- Email: [email protected]
ISAT and ISUIA: The Impact on Informed Consent
ISAT and ISUIA: The Impact on Informed Consent Kieran Murphy, MD The International Subarachnoid Aneurysm Trial (ISAT) was a multicenter randomized trial that compared the safety and efficacy of endovascular coil treatment versus surgical clipping for the treatment of ruptured brain aneurysms. To be eligible for enrollment in the ISAT trial, each patient had to be deemed equally suitable for either coiling or clipping. The investigators used the term “clinical equipoise” to describe this balance. This study more than any other has set the playing field for the future of interventional radiology/endovascular neurosurgery politics. Tech Vasc Interventional Rad 8:106-107 © 2005 Elsevier Inc. All rights reserved. KEYWORDS ISAT, ISUIA, coil clip, aneurysm
T
he International Subarachnoid Aneurysm Trial (ISAT)1and the International Study of Unruptured Intracranial Aneurysms (ISUIA)2,3 are two landmark studies of intracranial aneurysm therapy. Neither is perfect but both are changing how we manage this disease. They “moved people’s cheese.” They cast doubt on well-developed medical practices and challenged the livelihood of leaders of medical communities all over the world. Naturally they were interpreted differently by the coiling, clipping, and watchful waiting groups depending on how their ‘team” did. So where is the signal in the noise? The ISAT was a multicenter, randomized trial that compared the safety and efficacy of endovascular coil treatment versus surgical clipping for the treatment of ruptured brain aneurysms. To be eligible for enrollment in the ISAT trial, each patient had to be deemed equally suitable for either coiling or clipping. The investigators used the term “clinical equipoise” to describe this balance. The treatment was on average performed 1.7 days after aneurysm rupture. Two thousand one hundred forty-three patients were randomized in 43 centers worldwide: 1079 patients underwent coiling, and 1073 underwent clipping. The ISAT’s primary goal was to determine which procedure had better patient outcomes as defined by Rankin scores, a functional scoring system. The study was ended early by the Medical Research Counsel (MRC), because the 1-year posttreatment scores showed 31% of the surgical patients were disabled or died compared with 24% of coiled patients. There was a 22.3% overall improvement in the coiled patients. The response to ISAT in Europe was different than that in America. Our European colleagues accepted the results as
Johns Hopkins Medical Institution, Department of Radiology and Neurosurgery, Baltimore, MD. Address reprint requests to Kieran Murphy, MD, FRCPC, Johns Hopkins Medical Institution, Department of Radiology and Neurosurgery, Baltimore, MD 21287. E-mail: [email protected]
106
1089-2516/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.tvir.2005.10.001
recognition of technological progress (medical evolution?) and confirmation of established European medical practice. Approximately 60 to 70% of all ruptured cranial aneurysms are coiled in Europe. In the US, however, the study was attacked by neurosurgeons as being fundamentally flawed. Many arguments were put forth. It was said that American neurosurgeons were more skillful than the European counterparts, more experienced in dealing with ruptured aneurysms. We, at Hopkins, were the only US sites in the study, and though we randomized very few patients, we are very proud of our membership in this study. We entered because the relationship we had as a group of neurovascular specialists in interventional neuroradiology, neurosurgery, and neurology was strong enough to let us randomize. Such randomization fundamentally requires honesty about one’s own technical weakness and is not possible in combative politicized environments. Neither participation in, nor the results of, this study represented a change in our daily practice. It has always been our standard practice to obtain informed consent by offering both options when they are available, or if not, to explain the benefit of one over the other when equipoise does not exist. We have always documented these conversations in the permanent medical record.
The International Study of Unruptured Intracranial Aneurysms There have been two ISUIA studies; the first reported in 1998 was very controversial and widely attacked. It reported a 0.05% yearly rupture rate for intracranial aneurysms. The results were clearly affected by the inclusion of giant skull base aneurysms in elderly women, which have a very low rupture rate. The more recently reported ISUIA article from July 2003 in The Lancet is a more significant work and rep-
ISAT and ISUIA resents a softening of the previous position of the authors. In this study, unruptured aneurysms were randomized to coiling versus clipping, or observation. Once again, among the aneurysms randomized in the treatment arm, an endovascular approach had a 22% relative risk reduction over conventional surgery, reinforcing the results of the ISAT. In the ISUIA study patients with aneurysms of the anterior circulation (defined as MCA or anterior communicating artery) had better outcomes when they are clipped rather than coiled. Very few of these aneurysms were randomized in the ISAT study, a weakness in that study. This is consistent with our practice where in the past 8 years we very rarely treat MCA aneurysms. We have found it difficult to control coil position in these clipable aneurysms. In the hands of our five neurovascular surgeons, clips can be placed to remodel an MCA aneurysm, allowing all branches to be kept open in a way that would be impossible by coiling. The use of multiple neuroform stents is being popularized for these lesions but the published stroke rate exceeds the surgical complication rate so we do not do this in our practice. Despite the many criticisms leveled at the ISUIA prospective data, it is a helpful study and forces us to reflect on its implications. They conclude that patients with no history of subarachnoid hemorrhage and an asymptomatic anterior circulation aneurysm under 7 mm do not require treatment on a simple analysis of risk/benefit ratio alone. For other sizes or sites, ISUIA provides robust information for rupture risk analysis. If treatment is indicated on an individual risk-benefit analysis, which treatment should be provided? The ISUIA study failed to resolve one of the fundamental clinical problems, which is the discrepancy between their reported extremely low rupture risk in asymptomatic aneurysms under 7 mm at 0.7% per year compared with the large proportion of ruptured aneurysms in this same category. In our practice we see an average of 172 to 180 aneurysms a year, and as in ISAT, 61% of aneurysms that ruptured are 5 mm or less. The ISUIA rupture risk is higher for larger aneurysms. How can this be reconciled with the ISUIA position that these lesions, the very ones we see most often, have the lowest rupture rate? The ISUIA investigators (led by neurologists who have focused on this area for many years) state posterior circulation aneurysms (which includes by definition aneurysms of their posterior communicating artery and the vertebral basilar system) have a higher rupture rate and appear to be more appropriate for coiling than for clipping. Patients with a prior history of subarachnoid hemorrhage have a higher risk of bleeding from any intracranial aneurysm. Overall, looking at the results of ISUIA and ISAT when the anatomy is favorable, an endovascular approach seems to be the treatment of choice in patients over 50 years of age and in those with posterior circulation aneurysms. For those patients aged under 50 with anterior circulation aneurysms, the situation is not so clear. However, in those patients, treatment options and relative benefits and risks including post craniotomy epilepsy must be discussed carefully with patient and relatives before elective treatment and informed consent can be obtained. On a daily basis, we struggle with the balance of rupture risk per year versus patient’s life expectancy. If the patient is
107 greater than 70 years of age, we counsel the patient about risks/benefits. In our series, the risk of death from an endovascular approach in an unruptured aneurysm is well below 1%, but the risk of stroke is approximately 5%. The risk of death in an endovascular approach to a ruptured aneurysm is approximately 5%. The risk of stroke is also 5%, and any attempt to thrombolysis in this setting is usually fatal. It is critical not to overlook anesthesia in this mix, as their ability to hurt your patient during the procedure far exceeds that of your fellow, but is harder to identify. The most common anesthesia error is to keep the patient’s blood pressure too low (mistakenly applying open OR traditions to endovascular procedures), thus resulting in watershed hypofusion stroke in these often elderly patients. A study at Emory has shown that patient care in a neuro-ICU is linked with a significant reduction of length of stay for all subarachnoid patients. We believe that there are three types of intracranial aneurysms: ones that should be coiled (posterior circulation); ones that should be clipped (middle cerebral, and some if not most anterior communicating artery aneurysms); and a third group that can be treated either way. This third group relates to the ISAT study data. It is clear that ISAT represents an evolutionary technological trend toward an endovascular or more minimal approach to aneurysms when they are amenable to coiling. A collaborative multidisciplinary team that has trust at its center is essential to a successful outcome for any patient. CMS have prudently mandated there must be biannual national reporting of individual and site complication rates for carotid stenting. This approach mirrors the standard for CABG and cardiac surgery. We must adopt the same approach for intracranial aneurysm therapy. Informed consent on the morning of a coiling or clipping cannot be based on the complication rates from peer-reviewed research performed in centers of excellence. For that patient it can only be obtained based on the experience in that center. This data should be available on the Web so the patient/consumer can make an informed decision and the truth be told. After the ISAT study was published, many fine seasoned interventional neuroradiologists confronted aggressive actions to replace them with less trained neurosurgeons. This kind of political, tribal behavior has no place in medicine practiced in the pursuit of quality. The patient must be equally safe in all hands.
References 1. Molyneux A, Kerr R, Stratton I, et al: International Subarachnoid Aneurysm Trial (ISAT) Collaborative Group. Related Articles, Links. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet 360(9342):1267-1274, 2002 2. Wiebers DO, Whisnant JP, Huston J 3rd, et al: International Study of Unruptured Intracranial Aneurysms Investigators. Related Articles, Links, Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 362(9378):103-110, 2003 3. Wiebers DO, Piepgras DG, Thielen K, et al: Unruptured intracranial aneurysms—risk of rupture and risks of surgical intervention. International Study of Unruptured Intracranial Aneurysms Investigators. N Engl J Med 1998;339(24):1725-1733, 1998. Erratum in: N Engl J Med 340(9):744. PMID: 9867550, 1999
T
he International Subarachnoid Aneurysm Trial (ISAT)1and the International Study of Unruptured Intracranial Aneurysms (ISUIA)2,3 are two landmark studies of intracranial aneurysm therapy. Neither is perfect but both are changing how we manage this disease. They “moved people’s cheese.” They cast doubt on well-developed medical practices and challenged the livelihood of leaders of medical communities all over the world. Naturally they were interpreted differently by the coiling, clipping, and watchful waiting groups depending on how their ‘team” did. So where is the signal in the noise? The ISAT was a multicenter, randomized trial that compared the safety and efficacy of endovascular coil treatment versus surgical clipping for the treatment of ruptured brain aneurysms. To be eligible for enrollment in the ISAT trial, each patient had to be deemed equally suitable for either coiling or clipping. The investigators used the term “clinical equipoise” to describe this balance. The treatment was on average performed 1.7 days after aneurysm rupture. Two thousand one hundred forty-three patients were randomized in 43 centers worldwide: 1079 patients underwent coiling, and 1073 underwent clipping. The ISAT’s primary goal was to determine which procedure had better patient outcomes as defined by Rankin scores, a functional scoring system. The study was ended early by the Medical Research Counsel (MRC), because the 1-year posttreatment scores showed 31% of the surgical patients were disabled or died compared with 24% of coiled patients. There was a 22.3% overall improvement in the coiled patients. The response to ISAT in Europe was different than that in America. Our European colleagues accepted the results as
Johns Hopkins Medical Institution, Department of Radiology and Neurosurgery, Baltimore, MD. Address reprint requests to Kieran Murphy, MD, FRCPC, Johns Hopkins Medical Institution, Department of Radiology and Neurosurgery, Baltimore, MD 21287. E-mail: [email protected]
106
1089-2516/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.tvir.2005.10.001
recognition of technological progress (medical evolution?) and confirmation of established European medical practice. Approximately 60 to 70% of all ruptured cranial aneurysms are coiled in Europe. In the US, however, the study was attacked by neurosurgeons as being fundamentally flawed. Many arguments were put forth. It was said that American neurosurgeons were more skillful than the European counterparts, more experienced in dealing with ruptured aneurysms. We, at Hopkins, were the only US sites in the study, and though we randomized very few patients, we are very proud of our membership in this study. We entered because the relationship we had as a group of neurovascular specialists in interventional neuroradiology, neurosurgery, and neurology was strong enough to let us randomize. Such randomization fundamentally requires honesty about one’s own technical weakness and is not possible in combative politicized environments. Neither participation in, nor the results of, this study represented a change in our daily practice. It has always been our standard practice to obtain informed consent by offering both options when they are available, or if not, to explain the benefit of one over the other when equipoise does not exist. We have always documented these conversations in the permanent medical record.
The International Study of Unruptured Intracranial Aneurysms There have been two ISUIA studies; the first reported in 1998 was very controversial and widely attacked. It reported a 0.05% yearly rupture rate for intracranial aneurysms. The results were clearly affected by the inclusion of giant skull base aneurysms in elderly women, which have a very low rupture rate. The more recently reported ISUIA article from July 2003 in The Lancet is a more significant work and rep-
ISAT and ISUIA resents a softening of the previous position of the authors. In this study, unruptured aneurysms were randomized to coiling versus clipping, or observation. Once again, among the aneurysms randomized in the treatment arm, an endovascular approach had a 22% relative risk reduction over conventional surgery, reinforcing the results of the ISAT. In the ISUIA study patients with aneurysms of the anterior circulation (defined as MCA or anterior communicating artery) had better outcomes when they are clipped rather than coiled. Very few of these aneurysms were randomized in the ISAT study, a weakness in that study. This is consistent with our practice where in the past 8 years we very rarely treat MCA aneurysms. We have found it difficult to control coil position in these clipable aneurysms. In the hands of our five neurovascular surgeons, clips can be placed to remodel an MCA aneurysm, allowing all branches to be kept open in a way that would be impossible by coiling. The use of multiple neuroform stents is being popularized for these lesions but the published stroke rate exceeds the surgical complication rate so we do not do this in our practice. Despite the many criticisms leveled at the ISUIA prospective data, it is a helpful study and forces us to reflect on its implications. They conclude that patients with no history of subarachnoid hemorrhage and an asymptomatic anterior circulation aneurysm under 7 mm do not require treatment on a simple analysis of risk/benefit ratio alone. For other sizes or sites, ISUIA provides robust information for rupture risk analysis. If treatment is indicated on an individual risk-benefit analysis, which treatment should be provided? The ISUIA study failed to resolve one of the fundamental clinical problems, which is the discrepancy between their reported extremely low rupture risk in asymptomatic aneurysms under 7 mm at 0.7% per year compared with the large proportion of ruptured aneurysms in this same category. In our practice we see an average of 172 to 180 aneurysms a year, and as in ISAT, 61% of aneurysms that ruptured are 5 mm or less. The ISUIA rupture risk is higher for larger aneurysms. How can this be reconciled with the ISUIA position that these lesions, the very ones we see most often, have the lowest rupture rate? The ISUIA investigators (led by neurologists who have focused on this area for many years) state posterior circulation aneurysms (which includes by definition aneurysms of their posterior communicating artery and the vertebral basilar system) have a higher rupture rate and appear to be more appropriate for coiling than for clipping. Patients with a prior history of subarachnoid hemorrhage have a higher risk of bleeding from any intracranial aneurysm. Overall, looking at the results of ISUIA and ISAT when the anatomy is favorable, an endovascular approach seems to be the treatment of choice in patients over 50 years of age and in those with posterior circulation aneurysms. For those patients aged under 50 with anterior circulation aneurysms, the situation is not so clear. However, in those patients, treatment options and relative benefits and risks including post craniotomy epilepsy must be discussed carefully with patient and relatives before elective treatment and informed consent can be obtained. On a daily basis, we struggle with the balance of rupture risk per year versus patient’s life expectancy. If the patient is
107 greater than 70 years of age, we counsel the patient about risks/benefits. In our series, the risk of death from an endovascular approach in an unruptured aneurysm is well below 1%, but the risk of stroke is approximately 5%. The risk of death in an endovascular approach to a ruptured aneurysm is approximately 5%. The risk of stroke is also 5%, and any attempt to thrombolysis in this setting is usually fatal. It is critical not to overlook anesthesia in this mix, as their ability to hurt your patient during the procedure far exceeds that of your fellow, but is harder to identify. The most common anesthesia error is to keep the patient’s blood pressure too low (mistakenly applying open OR traditions to endovascular procedures), thus resulting in watershed hypofusion stroke in these often elderly patients. A study at Emory has shown that patient care in a neuro-ICU is linked with a significant reduction of length of stay for all subarachnoid patients. We believe that there are three types of intracranial aneurysms: ones that should be coiled (posterior circulation); ones that should be clipped (middle cerebral, and some if not most anterior communicating artery aneurysms); and a third group that can be treated either way. This third group relates to the ISAT study data. It is clear that ISAT represents an evolutionary technological trend toward an endovascular or more minimal approach to aneurysms when they are amenable to coiling. A collaborative multidisciplinary team that has trust at its center is essential to a successful outcome for any patient. CMS have prudently mandated there must be biannual national reporting of individual and site complication rates for carotid stenting. This approach mirrors the standard for CABG and cardiac surgery. We must adopt the same approach for intracranial aneurysm therapy. Informed consent on the morning of a coiling or clipping cannot be based on the complication rates from peer-reviewed research performed in centers of excellence. For that patient it can only be obtained based on the experience in that center. This data should be available on the Web so the patient/consumer can make an informed decision and the truth be told. After the ISAT study was published, many fine seasoned interventional neuroradiologists confronted aggressive actions to replace them with less trained neurosurgeons. This kind of political, tribal behavior has no place in medicine practiced in the pursuit of quality. The patient must be equally safe in all hands.
References 1. Molyneux A, Kerr R, Stratton I, et al: International Subarachnoid Aneurysm Trial (ISAT) Collaborative Group. Related Articles, Links. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet 360(9342):1267-1274, 2002 2. Wiebers DO, Whisnant JP, Huston J 3rd, et al: International Study of Unruptured Intracranial Aneurysms Investigators. Related Articles, Links, Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 362(9378):103-110, 2003 3. Wiebers DO, Piepgras DG, Thielen K, et al: Unruptured intracranial aneurysms—risk of rupture and risks of surgical intervention. International Study of Unruptured Intracranial Aneurysms Investigators. N Engl J Med 1998;339(24):1725-1733, 1998. Erratum in: N Engl J Med 340(9):744. PMID: 9867550, 1999