Flow diversion in Intracranial Aneurysm Treatment : A Randomized Trial Comparing Flow Diversion and Best-Standard-Treatment

The FIAT Trial Version 1.3 December 2014

Principal Investigator: Jean Raymond, MD CHUM – Notre Dame Hospital

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TABLE OF CONTENTS SECTION 1: BACKGROUND......................................................... 4 TREATMENT OF LARGE AND WIDE-NECKED ANEURYSMS ................................................ 4 STENTING ........................................................................................... 5 FLOW DIVERSION .................................................................................... 5 CLINICAL NEED FOR THE USE OF FLOW DIVERTERS ..................................................... 6 POTENTIAL COMPLICATIONS ASSOCIATED WITH THE USE OF FLOW DIVERTERS ........................... 7

SECTION 2: THE PROPOSED TRIAL ............................................... 8 FIAT IS A CLINICAL CARE TRIAL ...................................................................... 8 DESIGN ............................................................................................. 8 HYPOTHESES ........................................................................................ 9 INTERVENTIONS ..................................................................................... 9 SELECTION CRITERIA ............................................................................... 10 PRE-RANDOMIZATION AND DETERMINATION OF THE BEST STANDARD TREATMENT OPTION ............ 11 CHOICE OF COMPARATOR INTERVENTION, TECHNICAL FREEDOM AND TREATMENT FAILURES ........... 12 TYPE, FREQUENCY AND DURATION OF FOLLOW-UP .................................................. 12 TABLE 1: SCHEDULE OF EVALUATION .............................................................. 13 OUTCOMES ........................................................................................ 13 NUMBER OF PATIENTS ............................................................................. 14 RECRUITMENT RATE AND CENTRES .................................................................. 15 DURATION OF THE TRIAL ........................................................................... 15 PLANNED ANALYSES................................................................................ 15 SUBGROUPS ....................................................................................... 16 SAFETY MONITORING .............................................................................. 16 PROTECTION AGAINST BIAS ........................................................................ 17 PUBLICATION OF RESEARCH FINDINGS............................................................... 17 REGULATORY CONSIDERATIONS..................................................................... 17

SECTION 3: TRIAL MANAGEMENT ............................................... 19 INVESTIGATORS.................................................................................... 19 STEERING COMMITTEE ............................................................................. 19 DATA SAFETY AND MONITORING COMMITTEE (DSMC) .............................................. 19 IMAGING CENTER (CORE LAB) ...................................................................... 19 DAY TO DAY MANAGEMENT ......................................................................... 20 REFERENCES ...................................................................................... 21

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Flow diversion in Intracranial Aneurysm Treatment: A Randomized Trial Comparing Flow Diversion and Best-Standard-Treatment The FIAT Trial Section 1: Background Treatment of large and wide-necked aneurysms Intracranial aneurysms (IAs) are increasingly treated with endovascular techniques, deploying mainly platinum coils into the cerebral vasculature in order to promote aneurysm thrombosis1. The main drawback of this minimally invasive method is the higher incidence of aneurysm recurrences, which continues to affect at least 20% of coiled aneurysms, and may be as high as 30-50% for aneurysms larger than 10mm2-4. Coiling of the aneurysm is a poorly effective treatment of large and giant aneurysms which are still frequently treated, when possible, by parent vessel occlusion. Sometimes coiling is impossible. Recent attempts to promote durable aneurysm obliteration have recognized the potentially beneficial effects of diverting blood flow using an endoluminal stent5-7. A stent is a flexible tubular metallic mesh designed to normalize flow, close the aneurysm ostium and repair the parent vessel8-11, by triggering thrombosis within the stent-covered aneurysm. Three conceptual reasons for using stents in the treatment of IAs are thus recognized: a) To assist coil embolization in patients with wide neck aneurysms; b) To prevent recurrences after coiling, usually with high-porosity stents; c) To permanently occlude aneurysms by themselves, without the addition of coiling, using low porosity stents for flow diversion. Flow diversion (FD) will be the focus of the currently proposed trial. .

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Stenting Experience with intracranial stenting started more than a decade ago with the use of balloon-expendable coronary stents in rare, proximal and easily accessible cases. The introduction of more navigable dedicated high porosity stents led to much more common use, estimated in the range of 10-20% of aneurysm patients in the US, although there is little reliable data to justify their use. Originally approved to help retain detachable coils inside wide-necked aneurysms, stents are increasingly used as adjuncts to coiling12-13, but the additional risks due to implantation of a permanent potentially thrombogenic device remain poorly justified. Currently, more than 45 000 stents (Neuroform, Boston Scientific) have been implanted world-wide14, and this number continues to increase, driven primarily by fashion and market forces. The greatest clinical concern following deployment of these permanent intravascular foreign bodies are the thrombo-embolic risks to the parent vessel, as well as to branches covered or ‘jailed’ by the stent mesh. Most intracranial stents are thus designed to be porous, to occlude aneurysms in combination with coiling, while sparing the normal branches. The use of high porosity stenting in combination with coiling is currently the object of another Randomized Controlled Trial, the STAT trial (J. Raymond and the CHUM, Sponsor).

Flow diversion Nonetheless, as the prevalence of stenting has increased, the potential benefits of FD were recognized, and several attempts were made to treat aneurysms with stenting alone. Using high-porosity stents as mono-therapy (without coils) proved insufficient to promote aneurysm thrombosis in most cases15. However, subsequent attempts using overlapping, stent-in-stent techniques led to stable aneurysm occlusion in several small case series16-18. To capitalize on this property of stents, a new generation of flow diverters (FDs), with greater capacity to re-direct blood flow has been designed.

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The use of stents in treating IAs is sometimes perceived as a paradigm shift: a move from occlusion of the aneurysm via coil packing of the sac, to repair of the parent vessel with a stent (addressing the site of weakness that led to aneurismal dilation). These devices have provided reconstructive eradication of lesions that could henceforth only be treated effectively with parent vessel occlusion, such as giant carotid or vertebral aneurysms producing mass effects. The use of FDs in treating aneurysms has already expanded to more common lesions such as recurring lesions after coiling, and many users contemplate flow diversion as the optimal treatment of standard or „coilable‟ aneurysms, a question which will be the object of another recently launched trial, the Marco Polo trial (BALT International, Sponsor).

Clinical need for the use of flow diverters One of the problems in designing a trial to assess FD in the treatment of aneurysms is the diversity of clinical problems that may indicate the use of this device. This may entail a variety of pertinent clinical endpoints, a variety of realistic comparators, and thus a conventional approach would entail the design of multiple trials with various endpoints and inaccessible number of patients to come up with a meaningful answer to important clinical questions. Yet there is an equally urgent need to compile data about success of the initial procedure, peri-procedural or delayed complications, and long-term anatomical results in all cases. Hence the temptation to resort to registries, which cannot protect patients from wishful thinking, fashion and leaning curves19, is strong. Current indications for flow diversion may include: 1) Symptomatic large and giant cavernous carotid aneurysms (with very little risk of intracranial haemorrhage), previously treated with carotid occlusion, with or without bypass surgery. 2) Symptomatic or asymptomatic large or giant ophthalmic carotid and vertebral aneurysms (with a high risk of rupture), previously treated with coiling with or without stenting, sometimes coiling with parent vessel occlusion, sometimes with surgical clipping.

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3) Fusiform intradural lesions sometimes untreatable by other means, sometimes previously treated by parent vessel occlusion and surgical clipping. 4) Recurrent or persistent lesions after failed endovascular treatment or surgery, previously treated with new coil materials, stenting, clipping, sometimes parent vessel occlusion. 5) Patients that are judged nearly impossible to treat using other endovascular or surgical techniques

Potential complications associated with the use of flow diverters The greatest concern regarding FDs are the thrombo-embolic risks to the parent vessel, as well as to branches covered or „jailed‟ by the stent mesh. A recent registry reports 4% morbidity and 8% mortality with the use of these new devices20. These numbers will of course depend on the type of cases being recruited in the registries or trials, with a higher mortality and morbidity rate for complex and giant lesions21-23. Another recently recognized complication is the occurrence of aneurismal ruptures and intracranial haemorrhages days to months following FD of previously unruptured aneurysms (estimated in the range of 1-8%; 2nd ESMINT Congress, September 2010; Nice). Other reported or anticipated complications are the ones usually associated with all endovascular approaches, including access complications (thrombosis, haematomas, false aneurysms, infections) at the catheter entry site, vessel dissections or thrombosis during navigation, cerebral embolic complications with potential neurological deficits, transient or permanent, perforations with guidewires, branch occlusions, complications associated with the use of drugs, antiplatelet agents, contrast material, general anaesthesia. It is very difficult to draw conclusions for these numbers because series are so far small and collections of patients vary widely in severity of the aneurismal disease, natural history and risk and success of more conventional therapeutic options.

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Section 2: The Proposed Trial FIAT is a clinical care trial The purpose of the FIAT study is to provide a prudent, controlled clinical context for the use of flow diversion, a promising but yet to be proved beneficial treatment, in the care of patients with difficult intracranial aneurysms. Hence FIAT is a simple, multicenter, randomized trials integrated to daily practice. It addresses a true clinical dilemma, whether the use of FD truly offers a safe and more effective alternative to more conventional methods of treatment, including observation. Selection criteria are loose, to assist most current patients confronted with a difficult aneurysm suitable for FD. The trial does not obstruct clinical care, and does not include extra tests or risks beyond what is necessary and proven to be beneficial. Endpoints are simple, clinical, meaningful, valuable and resistant to bias. Follow-up visits and tests are “routine‟, imposing no extra burden on clinical transactions. Data is collected in simple case-report forms filled by physicians.

Design FIAT is a multicentric, randomized, pragmatic, clinical care trial comparing anatomical and clinical results of endovascular treatment with FDs with best standard treatment (BST) as judged by participating clinician. Patients with IAs in whom FD is considered an appropriate, if not the best but yet unproved therapeutic option, will be recruited. The trial includes a pilot and a pivotal phase, as well as a registry for eligible but non-randomized FD patients. The comparator treatment may include the most appropriate amongst surgical clipping, parent vessel occlusion, coiling, highporosity stenting with or without coiling, and conservative management, according to the clinical judgement of the treating physician. 344 patients with IAs judged to be treatable by FD will thus be enrolled and followed for one year. Patients that absolutely require FD treatment, or according to the clinical judgement of the physician responsible for the patient cannot be offered any other alternative (including conservative management) may also be recruited and will be analysed in the „registry‟ part of the study. Adjudication of angiographic results will be done by a

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committee in an independent core laboratory. Safety of trial subjects will be periodically assessed by an independent Data Safety and Monitoring Committee. The trial will be conducted in at least 10 centers, and will last for 5 years (4 years for recruitment and 1 year for follow-up).

Hypotheses Primary hypothesis Pilot and registry: For the pilot and registry phase, the primary hypothesis is that the FD procedure can be performed with an „acceptable‟ immediate complication rate. The acceptable immediate complication rate is defined as less than 15 % Morbidity and Mortality (M&M), with M&M defined as a modified Rankin Score (mRS) > 2 at 3 months. Two hundred patients (200) could suffice to show that, if the observed number of patients with mRS ≤ 2 is 10%, the 95% CI of the proportion is 7 to 14.9% (Newcomb method24).

Pivotal phase: For the pivotal phase, the primary hypothesis is that FD can increase the proportion of patients experiencing successful therapy, defined as complete or near complete occlusion of the aneurysm, in combination with a mRS ≤ 2 at 3 months posttreatment, from 75 to 90%. A number of patients of 112 in each group (not including losses) is sufficient to show an increase in success from 75% to 90%.

Interventions Treatment with flow diversion is to be evaluated against best standard treatment. The interventions are thus: A/ endovascular treatment with flow diversion, including standard management of thrombo-embolic risk Or B/ Best standard therapy, which may be any of the following:

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b1. Conservative management b2. Coiling with or without high porosity stenting b3. Parent vessel occlusion with or without bypass b4. Surgical clipping b5. Flow diversion itself when randomization between FD and BST is not possible and the only treatment alternative is FD for compassionate use. In this case, there will be no random allocation to intervention A/ or B/ and the patient will be entered into a registry. The aim of treatment is the complete angiographic exclusion of the aneurysm, or, as complete an exclusion from circulation as is possible while minimizing risks of the procedure. This goal is considered the standard of practice.

Selection criteria Inclusion criteria Any patient with a “difficult” intracranial aneurysm in whom FD is considered an appropriate if not the best but yet unproved therapeutic option by the participating clinician. Current indications may be (but not restricted to) symptomatic large or giant cavernous carotid, ophtalmic and vertebral aneurysms, fusiform intradural aneurysms, or recurring, persistent lesions after previous coiling. Aneurysm may be a recent rupture, although risks associated with antiplatelet regimens in this context should make this option rarely used. Exclusion criteria  Severe allergy, intolerance or bleeding disorder that prohibit the use of ASA or clopidogrel.

 Absolute contraindication to endovascular treatment or anesthesia.  Patients unable to give informed consent.

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Pre-Randomization and determination of the Best Standard Treatment option The patient’s aneurysm will be presented at the multidisciplinary meeting, as for any difficult aneurysm case. The various treatment modalities that could be used to treat the aneurysm will be reviewed, including observation, surgical clipping, parent vessel occlusion with or without surgical bypass, coiling with or without stenting, and flow diversion. If it is determined that flow diversion is a promising treatment option for that particular patient, the multidisciplinary team will discuss which standard therapeutic option is best for that particular patient, according to clinical judgment. The patient will be pre-randomized to flow diversion versus best standard treatment. The final treatment that will be allocated will be once more examined by the multidisciplinary team, to ensure it is considered appropriate care for that particular patient. The patient will then be informed of the decision of the multidisciplinary team, of the opinion that flow diversion is a promising option in this case, of the best standard treatment as determined by clinical judgment, and of the randomized allocation between these 2 options. The various options that were considered and the randomized nature of the final allocation will be disclosed, and the patient will be offered participation and asked to sign the consent form. If the patient refuses the allocated treatment, participation in the registry will be offered, and the patient asked to sign the consent form. Pre-randomization will use a minimization algorithm to ensure balance between groups with respect to the comparator intervention (i.e. type of BST selected by the multidisciplinary team).

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Choice of comparator intervention, technical freedom and treatment failures The goal of the treatment procedure is (as usual) to realize the most complete exclusion of the lesion that is judged to be possible, while keeping treatment-related risks as small as possible, whether using FD or not. At any time during the procedure the interventionist is permitted to use any device, technique or drug judged important to the safety and success of the endovascular or surgical procedure. In fact it is the physician’s responsibility to assure that the allocated procedure is conducted in the safest possible manner. The interventionist may switch to an alternative BST or switch to the alternative treatment group, if he has strong clinical reasons for judging that the one initially selected proves not to be in the best interest of the patient. In such cases, the operator details reasons on the endovascular procedure case report form. In case of primary treatment failure, any of the other options to ensure complete exclusion of the aneurysm may be carried out, depending on the judgment of the interventionist.

Type, frequency and duration of follow-up Clinical follow-up will be recorded at 24 hours, at discharge, at 1-3 months (according to standard of care or as required) and at 3-12 months (according to standard of care or as required; preferably including one visit close to 12 months). Clinical assessments will include evaluation according to the modified Rankin Scale at each follow-up. Follow-up CT-scan or MRI, if standard of care, could be performed at 24 hrs post-procedure or before discharge to detect silent periprocedural events. Adverse events will be recorded immediately after the procedure and during the 12month follow-up period. Follow-up angiography for treatment evaluation will be at 3-12 months (according to standard of care or as required; preferably including an evaluation close to 12 months). Catheter digital subtraction angiography (DSA) remains the gold standard to study residual lesions after coiling and stenting. In recent years, however, there has been a

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trend to rely on less sensitive but risk-free non-invasive imaging. Non-invasive imaging has become popular but the extent of metallic artefacts may not allow an appropriate assessment of results in some cases. Table 1: Schedule of Evaluation Evaluation

Entry

Informed consent

x

Documentation of Disease / disorder

x

Medical / treatment history

x

Clinical assessment

x

Neurological exam

x

Vascular imaging

x

3 - 12 m

x

x

x

x

x

x

Discharge

x

x**

x x*

Brain imaging mRS

1-3 m

Treatment

x

x

x

x

x* standard of care or clinical indication x** preferably close to 12 months

Outcomes Primary outcome Pilot phase: acceptable immediate complication rate for FD, defined as less than 15 % M&M, with M&M defined as mRS > 2. If the primary outcome is positive at the end of the pilot phase, the trial will proceed to the pivotal phase and already registered and randomized subjects will be added to newly randomized subjects in the pivotal phase

Pivotal phase: FD can increase success of therapy from 75% to 90%, with success defined as complete or near complete occlusion of the aneurysm combined with mRS ≤2.

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Secondary outcomes Secondary endpoint measures include: - mRS score at discharge, and at 3 and 12 months post-treatment (last observation carried forward) - Successful FD deployment / aneurysm clipping / aneurysm coiling, with patency of parent arteries at the end of the procedure, if appropriate - Peri-operative complications (ischemic strokes and intracranial hemorrhages) - Angiographic outcome (invasive or non-invasive imaging) results at 12 months (last observation carried forward) - Hospital stay (number of days) - Discharge disposition (home; other hospital; rehabilitation facility; death) - Any new stroke, neurological symptom or sign during follow-up - Re-treatment of the index aneurysm

Adverse events Adverse events will be recorded immediately after the procedure and during the 12month follow-up period. Severe adverse events (SAE), those that are life threatening, leading to hospitalizations or prolonged hospitalizations, as well as unexpected events will all be reported within 48 hours to the data coordination centre that will transmit the information to the Data Safety and Monitoring Committee. The number and severity of all reported adverse events will be recorded for each patient and for each treatment group.

Number of patients We expect to observe a rate of 10% clinically significant complications in the periprocedural period. In order to reach a 95% confidence interval that the estimate of the

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complication rate is less than 15%, we need to recruit 200 patients overall 24, that is in the randomized (counting only patients allocated to FD) and registry parts of the trial. To demonstrate an increase in the success rate of the intervention of 15% (from 75% to 90%), success defined as mRS ≤2 AND complete or near complete occlusion of the aneurysm at one year, we need to recruit 224 patients equally divided between FD and BST. Hence, the total number of patients may be as high as 344: 112 with FD from the RCT part; at least 88 more from the registry part to complete the safety analyses; 112 controls with BST; 32 (10%) added for losses at follow-up and cross-overs.

Recruitment rate and centres The targeted lesions are not frequent lesions, thus we expect less than 10 patients per year per center. We need to recruit at least 10 centers that will recruit 10 patients/year for 3 years to reach the necessary sample size. Because recruitment rates are usually less than expected, recruitment of 20 centers would be ideal. Centers will be experienced in endovascular treatment of aneurysms using both coiling (at least 100 patients will have been treated previously) and intracranial stenting (at least 10 patients previously treated).

Duration of the trial We plan a 3-year recruitment phase, followed by a follow-up period of 12 months for all patients. If we add a 6-month catch-up period, the trial should be completed within 5 years. Results will be available 6 months later to provide sufficient time for data analyses.

Planned analyses Descriptive statistics will be done on demographic variables and pre-operative and peri-operative data to compare the two groups at baseline.

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deviations and range will be presented for quantitative variables and frequency tables for categorical variables. Those statistics will be broken down by center and by treatment arm. Comparability of the groups will be assessed through independent ANOVAs (quantitative data) or Mantel-Haentzel and chi-square tests (categorical data). Assuming comparability of groups across centers, the primary outcome will be compared between groups through a z-test for independent proportions at 12 months. Secondary outcomes and safety data will be compared between groups through independent t-tests (quantitative variables) or chi-square statistics (categorical data). The analyses of neurological data at follow-up will control for baseline data when possible (for tests done before discharge and at follow-up) using logistic regression, ANCOVA or Cox regression multivariate models. Finally, a logistic regression will be used to find variables capable of predicting success in both groups at 12 months. The method planned is a stepwise forward with alpha < 0.05 to enter a predictor. Possible predictors include the type of the aneurysm (large aneurysms or recurrences), location, size of the aneurysm,, as well as other baseline characteristics.

Subgroups It will not be possible to reach statistical significant results for subgroups of patients or aneurysms. It is possible that treatment effect is affected by characteristics such as, for instance: location of the aneurysm, size of the aneurysm. These factors will be analyzed by introducing an interaction term in the logistic model. Predefined groups that will be analyzed separately include the ones corresponding to the minimization procedure (see above).

Safety monitoring All along the trial, the DSMC will verify recruitment rates, compliance to treatment group allocation, safety of the FD strategy, morbidity of treatment for the groups.

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Proposed review frequency will be when the following number of patients would have undergone their treatment procedure: 20 patients; 50 patients; 100 patients; 200 patients; 344 patients. The data will be reviewed and analyzed by the DSMC and recommendations will be forwarded to the Steering committee.

Protection against bias Classic biases such as selection bias or information bias will be dealt with by randomizing patients. Random allocation of treatment is best for insuring internal validity and is the best approach to control for confounding and selection bias. To control more carefully co-interventions that may differ from one centre to the other the minimization procedure will be used at the time of randomization (see above). Finally, control variables will be measured and compared between treatment groups in order to ensure group comparability (initial angiographic success, peri-procedural events, and disease characteristics).

Publication of research findings Publication of the results of this trial will be governed by the policies and procedures developed by the Steering Committee. Any presentation, abstract, or manuscript will be made available for review by the Steering Committee prior to submission.

Regulatory considerations The study will only start after approval by the Institutional Review Board/Institutional Ethics Committee (IRB/IEC) of each centre. The study will be performed in accordance with the national regulatory requirements of each participating centre. Participants will be fully aware of the study purposes, the procedure and the risks of each intervention. When signing the study consent form, they will be informed that participation is voluntary and they can request to be withdrawn from the study at any time. Patient enrolment in this trial will comply with the principles enunciated in this Declaration of

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Helsinki*. All the information collected with the questionnaires will be kept confidential and will be used on an anonymous basis.

* The Declaration of Helsinki (Document 17.C) is an official policy document of the World Medical Association, the global representative body for physicians. It was first adopted in 1964 (Helsinki, Finland) and revised in 1975 (Tokyo, Japan), 1983 (Venice, Italy), 1989 (Hong Kong), 1996 (Somerset-West, South Africa), 2000 (Edinburgh, Scotland), 2002 (Washington, USA)(Note of Clarification on paragraph 29 added), 2004 (Tokyo, Japan) (Note of Clarification on Paragraph 30 added) and 2008 (Seoul, Korea).

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Section 3: Trial Management Investigators Principal Investigator

Jean Raymond MD, Neuroradiologist, Montreal, Canada

Steering Committee To be determined

Data Safety and Monitoring Committee (DSMC) To be determined

Imaging Center (core lab) To be determined

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Day to day management The Steering Committee will be responsible for overseeing the administrative progress of the protocol. The Steering Committee will meet to monitor patient accrual, noncompliance with the protocol at individual centers, to act upon recommendations of the Data and Safety Monitoring Committee (DSMC). An independent Data Safety and Monitoring Committee (DSMC) will be led by a neurologist not involved in the conduct of the trial. He will be assisted by 2 members: an interventionist and a statistician. The DSMC will be notified of all SAE reported by the Clinical Adjudication Committee. Based on safety data, the DSMC may recommend that the Steering Committee modify or stop the trial. The Imaging Center (Core Lab) will determine the angiographic success of all procedures. The Coordinating Centre will be in Montreal (Centre de Recherche du CHUM, Hôpital Notre- Dame). Data management will be done using a Web-based application (Medscinet AB). The application is fully compliant with good clinical practice guidelines regarding electronic data transfer (US-FDA 21 CFR, part 11).

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9. Canton G, Levy DI, Lasheras JC, Nelson PK. Flow changes caused by the sequential placement of stents across the neck of sidewall cerebral aneurysms. J Neurosurg. Nov 2005;103(5):891-902. 10. Meyers PM, Schumacher HC, Tanji K, Higashida RT, Caplan LR. Use of stents to treat intracranial cerebrovascular disease. Annu Rev Med. 2007;58:107-122. 11. Darsaut T, Bouzeghrane F, Salazkin I, et al. The effects of stenting and endothelial denudation on aneurysm and branch occlusion in experimental aneurysm models. J Vasc Surg. Jun 2007;45(6):1228-1235. 12. Spelle L, Piotin M, Mounayer C, Moret J. Saccular intracranial aneurysms: endovascular treatment - devices, techniques and strategies, management of complications, results. Neuroimaging Clin N Am. Aug 2006;16(3):413-451, viii. 13. Piotin M, Blanc R, Spelle L, et al. Stent-assisted coiling of intracranial aneurysms: clinical and angiographic results in 216 consecutive aneurysms. Stroke. Jan;41(1):110-115. 14. Cognard C. For and Against Session: Does the use of stent for intracranial aneurysms coiling decrease the risk of long term recanalization? Presentation at the European Society of Minimally Invasive Neurological Therapy (ESMINT) First Congress, Sept 10-12, 2009; Nice, France 15. Lanzino G, Wakhloo AK, Fessler RD, Hartney ML, Guterman LR, Hopkins LN. Efficacy and current limitations of intravascular stents for intracranial internal carotid, vertebral, and basilar artery aneurysms. J Neurosurg. Oct 1999;91(4):538-546. 16. Benndorf G, Herbon U, Sollmann WP, Campi A. Treatment of a ruptured dissecting vertebral artery aneurysm with double stent placement: case report. AJNR Am J Neuroradiol. Nov-Dec 2001;22(10):1844-1848. 17. Doerfler A, Wanke I, Egelhof T, Stolke D, Forsting M. Double-stent method: therapeutic alternative for small wide-necked aneurysms. Technical note. J Neurosurg. Jan 2004;100(1):150-154. 18. Islak C, Kocer N, Albayram S, Kizilkilic O, Uzma O, Cokyuksel O. Bare stent-graft technique: a new method of endoluminal vascular reconstruction for the treatment of giant

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and fusiform aneurysms. AJNR Am J Neuroradiol. Oct 2002;23(9):1589-1595.Johnston SC, Gress DR, Kahn JG. Which unruptured cerebral aneurysms should be treated? A cost-utility analysis. Neurology. 1999;52:1806-1815. 19. Raymond J on behalf of the TEAM collaborative group. Reflections on the TEAM trial: Why clinical care and research should be reconciled. Submitted to CJNS. 20. Byrne JV, Beltechi R, Yarnold JA, Birks J, Kamran M. Early experience in the treatment of intra-cranial aneurysms by endovascular flow diversion: a multicentre prospective study. PLoS One. 2010 Sep 2;5(9). pii: e12492. 21. Lylyk P, Miranda C, Ceratto R, Ferrario A, Scrivano E, et al. Endovascular reconstruction of cerebral aneurysms with the pipeline embolization device: the Buenos Aires experience. Neurosurgery. 2009;64(4):632–42; discussion 642-3. 22. Fiorella D, Lylyk P, Szikora I, Kelly ME, Albuquerque FC, et al. Curative cerebrovascular reconstruction with the Pipeline embolization device: the emergence of definitive endovascular therapy for intracranial aneurysms. J NeuroInterv Surg. 2009;1:56–66. 23. Szikora I, Berentei Z, Kulcsar Z, Marosfoi M, Vajda ZS, et al. Treatment of intracranial aneurysms by functional reconstruction of the parent artery: The Budapest experience with the Pipeline embolization device. AJNR Am J Neuroradiol. 2010 Feb 11. 24. Newcombe RG, Two-sided confidence intervals for the single proportion: Comparison of seven methods. Statistics in Medicine 17: 857-872, 1998.

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