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. Author manuscript; available in PMC: 2012 Dec 21.
Published in final edited form as: Can J Neurol Sci. 2011 Mar;38(2):236–241. doi: 10.1017/s0317167100011392

The design of the Canadian UnRuptured Endovascular versus Surgery (CURES) trial

Tim E Darsaut 1,2, J Max Findlay 2, Jean Raymond 1,✉, for the CURES collaborative group
PMCID: PMC3528784  CAMSID: CAMS2574  PMID: 21320826

Abstract

Background

Once a decision has been made to treat an intact aneurysm, the best treatment remains uncertain. Both surgical and endovascular management strategies are commonly performed for these lesions. Surgical clipping, for years the standard treatment, is gradually becoming supplanted by endovascular treatment. However, there is no randomized data available to compare the results of surgery versus endovascular treatment of unruptured aneurysms (UIAs).

Methods

We report the design of the Canadian UnRuptured Endovascular versus Surgery (CURES) trial to compare angiographic and clinical outcomes following treatment of UIAs.

Results

The Canadian pilot phase will serve two purposes: i) to determine feasibility of the pivotal international study, and ii) to determine the incidence of treatment failure, a composite primary end-point comprising the occurrence of either: failure to accomplish aneurysm obliteration with the initial treatment modality, a major saccular aneurysm remnant or recurrence, or intracranial hemorrhage following treatment at one year. The pivotal international study will address which strategy leads to the best overall clinical outcomes in terms of mortality, morbidity, and clinical efficacy. CURES is designed to be a pragmatic management trial with loose inclusion criteria. The pilot study plans to enroll 260 patients, a size sufficient (at 80% power and 0.05 significance) to detect a decrease in the incidence of treatment failure from 13% to 4%. The formulation of specific hypotheses for the pivotal phase awaits the preliminary CURES morbidity and mortality results.

Conclusions

The CURES trial intends to test surgical versus endovascular management strategies for the treatment of unruptured intracranial aneurysms.

Background

The care of patients with unruptured aneurysms has been described as the most vexing scientific question confronting neurosurgeons, neurologists, and neuroradiologists1. Once the decision has been made to treat the aneurysm, the best treatment remains uncertain. Surgical clipping, for years considered the gold standard, has recently been challenged by the emergence of endovascular treatment (EVT), a minimally invasive alternative2–5. When successful, surgical clipping offers definitive aneurysm exclusion (re-treatment rates as low as 1.5%)6, with attendant mortality and morbidity estimated at 7–10%7–9. In contrast, proponents of EVT have claimed lower treatment-related risks of mortality and morbidity (3–5%) 10, 11, at the cost of lower efficacy (20–40% risk of aneurysm recurrence12, 13, with 11.4% requiring re-treatment)6. Although the hemorrhage rate from recurrent EVT-treated aneurysms is low (estimated at 0.3–1.1%)14, 15, it is not clearly different from the natural history of an unruptured aneurysms in general (assuming 0.9–1.2%/yr)8, 16.

Following ISAT, a randomized trial comparing clipping and coiling of ruptured aneurysms, the demonstration of better 1-year outcomes for ruptured aneurysms treated with EVT has led to a decrease in neurosurgical clipping of not only ruptured but also unruptured aneurysms, particularly in Europe17. However, ISAT results should not be applied to unruptured aneurysms. First, surgical repair of aneurysms in the setting of SAH can be more difficult than for unruptured aneurysms, due to increased cerebral swelling and aneurysm fragility. Second, endovascular treatment of UIAs may involve adjunct techniques and devices, such as stents, that are not frequently used for ruptured aneurysms. The additional risks due to use of these devices11 may increase the morbidity of EVT. Finally, while short-term benefit can be shown following SAH, for which acute re-bleeding is common, the much lower annual rupture rate of UIAs renders the demonstration of long-term efficacy more problematic, especially for EVT.

Because most patients are asymptomatic, preventive treatments must be very safe. Any less morbid approach would therefore be welcome, and EVT may offer this possibility. However, any risk, no matter how small, must be considered excessive if efficacy cannot be shown. The efficacy of EVT for UIAs has never been proven and is a concern because of aneurysm recurrence following coiling12, 13. Consequently, many neurosurgeons still rely on surgical clipping to offer life-time protection from rupture. Both treatments are currently used in most centers, and the crucial question is which treatment, when both are available, will lead to the best overall patient outcomes. Many physicians believe that coiling offers a less risky preventive treatment of UIAs than clipping, but this has never been formally proven in a randomized controlled trial (RCT). Conversely, other physicians believe that surgical clipping offers more frequent, complete occlusion of UIAs than coiling, but this too has never been proven in an RCT. The completeness of occlusion is judged by imaging studies, which, albeit a surrogate, remains an end-point that is widely regarded as a measure of the confidence of protection against future aneurysm rupture. The frequency of major angiographic recurrences after coiling, combined with the lack of definitive proof that peri-operative complications are less with coiling, are the main reasons why many physicians still offer clipping as the first option to patients eligible for coiling. Unfortunately, the results of even large, observational trials such as the ISUIA 18, 19, are of insufficient quality to guide clinical decision-making. Only the rigorous methodology of a randomized clinical trial can find a resolution to this problem.

We report the design of the CURES (Canadian UnRuptured aneurysm Surgery versus Endovascular) trial, the first multi-center randomized trial on the management of unruptured intracranial aneurysms.

Overview of Study Design

The CURES trial will be a two-phase trial: the pilot Canadian phase will examine the incidence of treatment failure by one year, using a composite primary end-point which includes anatomic outcomes. The pivotal international phase will be launched if the morbidity and mortality results and recruitment rates obtained in Phase I demonstrate feasibility. Although superior anatomic results following surgery compared to endovascular coiling are expected, this beneficial aspect of surgical clipping has never been demonstrated in a randomized controlled trial. Sufficient numbers (n = 260) could be obtained in Canadian centers alone to complete this pilot phase in a reasonable time-frame.

The comparisons most relevant to patients and physicians, the clinical efficacy and morbidity and mortality of surgical clipping vs. endovascular coiling for unruptured aneurysms, has also never been formally tested using RCT methods. However, it is expected that to demonstrate a significant difference in hard outcomes such as morbidity and mortality will require more patients (estimated n = 1000) than would be difficult to obtain within Canada alone, so the important second phase, if shown to be feasible in the lead-in pilot study, is hoped to expand and include sites outside Canada. The scope of this phase will depend on the projected required number of patients to demonstrate a clinically significant difference between treatment arms, using the CURES randomized morbidity and mortality results.

Primary Hypotheses of CURES

  1. Surgical clipping of intradural, saccular, unruptured intracranial aneurysms is superior to endovascular management in terms of decreasing the number of patients experiencing treatment failure from 13 to 4%.

  2. An RCT comparing the clinical outcomes of a surgical versus endovascular management strategy is feasible (260 patients can be recruited within 4 years).

Calculation of Sample Size

A previous systematic review of EVT for UIAs has shown that treatment failures, defined as immediate residual aneurysms and re-treatments during follow-up occurred in 14% and 10% of patients, respectively 20. Hence, a conservative estimate of treatment failures after EVT is 13% at one year. Treatment failures after surgical treatment has been reported to occur in approximately 2% of cases6. With target alpha 0.05 and Power 0.8032, a sample size of 236 patients (118 per group, no losses) would be sufficient to demonstrate a significant difference, using an estimated 3% and 14% treatment failure rates for surgical and endovascular management, respectively, at one year (two-sided Fisher’s exact test). Assuming losses at follow-up are less than 10%, we aim to enroll 260 patients in Canada.

End-points – Pilot Phase

The primary end-point of the pilot phase is the incidence of treatment failure, defined as failure of aneurysm obliteration at initial treatment, a major (saccular) angiographic aneurysm remnant or recurrence, or the occurrence of a hemorrhagic event during the follow-up period. Although the anatomic “major” recurrence portion of the primary endpoint is a surrogate, it remains an end-point that is widely regarded as measure of the confidence of protection against future aneurysm rupture. The comparison most relevant to patients and clinicians alike, that of morbidity and mortality, would not be possible to achieve with Canadian patients alone. Secondary end-points include: the individuated end-points from the composite primary end-point, the incidence of all-cause and treatment-related morbidity (mRS >2) and mortality, and the incidence of peri-treatment hospitalization lasting more than 5 days, or discharge to a location other than home.

End-points – Pivotal Phase

Without randomized data, it is too early to formulate the specific hypotheses and endpoints for the pivotal phase. However, the intent can be expressed as a comparison capturing overall clinical outcomes at a minimum of five years. Preliminary estimates with non-randomized data suggest that at least 1000 patients would be required in order to power a significant result.

Planned trial interventions

Surgical clipping or endovascular coiling is performed once for each patient and two or more lesions can be treated at the same sitting. Conservative management of behavioural risk factors (cessation of tobacco and alcohol abuse) and medical treatment of hypertension will be encouraged for both groups for the duration of the study. Treatment will be performed within 6 weeks of randomization, according to standards of practice, and under general anaesthesia. Details regarding surgical or endovascular technique, type of coils, use of adjunctive techniques such as balloon-remodeling or stents, as well as post-treatment medical management issues, will be left up to the treating physicians. Patients found to have an aneurysm recurrence during the follow-up can be treated, if felt appropriate, but this will be counted as having reached the primary end-point.

Method of Allocation

Patients will be randomly allocated into one of two groups: a) surgical management or b) endovascular management, using a centralized minimization procedure to ensure balance between groups, taking the following patient and aneurysm factors into account: (decreasing hierarchical order) i) age >60, ii) aneurysm size >15 mm, and iii) posterior circulation location.

Inclusion/Exclusion criteria

Selection criteria are described in Table 1.

Table 1.

CURES Inclusion and Exclusion Criteria

Inclusion Criteria

  • Patient at least 18 years of age with at least 10 years of remaining life expectancy

  • At least one documented, never ruptured, intradural, saccular intracranial aneurysm

  • The patient and aneurysm are considered appropriate for either surgical or endovascular treatment by the treating team

  • Aneurysm size 3–25 mm

Exclusion Criteria

  • Patients with any intracranial hemorrhage, including SAH, within the previous 12 months

  • Patients with previously incompletely treated intracranial aneurysm

  • Lesion characteristics not equally, readily suitable for endovascular or surgical treatment, in the opinion of the physician(s) intending to treat the aneurysm

  • Multiple aneurysms, where the treatment plan includes both surgical clipping as well as endovascular coiling

  • Aneurysm anticipated (pre-operatively) to require proximal vessel occlusion, a bypass, or other flow-redirecting therapy (including flow-diverter stents) as part of treatment plan

  • Patients with baseline mRS >2

  • Patients with a single cavernous aneurysm

  • Patients with dissecting, fusiform, or mycotic aneurysms

  • Patients with AVM-associated aneurysms

  • Pregnant patients (randomization (and treatment) may be delayed until after delivery)

  • Patients with absolute contraindications to anaesthesia, endovascular treatment or administration of contrast material, including low-osmolarity agents or gadolinium

  • Patients unable to give informed consent

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Justification of Inclusion and Exclusion and Minimization Criteria

Uncertainty and Equipoise

To be eligible for participation in this trial, the patient must be eligible for both treatment options. Because CURES is a pragmatic trial, we have not attempted to formalize which aneurysms would clearly be better treated with one modality over the other. In the absence of convincing evidence such criteria would be at best arbitrary, and at worst erroneous. The intra and inter-observer agreement in choosing treatment modalities has been shown to be ‘fair’ in a blinded prospective review of UIA patients treated at one institution 21. Furthermore, 73% of all patients treated with one or the other option were judged to be eligible for the other treatment option.

The process we propose is not to attempt to guess which option would be the best in one particular patient, but to consider the alternative option each time one treatment option is considered. If clipping is being considered, could coiling be a valuable option?, and vice versa. When both options are considered potentially good management strategies, the particular patient can be offer participation in CURES.

Aneurysm and Patient-related Factors

Size

The risk of harbouring an unruptured intracranial aneurysm smaller than 3 mm has been suggested to be low 8, and immediate risks of treatment may not be justified. Furthermore, endovascular treatment of very small lesions is associated with a greater risk of aneurysm perforation 22. Aneurysms smaller than 3 mm could be followed and then recruited if they enlarge on follow-up. The choice of 25 mm as an upper limit follows from the greater risk of treatment for giant aneurysms, as well as the higher recurrence rate following endovascular treatment of these lesions 23–27. Giant aneurysms (>25 mm) are rare lesions that commonly require more complex treatment techniques, and may have a different etio-pathogenesis than “routine” aneurysms 28–29. It is expected that the majority of aneurysms included in this study will be within the more frequent 5–15 mm range. Aneurysm size should be measured using a cross-sectional imaging study, measuring the longest axis of the aneurysm. For partially thrombosed aneurysms, the outer diameter (filling and non-filling portions) of the aneurysm should be measured.

Multiple Aneurysms

Many patients (up to 20–50% in some centers) 30 present with multiple unruptured aneurysms. We would like to include these patients if possible. In order to do our best to ensure that any observed end-points are a result of treatment allocation, we are excluding those patients with multiple aneurysms whose treatment plan includes both clipping and coiling. Patients previously successfully treated for other lesions can be recruited, provided they fit the inclusion and exclusion criteria. When all the aneurysms that will be treated (this need not include all the discovered aneurysms) can be treated with either a surgical management strategy or an endovascular management strategy, those patients can be included in CURES. In this case, the failure to occlude one of the intended aneurysms will be counted as a treatment failure for that modality. The treatment of multiple aneurysms can be staged, both for surgery and for endovascular treatment. These will not be counted as treatment failures.

Posterior Circulation Location

These aneurysms are commonly treated with EVT, but this practice pattern is not uncontroversial, as many posterior circulation aneurysms remain safely treatable by either clipping or coiling. In the spirit of a pragmatic trial, we prefer to leave the judgment as to the eligibility of each patient bearing such aneurysms to the discretion of the treating physician(s).

Patient age

Patients older than 60 years old are suspected to tolerate aneurysm treatment (both surgical and endovascular) poorly compared to younger patients8. To ensure that this risk factor remains balanced between treatment groups, we have included age>60 (date of randomization is beyond 60th birthdate) as a minimization criterion.

Patient follow-up

Patients from both trial arms will be seen in clinic at approximately 6 weeks as part of routine follow-up care. Patients will be followed with a telephone interview at six months, with another routine clinic visit at one year. These intervals will serve to determine mRS scores, and to inquire regarding possible aneurysm rupture or re-treatment. All patients will have non-invasive imaging (CTA or MRA) at one-year post-treatment to determine the presence of a major, saccular aneurysm recurrence. Non-invasive imaging at one year is considered standard follow-up care of these aneurysms.

Outcome Measures

End-point realization will be determined by the local investigators, with angiographic results sent to the CURES Core Lab for independent review. Outcome measures are detailed below:

Failure of initial treatment is defined as an initial treatment attempt that fails to obliterate the index aneurysm. This end-point will be determined by the treating physician immediately after treatment. Because endovascular treatment sessions conclude with the acquisition of a final series of angiographic images, and not all surgeons obtain immediate post-procedure imaging, there may be a perceived asymmetry of the likelihood that this end-point would be realized between surgery and endovascular. However, a major saccular aneurysm residual left after surgery would still be captured on the one-year imaging study and thus does not constitute a source of bias.

Aneurysm recurrence is defined as a major (saccular) aneurysm remnant or recurrence seen on CTA or MRA performed at one year. Aneurysms treated with clipping are expected to be imaged with CTA, whereas coiled aneurysms will be imaged with MRA due to the coil-related artifact. The relative ability of these imaging modalities to discover small aneurysm residuals remains a contested issue, however, since we are only interested in major, saccular aneurysm recurrences, both types of imaging are equally suitable for this study.

Hemorrhagic event is defined as: 1) cross-sectional imaging (CT or MRI) evidence of intracranial bleeding, or 2) acute headache and lumbar puncture positive for hemorrhage 3) sudden death preceded by severe headache 4) intracranial bleeding proven by postmortem CT-scanning or autopsy, or 5) unexplained sudden death.

Treatment-related mortality or morbidity is defined as any event occurring within 31 days of treatment leading to mortality or disability (mRS >2).

Planned Analyses

Descriptive statistics will be done on demographic variables and potential risk factors (age, aneurysm size, neck width, multiplicity, smoking status etc.) to compare the two groups at baseline. Means, standard deviations, and ranges will be presented for quantitative variables such as size of aneurysms and frequency tables for categorical variables (such as the number of patients with multiple aneurysms). Those statistics will be broken down by center and by treatment arm. Comparison of the groups will be assessed through independent ANOVA (quantitative data) or Mantel-Haentzel and χ2 tests (categorical data). The main statistical test will involve comparisons between the probability of reaching the primary end-point (treatment failure) with a surgical or endovascular management strategy (intent-to-treat analysis). Assuming comparability of groups across centers, the primary outcome (failure of treatment) will be compared between groups using a Fisher’s exact test at 1 year.

Secondary outcomes will be compared between groups using independent t-tests for quantitative variables and χ2 tests for categorical variables. The analyses of neurological data at follow-up will control for baseline data using logistic regression, ANCOVA or Cox regression multivariate methods. All tests will be interpreted with a 0.05 level of confidence.

Cross over to the alternate treatment arm

To minimize cross-overs that might occur between randomization and treatment, treatment will be planned to occur within 6 weeks of randomization. Cross-overs deemed necessary to treat patients (after treatment failures) will of course count as having reached the primary end-point.

Frequency of Analyses

To prevent the alpha spending that follows every additional analysis, the pilot Phase I data will only be analyzed once, after the one 1-year follow-up imaging study has been completed in all participants. Safety data (occurrence of severe adverse events, treatment-related complications, and hemorrhages) will be reviewed periodically by the DSMC that will meet at on at least a yearly basis. The primary outcome will be assessed at 1 year.

Stratification of results

Clinical outcomes will be stratified according to patient age, aneurysm size, and location, with two pre-designated strata for each factor: i) age < 60, and age ≥ 60; ii) aneurysm size <15 mm, and aneurysm size ≥ 15 mm; and iii) anterior vs. posterior circulation location. Pre-specified stratification of supposed different groups of patients can be required within the context of a pragmatic trial due to the possibility that a beneficial effect seen in one group of patients might be negated by another group with a different response to treatment. The justification for the chosen strata is as follows. Patients older than 60 years of age are suspected to tolerate aneurysm treatment (both surgical and endovascular) poorly compared to younger patients8. Supposed differences in ease of access to anterior versus posterior circulation aneurysms for surgical clipping or EVT may also lead to differences in treatment outcomes for these two groups of patients10.

Discussion

The most fundamental clinical dilemma, whether UIAs should be treated or not, will not be addressed by the CURES trial. A previous RCT designed to compare coiling and conservative management, the TEAM trial 31 was interrupted due to insufficient recruitment. Because UIAs are routinely treated by clipping or coiling in all neurovascular centers, this trial is designed to address the next important question: Which treatment modality is best for patients with UIAs ?

Large-scale international RCTs are difficult to organize and implement. The financial, regulatory, legal, contractual, and organizational hurdles are so numerous that launching such an effort requires years of hard work, during which time financial support is difficult to secure. Nevertheless, we must attempt to provide our patients with the best possible care in spite of the uncertainty.

What is needed is a large, simple, pragmatic randomized trial that is integrated into clinical practice. Follow-up visits and tests are the same as those performed as a part of routine care. End-points must be pre-defined, simple, meaningful, and resistant to bias. Data can be collected on simple electronic forms. The simplicity of the procedure and lack of extra requirements will help assure that the trial can be performed without extra cost to participating centers. The most significant result, whether patients have better clinical outcomes in the long-run, can only be obtained with a large-scale clinical trial, but we need to start somewhere. CURES was designed to provide a primary hypothesis that can be confirmed or refuted at the end of a pilot phase that is feasible within the network of Canadian centers.

Conclusion

Surgical treatment has long been the accepted standard for effective treatment of unruptured aneurysms, but it may suffer from increased treatment-related morbidity and mortality. Endovascular treatment holds promise as a minimally-invasive alternative, but doubts remain regarding the efficacy and durability of this modality. A randomized clinical trial comparing these two treatments is required to guide and deliver the best possible care to patients harbouring unruptured intracranial aneurysms.

Acknowledgments

We are thankful to Ken Butcher and Allan J. Fox for agreeing to participate on the DSMC (Data and Safety Monitoring Committee). Also, we wish to thank all our Canadian collaborators, current and future, for their help with the CURES study.

Footnotes

Competing interests

The authors have no competing interests to declare. The design of the CURES trial has been reviewed and approved by the Canadian Stroke Consortium. The CURES is registered: ClinicalTrials.gov identifier: NCT01139892.

References

  • 1.Weir B. Unruptured intracranial aneurysms: a review. J Neurosurg. 2002 Jan;96(1):3–42. doi: 10.3171/jns.2002.96.1.0003. [DOI] [PubMed] [Google Scholar]
  • 2.Guglielmi G. Coil over clip. J Neurosurg. 2009 Aug;111(2):410–1. doi: 10.3171/2009.2.JNS0951. author reply 411–2. [DOI] [PubMed] [Google Scholar]
  • 3.Pouratian N, Oskouian RJ, Jr, Jensen ME, Kassell NF, Dumont AS. Endovascular management of unruptured intracranial aneurysms. J Neurol Neurosurg Psychiatry. 2006 May;77(5):572–8. doi: 10.1136/jnnp.2005.078469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Prat R, Galeano I. Early surgical treatment of middle cerebral artery aneurysms associated with intracerebral haematoma. Clin Neurol Neurosurg. 2007 Jun;109(5):431–5. doi: 10.1016/j.clineuro.2007.03.005. [DOI] [PubMed] [Google Scholar]
  • 5.Molyneux A, Kerr R, Stratton I, et al. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet. 2002 Oct 26;360(9342):1267–74. doi: 10.1016/s0140-6736(02)11314-6. [DOI] [PubMed] [Google Scholar]
  • 6.Raja PV, Huang J, Germanwala AV, Gailloud P, Murphy KP, Tamargo RJ. Microsurgical clipping and endovascular coiling of intracranial aneurysms: a critical review of the literature. Neurosurgery. 2008 Jun;62(6):1187–202. doi: 10.1227/01.neu.0000333291.67362.0b. [DOI] [PubMed] [Google Scholar]
  • 7.Krisht AF, Gomez J, Partington S. Outcome of surgical clipping of unruptured aneurysms as it compares with a 10-year nonclipping survival period. Neurosurgery. 2006 Feb;58(2):207–16. doi: 10.1227/01.NEU.0000194638.61073.FC. [DOI] [PubMed] [Google Scholar]
  • 8.Wiebers DO, Whisnant JP, Huston J, 3rd, et al. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet. 2003 Jul 12;362(9378):103–10. doi: 10.1016/s0140-6736(03)13860-3. [DOI] [PubMed] [Google Scholar]
  • 9.Raaymakers TW, Rinkel GJ, Limburg M, Algra A. Mortality and morbidity of surgery for unruptured intracranial aneurysms: a meta-analysis. Stroke. 1998 Aug;29(8):1531–8. doi: 10.1161/01.str.29.8.1531. [DOI] [PubMed] [Google Scholar]
  • 10.Johnston SC, Wilson CB, Halbach VV, et al. Endovascular and surgical treatment of unruptured cerebral aneurysms: comparison of risks. Ann Neurol. 2000 Jul;48(1):11–9. doi: 10.1002/1531-8249(200007)48:1<11::aid-ana4>3.3.co;2-m. [DOI] [PubMed] [Google Scholar]
  • 11.Pierot L, Spelle L, Vitry F. Immediate clinical outcome of patients harboring unruptured intracranial aneurysms treated by endovascular approach: results of the ATENA study. Stroke. 2008 Sep;39(9):2497–504. doi: 10.1161/STROKEAHA.107.512756. [DOI] [PubMed] [Google Scholar]
  • 12.Raymond J, Guilbert F, Weill A, et al. Long-term angiographic recurrences after selective endovascular treatment of aneurysms with detachable coils. Stroke. 2003 Jun;34(6):1398–403. doi: 10.1161/01.STR.0000073841.88563.E9. [DOI] [PubMed] [Google Scholar]
  • 13.Choi DS, Kim MC, Lee SK, Willinsky RA, Terbrugge KG. Clinical and angiographic long-term follow-up of completely coiled intracranial aneurysms using endovascular technique. J Neurosurg. Mar;112(3):575–81. doi: 10.3171/2008.12.JNS08768. [DOI] [PubMed] [Google Scholar]
  • 14.Johnston SC, Dowd CF, Higashida RT, Lawton MT, Duckwiler GR, Gress DR. Predictors of rehemorrhage after treatment of ruptured intracranial aneurysms: the Cerebral Aneurysm Rerupture After Treatment (CARAT) study. Stroke. 2008 Jan;39(1):120–5. doi: 10.1161/STROKEAHA.107.495747. [DOI] [PubMed] [Google Scholar]
  • 15.Rates of delayed rebleeding from intracranial aneurysms are low after surgical and endovascular treatment. Stroke. 2006 Jun;37(6):1437–42. doi: 10.1161/01.STR.0000221331.01830.ce. [DOI] [PubMed] [Google Scholar]
  • 16.Wermer MJ, van der Schaaf IC, Algra A, Rinkel GJ. Risk of rupture of unruptured intracranial aneurysms in relation to patient and aneurysm characteristics: an updated meta-analysis. Stroke. 2007 Apr;38(4):1404–10. doi: 10.1161/01.STR.0000260955.51401.cd. [DOI] [PubMed] [Google Scholar]
  • 17.Gnanalingham KK, Apostolopoulos V, Barazi S, O’Neill K. The impact of the international subarachnoid aneurysm trial (ISAT) on the management of aneurysmal subarachnoid haemorrhage in a neurosurgical unit in the UK. Clin Neurol Neurosurg. 2006 Feb;108(2):117–23. doi: 10.1016/j.clineuro.2005.11.001. [DOI] [PubMed] [Google Scholar]
  • 18.Wiebers DO, Whisnant JP, Huston J, 3rd, et al. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet. 2003 Jul 12;362(9378):103–10. doi: 10.1016/s0140-6736(03)13860-3. [DOI] [PubMed] [Google Scholar]
  • 19.Raymond J, Guillemin F, Proust F, Molyneux AJ, Fox A, Johnston SC, Meder JF, Rouleau I The Trial on Endovascular Aneurysm Management (TEAM) collaborative group. Unruptured intracranial aneurysms: A critical review of available studies and of appropriate methods to address the clinical problem. Interventional Neuroradiology. 2008 Mar;14:85–96. doi: 10.1177/159101990801400111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Naggara O, White PM, Guilbert F, Roy D, Weill A, Raymond J. Endovascular treatment of unruptured intracranial aneurysms: A systematic review of the literature on safety and efficacy. Radiology. 2010 Jul 15; doi: 10.1148/radiol.10091982. [Epub ahead of print] [DOI] [PubMed] [Google Scholar]
  • 21.Johnston SC. Identifying confounding by indication through blinded prospective review. Am J Epidemiol. 2001 Aug 1;154(3):276–84. doi: 10.1093/aje/154.3.276. [DOI] [PubMed] [Google Scholar]
  • 22.Nguyen TN, Raymond J, Guilbert F, et al. Association of endovascular therapy of very small ruptured aneurysms with higher rates of procedure-related rupture. J Neurosurg. 2008 Jun;108(6):1088–92. doi: 10.3171/JNS/2008/108/6/1088. [DOI] [PubMed] [Google Scholar]
  • 23.Lawton MT, Spetzler RF. Surgical management of giant intracranial aneurysms: experience with 171 patients. Clin Neurosurg. 1995;42:245–66. [PubMed] [Google Scholar]
  • 24.Drake CG. Giant intracranial aneurysms: experience with surgical treatment in 174 patients. Clin Neurosurg. 1979;26:12–95. doi: 10.1093/neurosurgery/26.cn_suppl_1.12. [DOI] [PubMed] [Google Scholar]
  • 25.Gruber A, Killer M, Bavinzski G, Richling B. Clinical and angiographic results of endosaccular coiling treatment of giant and very large intracranial aneurysms: a 7-year, single-center experience. Neurosurgery. 1999 Oct;45(4):793–803. doi: 10.1097/00006123-199910000-00013. [DOI] [PubMed] [Google Scholar]
  • 26.Piepgras DG, Khurana VG, Whisnant JP. Ruptured giant intracranial aneurysms. Part II. A retrospective analysis of timing and outcome of surgical treatment. J Neurosurg. 1998 Mar;88(3):430–5. doi: 10.3171/jns.1998.88.3.0430. [DOI] [PubMed] [Google Scholar]
  • 27.Sluzewski M, Menovsky T, van Rooij WJ, Wijnalda D. Coiling of very large or giant cerebral aneurysms: Long-term clinical and serial angiographic results. AJNR Am J Neuroradiol. 2003 Feb;24(2):257–62. [PMC free article] [PubMed] [Google Scholar]
  • 28.Day AL, Gaposchkin CG, Yu CJ, Rivet DJ, Dacey RG., Jr Spontaneous fusiform middle cerebral artery aneurysms: characteristics and a proposed mechanism of formation. J Neurosurg. 2003 Aug;99(2):228–40. doi: 10.3171/jns.2003.99.2.0228. [DOI] [PubMed] [Google Scholar]
  • 29.Morley T, BHWK P. Giant intracranial aneurysm: diagnosis, course, and management. Clin Neurosurg. 1968;16:73–94. doi: 10.1093/neurosurgery/16.cn_suppl_1.73. [DOI] [PubMed] [Google Scholar]
  • 30.Roy D, Milot G, Raymond J. Endovascular treatment of unruptured aneurysms. Stroke. 2001 Sep;32(9):1998–04. doi: 10.1161/hs0901.095600. [DOI] [PubMed] [Google Scholar]
  • 31.Raymond J, Molyneux AJ, Fox AJ, Johnston SC, Collet JP, Rouleau I. The TEAM trial: safety and efficacy of endovascular treatment of unruptured intracranial aneurysms in the prevention of aneurysmal hemorrhages: a randomized comparison with indefinite deferral of treatment in 2002 patients followed for 10 years. Trials. 2008;9:43. doi: 10.1186/1745-6215-9-43. [DOI] [PMC free article] [PubMed] [Google Scholar]

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