Stenting for Carotid-Artery Stenosis
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《新英格兰医药杂志》
In the context of his original description of the pathoanatomical relationship of plaque at the carotid bifurcation to ipsilateral hemispheric stroke, C. Miller Fisher predicted that "one day surgeons might develop techniques to remove the offending plaque," thereby preventing stroke.1 We could forgive Miller Fisher if his prophecy did not extend into the age of endovascular therapies, which over the past decade have assumed an important role, if not a dominant one, in the management of a spectrum of vascular diseases. In the article by Yadav and colleagues in this issue of the Journal,2 readers are provided with the best clinical data to date indicating at least the noninferiority of carotid-artery angioplasty and stenting to carotid endarterectomy in the treatment of carotid-artery stenosis. Indeed, although the comparative data indicate the equivalence of the two procedures with regard to what are typically considered the "hard" end points of periprocedural stroke and death, with myocardial infarction (at one year after the intervention) included as an end point, the data favored stenting. On the basis of these and other data, the Food and Drug Administration (FDA) recently granted approval of the use of carotid-artery stenting in the treatment of high-risk patients with symptomatic or asymptomatic carotid-artery stenosis.
Interventions for carotid-artery stenosis (mainly endarterectomy) are performed frequently, at a rate second only to that of interventions directed at coronary disease. Against a background of an earlier literature that suggested unacceptable perioperative morbidity,3 the role of endarterectomy has been defined in a series of large, prospective clinical trials.4,5,6 These studies provided definitive, level I evidence of the benefit of endarterectomy (as compared with the best available medical therapy) for the prevention of stroke in both symptomatic and asymptomatic patients with flow-limiting carotid-artery stenosis. It should be our expectation that the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial, reported by Yadav et al., is the first of many clinical trials to define the comparative roles of endarterectomy and carotid-artery stenting in different subgroups of patients with carotid-artery stenosis.
Clinicians and regulatory organizations have been slow to embrace carotid-artery stenting. The reasons for this include the fundamental rationale and nature for endarterectomy, which is not the relief of arterial obstruction but, rather, the removal of a dynamic disease process in which plaque-related events leading to thrombosis and embolization are the principal causes of stroke. Whether luminal expansion and plaque compression resulting from the use of carotid-artery stenting will provide a level of stroke prevention equivalent to that provided by plaque excision with the use of endarterectomy is, as yet, unknown. However, the available data suggest that, indeed, carotid-artery stenting will do so.7
An important concern is intraprocedural embolization, because complex plaque at the carotid bifurcation is displaced during stenting. The brain, of course, is a rather unforgiving end organ as compared with other vascular beds that undergo endovascular manipulations. The technical evolution of carotid-artery stenting over the past decade has largely focused on ensuring the safety of stenting. Indeed, a previous study comparing endarterectomy and carotid-artery angioplasty, which was conducted before embolic-protection devices became available, showed an unacceptable rate of periprocedural stroke and death of 10 percent (for both procedures, in fact).8 As shown in the SAPPHIRE trial, embolic-protection devices, usually deployed as a "safety net" upstream from the arterial manipulation, appear to have largely resolved the concern about periprocedural safety with the use of carotid-artery stents. Finally, the safety and efficacy data from the earlier clinical trials of endarterectomy4,5,6 established an enviable standard for comparison. Such data are the presumed justification for the noncoverage policy toward carotid-artery stenting advanced by the Centers for Medicare and Medicaid Services; such stenting is generally reimbursed only in the context of FDA-approved clinical trials.
The importance of the SAPPHIRE trial notwithstanding, its controversial points have been debated ever since the original presentation of these data at scientific meetings more than a year ago. It is clear that the difference between the treatment groups in the composite end point at one year is related to the higher incidence of perioperative (mostly non–Q-wave) myocardial infarction in the endarterectomy group. Although the authors emphasize the importance of late myocardial infarction to bolster its inclusion as a study end point, most of the myocardial infarctions occurred during the periprocedural period. The inclusion of myocardial infarction as an end point in this trial (it was not included as an end point in the large endarterectomy trials) was perhaps a practical consideration, since the study was not sufficiently powered to detect differences in stroke and death between the treatment groups. Such complications must occur rarely if prophylactic interventions for carotid-artery stenosis are to be justified.
Certain specifics of the design and enrollment in the SAPPHIRE trial deserve comment. More patients (406) were entered into the stent registry than were randomly assigned to treatment (334). If the decision not to assign treatment randomly was based on advanced coexisting conditions or limited life expectancy, we could admire this "surgical restraint." But according to the study criteria, the SAPPHIRE surgeons did not randomly assign patients to a treatment group if they believed that endarterectomy "could not be safely performed." It is inconceivable to me that in a cohort of more than 740 patients enrolled in the study, nearly 60 percent would be classified as those in whom endarterectomy "could not be safely performed," irrespective of the risk-factor profile. The implications with respect to the surgical environments in which the patients in this trial were treated seem obvious. More than 20 percent of patients in each treatment group were treated for recurrent carotid-artery stenosis (i.e., they had previously undergone endarterectomy in a target vessel). Such a distribution is not surprising, since an initial response to recurrent disease is often a consideration for carotid-artery stenting. Yet the substantial number of patients with recurrent stenosis serves to bias the results in favor of stenting for two reasons. First, "redo" endarterectomy is typically associated with higher rates of complications (especially cranial-nerve injury) than is the primary operation, and second, carotid-artery stenting for recurrent disease is inherently less risky when the disease is intimal hyperplasia rather than complex plaque (i.e., there is less risk of embolization).
The inclusion of cranial-nerve injury as a secondary end point seems curious; most would acknowledge that it is a surgery-specific issue. Cranial-nerve dysfunction after endarterectomy should occur rarely, and even then, most deficits are transient. I do not think that the case for carotid-artery stenting should be made on the basis of the possible complication of cranial-nerve dysfunction as a result of endarterectomy, at least in primary procedures.
A final concern about the data reported in the SAPPHIRE trial is related to complications of endarterectomy and mortality at one year. Such data have major implications for clinical decision making with respect, in particular, to patients with asymptomatic carotid-artery stenosis. It has been clearly shown that among virtually all patients with symptomatic carotid-artery stenosis, the immediate risk of stroke justifies intervention (and its attendant risks).4 Indeed, the powerful benefit attributed to endarterectomy in the large trials involving patients with symptomatic stenosis is related to a risk of stroke of approximately 20 percent at two years — a composite figure drawn from three large, randomized trials of medical therapy. The benefit of endarterectomy in the trials involving patients with asymptomatic stenosis is not equivalent; indeed, although data on patients in the Asymptomatic Carotid Surgery Trial (ACST) indicate an impressive reduction of 50 percent in the risk of stroke with endarterectomy at five years, such a benefit is not realized until two years after endarterectomy. Thus, periprocedural complications must be kept minimal, in accordance with established guidelines, for there to be a benefit from intervention for carotid-artery stenosis.
The SAPPHIRE Trial is a pivotal study; its hypothesis that carotid-artery stenting is not inferior to endarterectomy is a valid conclusion. However, the small sample size and the study end points preclude major conclusions about the relative roles of endarterectomy and carotid-artery stenting in the treatment of carotid-artery stenosis. Physicians, industry sponsors, and regulatory agencies should collectively insist on large-scale, multicenter trials in order to clarify the appropriate role of carotid-artery stenting in patients in different clinical and anatomical subgroups. Such trials have been initiated in North America and Europe.
Dr. Cambria reports having received consulting fees from Cordis Endovascular.
Source Information
From the Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, Boston.
References
Fisher CM. Occlusion of the internal carotid artery. Arch Neurol Psychiatry 1951;65:346-77.
Yadav JS, Wholey MH, Kuntz RE, et al. Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med 2004;351:1493-1501.
Winslow CM, Solomon DH, Chassin MR, Kosecoff J, Merrick NJ, Brook RH. The appropriateness of carotid endarterectomy. N Engl J Med 1988;318:721-727.
North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991;325:445-453.
Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995;273:1421-1428.
MRC Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without neurological symptoms: randomised controlled trial. Lancet 2004;363:1491-1502.
Roubin GS, New G, Iyer SS, et al. Immediate and late clinical outcomes of carotid artery stenting in patients with symptomatic and asymptomatic carotid artery stenosis: a 5-year prospective analysis. Circulation 2001;103:532-537.
Endovascular versus surgical treatment in patients with carotid stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomised trial. Lancet 2001;357:1729-1737.(Richard P. Cambria, M.D.)
Interventions for carotid-artery stenosis (mainly endarterectomy) are performed frequently, at a rate second only to that of interventions directed at coronary disease. Against a background of an earlier literature that suggested unacceptable perioperative morbidity,3 the role of endarterectomy has been defined in a series of large, prospective clinical trials.4,5,6 These studies provided definitive, level I evidence of the benefit of endarterectomy (as compared with the best available medical therapy) for the prevention of stroke in both symptomatic and asymptomatic patients with flow-limiting carotid-artery stenosis. It should be our expectation that the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial, reported by Yadav et al., is the first of many clinical trials to define the comparative roles of endarterectomy and carotid-artery stenting in different subgroups of patients with carotid-artery stenosis.
Clinicians and regulatory organizations have been slow to embrace carotid-artery stenting. The reasons for this include the fundamental rationale and nature for endarterectomy, which is not the relief of arterial obstruction but, rather, the removal of a dynamic disease process in which plaque-related events leading to thrombosis and embolization are the principal causes of stroke. Whether luminal expansion and plaque compression resulting from the use of carotid-artery stenting will provide a level of stroke prevention equivalent to that provided by plaque excision with the use of endarterectomy is, as yet, unknown. However, the available data suggest that, indeed, carotid-artery stenting will do so.7
An important concern is intraprocedural embolization, because complex plaque at the carotid bifurcation is displaced during stenting. The brain, of course, is a rather unforgiving end organ as compared with other vascular beds that undergo endovascular manipulations. The technical evolution of carotid-artery stenting over the past decade has largely focused on ensuring the safety of stenting. Indeed, a previous study comparing endarterectomy and carotid-artery angioplasty, which was conducted before embolic-protection devices became available, showed an unacceptable rate of periprocedural stroke and death of 10 percent (for both procedures, in fact).8 As shown in the SAPPHIRE trial, embolic-protection devices, usually deployed as a "safety net" upstream from the arterial manipulation, appear to have largely resolved the concern about periprocedural safety with the use of carotid-artery stents. Finally, the safety and efficacy data from the earlier clinical trials of endarterectomy4,5,6 established an enviable standard for comparison. Such data are the presumed justification for the noncoverage policy toward carotid-artery stenting advanced by the Centers for Medicare and Medicaid Services; such stenting is generally reimbursed only in the context of FDA-approved clinical trials.
The importance of the SAPPHIRE trial notwithstanding, its controversial points have been debated ever since the original presentation of these data at scientific meetings more than a year ago. It is clear that the difference between the treatment groups in the composite end point at one year is related to the higher incidence of perioperative (mostly non–Q-wave) myocardial infarction in the endarterectomy group. Although the authors emphasize the importance of late myocardial infarction to bolster its inclusion as a study end point, most of the myocardial infarctions occurred during the periprocedural period. The inclusion of myocardial infarction as an end point in this trial (it was not included as an end point in the large endarterectomy trials) was perhaps a practical consideration, since the study was not sufficiently powered to detect differences in stroke and death between the treatment groups. Such complications must occur rarely if prophylactic interventions for carotid-artery stenosis are to be justified.
Certain specifics of the design and enrollment in the SAPPHIRE trial deserve comment. More patients (406) were entered into the stent registry than were randomly assigned to treatment (334). If the decision not to assign treatment randomly was based on advanced coexisting conditions or limited life expectancy, we could admire this "surgical restraint." But according to the study criteria, the SAPPHIRE surgeons did not randomly assign patients to a treatment group if they believed that endarterectomy "could not be safely performed." It is inconceivable to me that in a cohort of more than 740 patients enrolled in the study, nearly 60 percent would be classified as those in whom endarterectomy "could not be safely performed," irrespective of the risk-factor profile. The implications with respect to the surgical environments in which the patients in this trial were treated seem obvious. More than 20 percent of patients in each treatment group were treated for recurrent carotid-artery stenosis (i.e., they had previously undergone endarterectomy in a target vessel). Such a distribution is not surprising, since an initial response to recurrent disease is often a consideration for carotid-artery stenting. Yet the substantial number of patients with recurrent stenosis serves to bias the results in favor of stenting for two reasons. First, "redo" endarterectomy is typically associated with higher rates of complications (especially cranial-nerve injury) than is the primary operation, and second, carotid-artery stenting for recurrent disease is inherently less risky when the disease is intimal hyperplasia rather than complex plaque (i.e., there is less risk of embolization).
The inclusion of cranial-nerve injury as a secondary end point seems curious; most would acknowledge that it is a surgery-specific issue. Cranial-nerve dysfunction after endarterectomy should occur rarely, and even then, most deficits are transient. I do not think that the case for carotid-artery stenting should be made on the basis of the possible complication of cranial-nerve dysfunction as a result of endarterectomy, at least in primary procedures.
A final concern about the data reported in the SAPPHIRE trial is related to complications of endarterectomy and mortality at one year. Such data have major implications for clinical decision making with respect, in particular, to patients with asymptomatic carotid-artery stenosis. It has been clearly shown that among virtually all patients with symptomatic carotid-artery stenosis, the immediate risk of stroke justifies intervention (and its attendant risks).4 Indeed, the powerful benefit attributed to endarterectomy in the large trials involving patients with symptomatic stenosis is related to a risk of stroke of approximately 20 percent at two years — a composite figure drawn from three large, randomized trials of medical therapy. The benefit of endarterectomy in the trials involving patients with asymptomatic stenosis is not equivalent; indeed, although data on patients in the Asymptomatic Carotid Surgery Trial (ACST) indicate an impressive reduction of 50 percent in the risk of stroke with endarterectomy at five years, such a benefit is not realized until two years after endarterectomy. Thus, periprocedural complications must be kept minimal, in accordance with established guidelines, for there to be a benefit from intervention for carotid-artery stenosis.
The SAPPHIRE Trial is a pivotal study; its hypothesis that carotid-artery stenting is not inferior to endarterectomy is a valid conclusion. However, the small sample size and the study end points preclude major conclusions about the relative roles of endarterectomy and carotid-artery stenting in the treatment of carotid-artery stenosis. Physicians, industry sponsors, and regulatory agencies should collectively insist on large-scale, multicenter trials in order to clarify the appropriate role of carotid-artery stenting in patients in different clinical and anatomical subgroups. Such trials have been initiated in North America and Europe.
Dr. Cambria reports having received consulting fees from Cordis Endovascular.
Source Information
From the Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, Boston.
References
Fisher CM. Occlusion of the internal carotid artery. Arch Neurol Psychiatry 1951;65:346-77.
Yadav JS, Wholey MH, Kuntz RE, et al. Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med 2004;351:1493-1501.
Winslow CM, Solomon DH, Chassin MR, Kosecoff J, Merrick NJ, Brook RH. The appropriateness of carotid endarterectomy. N Engl J Med 1988;318:721-727.
North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991;325:445-453.
Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995;273:1421-1428.
MRC Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without neurological symptoms: randomised controlled trial. Lancet 2004;363:1491-1502.
Roubin GS, New G, Iyer SS, et al. Immediate and late clinical outcomes of carotid artery stenting in patients with symptomatic and asymptomatic carotid artery stenosis: a 5-year prospective analysis. Circulation 2001;103:532-537.
Endovascular versus surgical treatment in patients with carotid stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomised trial. Lancet 2001;357:1729-1737.(Richard P. Cambria, M.D.)