Key points

Introduction

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of mortality in the United States. In 2015 there were 15.5 million adults diagnosed with the lower respiratory disease with 335,000 Medicare hospitalizations and 150,350 associated deaths. Medical treatment consists of a combination of inhaled corticosteroids, bronchodilators, oxygen, and pulmonary rehabilitation. Despite treatment, mortality remains minimally changed over the past 30 years at approximately 40 deaths per 100,000 US population. As early as 1950, surgical lung resection of diseased lung was proposed as potentially beneficial COPD treatment. However, prohibitively high morbidity and mortality caused the procedure to fall out of favor. Lung-volume-reduction surgery (LVRS) was reborn in 2003 when Joel Cooper and colleagues demonstrated the ability to significantly improve outcomes of targeted lung resection by taking advantage of 40 years worth of advances in technology, technique, anesthesia, critical care, and rehabilitation.

The overall goal of LVRS is removal of emphysematous lung in order to enhance overall pulmonary function. Multiple mechanisms have been credited with this beneficial enhancement, including improvements in pulmonary elastic recoil, diaphragmatic function, left ventricular filling, endothelial health, as well as decreased functional residual capacity and intrathoracic pressure. Single-institution studies initially published demonstrated significant variation in operative mortality (2.5%–19%) with 1-year mortality as high as 23%. ^, Uncertainty around the operative morbidity, mortality, magnitude of benefit, duration of improvement, and prognostic predictors of LVRS led to the creation of the National Emphysema Treatment Trial (NETT). This federally funded, multicenter study was created to directly compare LVRS with maximal medical therapy for severe emphysema in a randomized controlled fashion. Much of our current treatment of COPD is still based on this trial.

National Emphysema Treatment Trial

The NETT was initiated in 1998 in order to clarify the benefit of LVRS. Previously published studies on the efficacy of LVRS were relatively small and included patient cohorts with differing clinical characteristics operated on using various surgical techniques. Almost all studies lacked long-term follow-up and did not comprehensively assess benefit, risk, or cost. NETT sought to reduce the variability in patient characteristics, surgical technique, patient care, and follow-up with the creation of a multiinstitution randomized study. Given the lack of clarity surrounding both the risk and the benefit of surgical intervention, both were evaluated as the study’s primary outcome measures. Survival was chosen as a primary outcome, given its ease and accuracy of measurement as well as its clinical significance in a population with emphysema and a resultant high baseline mortality. The other primary outcome measurement was exercise capacity as determined by cycle ergometry. This was chosen over other modalities due to its reproducibility, standardization, and administration. In addition, exercise capacity was favored over pulmonary function testing (PFT), as the latter had not demonstrated a consistent relationship with functional status. A 10-W change in exercise performance and an 8-point change in St. George Respiratory Questionnaire were deemed meaningful clinical changes in exercise capacity. The trial also looked at several secondary outcomes including quality of life (Medical Outcomes Study 36-Item Short Form and Quality of Well-Being Scale), cost, complications, PFTs, radiologic volumetric analysis, 6-minute walk distance, cardiovascular measures, and psychomotor function.

The study was designed as a randomized controlled non-crossover comparison of maximal medical therapy with medical therapy plus LVRS in patients with severe. Patients were randomized in a 1:1 fashion between treatment groups and then within the surgery group were randomized further between median sternotomy and video-assisted thoracoscopic surgery (VATS) in those institutions capable of performing both. Seventeen centers participated in the trial in total, with 8 performing sternotomies only, 3 performing VATS only, and 6 randomizing between the two. Regardless of the approach, the goal was to resect 20% to 35% of bilateral lungs, targeting the most diseased portions. Patients were required to have severe COPD with a forced expiratory volume in 1 second (FEV ₁ ) less than or equal to 45%, a total lung capacity greater than or equal to 100%, a residual volume (RV) greater than or equal to 150%, and Pa co ₂ less than or equal to 60 mm Hg. They were additionally expected to have quit smoking for more than 4 months and to have attended pulmonary rehabilitation for at least 6 to 10 weeks before intervention. Exclusion criteria included prior major lung surgery and/or infection, significant cardiac disease, severe obesity, recent malignancy, 6-minute walk less than 140 m after rehabilitation, or another significant comorbidity.

Before treatment, patient demographics, pulmonary function, imaging, functional status, exercise capacity, and quality of life were measured. Full assessment was repeated at 6 months, 12 months, and then yearly. As a safety measure, at the onset of the study, the monitoring board was providing stopping guidelines to be used to identify those that were clearly benefited and those that were clearly harmed by LVRS. An 8% 30-day mortality was used as the cutoff of unacceptable risk. Initially those predicted to benefit most from surgical intervention were those younger than 70 years with FEV ₁ between 15% and 35% of predicted, Pa co ₂ less than 50 mm Hg, RV greater than 200% of predicted, and with a heterogeneous pattern of emphysema with minimal perfusion. These variables were monitored by the board as well as diffusing capacity of the lungs for carbon monoxide (DLCO), work capacity, quality of life, race, and sex. In addition to the regular assessments discussed earlier, these variables were reviewed every 3 months for signs of clear patient benefit or risk. In April of 2001 low FEV ₁ , homogeneous emphysema, a high perfusion ratio, and low DLCO demonstrated an increased risk of mortality. Additional analyses were performed to define if these parameters met the unacceptable risk criteria. They found that the combination of an FEV ₁ less than or equal to 20% of predicted with either homogeneous emphysema or DLCO less than or equal to 20% of predicted led to an 18% 30-day surgical mortality compared with zero deaths in the medical arm of the study. These groups were labeled as “high risk” and subsequently excluded from the trial.

NETT continued to accrue until 2002, and by 2003 the first complete analysis was performed. In total 1218 patient were randomized out of 3777 evaluated, with 608 in the surgery arm and 610 in the medical arm. One hundred forty of these patients were in the preexclusion high-risk group with 42 and 30 in the surgical and medical arms, respectively. Baseline characteristics were similar between both treatment arms except that there was a higher proportion of men in the medical-therapy arm. Initial, analysis looked at the primary outcomes over the 4-year trial period and with a mean patient follow-up of 2.4 years. Over the following years, subsequent analyses looked at NETT’s secondary outcomes and were eventually followed by an updated publication of the primary outcomes. This latter long-term analysis published in 2006 had a median patient follow-up of 4.3 years with 40% more 2-year-postrandomization data than the initial report.

Primary outcomes

Mortality

On initial analysis, 90-day mortality was revealed to be 7.9% (95% confidence interval, 5.9–10.3) in the surgery group, significantly higher than the 1.3% (95% confidence interval, 0.6–2.6) of the medical group ( P <.001). This was however considered expected, given the immediate trauma of surgery and overall mortality was not significantly different between groups with a total morality of 0.11 deaths per person-year in both treatment arms. When the previously discussed high-risk group was removed from the analysis, 90-day mortality was 5.2% in the surgical arm compared with 1.5% in the medical arm, whereas overall mortality was 0.09 and 0.10 deaths per person-year, respectively ( P = .31) ( Table 1 ). Interestingly, despite increased early mortality in the LVRS arm, long-term analysis in 2006 demonstrated that total mortality was 0.11 deaths per person-year in the surgery group versus 0.13 in the medical group, a statistically significant difference ( P = .02). This benefit of surgery remained with removal of the high-risk group from analysis with 0.10 and 0.12 deaths per person-year, respectively. In subgroup analysis, mortality was reviewed in relation to the distribution of emphysema as well as exercise capacity. The 2003 initial analysis found that surgery most benefited patients with upper-lobe–predominant emphysema and low pretreatment exercise capacity. In this group, 90-day mortality was no different between the LVRS and medical arms (2.9% vs 3.3%, P = 1.0), and total mortality was significantly better after undergoing surgery (0.07 vs 0.15 death per person-year, P = .005). This benefit continued in the long-term follow-up ( Fig. 1 ). In patients with non–upper-lobe emphysema, 90-day mortality was significantly higher in the surgery group regardless of exercise capacity, and total mortality was significantly higher for those with a high exercise capacity.

Table 1

Ninety-day and total mortality among all patients and non–high-risk subgroups at 3 years

From 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; with permission.

Patients	90-Day Mortality			Total Mortality
	Surgery Group	Medical-Therapy Group	P Value	Surgery Group		Medical-Therapy Group		Risk Ratio	P Value
	No. of Deaths/Total no. (% [95% CI])			No. of Deaths/Total no.	No. Of Deaths/Person-Year	No. of Deaths/Total no.	No. of Deaths/Person-Year
All patients	48/608 (7.9 [5.9–10.3])	8/610 (1.3 [0.6–2.6])	<.001	157/608	0.11	160/610	0.11	1.01	0.90
High-risk †	20/70 (28.6 [18.4–40.6])	0/70 (0 [0–5.1])	<.001	42/70	0.33	30/70	0.18	1.82	0.06
Other	28/538 (5.2(3.5–7.4])	8/540 (1.5 [0.6–2.9])	.001	115/538	0.09	130/540	0.10	0.89	0.31
Subgroups ‡
Patients with predominantly upper-lobe emphysema
Low exercise capacity	4/139 (2.9 [0.8–7.2])	5/151 (3.3 [1.1–7.6])	1.00	26/139	0.07	51/151	0.15	0.47	0.005
High exercise capacity	6/206 (2.9 [1.1–6.2])	2/213 (0.9 [0.1–3.4])	.17	34/206	0.07	39/213	0.07	0.98	0.70
Patients with predominantly non–upper-lobe emphysema
Low exercise capacity	7/84 (8.3 [3.4–16.4])	0/65 (0 [0–5.5])	.02	28/84	0.15	26/65	0.18	0.81	0.49
High exercise capacity	11/109 (10.1 [5.1–17.3])	1/111 (0.9 [0.02–4.9])	.003	27/109	0.10	14/111	0.05	2.06	0.02

 

Mean patient follow-up of 29.2 months.

† High-risk patients were defined as those with a forced expiratory volume in one second (FEV1) that was 20 percent or less of the predicted value and either homogeneous emphysema on computed tomography or a carbon monoxide diffusing capacity that was 20 percent or less of the predicted value.

‡ High-risk patients were excluded from the subgroup analyses. For total mortality, P for interaction=0.004; this P value was derived from binary logistic-regression models with terms for treatment, subgroup, and the interaction between the two, with the use of an exact-score test with three degrees of freedom. Other factors that were considered as potential variables for the definition of subgroups included the base-line FEV1, carbon monoxide diffusing capacity, partial pressure of arterial carbon dioxide, residual volume, ratio of residual volume to total lung capacity, ratio of expired ventilation in one minute to carbon dioxide excretion in one minute, distribution of emphysema (heterogeneous vs. homogeneous), perfusion ratio, score for health-related quality of life, and Quality of Well-Being score; age; race or ethnic group; and sex.

Kaplan-Meier curves representing the cumulative probability of death after randomization of LVRS and medical treatment groups. ( A ) All patients. ( B ) Non–high-risk patients. ( C ) Upper-lobe-–predominant, low exercise capacity. ( D ) Upper-lobe–predominant, high exercise capacity.

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