Summary of The International Subarachnoid Aneurysm Trial Summary (ISAT)
What is the International Subarachnoid Aneurysm Trial?
The International Subarachnoid Aneurysm Trial — or ISAT — is the only multi-center, prospective randomized trial comparing the safety and efficacy of endovascular coil treatment and surgical clipping for the treatment of ruptured brain aneurysms1. The primary objective of ISAT was to determine whether endovascular treatment compared with neurosurgical treatment reduced the proportion of patients dependent or dead, defined by a modified Rankin score of 3-6.
What types of patients were included in the ISAT?
ISAT’s primary inclusion criterion was patients with ruptured aneurysms who were deemed equally suited for either neurosurgical clipping or endovascular coil treatment. Most patients were not deemed equally suitable for both treatment options and were therefore not randomized. Most of the 2,143 patients randomized into the trial had good-grade (88% in World Federation of Neurosurgical Societies (WFNS) grades I and II), small anterior circulation aneurysms (92 percent less than 11 mm in size).
What were the primary results of the ISAT?
The study found that, in patients equally suited for both treatment options, endovascular coil treatment produces substantially better patient outcomes than surgery in terms of survival free of disability at one year. The relative risk of death or significant disability at one year for patients treated with coils was 22.6% lower than in surgically-treated patients, an absolute risk reduction of 6.9%2. A one-year primary outcome point was chosen to ensure that the likelihood and effects of any subsequent procedures and the occurrence of early rebleeding would be taken into account.
What are the implications for the treatment of patients with ruptured aneurysms?
The ISAT findings are relevant to the types of patients randomized into the trial – good-grade patients with small anterior circulation aneurysms. The results suggest that these patients may be candidates for coiling and should receive an endovascular consultation as part of the treatment protocol. For patients that do not fit this profile, treatment decisions should be based on other research.
What were the rebleed rates during the first year for the two procedures?
The risk of rebleeding during the first year was low in both groups (2.4% for the endovascular group and 1.0% for the surgical group). The effects of rebleeds have been factored into the one-year finding that the relative risk of death or significant disability for endovascular patients was 22.6 percent lower than for surgical patients.
What are the long-term rebleed rates for the two procedures?
While complete long-term data from the ISAT is not yet available, significant follow-up data has been collected because patients were enrolled in the trial as early as 1997. There was no statistical difference between the post one-year rebleed rates in the two patient groups. The risk of rebleeding after one year was two per 1,276 follow-up years for endovascular patients and zero per 1,081 follow-up years for surgical patients. Patients will be followed through at least 2007.
How do the ISAT centers compare to hospitals in the United States?
ISAT centers, which treat between 60 and 200 ruptured aneurysm cases per year, and high-volume centers in the United States have reported similar surgical management mortality rates in the treatment of ruptured aneurysms3. However, most ruptured aneurysm patients in the United States are not treated at high-volume centers. Typical ruptured aneurysm patients are treated at hospitals that admit fewer than 18 ruptured aneurysm cases a year4. In fact, 75 percent of US SAH patients present at hospitals that see less than 36 cases a year. All of the centers that participated in ISAT had both surgical and endovascular expertise, whereas more than 75% of ruptured aneurysm patients in the United States are admitted to hospitals that do not have an endovascular service available.
How do the ISAT mortality results compare with other studies?
The surgical management mortality rate reported in ISAT is similar to that reported in the multicenter, randomized North American trial of tirilazad. Although there are some differences in the distribution of clinical grades in the two trials and in the timing of outcomes assessment, the tirilazad study does provide a reference point of surgical outcomes. In the tirilazad study, 9.2% of the grade I-III patients had died at three-months3. In ISAT, 8.3% and 10.1% of surgically-treated patients were dead at two months and one-year, respectively. Most other available research on the surgical treatment of aneurysms is from case series that are not directly comparable to ISAT. Randomized trials record the management mortality of all patients enrolled, including those who cross-over or rebleed prior to treatment. Self-reported case series usually do not include these cases and may under-report bad outcomes5.
How do the ISAT morbidity results compare with other studies?
Comparison of morbidity data across studies is unreliable because of the variations in methods of data collection. ISAT relied on patient-reported outcomes on the modified Rankin scale. Other studies on the surgical treatment of aneurysms have relied on physician or third-party assessment on the Glasgow Outcome Scale5,6.
Will there be more data forthcoming from the ISAT?
The Medical Research Council of Great Britain has granted funding for ISAT through 2007. Additional data on cost effectiveness, quality of life, angiographic findings and rebleed rates will be collected and analyzed for publication.
1Molyneux A, Kerr R, Stratton I, Sandercock P, Clarke M, Shrimpton J, Holman R. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet. 2002: 360: 1267-74.
2One-year data on 1,888 patients demonstrated a relative risk reduction of 26.8% in favor of coiling, an absolute risk reduction of 8.7%. Reference: Kerr R. The International Subarachnoid Aneurysm Trial: What have we learned? Presentation at the AANS Satellite Symposium: State of the Art Treatment for Acute Subarachnoid Hemorrhage. April 28, 2003.
3Haley EC, Kassell NF, Apperson-Hansen C, Moles MH, Alves WM. A randomized double-blind, placebo-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in North America. J Neurosurg. 1997;86: 467-74.
4Cross, DeWitte T et. al. Mortality Following Subarachnoid Hemorrhage Varies With Hospital Case Volume in 18 States. To be published.
5Grimes, David A and Schulz, Kenneth F. An overview of clinical research: the lay of the land. Lancet. 2002: 359: 57-61.
6Kassell NF, Haley EC, Apperson-Hansen C, et al. Randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in Europe, Australia, and New Zealand. J Neurosurg. 1996; 84: 221-228.