Endovascular Repair of Abdominal Aortic Aneurysm — Round Two
http://www.100md.com
《新英格兰医药杂志》
Last year saw the publication of the first randomized comparisons of the endovascular and open techniques for elective repair of abdominal aortic aneurysms. The Dutch Randomized Endovascular Aneurysm Management (DREAM) trial1 and the British Endovascular Aneurysm Repair Trial 1 (EVAR-1)2 each showed substantial reductions in 30-day postoperative mortality with endovascular repair, in agreement with the results of large observational studies published before3,4 and since5 then. These findings showed that endovascular repair was off to a good start, but there remained an obvious need for data on long-term outcomes.6 That need has increased in the interim, since the release of the U.S. Preventive Services Task Force recommendation of one-time ultrasonographic screening for abdominal aortic aneurysm in men 65 to 75 years of age who smoke or have smoked.7 This segment of the U.S. population is estimated to harbor 360,000 aneurysms.8 Although in most of these patients the aneurysm will be below the threshold for elective repair of 5.5 cm in diameter and will therefore be managed with periodic imaging surveillance,6 in many it will not, and for them a procedure must be selected. Recognizing this need, the U.S. Agency for Healthcare Research and Quality has commissioned a technology assessment to compare endovascular and open repair in terms of effectiveness, cost, and quality of life.
The publication of the two-year results of the DREAM trial in this issue of the Journal9 marks the beginning of round two of this comparison. The rather dramatic finding is that the promising trend favoring endovascular repair at 30 days has completely evaporated after 1 year, so that by the time of the report there were a few more deaths in the endovascular-repair group than in the open-repair group. Although the current report focuses primarily on long-term mortality, the study was not designed or powered to assess long-term outcomes, and there were only 38 deaths overall. The primary outcome in DREAM was a composite of 30-day mortality and severe or moderate complications. As stated in the initial report,1 the differences favoring endovascular repair in terms of the primary outcome and operative mortality alone were not significant, but they were very similar to the significant mortality difference observed in EVAR-1. The mortality data from the new DREAM study are also reminiscent of the data on quality of life and sexual functioning from the first 153 patients who underwent randomization.10,11 Scores for these measures favored endovascular repair in the early postoperative period, but by six months, scores in the open-repair group equaled or surpassed those in the endovascular-repair group.
In the current report, the authors note that endovascular repair has an advantage in terms of aneurysm-related deaths, based on a P value of 0.05, and argue that this finding is evidence against endovascular repair as the cause of the late deaths. This argument warrants questioning. The observed difference in the rate of aneurysm-related deaths is largely driven by the unequal rates of early postoperative death. It also reflects the high likelihood that late ruptures will be missed when autopsy is required for diagnosis. Because autopsies are now uncommon, sensitive identification of rupture requires that clinical and eyewitness reports be obtained and adjudicated.12 Inclusion of even one of the two late "possible" ruptures in the endovascular-repair group would eradicate the nominally significant P value. Furthermore, regardless of whether the authors are entitled to a fresh alpha level of 0.05 in a second report,13,14 that level of significance should probably not be used to draw conclusions about causality with respect to a secondary outcome such as aneurysm-related mortality. Finally, the accompanying confidence intervals do not support significance, suggesting that the P value may have been rounded down.
There are several plausible explanations for the preponderance of late deaths in the endovascular group. The first is the play of chance, given the small number of events. Second, as noted by the authors, open repair may have precipitated the death of frail patients who were likely to die in the coming year. According to this explanation, endovascular repair is beneficial in that, as compared with open repair, it delays death, increasing the area under the mortality curve. Third, endovascular repair may increase late mortality by failing to prevent rupture or by causing complications (resulting in a curve with a steeper slope) and so with longer follow-up might be shown to be inferior. Indeed, it remains to be proven that endovascular repair is beneficial as compared with no treatment, although this proof may be forthcoming in EVAR-2, a study of 319 patients who were not candidates for open repair and who were randomly assigned to endovascular repair or observation.15
Determining which explanation for the pattern of late deaths is correct will obviously require more data. The results of both EVAR-1 and EVAR-2, with at least four years of follow-up data for one third of the 1082 patients in EVAR-1, are expected soon.16 EVAR-1 was designed and powered to compare overall mortality in this analysis, so it is reasonably likely that the trial will show a difference between the two treatments. However, it is less likely that a difference observed in EVAR-1 will be sufficiently robust to withstand meta-analytic buffering by the new DREAM results.
Regardless of the outcome of round two, longer follow-up — to five years and beyond — will be essential to evaluate the durability of endovascular repair. If round two ends in a draw, the final outcome may not be decided until the completion of the American and French trials,6 in which patients are still being enrolled. Endovascular repair is rapidly evolving, so if it was not better than open repair several years ago, when patients were being enrolled in the currently reported trials, it might be better now. The American and French trials are both behind schedule in their enrollment. Unlike the situation with DREAM and EVAR-1, endovascular repair is readily available in the United States and France outside of the trials, making recruitment much more difficult. Although it is not surprising that industry-backed Web sites would persuade patients to select a new therapy over randomization, it is disappointing when patients refuse randomization because their physicians recommend that they ask for endovascular repair. Our rush to embrace the new may diminish our ability to learn whether the new is worth embracing. To properly evaluate endovascular repair for abdominal aortic aneurysm, we may need to go a few more rounds.
Source Information
From the Center for Epidemiological and Clinical Research, Veterans Affairs Medical Center, Minneapolis.
References
Prinssen M, Verhoeven ELG, Buth J, et al. A randomized trial comparing conventional and endovascular repair of abdominal aortic aneurysms. N Engl J Med 2004;351:1607-1618.
Greenhalgh RM, Brown LC, Kwong GP, Powell JT, Thompson SG. Comparison of endovascular aneurysm repair with open repair in patients with abdominal aortic aneurysm (EVAR trial 1), 30-day operative mortality results: randomised controlled trial. Lancet 2004;364:843-848.
Anderson PL, Arons RR, Moskowitz AJ, et al. A statewide experience with endovascular abdominal aortic aneurysm repair: rapid diffusion with excellent early results. J Vasc Surg 2004;39:10-19.
Lee WA, Carter JW, Upchurch G, Seeger JM, Huber TS. Perioperative outcomes after open and endovascular repair of intact abdominal aortic aneurysms in the United States during 2001. J Vasc Surg 2004;39:491-496.
Hua HT, Cambria RP, Chuang SK, et al. Early outcomes of endovascular versus open abdominal aortic aneurysm repair in the National Surgical Quality Improvement Program-Private Sector (NSQIP-PS). J Vasc Surg 2005;41:382-389.
Lederle FA. Abdominal aortic aneurysm -- open versus endovascular repair. N Engl J Med 2004;351:1677-1679.
Preventive Services Task Force. Screening for abdominal aortic aneurysm: recommendation statement. Ann Intern Med 2005;142:198-202.
Fleming C, Whitlock EP, Beil TL, Lederle FA. Screening for abdominal aortic aneurysm: a best-evidence systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2005;142:203-211.
Blankensteijn JD, de Jong SECA, Prinssen M, et al. Two-year results of a randomized trial comparing conventional and endovascular repair of abdominal aortic aneurysms. N Engl J Med 2005;352:2398-2405.
Prinssen M, Buskens E, Blankensteijn JD. Quality of life after endovascular and open AAA repair: results of a randomised trial. Eur J Vasc Endovasc Surg 2004;27:121-127.
Prinssen M, Buskens E, Nolthenius RP, van Sterkenburg SM, Teijink JA, Blankensteijn JD. Sexual dysfunction after conventional and endovascular AAA repair: results of the DREAM trial. J Endovasc Ther 2004;11:613-620.
Lederle FA, Johnson GR, Wilson SE, et al. Rupture rate of large abdominal aortic aneurysms in patients refusing or unfit for elective repair. JAMA 2002;287:2968-2972.
Perneger TV. What's wrong with Bonferroni adjustments. BMJ 1998;316:1236-1238.
Berger VW. On the generation and ownership of alpha in medical studies. Control Clin Trials 2004;25:613-619.
Brown LC, Epstein D, Manca A, Beard JD, Powell JT, Greenhalgh RM. The UK Endovascular Aneurysm Repair (EVAR) trials: design, methodology and progress. Eur J Vasc Endovasc Surg 2004;27:372-381.
Wyatt MG. Registries versus trials for the evaluation of the endovascular treatment of abdominal aortic aneurysms. Eur J Vasc Endovasc Surg 2005;29:560-562.(Frank A. Lederle, M.D.)
The publication of the two-year results of the DREAM trial in this issue of the Journal9 marks the beginning of round two of this comparison. The rather dramatic finding is that the promising trend favoring endovascular repair at 30 days has completely evaporated after 1 year, so that by the time of the report there were a few more deaths in the endovascular-repair group than in the open-repair group. Although the current report focuses primarily on long-term mortality, the study was not designed or powered to assess long-term outcomes, and there were only 38 deaths overall. The primary outcome in DREAM was a composite of 30-day mortality and severe or moderate complications. As stated in the initial report,1 the differences favoring endovascular repair in terms of the primary outcome and operative mortality alone were not significant, but they were very similar to the significant mortality difference observed in EVAR-1. The mortality data from the new DREAM study are also reminiscent of the data on quality of life and sexual functioning from the first 153 patients who underwent randomization.10,11 Scores for these measures favored endovascular repair in the early postoperative period, but by six months, scores in the open-repair group equaled or surpassed those in the endovascular-repair group.
In the current report, the authors note that endovascular repair has an advantage in terms of aneurysm-related deaths, based on a P value of 0.05, and argue that this finding is evidence against endovascular repair as the cause of the late deaths. This argument warrants questioning. The observed difference in the rate of aneurysm-related deaths is largely driven by the unequal rates of early postoperative death. It also reflects the high likelihood that late ruptures will be missed when autopsy is required for diagnosis. Because autopsies are now uncommon, sensitive identification of rupture requires that clinical and eyewitness reports be obtained and adjudicated.12 Inclusion of even one of the two late "possible" ruptures in the endovascular-repair group would eradicate the nominally significant P value. Furthermore, regardless of whether the authors are entitled to a fresh alpha level of 0.05 in a second report,13,14 that level of significance should probably not be used to draw conclusions about causality with respect to a secondary outcome such as aneurysm-related mortality. Finally, the accompanying confidence intervals do not support significance, suggesting that the P value may have been rounded down.
There are several plausible explanations for the preponderance of late deaths in the endovascular group. The first is the play of chance, given the small number of events. Second, as noted by the authors, open repair may have precipitated the death of frail patients who were likely to die in the coming year. According to this explanation, endovascular repair is beneficial in that, as compared with open repair, it delays death, increasing the area under the mortality curve. Third, endovascular repair may increase late mortality by failing to prevent rupture or by causing complications (resulting in a curve with a steeper slope) and so with longer follow-up might be shown to be inferior. Indeed, it remains to be proven that endovascular repair is beneficial as compared with no treatment, although this proof may be forthcoming in EVAR-2, a study of 319 patients who were not candidates for open repair and who were randomly assigned to endovascular repair or observation.15
Determining which explanation for the pattern of late deaths is correct will obviously require more data. The results of both EVAR-1 and EVAR-2, with at least four years of follow-up data for one third of the 1082 patients in EVAR-1, are expected soon.16 EVAR-1 was designed and powered to compare overall mortality in this analysis, so it is reasonably likely that the trial will show a difference between the two treatments. However, it is less likely that a difference observed in EVAR-1 will be sufficiently robust to withstand meta-analytic buffering by the new DREAM results.
Regardless of the outcome of round two, longer follow-up — to five years and beyond — will be essential to evaluate the durability of endovascular repair. If round two ends in a draw, the final outcome may not be decided until the completion of the American and French trials,6 in which patients are still being enrolled. Endovascular repair is rapidly evolving, so if it was not better than open repair several years ago, when patients were being enrolled in the currently reported trials, it might be better now. The American and French trials are both behind schedule in their enrollment. Unlike the situation with DREAM and EVAR-1, endovascular repair is readily available in the United States and France outside of the trials, making recruitment much more difficult. Although it is not surprising that industry-backed Web sites would persuade patients to select a new therapy over randomization, it is disappointing when patients refuse randomization because their physicians recommend that they ask for endovascular repair. Our rush to embrace the new may diminish our ability to learn whether the new is worth embracing. To properly evaluate endovascular repair for abdominal aortic aneurysm, we may need to go a few more rounds.
Source Information
From the Center for Epidemiological and Clinical Research, Veterans Affairs Medical Center, Minneapolis.
References
Prinssen M, Verhoeven ELG, Buth J, et al. A randomized trial comparing conventional and endovascular repair of abdominal aortic aneurysms. N Engl J Med 2004;351:1607-1618.
Greenhalgh RM, Brown LC, Kwong GP, Powell JT, Thompson SG. Comparison of endovascular aneurysm repair with open repair in patients with abdominal aortic aneurysm (EVAR trial 1), 30-day operative mortality results: randomised controlled trial. Lancet 2004;364:843-848.
Anderson PL, Arons RR, Moskowitz AJ, et al. A statewide experience with endovascular abdominal aortic aneurysm repair: rapid diffusion with excellent early results. J Vasc Surg 2004;39:10-19.
Lee WA, Carter JW, Upchurch G, Seeger JM, Huber TS. Perioperative outcomes after open and endovascular repair of intact abdominal aortic aneurysms in the United States during 2001. J Vasc Surg 2004;39:491-496.
Hua HT, Cambria RP, Chuang SK, et al. Early outcomes of endovascular versus open abdominal aortic aneurysm repair in the National Surgical Quality Improvement Program-Private Sector (NSQIP-PS). J Vasc Surg 2005;41:382-389.
Lederle FA. Abdominal aortic aneurysm -- open versus endovascular repair. N Engl J Med 2004;351:1677-1679.
Preventive Services Task Force. Screening for abdominal aortic aneurysm: recommendation statement. Ann Intern Med 2005;142:198-202.
Fleming C, Whitlock EP, Beil TL, Lederle FA. Screening for abdominal aortic aneurysm: a best-evidence systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2005;142:203-211.
Blankensteijn JD, de Jong SECA, Prinssen M, et al. Two-year results of a randomized trial comparing conventional and endovascular repair of abdominal aortic aneurysms. N Engl J Med 2005;352:2398-2405.
Prinssen M, Buskens E, Blankensteijn JD. Quality of life after endovascular and open AAA repair: results of a randomised trial. Eur J Vasc Endovasc Surg 2004;27:121-127.
Prinssen M, Buskens E, Nolthenius RP, van Sterkenburg SM, Teijink JA, Blankensteijn JD. Sexual dysfunction after conventional and endovascular AAA repair: results of the DREAM trial. J Endovasc Ther 2004;11:613-620.
Lederle FA, Johnson GR, Wilson SE, et al. Rupture rate of large abdominal aortic aneurysms in patients refusing or unfit for elective repair. JAMA 2002;287:2968-2972.
Perneger TV. What's wrong with Bonferroni adjustments. BMJ 1998;316:1236-1238.
Berger VW. On the generation and ownership of alpha in medical studies. Control Clin Trials 2004;25:613-619.
Brown LC, Epstein D, Manca A, Beard JD, Powell JT, Greenhalgh RM. The UK Endovascular Aneurysm Repair (EVAR) trials: design, methodology and progress. Eur J Vasc Endovasc Surg 2004;27:372-381.
Wyatt MG. Registries versus trials for the evaluation of the endovascular treatment of abdominal aortic aneurysms. Eur J Vasc Endovasc Surg 2005;29:560-562.(Frank A. Lederle, M.D.)