Behind The Medical Headlines

Lung volume reduction surgery for emphysema: the national emphysema treatment trial (NETT)

• Professor W MacNee, Professor of Respiratory & Environmental Medicine and Honorary Consultant Physician, University of Edinburgh, Scotland

Summary

Lung-volume reduction surgery has been proposed as a means of alleviating severe emphysema. How much of a benefit could this procedure have on alleviating symptoms and prolonging life? And do the benefits outweigh the costs? Prof Bill MacNee reviews a major study which set out to answer these questions.

Declaration of interests: No conflict of interests declared

Lung-volume-reduction surgery (LVRS) has been proposed as a palliative treatment for patients with severe emphysema. The procedure leads to a decrease in lung volumes and an increase in elastic recoil of the lungs. Decreasing lung volumes improves respiratory muscle geometry and hence performance, while increasing elastic recoil increases expiratory airflow, leading to improved exercise performance and reduced dyspnoea. However uncertainty over the preoperative predictors of benefit and the effects on morbidity and mortality led to a National Institutes of Health-sponsored multicentre randomised control trial in the US, comparing LVRS with medical therapy for patients with severe emphysema. The outcome of this trial has recently been published in the New England Journal of Medicine.^1,2

Before randomisation, all of the patients in this trial underwent pulmonary rehabilitation. The primary outcome measurements were overall mortality and maximum exercise capacity two years after randomisation with secondary outcomes including results of six-minute walking test, lung-function tests and general health-related quality of life.

In the trial, 1,218 patients with severe emphysema as shown on CT scan assessment were randomised to either LVRS or medical therapy. An interim analysis of the study showed that patients with the most severe disease (FEV1 20% predicted and either homogeneous emphysema on HRCT or a carbon monoxide diffusing capacity of 20% predicted) had a higher risk of death following surgery than medical treatment.³ In the subsequent analysis, 140 such patients were excluded leaving 538 patients randomly assigned to surgery and 540 assigned to medical therapy. Those assigned to surgery were more likely to have improvements in exercise capacity and quality of life but with no reduction in mortality during an average 29 months of follow-up.

However, secondary analyses showed that the effects of surgery on mortality varied widely depending on the presence of predominantly upper-lobe emphysema on high-resolution computed tomography of the chest and whether the patient had a high or low exercise capacity at baseline defined as a maximum work load at or below a cut-off value of 25 watts for women and 40 watts for men. In patients with predominantly upper-lobe emphysema and a low exercise capacity, the risk ratio for death in the surgery compared with the medical group was 0.47 (p=0.005), indicating a significant benefit of surgery. Those patients with predominantly upper lobe emphysema and high exercise capacity showed no benefit of surgery over medical treatment, and in those with non-upper-lobe emphysema and high exercise capacity the risk of death was higher among those who underwent surgery.

Mortality following LRVS varies greatly among centres. The NETT research group showed a 90-day surgical mortality of 7.9% in all randomised patients compared to 1.3% in a comparably medically treated arm.¹ The majority of this mortality was accounted for by high risk patients in whom the 90-day surgical mortality was 28.6% compared with 0% in the respective medical arm.¹ In non-high risk patients 90 day surgical mortality was 5.2% compared with 1.5% in medically treated patients.¹ During the first year of follow-up, the mean number of in-patient hospital days per person was significantly higher in the surgical group (24.9 days) compared with the medically treated group (4.9 days p<0.001). In contrast in the second year of the mean number of hospital days per person was significantly lower in the surgical group (3.2 days) than in the medically treated group (6.1 days, p<0.005) and in the third year there were no significant differences between the two groups in terms of the use of resources.

An economic evaluation revealed that the total medical costs were substantially higher in patients in the surgical group than for patients in the medical therapy group largely due to the costs of surgery during the course of the first six months, but from months 7-36 the mean medical cost was lower in the surgical group ($36,199) than in the medical group ($49,628, p<0.001), largely because patients in the surgical group had fewer hospital-admitted days during that period.

When the patients with high-riskconditions were excluded the cost effectiveness ratio for LVRS compared with medical therapy was $190,000 per quality-adjusted life-year gained. This compares, for example, with a $90,000 per quality-adjusted life-year gained for lung transplantation.⁵

The results of this trial have raised some questions about the interpretation of secondary analysis of the data collected in clinical trials. It was the purpose of the NETT trial to identify sub groups of patients who might benefit, or be at increased risk, from LVRS. Although there appears to be an interaction between upper-lobe disease and low exercise capacity in terms of reduced mortality, there is a risk when multiple characteristics of patients are considered that there is an increased probability that one or more tests will be statistically significant by chance.

Few studies have reported long-term results of LVRS, but they suggest widely varying long-term morbidity and mortality among centres, a return of spirometric function towards pre-operative baseline and worsening of dyspnoea over time.⁵

How then are we to interpret these results and translate them to clinical practice? It appears that the findings of the NETT study provide evidence that surgery has some benefit in terms of increased exercise tolerance and survival in patients with upper-lobe predominance of emphysema and low exercise capacity compared to medical treatment. The procedure is costly, but may be cost-effective if the benefits can be maintained over time.

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; 348:2059-73.
2. National Emphysema Treatment Trial Group. Cost effectiveness of lung-volume reduction surgery for patients with severe emphysema. N Engl J Med 2003; 348:2092-102.
3. National Emphysema Treatment Trial Research Group. Patients at high risk of death after lung-volume reduction surgery. N Engl J Med. 2001; 345:1075-83.
4. Ramsey SD, Patrick DL, Albert RK, Larson ED, Wood DE, Raghu G. The cost effectiveness of lung transplantation: a pilot study. Chest 1995; 108:1594-601
5. Gelb AF, Brenner M, McKenna RJ, Fischel R, Zamel N, Schein MJ. Serial lung function and elastic recoil after lung volume reduction surgery for emphysema. Chest 1998; 113:1497-1506.