Flow Diversion for the Treatment of Intracranial Aneurysms

The concept of flow diversion seems intuitive for the treatment of vascular disease. Flow diversion is stenting in a way that truly reconstructs the parent vessel, encouraging flow within the true vessel lumen and restricting it from surrounding pathology. This technique is possible because of the tightly braided nature of flow-diverting stents (30%-35% metal surface area coverage). When they are used to treat intracranial aneurysms, flow-diverting stents promote endothelialization and reconstruction of the diseased parent vessel while also promoting aneurysm thrombosis via intra-aneurysmal flow stagnation. Aneurysm occlusion occurs progressively over time with occlusion rates of 95% at 1 year with the Pipeline Embolization Device (PED; ev3/Covidien, Irvine, California) for flow diversion.1 Currently, the PED is the only flow-diverting stent approved by the US Food and Drug Administration for the treatment of intracranial aneurysms. Additional flow-diverting stents (ie, Silk [Balt Extrusion, Montmorency, France], Flow Redirection Endoluminal Device [FRED; MicroVention, Tustin, California], and Surpass [Cersys, Inc, a subsidiary of Surpass Medical Ltd, Miramar, Florida; now Stryker Neurovascular, Fremont, California]) are approved in Europe and undergoing clinical trials in the United States. The PED is approved by the US Food and Drug Administration for the endovascular treatment of adults (≥22 years of age) with large or giant wide-necked aneurysms of the internal carotid artery (ICA) from the petrous to the superior hypophyseal segments (Figure 1). Flow diversion technology has revolutionized the treatment of vascular disease in this region. For example, open surgical treatment typically includes extensive skull base approaches, including trapping and high-flow bypass, that are often associated with long operative times and high morbidity.2-6FIGURE 1: Example of a US Food and Drug Administration-approved indication for Pipeline Embolization Device (PED) treatment. A, anteroposterior projection of the early arterial phase of a digital subtraction cerebral angiogram demonstrating a large right cavernous internal carotid artery aneurysm. B, there is contrast material (and blood flow) stasis within the aneurysm (arrow) immediately after deployment of the PED. C, follow-up angiogram performed at 6 months demonstrates complete aneurysm occlusion.The Pipeline for Uncoilable or Failed Aneurysms (PUFS) trial was a multicenter, prospective study evaluating the efficacy of the PED for the treatment of large (at least 10 mm in diameter) and wide-necked (at least 4 mm) aneurysms in the approved segments of the ICA.7 At the 1-year follow-up, complete occlusion was observed in 79 of 81 (86.8%) treated aneurysms. The primary safety end point (major ipsilateral stroke or neurological death) was observed in 6 of 107 patients (5.6%). Similarly, Lylyk et al1 demonstrated complete occlusion of 95% of large and giant, nonsaccular, and recurrent aneurysms at 1 year with no aneurysm recurrences or major complications. Most recently, Kallmes et al8 retrospectively reviewed 906 cases of aneurysms treated with the PED at 17 institutions worldwide. Overall, neurological morbidity was 7.0% for anterior circulation aneurysms. Together, the aforementioned studies have demonstrated a higher rate of complete occlusion and slightly lower rate of adverse events than traditional endovascular techniques (eg, coiling, stent-assisted coiling) for the treatment of aneurysms in this location.9-13 A direct comparison of flow diversion and traditional endovascular strategies is ongoing in the multicenter, prospective Flow Diverter Stent for Endovascular Treatment of Unruptured Saccular Wide-necked Intracranial Aneurysms (EVIDENCE) trial. The growing implementation of flow diversion technology for the treatment of intracranial aneurysms also has prompted evaluation of previously established treatment paradigms. Traditionally, the treatment of cavernous ICA aneurysms was reserved for those that were symptomatic or had grown to the point of protruding into the subarachnoid space, thereby subjecting the patient to the risk of subarachnoid hemorrhage (SAH).14,15 This paradigm was based on the significant morbidity associated with traditional treatment strategies and the consequent unfavorable risk-benefit ratio. However, recent literature has suggested this treatment paradigm be revisited because of the low morbidity associated with flow diversion for these aneurysms. Zanaty et al16 reported their experience comparing flow diversion with traditional endovascular techniques for the treatment of cavernous ICA aneurysms. Multivariate analysis revealed treatment other than PED to be a predictor of no symptom improvement and need for retreatment. Furthermore, in their meta-analysis, Tanweer et al17 found a major morbidity rate of 4.1% for flow diversion treatment of cavernous ICA aneurysms. EXPANDING INDICATIONS Ruptured Aneurysms Many opponents of flow diversion cite the need for dual antiplatelet therapy as a prohibitive factor for its use in the setting of acute SAH. Furthermore, the fact that aneurysm thrombosis with flow-diverting stents occurs progressively over time may subject the patient to potential aneurysm rerupture. However, recent studies have demonstrated the use of flow-diverting stents to be safe even in this setting. Lin et al18 recently reviewed the use of the PED for the treatment of ruptured intracranial aneurysms at multiple US centers. Because of the widespread reluctance to administer the required dual antiplatelet therapy in the setting of acute SAH, only 26 patients were identified among 5 US centers between 2011 and 2013. Yet, hemorrhagic complications occurred in only 2 patients: 1 patient experienced rehemorrhage from the target aneurysm (occurring within 30 days), and another patient experienced asymptomatic ventriculostomy tract hemorrhage. Complete aneurysm occlusion occurred in 18 patients (69.2%); however, this was at a mean follow-up of only 5.9 months. Good neurological outcome (modified Rankin scale scores of 0-2) occurred in 20 patients (76.9%). Similarly, Cruz et al19 reported results for 20 patients with aneurysmal SAH treated with the PED at 4 Canadian sites. One hemorrhagic complication (intraparenchymal hemorrhage) was observed. Complete aneurysm occlusion occurred in 94% of patients at the 1-year follow-up. Good neurological outcome (Glasgow Outcome Scale scores of 4-5) was observed in 15 patients (75%). Most recently, Chalouhi et al20 reported their experience with 20 patients with aneurysmal SAH treated with the PED. Only 1 complication occurred, which was associated with intraoperative aneurysm rupture during adjunctive coiling. Complete occlusion was observed in 80% at a mean follow-up of 5.3 months. Ruptured blister aneurysms present a unique treatment challenge. Again, microsurgical options include trapping and high-flow bypass, which may be especially difficult in the setting of acute SAH because the brain is edematous and the blood vessels are affected by vasospasm. Because of the broad, expansive nature of these aneurysms, traditional endovascular techniques (eg, coiling and stent-assisted coiling) are often unsuccessful. Therefore, flow diversion is an attractive treatment strategy. Cinar et al21 described the successful treatment of ruptured blister carotid artery aneurysms using the PED. Their patients experienced no hemorrhagic or thromboembolic complications and reliable aneurysm occlusion. Similarly, Yoon et al22 demonstrated favorable clinical results in patients who survived their acute hemorrhage. Complete aneurysm occlusion was observed in 88% of their patients. These data demonstrate that the use of PED in the setting of acute aneurysmal SAH is feasible and safe, particularly when traditional endovascular techniques are suboptimal. Given that many of these studies included only early angiographic follow-up, additional follow-up is needed to assess the progression and durability of aneurysm occlusion in these patients. Beyond the ICA Restriction of approved indications for the PED to the ICA is founded on the ease of catheterization and relatively large caliber of the vessel. Most concern surrounding the application of flow-diverting stents distal to this location is associated with the risk for thrombosis in smaller-caliber vessels and the potential for perforating vessel occlusion as a result of the high metal surface area and progressive endothelialization process. Although still few in number, studies designed specifically to assess the application of flow diversion, including the PED, to vessels beyond the ICA have been published in recent years (Table23-25).TABLE: Summary of Studies Evaluating the Use of Flow Diversion Beyond the Circle of WillisaPistocchi et al24 treated 30 aneurysms with flow diversion and observed transient or reversible neurological complications in 7.4%. They observed 1 permanent neurological complication (right middle cerebral artery [MCA] infarction) that occurred as a result of in-stent thrombosis of a PED placed for a large, recurrent MCA aneurysm. No mortality was experienced in their series. At a mean follow-up of 13 months, aneurysm occlusion was seen in 82.6% of patients. Similarly, Martinez-Galdamez et al23 recently described their experience with using a PED to treat cerebral aneurysms “at the level of the circle of Willis and beyond.” Most treated aneurysms in their 25 patients were located in the MCA. They encountered 2 transient minor adverse events (8%), 1 major adverse event (4%), and no mortalities (0%). Both of these studies included several patients with fusiform or dissecting aneurysms of the MCA. Open surgical treatment of these aneurysms would require extensive clip reconstruction, trapping, and/or resection of the aneurysm with or without subsequent high-flow bypass.26 The morbidity and mortality of these techniques are not insignificant. Kivipelto et al27 reported a 21% rate of permanent morbidity and a 4% mortality rate in patients with these aneurysms who were treated with parent artery sacrifice and bypass. Similarly, Kalani et al28 reported an 18.8% rate of cerebrovascular accident. Even in uncomplicated cases, the average length of stay was 11.7 days in the series reported by Kalani et al. This is in stark contrast to the 1- to 2-day length of stay typically observed at our institution after aneurysm treatment with flow-diverting stents. The aforementioned PED studies demonstrate that the use of flow diversion at the level of the circle of Willis and beyond is a safe, technically feasible, and effective means of aneurysm treatment. However, it is important to note that the use of flow diversion in these locations is a relatively recent expansion of its use and is an unapproved indication (Figure 2). Therefore, additional long-term data are needed to assess stent patency and clinical outcome over time.FIGURE 2: Example of Pipeline Embolization Device (PED) placement beyond the circle of Willis. A, oblique anteroposterior projection of the arterial phase of a digital subtraction cerebral angiogram demonstrating a fusiform aneurysm of the distal right M1. B, follow-up angiogram performed at 3 months after PED treatment demonstrates good parent vessel reconstruction.Posterior Circulation The investigators of the International Study of Unruptured Intracranial Aneurysms (ISUIA) reported an increased risk of rupture for posterior circulation aneurysms (2.5% for aneurysms <7 mm, 14.5% for aneurysms 7-12 mm, 18.4% for aneurysms 13-24 mm) compared with those in the anterior circulation.29 Additionally, aneurysm location in the posterior circulation was a predictor of poor surgical outcome. However, similar to complex aneurysms in the anterior circulation, posterior circulation fusiform aneurysms and vertebrobasilar dolichoectasia require extensive skull base surgical approaches with parent vessel sacrifice and high-flow bypass. Flow-diverting stents provide a less invasive and perhaps less morbid approach to the treatment of these formidable lesions. However, the concern about the use of flow diversion in the posterior circulation is focused mainly on the risk of basilar perforating artery occlusion. Given that these arteries serve critical brainstem regions, their occlusion could be devastating. Indeed, our early experience with flow diversion for the treatment of vertebrobasilar dolichoectasia was associated with substantial morbidity.30 However, these suboptimal results may have been due in large part to the poor clinical state of these patients at presentation. Subsequently, Chalouhi et al31 reported 7 patients treated with PED for posterior circulation aneurysms (3 fusiform, 4 saccular). No morbidity or mortality occurred over a mean follow-up of 5.5 months. Munich et al32 demonstrated the safety and efficacy of flow diversion for the treatment of vertebrobasilar dolichoectasia. No patient in either of these 2 studies experienced postoperative clinical or radiological evidence of basilar perforator occlusion or brainstem infarction. Phillips et al33 also reported their experience with using a PED for the treatment of 32 posterior circulation aneurysms. Aneurysm occlusion was seen in 96% of patients with >1 year of follow-up. Permanent neurological morbidity was observed in 9.4%. In their review of the literature, Toth et al34 identified >100 patients who underwent flow diversion treatment of posterior circulation aneurysms, finding that good neurological outcome (modified Rankin scale score, 0-2) occurred in 71% to 100% (with the exception of 1 study in which only 28.6% had a modified Rankin scale score of 0-2). The treatment of posterior circulation aneurysms remains challenging, whether open microsurgical, traditional endovascular, or flow-diverting endovascular techniques are used. These challenges result mainly from the territory supplied by these vessels and the unforgiving nature for any deviation from pristine surgical technique and perioperative care. In cases of flow diversion in the posterior circulation, strict attention to antiplatelet administration and location of PED placement may be particularly important.32 However, taken together, these studies demonstrate that the use of a PED in the posterior circulation is technically feasible and relatively safe. OTHER FLOW-DIVERTING DEVICES As previously mentioned, additional flow-diverting stents are currently under study. The Silk stent is a Conformité Européene--approved self-expanding stent made of woven nitinol strands and platinum microfilament. Similar to the PED, it has low porosity and high metal surface area coverage (35%). Wagner et al35 reported their experience in treating 26 wide-necked or blister-like aneurysms with the Silk stent. They observed an 86% occlusion rate at the 1-year follow-up. Velioglu et al36 reported 87.8% of 82 aneurysms with complete occlusion and observed in-stent stenosis in 5.6% and parent artery occlusion in 4.2%. The Multicenter Randomized Trial on Selective Endovascular Aneurysm Occlusion With Coils vs Parent Vessel Reconstruction Using the Silk Flow Diverter is currently ongoing. The FRED flow diversion system is a uniquely designed stent within a stent. It consists of a low-porosity/high-metal-coverage inner stent within a high-porosity outer stent that has higher radial force. Initial experience with this stent resulted in 100% aneurysm occlusion.37 A phase 2/3 trial (Pivotal Study of the FRED Stent System in the Treatment of Intracranial Aneurysms) is currently underway. The Surpass NeuroEndoGraft system is a self-expandable braided cobalt, chromium, nickel, and platinum low-porosity mesh stent. The stent contains interwoven platinum-tungsten wires designed to aid in visualization during deployment. The initial 10-patient experience in the Netherlands demonstrated a 98.75% aneurysm occlusion rate at the 6-month follow-up; 2 patients experienced transient ischemic attacks.38 The Surpass Intracranial Aneurysm Embolization System Pivotal Trial to Treat Large or Giant Wide Neck Aneurysms (SCENT) is designed to assess the safety and efficacy of the Surpass flow diverter and is currently enrolling subjects. LIMITATIONS Although flow diversion has been an important advancement, it should not be considered a panacea for intracranial aneurysms. The application of this technique requires treatment with dual antiplatelet therapy, which may be a prohibitive factor in patients with underlying hematological disease or a history of serious hemorrhage. Given its relative infancy compared with other endovascular (and open microsurgical) techniques, there remains a paucity of very long-term follow-up data (eg, decades). Therefore, continued follow-up with both noninvasive imaging and traditional angiography may be necessary. Reliable treatment of bifurcation aneurysms also remains elusive to current flow-diverting technology. The increased metal surface coverage with a resultant decease in the size of stent tines prohibits the use of these devices in a Y configuration, which may be necessary for aneurysms in this location. As with most surgical and endovascular techniques, a learning curve exists for practitioners using flow diversion. Because of the nuances in the delivery of the device,39 this curve may be steeper compared with traditional endovascular techniques for aneurysm embolization. Jabbour et al40 reported a dramatic decrease in the rate of complications and procedural time in conjunction with increasing physician experience. Complications early in the practitioners' use of flow-diverting stents may not be representative of the device or its location of use. Therefore, early supervision and regular use of the device may be particularly important for practitioners using flow diversion. CONCLUSION Flow diversion technology has expanded the scope of aneurysms that can be successfully treated by endovascular means. Fusiform and wide-necked aneurysms may no longer be allocated unconditionally to extensive microsurgical vessel reconstruction. Treatment of aneurysms of the carotid siphon may no longer require extensive skull base drilling and exposure of the cavernous sinus. Expanding indications for the PED have demonstrated the safety and efficacy of the use of flow diversion in the posterior circulation, beyond the circle of Willis, and in the setting of acute SAH. With continued physician experience and long-term follow-up of aneurysms treated with flow diversion, we can expect improvements in results and techniques, which will ultimately improve the care of patients with intracranial aneurysms. Disclosures Dr Levy has shareholder/ownership interests in Intratech Medical Ltd., Blockade Medical LLC. and Medina Medical. He serves as a principal investigator for the Covidien US SWIFT PRIME Trials and receives honoraria for training and lecturing from that company. He receives compensation from Abbott for carotid training for physicians. He serves as a consultant to Pulsar, Medina Medical, and Blockade Medical. The other authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Acknowledgment We thank Paul H. Dressel, BFA, for preparation of the illustrations and Debra J. Zimmer for editorial assistance.