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Ann Thorac Surg 2006;81:314-321
© 2006 The Society of Thoracic Surgeons

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Original article: General thoracic

A Randomized Clinical Trial of Lung Volume Reduction Surgery Versus Best Medical Care for Patients With Advanced Emphysema: A Two-Year Study From Canada

^a Division of Thoracic Surgery, McMaster University/St. Joseph's Hospital, Hamilton, Ontario
^b Division of Thoracic Surgery, University of Western Ontario, London, Ontario
^c Division of Thoracic Surgery, University of Manitoba, Winnipeg, Manitoba
^d Respiratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada

Accepted for publication July 18, 2005.

^_* Address correspondence to Dr Miller, McMaster University, 50 Charlton Avenue East, Hamilton, Ontario, Canada, L8N 4A6 (Email: jmiller{at}mcmaster.ca).

Presented at the Forty-first Annual Meeting of The Society of Thoracic Surgeons, Tampa, FL, Jan 24–26, 2005.

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Discussion Acknowledgments References

 
BACKGROUND: We present a summary report evaluating the efficacy of lung volume reduction surgery (LVRS) in patients with advanced emphysema in the Canadian setting.

METHODS: Quality of Life measures assessed the efficacy of adding LVRS to best medical care including rehabilitation in this blinded randomized multicentered controlled trial with 2 years of follow-up. Health utility and quality-adjusted life years (QALY) were outcomes central to our economic assessment.

RESULTS: None of the 32 patients randomized to the LVRS arm or 30 patients in the best medical care (BMC) arm crossed-over and no patients were lost to follow-up. Overall surgical mortality was 16% at 2 years while the overall medical mortality was 13% (p = 0.914). There were no 30-day postoperative deaths but 2 deaths (6%) occurred within 90 days of randomization. Surgery reduced the residual volume measured at 6 months by 23% (5,385 mL to 4,322 mL, p = 0.007). There was an increase in forced expiratory volume in 1 second (FEV₁) of 30% (265 mL, p = 0.013) from baseline, an improvement in the six minute walk test (6MWT) of 78 meters (p = 0.045), and an increase in Health Utility Index 3 (HUI3) which peaked at 6 months with a difference of 0.16 (p = 0.129). There was a gain in QALYs of 0.21 (p = 0.19) in the LVRS-arm over the BMC-arm. The LVRS costs an additional $28,119 Canadian dollars (CAD) compared with BMC or $133,900/QALY gained.

CONCLUSIONS: The addition of LVRS to best medical care including pulmonary rehabilitation improves pulmonary function, exercise activity, and quality of life in selected patients with advanced emphysema. Cost is high but in keeping with other treatment modalities currently available.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment Discussion Acknowledgments References

 
Chronic obstructive pulmonary disease is the fifth most common cause of death and is the only leading cause of death that is rising in prevalence. Despite the results of seven randomized trials and several case series demonstrating a benefit to patients, physicians remain routinely reluctant to recommend surgery to their patients with emphysema as a palliative measure [1–10]. Information about the risks, benefits, and costs of lung volume reduction in a Canadian setting has been lacking. We report the final clinical and economic results of a multicenter Canadian trial with 2-year follow-up.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment Discussion Acknowledgments References

 
Patient Selection
Five Canadian centers enrolled patients into the CLVR study conditional on specific inclusion and exclusion criteria (Table 1). Patients were not excluded for homogeneous disease. After screening, patients who qualified for the trial were referred for a standardized pulmonary rehabilitation program. Medical therapy was optimized [11], baseline testing (prerandomization) was performed (Table 2), and patients who qualified were randomized in a 1:1 allocation ratio between lung volume reduction surgery (LVRS) and optimal medical therapy. Patients assigned to LVRS proceeded to surgery within 2 weeks. All outcome events were attributed on an intent-to-treat basis. Crossover between study arms was not permitted. Recruitment started July 1997 and finished January 2001. Institutional ethics approval of this study was obtained on June 1996 and each patient within the study gave informed consent for serving as a subject.

Outcome Measures
Outcome measurements included assessment of body function, activity, and participation. Body function was measured using pulmonary function and blood gases. Activity level was assessed by the six minute walk test (6MWT). The predetermined minimally clinically important difference (MCID) for FEV₁ was determined to be 200 mL or an increase from baseline of 20% [14] and a MCID for 6MWT was considered to be 30 meters [15]. Participation was assessed by Quality of Life (QOL) questionnaires; the disease-specific Chronic Respiratory Disease questionnaire (CRQ) [16], the generic Medical Outcomes Survey Short-Form 36 (SF-36) [17], and the most general Health Utility Index (HUI3), our primary outcome [18].

The CRQ is an interviewer-administered questionnaire that measures the patients' physical and emotional symptoms as they relate to emphysema. Each item is scored on a 7 point modified Likert Scale from 1 (maximum impairment) to 7 (no impairment). Changes in the score of 0.5, 1.0, and 1.5 were regarded as small, moderate, and large effects, respectively [19].

The Medical Outcome Study Short Form (SF-36) is a self-administered questionnaire with 8 domains and two components. Each domain is scored 0 to 100 with the highest number representing the best health state, while the Physical and Mental Component Summaries have a mean score of 50 and a standard deviation of 10. In this study 5 was considered a small clinical change while 10 was a large change. The HUI3 is a generic preference-based approach to the measurement of health status and health-related quality-of-life [20]. The scoring for HUI3 assigns a single summary number in the interval between 0.00 (death) and 1.00 (perfect health) with negative values for health states worse than death. The HUI3 difference between intervention arms over the 2 years of the study is expressed in quality-adjusted life years (QALYs) gained. A MCID of 0.05 was determined by review with a panel of stakeholders and experts, consisting of patients, thoracic surgeons, respirologists, and a methodologist. The QALYs have become essential outcome measures for clinical trials and are recommended by the United States Public Health Commission on Research in Health and Medicine [21].

A trained individual who was blinded to the patient treatment allocation administered all measurement of the 6MWT, pulmonary function studies, CRQ, and HUI3. The incremental cost-effectiveness of LVRS compared with BMC alone over a 2-year time horizon was assessed and was defined as the ratio of the difference between treatment groups in mean costs to the difference in quality-adjusted life years (cost per QALY). The economic analysis was conducted from the viewpoint of a provincial government healthcare payer.

Price weights were applied to resource use data to estimate the total healthcare cost for each patient. Price weights for hospital resources were provided by a large Ontario Case Costing Project teaching hospital in Ontario [22] that was participating in the CLVR study. Costs of physician services were taken from the Ontario Schedule of Benefits [23]. Unit costs for drugs were derived from the Ontario Drug Benefits Schedule [24]. Costs are reported in 2004 Canadian dollars (CAD).

Statistical Analysis
The primary outcome of the trial was the difference in QALYs between the two intervention arms using HUI3 as the basis of this calculation. The primary analysis was a two-way analysis of variance with center blocking and treatment as the two factors. Blocking was done in groups of 2 or 4. Randomization, in a 1:1 allocation ratio between treatment arms with surgeon stratification, was performed at the Data Coordinating Center to ensure concealment of the process. The sample size calculation was based on a two-tailed type I error rate, alpha of 5%, with a power of 90%, and clinically important difference of 0.10 over the 2-year period. We estimated a need of 350 patients. Nonparametric bootstrap methods were used to calculate a 95% interval for the incremental cost effectiveness ratio.

Quality-Adjusted Values
While it is common to integrate (health) utility values collected over time by using the area under the curve drawn between multiple time points to compute QALYs, this procedure is less common with clinical outcomes. Recent literature [20] has suggested that any measure that is either interval or a ratio, can be integrated to get an overall assessment over the time course of the trial. In this study, we used the outcome measures at each and every time point where the data were recorded. We then used the area over the 2 years (730 days) of the trial to determine a value. Dividing this value by 730 resulted in a quality-adjusted value for each patient for that variable. Comparing each arm of the study using this quality-adjusted value would measure the impact of surgery relative to medicine. This approach was preferred to comparing multiple values over time that are not statistically independent such that any differences could lead to confusion. The quality-adjusted value provides a global average assessment of each outcome and is intuitive and simple to interpret because it uses the same units as the original measurements.

	Results

Top Abstract Introduction Patients and Methods Results Comment Discussion Acknowledgments References

 
Sixty-two patients completed pulmonary rehabilitation and were candidates for randomization. Thirty-two patients were randomized to surgery and 30 to best medical care. The demographics of all patients randomized are outlined in Table 2. All patients were followed to 2 years or to their death.

There were 3 patients randomized to the LVRS arm who did not undergo LVRS. One withdrew from the study prior to the scheduled surgery date and refused to be followed further. A second patient's operation was postponed and on reassessment, four months later, he felt too well to accept the risks of surgery. All scheduled outcome measures were obtained for this patient and were included in the surgical cohort results (intent-to-treat). A third patient was disqualified in error because of an unexpected intraoperative discovery of a lung malignancy. Subsequent assessment of this patient was not carried out by the local study center.

Mortality
There were no 30-day postoperative deaths and 2 of 32 (6%) patients died within 90 days of surgery. There was a 1 of 30 (3%) patient death in the best-medical-care arm during the first 90 days. The overall 2-year survival was similar in each arm of the study: LVRS arm 5/32 deaths (16%) and the BMC arm 4/30 deaths (13%) (p = 0.935).

Participation: CRQ and SF-36
The difference between groups at 2 years in all four domains of the CRQ achieved statistical significance (Table 3). The quality-adjusted values were clinically important and statistically significant for all four domains. The CRQ-dyspnea domain score was better for the LVRS patients when compared with patients treated in the medical arm over the 2 years of the study (–1.14, 95% confidence interval [CI; 0.33–1.95]; (p = 0.008).

HUI3
The HUI3 showed a clinically important improvement in quality of life at the 2-year assessment (0.104) but had only an 80% certainty that the observation was a true finding (Table 4, Fig 1). The difference failed to achieve statistical significance (0.104, 95% CI –0.06–0.27; p = 0.19).

View larger version (16K): [in this window] [in a new window]   Fig 1. Health Utility Index (HUI3): Each treatment group is illustrated by a line marking the average value of the HUI3 at each of the assessment times of the study. The area under the line represents the accumulated value of the HUI3 for that treatment group. The area between the two lines (groups) is the difference between the two treatment arms and is conceptually the quality-adjusted value gained (or lost) over the 2-year study. Closed circles represent the LVRS group; open circles represent the medical group. (CI = confidence interval; LVRS = lung volume reduction surgery.)

Oxygen Requirement
There were no significant changes in arterial blood gas measurements over the 2-year study and no significant changes after LVRS. A small but not statistically significant difference between groups was observed in PaCO ₂ at 6 months (–4.3 mm Hg [standard error 2.23]) (p = 0.07), but this difference vanished by 12 months. Home oxygen was required by 37% of the patients before LVRS. This percentage was reduced to 28% postoperatively (p = 0.09). Six patients (50%) required less oxygen support and 3 patients (25%) required an increase in their oxygen.

Six Minute Walk Test
The 6MWT improved by 93.8 meters (95% CI [15.4–172.1]) (p = 0.021) over the 2-year period (Table 5). Twenty-two of the 32 patients (69%) in the surgical arm had a measurable increase in their six minute walk test while 10 (31%) patients deteriorated. In the medical arm 8 of 30 (27%) had a measurable increase in their 6MWT while 22 of the 30 (73%) patients deteriorated as the 2-year study progressed (Xi2 = 10.98, p < 0.0009; Fisher exact p2 < 0.0011).

Cost Effectiveness Analysis
Price weights and utilization of selected resource use by treatment group are presented (Table 6). Thirty-two patients were randomized to LVRS, and 30 to BMC. Three patients (1 LVRS, 2 BMC) were excluded from the economic analysis because of no data. Two LVRS patients did not undergo surgery but were included in this intent to treat analysis. The mean length-of-stay for the initial hospitalization was 31.1 days in the surgery group including a mean of 11.3 days in the intensive care unit. Over the 2 years of the study, the LVRS group experienced a mean of 0.8 hospitalization per patient and a mean number of hospital days of 10.3 compared with the medical care group who experienced a mean of 1.6 hospitalizations per patient and each hospitalization was 17.2 days in duration. The LVRS patients had a mean of 7.3 months of home oxygen vs 10.3 months for patients in the BMC arm. Of the LVRS patients, 51% returned to a rehabilitation program while 39% of the patients in the BMC arm went back into a rehabilitation program.

	Comment

Top Abstract Introduction Patients and Methods Results Comment Discussion Acknowledgments References

 
Across the five centers, 467 candidates were screened and 405 were excluded from the protocol. Sixty-two patients were selected. This ratio of successful selection was similar to the experience of others [6, 8]. The most common reasons for exclusion in our study were patients who were too ill with multisystem disease (25%) or not ill enough with lung volumes too small (24%). Other reasons included single large bullae (20%); 68 patients (17%) were excluded and considered for transplantation. Patients declined because of unwillingness to be randomized (9%). Twenty patients were excluded because they were referred while in an intensive care unit and were requiring mechanical ventilation. We hoped to enroll 350 patients, but stopped recruiting when 18% of our target number was met. This poor accrual was the result of several factors. Economics, politics, shifts in patients' perception, medical preference, and regional strategic needs all contributed to our failure to meet our goal and are a subject of another paper. Similar trials have met with similar struggles. The National Emphysema Treatment Trial (NETT) recruited 27% of their original target (1,200/4,500). Despite the fact that our study was underpowered for its primary outcome, it was well-powered for all other outcomes assessed.

The incremental cost effectiveness ratio of patients randomized to lung volume reduction surgery in this study was found to be $133,900/QALY gained. Based on conventional cost-effectiveness threshold where $20,000/QALY is within most healthcare budgets, treatments that cost more than $100,000/QALY are considered to be outside budget limits [25], LVRS would not be considered a cost-effective intervention. Nonetheless, society continues to subscribe to other treatments with similar or greater costs per QALY. The Harvard Center for Risk Assessment reports several such treatments [26]. Laparoscopic hernia repair costs $140,000/QALY gained when compared with open hernia repair. Lung transplantation costs $137,000 to $294,000 per QALY gained when compared with best care with no transplantation; radiologic screening for foreign bodies before MRI costs $504,000/QALY gained, autologous blood transfusion program costs between $420,000 and $42,000,000/QALY gained.

Our results are consistent with findings of other small randomized clinical trials, and the National Emphysema Treatment Trial (NETT) [1–10]. These studies suggest that the clinical and physiologic improvements peak 6 to 12 months after LVRS and are sustained for two years before an important decline in benefits is observed.

In the surgical arm of this study QOL measures improved after LVRS; however, this small improvement did not always achieve MCID. When comparison is made with the medical group who continued to deteriorate, however, the benefit of LVRS was clearly seen easily surpassing the MCID and achieving statistical significance in most domains. Although LVRS offers some improvements in QOL the major gain realized by the surgical patient is that while both groups deteriorate over the 2-year time horizon, the surgical group does so at a level persistently above the medical group.

Lung volume reduction surgery, in addition to best medical care including pulmonary rehabilitation, provides meaningful physiologic changes that reduces a patient's dyspnea and improves quality of life. Lung volume reduction surgery is feasible and is relatively safe. The cost to provide LVRS is high but in keeping with other treatment modalities currently available.

	Discussion

Top Abstract Introduction Patients and Methods Results Comment Discussion Acknowledgments References

 
DR MALCOLM M. DECAMP (Boston, MA): As you just heard, emphysema is one of the leading causes of adult death in North America; just yesterday it claimed the life of Johnny Carson. Along with ischemic heart disease, stroke, and lung cancer, emphysema is a major source of tobacco-related mortality and morbidity and healthcare expenditure. In their manuscript, Dr Miller points out that 62 million Canadian dollars were spent on the management of COPD (chronic obstructive pulmonary disease) in 1990, and those figures in the United States in the mid-1990s was estimated between $1 and $4 billion.

Unlike coronary artery disease and lung cancer, little new has been published regarding effective treatment for emphysema. The only therapy providing any documented survival advantage for this disease was the use of, first, nocturnal and then continuous ambulatory oxygen therapy, and these findings were published almost three decades ago.

Reintroduced by Cooper in the early 90s, lung volume reduction surgery has recently been validated as effective therapy for emphysema, especially by the National Emphysema Treatment Trial. For the first time since the publication of the supplemental oxygen trials, an intervention for emphysema has been shown to improve exercise capacity, quality of life and, in selected patients, survival.

Dr Miller and his colleagues should be congratulated for the design and execution of a multicenter prospective randomized trial of lung volume reduction surgery versus best medical therapy within the Canadian healthcare system. Five centers participated, though only four were clinically active.

There were several similarities with the NETT (National Emphysema Treatment) trial. Patients were similar with regard to age and the severity of their emphysema. There was no overall difference in survival in either study, but because of the smaller sample size in the Canadian study, no subsets could be analyzed. There was significant improvement in general and respiratory-specific quality of life that persisted throughout follow-up in both studies, and overall, the incremental cost, as you just heard at the conclusion of the presentation, was about 134,000 Canadian dollars for quality-adjusted life year. That figure for the overall group in the NETT trial was about $100,000, but again, because of the small sample size, they could not discern or perform any subset analysis.

There were some important differences between this study and the NETT trial. There was statistically significant improvement in respiratory function in this trial in FEV₁ and six-minute walk distance, but compared to the patient's baseline, these deteriorated in the first six to 12 months follow-up. Patient accrual of 62 patients represents only 5% of the 1,200 patients accrued in the NETT study, and accrual was only 18% of their target. The mean hospital length of stay was a little over one month, twice that seen in the NETT trial and the mean ICU length of stay in these patients was about 11 days; again, twice that ICU length of stay seen in the NETT trial.

I have four questions for the authors. First, your primary end point was quality-adjusted life years measured by the Health Utility Index. Unfortunately this outcome was not statistically different between treatment groups, yet you claimed that the observed difference was "clinically" important. How can you justify this concept of minimally clinically important difference for such a diffuse measure as Health Utility Index?

Why was your accrual so poor? Over what time period did you recruit centers and patients, and did you exclude centers and why?

Third, you conclude that LVR is feasible in small surgical volume centers, but I am not sure that your 6% to 10% operative mortality and one-month hospital length of stay, 11 days in the ICU, supports this. Were there non-study LVR patients operated on in these institutions during this study, and what is the minimum center and surgeon volume and experience that you think is necessary to run an LVR program?

And finally, your analysis reports results as comparisons of medicine versus surgery in terms of mean values relative to their baseline. How do you account for the heterogeneity of response following surgery or even following pulmonary rehabilitation? Would you continue to use the study inclusion and exclusion criteria for selection of patients for lung volume reduction surgery or would you modify these based on the heterogeneity of response that you saw in your patients or in those reported by other authors?

I would like to thank you for the manuscript in advance and the Society for the privilege of discussing this important paper.

DR MILLER: Thank you, Dr DeCamp, for your kind comments. The poor accrual I guess is a similar situation to all. I think the NETT trial accrued about 22 or 27% of their predicted numbers of 4,500, and this was 12%. So similar features, very complicated stories of each one, and again, would be reported elsewhere.

I think you are right, the fact that it can be done by this trial in small centers in Canada does not necessarily mean that that's a subscription for all small centers to start. We were highly specialized centers and had a run-in period with a larger volume of experience before we started. So I think that it implies that it can be done in small centers if they are highly qualified. I think the differences in numbers and experiences are generally reflective in the two groups, the medical system in Canada and the U.S.

Thank you again.

	Acknowledgments

Top Abstract Introduction Patients and Methods Results Comment Discussion Acknowledgments References

 
The Canadian Institute of Health Research (CIHR), MT-14386, funded the Canadian Lung Volume Reduction Surgery Study trial.

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Top Abstract Introduction Patients and Methods Results Comment Discussion Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): John D. Miller Richard A. Malthaner Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Miller, J. D. Search for Related Content PubMed PubMed Citation Articles by Miller, J. D. Related Collections Lung - other