Lung Volume Reduction Surgery

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The Centers for Medicare and Medicaid Services (CMS) has made the following determinations regarding lung volume reduction surgery: The evidence is adequate to conclude that lung volume reduction surgery (LVRS) is not reasonable and necessary for high-risk patients with severe emphysema. A high-risk patient is one who has a forced expiratory volume in the first second (FEV 1 ) that is 20% or less of their predicted value and either homogeneous distribution of emphysema on CT scan or low carbon monoxide diffusing capacity (D L CO) that is 20% or less of their predicted value. LVRS remains noncovered for this population group. The evidence is adequate to conclude that LVRS is reasonable and necessary for non-high risk patients who satisfy the inclusion and exclusion criteria outlined in the National Emphysema Treatment Trial (NETT) protocol and present with severe upper lobe emphysema. 1 Therefore, CMS intends to issue a national coverage determination covering LVRS for this indication. The evidence is adequate to conclude that LVRS is reasonable and necessary for non high-risk patients who satisfy the inclusion and exclusion criteria outlined in the NETT protocol and have severe non-upper lobe emphysema with low exercise capacity. Therefore, CMS intends to issue a national coverage determination covering LVRS for this indication. The evidence is adequate to conclude that LVRS is not reasonable and necessary for non high-risk patients who satisfy the inclusion and exclusion criteria outlined in the NETT protocol and have severe non-upper lobe emphysema with high exercise capacity. LVRS remains noncovered for this indication. All other patient indications for LVRS remain noncovered. Covered LVRS approaches are limited to bilateral excision of damaged lung with stapling performed via median sternotomy or video-assisted thoracoscopic surgery. In addition, CMS has determined that LVRS is reasonable and necessary only if preceded and followed by a program of diagnostic and therapeutic services consistent with those provided in the NETT and designed to maximize the patient's potential to successfully undergo and recover from surgery. The program must include a 6 to 10 week series of at least 16, and no more than 20, preoperative sessions each lasting a minimum of two hours. It must also include at least 6 and no more than 10 postoperative sessions each lasting a minimum of two hours, within 8 to 9 weeks of the LVRS. This program must be consistent with the care plan developed by the treating physician following performance of a comprehensive evaluation of the patient's medical, psychosocial and nutritional needs, be consistent with the pre-operative and post-operative services provided in the NETT, and arranged, monitored and performed under the coordination of the facility where the surgery takes place. Finally, CMS has determined that LVRS is reasonable and necessary only when performed at facilities that were identified by the National Heart, Lung, and Blood Institute (NHLBI) as meeting the thresholds for participation in the NETT and at sites that have been approved by Medicare as lung transplant facilities. Currently, CMS is developing accreditation standards for sites that perform LVRS and, when implemented, LVRS will be considered reasonable and necessary only at accredited facilities.

Decision Memo: To: Administrative File: CAG - 00115R Lung Volume Reduction Surgery (LVRS) From: Steve E. Phurrough, MD MPA Acting Director, Coverage and Analysis Group JoAnna Farrell Lead Analyst Carlos Cano, MD Lead Medical Officer Subject: Coverage Decision Memorandum for Lung Volume Reduction Surgery Date: August 20, 2003 I. Decision The Centers for Medicare and Medicaid Services (CMS) has made the following determinations regarding lung volume reduction surgery: The evidence is adequate to conclude that lung volume reduction surgery (LVRS) is not reasonable and necessary for high-risk patients with severe emphysema. A high-risk patient is one who has a forced expiratory volume in the first second (FEV 1 ) that is 20% or less of their predicted value and either homogeneous distribution of emphysema on CT scan or low carbon monoxide diffusing capacity (D L CO) that is 20% or less of their predicted value. LVRS remains noncovered for this population group. The evidence is adequate to conclude that LVRS is reasonable and necessary for non-high risk patients who satisfy the inclusion and exclusion criteria outlined in the National Emphysema Treatment Trial (NETT) protocol and present with severe upper lobe emphysema. 1 Therefore, CMS intends to issue a national coverage determination covering LVRS for this indication. The evidence is adequate to conclude that LVRS is reasonable and necessary for non high-risk patients who satisfy the inclusion and exclusion criteria outlined in the NETT protocol and have severe non-upper lobe emphysema with low exercise capacity. Therefore, CMS intends to issue a national coverage determination covering LVRS for this indication. The evidence is adequate to conclude that LVRS is not reasonable and necessary for non high-risk patients who satisfy the inclusion and exclusion criteria outlined in the NETT protocol and have severe non-upper lobe emphysema with high exercise capacity. LVRS remains noncovered for this indication. All other patient indications for LVRS remain noncovered. Covered LVRS approaches are limited to bilateral excision of damaged lung with stapling performed via median sternotomy or video-assisted thoracoscopic surgery. In addition, CMS has determined that LVRS is reasonable and necessary only if preceded and followed by a program of diagnostic and therapeutic services consistent with those provided in the NETT and designed to maximize the patient's potential to successfully undergo and recover from surgery. The program must include a 6 to 10 week series of at least 16, and no more than 20, preoperative sessions each lasting a minimum of two hours. It must also include at least 6 and no more than 10 postoperative sessions each lasting a minimum of two hours, within 8 to 9 weeks of the LVRS. This program must be consistent with the care plan developed by the treating physician following performance of a comprehensive evaluation of the patient's medical, psychosocial and nutritional needs, be consistent with the pre-operative and post-operative services provided in the NETT, and arranged, monitored and performed under the coordination of the facility where the surgery takes place. Finally, CMS has determined that LVRS is reasonable and necessary only when performed at facilities that were identified by the National Heart, Lung, and Blood Institute (NHLBI) as meeting the thresholds for participation in the NETT and at sites that have been approved by Medicare as lung transplant facilities. Currently, CMS is developing accreditation standards for sites that perform LVRS and, when implemented, LVRS will be considered reasonable and necessary only at accredited facilities. II. Background Pulmonary emphysema is a common, progressive, disabling disease with a high mortality rate. Emphysema is a condition of the lung characterized by abnormal, permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by destruction of alveolar walls and resulting in the chronic hyperinflation of the lung. This destruction of the alveolar-capillary membrane leads to a reduction in the surface area available for gas exchange and a loss of elastic recoil of the lung. As the disease progresses, the area of gas exchange decreases and patients become progressively short of breath and limited in activity. Advanced emphysema patients struggle for breath when they perform simple tasks such as climbing stairs or carrying groceries. Emphysema is usually the result of cigarette smoking, although it is less frequently associated with inhalation of coal dust and can also occur in a genetic condition known as alpha 1 antitrypsin deficiency. In 1996, almost 2 million people in the United States suffered from emphysema. The prevalence of emphysema is highest in the over-65 age group where it is 32.4 per 1,000 compared to 6.9 per 1,000 in the general population. Race, socioeconomic status and geography also influence the prevalence of emphysema with the highest rates among the lower income white population in the mid-west of the US. Death rates due to emphysema increase markedly for those over 65 years of age. In 1999, approximately 18,000 people died from the disease, making emphysema a major cause of death among the elderly in this country. 2 3 Medical therapy. The goals of medical therapy for emphysema are to delay the progressive decline in lung function, prevent exacerbations of the disease, prolong survival and improve exercise capacity and quality of life. To date, smoking cessation and long-term oxygen therapy for certain patient groups are the only non-surgical treatments that have demonstrated survival benefit. Immunizations can sometimes prevent or reduce exacerbations caused by infections. Exacerbations are treated with a variety of antibiotics, anti-inflammatory drugs, and bronchodilators. Exercise conditioning and educational, psychosocial and nutritional services provided in pulmonary rehabilitation programs may improve exercise capacity and reduce disability. Surgical approaches. Over the years, the limited success of medical therapy resulted in the development of numerous surgical procedures for different parts of the respiratory system in an attempt to alleviate symptoms and improve health outcomes. Although patients with severe emphysema have lungs that have become too large relative to the size of their chests, none of the operative procedures for the chest wall, diaphragm, pleura or nervous system to modify this condition have been shown to have lasting benefit. Lung volume reduction surgery (LVRS) was first reported in 1957 as an attempt to reduce pulmonary hyperinflation by removing overdistended and presumably nonfunctional areas of the lungs. A high operative mortality rate and lack of observable measurements to substantiate the reported patient improvement limited acceptance of the procedure and led to its abandonment. Subsequently, in the early 1990s, a variety of modifications in technique were introduced to retest the hypothesis that reduction in lung volume would restore the elastic recoil of the lungs, open the small airways, and improve ventilatory mechanics. In 1995, the apparent improvement in lung function with wedge resection of emphysematous lung tissue reported in uncontrolled case series studies prompted a surge in utilization of this surgical procedure. 4 In the 1990’s version of the LVRS procedure, the resection of emphysematous lung was done by either a median sternotomy (MS), which involves an incision through the breastbone to expose the lungs, or by video-assisted thoracoscopic surgery (VATS). Thoracoscopy is a less invasive procedure that requires three small incisions between the patient’s ribs and uses a video-scope to guide the surgeon. In both procedures the damaged lung tissue is cut away and the edge of the remaining organ tissue is stapled back together. As with any surgical procedure, there are risks and complications involved in LVRS. The most common complication is post-surgical air leakage through the stapled lung tissue. Chest tubes are placed to monitor this complication and prevent the collapse of the lung. Additional complications include pneumonia, infection, stroke, bleeding, myocardial infarction, and death. III. History of Medicare Coverage In the mid 1990s, LVRS diffused rapidly in clinical practice despite a paucity of clinical evidence concerning its safety and effectiveness. Prior to December 1995, Medicare coverage of LVRS was left to contractor discretion – there was no national policy on the procedure. A September 1995 workshop sponsored by the NHLBI had called for controlled studies of the surgical approach. In December 1995, CMS (then HCFA) issued a national noncoverage policy for all LVRS procedures based on the inadequacy of medical evidence and the potential for extensive morbidity and mortality among Medicare beneficiaries given its rapid diffusion. 5 One of the most important shortcomings of the literature at the time was the high percentage of treated patients who were lost to follow-up in the post-surgical period and the failure to assess their outcomes. The loss of patient data was most notable beyond 3 months post-surgery. As a result the validity of subsequent reported outcomes could not be ascertained since they could have been subject to considerable bias depending on whether the patients that maintained contact with providers had predominantly positive or negative results. Uncertainty about the post-operative survival rates for LVRS was a particular concern for CMS given the rapid dissemination of the intervention beyond the academic centers originally reporting results in the medical literature. To address this concern, a specific ICD-9 code was assigned to the procedure and CMS performed an analysis of Medicare claims between October 1995 and January 1996. The agency identified 722 claims for LVRS during this period and found that approximately 30% (N=215) of the Medicare beneficiaries had died within 18 months of their surgery – a mortality rate much higher than that reported or projected in published studies. In April 1996, the Agency for Healthcare Research and Quality (AHRQ, then the Agency for Health Care Policy and Research,) issued a pre-publication copy of a report requested by CMS on the available evidence on LVRS. The technology assessment found that the available evidence did not permit scientific conclusions regarding risks and benefits of LVRS. 6 Because some patients appeared to benefit in the short run, AHRQ recommended that Medicare coverage be provided within a controlled clinical study. Later that month, CMS and NHLBI concluded that data from controlled clinical trials were needed to reliably guide the appropriate use of LVRS and signed an agreement to participate in such study. As part of this memorandum of understanding, NHLBI would design and fund the clinical trial and CMS would reimburse for the health care services provided to beneficiaries treated under its protocol. Surgery outside the protocol of the NETT would not be covered under the Medicare program. Beneficiaries would be provided access to a promising but not yet proven procedure while scientifically valid data were generated to guide future clinical use and reimbursement decisions. Thus, the two agencies, in concert with a number of academic investigators skilled in the performance of the procedure, developed the National Emphysema Treatment Trial (NETT). The NETT became a multicenter, randomized clinical trial of medical therapy vs. medical therapy plus LVRS in the treatment of emphysema. Data resulting from the trial published in May 2003 provided the basis for this coverage determination. IV. Timeline of Recent Activities Date Action December 1995 CMS (then HCFA) issues a national non-coverage policy on LVRS procedures April 1996 CMS and NHLBI sign an agreement to sponsor a controlled clinical trial on LVRS October 1997 Patient screening for the NETT begins October 2001 NETT investigators publish a finding from the trial describing a subpopulation of severely ill patients for whom surgery increases the risk of death. July 2002 Patient enrollment for the NETT ends August 2002 Investigators perform last surgery under the trial protocol October 2002 CMS begins discussion of trial data with NETT investigators May 2003 NETT investigators publish report on primary outcomes for all study patients. May 20, 2003 CMS opens a national coverage determination (NCD) on LVRS V. FDA Status Lung volume reduction surgery is a procedure that does not require FDA approval. VI. General Methodological Principles of Study Design When making national coverage determinations, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service is reasonable and necessary. The overall objective for the critical appraisal of the evidence is to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve net health outcomes for patients. We divide the assessment of clinical evidence into three stages: 1) the quality of the individual studies; 2) the generalizability of findings from individual studies to the Medicare population; and 3) overarching conclusions that can be drawn from the body of the evidence on the direction and magnitude of the intervention’s potential risks and benefits. The methodological principles described below represent a broad discussion of the issues we consider when reviewing clinical evidence. However, it should be noted that each coverage determination has its unique methodological aspects. 1. Assessing Individual Studies Methodologists have developed criteria to determine weaknesses and strengths of clinical research. Strength of evidence generally refers to: 1) the scientific validity underlying study findings regarding causal relationships between health care interventions and health outcomes; and 2) the reduction of bias. In general, some of the methodological attributes associated with stronger evidence include those listed below: Use of randomization (allocation of patients to either intervention or control group) in order to minimize bias. Use of contemporaneous control groups (rather than historical controls) in order to ensure comparability between the intervention and control groups. Prospective (rather than retrospective) studies to ensure a more thorough and systematical assessment of factors related to outcomes. Larger sample sizes in studies to demonstrate both statistically significant as well as clinically significant outcomes that can be extrapolated to the Medicare population. Sample size should be large enough to make chance an unlikely explanation for what was found. Masking (blinding) to ensure patients and investigators do not know to which group patients were assigned (intervention or control). This is important especially in subjective outcomes, such as pain or quality of life, where enthusiasm and psychological factors may lead to an improved perceived outcome by either the patient or assessor. Regardless of whether the design of a study is a randomized controlled trial, a non-randomized controlled trial, a cohort study or a case-control study, the primary criterion for methodological strength or quality is the extent to which differences between intervention and control groups can be attributed to the intervention studied. This is known as internal validity. Various types of bias can undermine internal validity. These include: Different characteristics between patients participating and those theoretically eligible for study but not participating (selection bias). Co-interventions or provision of care apart from the intervention under evaluation (performance bias). Differential assessment of outcome (detection bias). Occurrence and reporting of patients who do not complete the study (attrition bias). In principle, rankings of research design have been based on the ability of each study design category to minimize these biases. A randomized controlled trial minimizes systematic bias (in theory) by selecting a sample of participants from a particular population and allocating them randomly to the intervention and control groups. Thus, in general, randomized controlled studies have been typically assigned the greatest strength, followed by non-randomized clinical trials and controlled observational studies. The design, conduct and analysis of trials are important factors as well. For example, a well designed and conducted observational study with a large sample size may provide stronger evidence than a poorly designed and conducted randomized controlled trial with a small sample size. The following is a representative list of study designs (some of which have alternative names) ranked from most to least methodologically rigorous in their potential ability to minimize systematic bias: Randomized controlled trials Non-randomized controlled trials Prospective cohort studies Retrospective case control studies Cross-sectional studies Surveillance studies (e.g., using registries or surveys) Consecutive case series Single case reports When there are merely associations but not causal relationships between a study’s variables and outcomes, it is important not to draw causal inferences. Confounding refers to independent variables that systematically vary with the causal variable. This distorts measurement of the outcome of interest because its effect size is mixed with the effects of other extraneous factors. For observational, and in some cases randomized controlled trials, the method in which confounding factors are handled (either through stratification or appropriate statistical modeling) are of particular concern. For example, in order to interpret and generalize conclusions to our population of Medicare patients, it may be necessary for studies to match or stratify their intervention and control groups by patient age or co-morbidities. Methodological strength is, therefore, a multidimensional concept that relates to the design, implementation and analysis of a clinical study. In addition, thorough documentation of the conduct of the research, particularly study selection criteria, rate of attrition and process for data collection, is essential for CMS to adequately assess and consider the evidence. 2. Generalizability of Clinical Evidence to the Medicare Population The applicability of the results of a study to other populations, settings, treatment regimens and outcomes assessed is known as external validity. Even well-designed and well-conducted trials may not supply the evidence needed if the results of a study are not applicable to the Medicare population. Evidence that provides accurate information about a population or setting not well represented in the Medicare program would be considered but would suffer from limited generalizability. The extent to which the results of a trial are applicable to other circumstances is often a matter of judgment that depends on specific study characteristics, primarily the patient population studied (age, sex, severity of disease and presence of co-morbidities) and the care setting (primary to tertiary level of care, as well as the experience and specialization of the care provider). Additional relevant variables are treatment regimens (dosage, timing and route of administration), co-interventions or concomitant therapies, and type of outcome and length of follow-up. The level of care and the experience of the providers in the study are other crucial elements in assessing a study’s external validity. Trial participants in an academic medical center may receive more or different attention than is typically available in non-tertiary settings. For example, an investigator’s lengthy and detailed explanations of the potential benefits of the intervention and/or the use of new equipment provided to the academic center by the study sponsor may raise doubts about the applicability of study findings to community practice. Given the evidence available in the research literature, some degree of generalization about an intervention’s potential benefits and harms is invariably required in making coverage determinations for the Medicare population. Conditions that assist us in making reasonable generalizations are biologic plausibility, similarities between the populations studied and Medicare patients (age, sex, ethnicity and clinical presentation) and similarities of the intervention studied to those that would be routinely available in community practice. A study’s selected outcomes are an important consideration in generalizing available clinical evidence to Medicare coverage determinations. The goal of our determination process is to assess net health outcomes. These outcomes include resultant risks and benefits such as increased or decreased morbidity and mortality. In order to make this determination, it is often necessary to evaluate whether the strength of the evidence is adequate to draw conclusions about the direction and magnitude of each individual outcome relevant to the intervention under study. In addition, it is important that an intervention’s benefits are clinically significant and durable, rather than marginal or short-lived. If key health outcomes have not been studied or the direction of clinical effect is inconclusive, we may also evaluate the strength and adequacy of indirect evidence linking intermediate or surrogate outcomes to our outcomes of interest. 3. Assessing the Relative Magnitude of Risks and Benefits An intervention is not reasonable and necessary if its risks outweigh its benefits. For all determinations, CMS evaluates whether reported benefits translate into improved net health outcomes. CMS places greater emphasis on health outcomes actually experienced by patients, such as quality of life, functional status, duration of disability, morbidity and mortality, and less emphasis on outcomes that patients do not directly experience, such as intermediate outcomes, surrogate outcomes, and laboratory or radiographic responses. The direction, magnitude, and consistency of the risks and benefits across studies are also important considerations. Based on the analysis of the strength of the evidence, CMS assesses the relative magnitude of an intervention or technology’s benefits and risk of harm to Medicare beneficiaries. 4. Specific LVRS Methodological Principles Certain principles of study design are particularly relevant in the evaluation of the evidence available on LVRS. Methodological principles designed to limit bias and increase the validity of the results were not always fully observed in the individual studies on LVRS reported before the NETT was initiated. These key methodological requirements are briefly discussed below and include the need for a comparison group (particularly when the natural history of the condition in the population of interest is not well known), random assignment of patients to experimental and control groups, limiting attrition in both study groups, following up subjects for an adequate length of time, taking confounding variables into account, and analyzing results according to patients’ original group assignment. 7 An issue of particular concern regarding the evidence available on LVRS prior to the initiation of the NETT trial was the absence of published prospective controlled trials (either randomized or non-randomized) comparing optimal medical therapy plus LVRS with optimal medical therapy alone. The clinical evidence available prior to 2000 came almost exclusively from case-series. While never as definitive as controlled studies, the value of case series can be increased when there is a detailed knowledge of the natural history of the disease for a population of interest, to serve as a reference point. Such detailed knowledge was not available for the population of patients with severe emphysema for whom LVRS was indicated. Epidemiological studies including emphysema patients had been based on data collected from populations of patients with chronic obstructive pulmonary disease (COPD) rather than patients with emphysema as their exclusive pulmonary disorder. Thus, given the lack of a comparable population for which LVRS would be indicated, evidence from case-series was not adequate to conclude that LVRS was safer or more effective than optimal medical treatment. One of the most important shortcomings of the LVRS literature was excessive attrition (i.e., a high percentage of treated patients were lost to follow up in the post-surgical period) raising the concern that reported outcomes for patients available for follow up were not representative of the group as a whole. Poor follow-up is seldom random and patients with better outcomes are usually over-represented. In the case of LVRS, it is likely that death occurs most commonly in those patients with a poor result after surgery and that subsequent data are measured only in those patients who are more robust or who have benefited from surgery. 8 All LVRS prospective studies reported prior to the NETT were affected by attrition ranging from 3% to 55% depending on follow-up time considered. 9 Unless studies follow patients beyond the first couple of months after a major therapeutic intervention, experience with the durability of reported benefits will remain uncertain. Given the potentially significant morbidity and mortality risks from a procedure such as LVRS, more than a transient improvement in health outcomes is necessary to offset the risk of surgery. It is important to have a substantial length of follow-up to capture the totality of the expected risks and benefits attributed to the procedure. Whereas none of the prior studies reported data beyond 12 months from surgery, the NETT investigators set out to report and published results on outcomes of interest up to at least two years after surgery. One of the most important aspects of clinical research is the inference that an association represents a cause-effect relation (in this case between LVRS and improved health outcomes). Services provided in pulmonary rehabilitation programs have been shown to have an effect on exercise capacity and quality of life in patients with COPD. 10 A confounding variable such as pulmonary rehabilitation may be associated with the surgical intervention and be in fact the cause of the outcome observed. One of the persistent questions unanswered by research prior to the NETT has been the impact of pulmonary rehabilitation services on outcomes observed from LVRS. To the extent that studies did not consistently include and document the use of comparable pulmonary rehabilitation services in both experimental and control groups, it was difficult to determine if the outcomes were the result of the surgical procedure or an effect of exercise conditioning, psychosocial interventions, or other rehabilitation services. Finally, most of the LVRS trials prior to the NETT were survivors-only analysis rather than the preferable intention-to-treat analysis. Differential early mortality due to surgery could make LVRS survivors appear healthier by removing weaker patients from follow-up. A survivors-only analysis could distort the interpretation of outcomes such as pulmonary function, exercise capacity, and quality of life. VII. Evidence A. Introduction Consistent findings across studies of net health outcomes associated with an intervention as well as the magnitude of its risks and benefits are key to the coverage decision process. For this decision memorandum, CMS reviewed the published clinical evidence on LVRS since the publication in September 1996 of the above-mentioned AHRQ technology assessment (TA) report to determine whether optimal medical management plus LVRS in comparison with optimal medical management alone improves the net health outcomes of patients with severe emphysema. A number of systematic reviews on LVRS summarizing and critically appraising the literature on the topic have covered studies published during this period through September 2001. CMS performed a search for additional, more recently published relevant articles to supplement these systematic reviews. This literature search was limited to comparative prospective studies including randomized and non-randomized controlled clinical trials. Prominent among the studies providing new evidence were two articles reporting clinical results from the NETT, which is the largest randomized clinical trial on the subject to date. In addition to our review of the clinical scientific literature, we requested information from experts and professional societies and sought available evidence-based practice guidelines, consensus statements, and position papers. Outcomes of interest were the beneficial or adverse clinical effects of LVRS: mortality, improvement in maximum exercise capacity, patient-reported quality of life, respiratory symptoms, and pulmonary function. Mortality measures over time and the durability of the other outcomes (e.g., at 12 and 24 months) were of particular interest as were the characteristics of patients most likely to benefit or be at risk for the procedure. Clinical investigators have utilized a variety of validated instruments and tests to measure outcomes other than survival for patients with pulmonary disease. Measures of exercise capacity include maximal, incremental, symptom-limited cycle ergometry (e.g., using a cycle ergometer with five or 10 watt/minute ramp on 30% oxygen, after three minutes of unloaded pedaling) and the 6-min walk test. General quality of life measures include the Medical Outcomes Study Short Form 36-item (MOS SF-36) questionnaire and the utility-weighted Quality of Well-Being Scale (QWB). The St. George's Respiratory Questionnaire (SGRQ) is an instrument validated in patients with COPD that assesses disease-specific quality of life. An instrument frequently used to measure dyspnea, the most important symptom of chronic lung disease, is the University of California at San Diego Shortness of Breath Questionnaire (SOBQ). The MOS SF-36, QWB, SGRQ, SOBQ are self-administered scales. Forced expiratory volume in one second (FEV1), forced vital capacity, total lung capacity and residual volume are among the pulmonary function tests typically utilized in clinical trials of LVRS. B. Summary of evidence reviewed 1. Assessment questions The development of an assessment in support of Medicare coverage decisions is based on the same general question for almost all requests: “Is the evidence sufficient to conclude that the application of the technology under study will improve final health outcomes for Medicare patients?” The formulation of specific questions for the assessment recognizes that the effect of an intervention can depend substantially on how it is delivered, to whom it is applied, the alternatives with which it is being compared, and the delivery setting. In order to appraise the net health outcomes of LVRS in comparison with medical therapy alone and identify relevant patient and facility selection criteria, CMS sought to address the following questions: Does LVRS with medical therapy improve health outcomes in Medicare patients with severe emphysema compared to medical therapy alone? What subgroups of patients with severe emphysema are likely to benefit from the procedure? Should the performance of LVRS be limited to specific facilities? 2. External systematic reviews/technology assessments Systematic reviews are based on a comprehensive and unbiased search of published studies to answer a clearly defined and specific clinical question such as that related to the effectiveness of LVRS. A well-defined strategy or protocol (established before the results of the individual studies are known) guides this literature search. Thus, the process of identifying studies for potential inclusion and the sources for finding such articles is explicitly documented at the start of the review. Finally, systematic reviews provide a detailed assessment of the studies included. 11 Three systematic reviews on LVRS that met these criteria were available to CMS at the start of this literature evaluation. 12 The following are summaries of these reports, which evaluated the clinical literature on LVRS published through September 2001. a) Blue Cross and Blue Shield Association TA on LVRS for Severe Emphysema. 13 This technology assessment reviewed the evidence available through March 1999 to determine whether optimal medical management plus LVRS in comparison with optimal medical management alone improved health outcomes for patients with severe emphysema. The TA reviewed the outcomes of LVRS performed by bilateral staple excision via median sternotomy (MS) and via video-assisted thoracoscopy (VATS) but did not review unilateral or laser approaches to LVRS. The health outcomes of interest were increased exercise tolerance, symptom reduction and improved quality of life. Intermediate outcomes were pulmonary function tests (which included FEV1, forced vital capacity, total lung capacity and residual volume). The harmful health outcomes of interest were procedure-related morbidity and mortality. In the absence of completed randomized clinical trials, reports of original data that specified patient selection criteria, treatment performed, and outcome measures were selected for review. Fourteen articles of the 32 reports selected for detailed review were included in the analysis of evidence. Eleven articles contained primary evidence and 3 additional papers included data on various subsets of a patient cohort described in one of the original articles. The 14 studies reported data for at least 475 patients undergoing LVRS performed by bilateral staple excision and followed patients anywhere from one to 36 months. The primary evidence consisted of 11 uncontrolled case series. One of the 3 supplemental reports was a retrospective case-controlled study that compared 65 LVRS recipients to 22 LVRS candidates who did not receive the operation. Results Morbidity and mortality: Pooling all morbidity data resulted in morbidity outcomes on 466 procedures. Prolonged air leak was the most common adverse event occurring in 40.6% of cases. Other frequent complications included pneumonia (8.8% incidence) and cardiovascular events (8.4% incidence). Reoperations were necessary in 19 cases (4.1% incidence). Twelve studies provided information on operative mortality. In studies of 30 patients or less, the operative death rate ranged from zero to 20%. The three largest series (involving 120 to 150 patients) reported operative mortality of 4 to 5%. The pooled operative mortality rate for 759 procedures was 4.1% and involved 31 deaths. Operative mortality was defined and reported variably (e.g., 30-day vs. 90-day definition). Exercise capacity outcomes measured by the 6-minute walk were reported in six studies. Each of these reports described short-term improvement in 6-minute walk distance measured one to six months after surgery. Longer-term data were reported for small subgroups at 12, 24 and 36 months post-surgery. For instance, for a subgroup of 56 patients, the walk distance had improved from 1150 feet at baseline to 1362 feet at six months, and 1357 feet at 12 months after surgery. Some studies reported improved work capacity measured in watts by bicycle ergometer testing. Preoperative and postoperative pulmonary rehabilitation protocols were variably reported. Quality of life outcomes were measured directly in a small minority of studies. The quality of information was also limited by the number and type of instruments utilized. For instance, two studies reported results of a single question (i.e., how patients viewed their overall health status compared with one year earlier). In the first study, the great majority (78%) of the 108 patients evaluated at six months (out of 127 eligible) responded “much better” and an additional 20% responded “somewhat better.” The second study reported similar results based on 17 of 26 patients available at the 3-month evaluation. Another study compared baseline and three-month scores on the St. George Respiratory Questionnaire in a small patient sample (11 of 14) and noted that mean total score had improved from 62 at baseline to 31 at 3 months post-operatively. Respiratory symptoms. Five studies used the Modified Medical Research Council (MMRC) dyspnea scale to measure the effect of LVRS on symptom change and reported improved scores up to three months post-operatively. Baseline MMRC scores were reported for 304 patients. Although improved for those reported, scores were only available for 218 patients at six months and for 17 patients at 12 months after surgery. Some studies also reported improvement in dyspnea symptoms for a subgroup of patients at three, six and twelve months after surgery as measured by other scales such as the Mahler Baseline Dyspnea Index (BDI) and Transitional Dyspnea Index (TDI). Pulmonary function measures. All papers reviewed consistently reported short-term improvements in pulmonary function variables including FEV1, forced vital capacity, total lung capacity and residual volume. Eight studies reported improvements in FEV1 measured during the first three months post-surgery. There were few data available to assess the durability of FEV1 change beyond six months. Appraisal Citing the following limitations of the available evidence, the BCBS report found the scientific evidence inadequate to permit conclusions concerning the effect of LVRS on health outcomes. The published articles presented case series data rather than evidence from well-designed and controlled clinical studies. Whether LVRS favorably or adversely affected morbidity and mortality rates relative to what would be experienced by end-stage emphysema patients in the absence of surgery could not be assessed adequately using the available data because of the absence of a comparison group or a good natural history for the group of patients selected. In addition, the inconsistent use and reporting of pre- and postoperative rehabilitation confounded the assessment of LVRS outcomes making it difficult to determine if the outcomes were the result of the surgical procedure or an effect of rehabilitation. The principal health outcomes of interest were measured inadequately in the articles reviewed. For instance, although a major objective of LVRS is to improve the patient’s quality of life, only three of 11 studies included data on quality of life and each used a different instrument to assess the outcome. Although, all available studies reported improvements in pulmonary function tests, these tests were not adequate surrogates for functional outcomes or quality of life. A high percentage of treated patients were lost to postoperative follow-up. The missing data created the potential for strong biases in the reported results. The morbidity and mortality risks associated with LVRS can be substantial. Given the potential complications, more than a transient improvement in health outcomes is necessary to offset the risks of surgery. In addition, experience with the durability of reported benefits remained uncertain based on studies reviewed. Although baseline data was reported for 506 operated patients, only 56 patients had 12 month outcomes, 20 patients had 24 month outcomes and 18 patients had 36 month outcomes for some variables. The report concluded that better data on longer-term health outcomes were needed to determine the risk/benefit balance of LVRS. Additionally, the report asserted the need for a randomized controlled trial with long-term postoperative follow-up to determine the effect of LVRS on health outcomes and expressed support of the NETT trial then in progress. b) LVRS for COPD with Underlying Severe Emphysema. 14 Young et al. published a systematic review of the literature on LVRS in September 1999 on the evidence of the effects of LVRS in patients with end stage COPD secondary to severe emphysema. Outcomes of interest included mortality, exercise capacity measured by the six minute walking distance, quality of life, dyspnea and lung function tests. The authors found that the most rigorous evidence on the effectiveness of LVRS came only from case series. Results The pattern of results across the 19 case series that met criteria for inclusion was consistent across individual studies. Statistically significant short-term benefits occurred across a range of outcomes. The authors re-calculated data when necessary and used additional statistics such as the interquartile range (IQR) to indicate the general size and direction of effect across studies. Mortality: Early and late mortality rates could be calculated for most series accounting for a total of 567 patients. The interquartile range (IQR) for early mortality (defined as hospital deaths or deaths occurring within 30 days of surgery) was 0-6% while the IQR for late mortality (deaths occurring in the home or more than 30 days after surgery) at 3-6 months was 0-8%. Exercise capacity: Ten studies collected data on this outcome for 486 patients performing the 6-minute walk test. The reviewers converted all results to meters to facilitate comparison. The baseline distance covered by study participants was 241-290 m (IQR). This rose to 306-434 m after treatment with a pre/post difference of 32-96 m. Only one study recorded these data in the longer term with differences of 64 m and 80 m at one and two years respectively. Quality of life: Only four series collected quality of life data before and after the procedure (187 patients) and only three of these used specific measurement tools. Different instruments were utilized in each of these studies (including the Chronic Respiratory Disease Questionnaire, the MOS SF36, the Nottingham Health Profile, and the Sickness Impact Profile.) Although limited data were presented, improvements in quality of life were observed across all studies and measurement tools. Respiratory symptoms: Twelve studies measured dyspnea before and after the intervention utilizing a variety of measurement tools. Only nine studies used validated standardized tools. The most commonly used instrument was the modified (American Thoracic Society) Medical Research Council of Great Britain scale (MMRC). Results were reported for 403 patients and showing improvement across studies with mean pre-post differences of 1.0 to 2.4 in dyspnea scale scores. Scales used in other studies included the Mahler baseline dyspnea index (BDI), the transitional dyspnea index (TDI) and the Borg scale. Pulmonary function measures: Most studies collected data on a range of physiological outcomes including the forced expiratory volume in one second (FEV1). FEV1 data were available for 925 patients. At baseline the FEV1 was 0.64-0.73 liters (IQR) which rose to 0.91-1.07 liters at 3-6 months after LVRS with a pre/post difference of 0.23-0.36 liters. Appraisal The authors noted that the available evidence appeared to support the effectiveness of LVRS but that the studies reviewed employed designs that made them susceptible to bias. The entire research base for the intervention at the time of the review was subject to the limitations of study designs without parallel control groups. Although studies provided outcome measures before and after an intervention, the attribution of all or any observed change to LVRS was uncertain. Particularly important was the role of pulmonary rehabilitation as a factor influencing the difference between the pre and post-treatment outcome measurements since the LVRS “package” would have likely included preoperative pulmonary rehabilitation in a number of studies. Without a parallel control group it was not possible to exclude the possibility that rehabilitation alone might have caused a considerable component of the improvement in outcomes of interest such as exercise capacity, quality of life and dyspnea. The possibility of detection bias was another concern for reviewers. With only one study arm, clinicians and patients were aware that they were on an active treatment and might have inadvertently provided outcome information that conformed to their expectations that LVRS would result in improvement. Therefore, although LVRS appeared to represent a promising option in the management of patients with severe end stage emphysema, the authors concluded that the considerable uncertainty that existed around the effectiveness of the procedure would remain until the results of randomized controlled clinical trials became available. c) ECRI (Emergency Care Research Institute) Technology Assessment Report: LVRS for emphysema. 15 Since the publication of these reviews calling for controlled studies, a number of randomized and non-randomized controlled trials have been conducted. ECRI published a report in September 2001 that summarized and analyzed newly available data from such studies. The ECRI report addressed a variety of questions pertaining to LVRS and its effectiveness in the palliative treatment of emphysema based on the findings of clinical trials reported in the published, peer-reviewed literature. In particular, the report addressed whether LVRS was an effective palliative treatment option for emphysema when compared to optimal medical therapy. To address this question, the authors identified morbidity and mortality, exercise tolerance, quality of life, dyspnea symptomatology and pulmonary function (including measures of blood gases) as the outcomes of interest. The authors systematically searched databases including the Cochrane Database of Systematic Reviews, the Cochrane Library and Registry of Clinical Trials, Embase, HealthSTAR, Medline and others. The search strategy employed free text key words and controlled vocabulary terms including “randomized controlled trials,” “controlled clinical trials,” “emphysema,” “pneumonectomy,” “lung/surgery,” “lung volume reduction” and “LVRS”. Hand searches of journal and non-journal literature were used to retrieve additional relevant information. A two-tiered approach was adopted to determine which studies to include in the technology assessment. A first set of criteria guided what articles identified by the search would be retrieved: The study concerned the treatment of emphysema with LVRS and provided data addressing the assessment question. The study was reported in the English-language peer-reviewed literature. The study must have utilized a suitable control or comparison (concurrent, contemporaneous, or historical) group. The study must have included at least ten patients in each arm, and The study could be retrospective if patients were selected consecutively. Criteria specific to the assessment question were subsequently applied: Study was reported as full article rather than as abstract. Study must have compared the effectiveness of LVRS directly with standard medical management in a comparable group of patients (concurrent or historical control group). Study patients had diffuse severe emphysema and significant functional limitation despite optimal medical therapy. LVRS techniques included were unilateral or bilateral median sternotomy or VATS using stapling, and Only the largest report from the same center was assessed. Results The authors found five controlled trials meeting these inclusion criteria to address the assessment question. Three of the five studies were prospective, randomized controlled trials. 16 Of the two non-randomized controlled studies only one was prospective. 17 The authors conducted meta-analyses of the studies reviewed whenever they considered it possible to calculate summary estimates of effect size for the required outcomes. (Details of the prospective studies and the characteristics of the patients enrolled in them are included in the evidence table in the appendix for purposes of comparison with more recent prospective controlled studies such as the NETT reports.) Perioperative morbidity. Only one of the five studies presented data on this measure of outcome. Air leaks were the predominant cause of postoperative morbidity affecting 50% to 60% of patients, followed by pneumonia (7% to 5%). Less frequently reported hospital complications were bleeding, ventilator dependence, and tracheostomy. Mortality. Inconsistencies in the summary findings of the meta-analyses precluded the authors from drawing conclusions regarding any difference between the experimental and control groups in short-term (<30 days) or long-term mortality (follow-up time ranging from 3 to 48 months in among studies). Exercise capacity. All four prospective studies reviewed presented data related to exercise tolerance (three used the six-minute walk test and the fourth used a “shuttle-walking test”). Meta-analysis of the data showed that patients who received LVRS demonstrated better tolerance to exercise at follow-up (time interval range between 3 and 24 months) than their counterparts in the medical group. This finding was robust and was not overturned by adjustments for attrition. Quality of life. Only one of the studies reported quality of life measures for both arms. Geddes et al. (2000) found that quality of life measured by Medical Outcomes Study Short Form 36-item (MOS SF-36) scores improved in patients who received LVRS and declined in those who received medical therapy. There was no statistically significant difference in between-group scores at three months post-surgery but one emerged at six-month and 12-month follow-ups. Respiratory symptoms. Two studies reported data on this measure. Pompeo et al. (2000) showed that patient-reported dyspnea was reduced at 24 months in both arms among patients who completed the study, with the greatest reduction in symptoms seen in the LVRS arm. Wilkens et al. (2000) al