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Ann Thorac Surg 2006;82:431-443
© 2006 The Society of Thoracic Surgeons
Accepted for publication May 11, 2006.
* Address correspondence to Dr Naunheim, St. Louis University, 3635 Vista Blvd, St. Louis, MO 63110–0250. (Email: naunheim{at}slu.edu).
Presented at the Forty-second Annual Meeting of The Society of Thoracic Surgeons, Chicago, IL, Jan 30–Feb 1, 2006. Winner of the J. Maxwell Chamberlain Memorial Award for General Thoracic Surgery.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsCommentNETT Credit RosterFootnotesAcknowledgmentsReferences |
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METHODS: A total of 1218 patients with severe emphysema were randomized to receive LVRS or medical treatment. We present updated analyses (4.3 versus 2.4 years median follow-up), including 40% more patients with functional measures 2 years after randomization.
RESULTS: The intention-to-treat analysis of 1218 randomized patients demonstrates an overall survival advantage for LVRS, with a 5-year risk ratio (RR) for death of 0.86 (p = 0.02). Improvement was more likely in the LVRS than in the medical group for maximal exercise through 3 years and for health-related quality of life (St. George's Respiratory Questionnaire [SGRQ]) through 4 years. Updated comparisons of survival and functional improvement were consistent with initial results for four clinical subgroups of non-high-risk patients defined by upper-lobe predominance and exercise capacity. After LVRS, the upper-lobe patients with low exercise capacity demonstrated improved survival (5-year RR, 0.67; p = 0.003), exercise throughout 3 years (p < 0.001), and symptoms (SGRQ) through 5 years (p < 0.001 years 1 to 3, p = 0.01 year 5). Upper-lobe-predominant and high-exercise-capacity LVRS patients obtained no survival advantage but were likely to improve exercise capacity (p < 0.01 years 1 to 3) and SGRQ (p < 0.01 years 1 to 4).
CONCLUSIONS: Effects of LVRS are durable, and it can be recommended for upper-lobe-predominant emphysema patients with low exercise capacity and should be considered for palliation in patients with upper-lobe emphysema and high exercise capacity.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsCommentNETT Credit RosterFootnotesAcknowledgmentsReferences |
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The initial full report of the NETT demonstrated a significant survival benefit from LVRS in patients with upper-lobe-predominant emphysema and low exercise capacity [10]. Upper-lobe-predominant patients treated with LVRS also demonstrated significant benefits in exercise improvement and dyspnea compared with their medically treated counterparts, and the non-upper-lobe-predominant LVRS-treated patients with low exercise capacity had improvement in dyspnea. Other subgroups were noted to be "high risk," with high mortality after surgery not offset by improvements in exercise capacity or quality of life, and therefore were poor LVRS candidates [10]. These reports were made on the basis of a median follow-up of 2.4 years.
Although this provided strong evidence of the mid-term efficacy of LVRS and guidelines regarding patient selection, the durability of LVRS remains open to question. This article compares the differences in survival, exercise capacity, and health-related quality of life between those patients undergoing LVRS and those receiving optimal medical therapy after a median follow-up of 4.3 years.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentNETT Credit RosterFootnotesAcknowledgmentsReferences |
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Patient Population and Assessments
At 17 centers, patients with severe emphysema underwent comprehensive medical evaluation to insure compliance with medical therapy and to exclude significant comorbidities [9]. Baseline measures before randomization were completed after pulmonary rehabilitation. Through December 2002, patients were reexamined at 6 months, 12 months, and yearly after randomization. From January 2003 through December 2003, patients returned for examinations at 6 months and 2, 3, and 5 years after randomization. Patients who were 1 year or 4 years postrandomization during this period completed a telephone interview and mailed quality-of-life questionnaires. From January 2004 through June 2004, patients completed quality-of-life questionnaires one final time by mail.
The primary outcome measures for the trial were the 2-year assessment of all-cause mortality and maximum exercise capacity. Secondary outcome measures included pulmonary function [11, 12] 6-minute walk distance [13, 14], and self-administered health-related quality-of-life (St. George's Respiratory Questionnaire [SGRQ]) [15], general quality-of-life (Quality of Well Being Scale) [16], and dyspnea (University of California San Diego Shortness of Breath Questionnaire [17]) questionnaires.
The distribution of emphysema was determined from high-resolution computed tomography (CT) scans as heterogeneous or homogeneous by using a visual scoring system [18]. In addition, the radiologist judged the craniocaudal distribution as upper-lobe-predominant, lower-lobe-predominant, diffuse, or superior segments of lower lobes predominantly involved; the latter three categories were grouped together as non-upper-lobe-predominant for analysis.
Before randomization, eligible patients completed 6 to 10 weeks of pulmonary rehabilitation supervised by NETT personnel. In May 2001, patients with forced expiratory volume in 1 second (FEV1) of 20% or less predicted and either homogenous distribution of emphysema or carbon monoxide diffusing capacity (DLCO) of 20% or less predicted were found to be at high risk of dying after LVRS, with a low probability of functional benefit, and were no longer deemed to be eligible for randomization [18].
Patients randomized to LVRS underwent bilateral, stapled, wedge resection through a median sternotomy or video-assisted thoracic surgery. Adherence to medications, tobacco abstinence, and pulmonary rehabilitation treatment at home were monitored through regular telephone calls and clinic visits in both medically and surgically randomized patients.
Definition of Outcomes
Vital status, ascertained as of September 2005, was determined by clinical center report and review of the most recent Social Security Master Death File [19, 20]. The total mortality rate from all causes was measured from the day of randomization for both treatment groups.
The investigators defined improvement in maximum exercise capacity as an increase in maximum work of more than 10 watts above the postrehabilitation baseline level. Improvement in health-related quality of life was defined as a decrease in SGRQ score of more than 8 units below postrehabilitation baseline. These thresholds are greater than those typically used as minimal clinically important differences (eg, 4 units for SGRQ [21]), but were selected to represent improvement appropriate to justify the risks of surgery in these patients with severe emphysema. Patients who died or were missing data required for the assessment were considered not improved.
Statistical Analysis
All analyses were conducted by comparing the treatment groups to which patients were assigned (intention-to-treat principle). The Fisher exact test was used to compare the proportions of deaths in each group and the proportions improved in exercise and in SGRQ in each group [22]. The NETT protocol specified that the primary comparison would be between the proportions of patients in the two groups who died. This was chosen rather than a comparison with the use of a typical rank-based test (eg, log-rank or Wilcoxon tests) for mortality differences because the hazard functions for death were expected to cross, resulting in nonproportional hazards. This crossing was anticipated as a consequence of perioperative mortality, potentially followed by lower mortality in the surgery group after 6 months [23]. The risk ratio (RR) for death was estimated from all-cause mortality rates in each group after a median of 4.3 years of follow-up [22].
Four subgroups of patients were defined by upper-lobe predominance (yes versus no) in combination with baseline exercise capacity (high versus low). Low exercise capacity was defined as postrehabilitation baseline maximum work of 25 watts or less for women and 40 watts or less for men. These four subgroups were examined for differential risk or benefit by treatment using a series of logistic regression analyses that included as the outcome mortality, improvement in exercise capacity or improvement in health-related quality of life (SGRQ) at the specified follow-up time. For each outcome, the model included terms for treatment group, the subgroup, and the interaction between treatment and the subgroup. The p values for the interaction terms were determined from exact score tests for logistic regression [24]. All p values are two-sided and were not corrected for multiple comparisons.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsCommentNETT Credit RosterFootnotesAcknowledgmentsReferences |
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Outcomes of All Randomized Patients
Of the 1218 randomized patients, 283 patients assigned to LVRS and 324 assigned to medical therapy died during follow-up (median, 4.3 years). The total mortality rate was 0.11 deaths per person-year in the surgical group and 0.13 in the medical group (overall RR, 0.85; p = 0.02). This statistically significant advantage in overall mortality occurred despite the expected increased early mortality in the LVRS group secondary to the procedure (Fig 1a).
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Health-related quality of life, as assessed by SGRQ, was consistently better for LVRS patients. Clinically significant improvement (>8 unit decline in SGRQ) was noted in 43%, 35%, 22%, 12%, and 15% of LVRS patients at 1, 2, 3, 4, and 5 years, respectively; corresponding figures in the medical group were 10%, 9%, 8%, 5%, and 7% (p < 0.01, years 1 to 4; p = 0.08, year 5; Fig 3b). Analysis of mean changes in survivors completing testing revealed an advantage for LVRS at all intervals (Fig 5b).
Histograms of changes from baseline in exercise capacity and SGRQ and proportions of patients missing the assessment or who died during the time window for the assessment are shown for all patients and all times in online Appendix Figures A6a–c and A7a–c, respectively.
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Upper-lobe emphysema and low exercise capacity
Among these 290 patients, the LVRS cohort had a marked survival advantage, demonstrating a markedly lower risk throughout 5 years of follow-up (overall RR, 0.57; p = 0.01; Fig 1c). These patients were also more likely to have a greater than 10-watt improvement in maximum work both initially and throughout the 3 years of follow-up testing (p < 0.001; Fig 2c and online Appendix
Fig A6d). Finally, the LVRS patients were more likely to have a greater than 8-point improvement in SGRQ score at 2 years than the medically treated patients (p < 0.001; Fig 3c). This effect proved durable throughout 5 years of follow-up (Fig 3c and online Appendix
Fig A7d). Mean changes from postrehabilitation baseline scores in exercise capacity and SGRQ in survivors are depicted in Figures 4c and 5c, respectively. At all time points, survivors in the LVRS group appeared to have an advantage for both exercise and SGRQ.
Upper-lobe emphysema and high exercise capacity
The 419 patients within this subgroup demonstrated no survival advantage. Mortality was similar regardless of treatment (overall RR, 0.86; p = 0.19; Fig 1d). However, LVRS patients were more likely to have greater than 10-watt improvement throughout 3 years of follow-up testing (p < 0.01; Fig 2d and online Appendix
Fig A6e) and to have an 8-point improvement in SGRQ score through 4 years of postoperative testing (p < 0.001 years 1 to 3; p = 0.003 year 4; Fig 3d and online Appendix
Fig A7e). Changes from baseline values for exercise and SGRQ in all surviving patients are depicted in Figures 4d and 5d, respectively. The changes from baseline for both outcomes at all time points favored the LVRS treated patients.
Non-upper-lobe emphysema and low exercise capacity
The 149 LVRS and medical patients within this subgroup had similar risk of death (overall RR, 0.80; p = 0.31; online Appendix
Fig A1b) and a similar low chance for more than 10-watt improvement in maximum work at 2 years (p = 0.27) and 3 years (p > 0.99) (online Appendix
Figs A2b and A6f). Although LVRS patients had a greater chance than medical patients of an 8-point improvement in SGRQ score at 1 year (33% versus 11%, p = 0.002) and at 2 years (27% versus 6%, p = 0.002), this advantage disappeared by 3 years (online Appendix
Fig A3b and A7f). Online Appendix
Figures A4b and A5b illustrate the mean changes from baseline in exercise and SGRQ scores among survivors. As with the above comparison of improved proportions, any advantage in SGRQ appeared to disappear by year 3 of follow-up.
Non-upper-lobe emphysema and high exercise capacity
Compared with medical patients, LVRS patients had a similar risk of death (overall RR, 1.10; p = 0.79; online Appendix
Fig A1c), a similar low chance of more than a 10-watt improvement in maximum work at 2 years (3% versus 4%; p > 0.99; online Appendix
Fig A2c and A6g), and a similar poor chance of an 8-point improvement in SGRQ score at 2 years (19% versus 9%, p = 0.07; online Appendix
Figs A3c and A7g). Longer follow-up demonstrated continued equivalence. Online Appendix
Figures A4c and A5c demonstrate that those LVRS patients who survived and returned for testing may have had a small, transient advantage over their medical counterparts for 6 months to 1 year.
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Comment |
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TopAbstractIntroductionPatients and MethodsResultsCommentNETT Credit RosterFootnotesAcknowledgmentsReferences |
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Analysis of prognostic factors allowed us to identify patient subsets with differential outcomes. We recognize the potential pitfalls of such subgroup analysis, but believe the heterogeneity of the patients treated and their outcomes allow us to provide findings that are clinically and statistically valid. Furthermore, prolonged follow-up has confirmed the soundness of the subgroup divisions. The process for identifying subgroups, including procedures and categorizations, was done prospectively under the supervision of the independent Data and Safety Monitoring Board.
After excluding high-risk patients [18], success in the remaining non-high-risk group seemed to hinge on two distinct clinical variables: the pattern of emphysema on CT scan (upper-lobe versus non-upper-lobe predominance) and gender-corrected postrehabilitation exercise capacity (low versus high) [10]. Although upper-lobe-predominant emphysema had been reported in small studies as a predictor of short-term improvement in pulmonary function after LVRS [25–27], low exercise capacity was a previously unreported and unanticipated predictor of benefit after LVRS. A statistically significant interaction of these two variables was noted, and this resulted in four additional clinically meaningful subgroups of patients.
The additional follow-up data obtained since December 2002 confirmed the beneficial effects of LVRS in patients with upper-lobe-predominant emphysema and low postrehabilitation exercise capacity. The survival advantage previously demonstrated after a median of 2.4 years of follow-up (overall RR, 0.47; p = 0.005) was sustained in the longer follow-up (median 4.3 years, overall RR, 0.57; p = 0.01). In addition, the significant advantages in function reported at 2 years in the LVRS cohort were maintained at 3 years for exercise capacity (minimal data were available at 4 and 5 years because of a change in the visit schedule after December 2002). Similarly, relief of dyspnea (as measured by SGRQ) was more likely in the LVRS group through the 5 years of follow-up. Our long-term follow-up strongly supports the performance of LVRS in this subgroup that comprised 24% of the NETT population.
For patients with upper-lobe-predominant disease and high postrehabilitation exercise capacity, extended observation yielded little if any change in results or recommendations. LVRS had no survival advantage or disadvantage. The procedure resulted in a greater improvement in exercise capacity through 3 years than did medical therapy, although the percentage of patients achieving more than a 10-watt improvement in exercise capacity over baseline was small. The chance for marked symptom improvement after LVRS was greater through 4 years of follow-up. Patients in this subgroup (34% of all enrolled patients) who are looking primarily for symptomatic improvement can benefit from LVRS.
Patients with non-upper-lobe-predominant emphysema and low postrehabilitation exercise capacity had limited improvement in exercise capacity regardless of treatment. Although LVRS patients initially had a greater chance for symptomatic improvement than those medically treated, this advantage disappeared by the 3-year follow-up point. Survival was not different between the LVRS and medical groups. Recommendations regarding LVRS in this subgroup are guarded because the primary benefit is improvement in health-related quality of life, which appears to dissipate within 3 years after surgery.
For patients in the subgroup characterized by non-upper-lobe-predominant emphysema and high postrehabilitation maximum work, LVRS leads initially to a higher mortality, although this becomes insignificant at 3 years. Extended follow-up confirms that these patients have little chance of functional or symptomatic improvement and thus are poor candidates for LVRS.
Patients with upper-lobe-predominant disease who underwent LVRS demonstrated significant advantages over the medical group in maximal exercise capacity and health-related quality of life. Over time, the absolute percentages of patients enjoying improvement over their own baseline values gradually diminished; however, their results in the aggregate remained superior to their counterparts in the medical group, who also experienced progressive decline in function and quality of life over time. Critics might cite this decline to baseline as evidence that LVRS has only a mild transient benefit. We believe this conclusion would be inappropriate. Comparing patients with their own baseline function can be valuable, but the primary benefit in a prospective randomized trial is that the surgical cohort can be rigorously compared with similar patients randomized to the medical group.
Such a comparison demonstrates that while the mean functional measures (exercise capacity, health-related QOL) in survivors in the LVRS group return to near baseline in 3 to 5 years, the functional measures in survivors in the medical group initially decline below baseline and then continue to deteriorate. For example, one can see in Figure 4a that at 2 years, the mean change from baseline in exercise for LVRS patients was +1.9 watts and the mean change in medical patients was –8.2 watts. We believe this cumulative difference of 10 watts between the 2 groups is likely to be very significant clinically. Similar differences in SGRQ changes strongly favor LVRS patients throughout 5 years of testing (Fig 5a–d).
The LVRS group had a significant advantage in exercise capacity and dyspnea-related quality of life compared with the medical group throughout the 5 years of follow-up. This supports the supposition that although LVRS may not maintain patients above baseline values for 5 years, it does provide a durable and clinically significant advantage compared with what would likely be achieved with best medical therapy.
Some new findings have come to light with extended observation. Perhaps the most notable was the emergence of a survival benefit in the surgical cohort when the entire NETT population was followed-up for approximately an additional 2 years. In our first publication of NETT outcome, no significant survival difference was found between the LVRS and medical groups when all 1218 patients enrolled were compared or when the non-high-risk group (n = 1078) was analyzed after exclusion of the high-risk subset. However, continued observation through 5 years revealed the emergence of a survival advantage with LVRS both for the entire NETT patient population and the non-high-risk subgroup. We believe this provides additional evidence supporting the validity of the original subgroup analysis and demonstrates the efficacy of LVRS in carefully selected subsets.
In summary, we demonstrate the prolonged benefits of LVRS compared with optimal medical therapy with regard to survival, exercise capacity, and health-related quality of life. Moreover we define patient characteristics that predict benefit or harm after LVRS and that should be considered when treatment options for patients with this devastating disorder are compared.
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NETT Credit Roster |
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TopAbstractIntroductionPatients and MethodsResultsCommentNETT Credit RosterFootnotesAcknowledgmentsReferences |
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Clinical Centers:
Baylor College of Medicine, Houston, Texas: Marcia Katz, MD (Principal Investigator); Carolyn Wheeler, RN, BSN (Principal Clinic Coordinator); Elaine Baker, RRT, RPFT; Peter Barnard, PhD, RPFT; Phil Cagle, MD; James Carter, MD; Sophia Chatziioannou, MD; Karla Conejo-Gonzales; Kimberly Dubose, RRT; John Haddad, MD; David Hicks, RRT, RPFT; Neal Kleiman, MD; Mary Milburn-Barnes, CRTT; Chinh Nguyen, RPFT; Michael Reardon, MD; Joseph Reeves-Viets, MD; Steven Sax, MD; Amir Sharafkhaneh, MD; Owen Wilson, PhD; Christine Young PT; Rafael Espada, MD (Principal Investigator 1996–2002); Rose Butanda (1999–2001); Minnie Ellisor (2002); Pamela Fox, MD (1999–2001); Katherine Hale, MD (1998–2000); Everett Hood, RPFT (1998–2000); Amy Jahn (1998–2000); Satish Jhingran, MD (1998–2001); Karen King, RPFT (1998–1999); Charles Miller III, PhD (1996–1999); Imran Nizami, MD (Co-Principal Investigator, 2000–2001); Todd Officer (1998–2000); Jeannie Ricketts (1998–2000); Joe Rodarte, MD (Co-principal Investigator 1996–2000); Robert Teague, MD (Co-principal Investigator 1999–2000); Kedren Williams (1998–1999).
Brigham and Women's Hospital, Boston, Massachusetts: John Reilly, MD (Principal Investigator); David Sugarbaker, MD (Co-principal Investigator); Carol Fanning, RRT (Principal Clinic Coordinator); Simon Body, MD; Sabine Duffy, MD; Vladmir Formanek, MD; Anne Fuhlbrigge, MD; Philip Hartigan, MD; Sarah Hooper, EP; Andetta Hunsaker, MD; Francine Jacobson, MD; Marilyn Moy, MD; Susan Peterson, RRT; Roger Russell, MD; Diane Saunders; Scott Swanson, MD (Co-principal Investigator, 1996–2001).
Cedars-Sinai Medical Center, Los Angeles, California: Rob McKenna, MD (Principal Investigator); Zab Mohsenifar, MD (Co-principal Investigator); Carol Geaga, RN (Principal Clinic Coordinator); Manmohan Biring, MD; Susan Clark, RN, MN; Jennifer Cutler, MD; Robert Frantz, MD; Peter Julien, MD; Michael Lewis, MD; Jennifer Minkoff-Rau, MSW; Valentina Yegyan, BS, CPFT; Milton Joyner, BA (1996–2002).
Cleveland Clinic Foundation, Cleveland, Ohio: Malcolm DeCamp, MD (Principal Investigator); James Stoller, MD (Co-principal Investigator); Yvonne Meli, RN,C (Principal Clinic Coordinator); John Apostolakis, MD; Darryl Atwell, MD; Jeffrey Chapman, MD; Pierre DeVilliers, MD; Raed Dweik, MD; Erik Kraenzler, MD; Rosemary Lann, LISW; Nancy Kurokawa, RRT, CPFT; Scott Marlow, RRT; Kevin McCarthy, RCPT; Pricilla McCreight, RRT, CPFT; Atul Mehta, MD; Moulay Meziane, MD; Omar Minai, MD; Mindi Steiger, RRT; Kenneth White, RPFT; Janet Maurer, MD (Principal Investigator, 1996–2001); Terri Durr, RN (2000–2001); Charles Hearn, DO (1998–2001); Susan Lubell, PA-C (1999–2000); Peter O'Donovan, MD (1998–2003); Robert Schilz, DO (1998–2002).
Columbia University, New York, in consortium with Long Island Jewish Medical Center, New Hyde Park, New York: Mark Ginsburg, MD (Principal Investigator); Byron Thomashow, MD (Co-principal Investigator); Patricia Jellen, MSN, RN (Principal Clinic Coordinator); John Austin, MD; Matthew Bartels, MD; Yahya Berkmen, MD; Patricia Berkoski, MS, RRT (Site Coordinator, LIJ); Frances Brogan, MSN, RN; Amy Chong, BS, CRT; Glenda DeMercado, BSN; Angela DiMango, MD; Sandy Do, MS, PT; Bessie Kachulis, MD; Arfa Khan, MD; Berend Mets, MD; Mitchell O'Shea, BS, RT, CPFT; Gregory Pearson, MD; Leonard Rossoff, MD; Steven Scharf, MD, PhD (Co-principal Investigator, 1998–2002); Maria Shiau, MD; Paul Simonelli, MD; Kim Stavrolakes, MS, PT; Donna Tsang, BS; Denise Vilotijevic, MS, PT; Chun Yip, MD; Mike Mantinaos, MD (1998–2001); Kerri McKeon, BS, RRT, RN (1998–1999); Jacqueline Pfeffer, MPH, PT (1997–2002).
Duke University Medical Center, Durham, North Carolina: Neil MacIntyre, MD (Principal Investigator); R. Duane Davis, MD (Co-principal Investigator); John Howe, RN (Principal Clinic Coordinator); R. Edward Coleman, MD; Rebecca Crouch, RPT; Dora Greene; Katherine Grichnik, MD; David Harpole, Jr., MD; Abby Krichman, RRT; Brian Lawlor, RRT; Holman McAdams, MD; John Plankeel, MD; Susan Rinaldo-Gallo, MED; Sheila Shearer, RRT; Jeanne Smith, ACSW; Mark Stafford-Smith, MD; Victor Tapson, MD; Mark Steele, MD (1998–1999); Jennifer Norten, MD (1998–1999).
Mayo Foundation, Rochester, Minnesota: James Utz, MD (Principal Investigator); Claude Deschamps, MD (Co-principal Investigator); Kathy Mieras, CCRP (Principal Clinic Coordinator); Martin Abel, MD; Mark Allen, MD; Deb Andrist, RN; Gregory Aughenbaugh, MD; Sharon Bendel, RN; Eric Edell, MD; Marlene Edgar; Bonnie Edwards; Beth Elliot, MD; James Garrett, RRT; Delmar Gillespie, MD; Judd Gurney, MD; Boleyn Hammel; Karen Hanson, RRT; Lori Hanson, RRT; Gordon Harms, MD; June Hart; Thomas Hartman, MD; Robert Hyatt, MD; Eric Jensen, MD; Nicole Jenson, RRT; Sanjay Kalra, MD; Philip Karsell, MD; Jennifer Lamb; David Midthun, MD; Carl Mottram, RRT; Stephen Swensen, MD; Anne-Marie Sykes, MD; Karen Taylor; Norman Torres, MD; Rolf Hubmayr, MD (1998–2000); Daniel Miller, MD (1999–2002); Sara Bartling, RN (1998–2000); Kris Bradt (1998–2002).
National Jewish Medical and Research Center, Denver, Colorado: Barry Make, MD (Principal Investigator); Marvin Pomerantz, MD (Co-principal Investigator); Mary Gilmartin, RN, RRT (Principal Clinic Coordinator); Joyce Canterbury; Martin Carlos; Phyllis Dibbern, PT; Enrique Fernandez, MD; Lisa Geyman, MSPT; Connie Hudson; David Lynch, MD; John Newell, MD; Robert Quaife, MD; Jennifer Propst, RN; Cynthia Raymond, MS; Jane Whalen-Price, PT; Kathy Winner, OTR; Martin Zamora, MD; Reuben Cherniack, MD (Principal Investigator, 1997–2000).
Ohio State University, Columbus, Ohio: Philip Diaz, MD (Principal Investigator); Patrick Ross, MD (Co-principal Investigator); Tina Bees (Principal Clinic Coordinator); Jan Drake; Charles Emery, PhD; Mark Gerhardt, MD, PhD; Mark King, MD; David Rittinger; Mahasti Rittinger.
Saint Louis University, Saint Louis, Missouri: Keith Naunheim, MD (Principal Investigator); Robert Gerber, MD (Co-principal Investigator); Joan Osterloh, RN, MSN (Principal Clinic Coordinator); Susan Borosh; Willard Chamberlain, DO; Sally Frese; Alan Hibbit; Mary Ellen Kleinhenz, MD; Gregg Ruppel; Cary Stolar, MD; Janice Willey; Francisco Alvarez, MD (Co-principal Investigator, 1999–2002); Cesar Keller, MD (Co-principal Investigator, 1996–2000).
Temple University, Philadelphia, Pennsylvania: Gerard Criner, MD (Principal Investigator); Satoshi Furukawa, MD (Co-principal Investigator); Anne Marie Kuzma, RN, MSN (Principal Clinic Coordinator); Roger Barnette, MD; Neil Brister, MD; Kevin Carney, RN, CCTC; Wissam Chatila, MD; Francis Cordova, MD; Gilbert D'Alonzo, DO; Michael Keresztury, MD; Karen Kirsch; Chul Kwak, MD; Kathy Lautensack, RN, BSN; Madelina Lorenzon, CPFT; Ubaldo Martin, MD; Peter Rising, MS; Scott Schartel, MD; John Travaline, MD; Gwendolyn Vance, RN, CCTC; Phillip Boiselle, MD (1997–2000); Gerald O'Brien, MD (1997–2000).
University of California, San Diego, San Diego, California: Andrew Ries, MD, MPH (Principal Investigator); Robert Kaplan, PhD (Co-principal Investigator); Catherine Ramirez, BS, RCP (Principal Clinic Coordinator); David Frankville, MD; Paul Friedman, MD; James Harrell, MD; Jeffery Johnson; David Kapelanski, MD; David Kupferberg, MD, MPH; Catherine Larsen, MPH; Trina Limberg, RRT; Michael Magliocca, RN, CNP; Frank J. Papatheofanis, MD, PhD; Dawn Sassi-Dambron, RN; Melissa Weeks.
University of Maryland at Baltimore, in consortium with Johns Hopkins Hospital, Baltimore, Maryland: Mark Krasna, MD (Principal Investigator); Henry Fessler, MD (Co-principal Investigator); Iris Moskowitz (Principal Clinic Coordinator); Timothy Gilbert, MD; Jonathan Orens, MD; Steven Scharf, MD, PhD; David Shade; Stanley Siegelman, MD; Kenneth Silver, MD; Clarence Weir; Charles White, MD.
University of Michigan, Ann Arbor, Michigan: Fernando Martinez, MD (Principal Investigator); Mark Iannettoni, MD (Co-principal Investigator); Catherine Meldrum, BSN, RN, CCRN (Principal Clinic Coordinator); William Bria, MD; Kelly Campbell; Paul Christensen, MD; Kevin Flaherty, MD; Steven Gay, MD; Paramjit Gill, RN; Paul Kazanjian, MD; Ella Kazerooni, MD; Vivian Knieper; Tammy Ojo, MD; Lewis Poole; Leslie Quint, MD; Paul Rysso; Thomas Sisson, MD; Mercedes True; Brian Woodcock, MD; Lori Zaremba, RN.
University of Pennsylvania, Philadelphia, Pennsylvania: Larry Kaiser, MD (Principal Investigator); John Hansen-Flaschen, MD (Co-principal Investigator); Mary Louise Dempsey, BSN, RN (Principal Clinic Coordinator); Abass Alavi, MD; Theresa Alcorn, Selim Arcasoy, MD; Judith Aronchick, MD; Stanley Aukberg, MD; Bryan Benedict, RRT; Susan Craemer, BS, RRT, CPFT; Ron Daniele, MD; Jeffrey Edelman, MD; Warren Gefter, MD; Laura Kotler-Klein, MSS; Robert Kotloff, MD; David Lipson, MD; Wallace Miller, Jr., MD; Richard O=Connell, RPFT; Staci Opelman, MSW; Harold Paleversusky, MD; William Russell, RPFT; Heather Sheaffer, MSW; Rodney Simcox, BSRT, RRT; Susanne Snedeker, RRT, CPFT; Jennifer Stone-Wynne, MSW; Gregory Tino, MD; Peter Wahl; James Walter, RPFT; Patricia Ward; David Zisman, MD; James Mendez, MSN, CRNP (1997–2001); Angela Wurster, MSN, CRNP (1997–1999).
University of Pittsburgh, Pittsburgh, Pennsylvania: Frank Sciurba, MD (Principal Investigator); James Luketich, MD (Co-principal Investigator); Colleen Witt, MS (Principal Clinic Coordinator); Gerald Ayres; Michael Donahoe, MD; Carl Fuhrman, MD; Robert Hoffman, MD; Joan Lacomis, MD; Joan Sexton; William Slivka; Diane Strollo, MD; Erin Sullivan, MD; Tomeka Simon; Catherine Wrona, RN, BSN; Gerene Bauldoff, RN, MSN (1997–2000); Manuel Brown, MD (1997–2002); Elisabeth George, RN, MSN (Principal Clinic Coordinator 1997–2001); Robert Keenan, MD (Co-principal Investigator 1997–2000); Theodore Kopp, MS (1997–1999); Laurie Silfies (1997–2001).
University of Washington, Seattle, Washington: Joshua Benditt, MD (Principal Investigator), Douglas Wood, MD (Co-principal Investigator); Margaret Snyder, MN (Principal Clinic Coordinator); Kymberley Anable; Nancy Battaglia; Louie Boitano; Andrew Bowdle, MD; Leighton Chan, MD; Cindy Chwalik; Bruce Culver, MD; Thurman Gillespy, MD; David Godwin, MD; Jeanne Hoffman; Andra Ibrahim, MD; Diane Lockhart; Stephen Marglin, MD; Kenneth Martay, MD; Patricia McDowell; Donald Oxorn, MD; Liz Roessler; Michelle Toshima; Susan Golden (1998–2000).
Other Participants:
Agency for Healthcare Research and Quality, Rockville, Maryland: Lynn Bosco, MD, MPH; Yen-Pin Chiang, PhD; Carolyn Clancy, MD; Harry Handelsman, DO.
Centers for Medicare and Medicaid Services, Baltimore, Maryland: Steven M Berkowitz, PhD; Tanisha Carino, PhD; Joe Chin, MD; JoAnna Baldwin; Karen McVearry; Anthony Norris; Sarah Shirey; Claudette Sikora; Steven Sheingold, PhD (1997–2004).
Coordinating Center, The Johns Hopkins University, Baltimore, Maryland: Steven Piantadosi, MD, PhD (Principal Investigator); James Tonascia, PhD (Co-principal Investigator); Patricia Belt; Amanda Blackford, ScM; Karen Collins; Betty Collison; Ryan Colvin, MPH; John Dodge; Michele Donithan, MHS; Vera Edmonds; Gregory L. Foster, MA; Julie Fuller; Judith Harle; Rosetta Jackson; Shing Lee, ScM; Charlene Levine; Hope Livingston; Jill Meinert; Jennifer Meyers; Deborah Nowakowski; Kapreena Owens; Shangqian Qi, MD; Michael Smith; Brett Simon, MD; Paul Smith; Alice Sternberg, ScM; Mark Van Natta, MHS; Laura Wilson, ScM; Robert Wise, MD.
Cost Effectiveness Subcommittee: Robert M. Kaplan, PhD (Chair); J. Sanford Schwartz, MD (Co-chair); Yen-Pin Chiang, PhD; Marianne C. Fahs, PhD; A. Mark Fendrick, MD; Alan J. Moskowitz, MD; Dev Pathak, PhD; Scott Ramsey, MD, PhD; Steven Sheingold, PhD; A. Laurie Shroyer, PhD; Judith Wagner, PhD; Roger Yusen, MD.
Cost Effectiveness Data Center, Fred Hutchinson Cancer Research Center, Seattle, Washington: Scott Ramsey, MD, PhD (Principal Investigator); Ruth Etzioni, PhD; Sean Sullivan, PhD; Douglas Wood, MD; Thomas Schroeder, MA; Karma Kreizenbeck; Kristin Berry, MS; Nadia Howlader, MS.
CT Scan Image Storage and Analysis Center, University of Iowa, Iowa City, Iowa: Eric Hoffman, PhD (Principal Investigator); Janice Cook-Granroth, BS; Angela Delsing, RT; Junfeng Guo, PhD; Geoffrey McLennan, MD; Brian Mullan, MD; Chris Piker, BS; Joseph Reinhardt, PhD; Blake Wood; Jered Sieren, RTR; William Stanford, MD.
Data and Safety Monitoring Board: John A. Waldhausen, MD (Chair); Gordon Bernard, MD; David DeMets, PhD; Mark Ferguson, MD; Eddie Hoover, MD; Robert Levine, MD; Donald Mahler, MD; A. John McSweeny, PhD; Jeanine Wiener-Kronish, MD; O. Dale Williams, PhD; Magdy Younes, MD.
Marketing Center, Temple University, Philadelphia, Pennsylvania: Gerard Criner, MD (Principal Investigator); Charles Soltoff, MBA.
Project Office, National Heart, Lung, and Blood Institute, Bethesda, Maryland: Gail Weinmann, MD (Project Officer); Joanne Deshler (Contracting Officer); Dean Follmann, PhD; James Kiley, PhD; Margaret Wu, PhD (1996–2001).
Other Acknowledgments
Arthur Gelb, MD, Lakewood Regional Medical Center, Lakewood, California.
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Due to the time limit, I will concentrate my discussion on three points. First, the long-term follow-up demonstrates impressively and proves for the first time that LVRS has a survival benefit compared to medically treated patients over an observation time of 5 years. This positive result of the primary end point of the NETT is important for the medical community, since medically treated patients are at a high risk to die if LVRS is not offered. This information is, in my opinion, far more important than the previous NETT report 2 years ago on 16% perioperative mortality in patients with very advanced destroyed emphysematous lungs. This high-risk constellation was recognized in most centers before and patients were excluded from LVRS for sound physiologic reasons. It was in the responsibility of the leaders in the NETT to expose them to this risk. Nevertheless, the information was considered to be so important that it was sent as a headliner to the New England Journal of Medicine for early release. I assume this information policy will also be used by the NETT, with the important finding that selected patients nonsurgically treated are at high risk to die. I wait for the headline.
This brings me to my first question. Is the NETT now offering LVRS to emphysema patients as a lifesaving procedure and not primarily as a treatment to improved quality of life?
My second point is on quality of life and exercise capacity. The NETT found a highly significant improvement in exercise capacity and quality of life in surgically treated patients over a period of at least 3 and 5 years respectively. But in comparison to some large single center studies from the US and the other parts of the world, the improvement is lower in the NETT in regard to the number of patients who profit and the magnitude and the duration of the improvement.
(Slide) This histogram, which was previously published in the European Respiratory Journal, shows that in a single center study the improvement in FEV1 was 88% compared to 65% in the NETT study, and the magnitude of improvement was higher. So how do you explain such a difference? Do these centers select different patients despite the functional parameters and the age are the same, or is the learning curve and experience associated with the outcome? In the NETT, 17 centers performed the 600 procedures over a period of 4.5 years, which gives an average number of six procedures only per center per year. Your statistician may argue this reflects clinical practice, but we as surgeons know that we do better with more experience. Do you agree that LVRS should be performed in centers only with a high interest in emphysema surgery and with an adequate number of cases done?
The third and last point concerns patients with non-upper-lobe-predominant emphysema. These patients had a minimal profit of 1 to 2 years only in quality of life in the NETT. This is physiologically difficult to explain, since volume reduction decreases dynamic hyperinflation and improves respiratory mechanics, and this should occur independent from the location of the disease and hence the site of the resection. It is also in contrast to our data.
(Slide) This graph shows the improvement in FEV1 in patients with heterogenous, in blue, and nonheterogenous emphysema, in red, over several years after LVRS. Please note that the magnitude of improvement is higher in the heterogeneous group, mostly upper lobe emphysema, but over time both groups keep a statistically significant improvement over several years. Patients in the NETT were operated in 70% through a median sternotomy, which is not an ideal approach to the dorsal and lower part of the lungs and might have played a certain role for this unsatisfying outcome.
My last question, and this question concerns me the most, will there be room after the NETT for further research in the fine tuning of patient selection and other issues, or will the NETT integrate finding of others or just dictate the final answers? In my mind, it is now time for a consensus conference in order to give guidelines and relaunch emphysema research and surgery.
I thank you for your attention.
DR NAUNHEIM: I would like to thank Dr Weder for his insightful questions. He is, as you all know, a leader in European thoracic surgery and one of the world's experts on lung volume reduction surgery.
We can indeed now offer lung volume reduction surgery as a lifesaving procedure, something not possible prior to the NETT. However, careful patient selection must be undertaken according to the NETT protocol if we are going to identify the appropriate patients. Not just exercise, not just quality of life, but now survival can be improved, and it is something that we really ought to press home, because there is a large population of emphysema patients out there who currently could benefit from this procedure.
Another question from Dr Weder was why was there a lower improvement in FEV1 for the NETT patients as compared to Dr. Weder's patients? It is difficult for me to be certain why this is. One could bring up the issue of interinstitutional consistency and different types of pulmonary function measurement. However, we actually did not really concentrate our analysis on FEV1 or RV or DLCO. Those are surrogates for what we wanted to ascertain, that is, did patients live longer, could they do more, and did they feel better? Still, our FEV1s did not improve as much as Dr Weder's. It could potentially be due to surgical technique or perhaps to patient selection. It is interesting to note that because the NETT trial was funded by Medicare, it included virtually only Medicare patients, and thus our mean age of about 67 years is 5 years older than nearly every other series in the literature. That could also have something to do with differing levels of improvement.
Dr Weder asked about non-upper-lobe-predominant emphysema and whether or not homogeneous patients should be undergo LVRS. Our results and the results of many other investigators suggest that homogeneous patients did not enjoy the same level of benefit as patients with heterogeneous disease. At least in the study, homogeneous disease patients did not respond as well as those with heterogeneous disease, and thus we can't say that homogeneous patients shouldn't be done, but we can say that homogeneous disease is not a predictor of success.
Finally, will there be room for fine-tuning in this area of COPD treatment? Absolutely. I would hate to think that this paper was the last and final statement on lung volume reduction. There are many more vistas to be explored including results in unilateral disease, differing surgical techniques, and newer endobronchial approaches to LVR. I agree with Dr Weder that the results of the NET trial, while definitive for this particular population, should not viewed as being the end of the story of lung volume reduction but rather just the beginning. [24]
Thank you.
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The online version of this article contains extensive additional information and subgroup analyses of these patients in an Appendix, and is highly recommended for students of this National Institutes of Health trial. To access the online-only Appendix, please visit http://ats.ctsnetjournals.org and search for the article by Naunheim, Vol. 82, pages 431–43.e1–19.
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