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Ann Thorac Surg 2006;82:385-387
© 2006 The Society of Thoracic Surgeons
Former Director, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
* Address correspondence to Dr Lenfant, PO Box 83027, Gaithersburg, MD 20883 (Email: lenfantc{at}prodigy.net).
The article titled "Long-Term Follow-Up of Patients Receiving Lung-Volume-Reduction Surgery Versus Medical Therapy for Severe Emphysema" [1] published in this issue of The Annals of Thoracic Surgery is the latest in a series of papers by the National Emphysema Treatment Trial (NETT) Research Group. The first, published in 1999, introduced the rationale and design of the NETT [2]. In 2001, a publication [3] presented data from a well-defined group (69) of high-risk patients who were found to be unlikely to benefit from the surgery. Thereafter, patients meeting the criteria described in this publication were no longer recruited in the NETT. A 2003 paper [4] presented data from 608 surgical-therapy patients and 610 medical-therapy patients who had been followed for a median of 2.4 years [4], some for over 4 years. This paper also included data from the previously identified high-risk patient group [2]: after a median follow-up of 2.4 years, mortality rates in this high-risk group were 60% in surgical-therapy patients and 42.8% in medical-therapy patients (Table 1). The article included in this issue of The Annals reports on the same patients who were presented in the 2003 publication, but now with a median follow-up of 4.3 years, with some patients followed for over 7 years.
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All patients enrolled in either group were stage III or IV of the GOLD classification [5]. These are patients whose life expectancy is generally limited to a few years and who have severe functional limitations. A very recent report by Martinez and colleagues carefully and comprehensively analyzed the predictors of mortality in the NETT patients assigned to medical therapy [6], and it supports the notion that these patients had a limited life expectancy.
After exclusion of the aforementioned high-risk patients, a post-hoc analysis identified four subgroups according to emphysema distribution in the lung and baseline exercise capacity:
The 2003 publication based on a median 2.4 years follow-up concluded that:
The paper in this current issue of The Annals reports on the same goals and end points in the same patients described in the 2003 publication, but after a median of 4.3 years follow up. The conclusions of this new report are:
The findings also suggest that LVRS should be considered in UL–HE patients. At the end of the median 2.4 years follow-up, the death rate among such patients was 16.5% for the surgical-therapy group and 18.3% for the medical-therapy group. After a median 4.3 years follow-up, the death rate was 35.9% for the surgical-therapy group and 42.3% for the medical-therapy group, and the surgery group experienced greater functional benefits.
In an editorial accompanying the 2003 publication, it was stated that "the finding of NETT provides some evidence that the relative efficacy of surgery as compared to medical therapy has a clinical dependence on the presence or absence of upper-lobe disease and on the patient's exercise capacity, but the evidence does not meet the highest standard of proof" [7]. This commentary rightly pointed out that, ideally, further studies should be undertaken to confirm or negate the data that were available at that time. However, it also recognized that "the strength of the findings in the subgroup with upper-lobe disease and low exercise capacity" may preclude doing additional studies.
Compared with the situation a decade or so ago, the treatment of chronic obstructive pulmonary disease, of which emphysema is a component, has progressed considerably, in great part because of a surge in research interest, a better understanding of the disease, and the development of new pharmacological interventions. In addition, patient advocacy and support groups are now firmly established, and they expect the biomedical community to respond to their own personal health problems and to what they appropriately see as a huge and still-increasing public health problem.
In this area of health care, as in many if not in all areas, today's medical and surgical communities most often base their practice on what is known as evidence-based medicine. Evidence is derived from clinical research outcomes, and primarily from original clinical trials and systematic reviews of the literature. The NETT's large sample size, its rigorous randomization, the participation of multiple sites, and the extensive analysis of results all assure its quality and therefore the validity of the guidance it provides. Evidence-based medicine is defined as "the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients" [8]. In view of this definition, two questions need to be considered: Is it "judicious" to transport the current available evidence about LVRS to the practice of medicine? And, if so, to which individual patients?
The answer to the second question is readily available from the data presented in this report and its 2003 predecessor. Only the UL–LE subgroup experienced significantly better survival with surgery, as well as very significantly improved function early after surgery and, as time progressed, much slower functional declines. After a median 4.3 years of follow-up, the death rate differential between the surgical-therapy and the medical-therapy UL–LE patients was 15.7% (44.6% vs 60.3%; Table 1); this is the highest of all the subgroups. The death rates in the NUL–HE subgroup were 44.0% and 41.4%, respectively, in the surgical-therapy and medical-therapy patients—quite similar to the death rate of the UL–LE surgical-therapy patients. However, the surviving patients in the NUL–HE surgical-therapy group did not experience the significant and durable functional improvement that was observed in the UL–LE subgroup assigned to surgical therapy. While patients enrolled in the trial were not selected on the basis of their subgroup characteristics, the post-hoc identification of subgroups was based on a number of predetermined clinical variables. Thus, this undoubtedly reinforces the conclusion that UL–LE patients are the ones to be carefully considered for LVRS.
Much more difficult is the question of whether it is "judicious" to transport the evidence of this study to the practice of medicine. The quality of the study and the strength of the statistical evidence weigh in favor of an affirmative judgment, but these considerations must be balanced by other less-positive factors. The statistical analysis of the results in the subgroup of patients who appear to be the most preferred candidates for LVRS (ie, the UL–LE subgroup) shows a survival advantage with a p = 0.01 and functional improvements with a p < 0.001. Putting aside the statistical significance, the mortality after a median 4.3 years follow-up was over 44% and it would have been higher if the intention-to-treat analysis had not been used. Although this death rate for the surgical-therapy cohort is much better than for the medical-therapy counterparts, it is still high. Furthermore, LVRS surgery, including the pre-operative and post-operative care, is quite expensive and this factor is likely to limit the application of LVRS.
Nonetheless, the NETT has established and demonstrated the value of LVRS in a specific group of patients suffering from emphysema. It provides an opportunity that may be of significant benefit to selected patients. However, to go from 1,218 patients in the NETT to the hundreds of thousands of patients who could become candidates for LVRS will require extensive thoughtful consideration on the part of the physicians and surgeons, as well as the active participation of the patients and their families in the decision-making process.
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