Revolution in Aneurysm Treatment (2014)

The safety profile of coil embolization has proven to be superior to standard surgical treatment for ruptured and unruptured intracranial aneurysms.1,2 Thus, endovascular treatment (EVT) has progressively replaced the latter.3 However, the occlusion rate of EVT is highly dependent on aneurysm morphology and location, coils used, and operator experience.4-7 Large, giant, and wide-neck aneurysms, fusiform and blister aneurysms, as well as aneurysms associated with segmental artery disease remain difficult to treat because of the significant risk of coil herniation from the aneurysm into the parent artery. Subtotal aneurysm occlusion and recanalization remains a challenge in 20% to 80% of cases because of coil compaction, migration of coils into the aneurysm thrombus, or aneurysm growth.6,8,9 Computational fluid dynamic (CFD) studies show that the complex interaction between parent artery and aneurysm hydrodynamics induces significant forces on the coil mass.10,11 These studies show that, besides higher coil-packing density, lower permeability of the coil mass at a given packing density could also promote fast intra-aneurysmal thrombosis due to increased blood residence time. To avoid (re)rupture, the goal of EVT remains a complete exclusion of the aneurysm from the circulation that entails complete endothelial coverage of the aneurysm neck while preserving side branches and perforators. Adjunctive techniques such as balloon-assisted EVT and intracranial stents have been introduced to enable coil embolization of giant and wide-neck aneurysms and to reduce recanalization.9,12-19 However, recanalization requiring re-treatment remains a challenge.20-22 In addition, a subset of aneurysms are neither amenable to EVT nor to safe surgical repair. More recently, flow-modifying meshlike tubular implants, also known as flow diverters (FDs), are being introduced into the clinical realm that create a substantial resistance to blood flow momentum exchange between parent artery and the aneurysm. PRELIMINARY OBSERVATIONS Preliminary studies in a canine side-wall venous pouch aneurysm model showed that the placement of stents within the parent artery led to blood flow reduction within the aneurysm pouch (Figure 1).23-27 Depending on the stent used, a stable clot formation was observed along with ultimate scarring of the aneurysm and remodeling of the parent vessel including endothelial growth at the aneurysm neck.FIGURE 1: Placement of a woven nitinol stent across a canine venous pouch side-wall aneurysm model. A, internal carotid artery (ICA) angiogram shows a wide-neck aneurysm with associated narrowing of the ICA due to surrounding scar tissue (arrow, Left). A typical flow pattern is seen within the aneurysm pouch (open arrow, Center). Follow-up angiogram after deployment of a stent across the aneurysm neck shows an incomplete aneurysm filling and change of inflow pattern (double arrow, Right); a reduction of previously seen narrowing is noted (curved arrow). B, ICA angiogram before stent placement. C, 6-month follow-up angiogram after stent placement shows lack of aneurysm filling. D, cross-section of venous pouch side-wall aneurysm without a device. E, cross-section through an aneurysm 6 months following a stent placement shows complete aneurysm thrombosis, remodeling of the artery, and endothelial coverage of the stent. Note surgical sutures between artery and vein (arrows). F, longitudinal section through the stented artery of a treated aneurysm shows endothelial coverage of the implant (curved arrow), scarring, and size reduction of aneurysm (arrow) (with permission from reference 24). Aneu, aneurysm; Art, artery.PRINCIPLE OF FLOW DIVERSION—IN VITRO AND IN VIVO FINDINGS The initial experience with stents in the cerebrovascular circulation was hampered by access to the tortuous cerebrovasculature with technology designed for the coronary circulation.28,29 However, improvements in plastics, catheter-coating materials, laser etching and cutting, as well as in fine wire braiding enabled a more aggressive approach to the brain. CFD as well as laser-induced fluorescence studies followed by particle imaging velocimetry were introduced to refine and optimize the properties of an endoluminal graft for optimal treatment of an aneurysm with preservation of perforators (Figures 2 and 3).30-33 These endoluminal scaffolds for vascular reconstruction are tubular low-porosity stent-like devices that we coined as FDs.34,35 Two major parameters were found to be important for the FD to be hydrodynamically effective: (1) porosity and (2) pore or mesh density of the implant.FIGURE 2: Laser-induced fluorescence (LIF) study in a simplified side-wall aneurysm model. Woven nitinol stents with various porosities (76%–85% metal free/metal area, Left column) have been placed across the aneurysm. The flow condition is similar to that found in the vertebral artery (VA, upper 4 rows) and the internal carotid artery (ICA, lower row). A decrease in stent porosity (from top row to bottom row) leads to increased accumulation of laser dye inside the aneurysm during systole (Center column), and diastole (Right column). However, at same stent porosity (76%, Lower panel), flow resumes within the aneurysm pouch under ICA as compared with VA flow conditions, indicating less effectiveness of the stent in a higher flow environment (with permission from reference 31).FIGURE 3: Particle imaging velocimetry (PIV) in a silicone replica of a rabbit elastase aneurysm model. A, shows direction and magnitude of flow in the aneurysm during the entire pulse cycle before (Upper) and after placement of a flow diverter (Lower). Note the change in flow magnitude and pattern. B, change in shear rate at distal and proximal aneurysm neck during the pulse cycle before and after placement of 2 different flow diverters (FDs). C, temporal evolution of intra-aneurysmal circulation before and after placement of FDs (with permission from reference 33).In vivo and in vitro hemodynamic experimental studies showed that fine tuning was required to balance the porosity (metal free/metal area) and pore or mesh density (number of pores/mm2) of the FD to optimize the effect on flow reduction within the aneurysm pouch while keeping the side branches (perforators) patent.35,36 The FD creates impedance to the flow at the neck of the aneurysm, thus reducing the hydrodynamic circulation and the peak and mean kinetic energy transferred from the parent artery into the aneurysm with each pulse cycle. As in vivo experimental studies showed, the flow reduction leads to progressive aneurysm thrombosis, scarring, and finally endothelialization of the FD and the aneurysm neck.36 However, to maintain a consistent effect on the flow exchange between the parent artery and the aneurysm, the increased vessel diameter with larger blood flow has to be taken into consideration. Thus, to maintain nearly consistent mesh density in various parent vessel diameters and to keep the optimal diamond shape of the pores consistent over various implant sizes, the number of wires had to be increased. In addition, the braid angle of the implant has to withstand any major deformity to maintain consistent mesh density across the neck, ie, minimized the “herniation” of the construct into the aneurysm that would alter the device structure and change the effect on flow diversion, as recently shown with some nitinol-based FD implants.37 This eliminates the potential risk of pockets of large openings or high metal density, especially in the aneurysm located in tight bends, and creating an inconsistent pattern of intra-aneurysmal flow and necessitating the use of multiple FDs. In vitro evaluation of FDs in a rabbit elastase aneurysm model showed that a progressive thrombosis of the aneurysm pouch occurs within the first 3 weeks with gradual transformation of the stable intra-aneurysmal clot to collagen, while the FD serves as a scaffold for endothelial growth (Figure 4).36,38 This enables an exclusion of the aneurysm sac from the circulation while a remodeling of the parent artery occurs around the implant. Vertebral arteries that were covered by the implant and served as surrogate for side branches remained patent.FIGURE 4: Histology of rabbit elastase aneurysms after the treatment with flow diverters at various time points. A, amorphous clot is found initially within the aneurysm pouch. Progressive replacement of clot by collagen starting at the aneurysm perimeter toward the neck and endothelialization of the flow diverter (FD). B, patency of the vertebral artery (VA) that is covered by FD implanted in the subclavian artery (SA) and serves as surrogate for side branches. C, Scanning Electron Microscopy (SEM) of the VA origin shows no endothelial coverage (adapted with permission from Lippincott Williams and Wilkins/Wolters Kluwer Health: reference 35).CLINICAL FINDINGS Introduction of FDs represents a paradigm shift in EVT from saccular treatment to parent artery reconstruction and preservation of vital para-aneurysmal perforating arteries (Figure 5). In a recently published randomized trial for difficult-to-treat intracranial aneurysms (PUFS: Pipeline for Uncoilable or Failed aneurySms), one currently existing FD (PED, Pipeline Embolization Device, EV3-MTI, Irvine, California) has shown improved durable-occlusion rates with an acceptable safety profile.39 Our initial clinical experience in a small group of 37 patients treated with the Surpass FD (Stryker Neurovascular, Fremont, California) reinforces the experimental findings.40 The use of a single FD could achieve a high rate of progressive aneurysm occlusion (>90% complete occlusion at 6 months) with an acceptable safety profile (3% risk of thromboembolic stroke, no mortality). Similar to our observations, the PUFS study confirmed the progressive nature of aneurysm occlusion; at 6 months, 73.6% of aneurysms were obliterated, and at 12 months, 86.8% were thrombosed. As in our experience, a high complete occlusion rate was observed in large or giant aneurysms. The use of a single device, especially in large aneurysms with adjacent perforators, may be preferred and eliminates the random distribution of wires across aneurysm neck and perforators, which potentially can be hazardous.41FIGURE 5: Placement of a FD across a small left middle cerebral artery aneurysm (arrow) involving lenticulostriate arteries. Left frontal ICA angiogram before (A), and after placement of a FD (B). C, 6-month follow-up angiogram shows a complete aneurysm occlusion and preservation of lenticulostriate arteries. D-F, contrast-enhanced cone-beam CT shows the relationship between the FD, the aneurysm, and the lenticulostriate arteries. ICA, internal carotid artery; FD, flow diverter.The goal of an appropriate FD vessel wall apposition is to prevent an endoleak and possibly incomplete aneurysm occlusion as seen in some of patients that have an underlying previous stent in the treated segment. Balloon dilatation following the FD placement can be performed with a compliant or supercompliant balloon and may augment device apposition. ANTIPLATELETS Similar to stent-assisted coil embolization, FDs require dual-antiplatelet treatment, and, thus, their use in acutely ruptured aneurysms may be limited. Recently, however, successful implantation of the PED has been reported in ruptured aneurysms.42 But, the periprocedural mortality and symptomatic morbidity was higher, with 15% as compared with treatment of nonruptured aneurysms. A proper titration of platelet inhibition remains a challenge, and, frequently, clinical resistance to clopidogrel or aspirin is associated with higher risk of thromboembolic complications as recently described for neurovascular stenting.43 In our own experience, perforator occlusion may be associated with a clinical clopidogrel resistance or inappropriate FD wall apposition. Other antiplatelet agents such as prasugrel (Effient) have been proposed for neurovascular interventions, but only limited experience exists. A recent study indicated a 2-fold increase in hemorrhagic complications for patients on prasugrel combined with aspirin undergoing neurointerventional EVT in comparison with a clopidogrel/aspirin group.44 PATIENT SELECTION AND ANGIOGRAPHIC OCCLUSION Currently, the PED is the only available FD in the United States, while several other products are in various stages of clinical investigational device exemption studies. When comparing with other FDs, the assessment of safety and occlusion rates remains challenging, because patient selection and trial design may affect outcome. In our own series with the Surpass FD, only 14% of 165 patients presented with extradural aneurysms; whereas, in the PUFS trial, a large subgroup had petrous and cavernous aneurysms (44.4%), and only 64 of 107 treated aneurysms were intradural.39,45 Thus, the risk of spontaneous aneurysm rupture until a complete aneurysm thrombosis may occur after FD during the observation period differs. Similarly, because multiple FDs were used in the PUFS trial (a median of 3) and in other reported series46-48 in comparison with our study (mean number of devices per aneurysm was 1.05), the time course of aneurysm obliteration with a single implant remains to be determined. Other areas where FD technology in selected cases may be helpful are challenging aneurysms of the middle cerebral artery bifurcation and anterior communicating artery (Figure 6). Multiple case reports and small series studies have shown that a variety of aneurysms with complex angiographic appearances (segmental disease, multiple adjacent aneurysms, and dissecting aneurysms) can be treated, although they may not reflect the same underlying disease or disease stage (Figure 7).40,49FIGURE 6: Placement of a FD for treatment of calcified right middle cerebral artery aneurysms (arrows) after failed attempted surgery. A, ICA 3-D angiogram before placement of a FD. B, 6-month follow-up angiogram shows obliteration of both MCA aneurysms and some narrowing of the anterior temporal branch and the anterior M2 division covered by the FD. Well-maintained antegrade flow in both branches and lenticulostriate arteries. ICA, internal carotid artery; FD, flow diverter; MCA, middle cerebral artery. (with courtesy of Dr. Joost de Vries, Nijmegen, The Netherlands).FIGURE 7: Treatment of a right wide-neck multilobed ophthalmic artery (OA) aneurysm with a FD. Three-dimensional (A) and an oblique view angiogram (B) show the extension of the aneurysm and its relationship to the OA. Note previously treated anterior communicating artery aneurysm (arrow). C, placement of a FD. D, 6-month follow-up angiogram shows a complete aneurysm occlusion and patency of the OA (curved arrow). (with courtesy of Dr. Anil Ghoklar, New Castle, UK).BLEEDING AND THROMBOEMBOLIC COMPLICATIONS With growing experience and patient selection over the past few years, several preclinical and clinical studies and case reports have demonstrated efficacy of the FD concept and reduction of periprocedural complications.42 Previously published studies and case series report a mortality and morbidity of as high as 6% and 9%, respectively.39,46,50-53 Morbidity and mortality with the Silk device are reported to be higher with up to 15% and 8%, respectively.48,54,55 Recently published meta-analyses on FD treatment in 1451 patients with 1654 aneurysms reported noticeable high procedure-related morbidity and mortality of 5% to 10% and 4%, respectively.56,57 The authors summarized an occurrence of postoperative subarachnoid hemorrhage (SAH), intraparenchymal hemorrhage (IPH), and perforator infarctions of 3% in each category. The rate of SAH, IPH, and ischemic stroke at ≤30 days was 3%, 3%, and 5%, respectively. SAH, IPH, and ischemic stroke at >30 days occurred in 2%, 2%, and 3% of treated cases, respectively. Treated aneurysms of the posterior circulation had a significantly higher incidence of perforator occlusions in comparison with implants located in the anterior circulation. Ischemic stroke was encountered in 6% of patients.56 Our results are comparable to other studies.45 Permanent neurological morbidity and mortality was seen in 3.7% and 1.5%, respectively, of the treated patients with anterior circulation aneurysms. Unlike with the PED and Silk, our experience with the Surpass FD in the posterior circulation has been encouraging. We observed neurological morbidity in 1 (3.7%) patient, and 4 (14.8%) patients died (2 of neurological events related to the implant, and the remaining 2 of other causes unrelated to the procedure or implant). Three of the latter patients harbored aneurysms that consumed the entire basilar trunk with extension in the posterior cerebral arteries or the vertebrobasilar junction. It seems that treatment of fusiform aneurysms involving the entire basilar trunk is problematic and may represent its own disease entity among posterior circulation aneurysms. Siddiqui et al58 reported, in 7 patients treated for large or giant fusiform vertebrobasilar aneurysms treated with the Silk or PED, a mortality in 4 patients, and 3 patients were left with a severe disability following the procedure. Our favorable results may be related to the use of a single long Surpass implant in comparison with the need of telescoping PEDs with potential risk of perforator occlusion. Parenchymal hemorrhage not related to aneurysm rupture has infrequently been described. The etiology of these delayed ipsilateral bleedings remains unclear and does not correlate with the size of the aneurysm or location. Most likely, it may represent thromboembolic ischemic infarction with secondary conversion into hemorrhagic stroke. In a recently published report on PED, the incidence of parenchymal hemorrhage was 8.5%.42 Similar phenomena are seen with other neurovascular interventions. In a larger series, intracranial hemorrhage was observed in 4 of 474 patients treated with carotid artery stenting.59 The use of dual-antiplatelet agents may also increase the risk of hemorrhage. The MATCH trial showed that the use of aspirin in conjunction with clopidogrel significantly increased major bleedings in patients with acute ischemia or transient ischemic attack in comparison with clopidogrel alone (2.6% vs 1.3%).60,61 Thus, some of the patients treated with FDs may harbor underlying small vessel disease, and an effort should be made to screen them by using magnetic resonance imaging (MRI). Another feared complication is an acute or delayed aneurysm rupture after the placement of a FD. Bleeding from dissecting aneurysms after treatment has been described previously with stent-assisted coil embolization as well.62 Acute and delayed aneurysm bleeds have been extensively addressed in the literature after placement of PED and Silk and are observed in 1% of the patients, generally having aneurysms of >10 mm.39,63-66 The etiology remains unclear. Potential mechanisms include changes in parent artery/aneurysm complex hemodynamics, dysfunction of autoregulation, perforator occlusion, intra-aneurysmal clot formation with the breakdown of vessel wall ultrastructure associated with the upregulation of inflammation in conjunction with dual-antiplatelet therapy, and an iatrogenic effect.63,65,66 While hemodynamic changes leading to delayed and inflammation of an aneurysm wall to delayed is Another for delayed aneurysm may be the use of dual-antiplatelet agents that prevent aneurysm thrombosis, and the observed rupture rate represents the course of an large aneurysm. To prevent rupture after FD several the use of a few coils placed with the aneurysm and therapy, especially in large and giant aneurysms. larger studies are available to the reduction of rupture risk for a combined occlusion remains but has been described and may from thromboembolic occlusion by the FD. These may reflect to antiplatelet treatment or an endothelial a platelet A delayed occlusion of the FD mesh may occur from especially an inappropriate wall apposition has been that may create delayed clot formation at the This the need for a long or As with stent-assisted coil embolization, a delayed significant implant has been described with PED in of the treated a device thrombosis may as recently observed in a case of a vertebral artery aneurysm treated with PEDs at more 1 and may be related to the use of a large number of telescoping Multiple devices could prevent proper and complete The of with implants has to be for the neurovascular This not only to reduce perforator occlusions and thromboembolic but also spontaneous parenchymal hemorrhage and potential from treated aneurysms. through in vitro and in vivo experimental the concept of flow is its into the clinical realm of intracranial aneurysm Preliminary acceptable safety and high efficacy of FDs for a of intracranial aneurysms of the anterior and posterior circulation without the need for and with the use of a single implant. and high rate of progressive occlusion and a of aneurysms observed are but require follow-up studies. antiplatelet treatment to prevent periprocedural and delayed thromboembolic events and parenchymal hemorrhage. The treatment of a subset of fusiform aneurysms the entire basilar artery remains difficult to the risk of perforator occlusion. and are for and from of the presented summarized from of New at