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OBJECTIVE The role of endovascular treatment in the management of patients with brain arteriovenous malformations (AVMs) remains uncertain. AVM embolization can be offered as stand-alone curative therapy or prior to surgery or stereotactic radiosurgery (SRS) (pre-embolization). The Treatment of Brain AVMs Study (TOBAS) is an all-inclusive pragmatic study that comprises two randomized trials and multiple registries. METHODS Results from the TOBAS curative and pre-embolization registries are reported. The primary outcome for this report is death or dependency (modified Rankin Scale [mRS] score > 2) at last follow-up. Secondary outcomes include angiographic results, perioperative serious adverse events (SAEs), and permanent treatment-related complications leading to an mRS score > 2. RESULTS From June 2014 to May 2021, 1010 patients were recruited in TOBAS. Embolization was chosen as the primary curative treatment for 116 patients and pre-embolization prior to surgery or SRS for 92 patients. Clinical and angiographic outcomes were available in 106 (91%) of 116 and 77 (84%) of 92 patients, respectively. In the curative embolization registry, 70% of AVMs were ruptured, and 62% were low-grade AVMs (Spetzler-Martin grade I or II), while the pre-embolization registry had 70% ruptured AVMs and 58% low-grade AVMs. The primary outcome of death or disability (mRS score > 2) occurred in 15 (14%, 95% CI 8%–22%) of the 106 patients in the curative embolization registry (4 [12%, 95% CI 5%–28%] of 32 unruptured AVMs and 11 [15%, 95% CI 8%–25%] of 74 ruptured AVMs) and 9 (12%, 95% CI 6%–21%) of the 77 patients in the pre-embolization registry (4 [17%, 95% CI 7%–37%] of 23 unruptured AVMs and 5 [9%, 95% CI 4%–20%] of 54 ruptured AVMs) at 2 years. Embolization alone was confirmed to occlude the AVM in 32 (30%, 95% CI 21%–40%) of the 106 curative attempts and in 9 (12%, 95% CI 6%–21%) of 77 patients in the pre-embolization registry. SAEs occurred in 28 of the 106 attempted curative patients (26%, 95% CI 18%–35%, including 21 new symptomatic hemorrhages [20%, 95% CI 13%–29%]). Five of the new hemorrhages were in previously unruptured AVMs (n = 32; 16%, 95% CI 5%–33%). Of the 77 pre-embolization patients, 18 had SAEs (23%, 95% CI 15%–34%), including 12 new symptomatic hemorrhages [16%, 95% CI 9%–26%]). Three of the hemorrhages were in previously unruptured AVMs (3/23; 13%, 95% CI 3%–34%). CONCLUSIONS Embolization as a curative treatment for brain AVMs was often incomplete. Hemorrhagic complications were frequent, even when the specified intent was pre-embolization before surgery or SRS. Because the role of endovascular treatment remains uncertain, it should preferably, when possible, be offered in the context of a randomized trial.

OBJECTIVE The Treatment of Brain Arteriovenous Malformations Study (TOBAS) is a pragmatic study that includes 2 randomized trials and registries of treated or conservatively managed patients. The authors report the results of the surgical registry. METHODS TOBAS patients are managed according to an algorithm that combines clinical judgment and randomized allocation. For patients considered for curative treatment, clinicians selected from surgery, endovascular therapy, or radiation therapy as the primary curative method, and whether observation was a reasonable alternative. When surgery was selected and observation was deemed unreasonable, the patient was not included in the randomized controlled trial but placed in the surgical registry. The primary outcome of the trial was mRS score > 2 at 10 years (at last follow-up for the current report). Secondary outcomes include angiographic results, perioperative serious adverse events, and permanent treatment-related complications leading to mRS score > 2. RESULTS From June 2014 to May 2021, 1010 patients were recruited at 30 TOBAS centers. Surgery was selected for 229/512 patients (44%) considered for curative treatment; 77 (34%) were included in the surgery versus observation randomized trial and 152 (66%) were placed in the surgical registry. Surgical registry patients had 124/152 (82%) ruptured and 28/152 (18%) unruptured arteriovenous malformations (AVMs), with the majority categorized as low-grade Spetzler-Martin grade I–II AVM (118/152 [78%]). Thirteen patients were excluded, leaving 139 patients for analysis. Embolization was performed prior to surgery in 78/139 (56%) patients. Surgical angiographic cure was obtained in 123/139 all-grade (89%, 95% CI 82%–93%) and 105/110 low-grade (95%, 95% CI 90%–98%) AVM patients. At the mean follow-up of 18.1 months, 16 patients (12%, 95% CI 7%–18%) had reached the primary safety outcome of mRS score > 2, including 11/16 who had a baseline mRS score ≥ 3 due to previous AVM rupture. Serious adverse events occurred in 29 patients (21%, 95% CI 15%–28%). Permanent treatment-related complications leading to mRS score > 2 occurred in 6/139 patients (4%, 95% CI 2%–9%), 5 (83%) of whom had complications due to preoperative embolization. CONCLUSIONS The surgical treatment of brain AVMs in the TOBAS registry was curative in 88% of patients. The participation of more patients, surgeons, and centers in randomized trials is needed to definitively establish the role of surgery in the treatment of unruptured brain AVMs. Clinical trial registration no.: NCT02098252 (ClinicalTrials.gov)

BACKGROUND AND PURPOSE Delayed cerebral ischemia (DCI) and angiographic vasospasm following subarachnoid hemorrhage (SAH) have been associated for more than 50years. We aimed to examine whether the knowledge gained by theoretical research on vasospasm has actually translated into better patient outcomes in practice. METHODS This is a narrative review of the concept of vasospasm as a cause of DCI after SAH. We discuss recent studies that have assessed the accuracy and reliability of the diagnostic tests (transcranial Doppler ultrasound [TCD], CT angiography, and catheter angiography), which are used to identify SAH patients at-risk of DCI. RESULTS Both the diagnostic accuracy of TCD and the reliability of CT angiography to identify patients in severe vasospasm are poor. For the gold standard catheter angiography, the repeatability of the diagnosis of vasospasm, made by multiple raters, is only fair. Interventions on angiographic vasospasm have never been proven to improve patient outcomes. A pragmatic trial integrating the meaning of the diagnosis of vasospasm into a study protocol that assesses the value of endovascular interventions in the prevention of DCI after SAH seems to be in order. Such a trial could provide a pragmatic definition of clinically meaningful vasospasm. CONCLUSION We must move beyond research conceived as an enterprise aiming to acquire theoretical knowledge to one where research is integrated into clinical practice to improve clinical outcomes in real time.

The Comprehensive Aneurysm Management (CAM) study is a pragmatic trial designed to manage unruptured intracranial aneurysm (UIA) patients within a care research framework.CAM is an all-inclusive study. Management options are allocated according to an algorithm combining pre-randomization and clinical judgment. Eligible patients are offered 1:1 randomized allocation of intervention versus conservative management and 1:1 randomization allocation of surgical versus endovascular treatment. Ineligible patients are registered. The primary outcome is survival without dependency (modified Rankin Scale score3) at 10 years. All UIA patients at 1 center are reported.Between February 2020 and July 2021, 403 UIA patients were recruited: 179 (44%) in one of the randomized controlled trials (RCTs) and 224 (56%) in one of the registries. Conservative management was recommended for 205 of 403 patients (51%); of 198 (49%) patients considered for curative treatment, 159 (80%) were randomly allocated conservative (n = 81) or curative treatment (n = 78). These patients were younger and had larger aneurysms than those in the observation registry (P = 0.004). In 39 of 198 patients (20%), conservative management was not considered reasonable (17 patients were recommended endovascular, 2 surgery, and 20 the RCT comparing endovascular with surgical treatment). In total, 70 patients were recruited in the RCT comparing surgery and endovascular treatment. After informed discussion at time of consent, 141 of 159 patients (89%) agreed with the randomly allocated management plan, while 11% crossed over to the alternative management option.CAM was successfully integrated into routine practice. Meaningful conclusions can be obtained if multiple centers actively participate in the trial.

Background: The prognosis for patients with recurrent glioblastoma (GBM) is dismal, and the question of repeat surgery at time of recurrence is common. Re-operation in the management of these patients remains controversial, as there is no randomized evidence of benefit. An all-inclusive pragmatic care trial is needed to evaluate the role of repeat resection. Methods: 3rGBM is a multicenter, pragmatic, prospective, parallel-group randomized care trial, with 1:1 allocation to repeat resection or standard care with no repeat resection. To test the hypothesis that repeat resection can improve overall survival by at least 3 months (from 6 to 9 months), 250 adult patients with prior resection of pathology-proven glioblastoma for whom the attending surgeon believes repeat resection may improve quality survival will be enrolled. A surrogate measure of quality of life, the number of days outside of hospital/nursing/palliative care facility, will also be compared. Centers are invited to participate without financial compensation and without contracts. Clinicians may apply to local authorities to approve an investigator-led in-house trial, using a common protocol, web-based randomization platform, and simple standardized case report forms. Discussion: The 3rGBM trial is a modern transparent care research framework with no additional risks, tests, or visits other than what patients would encounter in normal care. The burden of proof remains on repeat surgical management of recurrent GBM, because this management has yet to be shown beneficial. The trial is designed to help patients and surgeons manage the uncertainty regarding optimal care. Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT04838782.

BACKGROUND AND PURPOSE: Noninvasive angiography is commonly used to assess the outcome of surgical or endovascular treatment of intracranial aneurysms in clinical series or randomized trials. We sought to assess whether a standardized 3-grade classification system could be reliably used to compare the CTA and MRA results of both treatments. MATERIALS AND METHODS: An electronic portfolio composed of CTAs of 30 clipped and MRAs of 30 coiled aneurysms was independently evaluated by 24 raters of diverse experience and training backgrounds. Twenty raters performed a second evaluation 1 month later. Raters were asked which angiographic grade and management decision (retreatment; close or long-term follow-up) would be most appropriate for each case. Agreement was analyzed using the Krippendorff α (α(K)) statistic, and the relationship between angiographic grade and clinical management choice, using the Fisher exact and Cramer V tests. RESULTS: Interrater agreement was substantial (α(K) = 0.63; 95% CI, 0.55–0.70); results were slightly better for MRA results of coiling (α(K) = 0.69; 95% CI, 0.56–0.76) than for CTA results of clipping (α(K) = 0.58; 95% CI, 0.44–0.69). Intrarater agreement was substantial to almost perfect. Interrater agreement regarding clinical management was moderate for both clipped (α(K) = 0.49; 95% CI, 0.32–0.61) and coiled subgroups (α(K) = 0.47; 95% CI, 0.34–0.54). The choice of clinical management was strongly associated with the size of the residuum (mean Cramer V = 0.77 [SD, 0.14]), but complete occlusions (grade 1) were followed more closely after coiling than after clipping (P = .01). CONCLUSIONS: A standardized 3-grade scale was found to be a reliable and clinically meaningful tool to compare the results of clipping and coiling of aneurysms using CTA or MRA.

Background A significant proportion of glioblastoma (GBM) patients are considered for repeat resection, but evidence regarding best management remains elusive. Our aim was to measure the degree of clinical uncertainty regarding reoperation for patients with recurrent GBM. Methods We first performed a systematic review of agreement studies examining the question of repeat resection for recurrent GBM. An electronic portfolio of 37 pathologically confirmed recurrent GBM patients including pertinent magnetic resonance images and clinical information was assembled. To measure clinical uncertainty, 26 neurosurgeons from various countries, training backgrounds, and years' experience were asked to select best management (repeat surgery, other nonsurgical management, or conservative), confidence in recommended management, and whether they would include the patient in a randomized trial comparing surgery with nonsurgical options. Agreement was evaluated using κ statistics. Results The literature review did not reveal previous agreement studies examining the question. In our study, agreement regarding best management of recurrent GBM was slight, even when management options were dichotomized (repeat surgery vs. other options; κ=0.198 [95% confidence interval: 0.133-0.276]). Country of practice, years' experience, and training background did not change results. Disagreement and clinical uncertainty were more pronounced within clinicians with (κ=0.167 [0.055-0.314]) than clinicians without neuro-oncology fellowship training (κ=0.601 [0.556-0.646]). A majority (51%) of responders were willing to include the patient in a randomized trial comparing repeat surgery with nonsurgical alternatives in 26/37 (69%) of cases. Conclusion There is sufficient uncertainty and equipoise regarding the question of reoperation for patients with recurrent glioblastoma to support the need for a randomized controlled trial.

Results of surgical or endovascular treatment of intracranial aneurysms are often assessed using angiography. A reliable method to report results irrespective of treatment modality is needed to enable comparisons. Our goals were to systematically review existing classification systems, and to propose a 3-point classification applicable to both treatments and assess its reliability. We conducted two systematic reviews on classification systems of angiographic results after clipping or coiling to select a simple 3-category scale that could apply to both treatments. We then circulated an electronic portfolio of angiograms of clipped (n=30) or coiled (n=30) aneurysms, and asked raters to evaluate the degree of occlusion using this scale. Raters were also asked to choose an appropriate follow-up management for each patient based on the degree of occlusion. Agreement was assessed using Krippendorff’s α statistics (αK), and relationship between occlusion grade and clinical management was analyzed using Fisher’s exact and Cramer’s V tests. The systematic reviews found 70 different grading scales with heterogeneous reliability (kappa values from 0.12 to 1.00). The 60-patient portfolio was independently evaluated by 19 raters of diverse backgrounds (neurosurgery, radiology, and neurology) and experience. There was substantial agreement (αK=0.76, 95%CI, 0.67–0.83) between raters, regardless of background, experience, or treatment used. Intra-rater agreement ranged from moderate to almost perfect. A strong relationship was found between angiographic grades and management decisions (Cramer’s V: 0.80±0.12). A simple 3-point scale demonstrated sufficient reliability to be used in reporting aneurysm treatments or in evaluating treatment results in comparative randomized trials.

BACKGROUND AND PURPOSE: Conventional angiography is the benchmark examination to diagnose cerebral vasospasm, but there is limited evidence regarding its reliability. Our goals were the following: 1) to systematically review the literature on the reliability of the diagnosis of cerebral vasospasm using conventional angiography, and 2) to perform an agreement study among clinicians who perform endovascular treatment. MATERIALS AND METHODS: Articles reporting a classification system on the degree of cerebral vasospasm on conventional angiography were systematically searched, and agreement studies were identified. We assembled a portfolio of 221 cases of patients with subarachnoid hemorrhage and asked 17 raters with different backgrounds (radiology, neurosurgery, or neurology) and experience (junior ≤10 and senior >10 years) to independently evaluate cerebral vasospasm in 7 vessel segments using a 3-point scale and to evaluate, for each case, whether findings would justify endovascular treatment. Nine raters took part in the intraobserver reliability study. RESULTS: The systematic review showed a very heterogeneous literature, with 140 studies using 60 different nomenclatures and 21 different thresholds to define cerebral vasospasm, and 5 interobserver studies reporting a wide range of reliability (κ = 0.14–0.87). In our study, only senior raters reached substantial agreement (κ ≥ 0.6) on vasospasm of the supraclinoid ICA, M1, and basilar segments and only when assessments were dichotomized (presence or absence of ≥50% narrowing). Agreement on whether to proceed with endovascular management of vasospasm was only fair (κ ≤ 0.4). CONCLUSIONS: Research on cerebral vasospasm would benefit from standardization of definitions and thresholds. Dichotomized decisions by experienced readers are required for the reliable angiographic diagnosis of cerebral vasospasm.

Background Pragmatic care trials have been designed to provide optimal neurovascular care in the presence of uncertainty. The feasibility, benefits, and drawbacks of using this novel approach remain unknown. Methods We report the progress of 9 randomized trials integrated into routine practice to guide the endovascular or surgical treatment of intracranial aneurysms, arteriovenous malformations, and acute stroke. We review the criticisms and commentaries we have received and discuss the corresponding ethical and scientific concepts that need to be revised to practice outcome-based neurovascular care. Results Pragmatic care trials were used to address long standing dilemmas regarding rival management options or to offer innovative treatments for 1212 neurovascular patients recruited in an elective or acute care context. Adopting care trial methodology had an immediate impact on clinical practice, replacing unrepeatable treatment decisions by 1:1 randomized allocation whenever reliable knowledge about best management was not available. The care trial approach transformed unfounded medical practice into verifiable outcome-based medical care and reserved authoritative recommendations for care options that had previously been validated. Criticisms we have encountered include mainly the pragmatic trial design choices, with insufficient selection of patients and clinicians, too-flexible protocols, lack of funding and feasibility. Conclusion Care trials can be integrated into neurovascular practice. Although they remain a work in progress, the approach curtails the practice of unverifiable medicine and offers patients optimal care in the presence of uncertainty.

BACKGROUND AND PURPOSE: Computed tomography angiography offers a non-invasive alternative to DSA for the assessment of cerebral vasospasm following subarachnoid hemorrhage but there is limited evidence regarding its reliability. Our aim was to perform a systematic review (Part I) and to assess (Part II) the inter- and intraobserver reliability of CTA in the diagnosis of cerebral vasospasm. MATERIALS AND METHODS: In Part I, articles reporting the reliability of CTA up to May 2018 were systematically searched and evaluated. In Part II, 11 raters independently graded 17 arterial segments in each of 50 patients with SAH for the presence of vasospasm using a 4-category scale. Raters were additionally asked to judge the presence of any moderate/severe vasospasm (≥ 50% narrowing) and whether findings would justify augmentation of medical treatment or conventional angiography ± balloon angioplasty. Four raters took part in the intraobserver reliability study. RESULTS: In Part I, the systematic review revealed few studies with heterogeneous vasospasm definitions. In Part II, we found interrater reliability to be moderate at best (κ ≤ 0.6), even when results were stratified according to specialty and experience. Intrarater reliability was substantial (κ > 0.6) in 3/4 readers. In the per arterial segment analysis, substantial agreement was reached only for the middle cerebral arteries, and only when senior raters’ judgments were dichotomized (presence or absence of ≥50% narrowing). Agreement on the medical or angiographic management of vasospasm based on CTA alone was less than substantial (κ ≤ 0.6). CONCLUSIONS: The diagnosis of vasospasm using CTA alone was not sufficiently repeatable among observers to support its general use to guide decisions in the clinical management of patients with SAH.

Posterior fossa arteriovenous malformations (pfAVMs) can be challenging lesions to manage. AVMs in this location may have distinct features compared with supratentorial AVMs. Our aim was to systematically review the literature on the presenting characteristics of pfAVMs and compare clinical and angiographic outcomes after the various types of treatment employed. The review was conducted according to the Cochrane Collaboration guidelines. Electronic databases from 1900 to March 2018 were searched and complemented by hand-searching and cross-referencing. Articles were categorized into (i) AVM studies that included those in the posterior fossa, (ii) those that focused exclusively on pfAVM, and (iii) those that further specified a cerebellar or brainstem location of the AVM. Seventy-seven articles with 4512 pfAVM patients were retained for analyses. Compared with historical supratentorial controls, pfAVMs were reported to more frequently present with rupture, to more commonly have associated arterial aneurysms, and to more frequently lead to poor clinical and angiographic outcomes. The quality of the literature and lack of standardization of outcome reporting precluded performing a meta-analysis on the results of the various different treatment modalities. Posterior fossa AVMs may have some distinct features compared with supratentorial AVMs. The available reports on pfAVMs are not sufficiently standardized to provide reliable guidance for patient management decisions. This goal will require future studies to be multicentric and to focus on standardized, repeatable clinical and angiographic outcomes.

BACKGROUND AND PURPOSE: After aneurysmal SAH, transcranial Doppler is commonly used to monitor cerebral vasospasm. The diagnostic accuracy of transcranial Doppler flow velocity values in detecting angiographic vasospasm in patients requiring urgent endovascular intervention has not been established. MATERIALS AND METHODS: We performed a retrospective analysis of a consecutive series of patients with aneurysmal SAH who underwent transcranial Doppler (index test) within 24 hours of conventional angiography (reference test). The judgment of 33%, 50%, and 66% degree of vessel narrowing on angiography was independently established by multiple neuroendovascular clinicians. Vessel-specific per-segment and per-patient transcranial Doppler velocities were studied using receiver operating characteristic curves, the Youden index, and minimal acceptable sensitivity models. Optimal mean flow-velocity thresholds were explored to calculate sensitivity and specificity using a per-patient judgment of vasospasm of at least 50% angiographic narrowing in any large arterial segment except A1. RESULTS: In 221 patients, vasospasm was found in 15%, 8%, and 4% of arteries when the degree of reference angiographic luminal narrowing was 33%, 50%, and 66%, respectively. Mean flow velocities were significantly higher in vasospastic segments (P = . 001), but per-segment exploratory analyses yielded unsound mean flow velocity thresholds. The Youden and minimal acceptable sensitivity models proposed mean flow velocity thresholds of approximately 160 cm/s for the anterior circulation and 80 cm/s for the posterior circulation in the per-patient diagnosis of angiographic vasospasm (≥50%), yielding a sensitivity of 80%–90% (95% CI, 0.77–0.96), but with a corresponding specificity of 50% (95% CI, 0.40–0.56). CONCLUSIONS: In this study, a threshold transcranial Doppler mean flow-velocity value that would accurately diagnose ≥50% angiographic vasospasm remained elusive.

Background: Micro-arteriovenous malformations (mAVM), defined with a nidus smaller than one centimeter, can lead to intracranial hemorrhage. Surgery can be curative, but precise intra-operative localization of the nidus is often challenging. Finding the mAVM is particularly important when in an eloquent area. Due to their small size, mAVMs that are diagnosed on high quality angiography (occult on non-invasive imaging) may not be seen with intra-operative image guidance systems. Time-resolved 3D angiography (4D DSA) fuses the 3D volumes from different angiographic acquisition phases, and may help with mAVM localization. To illustrate the utility of 4D DSA in the localization of mAVMs for pre-operative surgical planning and during intra-operative resection. Methods: We present 4 surgically managed cases of ruptured paracentral mAVM where 4D DSA proved useful. First, 3D FLAIR MRI was used for cortical surface segmentation.4D DSA was then used to select two 3D volumes; one at time of maximal shunting (to show the mAVM nidus) and one with maximal venous filling (to show normal venous anatomy). These were merged using a neuronavigation system as 3D objects, fused to the 3D FLAIR volume, and used pre- and intra-operatively to precisely locate the mAVM. Results: Intra-operatively, segmentation of sulco-gyral and normal venous anatomy were used to confirm the accuracy of surgical planning. In all cases, the mAVM at ‘maximal shunt’ time guided the dissection to precisely locate the nidus. There were no instances of neurological deterioration with surgery, and complete resection was confirmed by indocyanine green fluorescent angiography, followed by delayed (3 months) catheter angiography. Conclusions: 4D DSA may be useful for surgical planning and precise intra-operative localization of mAVMs.

Whether the best management of middle cerebral artery (MCA) aneurysm patients is surgical or endovascular remains uncertain, with little evidence to guide decision-making. A randomized care trial offering MCA aneurysm patients a 50% chance of surgical and a 50% chance of endovascular management may optimize outcomes in the presence of uncertainty.The Middle Cerebral Artery Aneurysm Trial (MCAAT) is an investigator-initiated, multicenter, parallel group, prospective, 1:1 randomized controlled clinical trial. All adult patients with MCA aneurysms, ruptured or unruptured, amenable to surgical and endovascular treatment can be included. The composite primary outcome is "Treatment Success": (i) occlusion or exclusion of the aneurysm using the allocated treatment modality; (ii) no intracranial hemorrhage during follow-up; (iii) no retreatment of the target aneurysm during follow-up, (iv) no residual aneurysm on angiographic follow-up; and (v) independence (mRS3) at 1 year. The trial tests 2 versions of the same hypothesis (one for ruptured and one for unruptured MCA aneurysm patients): Surgical management will lead to a 15% absolute increase in the proportion of patients reaching Treatment Success from 55% to 70% (ruptured) or from 75% to 90% (unruptured aneurysm patients) compared with endovascular treatment (any method). In this pragmatic trial, outcome evaluations are by treating physicians, except for 1-year angiographic results which will be core lab assessed. The trial will be monitored by an independent data safety monitoring committee to assure safety of participants. MCAAT is registered at clinicaltrials.gov: NCT05161377.Patients with MCA aneurysms can be optimally managed within a care trial protocol.

Background and purpose Appropriate management of ruptured intracranial aneurysm (RIA) in patients eligible for surgical clipping but under-represented in or excluded from previous randomized trials remains undetermined. Methods The International Subarachnoid Aneurysm Trial-2 (ISAT-2) is a randomized care trial comparing surgical versus endovascular treatment (EVT) of RIA. All patients considered for surgical clipping but eligible for endovascular treatment can be included. The primary endpoint is death or dependency on modified Rankin score (mRS > 2) at 1 year. Secondary endpoints are 1 year angiographic results and length of hospital stay. Results An interim analysis was performed after 103 patients were treated from November 2012 to July 2017 in 4 active centers. Fifty-two of the 55 patients allocated to surgery were treated by clipping, and 45 of the 48 allocated to EVT were treated by coiling, with 3 crossovers in each arm. The main endpoint (1 year mRS > 2), available for 76 patients, was reached in 16/42 patients allocated to clipping (38%; 95%CI: 25%–53%), and 10/34 patients allocated to coiling (29%; 17%–46%). One year imaging results were available in 54 patients: complete aneurysm occlusion was found in 23/27 patients allocated to clipping (85%; 67%–94%), and 18/27 patients allocated to coiling (67%; 47%–81%). Hospital stay exceeding 20 days was more frequent in surgery (26/55 [47%; 34%–60%]) than EVT (9/48 [19%; 10%–31%]). Conclusion Ruptured aneurysm patients for whom surgical clipping may still be best can be managed in a randomized care trial, which is feasible in some centers. More participating centers are needed.

Objectives A central question of medical care ethics is what is “good medical practice?” We will defend the argument that medical ethics must include care research not only to find out what “good” practice will turn out to be in the future once results are available but also to guide practice in the meantime, when no one knows what to do, optimizing patient outcomes in real time. Study Design and Setting This work is a summary of our reflections on the barriers to progress we have encountered after many years of implementing small randomized controlled trials in our clinical field, but which are certainly present in other fields as well. Results We review nine conceptions regarding care and research that need to be revised if we are to practice outcome-based medical care. Conclusions These revisions lead to a reconstruction of the care-research separation, where care research is reintegrated into care using trials specifically designed to offer optimal care in spite of uncertainty, in the best medical interest of participating patients.

Background Wide-necked bifurcation aneurysms (WNBA) are a difficult subset of aneurysms to successfully repair endovascularly, and a number of treatment adjuncts have been designed to improve on the results of coiling, including stenting and flow diversion of the parent vessel. Surgical clipping is commonly performed for certain WNBAs, such as middle cerebral aneurysms, in some centres. Intra-saccular flow diversion (ISFD) using the Woven Endo-Bridge (WEB) or similar devices, has been developed as a new endovascular alternative to coiling for WNBAs. Meta-analyses of case series suggest satisfactory results, both in terms of safety and efficacy, but in the absence of randomized evidence, whether ISFD leads to better outcomes for patients with WNBA remains unknown. There is a need to offer ISFD within the context of a randomized care trial. Methods The proposed trial is a multicentre, randomized controlled care trial comparing ISFD and best conventional management option (surgical or endovascular), as determined by the treating physician prior to randomized allocation. At least 250 patients will be recruited in at least 10 centres over a four-year period, and followed for one year, to show that ISFD can increase the incidence of successful therapy from 75 to 90% of patients, defined as complete or near-complete occlusion of the aneurysm AND a good clinical outcome (mRS ≤ 2) at one year. The trial will be followed by an independent data safety monitoring committee to assure the safety of participants. Conclusion Introduction of intra-saccular flow diversion can be accomplished within a care trial context.

OBJECTIVEThe Medina embolization device (MED) is a novel, braided self-expanding endovascular device designed to occlude aneurysms by constructing an in situ intrasaccular flow diverter. Although a single device can be positioned at the neck of simple spherical in vitro aneurysms, the best way to occlude more complex in vivo aneurysms (using multiple MEDs or a combination of MEDs and platinum coils) is currently unknown.METHODSFifty-two aneurysms of 3 different types were created in 31 canines, yielding 48 patent aneurysms. Treatments were randomly allocated by drawing lots: group 1, MEDs alone (n = 16); group 2, MEDs plus standard platinum coils (n = 16); and group 3, control aneurysms treated with coils alone (n = 16). Angiographic results were scored and compared immediately following treatment completion and at 3 months. Specimens were photographed and the extent of neointimal closure of the aneurysmal neck scored, followed by histopathological analyses.RESULTSAngiographic scores of 0 or 1 (occlusion or near occlusion) were initially obtained in 2 of 16 (12.5%, 95% CI 1.6%–38.3%) group 1 (MEDs alone), 3 of 16 (18.7%, 95% CI 4%–45.6%) group 2 (MEDs plus coils), and 10 of 16 (62.5%, 95% CI 35.4%–84.8%) group 3 (coils alone) aneurysms (p = 0.005). At 3 months, scores of 0 or 1 were found in 11 of 16 (68.7%, 95% CI 41.3%–89.0%) group 1, 9 of 16 (56.2%, 95% CI 29.9%–80.2%) group 2, and 8 of 16 (50%, 95% CI 24.7%–75.3%) group 3 aneurysms (p = 0.82). Neointimal scores were similar for the 3 treated groups (p = 0.66).CONCLUSIONEndovascular treatment of experimental aneurysms with MEDs or MEDs and coils showed angiographic occlusion and neointimal scores at 3 months that were similar to those achieved with standard platinum coiling.

Background Randomized trials of commonly performed surgical interventions are notoriously difficult to conduct. The trial methodology may nevertheless be the best way to offer outcome-based neurovascular care in the presence of uncertainty. One obstacle to promoting such trials is the conventional prohibition of publication and dissemination of interim results as the trial progresses. Methods We review the scientific and statistical reasons against the publication of interim analyses as well as exceptions that can occur when 1 treatment is unexpectedly shown to be harmful or when the results of other trials have convincingly shown the comparative benefits of a new intervention. We also discuss the promotion of difficult surgical trials. Results Reasons to support the conventional ban on publication of interim results include control of statistical errors, prevention of invalid conclusions, and dissemination of false claims of equivalence of rival interventions. In the early phases of a trial, usually 1 treatment cannot be shown superior to the other. We believe, contrary to the received view, that a transparent report of the early progress of certain trials can be justified, even when interim results are inconclusive, to promote the recruitment of participating centers and the practice of a novel way to offer neurovascular care in the presence of uncertainty in the best medical interest of patients. Conclusions In our opinion, the early publication of inconclusive interim results may increase awareness of the feasibility of surgical care trials.

Background The current research-care separation was introduced to protect patients from explanatory studies designed to gain knowledge for future patients. Care trials are all-inclusive pragmatic trials integrated into medical practice, with no extra tests, risks, or cost, and have been designed to guide practice under uncertainty in the best medical interest of the patient. Proposed revision Patients need a distinction between validated care, previously verified to provide better outcomes, and promising but unvalidated care, which may include unnecessary or even harmful interventions. While validated care can be practiced normally, unvalidated care should only be offered within declared pragmatic care research, designed to protect patients from harm. The validated/unvalidated care distinction is normative, necessary to the ethics of medical practice. Care trials, which mark the distinction and allow the tentative use of promising interventions necessarily involve patients, and thus the design and conduct of pragmatic care research must respect the overarching rule of care ethics “to always act in the best medical interest of the patient.” Yet, unvalidated interventions offered in contexts of medical uncertainty cannot be prescribed or practiced as if they were validated care. The medical interests of current patients are best protected when unvalidated practices are restricted to a care trial protocol, with 1:1 random allocation (or “hemi-prescription”) versus previously validated care, to optimize potential benefits and minimize risks for each patient. Conclusion Pragmatic trials can regulate medical practice by providing (i) a transparent demarcation between unvalidated and validated care; (ii) norms of medical conduct when using tests and interventions of yet unknown benefits in practice; and eventually (iii) a verdict regarding optimal care.

Objective There are few randomized data comparing clipping and coiling for middle cerebral artery (MCA) aneurysms. We analyzed results from patients with MCA aneurysms enrolled in the CURES (Collaborative UnRuptured Endovascular vs. Surgery) and ISAT-2 (International Subarachnoid Aneurysm Trial II) randomized trials. Methods Both trials are investigator-led parallel-group 1:1 randomized studies. CURES includes patients with 3-mm to 25-mm unruptured intracranial aneurysms (UIAs), and ISAT-2 includes patients with ruptured aneurysms (RA) for whom uncertainty remains after ISAT. The primary outcome measure of CURES is treatment failure: 1) failure to treat the aneurysm, 2) intracranial hemorrhage during follow-up, or 3) residual aneurysm at 1 year. The primary outcome of ISAT-2 is death or dependency (modified Rankin Scale score >2) at 1 year. One-year angiographic outcomes are systematically recorded. Results There were 100 unruptured and 71 ruptured MCA aneurysms. In CURES, 90 patients with UIA have been treated and 10 await treatment. Surgical and endovascular management of unruptured MCA aneurysms led to treatment failure in 3/42 (7%; 95% confidence interval [CI], 0.02–0.19) for clipping and 13/48 (27%; 95% CI, 0.17–0.41) for coiling (P = 0.025). All 71 patients with RA have been treated. In ISAT-2, patients with ruptured MCA aneurysms managed surgically had died or were dependent (modified Rankin Scale score >2) in 7/38 (18%; 95% CI, 0.09–0.33) cases, and 8/33 (24%; 95% CI, 0.13–0.41) for endovascular. One-year imaging results were available in 80 patients with UIA and 62 with RA. Complete aneurysm occlusion was found in 30/40 (75%; 95% CI, 0.60–0.86) patients with UIA allocated clipping, and 14/40 (35%; 95% CI, 0.22–0.50) patients with UIA allocated coiling. Complete aneurysm occlusion was found in 24/34 (71%; 95% CI, 0.54–0.83) patients with RA allocated clipping, and 15/28 (54%; 95% CI, 0.36–0.70) patients with RA allocated coiling. Conclusions Randomized data from 2 trials show that better efficacy may be obtained with surgical management of patients with MCA aneurysms.

Surrogate outcomes (indicators or signs used in place of the true clinical outcome measure) are often used in the evaluation of neurovascular treatments, but there are many pitfalls.[1][1] The various ways surrogate angiographic outcomes are handled in our literature can be sources of confusion

Background The pressure cooker (PC) technique uses a second microcatheter to produce a proximal occlusion to prevent the reflux of liquid embolic agent (LEA) injected through a more distal microcatheter, and can be used to treat arteriovenous malformations and dural arteriovenous fistulae. The liquid embolic Magic Glue (MG) (N-hexyl cyanoacrylate (NHCA)) has been introduced as an alternative to N-butyl cyanoacrylate (NBCA). Our goals were to compare the extent of embolization of rete mirabile with or without the PC technique using NBCA or MG, and to compare the proximal occlusions obtained with MG or NBCA while using the PC technique in a renal arterial model. Methods Rete mirabile were embolized with (n = 4) and without (n = 4) the PC technique, using MG (n = 4) or NBCA (n = 4). A renal arterial model was then used to study the characteristics of the MG plug (n = 10) used for the PC technique, and resistance to catheter withdrawal as compared to NBCA (n = 4). Specimens were analyzed macro- and microscopically and compared to angiographic results. Results Extent of rete embolization with CYA agents was not significantly greater when using the PC technique. Results were similar with both types of cyanoacrylate (p = 0.657). The force necessary to withdraw the microcatheter was less with MG than with NBCA (p = 0.035). Conclusion MG was similar to NBCA in extent of rete embolization. Less traction force was necessary to withdraw trapped non-detachable microcatheters using MG compared to NBCA.

Background The best management of unruptured intracranial aneurysms (UIAs) remains unknown, despite multiple observational studies. A randomized trial (RCT) is in order. Yet, a National Institute Neurological Disorders and Stroke workshop has once again proposed to use prospective observational studies (POS) of large databases to address such problems. Methods We review the historical misconceptions that have been associated with observations of UIAs and their treatments. We critically examine some recent methods that have been proposed to address shortcomings of observational studies. We finally review the ethical principles underlying the use of trial methods in the care of patients. Results Replacing RCTs with POS submits patients to management options that have never been proven beneficial, while making them involuntary research subjects of studies that are inevitably biased. A science of practice cannot be an outsider's examination of the behavior of clinicians incapable of questioning their practice. The thesis we propose is that a science of practice must not only eventually determine what best practice will be; It must engage agents involved in medical practice to transparently reveal the uncertainty that calls for management options to be offered under the guidance of declared and controlled care research, to optimize patient outcomes in spite of the uncertainty. Conclusion To use POS rather than RCTs in medical practice is to renege on scientific and ethical principles that characterize modern medicine. Instead, we must learn to integrate care research into our practice to provide optimal medical care in real time.

Background: Clinical uncertainty and equipoise are vague notions that play important roles in contemporary problems of medical care and research, including the design and conduct of pragmatic clinical trials. Our goal was to show how the reliability study methods normally used to assess diagnostic tests can be applied to particular management decisions to measure the degree of clinical uncertainty and equipoise regarding the use of rival management options prior to the conduct of randomized trials.Methods: We first illustrate how we have used the reliability study methodology to measure uncertainty in clinical decision-making regarding mechanical thrombectomy in acute stroke. We then follow the layout provided by standard guidelines to review how the various design elements of diagnostic reliability studies can be adapted to assess the repeatability of management decisions and measure clinical uncertainty.Results: The example shows how this methodology can be used to show disagreement in decisions for thrombectomy, and justify that sufficient clinical uncertainty exists to warrant the conduct of additional randomized trials. The general method we propose is that a sufficient number of diverse individual cases sharing a similar clinical problem and covering a wide spectrum of clinical presentations be assembled into a portfolio that is submitted to a variety of clinicians who routinely manage patients with the clinical problem. Clinicians are asked to independently choose one of the predefined management options, which are selected from those that would be compared within a randomized trial that would address the clinical dilemma. Intra-rater agreement can be assessed at a later time with a second evaluation. Various professional judgments concerning individual patients can then be compared and analyzed using kappa statistics or similar methods. Interpretation of results can be facilitated by providing examples or by translating the results into clinically meaningful summary sentences. Conclusions: Measuring the uncertainty regarding management options for clinical problems may reveal substantial disagreements, provide an empirical foundation for the notions of clinical uncertainty and equipoise, and inform or facilitate the design/conduct of clinical trials to address the clinical dilemma.

Background A sustained release microparticle formulation of nimodipine (EG-1962) was developed for treatment of patients with aneurysmal subarachnoid hemorrhage (aSAH). Objective To assess safety, tolerability, and pharmacokinetics of intracisternal EG-1962 in an open-label, randomized, phase 2 study of up to 12 subjects. Methods Subjects were World Federation of Neurological Surgeons grades 1 to 2, modified Fisher grades 2 to 4, and underwent aneurysm clipping within 48 h of aSAH. EG-1962, containing 600 mg nimodipine, was administered into the basal cisterns. Outcome on the extended Glasgow Outcome Scale (eGOS), pharmacokinetics, delayed cerebral ischemia and infarction, rescue therapy, and safety were evaluated. Results The study was halted when a phase 3 study of intraventricular EG-1962 stopped because that study was unlikely to meet its primary endpoint. Six subjects were randomized (5 EG-1962 and 1 oral nimodipine). After 90-d follow-up, favorable outcome on the eGOS occurred in 1 of 5 EG-1962 and in the single oral nimodipine patient. Four EG-1962 and the oral nimodipine subject had angiographic vasospasm. One EG-1962 subject had delayed cerebral ischemia, and all subjects with angiographic vasospasm received rescue therapy except 1 EG-1962 patient. One subject treated with EG-1962 developed right internal carotid and middle cerebral artery narrowing 5 mo after placement of EG-1962, leading to occlusion and cerebral infarction. Pharmacokinetics showed similar plasma concentrations of nimodipine in both groups. Conclusion Angiographic vasospasm and unfavorable clinical outcome still occurred after placement of EG-1962. Internal carotid artery narrowing and occlusion after placement of EG-1962 in the basal cisterns has not been reported.

We would like to comment on the conclusions of the recent paper reporting the 3 year follow-up results of the Webcast studies1: ‘This analysis confirms the high safety profile of WEB…the great stability of aneurysm occlusion in 83.6% of aneurysms’. It is not easy to criticize a manuscript written by 17 experts, including many prominent leaders of the neurovascular field and several close friends, particularly one where superlatives (‘high safety’ and ‘great stability’) and ‘GCP’ (n=8) are used repeatedly. Yet, as true friends, we must tell the ‘ugly truth’: 10 years after its introduction, the evidence supporting the use of WEB in the treatment of aneurysms (mainly small unruptured aneurysms) is weak; a case series of 100 or so highly selected patients, recruited in …

In the absence of randomized evidence, the optimal management of patients with unruptured intracranial aneurysms (UIA) remains uncertain.Comprehensive Aneurysm Management (CAM) is an all-inclusive care trial combined with a registry. Any patient with a UIA (no history of intracranial hemorrhage within the previous 30 days) can be recruited, and treatment allocation will follow an algorithm combining clinical judgment and randomization. Patients eligible for at least 2 management options will be randomly allocated 1:1 to conservative or curative treatment. Minimization will be used to balance risk factors, using aneurysm size (≥7 mm), location (anterior or posterior circulation), and age60 years.The CAM primary outcome is survival without neurologic dependency (modified Rankin Scale [mRS] score3) at 10 years. Secondary outcome measures include the incidence of subarachnoid hemorrhage during follow-up and related morbidity and mortality; morbidity and mortality related to endovascular treatment or surgical treatment of the UIA at 1 year; overall morbidity and mortality at 1, 5, and 10 years; when relevant, duration of hospitalization; and, when relevant, discharge to a location other than home. The primary hypothesis for patients randomly allocated to at least 2 options, 1 of which is conservative management, is that active UIA treatment will reduce the 10-year combined neurologic morbidity and mortality (mRS score2) from 24% to 16%. At least 961 patients recruited from at least 20 centers over 4 years will be needed for the randomized portion of the study.Patients with unruptured intracranial aneurysms can be comprehensively managed within the context of an all-inclusive care trial.

OBJECTIVEThe management of brain arteriovenous malformations (bAVMs) remains controversial. The Treatment of Brain AVMs Study (TOBAS) was designed to manage patients with bAVMs within a clinical research framework. The objective of this study was to study trial feasibility, recruitment rates, patient allocation to the various management groups, and compliance with treatment allocation.METHODSTOBAS combines two randomized care trials (RCTs) and a registry. Designed to be all-inclusive, the study offers randomized allocation of interventional versus conservative management to patients eligible for both options (first RCT), a second RCT testing the role of preembolization as an adjunct to surgery or radiotherapy, and a registry of patients managed using clinical judgment alone. The primary outcome of the first RCT is death from any cause or disabling stroke (modified Rankin Scale score > 2) at 10 years. A pilot phase was initiated at one center to test study feasibility, record the number and characteristics of patients enrolled in the RCTs, and estimate the frequency of crossovers.RESULTSAll patients discussed at the multidisciplinary bAVM committee between June 2014 and June 2016 (n = 107) were recruited into the study; 46 in the randomized trials (23 in the first RCT with 21 unruptured bAVMs, 40 in the second RCT with 17 unruptured bAVMs, and 17 in both RCTs), and 61 patients in the registry. Three patients crossed over from surgery to observation (first RCT).CONCLUSIONSClinical research was successfully integrated with normal practice using TOBAS. Recruitment rates in a single center are encouraging. Whether the trial will provide meaningful results depends on the recruitment of a sufficient number of participating centers.Clinical trial registration no.: NCT02098252 (clinicaltrials.gov)

Background When to proceed with a randomized trial (RCT) that tests the merits of innovative treatments has been controversial. Tom Chalmers proposed that we should randomize the first patient. Methods We examine various scenarios and compare hypothetical results of early and delayed RCTs and case series. Then we review potential reasons why Chalmers’ idea has not yet been widely applied. Results Case series of innovative treatments followed by delayed RCTs put many more patients at risk of a poor outcome. In all scenarios, it is better to start with an RCT. The apparent dilemma comes from a failure to recognize that the clinical choices are not between standard and innovative treatment, but between standard care and care research. If the clinician believes that the patient may benefit from the innovative treatment, he can propose the innovative treatment within a randomized trial. This is true for all patients, including the first patients, until the innovative treatment is shown superior, at which time it can be prescribed as the new standard of care. Conclusion Randomize treatment for the first patients.

The best management of brain arteriovenous malformation (bAVM) patients remains unknown. Randomized allocation may be more readily accepted when there is uncertainty and disagreement regarding the management of potential participants. In planning for a trial, we aimed to assess variability and agreement among physicians managing bAVM patients.A portfolio composed of 35 patients was sent to 47 clinicians of various specialties managing bAVM patients. For each patient, physicians were asked their best management decision (surgery/embolization/radiosurgery/conservative), their confidence level, and whether they would include the patient in a randomized trial comparing conservative and curative management. Seven physicians, who had access to all images of each patient, independently responded twice, to assess inter and intra-rater agreement using kappa statistics.The inter-rater agreement (30 raters, including 16 neuroradiologists) for best management decision was only "fair" (κ [95%CI]=0.210[0.157; 0.295]). Agreement remained below 'substantial' (κ.6) between physicians of the same specialty, and when no distinctions were made between various treatments (when responses were dichotomized as conservative versus curative). With access to all images the inter-rater agreement remained fair. The intra-rater agreement reached "substantial" only for the dichotomized decisions. Responding clinicians were willing to include 54.4% of patients (mainly unruptured bAVMs) in a randomized trial.There is a lack of agreement among clinicians involved in the management of bAVM patients. In this study a substantial proportion of clinicians were willing to offer randomized allocation of management options to a substantial number of patients.

Background Until recently, the benefits of endovascular treatment in stroke were not proven. Care trials have been designed to simultaneously offer yet-to-be validated interventions and verify treatment outcomes. Our aim was to implement a care trial for patients with acute ischemic stroke. Methods The study was offered to all patients considered for endovascular management of acute ischemic stroke in one Canadian hospital. Inclusion criteria were broad: onset of symptoms ≤ 5 h or at any time in the presence of clinical-imaging mismatch and suspected or demonstrated proximal large vessel occlusion. Exclusion criteria were few: established infarction or hemorrhagic transformation of the target symptomatic territory and poor 3-month prognosis. The primary outcome was mRS ≤ 2 at 3 months. Patients were randomly allocated to standard care or standard care plus endovascular treatment. ClinicalTrials.gov: Identifier NCT02157532 . Results Seventy-seven patients were recruited in 19 months (March 2013–October 2014) at a single center. Randomized allocation was interrupted when other trials showed the benefits of endovascular therapy. At 3 months, 20 of 40 patients (50.0%; 95% CI: 35%–65%) in the intervention group had reached the primary outcome, compared to 14 of 37 patients (37.8%; 95% CI: 24%–54%) in the control group (P = 0.36). Eleven patients in the intervention group died within 3 months compared to 9 patients in the standard care group. Conclusion A care trial was implemented to offer verifiable care to acute stroke patients. This approach offers a promising means to manage clinical dilemmas and guide uncertain practices.

OBJECTIVEEndovascular treatment of aneurysms may result in incomplete initial occlusion and aneurysm recurrence at angiographic follow-up studies. This study aimed to assess the feasibility and efficacy of bipolar radiofrequency ablation (RFA) of aneurysm remnants after coil embolization.METHODSBipolar RFA was accomplished using the coil mass as 1 electrode, while the second electrode was a stent placed across the aneurysmal neck. After preliminary experiments and protocol approval from the Animal Care committee, wide-necked bifurcation aneurysms were constructed in 24 animals. Aneurysms were allocated to 1 of 3 groups: partial intraoperative coil embolization, followed by RFA (n = 12; treated group) or without RFA (n = 6; control group 1); or attempted complete endovascular coil embolization 2–4 weeks later (n = 6; control group 2). Angiographic results were compared at baseline, immediately after RFA, and at 12 weeks, using an ordinal scale. Pathological results and neointima formation at the neck were compared using a semiquantitative grading scale.RESULTSBipolar RFA was able to reliably target the aneurysm neck when the coil mass and stent were used as electrodes. RFA improved angiographic results immediately after partial coiling (p = 0.0024). Two RFA-related complications occurred, involving transient occlusion of 1 carotid artery and 1 hemorrhage from an adventitial arterial blister. At 12 weeks, angiographic results were improved with RFA (median score of 0), when compared with controls (median score of 2; p = 0.0013). Neointimal closure of the aneurysm neck was better with RFA compared with controls (p = 0.0003).CONCLUSIONSBipolar RFA can improve results of embolization in experimental models by selectively ablating residual lesions after coil embolization.

Flow diversion is increasingly used for treating intracranial aneurysms. This article aims to review the evidence obtained from animal models and summarizes the findings that might be of clinical interest. From a systematic review of studies published between 2000 and 2016, we extracted the data on the following questions: What roles do aneurysm dimension, morphology, and vascular geometry have on success of flow diversion? What characteristics of a flow diverter can influence aneurysm occlusion? What are the risk factors for jailed branch occlusion? Flow diversion has been shown to be less effective in occluding large aneurysms with wide or undefined necks, as compared to smaller aneurysms with narrower necks. Straight sidewall aneurysms were more likely to occlude after flow diversion than curved sidewall aneurysms or bifurcation aneurysms with branches originating from the neck or the fundus. The main characteristics of devices that may impact on the success of flow diversion are porosity and pore-density, but challenging aneurysm models were not better occluded with devices of lower porosity. Porosity is not uniform when devices deform to adapt to local in vivo anatomy when deployed. Neointima formation on devices correlates with low porosity. Branches are rarely occluded when they are jailed, but persistent branch flow may prevent aneurysm occlusion. Experimental models may help anticipate clinical results of flow diversion.

OBJECTIVE The ARUBA study (A Randomized Trial of Unruptured Brain Arteriovenous Malformations [AVMs]) on unruptured brain AVMs has been the object of comments and editorials. In the present study the authors aim to systematically review critiques, discuss design issues, and propose a framework for future trials. METHODS The authors performed a systematic review of the French and English literature on the ARUBA study published between January 2006 and February 2015. The electronic search, including the Cochrane Library, MEDLINE (PubMed and Ovid), CINAHL, and EMBASE databases, was complemented by hand searching and cross-referencing. The comments were categorized as items related to the design, the conduct, and the analysis and interpretation of the trial. RESULTS Thirty-one articles or letters were identified. The pragmatic design, with heterogeneity of patients and lack of standardization of the treatment arm, were frequently stated concerns. The choice of outcome measures was repeatedly criticized. During the trial, low enrollment rates, selection bias, and premature interruption of enrollment were frequent comments. The short follow-up period, the lack of subgroup analyses, the lack of details on the results of the various treatments, and a contentious interpretation of results were noted at the analysis stage. A fundamental problem was the primary hypothesis testing conservative management. The authors believe that other trials are needed. Future trials could be pragmatic, test interventions stratified at the time of randomization, and look for long-term, hard clinical outcomes in a large number of patients. CONCLUSIONS In the authors' view, the ARUBA trial is a turning point in the history of brain AVM management; future trials should aim at integrating trial methodology and clinical care in the presence of uncertainty.

BACKGROUND AND PURPOSE: Some patients are at high risk of aneurysm recurrence after endovascular treatment: patients with large aneurysms (Patients Prone to Recurrence After Endovascular Treatment PRET-1) or with aneurysms that have previously recurred after coiling (PRET-2). We aimed to establish whether the use of hydrogel coils improved efficacy outcomes compared with bare platinum coils. MATERIALS AND METHODS: PRET was an investigator-led, pragmatic, multicenter, parallel, randomized (1:1) trial. Randomized allocation was performed separately for patients in PRET-1 and PRET-2, by using a Web-based platform ensuring concealed allocation. The primary outcome was a composite of a residual/recurrent aneurysm, adjudicated by a blinded core laboratory, or retreatment, intracranial bleeding, or mass effect during the 18-month follow-up. Secondary outcomes included adverse events, mortality, and morbidity (mRS > 2). The hypothesis was that hydrogel would decrease the primary outcome from 50% to 30% at 18 months, necessitating 125 patients per group (500 for PRET-1 and PRET-2). RESULTS: The trial was stopped once 250 patients in PRET-1 and 197 in PRET-2 had been recruited because of slow accrual. A poor primary outcome occurred in 44.4% (95% CI, 35.5%–53.2%) of those in PRET-1 allocated to platinum compared with 52.5% (95% CI, 43.4%–61.6%) of patients allocated to hydrogel (OR, 1.387; 95% CI, 0.838–2.295; P = .20) and in 49.0% (95% CI, 38.8%–59.1%) in PRET-2 allocated to platinum compared with 42.1% (95% CI, 32.0%–52.2%) allocated to hydrogel (OR, 0.959; 95% CI, 0.428–1.342; P = .34). Adverse events and morbidity were similar. There were 3.6% deaths (1.4% platinum, 5.9% hydrogel; P = .011). CONCLUSIONS: Coiling of large and recurrent aneurysms is safe but often poorly effective according to angiographic results. Hydrogel coiling was not shown to be better than platinum.

Most endovascular innovations have been introduced into clinical care by showing good outcomes in small enthusiastic case series of selected patients. Randomized clinical trials (RCTs) have rarely been performed, except for acute ischemic stroke, but even then most trial designs were too explanatory to inform clinical decisions. In this article, we review 2 × 2 tables and forest plots that summarize RCT results to examine methodological issues in the design and interpretation of clinical studies. Research results can apply in practice when RCTs are all-inclusive, pragmatic trials. Common problems include the following: (i) using restrictive eligibility criteria in explanatory trials, instead of including the diversity of patients in need of care, which hampers future generalizability of results; (ii) ignoring an entire line of the 2 × 2 table and excluding patients who do not meet the proposed criteria of a diagnostic test in its evaluation (perfusion studies) which renders clinical inferences misleading; (iii) ignoring an entire column of the 2 × 2 table and comparing different patients treated using the same treatment instead of different treatments in the same patients (the “wrong axis” comparisons of prognostic studies and clinical experience) which leads to unjustified treatment decisions and actions; or (iv) combining all aforementioned problems (case series and epidemiological studies). The most efficient and reliable way to improve patient outcomes, after as well as long before research results are available, is to change the way we practice: to use care trials to guide care in the presence of uncertainty.

Background Endovascular coil embolization of cerebral aneurysms is an effective treatment for the prevention of aneurysm rebleeding after subarachnoid hemorrhage. It is also often used in unruptured aneurysms, but it is associated with aneurysm remnants and recurrences in up to 20%–33% of patients. We hypothesized that better aneurysm occlusion rates can be achieved with coils of larger caliber. Methods The Does Embolization with Larger coils lead to better Treatment of Aneurysms (DELTA) trial is an investigator-initiated, multicenter, prospective, randomized, controlled clinical trial. To test the hypothesis that 15-caliber coiling systems are superior to 10-caliber coils, 564 patients with aneurysms measuring 4–12 mm will be randomized 1:1 to embolization with either 10-caliber coils exclusively (control group) or the highest safely achievable proportion of 15-caliber coils (intervention group). The primary efficacy endpoint of the trial is the occurrence of a major recurrence or a residual aneurysm at one year. A pilot phase of 165 patients will be conducted to verify feasibility of the coiling strategy, compliance to treatment allocation, safety of a 15-caliber platinum coil embolization strategy, recruitment rates, and the capacity to improve packing density. Discussion The DELTA trial will test the hypothesis that the use of coils of larger caliber can improve angiographic results of endovascular coiling.