and high resolution computed tomography (HRCT)
Screening and eligibility procedures
Patient referred to study physician
Patient consent obtained
Screening Assessment 1: medical history, supplemental oxygen use and physical exam
Determine if patient meets eligibility criteria
Screening Assessment 2: electrocardiogram, spirometry, plethysmography, DLco, 6 MWT, Computed Tomography Scan, PaO2, PaCO2, arterial saturation, continine level, alpha-1 antitrypsin concentration
Determine if patient continues to meet eligibility criteria
Patient enters and completes pulmonary rehabilitation program
Baseline measurements taken: medications, supplemental oxygen use, physical exam, electrocardiogram, spirometry, plethysmography, DLco, 6 MWT, cycle ergometry, quality of life surveys, chest x-ray, ventilation/perfusion (V/Q) scan, PaO2, PaCO2, arterial saturation, blood electrolytes, liver profile, renal profile, CBC, pregnancy test (where appropriate), and continine level
Final determination of patient eligibility
Randomization to Control or Treatment arm of the VENT study.
The standardized volume acquisition CT was performed under the auspices of the imaging core at the David Geffen School of Medicine at UCLA. All images were acquired on multi-detector scanner platforms whose acquisition parameters were standardized to ensure similar image noise characteristics. Two sequences were acquired supine at suspended TLC and at RV, each in a single breathhold. The two sequences were reconstructed in both thick (5 or 10 mm) and thin (1.25 to 3 mm) series. Other sample acquisition parameters were customized for each site based on the scanner being utilized (e.g.: for the Siemens Sensation 16 scanner, the settings would be 120 kVp, 80 effective mAs, 0.5 sec. rotation time, 16 × 0.75 mm collimation, and 18 mm/rotation table feed with pitch 1.5).
VENT inclusion criteria
History and physical
Age from 40 to 75 years.
BMI ≤ 31.1 kg/m2 (men) or ≤ 32.3 kg/m2 (women).
Stable with < 20 mg prednisone (or equivalent) daily.
The patient has no child bearing potential OR a negative pregnancy test in a woman of childbearing potential.
Patient diagnosed by HRCT Core Lab with eligible heterogeneous emphysema.
FEV1 < 45% of predicted value.
TLC > 100% predicted.
RV > 150% predicted.
PaCO2 < 50 mm Hg (Denver < 55 mm Hg).
PaO2 > 45 mm Hg (Denver > 30 mm Hg) on room air.
Post rehabilitation 6-minute walk of ≥ 140 meters.
Nonsmoking for 4 months prior to initial interview and throughout screening.
Plasma continine level < 13.7 ng/ml (or arterial carboxyhemoglobin < 2.5% if using nicotine products).
Patient has provided written informed consent using a form that has been reviewed and approved by the IRB/EC.
Rehabilitation and follow-up
The patient is willing and able to complete protocol required baseline assessments and procedures.
The patient agrees to all protocol required follow-up intervals.
VENT exclusion criteria
An HRCT Emphysema Score of 4-4-4 in the right lung or 4-4 in the left lung.
Evidence of large bullae (encompassing >30% of either lung) in a non-target lobe.
FEV1 < 15% predicted value.
DLco < 20% predicted value.
Clinically significant bronchiectasis.
Pulmonary nodule requiring surgery.
History of recurrent respiratory infections (>1 hospitalization in the last year).
Clinically significant (> 4 tablespoons per day) sputum production.
Cardiovascular and exercise
Dysrhythmia that might pose a risk during exercise or training.
Congestive heart failure within 6 mo and LVEF < 45%.
Resting bradycardia (< 50 beats/min), frequent multifocal PVCs, complex ventricular arrhythmia, or sustained SVT.
Myocardial infarction within 6 mo and LVEF < 45%.
Clinical suspicion or proven history of pulmonary hypertension.
History of exercise-related syncope.
Patient is unable to complete 3 minutes of unloaded peddling on cycle ergometer.
Prior lung transplant, lung volume reduction surgery, median sternotomy, bullectomy or lobectomy.
Unplanned weight loss of >10% usual weight in 90 days prior to enrollment or total body weight < 70% of ideal body weight.
Alpha-1 antitrypsin deficiency.
Fever, elevated white cell count, or other evidence of active infection.
Evidence of systemic disease or neoplasia expected to compromise survival during 5-yr period.
Any disease or condition that interferes with completion of initial or follow-up assessments.
Patient is currently enrolled in another clinical trial or has been previously enrolled in the VENT Trial for which protocol required follow up is not complete.
In the NETT, all HRCT data was analyzed visually by study site radiologists, and the lung was analyzed by zones that represented 33% of each lung. Visual grading of lung destruction due to emphysema has been shown to be highly dependent on the radiologist performing the analysis, and to be much less consistent than quantitative computer analysis. The NETT study has subsequently applied computer based analysis to the HRCT scan data, although using the same lung zone convention that was establish for the radiologist reads. For this reason, automated computer analysis of the thick section CT scan data taken prior to randomization was used in VENT to determine patient eligibility for the study as well as to determine implant targeting for those patients in the treatment arm. The core radiology laboratory established CT scan acquisition quality standards to ensure that all scans, regardless of study site location, were taken under repeatable and consistent conditions. In addition, the core lab subdivided the lung into lobes and provided emphysema scoring on a lobar basis. Unlike the NETT study which used a zonal scoring system that did not correspond to lobar anatomy, the lobar scoring in VENT allowed targeting of the EBV implantation procedure to the most emphysematous lobe.
Lobar emphysema scoring
% of Parenchyma with Abnormalities Suggestive of Emphysema
VENT study treatments
Medical treatment and pulmonary rehabilitation
After preliminary determination of eligibility, all subjects received an optimal medical management program. Optimal medical therapy was defined, for the purposes of this protocol, as maximal medical treatment for stable chronic obstructive pulmonary disease (COPD) as presented in the 2001 National Institutes of Health/World Health Organization Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. As recommended in the GOLD standards, each patient enrolled in the study received therapy consisting of the following components: education and smoking cessation support, pharmacological treatments including bronchodilators and influenza and pneumococcal vaccinations, non-pharmacological treatment including a 6–8 week pulmonary rehabilitation program and oxygen therapy if needed.
Pulmonary rehabilitation was an essential component of the pre-randomization optimal medical management program. Pulmonary rehabilitation has been shown to significantly improve exercise capacity and quality of life in COPD. A pulmonary rehabilitation program was required for both control and treatment patients in the NETT study, and thus its inclusion in VENT allows more accurate comparisons between the results of both trials. Pulmonary rehabilitation prior to randomization was required in VENT to insure that any outcome differences between the treatment and control groups were due to the effect of the device rather than due to a training effect. It also minimized the chance for differences in health care exposure and treatment differences between randomly assigned treatment groups. Upon successful completion of the pulmonary rehabilitation program, a full baseline assessment was performed in each patient as outlined in table 2. If the patient continued to meet all protocol entry criteria shown in Tables 3 and 4, the patient was randomized to either the treatment or control group.
Once patients were randomized, the control group continued to receive optimal medical care at the participating center. Exercise continued at a minimum frequency of three times weekly. The control patients received the same follow-up as the treatment arm, including an office visit in lieu of EBV implantation. At the time of the control arm office visit, all patients were provided with a study diary to be used as a memory aid throughout the study duration.
The study group received the EBV implantation procedure within three weeks of randomization, and continued optimal medical management and exercise similar to the control group.
The goal of the implantation procedure was to completely isolate a single diseased lobe of the lungs by implanting EBV devices occluding all bronchial lumina leading to the targeted lobe. Bilateral treatment was not allowed in this study and acceptable target lobes did not include the right middle lobe. A single segmental airway not isolated by valves may allow ventilation to the lobe, thus reducing the potential benefit of the EBV devices. EBV devices were placed at the lobar, segmental, or sub segmental levels in this order of preference, depending on the anatomy of the patient noted at the time of the procedure.
The EBV implantation procedure was performed with the patient under general anesthesia and on a ventilator, or under moderate sedation with unassisted breathing. All patients were given antibiotics before and for 7 days following the procedure. Anesthesia was administered according to standard local protocols for bronchoscopy. For general anesthetic procedures, a rigid bronchoscope in conjunction with a flexible bronchoscope or a flexible bronchoscope alone through an endotracheal tube was allowed for valve placement.
Patients in both control and treatment arms were monitored for 1 year, with scheduled assessments at 1, 2–3, 7–10, 30, 90, 180, and 365 days post-procedure. Follow-up assessment includes the same variables as in the baseline assessment (see Table 2) with the primary outcome measures defined from the 180 ± 14 day follow-up visit.
The power analysis is based on a pilot study in 38 patients in which FEV1 improved 14.9% ± 33.7 (mean ± SD) and 6 MWT distance improved 20.4% ± 41.5%. The samples size required to detect a 15% improvement in the treatment arm in FEV1 and a 17% improvement in 6 MWT distance at an alpha of 0.05 and a power of 0.90 is a minimum of 270 subjects with a 2:1 randomization to EBV procedure. Both of these values are above the threshold for minimal clinically important differences for these tests[17–19].
The study is designed as a superiority trial. For the two primary outcomes, the study is only considered a success if both endpoints show an improvement (one-sided test at p < 0.025). A one-sided test is appropriate to test for superiority. The actual probability of a false positive is lower than 0.025 given the imperfect correlation of the two endpoints. If change in FEV1 and change in 6 MWT were independent, the probability of a false positive would be 0.025*0.025 = 0.000625. In the pilot study generating the null hypothesis, the correlation coefficient between the change in FEV1 and 6 MWT was 0.3889. Given this r, the alpha for achieving a positive outcome is actually 0.005 (0.025*0.025^(1/(1+0.3889))). This is an assurance of avoiding a false positive well beyond convention.
The 2:1 randomization is chosen to enhance enrollment and increase the EBV population numbers in order to study covariates of treatment response. Although the 2:1 randomization increases the number of subjects required for the study, more robust subgroup comparisons may be possible.
For safety the 95% upper confidence interval for the Major Complication Composite rate delta between the EBV arm and the control arm is ≤ 30%.
The primary analysis cohort is intent to treat. As such, all 180 day missing data will be imputed using either a regression methodology if 30 and 90 day data are present or hot-deck imputation if there are not multiple datapoints available for a particular subject for regression analysis. Three unbiased imputations will be performed and the imputation resulting in the highest p-values will be selected as the final intent to treat dataset.
Plethysmography, spirometry and HRCT derived baseline potential covariates*
HRCT at TLC
HRCT at RV
TLC and RV HRCT †
RV % Predicted
TLC % Predicted
FVC % Predicted
FEV1 % Predicted
Destruction Score of Target Lobe
Whole Lung Heterogeneity††
For RUL Treatment Subset only: RUL-RML Heterogeneity††
Target Lobe Volume % of TLC
Target Lobe Volume % of RV
Max Destruction Score other than target
Min Destruction Score other than target
Target Lobe Destruction Score % TLC-RV Delta
Target Lobe Volume % TLC-RV Delta
Other baseline and procedure potential covariates
DLCO % Predicted
Upper vs. Lower
Right vs. Left
Composite or other potential covariate interactions
Composite or Interactions
BMI, FEV1% predicted, MMRC, 6 MWT Composite Score
Randomization Stratification by Baseline Cycle Ergometry and HRCT at TLC
NETT Strata by Right vs. Left
Randomization Stratification by Baseline Cycle Ergometry and HRCT at TLC, by Right or Left Lung
Lobar Exclusion by Fissure Interaction*
Fissure Score = 3 AND Lobar Exclusion = Yes vs. all others
Lobar Exclusion, Fissure, and RV % Predicted*
Lobar Exclusion = Yes AND Fissure Score = 3 AND RV % Predicted ≥ 200% vs. all others
Lobar Exclusion, Fissure, and RV % Predicted*
Lobar Exclusion = Yes AND Fissure Score = 3 AND RV % Predicted ≥ 200% vs. all others
Large Valve by Right vs. Left*
Right vs. Left Lung AND Large Only vs. Others
Small Valve by Right vs. Left*
Right vs. Left Lung AND Small Only vs. Others
Expectorated Valve Replaced*
Valve(s) Expectorated AND Lobar Exclusion = Yes vs. all others
Expectorated Valve Not Replaced*
Valve(s) Expectorated AND Lobar Exclusion = No vs. all others
Lobar Exclusion by Site*
Technical Success by Site
First Case by Site*
First Treatment Case by Site vs. All Others
Learning Curve by Site*
Experience Level: Case 1, vs. 2 & 3, vs. 4–6, vs. 7–9, vs. ≥10 by site.
180 day follow-up CT potential covariate*
180 Day HRCT at TLC
Baseline and 180 Day HRCT at TLC
Baseline and 180 Day HRCT at RV
Target Lobe Atelectasis Score†
Lobar Exclusion†† (yes/no)
Covariate variable derivations
Residual Volume by Spirometry and Plethysmography (TLC - Max (FVC or VC))
Total Lung Capacity by Plethysmography
Vital Capacity by Plethysmography
Forced Vital Capacity by Spirometry
Forced Expiratory Volume in the First Second by Spirometry
RUL, RLL, LUL, or LLL
RUL Target vs. Others
Density Score by Lobe
Total Density Score
Sum of all Lobar Density Scores (including RML)
Ipsilateral DS Heterogeneity
Target - Max DS of Non-treated Lobes within Treated Lung [e.g.: RUL - Max(RML, RLL)]
Thorax DS Heterogeneity
Target DS - Max DS of All Non-treated Lobes [e.g.: RUL - MAX (RML, RLL, LUL, LLL)]
Target Lobe DS % Delta
(TLC HRCT - RV HRCT)/TLC HRCT Density Score of Target Lobe
Target Lobe Volume % Delta
(TLC HRCT Volume - RV HRCT)/TLC HRCT Volume of Target Lobe
Categorical Fissure Assessment Surrounding Target Lobe
1 = Absent
2 = Incomplete
3 = Complete
1 = Upper-Lobe Predominance, Low Baseline Exercise Capacity*
2 = Upper-Lobe Predominance, High Baseline Exercise Capacity
3 = Non-Upper-Lobe Predominance, Low Baseline Exercise Capacity
4 = Non-Upper-Lobe Predominance, High Baseline Exercise Capacity
Target Lobe Atelectasis Scores
% change in Target Lobe Volume at TLC and at RV between Baseline and 180-day HRCT
Yes, If all bronchial pathways to target lobe are sealed by valve(s) – adjudicated by HRCT Core Lab
1. Small ONLY
2. Small AND Large
3. Large Only
Any procedure with Only Large Valves vs. all others
Any procedure with Only Small Valves vs. all others
Thirty, 90, and 365 day results will also be collected and reported. Post hoc analysis will use these datapoints to define the speed of treatment success if present.
Bronchoscopic lung volume reduction holds the promise of improving outcomes for carefully selected individuals with lung hyperinflation from heterogeneous emphysema. Pilot studies have been performed in small numbers of patients that demonstrate improvements in FEV1 and exercise tolerance [4, 21–24].
The current trial serves dual purposes. The first was to treat enough of the hyper-inflated lung to achieve a statistically significant improvement in physiology and symptoms. While there is certainly limitation to the amount of lung that can be safely treated without suffering hypoventilation or respiratory failure, the optimal amount of lung that can be safely targeted remains unknown. An analysis of pilot studies has suggested that a single lobar treatment strategy may be a reasonable goal for obtaining meaningful physiologic improvements in some patients. However, the outcome of this study is not expected to achieve the same physiologic outcomes that might be obtained by LVRS that targets 20–30% of both lungs during a single operative procedure.
The second goal was to carefully evaluate the safety of the EBV procedure and post procedural course. Pilot studies have documented a high frequency of pneumothorax following the procedure. Whether this represents pleural disruption by valve placement, rupture of residual blebs subsequent to stress relaxation in non-treated segments or a delay in lung remodeling following significant atelectasis of targeted lung remains unknown. Some clues to the pathogenesis will be obtained by an observation strategy imbedded in the protocol. Treatment of pneumothorax with a thoracostomy tube will be reserved for pneumothoraces that enlarge or cause respiratory failure.
COPD outcome is heavily influenced by exacerbation frequency. Since EBV valves are foreign bodies in an airway that may have some baseline hyper-responsiveness, the frequency and severity of exacerbations and the frequency of post-obstructive pneumonia are important safety considerations that warrant a long follow-up time.
Advanced emphysema is characterized by destruction of lung parenchyma and augmentation of anatomic connections for air passage between adjacent lung lobules. Unfortunately for endobronchial lung volume reduction procedures, these collateral communications may traverse lobar fissures . These peripheral communications between lobes then may allow for continued lobar ventilation despite completely occluded lobar airways. Because this collateral ventilation is not easily quantified by current detection methods, the outcome of EBV valve placement may be heterogeneous. Ultimately, secondary analyses will include responder analysis, in order to determine the proportion of patients with clinically meaningful responses.
Given the complex mechanical and gas exchange consequences of valve insertion, it is possible that the magnitude of volume reduction in a lobe may not be associated with changes in other meaningful physiologic or functional indices following the procedure. For example, the impact of valve placement on symptoms associated with dynamic hyperinflation or variations in gas exchange utilizing collateral channels may be associated with clinical improvements independent of changes in conventional resting pulmonary tests. The composite primary endpoint was chosen to include a functional exercise measure to capture such changes.
Ultimately, the future of the EBV valve will be determined by the balance between efficacy and safety. Since the valves are removable for mild or moderate adverse events, valve safety will be impacted by the frequency of severe adverse events that might affect survival in a compromised patient population. In fact, individuals who demonstrate improvements in lung function may also demonstrate an increase in exacerbation frequency. For this reason, quality of life indices including the Quality of Well Being Scale and the Saint George's Respiratory Questionnaire are considered integrative parameters which can determine the balanced impact of the intervention [26, 27]. One strategy to minimize overall adverse response would be to remove valves earlier in the patients who do not have clinically important responses. If a meaningful outcome is measurable in the first few days after the procedure, future alternative targeting strategies might be employed to determine response at earlier times after randomization.
One limitation of this study is the difficulty in performing a double-blind sham procedure study for reasons discussed earlier. As such, a potential placebo effect could influence the quality of life and exercise measurements. From the investigator's perspective the frequency of adverse events attributable to the valve will obviously be different for the control and valve cohorts. Common but potentially serious adverse events such as exacerbation frequency may be interpreted differently given the knowledge of treatment assignment. Despite attempts to standardize insertion protocol, there remains considerable variability related to delivery of general or moderate sedation anesthesia that could affect procedure time and possibly outcome. Finally, the rigid inclusion criteria and targeting algorithms utilized in this trial limit the discovery of other potentially effective emphysema treatment strategies. Given the many subtypes of emphysema, the outcome of this study may not generalize to all individuals with the disease.
The VENT study evaluates the effectiveness of endobronchial valve placement to reduce lung volume in emphysematous patients as compared to optimal medical management. Due to the similarities between this study and the NETT study of lung volume reduction surgery, efficacy and safety comparisons to those achievable with LVRS are anticipated.
We thank John McCutcheon and Tony Fields who provided medical writing services on behalf of Emphasys Medical, Inc. The VENT Study Group are listed in Additional File 1.
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