SEATTLE—Now that the National Emphysema Treatment Trial (NETT) results are available, patients and their physicians can begin making better-informed decisions about the appropriateness of lung-volume–reduction surgery (LVRS) for severe emphysema.[1] The results suggest that for carefully selected patients, the procedure can prolong survival and improve function. For other patients, however, LVRS may adversely affect outcome.

The reason that NETT was conducted was simple: “NETT was developed in response to concerns … about a new procedure that was diffusing rapidly into practice but had unclear risks and benefits,” explained Gail G. Weinmann, MD, Director of the Airway Biology and Disease Program at the National Heart, Lung, and Blood Institute in Bethesda, Maryland.

Because of NETT, the mortality risk associated with LVRS is now much clearer, as is the procedure’s effect on exercise capacity, lung function, and quality of life in patients with severe emphysema.[1] Surprisingly, an economic analysis also suggests that for some patients, LVRS may be cost-effective—if the benefits it produces are maintained for five years or longer.[2]

“But obviously, that is a big if,” acknowledged Scott D. Ramsey, MD, associate member of the Division of Public Health Sciences at the Fred Hutchinson Cancer Research Center in Seattle. He, Dr. Weinmann, and seven other NETT investigators presented the clinical results and cost-effectiveness data from the trial at the annual conference of the American Thoracic Society in Seattle.[3]

TRIAL WAS ADEQUATELY POWERED

Of the 3,777 patients evaluated for NETT, 1,218 were randomized to medical treatment alone or medical treatment in conjunction with LVRS. Before randomization, eligible patients completed six to 10 weeks of supervised pulmonary rehabilitation.

About two thirds of the way into the trial, an interim analysis showed that patients with a predicted forced expiratory volume in one second (FEV1) of 20% or less and either a homogeneous distribution of emphysema or a predicted carbon monoxide–diffusing capacity (DLCO) of 20% or less were unlikely to benefit from LVRS; in fact, such patients faced an increased risk of death if the procedure was done. Following the interim analysis, these patients were no longer eligible for randomization.

The 608 patients assigned to LVRS underwent bilateral stapled wedge resection via median sternotomy or video-assisted thoracic surgery. The goal of surgery was to resect 20% to 35% of each lung through removal of the most diseased portions.

The investigators had planned to include 2,500 patients to ensure that NETT would be adequately sized to assess mortality. However, enrollment was slow; by the end of the study, only half that many patients had been enrolled. The investigators could nonetheless assess differences in mortality because the death rate in the medically treated patients was higher than expected, and the crossover rate was lower. “So, NETT … is adequately powered and sufficiently precise for the mortality outcome,” stressed Steven Piantadosi, MD, PhD, Professor of Biostatistics at the Johns Hopkins Bloomberg School of Public Health in Baltimore.

The LVRS group and the 610 patients assigned to medical therapy were clinically and demographically similar at the time of randomization, except that the latter group had a higher proportion of men. Treatment adherence was high in both groups—95.4% and 94.6%, respectively—and 99% of the survivors were evaluated by telephone quarterly or in a clinic annually during follow-up, which averaged 29.2 months.

OVERALL MORTALITY, OUTCOMES

Many physicians do not view survival as an important indicator of LVRS’s value because it is possible for patients to survive yet have a worse functional outcome. Nevertheless, the investigators felt that survival was a key component of procedural success, said Keith S. Naunheim, MD. “It is damned hard to have a successful outcome without survival,” asserted Dr. Naunheim, Professor of Cardiothoracic Surgery at St. Louis University.

Short-term mortality results did not seem to favor LVRS: Overall 90-day mortality was 7.9% in the LVRS patients versus 1.3% in the medical group. Even after the investigators excluded the 140 patients who were identified by the interim analysis as being at high risk for death after LVRS (those with an FEV1 of 20% or less and either a homogeneous distribution of emphysema or a predicted DLCO of 20% or less), 90-day mortality in the two groups was 5.2% and 1.5%, respectively. Clearly, “there is [an up-front] cost to be paid for lung-volume reduction,” Dr. Naunheim observed.

By the end of the study, though, overall mortality in the two groups was the same—157 and 160 deaths, respectively. The total mortality rate was 0.11 deaths per person-year in both groups.

Among survivors, however, LVRS was more likely to produce functional improvement, even shortly after the surgery. At six months, for example, clinically significant increases in exercise capacity were observed in 28% of the LVRS patients but in only 4% of the medical group. At 12 months, such increases were seen in 22% and 5% of patients, respectively; at 24 months, the corresponding figures were 15% and 3%. The LVRS group was also more likely to experience improvements in the distance they could walk in six minutes, percentage of predicted FEV1, degree of dyspnea, and general and health-related quality of life.

MAJOR INFLUENCE: DISEASE DISTRIBUTION

Among the 1,078 patients who were not considered to be at high risk, the craniocaudal distribution of emphysema—specifically, the presence or absence of upper-lobe predominance—and exercise capacity were the only baseline factors that could predict mortality in the two groups. The distribution of emphysema, but not exercise capacity, could also predict functional improvement. No baseline factors could predict changes in quality of life.

When the authors stratified patients into four subgroups based on emphysema distribution and baseline exercise capacity, some important differences in 24-month outcome were observed. The benefits of LVRS were most pronounced in the subgroup of 290 patients with primarily upper-lobe emphysema and low exercise capacity at baseline. In this cohort, those who underwent LVRS were less likely to die than were those who received medical therapy; the LVRS group was also more likely to experience clinically significant improvements in exercise capacity and in health-related quality of life.

Among the 419 patients with primarily upper-lobe disease and high baseline exercise capacity, no difference in mortality was observed. However, LVRS produced greater improvements in exercise capacity and health-related quality of life.

Among the 149 patients with primarily lower-lobe or diffuse emphysema and low baseline exercise capacity, no differences in mortality or exercise capacity were seen. The LVRS group did have a greater improvement in health-related quality of life, though.

In contrast, among the 220 patients who had lower-lobe or diffuse emphysema and high baseline exercise capacity, LVRS doubled the risk of death. Furthermore, surgery was no more likely than medical therapy to produce improvements in exercise capacity or quality of life.

COST-EFFECTIVENESS DATA

The economic analysis, which excluded the high-risk patients, found (not surprisingly) that by the end of the follow-up period, the average total costs per patient were much higher in the patients who underwent LVRS than in those given medical therapy—$98,952 versus $62,560. However, the LVRS group gained an average of 1.46 quality-adjusted life-years (QALYs), whereas the medical cohort gained only 1.27 years; this difference was statistically significant.

Thus, the cost-effectiveness ratio (ie, the cost per QALY gained) for LVRS, as compared with medical treatment, was calculated to be $190,000 at the end of follow-up; however, it was estimated to be only $53,000 after 10 years. The most favorable cost-effectiveness ratio was found in the patients with predominantly upper-lobe emphysema and low baseline exercise capacity: $98,000.

Dr. Ramsey concluded, therefore, that shortly after the surgery, LVRS is quite costly when compared with many other operative procedures. However, it may prove cost-effective in the long run.

The NETT data “will shape our thinking about this procedure for years to come,” commented Jeffrey M. Drazen, MD, and Arnold M. Epstein, MD, in an editorial that accompanied publication of the NETT studies.[4] It does not make sense, the editorialists suggested, to offer LVRS to patients who have anatomically unfavorable emphysema or who are at high risk for death from the procedure; such patients represent approximately 30% of the NETT population. “For the remaining patients, the NETT results provide guidance but not direction,” they concluded.

—Timothy Begany

References
1. National Emphysema Treatment Trial Research Group. A randomized trial comparing lung-volume–reduction surgery with medical therapy for severe emphysema. N Engl J Med. 2003;348: 2059-2073.
2. National Emphysema Treatment Trial Research Group. Cost effectiveness of lung-volume–reduction surgery for patients with severe emphysema. N Engl J Med. 2003;348:2092-2102.
3. Weinmann GG, Piantadosi S, Naunheim KS, et al. Results of the National Emphysema Treatment Trial. Presented at: annual conference of the American Thoracic Society; May 20, 2003; Seattle, Wash.
4. Drazen JM, Epstein AM. Guidance concerning surgery for emphysema. N Engl J Med. 2003; 348:2134-2136.

Return to table of contents