Mary Sneade

International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion

BACKGROUND Two types of treatment are being used for patients with ruptured intracranial aneurysms: endovascular detachable-coil treatment or craniotomy and clipping. We undertook a randomised, multicentre trial to compare these treatments in patients who were suitable for either treatment because the relative safety and efficacy of these approaches had not been established. Here we present clinical outcomes 1 year after treatment. METHODS 2143 patients with ruptured intracranial aneurysms, who were admitted to 42 neurosurgical centres, mainly in the UK and Europe, took part in the trial. They were randomly assigned to neurosurgical clipping (n=1070) or endovascular coiling (n=1073). The primary outcome was death or dependence at 1 year (defined by a modified Rankin scale of 3-6). Secondary outcomes included rebleeding from the treated aneurysm and risk of seizures. Long-term follow up continues. Analysis was in accordance with the randomised treatment. FINDINGS We report the 1-year outcomes for 1063 of 1073 patients allocated to endovascular treatment, and 1055 of 1070 patients allocated to neurosurgical treatment. 250 (23.5%) of 1063 patients allocated to endovascular treatment were dead or dependent at 1 year, compared with 326 (30.9%) of 1055 patients allocated to neurosurgery, an absolute risk reduction of 7.4% (95% CI 3.6-11.2, p=0.0001). The early survival advantage was maintained for up to 7 years and was significant (log rank p=0.03). The risk of epilepsy was substantially lower in patients allocated to endovascular treatment, but the risk of late rebleeding was higher. INTERPRETATION In patients with ruptured intracranial aneurysms suitable for both treatments, endovascular coiling is more likely to result in independent survival at 1 year than neurosurgical clipping; the survival benefit continues for at least 7 years. The risk of late rebleeding is low, but is more common after endovascular coiling than after neurosurgical clipping.

Retreatment of Ruptured Cerebral Aneurysms in Patients Randomized by Coiling or Clipping in the International Subarachnoid Aneurysm Trial (ISAT)

Background and Purpose— Because the long-term security of endovascular treatments remains uncertain, a follow-up study of the patients treated in the International Subarachnoid Aneurysm Trial was performed to compare the frequency, timing, and consequences of aneurysm recurrence. Methods— Patient data were reclassified by actual treatment performed. Aneurysm and patient characteristics, including occlusion grades, time and type of retreatment, and clinical outcomes, were compared. The relationship between these variables and late retreatment as a surrogate for recurrence was analyzed by means of the Cox proportional hazards model. Results— Retreatment was performed in 191 of 1096 (17.4%) patients after primary endovascular coiling (EVT) and in 39 of 1012 patients (3.8%) after neurosurgical clipping. After EVT, 97 (8.8%) patients were retreated early and 94 (9.0%) late, 7 (0.6%) after rebleeding and 87 (8.3%) without. The mean time to late retreatment was 20.7 months. After neurosurgical clipping, 30 (2.9%) patients were retreated early and 9 (0.85%) late, 3 (0.3%) after rebleeding and 6 (0.6%) without. The mean time to late retreatment was 5.7 months. The hazard ratio (HR) for retreatment after EVT was 6.9 (95% CI=3.4 to 14.1) after adjustment for age (P=0.001, HR=0.97, 95% CI=0.95 to 0.98), lumen size (P=0.006, HR=1.1, 95% CI=1.03 to 1.18), and incomplete occlusion (P<0.001, HR=7.6, 95% CI=3.3 to 17.5). Conclusions— Late retreatment was 6.9 times more likely after EVT. Younger age, larger lumen size, and incomplete occlusion were risk factors for late retreatment after EVT. After neurosurgical clipping, retreatments were earlier; whereas EVT retreatments continued to be performed throughout the follow-up period. Short-term follow-up imaging is therefore insufficient to detect recurrences after EVT.

The durability of endovascular coiling versus neurosurgical clipping of ruptured cerebral aneurysms: 18 year follow-up of the UK cohort of the International Subarachnoid Aneurysm Trial (ISAT)

Summary Background Previous analyses of the International Subarachnoid Aneurysm Trial (ISAT) cohort have reported on the risks of recurrent subarachnoid haemorrhage and death or dependency for a minimum of 5 years and up to a maximum of 14 years after treatment of a ruptured intracranial aneurysm with either neurosurgical clipping or endovascular coiling. At 1 year there was a 7% absolute and a 24% relative risk reduction of death and dependency in the coiling group compared with the clipping group, but the medium-term results showed the increased need for re-treatment of the target aneurysm in the patients given coiling. We report the long-term follow-up of patients in this UK cohort. Methods In ISAT, patients were randomly allocated to either neurosurgical clipping or endovascular coiling after a subarachnoid haemorrhage, assuming treatment equipoise, between Sept 12, 1994, and May 1, 2002. We followed up 1644 patients in 22 UK neurosurgical centres for death and clinical outcomes for 10·0–18·5 years. We assessed dependency as self-reported modified Rankin scale score obtained through yearly questionnaires. Data for recurrent aneurysms and rebleeding events were collected from questionnaires and from hospital and general practitioner records. The Office for National Statistics supplied data on deaths. This study is registered, number ISRCTN49866681. Findings At 10 years, 674 (83%) of 809 patients allocated endovascular coiling and 657 (79%) of 835 patients allocated neurosurgical clipping were alive (odds ratio [OR] 1·35, 95% CI 1·06–1·73). Of 1003 individuals who returned a questionnaire at 10 years, 435 (82%) patients treated with endovascular coiling and 370 (78%) patients treated with neurosurgical clipping were independent (modified Rankin scale score 0–2; OR 1·25; 95% CI 0·92–1·71). Patients in the endovascular treatment group were more likely to be alive and independent at 10 years than were patients in the neurosurgery group (OR 1·34, 95% CI 1·07–1·67). 33 patients had a recurrent subarachnoid haemorrhage more than 1 year after their initial haemorrhage (17 from the target aneurysm). Interpretation Although rates of increased dependency alone did not differ between groups, the probability of death or dependency was significantly greater in the neurosurgical group than in the endovascular group. Rebleeding was more likely after endovascular coiling than after neurosurgical clipping, but the risk was small and the probability of disability-free survival was significantly greater in the endovascular group than in the neurosurgical group at 10 years. Funding UK Medical Research Council.

Cerecyte Coil Trial Angiographic Outcomes of a Prospective Randomized Trial Comparing Endovascular Coiling of Cerebral Aneurysms With Either Cerecyte or Bare Platinum Coils

Background and Purpose— We report the primary outcome of the Cerecyte Coil Trial, a randomized trial to determine whether polymer-loaded Cerecyte coils compared with Micrus bare platinum coils improved the proportion of patients with angiographic occlusion of the aneurysm at 6 months when assessed by a core laboratory. The secondary objectives were to compare the clinical outcomes and retreatment rates in the 2 groups. Methods— Five hundred patients between 18 and 70 years of age with a ruptured or unruptured target aneurysm were randomized to be treated with either Cerecyte or bare platinum coils in 23 centers worldwide. Two hundred forty-nine patients were assigned to Cerecyte coils and 251 to bare platinum coils. Analysis was by intention to treat. Results— Four hundred ninety-four patients were eligible for analysis. Four hundred eighty-one patients underwent coil treatment of their aneurysm, 227 patients with recently ruptured aneurysms and 254 with unruptured aneurysms. Four hundred thirty-three follow-up angiograms were assessed by the core laboratory; 127 of 215 (59%) and 118 of 218 (54%) in the Cerecyte and bare platinum groups, respectively, fulfilled the trial prespecified definition of success, namely that the treated aneurysm showed complete angiographic occlusion, had stable neck remnant, or improved in angiographic appearance compared with the end-of-treatment angiogram (P=0.17). Late retreatment was performed in 25 of 452 (5.5%) patients, 17 (7.7%) Cerecyte versus 8 (3.5%) bare platinum (P=0.064; range, 4–34 months). The clinical outcomes did not differ between the groups. Conclusion— There was no significant difference at 6 months in the angiographic outcomes between Cerecyte coils and bare platinum coils when assessed by the core laboratory. Clinical Trial Registration Information— URL: www.controlled-trials.com. Unique Identifier: ISRCTN82461286.

Treatment Pathways, Resource Use, and Costs of Endovascular Coiling Versus Surgical Clipping After aSAH

Background and Purpose— The International Subarachnoid Aneurysm Trial (ISAT) reported that endovascular coiling yields better clinical outcomes than surgical clipping at 1 year. The high cost of the consumables associated with the endovascular coiling procedure (particularly the coils) led health care purchasers to conclude that coiling was a more costly procedure overall. To examine this assumption and provide evidence for future policy, accurate and comprehensive data are required on the overall resource usage and cost of each strategy. Methods— We provide detailed results of patient treatment pathways, resource utilization, and costs up to 24 months postrandomization for endovascular and neurosurgical treatment of aSAH. We report data on costs related to initial and subsequent procedures (ward days, ITU, equipment, staff, consumables, etc), adverse events, complications, and follow up. The data are based on a subsample of all patients randomized in ISAT, containing all patients across 22 UK centers (n=1644). Results— There was a nonsignificant difference −£1740 (−£3582 to £32) in the total 12-month cost of treatment in favor of endovascular treatment. Endovascular patients had higher costs than neurosurgical patients for the initial procedure, for the number and length of stay of subsequent procedures, and for follow-up angiograms. These were more than offset by lower costs related to length of stay for the initial procedure. In the following 12- to 24-month period, costs for subsequent procedures, angiograms, complications, and adverse events were greater for the endovascular patients, reducing the difference in total per patient cost to −£1228 (−£3199 to £786) over the first 24 months of follow-up. Conclusions— No significant difference in costs between the endovascular and neurosurgery groups existed at 12- or 24-month follow up.

Cerecyte Coil Trial: Procedural Safety and Clinical Outcomes in Patients with Ruptured and Unruptured Intracranial Aneurysms

BACKGROUND AND PURPOSE: This study arose from a need to systematically evaluate the clinical and angiographic outcomes of intracranial aneurysms treated with modified coils. We report the procedural safety and clinical outcomes in a prospective randomized controlled trial of endovascular coiling for ruptured and unruptured intracranial aneurysms, comparing polymer-loaded Cerecyte coils with bare platinum coils in 23 centers worldwide. MATERIALS AND METHODS: Five hundred patients between 18 and 70 years of age with a ruptured or unruptured target aneurysm planning to undergo endovascular coiling were randomized to receive Cerecyte or bare platinum coils. Analysis was by intention to treat. RESULTS: Two hundred forty-nine patients were allocated to Cerecyte coils and 251 to bare platinum coils. Baseline characteristics were balanced. For ruptured aneurysms, in-hospital mortality was 2/114 (1.8%) with Cerecyte versus 0/119 (0%) bare platinum coils. There were 8 (3.4%) adverse procedural events resulting in neurological deterioration: 5/114 (4.4%) with Cerecyte versus 3/119 (2.5%) with bare platinum coils (P = .22). The 6-month mRS score of ≤2 was not significantly different in 103/109 (94.5%) patients with Cerecyte and 110/112 (98.2%) patients with bare platinum coils. Poor outcome (mRS score of ≥3 or death) was 6/109 (5.5%) with Cerecyte versus 2/112 (1.8%) with bare platinum coils (P = .070). For UIAs, there was no in-hospital mortality. There were 7 (2.7%) adverse procedural events with neurological deterioration, 5/133 (3.8%) with Cerecyte versus 2/131 (1.5%) with bare platinum coils (P = .13). There was a 6-month mRS score of ≤2 in 114/119 (95.8%) patients with Cerecyte versus 123/123 (100%) patients with bare platinum coils. There was poor outcome (mRS ≥3 and 1 death) in 5/119 (4.2%) patients with Cerecyte versus 0/123 (0%) patients with bare platinum coils (P = .011). CONCLUSIONS: There was a statistical excess of poor outcomes in the Cerecyte arm at discharge in the ruptured aneurysm group and at 6-month follow-up in the unruptured group. Overall adverse clinical outcomes and in-hospital mortality were exceptionally low in both groups.

Epilepsy after subarachnoid hemorrhage: the frequency of seizures after clip occlusion or coil embolization of a ruptured cerebral aneurysm: results from the International Subarachnoid Aneurysm Trial.

OBJECT The aim of this study was to determine the probability of seizures after treatment of a ruptured cerebral aneurysm by clip occlusion and coil embolization, and to identify the risks and predictors of seizures over the short- and long-term follow-up period. METHODS The study population included 2143 patients with ruptured intracranial aneurysms who were enrolled in 43 centers and randomly assigned to clip application or coil placement. Those patients suffering a seizure were identified prospectively at various time points after randomization, as follows: before treatment; after treatment and before discharge; after discharge to 1 year; and annually thereafter. RESULTS Two hundred thirty-five (10.9%) of the 2143 patients suffered a seizure after randomization; 89 (8.3%) of 1073 and 146 (13.6%) of 1070 in the endovascular and neurosurgical allocations, respectively (p = 0.014). In 19 patients the seizure was associated with a rehemorrhage. Of those patients who underwent coil placement alone, without additional procedures, 52 suffered a seizure, and in the group with clip occlusion alone, 91 patients suffered a seizure. The risk of a seizure after discharge in the endovascular group was 3.3% at 1 year and 6.4% at 5 years. In the neurosurgical group it was 5.2% at 1 year and 9.6% at 5 years. The risk of seizure was significantly greater in the neurosurgical group at both 2 years and at up to 14 years (p = 0.005 and p = 0.013, respectively). The significant predictors of increased risk were as follows: neurosurgical treatment allocation, hazard ratio (HR) 1.64 (95% CI 1.19-2.26); younger age, HR 1.54 (95% CI 1.14-2.13); Fisher grade > 1 on CT scans, HR 1.34 (95% CI 0.62-2.87); delayed ischemic neurological deficit due to vasospasm, HR 2.10 (95% CI 1.49-2.94); and thromboembolic complication, HR 5.08 (95% CI 3.00-8.61). A middle cerebral artery (MCA) aneurysm location was also a significant predictor of increased risk in both groups; the HR was 2.23 (95% CI 1.57-3.17), with the probability of seizure at 6.1% and 11.5% at 1 year in the endovascular and neurosurgery groups, respectively. CONCLUSIONS The risk of seizures after coil embolization is significantly lower than that after clip occlusion. An MCA aneurysm location increased the risk of seizures in both groups.

Differences in the angiographic evaluation of coiled cerebral aneurysms between a core laboratory reader and operators: results of the Cerecyte Coil Trial.

BACKGROUND AND PURPOSE: Independent evaluation of angiographic images is becoming widely applied in the assessment of treatment outcomes of cerebral aneurysms. In the current study, we assessed the agreement between an independent core laboratory and the operators regarding angiographic appearance in a recent randomized, controlled trial. MATERIALS AND METHODS: Data were derived from the Cerecyte Coil Trial. Angiographic images of each coiled aneurysm, taken immediately after embolization and at 5- to 7-month follow-up, were evaluated by the operator at the treating center and by an independent neuroradiologist at the core laboratory. For the purpose of this study, images were interpreted on a 3-point scale to provide uniformity for analysis; grade 1: complete occlusion, grade 2: neck remnant; and grade 3: sac filling. “Unfavorable angiographic appearance” was defined as grade 3 at follow-up or interval worsening of grade between the 2 time points. RESULTS: The study included 434 aneurysms. Immediately after embolization, grade 3 was reported by operators in 39 (9%) compared with 52 (12%) by the core laboratory (P = .159). On follow-up, grade 3 was reported by operators in 44 (10%) compared with 81 (19%) by the core laboratory (P < .0001). Overall, operators noted unfavorable angiographic appearance in 78 (18%) compared with 134 (31%) by the core laboratory (P < .0001). At every time point, agreement between the core laboratory and the operators was slight. CONCLUSIONS: Unfavorable angiographic appearance was noted almost twice as frequently by an independent core laboratory as compared with the operators. Planning of trials and interpretation of published studies should be done with careful attention to the mode of angiographic appearance interpretation.

Prediction of two month modified Rankin Scale with an ordinal prediction model in patients with aneurysmal subarachnoid haemorrhage

BackgroundAneurysmal subarachnoid haemorrhage (aSAH) is a devastating event with a frequently disabling outcome. Our aim was to develop a prognostic model to predict an ordinal clinical outcome at two months in patients with aSAH.MethodsWe studied patients enrolled in the International Subarachnoid Aneurysm Trial (ISAT), a randomized multicentre trial to compare coiling and clipping in aSAH patients.Several models were explored to estimate a patients outcome according to the modified Rankin Scale (mRS) at two months after aSAH. Our final model was validated internally with bootstrapping techniques.ResultsThe study population comprised of 2,128 patients of whom 159 patients died within 2 months (8%). Multivariable proportional odds analysis identified World Federation of Neurosurgical Societies (WFNS) grade as the most important predictor, followed by age, sex, lumen size of the aneurysm, Fisher grade, vasospasm on angiography, and treatment modality. The model discriminated moderately between those with poor and good mRS scores (c statistic = 0.65), with minor optimism according to bootstrap re-sampling (optimism corrected c statistic = 0.64).ConclusionWe presented a calibrated and internally validated ordinal prognostic model to predict two month mRS in aSAH patients who survived the early stage up till a treatment decision. Although generalizability of the model is limited due to the selected population in which it was developed, this model could eventually be used to support clinical decision making after external validation.Trial RegistrationInternational Standard Randomised Controlled Trial, Number ISRCTN49866681

The falling rates of hospital admission, case fatality, and population-based mortality for subarachnoid hemorrhage in England, 1999–2010

OBJECTIVE In this study, the authors examined trends in population-based hospital admission rates, patient-level case fatality rates (CFRs), and population-based mortality rates for nontraumatic (spontaneous) subarachnoid hemorrhage (SAH) in England. METHODS Population-based admission and mortality data (59,599 people admitted to a hospital with SAH, 1999-2010; 37,836 people whose death certificates mentioned SAH, 1995-2010) were analyzed. RESULTS Hospital admission rates for SAH per million population declined by 18.3%, from 100.4 (95% CI 97.6-103.1) in 1999 to 82.0 (95% CI 79.7-84.4) in 2010. CFRs at less than 30 days per 100 patients decreased by 18.2%, from 29.7 (95% CI 28.5-31.0) in 1999 to 24.3 (95% CI 23.2-25.5) in 2010. Population-based mortality rates per million population, where SAH was recorded as underlying cause of death on the death certificate, declined by 39.8%, from 41.2 (95% CI 39.5-43.0) in 1999 to 24.8 (95% CI 23.6-26.1) in 2010. CONCLUSIONS Population-based hospital admission rates, patient-level CFRs, and population-based mortality rates all declined between 1999 and 2010. Part of the decline in mortality rates for SAH is likely to be attributable to a decline in incidence. It is also, in part, attributable to increased survival after SAH. The available data do not allow us to compare the effects of different treatment methods for SAH on case fatality and mortality. During the period of study, mortality rates declined by almost 40%, and it is likely that there are a number of factors contributing to this substantial improvement in outcomes for SAH patients in England.