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National Emphysema Treatment Trial (NETT):
The National Emphysema Treatment Trial (NETT), supported by the National Heart, Lung, and Blood Institute (NHLBI), the Center for Medicare & Medicaid Service (CMS), which was formerly known as the Health Care Financing Administration (HCFA), and the Agency for Healthcare Research and Quality (AHRQ), is the first multi-center clinical trial designed to determine the role, safety, and effectiveness of bilateral lung volume reduction surgery (LVRS) in the treatment of emphysema. A secondary objective is to develop criteria for identifying patients who are likely to benefit from the procedure.
Emphysema is a chronic lung condition that is a major cause of death and disability in the United States. Two million Americans are affected, largely those who are over age 50. With emphysema, breathing becomes difficult as the fine architecture of the lung is destroyed, leading to large holes in the lung, obstruction of the airways, trapping of air, and difficulty exchanging oxygen because of reduced elasticity of the lungs.
In the United States, cigarette smoking is by far the most important risk factor for emphysema. Emphysema costs more than $2.5 billion in annual health care expenses and causes or contributes to 100,000 deaths in the U.S. each year.
Current medical treatments include smoking cessation for those who still smoke, exercise rehabilitation, oxygen therapy for those with low blood oxygen levels, supportive and preventive measures such as flu shots, pneumonia vaccine, medications such as bronchodilators to help open airways, prompt treatment of respiratory infections, and lung transplantation.
Emphysema is one form of chronic obstructive pulmonary disease (COPD) -- a slowly progressive disease of the airways that is characterized by a gradual loss of lung function. Chronic bronchitis, chronic obstructive bronchitis, or a combination of these conditions with emphysema also are forms of COPD. COPD is the fourth most common and the most rapidly increasing cause of death in the United States.
In patients with emphysema, the walls between the tiny air sacs in the lungs are damaged. While healthy lungs expand with each inhalation and collapse with each exhalation, helping to move air in and out -- lungs damaged by emphysema gradually lose their elasticity, becoming floppy and over-expanded like a spent rubber band. The airways, normally held open by the elastic pull of the lungs, also become floppy and collapse on exhalation. As a result, patients with emphysema have increasing difficulty moving air in and out of their lungs.
In lung volume reduction surgery (LVRS), the size of the lungs is reduced. The theory underlying the surgery is that reducing the lung size will pull open the airways and allow the breathing muscles to return to a more normal and comfortable position, making breathing easier.
LVRS was first used to treat emphysema in the 1950s. Although some patients seemed to improve following the surgery, high mortality and morbidity associated with LVRS prevented its wide-spread use. In the early 1990s, some physicians began using the procedure again. Early reported successes led to the procedure's rapid spread, despite variable results, small sample sizes, short-term and incomplete follow-ups, and lack of data on risk and patient selection criteria.
In response to concerns about the safety and effectiveness of LVRS, the NHLBI convened a workshop of experts in the treatment of emphysema in 1995. The workshop participants reviewed the available data and were unanimous in their opinion that, before the surgery became widely practiced, a systematic evaluation of patient selection criteria and long-term outcomes should be undertaken.
An independent assessment of LVRS performed for CMS concluded that the current data on the risks and benefits of LVRS were too inconclusive to justify unrestricted Medicare reimbursement for the surgery. However, because it appeared that some patients benefited from the procedure, the Center for Health Care Technology of the AHRQ, which performed the assessment, advised CMS that a trial evaluating the effectiveness of the surgery was essential.
As a result, the NHLBI and CMS announced in April 1996 that they would conduct a scientific study of LVRS to evaluate the safety and effectiveness of the current best available medical treatment alone and in conjunction with LVRS by excision. The agencies undertook NETT with the expectation that it would provide definitive answers to important questions such as:
In late 1996, the participating clinical centers and a coordinating center were announced. Patient screening for entry into the study began in the fall of 1997.
Even after the start of the study, the NETT investigators and CMS continued to review data on the effectiveness of LVRS, but found insufficient follow-up data on too many of the patients to permit conclusions. Medicare claims data showed a 6 month mortality of 16.9% and a 12 month mortality of 23%. Because there was no control group, it was not known whether these outcomes could be attributed to the surgery or to the natural history of the underlying disease.
The trial was designed to take up to 5 years to complete. Recruitment ended on schedule in July 2002, and follow up in December 2002.
After screening, eligible and consenting patients completed a 6-10 week rehabilitation program in which they received medicines and oxygen as needed and participated in a program of exercise and breathing methods.
After successful completion of this rehabilitation program, consenting patients were randomly assigned either to continue this treatment or to have LVRS in addition to continued medical treatment.
For this trial, surgery was performed on both lungs, either by insertion of a tube through the chest wall (bilateral video-assisted thorascopy) or through an incision through the center of the breast bone (median sternotomy). In centers with experience in both techniques, patients assigned to surgery were randomly assigned to one of the surgical methods.
Patients remained under the care of their own physicians while enrolled, but they were evaluated periodically for response to treatment by NETT physicians. These evaluations were scheduled at 6 months, 1 year, and every year thereafter until the conclusion of the trial. Follow-up evaluations included tests of exercise tolerance and pulmonary and cardiovascular function, laboratory and radiologic tests, and psychosocial and quality-of-life assessments.
To be eligible for NETT, participants had a diagnosis of emphysema that substantially reduced their ability to function. They met certain pulmonary function and CT scan requirements and were approved for surgery by a cardiologist, a pulmonologist, and a thoracic surgeon. They could not participate if they were smoking or had smoked tobacco within 4 months, had unstable angina or cardiac arrhythmia, had a heart attack within 6 months, had certain, selected thoracic or cardiac surgeries or had another disease that was likely to interfere with participation in the trial or to reduce survival.
The NETT (National Emphysema Treatment Trial) is a landmark study which clarified short-term and long-term risks and benefits of bilateral lung volume reduction surgery (LVRS) to treat severe emphysema. NETT also identified characteristics that help determine which patients are most likely to benefit from LVRS and which patients are at greater risk of death and complications from LVRS. The results of NETT were presented at the American Thoracic Society International Conference on May 20, 2003, and published in the May 22, 2003, issue of the New England Journal of Medicine (NEJM).
Editorial: Guidance Concerning Surgery for Emphysema
Between January 1998 and July 2002, 3777 people were evaluated at one of the 17 clinical sites participating in the study; 1218 individuals were selected for the trial. All participants initially received 6 to 10 weeks of medical therapy (also known as pulmonary rehabilitation), which included education, counseling, exercise training, and other techniques to help patients understand and manage their condition, and optimize their ability to perform activities of daily living. Participants were then randomly (by chance) assigned to treatment in NETT: 608 were assigned to undergo surgery in addition to medical therapy (LVRS group), and 610 were assigned to medical therapy only (Medical group). Approximately 95 percent of the patients in each group received treatment as directed, and as of January 2003, 99 percent of surviving participants continued to complete telephone or clinic visits with NETT staff. The average follow-up (time since study enrollment) was just over 2 years (29 months).
In LVRS, 20 percent to 35 percent of the most damaged regions of each lung is removed, helping the remaining lung to function better, thereby easing symptoms associated with advanced emphysema. NETT was designed in response to concerns by medical experts that sufficient evidence regarding safety and effectiveness of the LVRS was lacking, even though the procedure was proposed as a treatment for patients with severe emphysema. The experts debated the risks and benefits of LVRS and patient selection criteria. Two Federal agencies - the National Heart, Lung, and Blood Institute of the National Institutes of Health, and the Agency for Health Care Policy and Research (now the Agency for Healthcare Research and Quality), as requested by the Health Care Financing Administration (now the Centers for Medicare & Medicaid Services) -- independently and simultaneously sought outside expert opinion. Each agency was advised that a large, prospective clinical trial that studied long-term outcomes of LVRS was needed.
NETT researchers found that, on average, patients with severe emphysema who undergo LVRS with medical therapy are more likely to function better and do not face an increased risk of death compared to those who receive only medical therapy. However, results for individual patients varied widely. Details about the results are provided below.
Risks of LVRS
Overall, the mortality (death rate) was the same for the LVRS and medical groups over the 29 months of follow-up. However, the risk of death during the first three months after randomization was higher in the LVRS group compared to the Medical group: 7.9 percent for the LVRS group versus 1.3 percent for the Medical group.
In May 2001, NETT investigators stopped enrolling people with severe lung obstruction and either limited ability to exchange oxygen when breathing or emphysema that was evenly distributed throughout their lungs. These participants had an unacceptably high risk of mortality after surgery and little chance of functional benefit. The results on these 140 patients were published in the New England Journal of Medicine in October 2001. (See NHLBI news release, "NHLBI-Funded Emphysema Study Finds Certain Patients at High Risk for Death Following Lung Surgery,") The most recent results confirm the results seen in 2001.
After excluding the high-risk patients identified above, the mortality for the remaining 1048 participants was still about the same for the LVRS and Medical groups measured throughout follow-up. During the first three months after randomization, the risk of death for the non-high-risk LVRS group was 5.2 percent, still higher than the 1.5 percent mortality for the Medical group. In addition, more surgical than medical patients required hospitalization or nursing home placement for the first eight months after treatment assignment.
Benefits of LVRS
To study the benefits of LVRS added to medical therapy, NETT researchers measured lung function, quality of life scores, dyspnea (shortness of breath), and exercise capacity, in addition to survival, illness and hospitalization rates. Exercise capacity was measured in units called watts using a bicycle test; the test was done while patients received oxygen and after they completed pulmonary rehabilitation. Assessments were made at screening, following the initial pulmonary rehabilitation, at 6 months, 12 months, and yearly thereafter, for an average follow up of 29 months. Patients were considered to have improved exercise capacity when their bicycle test score increased by more than 10 watts. The investigators established this parameter because they believed that this degree of improvement justified the risks associated with surgery.
The effects of LVRS on the many follow-up measures varied widely. Overall, more patients in the surgical group than in the medical group improved in function, symptoms, and quality of life. For example, 15 percent of those treated with surgery had more than a 10 watt change in exercise capacity at two years compared to 3 percent for those treated with medical therapy alone.
The non-high-risk survivors in the surgery group initially improved their scores (e.g., lung function, exercise capacity on a bicycle, distance walked in 6 minutes, assessment of quality of life, feelings of shortness of breath); however, over the two years of follow up, the scores declined, on average, to about the same level as before LVRS. In contrast, functional ability in participants who received medical therapy without surgery consistently worsened over two years, resulting in functional levels falling below the level at the visit just before randomization in NETT.
Patient Characteristics That Predict Outcome for Surgery
Although the effects of LVRS added to medical therapy varied widely among participants in the non-high-risk group, researchers found two characteristics that helped predict whether an individual participant would benefit from LVRS. These were whether the emphysema was concentrated in the upper lobes (areas) of the lungs and whether exercise capacity was low or high. Exercise capacity was measured as described above - after medical therapy but before surgery, for those in the LVRS group. A low exercise capacity score was less than or equal to 25 watts for females, or less than or equal to 40 watts for males; a high score was more than 25 watts for females or more than 40 watts for males. These two characteristics combined to form four groups of participants who had different risks and benefits from LVRS:
NETT investigators also conducted a prospective cost-effectiveness analysis over three years of follow up as part of the trial. They found that in the short term, LVRS added to medical therapy was less cost effective than many surgical procedures, in part because of high costs related to the procedure. For the LVRS group, average costs were very high in the first year following surgery due to expected procedure-related expenses as well as prolonged postoperative inpatient care, which was needed by most patients.
In the third year of follow up, however, total medical care costs were equivalent in both the LVRS and the medical therapy only groups. Nonmedical costs such as transportation for and time in treatment, and time spent by unpaid caregivers (family and friends), were similar overall in both treatment groups.
Whether LVRS will prove cost effective over the long term remains uncertain. To estimate cost effectiveness beyond the trial, NETT investigators applied statistical modeling based on observed trends in survival, cost, and quality-of-life measures. They concluded that if the benefits from LVRS are maintained, the cost effectiveness for surgery added to medical therapy could ultimately approach levels consistent with other treatments that are considered good value for expenditure. This outcome would be especially likely for patients found to gain the most from LVRS -- those with upper-lobe emphysema and low exercise capacity - who demonstrated higher survival rates and quality-of-life scores at the end of the three-year period.
The Centers for Medicare & Medicaid Services (CMS) (formerly the Health Care Financing Administration) was a co-sponsor of NETT. With the availability of NETT data, Medicare is re-evaluating its policy on coverage of LVRS for its beneficiaries. While NETT was ongoing, Medicare covered LVRS only for patients who were participants in the study.
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May 20, 2003
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