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Stent-Assisted Coiling in the Treatment of Unruptured Intracranial Aneurysms: A Randomized Clinical Trial

Stent-Assisted Coiling in the Treatment of Unruptured Intracranial Aneurysms: A Randomized... LEVEL 1 EBM EXPEDITED PUBLICATION INTERVENTIONAL Stent-Assisted Coiling in the Treatment of Unruptured Intracranial Aneurysms: A Randomized Clinical Trial W. Boisseau, T.E. Darsaut, R. Fahed, B. Drake, H. Lesiuk, J.L. Rempel, J.-C. Gentric, J. Ognard, L. Nico, D. Iancu, D. Roy, A. Weill, M. Chagnon, J. Zehr, P. Lavoie, T.N. Nguyen, and J. Raymond ABSTRACT BACKGROUND AND PURPOSE: Stent-assisted coiling may improve angiographic results of endovascular treatment of unruptured in- tracranial aneurysms compared with coiling alone, but this has never been shown in a randomized trial. MATERIALS AND METHODS: The Stenting in the Treatment of Aneurysm Trial was an investigator-led, parallel, randomized (1:1) trial conducted in 4 university hospitals. Patients with intracranial aneurysms at risk of recurrence, defined as large aneurysms ($10 mm), postcoiling recurrent aneurysms, or small aneurysms with a wide neck ($4 mm), were randomly allocated to stent-assisted coiling or coiling alone. The composite primary efficacy outcome was “treatment failure,” defined as initial failure to treat the aneurysm; aneurysm rupture or retreatment during follow-up; death or dependency (mRS. 2); or an angiographic residual aneurysm adjudi- cated by an independent core laboratory at 12 months. The primary hypothesis (revised for slow accrual) was that stent-assisted coiling would decrease treatment failures from 33% to 15%, requiring 200 patients. Primary analyses were intent to treat. RESULTS: Of 205 patients recruited between 2011 and 2021, ninety-four were allocated to stent-assisted coiling and 111 to coiling alone. The primary outcome, ascertainable in 203 patients, was reached in 28/93 patients allocated to stent-assisted coiling (30.1%; 95% CI, 21.2%–40.6%) compared with 30/110 (27.3%; 95% CI, 19.4%–36.7%) allocated to coiling alone (relative risk ¼ 1.10; 95% CI, 0.7– 1.7; P ¼ .66). Poor clinical outcomes (mRS.2) occurred in 8/94 patients allocated to stent-assisted coiling (8.5%; 95% CI, 4.0%– 16.6%) compared with 6/111 (5.4%; 95% CI, 2.2%–11.9%) allocated to coiling alone (relative risk ¼ 1.6; 95% CI, 0.6%–4.4%; P ¼ .38). CONCLUSIONS: The STAT trial did not show stent-assisted coiling to be superior to coiling alone for wide-neck, large, or recurrent unruptured aneurysms. ABBREVIATIONS: CA ¼ coiling alone; DSMC ¼ Data and Safety Monitoring Committee; RR ¼ relative risk; SAC ¼ stent-assisted coiling; UIA ¼ unruptured intracranial aneurysm he use of stents for the treatment of unruptured intracranial Antiplatelet regimens are therefore necessary to prevent arterial Taneurysms (UIAs) was first approved in the United States in thromboembolic complications, rendering the use of stents 2002 as a Humanitarian Device Exemption. The initial indication problematic in recently ruptured aneurysms. There may be was to mechanically assist the coiling of wide-neck ($4 mm) benefits to the use of stent-assisted coiling (SAC), in addition to aneurysms not amenable to endovascular or surgical treat- mechanically preventing coil protrusion into the parent artery 1,2 ment. Subsequently, clinical usage has expanded to all types during the coiling procedure, which may improve the long-term 3-12 of aneurysms. While coiling is strictly an intrasaccular treat- angiographic results of endovascular treatments such as a flow- 14-16 ment, stents are deployed in the artery bearing the aneurysm. diverting effect or better healing due to the provision of a scaffold for neointimal closure of the neck. However, these Received January 25, 2023; accepted after revision February 16. potential benefits were not observed in experimental models. From the Department of Radiology (W.B., D.I., D.R., A.W., J.R.), Service of Whether SAC increases procedural risks or improves long-term Neuroradiology, Centre Hospitalier de l’Université de Montréal, Montreal, Québec, angiographic results has not been convincingly shown despite Canada; Department of Surgery (T.E.D.), Division of Neurosurgery and Department of Radiology and Diagnostic Imaging (J.L.R.), University of Alberta Hospital, Mackenzie Health Sciences Centre, Edmonton, Alberta, Canada; Departments of Please address correspondence to Jean Raymond, MD, Centre Hospitalier de Neurology (R.F.), and Neurosurgery (B.D., H.L.), University of Ottawa, the Ottawa l’Université de Montréal (CHUM), Department of Radiology, Room D03.5462b, Hospital, Ottawa, Ontario, Canada; Department of Radiology (J.-C.G., J.O.), Montreal, Québec, Canada H2X 0C1; e-mail: jean.raymond@umontreal.ca University Hospital of Brest, Brest, France; Departement of Radiology (L.N.), Service Indicates open access to non-subscribers at www.ajnr.org of Interventional Neuroradiology, Centre Hospitalo-universitaire de Saint-Etienne, Saint-Etienne, France; Department of Mathematics and Statistics (M.C., J.Z.), Indicates article with online supplemental data. Pavillon André-Aisenstadt, Montreal, Québec, Canada; Department of Neurosurgery (P.L.), Centre Hospitalier Universitaire de Québec-Université Laval, Evidence-Based Medicine Level 1. Québec, Canada; and Departments of Neurology (T.N.N.) and Radiology (T.N.N.), Boston Medical Center, Boston, Massachusetts. http://dx.doi.org/10.3174/ajnr.A7815 AJNR Am J Neuroradiol 44:381–89 Apr 2023 www.ajnr.org 381 multiple case series and meta-analyses published during site. Details regarding the endovascular technique; type of coils; 3-12 20 years. A randomized trial comparing the results of coiling use of adjunctive techniques such as balloon remodeling (routine with or without stent placement has never been published. in STAT centers for large or wide-neck aneurysms); whether the The Stenting in the Treatment of Aneurysm Trial (STAT) was stent was deployed before or following coiling; the use of multiple launched in 2011 to provide a clinical research context for the use stents; and posttreatment medical management decisions were left of SAC in UIAs. The trial compared a policy of coiling alone to the discretion of the treating physicians. A stent could be used (CA) versus the use of a self-expandable stent (any stent, not a as a bailout maneuver in patients allocated to CA if this was judged flow diverter) in addition to the coiling procedure. The primary appropriate by the treating physician, to ensure the safety of hypothesis of the trial was that in patients with aneurysms prone patients. Similarly, the physician could choose not to use the stent to recurrence, SAC would decrease the proportion of patients in patients allocated to SAC when it was judged impossible or dan- reaching “treatment failure,” a composite clinical and angiographic gerous at the time of the procedure. primary outcome measure that included aneurysmal rupture or Follow-up tests and visits were limited to those considered retreatment during follow-up or a recurrent or residual aneurysm clinically indicated, such as neurologic examinations, brain imag- on follow-up angiography at 12 months. We here report the final ing studies, and a functional assessment according to the mRS results of the trial. score at discharge, 1 month, and 12 (63) months. Follow-up an- giography (invasive or noninvasive) at 12 (63) months was con- sidered standard of practice. MATERIALS AND METHODS Data capture and management through secure servers (MedSciNet; This report follows the Consolidated Standards of Reporting https://medscinet.com/about.aspx) were in compliance with Trials (CONSORT) recommendations. STAT was an investi- good clinical practice requirements. Case report forms were gator-led, multicenter randomized controlled trial integrated simple, and the data collected were parsimonious, to facilitate into clinical practice. The trial proposed randomized allocation completion by care personnel, because no financial compensa- to SAC or CA in patients eligible for both options. There were 4 tion was provided to participating centers. participating centers (Montreal, Ottawa, and Edmonton in Canada, and Brest in France). All sites received institutional Primary and Secondary Outcome Measures review board approval. The protocol was published, and the The primary end point of the 2011 protocol was the incidence of trial was registered at http://www.clinicaltrials.gov number angiographic recurrences at 12 (63) months, defined as the fol- NCT01340612. lowing: 1) an angiographic recurrence of the lesion, as judged by an independent core lab (composed of 2 raters) according to a Patients previously published classification; 2) an episode of intracranial All patients were 18 years of age or older with a life expectancy of bleeding; or 3) retreatment of the same lesion by endovascular or at least 2 years. Patients had at least 1 UIA prone to recurrence, surgical means during the follow-up period. Furthermore, the defined and categorized at the time of registration before random- protocol stipulated that “recurrences would be recorded (present ization as a large ($10 mm) aneurysm (STAT-1), a recurrent an- or absent) as they are discovered, at the follow-up assessment eurysm after previous coiling (STAT-2), or a wide-neck ($4 mm) (12 6 3 months), as clinical symptoms appear at any time, or at aneurysm of ,10 mm (STAT-3). There were few exclusion crite- time of death.” ria: 1) absolute contraindications to endovascular treatment, anes- Because this definition lacked precision and may not be ascer- thesia, or the use of dual antiplatelet regimens; 2) the presence of tainable in some patients, the primary outcome was modified in other aneurysms requiring treatment during the same session; 3) July 2021, after consulting with the Data and Safety Monitoring thepresenceof an associated cerebral arteriovenous malformation; Committee (DSMC) but before any data examination, to be in 4) recently ruptured aneurysms (,3 months); and 5) the presence 22-24 line with other endovascular trials. Two other components of a recurring, previously stented aneurysm. Screening logs of all have been added to the composite primary outcome, treatment potentially eligible patients with UIAs were not required per proto- failure (initial treatment failure using any device and treatment- col. All patients signed an informed consent form. or aneurysm-related death or dependency precluding follow-up angiography). If the coiling procedure was not feasible, for exam- Randomization and Masking ple due to coil instability, the physician had the option of using a SAC or CA was randomly allocated (1:1) using a Web-based plat- stent, a use that was not considered a failure of the initial treat- form assuring concealment of the allocation. The randomized ment (but was counted as a crossover in “as-treated analyses”). allocation was stratified according to the STAT1–3 subgroups One primary poor outcome was attributed per patient. When a and minimized for the type of coils to be used (platinum or sec- patient met .1 of the criteria, the following hierarchical order ond generation). Patients, interventionists, and outcome assessors was prespecified to classify the patient for final analyses: death or were not blinded to treatment assignment. mRS 3–5 (from any cause within 30 days of the intervention and from related causes during follow-up) . aneurysm rupture dur- Interventions and Follow-up Tests and Visits Coiling with or without stent placement was performed according ing follow-up . retreatment during follow-up . initial treatment to standards of practice, with the patient under general anesthesia. failure (defined as the inability to perform endovascular treat- Antiplatelet and anticoagulation regimens and testing for platelet ment) . major recurrence or residual aneurysm at imaging fol- inhibition were prescribed according to routine practice at each low-up (3–12 months) as adjudicated by an independent core 382 Boisseau Apr 2023 www.ajnr.org laboratory of 2 neuroradiologists blinded to treatment groups 25,26 and according to a previously validated classification. Secondary outcomes included the individual components of the composite primary outcome: the mRS score at discharge and 12 months posttreatment; the success in occluding the aneurysm at the end of the procedure; perioperative complications (ischemic strokes and intracranial hemorrhages within 31 days of the inter- vention and during follow-up); angiographic results at 12 months; length of hospital stay (number of days); discharge disposition (home, other hospital, rehabilitation facility; death); and retreat- ment of the index aneurysm at any time. Hypotheses and Number of Patients The 2011 protocol planned for the recruitment of 600 patients. This number was based on 2 hypotheses: The primary efficacy hy- pothesis was that SAC would decrease angiographic recurrences by 20% at 12 months and a total sample size of 536 patients would allowthe detectionof sucha difference withapower of 80% and an error of 0.0125 (to account for subgroup analyses for the 3 main categories of lesions: large, wide neck, and recurrent aneur- FIG 1. STAT participant flow CONSORT diagram. ysms). The secondary safety hypothesis was that the use of intra- cranial stent placement would not double the number of dead or and aneurysm subgroups were examined as prespecified in 2011, dependent patients (mRS. 2) from 6% to 12% at 12 months. In regardless of the results of tests for interaction. Subgroup results July 2021, before any knowledge of the data, the steering commit- according to STAT 1–3 categories indicated at the time of registra- tee (SC), in agreement with the DSMC, dropped the safety hypoth- tion, according to aneurysm size (,10 mm or $10 mm), neck esis and modified the primary efficacy hypothesis: SAC was size (,4mm or $4 mm), and location (posterior circulation and hypothesized to decrease treatment failures from 33% to 15%, anterior circulation subdivided into carotid, anterior cerebral ar- which would require approximately 200 patients (88 patients per tery, and MCA aneurysms) are reported. As-treated exploratory group; power of 80% and a of 5%, plus 10% to account for cross- analyses (defined as coiling with or without any attempt or use of overs and losses to follow-up). Details are provided in the Online stent placement, regardless of treatment allocation) are also pro- Supplemental Data. vided. We also explored what results would have been if complete occlusion (rather than the combination of complete and near- Trial Interruption complete occlusion) had been used as the criterion for a good On August 31, 2021, after a blinded examination of interim angiographic outcome. One adverse event is reported per patient. results, the DSMC recommended trial continuation. However, in When a patient had .1 event, we used the most severe to catego- September 2021, ten years after the recruitment of the first patient, rize the patient. Analyses were performed using SAS software, the SC decided to finalize and report the trial. Version 9.4 (SAS Institute) and SPSS, Version 26 (IBM) with a significance level of 5%. Statistical Analyses Blinded data were examined at prespecified intervals by an inde- Roles of the Sponsor and Funding Source pendent DSMC, composed of an interventional neurologist, a The trial was sponsored by the Center Hospitalier de l’Université dual-trained neurosurgeon, and a statistician; but no hypothesis de Montréal. The sponsor had no part in the study design, data testing was performed. collection, analysis, or reporting and no access to the data or Descriptive statistics on demographic variables and preopera- source documents. The corresponding author had full access to tive data are provided to compare the 2 groups at baseline. Means, all the data and had final responsibility for the decision to submit SDs, medians, and ranges are presented for quantitative variables, for publication. There was no funding source for this study. and frequency tables for categoric variables. Primary safety and ef- ficacy outcomes are described using percentages and 95% CIs. The RESULTS intent-to-treat analyses for the primary efficacy hypothesis were performed on available observations. The relative risks (RRs and Between August 2011 and August 2021, we recruited 205 patients: 95% CIs) were estimated using a generalized estimating equation Ninety-four were assigned to SAC, and 111 to CA. For each group, with a binomial distribution and a log-link function. The groups the number of participants who were randomly assigned, received were not different with respect to risk factors for poor outcomes, intended treatment, and were analyzed for the primary outcome is and no adjustments for residual confounding factors were made. illustrated in the trial profile (Fig 1). The analyses of interaction between prespecified subgroups of The baseline patient and aneurysm characteristics are shown in interest and treatment were made by adding subgroup variables Table 1. Groups were comparable: Ninety-two (44.9%) patients and interaction in generalized estimating equation models. Patient had small wide-neck aneurysms (STAT-3); 75 (36.6%), a recurrent AJNR Am J Neuroradiol 44:381–89 Apr 2023 www.ajnr.org 383 Table 1: Patient and index aneurysm characteristics Characteristics CA (n = 111) SAC (n = 94) Total (n = 205) Patient Age at treatment (mean) (SD) (yr) 58.6 (10.4) 58.0 (8.8) 58.3 (9.7) Female (No.) (%) 77 (69.4) 65 (69.1) 142 (69.3) STAT type lesion STAT-1: unruptured aneurysm, never treated, with a dimension 21 (18.9) 17 (18.1) 38 (18.5) of$ 10 mm (No.) (%) STAT-2: major recurrent aneurysm after previous coiling, but no 41 (36.9) 34 (36.2) 75 (36.6) previous stent placement (No.) (%) STAT-3: small (,10 mm), wide-neck ($ 4 mm) aneurysm (No.) (%) 49 (44.1) 43 (45.7) 92 (44.9) Pretreatment mRS score (No.) (%) 0 84 (75.7) 70 (74.5) 154 (75.1) 1 21 (18.9) 20 (21.3) 41 (20.0) 2 5 (4.5) 2 (2.1) 7 (3.4) 3 1 (0.9) 1 (1.1) 2 (1.0) 4 0 1 (1.1) 1 (0.5) Presentation Symptomatic 4 (3.6) 4 (4.3) 8 (3.9) Additional aneurysm to a previously ruptured and treated one 13 (11.7) 6 (6.4) 19 (9.3) Incidental finding 94 (84.7) 84 (89.4) 178 (86.8) Index aneurysm location (No.) (%) Anterior circulation 78 (70.3) 58 (61.7) 136 (66.3) Ophthalmic/paraophthalmic 7 (6.3) 3 (3.2) 10 (4.9) Posterior communicating/anterior choroidal 7 (6.3) 13 (13.8) 20 (9.8) Carotid terminus 6 (5.4) 1 (1.1) 7 (3.4) MCA bifurcation/M1 18 (16.2) 14 (14.9) 32 (15.6) Anterior communicating/A1 40 (36.0) 25 (26.6) 65 (31.7) Distal ACA 0 2 (2.1) 2 (1.0) Posterior circulation 33 (29.7) 36 (38.3) 69 (33.7) PCA 0 3 (3.2) 3 (1.5) Basilar terminus 24 (21.6) 23 (24.5) 47 (22.9) SCA 3 (2.7) 5 (5.3) 8 (3.9) Basilar trunk 2 (1.8) 0 2 (1.0) Vertebrobasilar junction 2 (1.8) 2 (2.1) 4 (2.0) PICA 2 (1.8) 3 (3.2) 5 (2.4) Index aneurysm maximal external size (mean) (SD) (range) (mm) 9.2 (6.4) 9.2 (5.9) 9.2 (6.1) (2–50) (3–35) (2–50) ,10 (No.) (%) 74 (66.7) 63 (67.0) 137 (66.8) $10 (No.) (%) 37 (33.3) 31 (33.0) 68 (33.2) Index aneurysm neck size (mean) (SD) (range) (mm) 4.4 (2.2) 4.1 (1.6) 4.3 (1.9) (2–20) (2–9) (2–20) Aneurysm neck $4 mm (No.) (%) 72 (64.9) 58 (61.7) 130 (63.4) Note:—ACA indicates anterior cerebral artery; PCA, posterior cerebral artery; SCA, superior cerebellar artery. aneurysm (STAT-2); and 38 (18.5%), a large aneurysm (STAT-1). 1.7; P ¼ .66). Details of each component of the primary outcome The most frequent locations were the anterior communicating ar- in the intent to treat analysis are provided in Table 2. tery (65; 31.7%), basilar bifurcation (47; 22.9%), and MCA bifurca- There were no incidences of aneurysm rupture during follow-up. tion (32; 15.6%). Three patients were retreated (all in the SAC group). Angiographic Seventeen of 111 patients (15.3%) allocated to CA underwent resultsat 12monthsaccounted for most of the primary out- SAC, while 10/94 (10.6%) patients allocated to SAC were treated come adjudications (185/203; 91%). Follow-up vascular imag- with CA. Technical details regarding treatment for both groups are ing studies, available in 198 patients (96.6%), were performed provided in the Online Supplemental Data. In 4 patients from by MRA in 135 (68.2%), by catheter angiography in 59 STAT-2, residual aneurysms were judged too small for any treat- (29.8%), and by CTA in 4 (2%) patients. More patients were ment (3 in the SAC arm and 1 in the CA arm). Seven patients were followed by catheter angiography in the SAC group (37.2%) treated with flow diverters (3 in the SAC arm and 4 in the CA than in the CA group (21.6%) (Table 3). The mean time of arm). Patients allocated to SAC were initially treated with a single angiographic follow-up was 14.8 (SD, 9.5) months for patients (n ¼ 64) or 2 (n ¼ 14) stents. Stents were delivered before coiling allocated to SAC, and 13.5 (SD, 5.2) months for patients allo- in 20/78 (25.6%) and after coiling in 58/78 (74.4%) patients. cated to CA. The mean time of the follow-up mRS evaluation The primary outcome is available for 203/205 patients (99%), was 15.3 (SD, 8.0) months for SAC and 15.7 (SD, 10.5) months with 1 patient missing in each group (Fig 1 and Tables 2 and 3). for CA. Treatment failure occurred in 28/93 patients allocated to SAC Results for predefined subgroups of interest are illustrated in (30.1%; 95% CI, 21.2%–40.6%) compared with 30/110 (27.3%; the forest plot (Fig 2), even though none of the interaction tests 95% CI, 19.4%–36.7%) allocated to CA (RR ¼ 1.10; 95% CI, 0.7– were significant. 384 Boisseau Apr 2023 www.ajnr.org Poor clinical outcomes (mRS . 2) in the intent to treat analysis (RR ¼ 1.6; 95% CI, 0.6–4.4; P ¼ .38). Five deaths were related to are detailed in Table 4. A poor clinical outcome (mRS. 2) treatment complications (2 in the CA and 3 in the SAC arms). occurred in 8/94 patients allocated to SAC (8.5%; 95% CI, 4.0%– Deaths unrelated to the aneurysm or treatment (and not included 16.6%) compared with 6/111 (5.4%; 95% CI, 2.2%–11.9%) with CA in the primary outcome measure) were reported in 3 patients (1 in the CA and 2 in the SAC groups). Details of poor clinical outcomes Table 2: Primary outcome in intent-to-treat analysis at any time point are provided in the Online Supplemental Data. CA SAC Adverse events occurred in 25/94 (26.6%) patients with SAC Intent-to-treat analysis 1-year outcome (n = 111) (n = 94) and 23/111 (20.7%) with CA (RR ¼ 1.28; 95% CI, 0.78–2.11; Treatment failure (composite) (No.) (%) 30 (27.3) 28 (30.1) P ¼ .323). Cerebrovascular ischemic and hemorrhagic events Clinical occurred in 21/94 (22.3%) patients with SAC, and in 18/111 mRS 6 2 (1.8) 3 (3.2) (16.2%) with CA (RR ¼ 1.38; 95% CI, 0.78–2.43; P ¼ .268). mRS 3–5 3 (2.7) 3 (3.2) Intracranial hemorrhage 0 0 Complication rates according to subgroups of interest are pro- Retreatment 0 3 (3.2) vided in the Online Supplemental Data. The test of interaction Angiographic was significant for aneurysm size (P ¼ .02): complications were Immediate failure 3 (2.7) 1 (1.1) more frequent in patient with aneurysms ,10 mm allocated to Residual aneurysm (core lab) 22 (19.8) 18 (19.4) SAC than in those allocated to CA (RR 2.0 6 0.69 95% CI 1.0– Missing primary outcome 1 (0.9) 1 (1.1) 3.9; P ¼ .04). RR ¼ 1.10; 95% CI, 0.71–1.71; P ¼ .656. Table 3: Secondary outcomes in intent-to-treat analysis CA (n = 111) SAC (n = 94) RR (95% CI) P Value Hospitalization 0.78 (0.48–1.28) .325 Patients hospitalized for .3 days (No.) (%) 30 (27.3) 20 (21.3) Discharge location (No.) (%) 1.18 (0.35–3.96) .788 Home 106 (95.5) 89 (94.7) Other than home 5 (4.5) 5 (5.3) Other hospital 1 (0.9) 0 Rehabilitation center 2 (1.8) 2 (2.1) Death 2 (1.8) 3 (3.2) mRS at discharge (No.) (%) 1.18 (0.35–3.96) .788 0 84 (75.7) 69 (73.4) 1 17 (15.3) 16 (17.0) 2 5 (4.5) 4 (4.3) 3 2 (1.8) 1 (1.1) 4 1 (0.9) 0 (0.0) 5 0 (0.0) 1 (1.1) 6 2 (1.8) 3 (3.2) 1 -Year mRS (No.) (%) 1.17 (0.43–3.22) .761 0 66 (60.0) 54 (57.4) 1 30 (27.3) 26 (27.7) 2 7 (6.4) 7 (7.4) 3 1 (0.9) 2 (2.1) 4 2 (1.8) 0 (0.0) 5 1 (0.9) 0 (0.0) 6 3 (2.7) 5 (5.3) Missing mRS data 1 (0.9) 0 Time of 1-year mRS assessment (mean) (SD) (mo) 15.7 (10.5) 15.3 (8.0) Morbidity and mortality at 1 year (mRS. 2), (No.) (%) 6 (5.4%) 8 (8.5%) Retreatment of index aneurysm during follow-up (No.) (%) 0 3 (3.2) Immediate angiographic outcome 0.97 (0.42–2.23) .936 Complete occlusion (No.) (%) 67 (60.4) 55 (58.5) Residual neck (No.) (%) 33 (29.7) 30 (31.9) Residual saccular aneurysm (No.) (%) 11 (9.9) 9 (9.6) Angiographic outcome at 1 year (core lab) (Detailed results in Online Supplemental Data) Complete occlusion (No.) (%) 38 (34.2) 42 (44.7) Residual neck (No.) (%) 43 (38.7) 24 (25.5) Residual saccular aneurysm (No.) (%) 27 (24.3) 24 (25.5) 1-year imaging not available (No.) (%) 3 (2.7) 4 (4.3) Time of 1-year imaging assessment (mean) (SD) (mo) 13.5 (5.2) 14.8 (9.5) Follow-up vascular imaging (No.) (%) 108 (97.3) 90 (95.7) MRA (No.) (%) 82 (73.9) 53 (56.4) Catheter angiography (No.) (%) 24 (21.6) 35 (37.2) CTA (No.) (%) 2 (1.8) 2 (2.1) Three deaths in the CA group, 4 deaths in the SAC group. For 1 patient in the SAC group (who died 298 days after treatment), the 1-year imaging was adjudicated using the 3-month follow-up angiogram. AJNR Am J Neuroradiol 44:381–89 Apr 2023 www.ajnr.org 385 FIG 2. Subgroup analysis of the primary outcome at 1 year. ACA indicates anterior cerebral artery. Predefined as-treated subgroup analyses of the primary out- Table 4: Clinical outcomes (mRS > 2 at 12 months) in intent-to- treat analysis come are detailed and illustrated in the forest plot (Online Intent to treat CA (n = 111) SAC (n = 94) Supplemental Data). There were no significant interactions, and Death (No.) (%) 3 (2.7) 5 (5.3%) subgroup results were similar. Related 2 3 In as-treated analyses, all-cause death or dependency at 1 year Unrelated 1 2 occurred in 10of 104 (9.6%) SAC patientsand in 4of 94CA mRS 3–5 (No.) (%) 3 (2.7) 3 (3.2) patients (4.3%) (RR ¼ 2.26; 95% CI, 0.73–9.96; P ¼ .156) (Table 6). Total (No.) (%) 6 (5.4) 8 (8.5) Other secondary outcomes (Online Supplemental Data) (immediate angiographic outcomes, days of hospitalization, discharge disposi- Results for the secondary outcomes in the intent-to-treat tion, and mRS at discharge and at 12 months) were similar between analyses are detailed in Table 3. Secondary outcomes (imme- groups. diate and 12 month angiographic outcomes, days of hospitali- As-treated angiographic results at 12 months, categorized as zation, discharge disposition, mRS at discharge and at 12 the presence of a residual aneurysm or not, were not signifi- months) were similar between groups. Angiographic results at cantly different (RR ¼ 0.77; 95% CI, 0.48–1.2; P ¼ .300). SAC 12 months were similar (RR 1.1; 95% CI 0.66–1.71; was significantly better than CA in as-treated analyses when P ¼ .789). Changing the definition of a good angiographic “complete occlusion” was used as the definition of a good angio- outcome as a complete occlusion did not change results (Online graphic outcome (RR ¼ 0.74; 95% CI, 0.59–0.94; P ¼ .012) supplemental data). (Online Supplemental Data). As-treated analyses included 198/205 patients (97%; seven Adverse events (any severity) occurred in 34/104 (32.7%) patients treated with flow diverters were excluded). The primary patients who underwent SAC, compared with 12/94 (12.8%) outcome (treatment failure) occurred in 27/102 patients treated patients with CA (RR ¼ 2.56; 95% CI, 1.41–4.65; P ¼ .002). Details with SAC (26.5%; 95% CI, 18.4%–36.3%) compared with 29/94 are provided in the Online Supplemental Data. Ischemic and hem- (30.8%; 95% CI, 21.9%–41.3%) treated with CA (RR ¼ 0.86; 95% orrhagic events were more frequent in patients who underwent CI, 0.55–1.34; P ¼ .498). Details of each component of the pri- SAC (30/104 [28.8%]) compared with 7/94 (7.4%) patients who mary outcome are provided in Table 5. received CA (RR ¼ 3.87; 95% CI, 1.79–8.40; P ¼ .001). 386 Boisseau Apr 2023 www.ajnr.org Table 5: Primary outcome in as-treated analysis of UIA treatment is to prevent future ruptures, these are rare 22-24 CA SAC events. Using death or disability from rupture during follow-up As-treated analysis 1-year outcome (n = 94) (n = 104) would necessitate the recruitment of thousands of patients followed Treatment failure (composite) (No.) (%) 29 (30.9) 27 (26.0) for a long time. Most clinicians rely on angiographic results to Clinical assess the efficacy of treatment, and most endovascular trials have mRS 6 1 (1.1) 4 (3.9) 22-24 used angiographic outcomes as primary end points. The resid- mRS 3–5 3 (3.2) 3 (3.1) ual aneurysm cutoff category was chosen to judge treatment failure Intracranial hemorrhage 0 0 Retreatment 0 3 (3.2) because it has been shown to be more repeatable, and its clinical sig- Angiographic nificance more constant than other categories. The clinical criteria Immediate failure 3 (3.3) 1 (1.1) included in the composite primary outcome measure ensured that Residual aneurysm (core lab) 22 (25.3) 16 (17.6) a patient becoming dependent or dying because of a treatment- Missing primary outcome 0 2 (1.9) a related complication (or because the treatment was clinically inef- RR ¼ 0.86; 95% CI, 0.55–1.34; P ¼ .498. fective) would not count as a good outcome. However, clinical out- comes weighed little in the final comparison between treatments, Table 6: Clinical outcomes (mRS > 2 at 12 months) in as-treated analysis which was driven mainly by angiographic results. As-treated CA (n = 94) SAC (n = 104) Primary Outcome Results Death (No.) (%) 1 (1.1) 7 (6.7) Related 1 4 STAT did not show a large benefit of SAC over CA for the treat- Unrelated 0 3 ment of UIAs. This was true for patients with large (STAT-1), mRS 3–5 (No.) (%) 3 (3.2) 3 (2.9) recurrent (STAT-2), or wide-neck aneurysms (STAT-3). The trial Total (No.) (%) 4 (4.3) 10 (9.6) was only powered to show a large effect (a decrease in the failure rate from 33% to 15%). We cannot exclude that with the inclusion DISCUSSION of a larger number of patients, a more modest but still clinically The Problem of Residual Aneurysms after Coiling significant benefit could have been demonstrated. Residual or recurrent aneurysms after coiling occur in 10%–33% of In STAT, a substantial number of crossovers diluted the con- 27,28 patients. In ruptured aneurysms, they have been associated with trast between treatments. The classic way of analyzing results 27,28 a persistent risk of subarachnoid hemorrhage. In UIAs, they are (intent to treat) remains clinically appropriate for practical rea- more likely to occur in large, wide-neck, and recurrent aneurysms. sons. First, many crossovers, such as bailout stent placement in In the context of a preventive treatment against ruptures, recur- patients with coil protrusion and parent vessel or branch occlu- rences lead to a number of clinical consequences, such as routine sion (in the CA group) or failure to catheterize the branch neces- angiographic surveillance of nearly all patients and retreatment in sary to land the stent (in the SAC group), were inevitable. Second, 29 30 5%–15% (even up to 25% of patients at 10 years in some series). the goal of the trial was to assess the role of stent placement to Potentially more effective coils have been developed with varying intentionally improve the results of endovascular treatment. 31-36 but mostly disappointing results, particularly for large and Perhaps the groups being compared could have been more pre- recurrent aneurysms. cisely defined as SAC (if possible) versus CA plus bailout stent placement (only if necessary). Stent Placement and Residual Aneurysms From an explanatory or mechanistic perspective, it is worth The use of SAC, originally designed to treat otherwise untreatable looking at the as-treated results: Does stent placement have the aneurysms, has expanded in the hope of decreasing the risk of 3,6-8,10-12,37-40 potential to improve the angiographic results of coiling? recurrences. This hypothesis has never been tested 3-10 Only by redefining a good angiographic outcome as a complete in a randomized trial. Previous studies, including systematic 11,12 occlusion and only by looking at as-treated analyses could SAC be reviews and meta-analyses, have shown diverging results. Some shown superior to CA (Online Supplemental Data). The clinical studies have reported that aneurysms treated with SAC were less 3,5,8,10-12 significance of this finding remains questionable, but it may be a prone to recurrence, while other studies did not show such 4,6,7,9 signal in favor of the capacity of stent placement to improve angio- an effect. Higher treatment-related risks of mortality and mor- 3,7,11 4-6,8,10 graphic results of coiling in the long term. This capacity may come bidity were shown in some reports, but not in others. at a cost in terms of complications: As-treated analyses also showed Many studies reported significant baseline differences between the groups being compared, most often with characteristics that could complications to be more frequent with SAC, particularly for small favor SAC (ie, a high proportion of unruptured sidewall aneurysms aneurysms. Although in some of these cases, complications 3-5 and shorter follow-up time). Thus, after 20 years, we still lack occurred when stents were being used as a rescue strategy (ie, a reliable evidence regarding the risks and potential benefits of add- technical complication had already occurred), thromboembolic ing a stent to a coiling procedure in patients with UIAs eligible for complications with stent placement remain a concern. both options. It is in this context of uncertainty that STAT was launched in 2011. Safety of Treatments The overall morbidity and mortality of patients treated in STAT The Choice of Primary Outcome were within the range of our initial estimate (between 6% and The primary end point of STAT was a composite that included clin- 12%). Safety end points were similar between the 2 groups in ical and angiographic outcome measures. Although the main goal intent-to-treat analyses, but the trial was underpowered to draw AJNR Am J Neuroradiol 44:381–89 Apr 2023 www.ajnr.org 387 any conclusions about the safety of SAC over CA. The upper limit the crucial question remains: Should they be offered preventive of the 95% CI of the risk ratio of 4.4 cannot exclude SAC being treatment at all? associated with a large increase in initial or long-term neurologic The use of stents for the treatment of UIAs is an example of deficits compared with CA. Cerebrovascular ischemic and hemor- the failure of our community to use randomized trials to safely rhagic events in STAT were relatively high compared with previ- introduce innovations in neurovascular care. We must find ways 6,7 11 ous registries and meta-analysis. However, those comparisons to integrate clinical research into practice to optimize care in real are not valid, and aneurysms randomized in STAT were typically 42 time. Future trials on SAC should probably be integrated into larger and many were difficult to treat by any and all methods. 41,43,44 ongoing randomized clinical trials. Trial Limitations CONCLUSIONS Before we examine the potential impact on clinical practice, we STAT did not show SAC to be superior to CA for wide-neck, must review the trial limitations. Only 4 centers participated, large, or recurrent unruptured aneurysms. More randomized which limits the generalizability of results. Although STAT is the data are needed to determine the role of SAC in the treatment of only randomized controlled trial comparing SAC and CA, the aneurysms. number of patients remains small. The introduction of flow diverters likely directed many patients with difficult aneurysms to Disclosure forms provided by the authors are available with the full text and other clinical trials. The original plan was to recruit 40–50 cen- PDF of this article at www.ajnr.org. ters, but the lack of financial support deterred many potential cen- ters from participating. As many as 600 patients would have been REFERENCES necessary to exclude the possibility that SAC would double the 1. U.S. Department of Health and Human Services; US Food & Drug Administration. Humanitarian Device Exemption (HDE). https:// risk of death or dependency. Yet, safety is of primary importance www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfhde/hde.cfm?id=H02000 when a preventive treatment is offered to mostly asymptomatic 2. 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World Neurosurg 2022;160:e49–54 CrossRef Medline AJNR Am J Neuroradiol 44:381–89 Apr 2023 www.ajnr.org 389 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Neuroradiology American Journal of Neuroradiology

Stent-Assisted Coiling in the Treatment of Unruptured Intracranial Aneurysms: A Randomized Clinical Trial

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American Journal of Neuroradiology
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© 2023 by American Journal of Neuroradiology. Indicates open access to non-subscribers at www.ajnr.org
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0195-6108
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1936-959X
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10.3174/ajnr.a7815
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Abstract

LEVEL 1 EBM EXPEDITED PUBLICATION INTERVENTIONAL Stent-Assisted Coiling in the Treatment of Unruptured Intracranial Aneurysms: A Randomized Clinical Trial W. Boisseau, T.E. Darsaut, R. Fahed, B. Drake, H. Lesiuk, J.L. Rempel, J.-C. Gentric, J. Ognard, L. Nico, D. Iancu, D. Roy, A. Weill, M. Chagnon, J. Zehr, P. Lavoie, T.N. Nguyen, and J. Raymond ABSTRACT BACKGROUND AND PURPOSE: Stent-assisted coiling may improve angiographic results of endovascular treatment of unruptured in- tracranial aneurysms compared with coiling alone, but this has never been shown in a randomized trial. MATERIALS AND METHODS: The Stenting in the Treatment of Aneurysm Trial was an investigator-led, parallel, randomized (1:1) trial conducted in 4 university hospitals. Patients with intracranial aneurysms at risk of recurrence, defined as large aneurysms ($10 mm), postcoiling recurrent aneurysms, or small aneurysms with a wide neck ($4 mm), were randomly allocated to stent-assisted coiling or coiling alone. The composite primary efficacy outcome was “treatment failure,” defined as initial failure to treat the aneurysm; aneurysm rupture or retreatment during follow-up; death or dependency (mRS. 2); or an angiographic residual aneurysm adjudi- cated by an independent core laboratory at 12 months. The primary hypothesis (revised for slow accrual) was that stent-assisted coiling would decrease treatment failures from 33% to 15%, requiring 200 patients. Primary analyses were intent to treat. RESULTS: Of 205 patients recruited between 2011 and 2021, ninety-four were allocated to stent-assisted coiling and 111 to coiling alone. The primary outcome, ascertainable in 203 patients, was reached in 28/93 patients allocated to stent-assisted coiling (30.1%; 95% CI, 21.2%–40.6%) compared with 30/110 (27.3%; 95% CI, 19.4%–36.7%) allocated to coiling alone (relative risk ¼ 1.10; 95% CI, 0.7– 1.7; P ¼ .66). Poor clinical outcomes (mRS.2) occurred in 8/94 patients allocated to stent-assisted coiling (8.5%; 95% CI, 4.0%– 16.6%) compared with 6/111 (5.4%; 95% CI, 2.2%–11.9%) allocated to coiling alone (relative risk ¼ 1.6; 95% CI, 0.6%–4.4%; P ¼ .38). CONCLUSIONS: The STAT trial did not show stent-assisted coiling to be superior to coiling alone for wide-neck, large, or recurrent unruptured aneurysms. ABBREVIATIONS: CA ¼ coiling alone; DSMC ¼ Data and Safety Monitoring Committee; RR ¼ relative risk; SAC ¼ stent-assisted coiling; UIA ¼ unruptured intracranial aneurysm he use of stents for the treatment of unruptured intracranial Antiplatelet regimens are therefore necessary to prevent arterial Taneurysms (UIAs) was first approved in the United States in thromboembolic complications, rendering the use of stents 2002 as a Humanitarian Device Exemption. The initial indication problematic in recently ruptured aneurysms. There may be was to mechanically assist the coiling of wide-neck ($4 mm) benefits to the use of stent-assisted coiling (SAC), in addition to aneurysms not amenable to endovascular or surgical treat- mechanically preventing coil protrusion into the parent artery 1,2 ment. Subsequently, clinical usage has expanded to all types during the coiling procedure, which may improve the long-term 3-12 of aneurysms. While coiling is strictly an intrasaccular treat- angiographic results of endovascular treatments such as a flow- 14-16 ment, stents are deployed in the artery bearing the aneurysm. diverting effect or better healing due to the provision of a scaffold for neointimal closure of the neck. However, these Received January 25, 2023; accepted after revision February 16. potential benefits were not observed in experimental models. From the Department of Radiology (W.B., D.I., D.R., A.W., J.R.), Service of Whether SAC increases procedural risks or improves long-term Neuroradiology, Centre Hospitalier de l’Université de Montréal, Montreal, Québec, angiographic results has not been convincingly shown despite Canada; Department of Surgery (T.E.D.), Division of Neurosurgery and Department of Radiology and Diagnostic Imaging (J.L.R.), University of Alberta Hospital, Mackenzie Health Sciences Centre, Edmonton, Alberta, Canada; Departments of Please address correspondence to Jean Raymond, MD, Centre Hospitalier de Neurology (R.F.), and Neurosurgery (B.D., H.L.), University of Ottawa, the Ottawa l’Université de Montréal (CHUM), Department of Radiology, Room D03.5462b, Hospital, Ottawa, Ontario, Canada; Department of Radiology (J.-C.G., J.O.), Montreal, Québec, Canada H2X 0C1; e-mail: jean.raymond@umontreal.ca University Hospital of Brest, Brest, France; Departement of Radiology (L.N.), Service Indicates open access to non-subscribers at www.ajnr.org of Interventional Neuroradiology, Centre Hospitalo-universitaire de Saint-Etienne, Saint-Etienne, France; Department of Mathematics and Statistics (M.C., J.Z.), Indicates article with online supplemental data. Pavillon André-Aisenstadt, Montreal, Québec, Canada; Department of Neurosurgery (P.L.), Centre Hospitalier Universitaire de Québec-Université Laval, Evidence-Based Medicine Level 1. Québec, Canada; and Departments of Neurology (T.N.N.) and Radiology (T.N.N.), Boston Medical Center, Boston, Massachusetts. http://dx.doi.org/10.3174/ajnr.A7815 AJNR Am J Neuroradiol 44:381–89 Apr 2023 www.ajnr.org 381 multiple case series and meta-analyses published during site. Details regarding the endovascular technique; type of coils; 3-12 20 years. A randomized trial comparing the results of coiling use of adjunctive techniques such as balloon remodeling (routine with or without stent placement has never been published. in STAT centers for large or wide-neck aneurysms); whether the The Stenting in the Treatment of Aneurysm Trial (STAT) was stent was deployed before or following coiling; the use of multiple launched in 2011 to provide a clinical research context for the use stents; and posttreatment medical management decisions were left of SAC in UIAs. The trial compared a policy of coiling alone to the discretion of the treating physicians. A stent could be used (CA) versus the use of a self-expandable stent (any stent, not a as a bailout maneuver in patients allocated to CA if this was judged flow diverter) in addition to the coiling procedure. The primary appropriate by the treating physician, to ensure the safety of hypothesis of the trial was that in patients with aneurysms prone patients. Similarly, the physician could choose not to use the stent to recurrence, SAC would decrease the proportion of patients in patients allocated to SAC when it was judged impossible or dan- reaching “treatment failure,” a composite clinical and angiographic gerous at the time of the procedure. primary outcome measure that included aneurysmal rupture or Follow-up tests and visits were limited to those considered retreatment during follow-up or a recurrent or residual aneurysm clinically indicated, such as neurologic examinations, brain imag- on follow-up angiography at 12 months. We here report the final ing studies, and a functional assessment according to the mRS results of the trial. score at discharge, 1 month, and 12 (63) months. Follow-up an- giography (invasive or noninvasive) at 12 (63) months was con- sidered standard of practice. MATERIALS AND METHODS Data capture and management through secure servers (MedSciNet; This report follows the Consolidated Standards of Reporting https://medscinet.com/about.aspx) were in compliance with Trials (CONSORT) recommendations. STAT was an investi- good clinical practice requirements. Case report forms were gator-led, multicenter randomized controlled trial integrated simple, and the data collected were parsimonious, to facilitate into clinical practice. The trial proposed randomized allocation completion by care personnel, because no financial compensa- to SAC or CA in patients eligible for both options. There were 4 tion was provided to participating centers. participating centers (Montreal, Ottawa, and Edmonton in Canada, and Brest in France). All sites received institutional Primary and Secondary Outcome Measures review board approval. The protocol was published, and the The primary end point of the 2011 protocol was the incidence of trial was registered at http://www.clinicaltrials.gov number angiographic recurrences at 12 (63) months, defined as the fol- NCT01340612. lowing: 1) an angiographic recurrence of the lesion, as judged by an independent core lab (composed of 2 raters) according to a Patients previously published classification; 2) an episode of intracranial All patients were 18 years of age or older with a life expectancy of bleeding; or 3) retreatment of the same lesion by endovascular or at least 2 years. Patients had at least 1 UIA prone to recurrence, surgical means during the follow-up period. Furthermore, the defined and categorized at the time of registration before random- protocol stipulated that “recurrences would be recorded (present ization as a large ($10 mm) aneurysm (STAT-1), a recurrent an- or absent) as they are discovered, at the follow-up assessment eurysm after previous coiling (STAT-2), or a wide-neck ($4 mm) (12 6 3 months), as clinical symptoms appear at any time, or at aneurysm of ,10 mm (STAT-3). There were few exclusion crite- time of death.” ria: 1) absolute contraindications to endovascular treatment, anes- Because this definition lacked precision and may not be ascer- thesia, or the use of dual antiplatelet regimens; 2) the presence of tainable in some patients, the primary outcome was modified in other aneurysms requiring treatment during the same session; 3) July 2021, after consulting with the Data and Safety Monitoring thepresenceof an associated cerebral arteriovenous malformation; Committee (DSMC) but before any data examination, to be in 4) recently ruptured aneurysms (,3 months); and 5) the presence 22-24 line with other endovascular trials. Two other components of a recurring, previously stented aneurysm. Screening logs of all have been added to the composite primary outcome, treatment potentially eligible patients with UIAs were not required per proto- failure (initial treatment failure using any device and treatment- col. All patients signed an informed consent form. or aneurysm-related death or dependency precluding follow-up angiography). If the coiling procedure was not feasible, for exam- Randomization and Masking ple due to coil instability, the physician had the option of using a SAC or CA was randomly allocated (1:1) using a Web-based plat- stent, a use that was not considered a failure of the initial treat- form assuring concealment of the allocation. The randomized ment (but was counted as a crossover in “as-treated analyses”). allocation was stratified according to the STAT1–3 subgroups One primary poor outcome was attributed per patient. When a and minimized for the type of coils to be used (platinum or sec- patient met .1 of the criteria, the following hierarchical order ond generation). Patients, interventionists, and outcome assessors was prespecified to classify the patient for final analyses: death or were not blinded to treatment assignment. mRS 3–5 (from any cause within 30 days of the intervention and from related causes during follow-up) . aneurysm rupture dur- Interventions and Follow-up Tests and Visits Coiling with or without stent placement was performed according ing follow-up . retreatment during follow-up . initial treatment to standards of practice, with the patient under general anesthesia. failure (defined as the inability to perform endovascular treat- Antiplatelet and anticoagulation regimens and testing for platelet ment) . major recurrence or residual aneurysm at imaging fol- inhibition were prescribed according to routine practice at each low-up (3–12 months) as adjudicated by an independent core 382 Boisseau Apr 2023 www.ajnr.org laboratory of 2 neuroradiologists blinded to treatment groups 25,26 and according to a previously validated classification. Secondary outcomes included the individual components of the composite primary outcome: the mRS score at discharge and 12 months posttreatment; the success in occluding the aneurysm at the end of the procedure; perioperative complications (ischemic strokes and intracranial hemorrhages within 31 days of the inter- vention and during follow-up); angiographic results at 12 months; length of hospital stay (number of days); discharge disposition (home, other hospital, rehabilitation facility; death); and retreat- ment of the index aneurysm at any time. Hypotheses and Number of Patients The 2011 protocol planned for the recruitment of 600 patients. This number was based on 2 hypotheses: The primary efficacy hy- pothesis was that SAC would decrease angiographic recurrences by 20% at 12 months and a total sample size of 536 patients would allowthe detectionof sucha difference withapower of 80% and an error of 0.0125 (to account for subgroup analyses for the 3 main categories of lesions: large, wide neck, and recurrent aneur- FIG 1. STAT participant flow CONSORT diagram. ysms). The secondary safety hypothesis was that the use of intra- cranial stent placement would not double the number of dead or and aneurysm subgroups were examined as prespecified in 2011, dependent patients (mRS. 2) from 6% to 12% at 12 months. In regardless of the results of tests for interaction. Subgroup results July 2021, before any knowledge of the data, the steering commit- according to STAT 1–3 categories indicated at the time of registra- tee (SC), in agreement with the DSMC, dropped the safety hypoth- tion, according to aneurysm size (,10 mm or $10 mm), neck esis and modified the primary efficacy hypothesis: SAC was size (,4mm or $4 mm), and location (posterior circulation and hypothesized to decrease treatment failures from 33% to 15%, anterior circulation subdivided into carotid, anterior cerebral ar- which would require approximately 200 patients (88 patients per tery, and MCA aneurysms) are reported. As-treated exploratory group; power of 80% and a of 5%, plus 10% to account for cross- analyses (defined as coiling with or without any attempt or use of overs and losses to follow-up). Details are provided in the Online stent placement, regardless of treatment allocation) are also pro- Supplemental Data. vided. We also explored what results would have been if complete occlusion (rather than the combination of complete and near- Trial Interruption complete occlusion) had been used as the criterion for a good On August 31, 2021, after a blinded examination of interim angiographic outcome. One adverse event is reported per patient. results, the DSMC recommended trial continuation. However, in When a patient had .1 event, we used the most severe to catego- September 2021, ten years after the recruitment of the first patient, rize the patient. Analyses were performed using SAS software, the SC decided to finalize and report the trial. Version 9.4 (SAS Institute) and SPSS, Version 26 (IBM) with a significance level of 5%. Statistical Analyses Blinded data were examined at prespecified intervals by an inde- Roles of the Sponsor and Funding Source pendent DSMC, composed of an interventional neurologist, a The trial was sponsored by the Center Hospitalier de l’Université dual-trained neurosurgeon, and a statistician; but no hypothesis de Montréal. The sponsor had no part in the study design, data testing was performed. collection, analysis, or reporting and no access to the data or Descriptive statistics on demographic variables and preopera- source documents. The corresponding author had full access to tive data are provided to compare the 2 groups at baseline. Means, all the data and had final responsibility for the decision to submit SDs, medians, and ranges are presented for quantitative variables, for publication. There was no funding source for this study. and frequency tables for categoric variables. Primary safety and ef- ficacy outcomes are described using percentages and 95% CIs. The RESULTS intent-to-treat analyses for the primary efficacy hypothesis were performed on available observations. The relative risks (RRs and Between August 2011 and August 2021, we recruited 205 patients: 95% CIs) were estimated using a generalized estimating equation Ninety-four were assigned to SAC, and 111 to CA. For each group, with a binomial distribution and a log-link function. The groups the number of participants who were randomly assigned, received were not different with respect to risk factors for poor outcomes, intended treatment, and were analyzed for the primary outcome is and no adjustments for residual confounding factors were made. illustrated in the trial profile (Fig 1). The analyses of interaction between prespecified subgroups of The baseline patient and aneurysm characteristics are shown in interest and treatment were made by adding subgroup variables Table 1. Groups were comparable: Ninety-two (44.9%) patients and interaction in generalized estimating equation models. Patient had small wide-neck aneurysms (STAT-3); 75 (36.6%), a recurrent AJNR Am J Neuroradiol 44:381–89 Apr 2023 www.ajnr.org 383 Table 1: Patient and index aneurysm characteristics Characteristics CA (n = 111) SAC (n = 94) Total (n = 205) Patient Age at treatment (mean) (SD) (yr) 58.6 (10.4) 58.0 (8.8) 58.3 (9.7) Female (No.) (%) 77 (69.4) 65 (69.1) 142 (69.3) STAT type lesion STAT-1: unruptured aneurysm, never treated, with a dimension 21 (18.9) 17 (18.1) 38 (18.5) of$ 10 mm (No.) (%) STAT-2: major recurrent aneurysm after previous coiling, but no 41 (36.9) 34 (36.2) 75 (36.6) previous stent placement (No.) (%) STAT-3: small (,10 mm), wide-neck ($ 4 mm) aneurysm (No.) (%) 49 (44.1) 43 (45.7) 92 (44.9) Pretreatment mRS score (No.) (%) 0 84 (75.7) 70 (74.5) 154 (75.1) 1 21 (18.9) 20 (21.3) 41 (20.0) 2 5 (4.5) 2 (2.1) 7 (3.4) 3 1 (0.9) 1 (1.1) 2 (1.0) 4 0 1 (1.1) 1 (0.5) Presentation Symptomatic 4 (3.6) 4 (4.3) 8 (3.9) Additional aneurysm to a previously ruptured and treated one 13 (11.7) 6 (6.4) 19 (9.3) Incidental finding 94 (84.7) 84 (89.4) 178 (86.8) Index aneurysm location (No.) (%) Anterior circulation 78 (70.3) 58 (61.7) 136 (66.3) Ophthalmic/paraophthalmic 7 (6.3) 3 (3.2) 10 (4.9) Posterior communicating/anterior choroidal 7 (6.3) 13 (13.8) 20 (9.8) Carotid terminus 6 (5.4) 1 (1.1) 7 (3.4) MCA bifurcation/M1 18 (16.2) 14 (14.9) 32 (15.6) Anterior communicating/A1 40 (36.0) 25 (26.6) 65 (31.7) Distal ACA 0 2 (2.1) 2 (1.0) Posterior circulation 33 (29.7) 36 (38.3) 69 (33.7) PCA 0 3 (3.2) 3 (1.5) Basilar terminus 24 (21.6) 23 (24.5) 47 (22.9) SCA 3 (2.7) 5 (5.3) 8 (3.9) Basilar trunk 2 (1.8) 0 2 (1.0) Vertebrobasilar junction 2 (1.8) 2 (2.1) 4 (2.0) PICA 2 (1.8) 3 (3.2) 5 (2.4) Index aneurysm maximal external size (mean) (SD) (range) (mm) 9.2 (6.4) 9.2 (5.9) 9.2 (6.1) (2–50) (3–35) (2–50) ,10 (No.) (%) 74 (66.7) 63 (67.0) 137 (66.8) $10 (No.) (%) 37 (33.3) 31 (33.0) 68 (33.2) Index aneurysm neck size (mean) (SD) (range) (mm) 4.4 (2.2) 4.1 (1.6) 4.3 (1.9) (2–20) (2–9) (2–20) Aneurysm neck $4 mm (No.) (%) 72 (64.9) 58 (61.7) 130 (63.4) Note:—ACA indicates anterior cerebral artery; PCA, posterior cerebral artery; SCA, superior cerebellar artery. aneurysm (STAT-2); and 38 (18.5%), a large aneurysm (STAT-1). 1.7; P ¼ .66). Details of each component of the primary outcome The most frequent locations were the anterior communicating ar- in the intent to treat analysis are provided in Table 2. tery (65; 31.7%), basilar bifurcation (47; 22.9%), and MCA bifurca- There were no incidences of aneurysm rupture during follow-up. tion (32; 15.6%). Three patients were retreated (all in the SAC group). Angiographic Seventeen of 111 patients (15.3%) allocated to CA underwent resultsat 12monthsaccounted for most of the primary out- SAC, while 10/94 (10.6%) patients allocated to SAC were treated come adjudications (185/203; 91%). Follow-up vascular imag- with CA. Technical details regarding treatment for both groups are ing studies, available in 198 patients (96.6%), were performed provided in the Online Supplemental Data. In 4 patients from by MRA in 135 (68.2%), by catheter angiography in 59 STAT-2, residual aneurysms were judged too small for any treat- (29.8%), and by CTA in 4 (2%) patients. More patients were ment (3 in the SAC arm and 1 in the CA arm). Seven patients were followed by catheter angiography in the SAC group (37.2%) treated with flow diverters (3 in the SAC arm and 4 in the CA than in the CA group (21.6%) (Table 3). The mean time of arm). Patients allocated to SAC were initially treated with a single angiographic follow-up was 14.8 (SD, 9.5) months for patients (n ¼ 64) or 2 (n ¼ 14) stents. Stents were delivered before coiling allocated to SAC, and 13.5 (SD, 5.2) months for patients allo- in 20/78 (25.6%) and after coiling in 58/78 (74.4%) patients. cated to CA. The mean time of the follow-up mRS evaluation The primary outcome is available for 203/205 patients (99%), was 15.3 (SD, 8.0) months for SAC and 15.7 (SD, 10.5) months with 1 patient missing in each group (Fig 1 and Tables 2 and 3). for CA. Treatment failure occurred in 28/93 patients allocated to SAC Results for predefined subgroups of interest are illustrated in (30.1%; 95% CI, 21.2%–40.6%) compared with 30/110 (27.3%; the forest plot (Fig 2), even though none of the interaction tests 95% CI, 19.4%–36.7%) allocated to CA (RR ¼ 1.10; 95% CI, 0.7– were significant. 384 Boisseau Apr 2023 www.ajnr.org Poor clinical outcomes (mRS . 2) in the intent to treat analysis (RR ¼ 1.6; 95% CI, 0.6–4.4; P ¼ .38). Five deaths were related to are detailed in Table 4. A poor clinical outcome (mRS. 2) treatment complications (2 in the CA and 3 in the SAC arms). occurred in 8/94 patients allocated to SAC (8.5%; 95% CI, 4.0%– Deaths unrelated to the aneurysm or treatment (and not included 16.6%) compared with 6/111 (5.4%; 95% CI, 2.2%–11.9%) with CA in the primary outcome measure) were reported in 3 patients (1 in the CA and 2 in the SAC groups). Details of poor clinical outcomes Table 2: Primary outcome in intent-to-treat analysis at any time point are provided in the Online Supplemental Data. CA SAC Adverse events occurred in 25/94 (26.6%) patients with SAC Intent-to-treat analysis 1-year outcome (n = 111) (n = 94) and 23/111 (20.7%) with CA (RR ¼ 1.28; 95% CI, 0.78–2.11; Treatment failure (composite) (No.) (%) 30 (27.3) 28 (30.1) P ¼ .323). Cerebrovascular ischemic and hemorrhagic events Clinical occurred in 21/94 (22.3%) patients with SAC, and in 18/111 mRS 6 2 (1.8) 3 (3.2) (16.2%) with CA (RR ¼ 1.38; 95% CI, 0.78–2.43; P ¼ .268). mRS 3–5 3 (2.7) 3 (3.2) Intracranial hemorrhage 0 0 Complication rates according to subgroups of interest are pro- Retreatment 0 3 (3.2) vided in the Online Supplemental Data. The test of interaction Angiographic was significant for aneurysm size (P ¼ .02): complications were Immediate failure 3 (2.7) 1 (1.1) more frequent in patient with aneurysms ,10 mm allocated to Residual aneurysm (core lab) 22 (19.8) 18 (19.4) SAC than in those allocated to CA (RR 2.0 6 0.69 95% CI 1.0– Missing primary outcome 1 (0.9) 1 (1.1) 3.9; P ¼ .04). RR ¼ 1.10; 95% CI, 0.71–1.71; P ¼ .656. Table 3: Secondary outcomes in intent-to-treat analysis CA (n = 111) SAC (n = 94) RR (95% CI) P Value Hospitalization 0.78 (0.48–1.28) .325 Patients hospitalized for .3 days (No.) (%) 30 (27.3) 20 (21.3) Discharge location (No.) (%) 1.18 (0.35–3.96) .788 Home 106 (95.5) 89 (94.7) Other than home 5 (4.5) 5 (5.3) Other hospital 1 (0.9) 0 Rehabilitation center 2 (1.8) 2 (2.1) Death 2 (1.8) 3 (3.2) mRS at discharge (No.) (%) 1.18 (0.35–3.96) .788 0 84 (75.7) 69 (73.4) 1 17 (15.3) 16 (17.0) 2 5 (4.5) 4 (4.3) 3 2 (1.8) 1 (1.1) 4 1 (0.9) 0 (0.0) 5 0 (0.0) 1 (1.1) 6 2 (1.8) 3 (3.2) 1 -Year mRS (No.) (%) 1.17 (0.43–3.22) .761 0 66 (60.0) 54 (57.4) 1 30 (27.3) 26 (27.7) 2 7 (6.4) 7 (7.4) 3 1 (0.9) 2 (2.1) 4 2 (1.8) 0 (0.0) 5 1 (0.9) 0 (0.0) 6 3 (2.7) 5 (5.3) Missing mRS data 1 (0.9) 0 Time of 1-year mRS assessment (mean) (SD) (mo) 15.7 (10.5) 15.3 (8.0) Morbidity and mortality at 1 year (mRS. 2), (No.) (%) 6 (5.4%) 8 (8.5%) Retreatment of index aneurysm during follow-up (No.) (%) 0 3 (3.2) Immediate angiographic outcome 0.97 (0.42–2.23) .936 Complete occlusion (No.) (%) 67 (60.4) 55 (58.5) Residual neck (No.) (%) 33 (29.7) 30 (31.9) Residual saccular aneurysm (No.) (%) 11 (9.9) 9 (9.6) Angiographic outcome at 1 year (core lab) (Detailed results in Online Supplemental Data) Complete occlusion (No.) (%) 38 (34.2) 42 (44.7) Residual neck (No.) (%) 43 (38.7) 24 (25.5) Residual saccular aneurysm (No.) (%) 27 (24.3) 24 (25.5) 1-year imaging not available (No.) (%) 3 (2.7) 4 (4.3) Time of 1-year imaging assessment (mean) (SD) (mo) 13.5 (5.2) 14.8 (9.5) Follow-up vascular imaging (No.) (%) 108 (97.3) 90 (95.7) MRA (No.) (%) 82 (73.9) 53 (56.4) Catheter angiography (No.) (%) 24 (21.6) 35 (37.2) CTA (No.) (%) 2 (1.8) 2 (2.1) Three deaths in the CA group, 4 deaths in the SAC group. For 1 patient in the SAC group (who died 298 days after treatment), the 1-year imaging was adjudicated using the 3-month follow-up angiogram. AJNR Am J Neuroradiol 44:381–89 Apr 2023 www.ajnr.org 385 FIG 2. Subgroup analysis of the primary outcome at 1 year. ACA indicates anterior cerebral artery. Predefined as-treated subgroup analyses of the primary out- Table 4: Clinical outcomes (mRS > 2 at 12 months) in intent-to- treat analysis come are detailed and illustrated in the forest plot (Online Intent to treat CA (n = 111) SAC (n = 94) Supplemental Data). There were no significant interactions, and Death (No.) (%) 3 (2.7) 5 (5.3%) subgroup results were similar. Related 2 3 In as-treated analyses, all-cause death or dependency at 1 year Unrelated 1 2 occurred in 10of 104 (9.6%) SAC patientsand in 4of 94CA mRS 3–5 (No.) (%) 3 (2.7) 3 (3.2) patients (4.3%) (RR ¼ 2.26; 95% CI, 0.73–9.96; P ¼ .156) (Table 6). Total (No.) (%) 6 (5.4) 8 (8.5) Other secondary outcomes (Online Supplemental Data) (immediate angiographic outcomes, days of hospitalization, discharge disposi- Results for the secondary outcomes in the intent-to-treat tion, and mRS at discharge and at 12 months) were similar between analyses are detailed in Table 3. Secondary outcomes (imme- groups. diate and 12 month angiographic outcomes, days of hospitali- As-treated angiographic results at 12 months, categorized as zation, discharge disposition, mRS at discharge and at 12 the presence of a residual aneurysm or not, were not signifi- months) were similar between groups. Angiographic results at cantly different (RR ¼ 0.77; 95% CI, 0.48–1.2; P ¼ .300). SAC 12 months were similar (RR 1.1; 95% CI 0.66–1.71; was significantly better than CA in as-treated analyses when P ¼ .789). Changing the definition of a good angiographic “complete occlusion” was used as the definition of a good angio- outcome as a complete occlusion did not change results (Online graphic outcome (RR ¼ 0.74; 95% CI, 0.59–0.94; P ¼ .012) supplemental data). (Online Supplemental Data). As-treated analyses included 198/205 patients (97%; seven Adverse events (any severity) occurred in 34/104 (32.7%) patients treated with flow diverters were excluded). The primary patients who underwent SAC, compared with 12/94 (12.8%) outcome (treatment failure) occurred in 27/102 patients treated patients with CA (RR ¼ 2.56; 95% CI, 1.41–4.65; P ¼ .002). Details with SAC (26.5%; 95% CI, 18.4%–36.3%) compared with 29/94 are provided in the Online Supplemental Data. Ischemic and hem- (30.8%; 95% CI, 21.9%–41.3%) treated with CA (RR ¼ 0.86; 95% orrhagic events were more frequent in patients who underwent CI, 0.55–1.34; P ¼ .498). Details of each component of the pri- SAC (30/104 [28.8%]) compared with 7/94 (7.4%) patients who mary outcome are provided in Table 5. received CA (RR ¼ 3.87; 95% CI, 1.79–8.40; P ¼ .001). 386 Boisseau Apr 2023 www.ajnr.org Table 5: Primary outcome in as-treated analysis of UIA treatment is to prevent future ruptures, these are rare 22-24 CA SAC events. Using death or disability from rupture during follow-up As-treated analysis 1-year outcome (n = 94) (n = 104) would necessitate the recruitment of thousands of patients followed Treatment failure (composite) (No.) (%) 29 (30.9) 27 (26.0) for a long time. Most clinicians rely on angiographic results to Clinical assess the efficacy of treatment, and most endovascular trials have mRS 6 1 (1.1) 4 (3.9) 22-24 used angiographic outcomes as primary end points. The resid- mRS 3–5 3 (3.2) 3 (3.1) ual aneurysm cutoff category was chosen to judge treatment failure Intracranial hemorrhage 0 0 Retreatment 0 3 (3.2) because it has been shown to be more repeatable, and its clinical sig- Angiographic nificance more constant than other categories. The clinical criteria Immediate failure 3 (3.3) 1 (1.1) included in the composite primary outcome measure ensured that Residual aneurysm (core lab) 22 (25.3) 16 (17.6) a patient becoming dependent or dying because of a treatment- Missing primary outcome 0 2 (1.9) a related complication (or because the treatment was clinically inef- RR ¼ 0.86; 95% CI, 0.55–1.34; P ¼ .498. fective) would not count as a good outcome. However, clinical out- comes weighed little in the final comparison between treatments, Table 6: Clinical outcomes (mRS > 2 at 12 months) in as-treated analysis which was driven mainly by angiographic results. As-treated CA (n = 94) SAC (n = 104) Primary Outcome Results Death (No.) (%) 1 (1.1) 7 (6.7) Related 1 4 STAT did not show a large benefit of SAC over CA for the treat- Unrelated 0 3 ment of UIAs. This was true for patients with large (STAT-1), mRS 3–5 (No.) (%) 3 (3.2) 3 (2.9) recurrent (STAT-2), or wide-neck aneurysms (STAT-3). The trial Total (No.) (%) 4 (4.3) 10 (9.6) was only powered to show a large effect (a decrease in the failure rate from 33% to 15%). We cannot exclude that with the inclusion DISCUSSION of a larger number of patients, a more modest but still clinically The Problem of Residual Aneurysms after Coiling significant benefit could have been demonstrated. Residual or recurrent aneurysms after coiling occur in 10%–33% of In STAT, a substantial number of crossovers diluted the con- 27,28 patients. In ruptured aneurysms, they have been associated with trast between treatments. The classic way of analyzing results 27,28 a persistent risk of subarachnoid hemorrhage. In UIAs, they are (intent to treat) remains clinically appropriate for practical rea- more likely to occur in large, wide-neck, and recurrent aneurysms. sons. First, many crossovers, such as bailout stent placement in In the context of a preventive treatment against ruptures, recur- patients with coil protrusion and parent vessel or branch occlu- rences lead to a number of clinical consequences, such as routine sion (in the CA group) or failure to catheterize the branch neces- angiographic surveillance of nearly all patients and retreatment in sary to land the stent (in the SAC group), were inevitable. Second, 29 30 5%–15% (even up to 25% of patients at 10 years in some series). the goal of the trial was to assess the role of stent placement to Potentially more effective coils have been developed with varying intentionally improve the results of endovascular treatment. 31-36 but mostly disappointing results, particularly for large and Perhaps the groups being compared could have been more pre- recurrent aneurysms. cisely defined as SAC (if possible) versus CA plus bailout stent placement (only if necessary). Stent Placement and Residual Aneurysms From an explanatory or mechanistic perspective, it is worth The use of SAC, originally designed to treat otherwise untreatable looking at the as-treated results: Does stent placement have the aneurysms, has expanded in the hope of decreasing the risk of 3,6-8,10-12,37-40 potential to improve the angiographic results of coiling? recurrences. This hypothesis has never been tested 3-10 Only by redefining a good angiographic outcome as a complete in a randomized trial. Previous studies, including systematic 11,12 occlusion and only by looking at as-treated analyses could SAC be reviews and meta-analyses, have shown diverging results. Some shown superior to CA (Online Supplemental Data). The clinical studies have reported that aneurysms treated with SAC were less 3,5,8,10-12 significance of this finding remains questionable, but it may be a prone to recurrence, while other studies did not show such 4,6,7,9 signal in favor of the capacity of stent placement to improve angio- an effect. Higher treatment-related risks of mortality and mor- 3,7,11 4-6,8,10 graphic results of coiling in the long term. This capacity may come bidity were shown in some reports, but not in others. at a cost in terms of complications: As-treated analyses also showed Many studies reported significant baseline differences between the groups being compared, most often with characteristics that could complications to be more frequent with SAC, particularly for small favor SAC (ie, a high proportion of unruptured sidewall aneurysms aneurysms. Although in some of these cases, complications 3-5 and shorter follow-up time). Thus, after 20 years, we still lack occurred when stents were being used as a rescue strategy (ie, a reliable evidence regarding the risks and potential benefits of add- technical complication had already occurred), thromboembolic ing a stent to a coiling procedure in patients with UIAs eligible for complications with stent placement remain a concern. both options. It is in this context of uncertainty that STAT was launched in 2011. Safety of Treatments The overall morbidity and mortality of patients treated in STAT The Choice of Primary Outcome were within the range of our initial estimate (between 6% and The primary end point of STAT was a composite that included clin- 12%). Safety end points were similar between the 2 groups in ical and angiographic outcome measures. Although the main goal intent-to-treat analyses, but the trial was underpowered to draw AJNR Am J Neuroradiol 44:381–89 Apr 2023 www.ajnr.org 387 any conclusions about the safety of SAC over CA. The upper limit the crucial question remains: Should they be offered preventive of the 95% CI of the risk ratio of 4.4 cannot exclude SAC being treatment at all? associated with a large increase in initial or long-term neurologic The use of stents for the treatment of UIAs is an example of deficits compared with CA. Cerebrovascular ischemic and hemor- the failure of our community to use randomized trials to safely rhagic events in STAT were relatively high compared with previ- introduce innovations in neurovascular care. We must find ways 6,7 11 ous registries and meta-analysis. However, those comparisons to integrate clinical research into practice to optimize care in real are not valid, and aneurysms randomized in STAT were typically 42 time. Future trials on SAC should probably be integrated into larger and many were difficult to treat by any and all methods. 41,43,44 ongoing randomized clinical trials. Trial Limitations CONCLUSIONS Before we examine the potential impact on clinical practice, we STAT did not show SAC to be superior to CA for wide-neck, must review the trial limitations. Only 4 centers participated, large, or recurrent unruptured aneurysms. More randomized which limits the generalizability of results. Although STAT is the data are needed to determine the role of SAC in the treatment of only randomized controlled trial comparing SAC and CA, the aneurysms. number of patients remains small. The introduction of flow diverters likely directed many patients with difficult aneurysms to Disclosure forms provided by the authors are available with the full text and other clinical trials. The original plan was to recruit 40–50 cen- PDF of this article at www.ajnr.org. ters, but the lack of financial support deterred many potential cen- ters from participating. As many as 600 patients would have been REFERENCES necessary to exclude the possibility that SAC would double the 1. U.S. Department of Health and Human Services; US Food & Drug Administration. Humanitarian Device Exemption (HDE). https:// risk of death or dependency. Yet, safety is of primary importance www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfhde/hde.cfm?id=H02000 when a preventive treatment is offered to mostly asymptomatic 2. 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World Neurosurg 2022;160:e49–54 CrossRef Medline AJNR Am J Neuroradiol 44:381–89 Apr 2023 www.ajnr.org 389

Journal

American Journal of Neuroradiology – American Journal of Neuroradiology

Published: Apr 1, 2023

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