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CREST: Carotid Revascularization Endarterectomy versus Stent Trial
Cardiovascular Surgery, Vol. 5, No. 5, pp. 457–458, 1997 1997 Published by Elsevier Science Ltd. Printed in Great Britain 0967–2109/97 $17.00 + 0.00
PII: S0967-2109(97)00048-3
CREST: Carotid Revascularization Endarterectomy versus Stent Trial R. W. Hobson II, T. Brott, R. Ferguson, G. Roubin, W. Moore, R. Kuntz, G. Howard and J. Ferguson Executive Committee, CREST, USA
Carotid endarterectomy has become the preferred method for treatment of symptomatic [1–3] and symptomless [4, 5] patients with high-grade carotid stenosis, displacing optimal medical management alone as an ethical alternative in managing these patients. However, during the past several years, the performance of carotid angioplasty–stenting has been recommended by some clinicians as an alternative to carotid endarterectomy for patients who have symptomatic extracranial carotid occlusive disease. Emergence of a position of clinical equipoise [6] on the relatively equivalent value of these alternatives, as defined by different specialists who manage patients with cerebrovascular insufficiency, has resulted in the initiation of one randomized clinical trial in Great Britain comparing the efficacy of carotid endarterectomy with angioplasty–stenting [7] as well as the organization of at least one study group (CREST) planning for a clinical trial on this topic. As recently emphasized by the membership of the Joint Council of the Society for Vascular Surgery and the International Society for Cardiovascular Surgery, North American Chapter [8], the combined stroke/death rate for carotid endarterectomy should be ⬍ 6% for symptomatic patient and ⬍ 3% for symptomless patients with high-grade carotid stenosis. These clinicians correctly have called for establishment of safety standards for carotid angioplasty– stenting before recommending a randomized clinical trial. One of the largest prospective experiences to date on carotid angioplasty–stenting comes from the North American Cerebral Percutaneous Transluminal Angioplasty Registry (NACPTAR) [9]. These investigations, performed at several cooperating centers, reported the results of 165 angioplasties in 147
Correspondence to: R. W. Hobson II, New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103-2714, USA
CARDIOVASCULAR SURGERY
OCTOBER 1997 VOL 5 NO 5
symptomatic patients. Although their reported 30day mortality rate (3%) and stroke risk (6%) exceeded an upper limit of acceptability for carotid endarterectomy [8], patients treated by these trialists generally were referred by specialists who considered them as being ineligible for endarterectomy based on published exclusion criteria for trials evaluating the efficacy of carotid endarterectomy in symptomatic patients [1–3]. That this may be true is suggested by the most recent prospective single institutional data reported by Iyer, Roubin and colleagues [10]. These investigators reported two strokes (3.3%) and no deaths among a group of 60 symptomatic patients treated by carotid angioplasty–stenting for highgrade carotid bifurcation stenosis. Stimulated by these and other reports, the CREST trialists have been meeting at regular intervals during the past 18 months to design a randomized clinical trial, which would compare the clinical efficacy of carotid endarterectomy with angioplasty–stenting. Recognizing that carotid angioplasty–stenting remains a relatively new procedure, however, each participating center will be required to complete a credentialing phase so as to reassure surgeons that the safety of these procedures has been reviewed and established before proceeding with the randomized clinical trial. Assuming that a credentialing phase which requires performance of up to 30 interventional procedures at each of the approximately 50 participating centers is completed to the satisfaction of the study’s Data Safety and Monitoring Board, randomization of patients between the two treatments will then proceed. The primary outcome events for this randomized clinical trial will include: (1) any stroke, myocardial infarction or death during the 30-day perioperative or peri-procedural period; or (2) ipsilateral stroke after 30 days. End-points will be reviewed by an Adjudication Committee blinded to the assigned treatment. Stroke will be determined by 457
CREST: Carotid Revascularization Endarterectomy versus Stent Trial: R.W. Hobson II et al.
a positive transient ischemic attack/stroke questionnaire confirmed by an evaluation of a neurologist. Myocardial infarction will be determined by ECG and enzyme abnormalities. Secondary goals include: (1) to contrast the perioperative/-procedural 30-day morbidity and mortality of angioplasty–stenting and endarterectomy; (2) to contrast the postoperative/postprocedural morbidity and mortality of the two alternatives; (3) to estimate and contrast the restenosis rates for the two procedures; (4) to identify subgroups of participants at differential risk for the two procedures; (5) to evaluate differences in health-related quality of life issues and cost effectiveness; and (6) to describe differences and complications by stent type, technique and experience of operators (from the credentialing phase data). Patients will be evaluated at baseline, postprocedure, 30 days, 6 months and thereafter at 6-month intervals. Baseline procedures will include a brief medical history and physical examination, a risk factor evaluation, performance of neurological status questionnaires, a neurological examination, ECG, and a baseline carotid duplex scan. The 30-day follow-up will include evaluation of the neurological status through questionnaires, ECG, and a followup carotid duplex scan. All 6-month follow-up visits will include a brief physical, completion of the neurological questionnaire, risk factor evaluation and carotid duplex scan. All patients with a positive neurological status questionnaire will be evaluated by a neurologist. The sample size for the study is approximately 3000 symptomatic patients which will be sufficient to detect a relative difference of 25–30% between treatment groups. Should neither treatment be established as superior, the efficacy difference will be within an absolute difference of 1.8% at 1 year. Differences of this magnitude or smaller would be considered sufficiently small to declare the treatments equivalent. An average center should commit itself to recruit approximately 20 patients per year, allowing recruitment to be completed among 50 centers during a 3-year period. Patients will be followed for 1 year after recruitment closes. Opinions have varied about the participation of vascular surgeons in randomized clinical trials on
458
carotid endarterectomy. While the value of our participation has been discussed [11, 12], the emergence of clinical equipoise [6] between treatment groups as supported by a rigorous credentialing phase of CREST should reassure our colleagues about their participation as well as the ethical conduct of this trial [6].
References 1. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. New England Journal of Medicine, 1991, 325, 445–453. 2. European Carotid Surgery Trialists’ Collaborative Group. MCR European Carotid Surgery Trial: Interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis. Lancet, 1991, 337, 1235–1243. 3. The VA Symptomatic Carotid Stenosis Group. Mayberg, M. R., Wilson, S. E. and Yatsu, F., Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis. Journal of the American Medical Association, 1991, 266, 3289–3294. 4. The Veterans Affairs Cooperative Study Group. Hobson, R. W., Weiss, D. G., Fields, W. S., Goldstone, J., Moore, W. S., Towne, J. B. and Wright, C. B., Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. New England Journal of Medicine, 1993, 328, 221–227. 5. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid stenosis. Journal of American Medical Association, 1995, 273, 1421– 1428. 6. Freedman, B., Equipoise and the ethics of clinical research. New England Journal of Medicine, 1987, 317, 141–145. 7. Brown, M., Personal communication, The carotid and vertebral artery transluminal angioplasty trial (CAVATAS), 1996. 8. Joint Council of the Society for Vascular Surgery and the International Society for Cardiovascular Surgery, North American Chapter. Point of view: statement regarding carotid angioplasty and stenting. Journal of Vascular Surgery, 1996, 24, 900. 9. The NACPTAR Investigators. Update on the immediate angiographic results and in-hospital central nervous system complications of cerebral percutaneous transluminal angioplasty. Circulation Supplement, 1995, 92(8), 1–393. 10. Iyer, S. S., Yadav, S., Vitek, J., Wadlington, V. and Roubin, G. S., Technical approaches to angioplasty and stenting of the extracranial carotid arteries. Circulation Supplement, 1995, 92(8), 1– 383. 11. Barnes, R. W., Understanding investigative clinical trials. Journal of Vascular Surgery, 1989, 9, 609–618. 12. Hobson, R. W., Randomized clinical trials: What can we expect?. Journal of Vascular Surgery, 1991, 13, 539–543. Paper accepted 24 March 1997
CARDIOVASCULAR SURGERY
OCTOBER 1997 VOL 5 NO 5
PII: S0967-2109(97)00048-3
CREST: Carotid Revascularization Endarterectomy versus Stent Trial R. W. Hobson II, T. Brott, R. Ferguson, G. Roubin, W. Moore, R. Kuntz, G. Howard and J. Ferguson Executive Committee, CREST, USA
Carotid endarterectomy has become the preferred method for treatment of symptomatic [1–3] and symptomless [4, 5] patients with high-grade carotid stenosis, displacing optimal medical management alone as an ethical alternative in managing these patients. However, during the past several years, the performance of carotid angioplasty–stenting has been recommended by some clinicians as an alternative to carotid endarterectomy for patients who have symptomatic extracranial carotid occlusive disease. Emergence of a position of clinical equipoise [6] on the relatively equivalent value of these alternatives, as defined by different specialists who manage patients with cerebrovascular insufficiency, has resulted in the initiation of one randomized clinical trial in Great Britain comparing the efficacy of carotid endarterectomy with angioplasty–stenting [7] as well as the organization of at least one study group (CREST) planning for a clinical trial on this topic. As recently emphasized by the membership of the Joint Council of the Society for Vascular Surgery and the International Society for Cardiovascular Surgery, North American Chapter [8], the combined stroke/death rate for carotid endarterectomy should be ⬍ 6% for symptomatic patient and ⬍ 3% for symptomless patients with high-grade carotid stenosis. These clinicians correctly have called for establishment of safety standards for carotid angioplasty– stenting before recommending a randomized clinical trial. One of the largest prospective experiences to date on carotid angioplasty–stenting comes from the North American Cerebral Percutaneous Transluminal Angioplasty Registry (NACPTAR) [9]. These investigations, performed at several cooperating centers, reported the results of 165 angioplasties in 147
Correspondence to: R. W. Hobson II, New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103-2714, USA
CARDIOVASCULAR SURGERY
OCTOBER 1997 VOL 5 NO 5
symptomatic patients. Although their reported 30day mortality rate (3%) and stroke risk (6%) exceeded an upper limit of acceptability for carotid endarterectomy [8], patients treated by these trialists generally were referred by specialists who considered them as being ineligible for endarterectomy based on published exclusion criteria for trials evaluating the efficacy of carotid endarterectomy in symptomatic patients [1–3]. That this may be true is suggested by the most recent prospective single institutional data reported by Iyer, Roubin and colleagues [10]. These investigators reported two strokes (3.3%) and no deaths among a group of 60 symptomatic patients treated by carotid angioplasty–stenting for highgrade carotid bifurcation stenosis. Stimulated by these and other reports, the CREST trialists have been meeting at regular intervals during the past 18 months to design a randomized clinical trial, which would compare the clinical efficacy of carotid endarterectomy with angioplasty–stenting. Recognizing that carotid angioplasty–stenting remains a relatively new procedure, however, each participating center will be required to complete a credentialing phase so as to reassure surgeons that the safety of these procedures has been reviewed and established before proceeding with the randomized clinical trial. Assuming that a credentialing phase which requires performance of up to 30 interventional procedures at each of the approximately 50 participating centers is completed to the satisfaction of the study’s Data Safety and Monitoring Board, randomization of patients between the two treatments will then proceed. The primary outcome events for this randomized clinical trial will include: (1) any stroke, myocardial infarction or death during the 30-day perioperative or peri-procedural period; or (2) ipsilateral stroke after 30 days. End-points will be reviewed by an Adjudication Committee blinded to the assigned treatment. Stroke will be determined by 457
CREST: Carotid Revascularization Endarterectomy versus Stent Trial: R.W. Hobson II et al.
a positive transient ischemic attack/stroke questionnaire confirmed by an evaluation of a neurologist. Myocardial infarction will be determined by ECG and enzyme abnormalities. Secondary goals include: (1) to contrast the perioperative/-procedural 30-day morbidity and mortality of angioplasty–stenting and endarterectomy; (2) to contrast the postoperative/postprocedural morbidity and mortality of the two alternatives; (3) to estimate and contrast the restenosis rates for the two procedures; (4) to identify subgroups of participants at differential risk for the two procedures; (5) to evaluate differences in health-related quality of life issues and cost effectiveness; and (6) to describe differences and complications by stent type, technique and experience of operators (from the credentialing phase data). Patients will be evaluated at baseline, postprocedure, 30 days, 6 months and thereafter at 6-month intervals. Baseline procedures will include a brief medical history and physical examination, a risk factor evaluation, performance of neurological status questionnaires, a neurological examination, ECG, and a baseline carotid duplex scan. The 30-day follow-up will include evaluation of the neurological status through questionnaires, ECG, and a followup carotid duplex scan. All 6-month follow-up visits will include a brief physical, completion of the neurological questionnaire, risk factor evaluation and carotid duplex scan. All patients with a positive neurological status questionnaire will be evaluated by a neurologist. The sample size for the study is approximately 3000 symptomatic patients which will be sufficient to detect a relative difference of 25–30% between treatment groups. Should neither treatment be established as superior, the efficacy difference will be within an absolute difference of 1.8% at 1 year. Differences of this magnitude or smaller would be considered sufficiently small to declare the treatments equivalent. An average center should commit itself to recruit approximately 20 patients per year, allowing recruitment to be completed among 50 centers during a 3-year period. Patients will be followed for 1 year after recruitment closes. Opinions have varied about the participation of vascular surgeons in randomized clinical trials on
458
carotid endarterectomy. While the value of our participation has been discussed [11, 12], the emergence of clinical equipoise [6] between treatment groups as supported by a rigorous credentialing phase of CREST should reassure our colleagues about their participation as well as the ethical conduct of this trial [6].
References 1. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. New England Journal of Medicine, 1991, 325, 445–453. 2. European Carotid Surgery Trialists’ Collaborative Group. MCR European Carotid Surgery Trial: Interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis. Lancet, 1991, 337, 1235–1243. 3. The VA Symptomatic Carotid Stenosis Group. Mayberg, M. R., Wilson, S. E. and Yatsu, F., Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis. Journal of the American Medical Association, 1991, 266, 3289–3294. 4. The Veterans Affairs Cooperative Study Group. Hobson, R. W., Weiss, D. G., Fields, W. S., Goldstone, J., Moore, W. S., Towne, J. B. and Wright, C. B., Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. New England Journal of Medicine, 1993, 328, 221–227. 5. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid stenosis. Journal of American Medical Association, 1995, 273, 1421– 1428. 6. Freedman, B., Equipoise and the ethics of clinical research. New England Journal of Medicine, 1987, 317, 141–145. 7. Brown, M., Personal communication, The carotid and vertebral artery transluminal angioplasty trial (CAVATAS), 1996. 8. Joint Council of the Society for Vascular Surgery and the International Society for Cardiovascular Surgery, North American Chapter. Point of view: statement regarding carotid angioplasty and stenting. Journal of Vascular Surgery, 1996, 24, 900. 9. The NACPTAR Investigators. Update on the immediate angiographic results and in-hospital central nervous system complications of cerebral percutaneous transluminal angioplasty. Circulation Supplement, 1995, 92(8), 1–393. 10. Iyer, S. S., Yadav, S., Vitek, J., Wadlington, V. and Roubin, G. S., Technical approaches to angioplasty and stenting of the extracranial carotid arteries. Circulation Supplement, 1995, 92(8), 1– 383. 11. Barnes, R. W., Understanding investigative clinical trials. Journal of Vascular Surgery, 1989, 9, 609–618. 12. Hobson, R. W., Randomized clinical trials: What can we expect?. Journal of Vascular Surgery, 1991, 13, 539–543. Paper accepted 24 March 1997
CARDIOVASCULAR SURGERY
OCTOBER 1997 VOL 5 NO 5