1. Aetna considers lung volume reduction surgery (LVRS) medically necessary for members who meet the selection criteria outlined below.  The standards for pre-operative assessment and criteria for surgery have been evolving and have varied from institution to institution.  There is medical consensus that the candidate for LVRS should have severe emphysema, disabling dyspnea, and evidence of severe air trapping.

   The selection criteria, which are based on the results of the National Emphysema Treatment Trial, are as follows:

   1. For members with cardiac ejection fraction less than 45 %, there is no history of congestive heart failure or myocardial infarction within 6 months of consideration for surgery; and
   2. The member has a history and physical examination consistent with emphysema; and
   3. The member has not smoked for 4 or more months; and

   4. The member has all of the following on pre-operative work-up:

      1. CT scan evidence of bilateral emphysema; and
      2. Forced expiratory volume in 1 second (FEV1) (maximum of pre- and post-bronchodilator values) less than or equal to 45 % of predicted and, if aged 70 year or older, FEV1 15 % of predicted or more; and
      3. Plasma cotinine less than or equal to 13.7 ng/ml (if not using nicotine products) or carboxyhemoglobin less than or equal to 2.5 % (if using nicotine products); and
      4. Post-bronchodilator total lung capacity (TLC) greater than or equal to 100 % of the predicted value and residual volume (RV) greater than or equal to 150 % of predicted value; and
      5. Resting partial pressure of carbon dioxide (PaCO2) less than or equal to 60 mm Hg on room air; and
      6. Resting partial pressure of oxygen (PaO2) 45 mm Hg or greater; and

      7. Six-minute walk test greater than 140 meters

   5. Lung volume reduction surgery is considered experimental and investigational if the member has either of the following contraindications:

      1. Post-bronchodilator FEV1 is 20 % or less than its predicted value and member has either

         1. a carbon monoxide diffusion capacity (DLCO) is 20 % or less than its predicted value.  (Persons in this category have been found to be at high risk for death after LVRS, with little chance of functional benefit); or

         2. a homogenous distribution of emphysema on CT scan

      2. Members with predominantly non-upper lobe emphysema and a high maximal work-load.  

         1. For purposes of this policy, a high maximal workload is defined as a maximal workload (on cycle ergometry with an increment of 5 or 10 W/min after 3 mins of pedaling with the ergometer set at 0 W and the person breathing 30 % oxygen) above the sex-specific 40th percentile (25 W for women, 40 W for men).

         2. For purposes of this policy, predominantly non-upper lobe predominance of emphysema is defined to exclude disease on CT that is judged by the radiologist as affecting primarily the upper lobes of the lung, and to include disease that is judged to be predominantly lower lobe, diffuse, or predominantly affecting the superior segments of the lower lobes.

         (Note: Persons with predominantly non-upper-lobe emphysema and a high maximal work-load have been found to have higher mortality from LVRS than from medical therapy alone, and have been found to have little chance of functional improvement regardless of the treatment they receive).

   6. The member should have none of the following exclusion criteria:

      1. Alpha-1 antitrypsin deficiency
      2. Clinically significant bronchiectasis
      3. Evidence of systemic disease or neoplasia that is expected to compromise survival
      4. Giant bulla (greater than 1/3 the volume of the lung in which the bulla is located)
      5. History of recurrent infections with clinically significant production of sputum
      6. Oxygen requirement greater than 6 L/min during resting to keep oxygen saturation greater than or equal to 90 %
      7. Pleural or interstitial disease which precludes surgery
      8. Previous lobectomy
      9. Previous LVRS (laser or excision)
      10. Pulmonary hypertension, defined as mean pulmonary artery pressure of 35 mm Hg or greater on right heart catheterization or peak systolic pulmonary artery pressure of 45 mm Hg or greater.  (Right heart catheterization is required to rule out pulmonary hypertension if peak systolic pulmonary artery pressure is greater than 45 mm Hg on echocardiogram)
      11. Pulmonary nodule requiring surgery
      12. Resting bradycardia (less than 50 beats/min), frequent multifocal premature ventricular contractions (PVCs), of complex ventricular arrhythmia or sustained supraventricular tachycardia (SVT)
      13. Uncontrolled hypertension (systolic greater than 200 mm Hg or diastolic greater than 110 mm Hg)
      14. Unplanned weight loss greater than 10 % within 3 months prior to consideration for surgery.

   Aetna considers lung volume reduction surgery experimental and investigational for all other indications because its effectiveness for indications other than the ones listed above has not been established.

2. Aetna considers bullectomy medically necessary for the treatment of dyspneic members with giant bulbous emphysema when they have a single large bulla producing significant respiratory compromise (FEV1 of less than 50 % predicted). 

   Aetna considers bullectomy experimental and investigational for all other indications because its effectiveness for indications other than the one listed above has not been established.

3. Aetna considers thoracoscopic laser bullectomy experimental and investigational in the treatment of members with emphysematous lung disease because the benefit of this procedure has not been conclusively demonstrated.  Furthermore, outcomes of thoracoscopic laser surgery for persons with diffuse disease need to be compared with current non-laser surgical techniques and medical therapy.  Additionally, the long-term benefits of this surgery, including decreased symptoms and improved pulmonary function compared to persons without surgical intervention, need to be demonstrated.

4. Aetna considers bronchoscopic lung volume reduction procedures experimental and investigational because of insufficient evidence of their effectiveness, including: 

   1. Biologic lung volume reduction (e.g., Aeris Therapeutics, Inc., Woburn, MA, Biologic Lung Volume Reduction (BLVR) System, ); and

   2. The placement of bronchial valves (e.g., IntraBronchial Valve (IBV), Spiration IBV, Zephyr Endobronchial Valve (EBV)).

Lung volume reduction surgery (LVRS) is a general term encompassing a variety of surgical procedures that are offered to alleviate the symptoms of advanced chronic obstructive pulmonary disease (COPD) due to emphysema.  Currently the operations used to treat emphysema include the excision of large bullae by thoracotomy or thoracoscopy and the resection of diffusely emphysematous lung tissue.

This latter surgery, variably referred to as a lung reduction surgery, pneumectomy, and reduction pneumoplasty can be accomplished through a variety of incisions (sternotomy, clam shell, thoracotomy) or by thoracoscopy using a staple procedure or laser applications.  Currently the choice of techniques depends on the surgical expertise and preference of the operator.

Based on results reported in peer review journals, abstracts and presentations at national meetings, LVRS appears efficacious for some, but not all, patients with advanced COPD due to emphysema.

Several centers have documented post-operative improvement in exertional dyspnea, measurements of pulmonary function, exercise capacity and objectively scored quality of life indices.  Improvements in exercise capacity have been reported in patients undergoing a comprehensive program of pulmonary rehabilitation in preparation for surgery.

It appears that bilateral pneumectomy yields improvements in spirometry that are roughly twice as great as unilateral procedures.

In the 1 available randomized prospective trial that compared stapled lung reduction to laser bullectomy surgery, patients who received the latter procedure were more likely to develop a delayed pneumothorax and less likely to eliminate dependency on supplemental oxygen.  Also, the mean post-operative improvement in the FEV1 at 6 months was greater in those who received the stapled lung reduction technique (32.9 % improvement) than the laser treatment (13.4 % improvement).

Fishman et al (2003) reported on the results of the National Emphysema Treatment Trial, a randomized, multi-center clinical trial comparing LVRS with medical treatment.  A total of 1,218 patients with severe emphysema were randomly assigned to undergo LVRS or to receive continued medical treatment.  Lung volume reduction surgery was found to improve exercise capacity in a significant proportion of patients, but to have no significant effect on overall mortality.  After 24 months, exercise capacity had improved by more than 10 W in 15 % of the patients in the surgery group, as compared with 3 % of patients in the medical-therapy group.

Lung volume reduction surgery was found to yield a survival advantage for patients with both predominantly upper-lobe emphysema and low base-line exercise capacity (Fishman et al, 2003).  Among patients with predominantly upper-lobe emphysema and low exercise capacity, mortality was more than 50 % lower in the surgery group than in the medical-therapy group.

In contrast, LVRS was associated with an increase in mortality and negligible functional gain among patients with predominantly non-upper lobe emphysema and a high base-line exercise capacity (Fishman et al, 2003).  Among patients with non-upper-lobe emphysema and high exercise capacity, mortality was twice as high in the surgery group as in the medical-therapy group.

Lung volume reduction surgery was also associated with an increase in mortality among persons who were, in previous reports (National Emphysema Treatment Trial Research Group, 2001) considered to be at high-risk of death after surgery, namely patients with a low FEV1 (20 % or less than predicted) and either homogenous emphysema or a very low carbon monoxide diffusing capacity (20 % or less than predicted) (Fishman et al, 2003).  A meta analysis (Berger et al, 2005) reported that a selected subset of patients with advanced, heterogeneous emphysema and low exercise tolerance (as indexed by the 6-min walk distance) experienced better outcomes from LVRS than from medical therapy.

Functional benefits but no improvements in survival were found in patients with predominantly upper-lobe emphysema and a high base-line exercise capacity and patients with non-upper lobe emphysema and a low base-line exercise capacity (Fishman et al, 2003).

Patients usually need pulmonary rehabilitation after LVRS to better ensure return to function.

Stoller et al (2007) noted that the role of LVRS for individuals with alpha-1 antitrypsin (AAT) deficiency is unclear.  These investigators evaluated the role of LVRS in individuals with severe deficiency of AAT, and analyzed outcomes within the National Emphysema Treatment Trial.  Of 1,218 randomized subjects, 16 (1.3 %) had severe AAT deficiency (serum level less than 80 mg/dL) and a consistent phenotype (when available).  Characteristics of these 16 patients were 87.5 % male; median serum AAT level of 55.5 mg/dL; age of 66 years; FEV1 27 % predicted; and 50 % had upper-lobe-predominant emphysema.  All 10 subjects randomized to LVRS underwent the procedure.  Although the small number of subjects hampered statistical analysis, 2-year mortality was higher with surgery (20 % versus 0 %) than with medical treatment.  Comparison of outcomes between the 10 AAT-deficient and the 554 AAT-replete subjects undergoing LVRS showed a greater increase in exercise capacity at 6 months in replete subjects and a trend toward lower and shorter duration FEV1 rise in deficient individuals.  The authors concluded that the findings of this study extended to 49 cases the published experience of LVRS in severe AAT deficiency.  Although the small number of subjects precluded firm conclusions, trends of lower magnitude and duration of FEV1 rise after surgery in AAT-deficient versus AAT-replete subjects and higher mortality in deficient individuals randomized to surgery versus medical treatment suggest caution in recommending LVRS in AAT deficiency.

Giant bullous emphysema (GBE) is a rare subset of patients with COPD in whom single or multiple large bullae encompass 30 % or more of a hemi-thorax, often displacing potentially functional lung tissue as these large airspaces increase in volume.  In appropriate cases, surgical resection of these bullae can restore significant pulmonary function and improve symptoms.  Computed tomography (CT) scan is essential in evaluating these patients. 

According to guidelines from the Institute for Clinical Systems Improvement (ICSI, 2004), bullectomy is indicated in these patients.  This is in accordance with guidelines on COPD from the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) (NHLBI, 2005): “In carefully selected patients, this procedure is effective in reducing dyspnea and improving lung function.  A thoracic computed tomography scan, arterial blood gas measurement, and comprehensive respiratory function tests are essential before making a decision regarding a patient's suitability for resection of a bulla.”

Furthermore, according to guidelines from National Institute for Clinical Excellence (NICE, 2004), patients who are breathless, and have a single large bulla on a CT scan and an FEV1 less than 50 % predicted should be referred for consideration of bullectomy.

In a prospective study, Palla and colleagues (2005) evaluated patients who have undergone elective surgery due to GBE, early and late mortality following surgery, the early and late reappearance of bullae, and the early and late modifications of clinical and functional data.  A total of 41 consecutive patients who underwent elective surgery for GBE were studied both before and after undergoing bullectomy for a 5-year-follow-up period.  Analyses were performed on the whole population and on 2 subgroups of patients who were divided on the basis of the absence of underlying diffuse emphysema (group A; n = 23) or the presence of underlying diffuse emphysema (group B; n = 18).  The early mortality rate was 7.3 % (within the 1st year), and the late mortality rate was 4.9 % (overall mortality rate at 5 years, 12.2 %; mortality rate in group B, 27.8 %).  Bullae did not re-appear and residual bullae did not become enlarged in any patients at the site of the bullectomy.  During the follow-up, the dyspnea score was reduced significantly soon after bullectomy and up to the fourth year of follow-up; intra-thoracic gas volume also was reduced significantly (average, 0.7 L).  The same was true for the FEV1 percent predicted and the FEV1/vital capacity ratio, which kept increasing until the 2nd year; then, from the 3rd year of follow-up these values were reduced, yet remained above the pre-bullectomy values until the 5th year of follow-up.  When considered separately, the patients in group B appeared to be the most impaired, clinically and functionally (e.g., FEV1 showed a similar significant increase up to the 2nd year in both groups after surgery, while a different mean annual decrease was appreciable from the second to the 5th year of follow-up: group A, 25 ml/year; group B, 83 ml/year.  Furthermore, patients in group B were the only ones who contributed to the mortality rate, on the whole showing a behavior similar to that of patients who had undergone LVRS.  These investigators concluded that in patients with GBE who were enrolled in the study prospectively and were investigated yearly during a 5-year-follow-up period, bullectomy appears to have been fairly safe, and allowed clinical and functional improvement for at least 5 years.  Better results may be expected in patients without underlying diffuse emphysema.

Donahue and Cassivi (2009) noted that currently alpha-1 antitrypsin deficiency (A1AD) is recognized in approximately 2 % of patients who have emphysema, although this may be an under-estimation of the prevalence of this disease.  Given the relatively young age at which patients who have A1AD present with emphysema, therapies aimed at slowing the progression of this disease are imperative.  In addition to abstaining from smoking, the use of augmentation therapy may benefit some patients who have moderate airflow obstruction.  For patients who have severe airflow obstruction, the most effective therapy is surgical.  Despite a possible increased risk for infectious complications, transplantation remains a viable option for these patients who have long-term results mirroring those of patients transplanted for smoking-related COPD.  Given limited donor availability, however, LVRS must be considered in these patients possibly as definitive therapy but more likely as a bridge to transplantation.  Lung volume reduction surgery for patients who have A1AD remains relatively uncommon despite a general perception that it remains a surgical option.  In a survey of European thoracic surgical centers, Hamacher and colleagues found that 2/3 of respondents included A1AD in their list of indications for LVRS.  Although the durability of the benefits derived from LVRS in patients who have A1AD seems inferior to that of patients who have COPD, the available data show improved 6-min walk distances and decreased dyspnea persisting for 1 to 2 years after LVRS in patients who had A1AD.  The authors stated that further experience is needed to determine whether or not subgroups of patients who have A1AD, such as those who have clear heterogeneous distribution, may derive more long-lasting improvement from LVRS.

Since LVRS is associated with high morbidity, mortality, and cost, several bronchoscopic methods for reducing lung volume in patients with advanced emphysema have been developed and are currently being evaluated in clinical trials as potential alternatives to LVRS.  These techniques include: (i) placement of endobronchial 1-way valves designed to promote atelectasis by blocking inspiratory flow; (ii) formation of airway bypass tracts using a radiofrequency catheter designed to facilitate emptying of damaged lung regions with long expiratory times; and (iii) instillation of biological adhesives designed to collapse and remodel hyper-inflated lung.  The limited clinical data currently available suggest that all 3 techniques are reasonably safe.  However, efficacy signals have been substantially smaller and less durable than those observed after LVRS.  Clinical studies to optimize patient selection, refine treatment strategies, characterize procedural safety, elucidate mechanisms of action, and characterize short- and long-term effectiveness of these approaches are ongoing (Ingenito et al, 2008). 

Bronchoscopic placement of small self-expanding 1-way valves into airways is a minimally invasive approach currently under investigation as an alternative to open LVRS.  The valves are designed to prevent incoming airflow from reaching over-inflated regions of the lung while permitting trapped gas to escape.  In addition to isolating non-functional areas of the lungs, the valves have the potential to reduce hypoxemia and hypercarbia by directing airflow to areas where gas exchange is less impaired. 

The Zephyr Endobronchial Valve (EBV) (Emphasys Medical, Inc., Redwood City, CA) consists of a 1-way silicone duckbill valve attached to a self-expanding nitinol stent retainer.  It is currently being evaluated in a phase III clinical trial, the Endobronchial Valve for Emphysema PalliatioN Trial (VENT), that compares it to optimal medical management in patients aged 40 to 75 years with heterogeneous emphysema.  Patients were randomized into 2 groups: EBV procedure (n = 180) and optimal medical therapy (n = 90).  Efficacy end-points include pulmonary function, exercise tolerance, and quality of life compared to baseline at various times throughout the course of 1 year.  The valves are designed to be removable so the procedure has the potential to be fully reversible.  The device is not yet commercially available in the United States; however, in September 2007 Emphasys Medical, Inc. submitted a pre-market application to the U.S. Food and Drug Administration (FDA) seeking approval to market the device in the U.S. 

The Umbrella Implantable IntraBronchial Valve (IBV) (Spiration, Inc., Redmond, WA) consists of a polyurethane membrane over an umbrella-shaped nitinol (nickel/titanium) frame.  The proximal portion is made up of 6 support stents that expand radially.  The valve is designed to limit airflow distally, but the membrane and support stents allow mucociliary clearance, air and mucous to flow proximally past the valve in order to allow decompression of collateral ventilation and to reduce the hazards of mucous impaction and obstruction pneumonia.  The valve design includes a proximal center rod that allows re-positioning or removal if needed.  The FDA approved the IBV Valve system to control prolonged air leaks of the lung or significant air leaks that are likely to become prolonged following lobectomy, segmentectomy or LVRS via the humanitarian device exemption process.  It is also currently under investigation in the U.S. as a new treatment option for patients with severe emphysema, however, the effectiveness of this device has not been demonstrated in the peer-reviewed medical literature and it has not received FDA approval for this indication.

The Biologic Lung Volume Reduction (BLVR) System (Aeris Therapeutics, Inc., Woburn, MA) is an investigational procedure that uses pharmacologic agents to selectively collapse over-inflated regions of the lung.  During a BLVR procedure, the physician targets diseased portions of the lung tissue with a bronchoscope and applies a washout solution to disrupt pulmonary surfactant and remove pulmonary epithelium.  This causes air space to collapse on exhalation.  A fibrin-based hydrogel is then applied to the treated tissue sealing it off from the rest of the lung and causing it to scar and shrink.  The procedure is intended to reduce lung volume over a period of weeks as diseased lung tissue continues to collapse.  It is performed in a hospital under general anesthesia and requires an overnight stay.

Aeris Therapeutics, Inc. is currently conducting a phase III study to evaluate the safety and effectiveness of the BLVR procedure.  Unpublished results from two U.S. phase II studies indicated that the treatment was well-tolerated and improved pulmonary function in some emphysema patients.

The BLVR procedure may be a promising treatment for individuals with advanced upper lobe predominant emphysema; however, there is insufficient evidence of its effectiveness.  Studies to determine patient selection, safety, mechanism of action, as well as short- and long-term effectiveness in patients with advanced emphysema are on-going.

In a pilot study, Snell et al (2009) reported the safety and feasibility of novel 2nd-generation bronchoscopic lung volume reduction (LVR) technology, independent of collateral ventilation.  A total of 11 patients with severe heterogeneous emphysema underwent unilateral bronchoscopic application of vapor thermal energy (mean of 4.9 cal/g alveolar tissue; range of 3 to 7.5) with bronchial thermal vapor ablation (BTVA) aiming to induce a controlled inflammatory airway and parenchymal response with resultant LVR.  Nine women and 2 men, with a mean age of 61 years, FEV1 of 0.77 +/- 0.17 L (32 % predicted), residual volume (RV) of 4.1 +/- 0.9 L (219 % predicted), and gas transfer of 7.8 +/- 2.2 (34 % predicted), underwent unilateral upper lobe treatments.  Serious adverse events in 5 included probable bacterial pneumonia and exacerbations of airways disease in 2.  Although no important FEV1 or RV changes occurred during 6 months of follow-up, gas transfer improved, 16 % to 9.0 % +/- 2.1 % (38 % predicted), the Medical Research Council Dyspnoea Score improved from 2.6 to 2.1, and the St. George Respiratory Questionnaire Total Score improved from 64.4 at baseline to 49.1.  The authors conclued that these preliminary data on unilateral BTVA therapy confirm feasibility, an acceptable safety profile, and the potential for efficacy.

Eberhardt and colleagues (2009) stated that after bronchoscopic LVR, improvement in pulmonary function and exercising tolerance can be achieved in patients with severe heterogeneous lung emphysema.  Feasibility and safety for 1-way valve placement in homogeneous emphysema were evaluated.  A total of 10 patients entered this prospective study.  In all cases, a homogeneous distribution was confirmed by computer analysis of the CT-scans.  These researchers performed unilateral LVR and occluded the lobe with the lowest perfusion, measured by nuclear scintigraphy.  Endpoints of the study were changes in lung function test, quality of life and 6-minute walk-test (6-MWT) at day 30 and 90 and the safety of the procedure.  Pre-operative mean FEV1 was 0.93 L (range of 0.55 to 1.35 L), mean residual volume was 5.23 L (3.55 to 8.24 L) and 6-MWT was 325 m (150 to 480 m).  Improvement of dyspnoe and exercising tolerance was reported in 7 cases.  No major changes in lung function were evident at days 30 and 90.  A trend towards improvement was observed in 6-MWT (DeltaMW + 10.4 +/- 9.8 %).  One pneumothorax was noticed, in 1 case the valves were removed after 90 days because of recurrent infections.  The authors concluded that the findings of this study showed that bronchoscopic LVR in patients with severe homogeneous emphysema is feasible and seems to be safe.  In contrast to surgical LVR, patients may have a cinical benefit by bronchoscopic treatment.  They stated that long-term follow-up and patient selection criteria have to be examined in larger trials.

In a clinical pilot study, Herth et al (2010) examined the safety and feasibility of a new endoscopic LVR approach independent of the effects of collateral ventilation (CV).  Patients with severe emphysema were eligible.  Inclusion and exclusion criteria were modeled after the National Emphysema Treatment Trial (NETT) study.  Homogenous and heterogeneous disease was allowed.  Treatment consisted of the placement of coils into the parenchyma of the most diseased area with the intent of achieving parenchymal compression.  Primary end points were safety and feasibility assessments.  Secondary endpoints were efficacy outcomes.  A total of 11 patients underwent 21 procedures.  Procedures were performed under general anesthesia and lasted 45 +/- 15 mins and per procedure 4.9 +/- 0.6 coils were placed.  All procedures were well-tolerated.  The total follow-up time was 7 to 11 months and in that time 33 adverse events were reported, none of them severe.  No pneumothorax occurred.  Efficacy seemed better in heterogeneous rather than homogenous disease.  The authors concludedthat endoscopic LVR with coils is safe and feasible.  Moreover, they stated that further studies of the efficacy are indicated.