Endovascular Therapies for Cerebral Revascularization

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20 Endovascular Therapies for Cerebral Revascularization

C. Benjamin Newman, Yin Hu, Cameron G. McDougall, Felipe C. Albuquerque

Introduction

Stroke is the third leading cause of death in the United States and the second leading cause of death worldwide. The AHA estimates that the direct and indirect costs of stroke in the United States in 2009 at $69.9 billion.¹ Stroke has been recognized as a clinical entity for millennia, dating at least to ancient Greece. Hippocrates first described and documented the syndrome of stroke, which he called “apoplexy” (from the Greek apoplēssein, to strike down and incapacitate). Prior to the advent and widespread accessibility of high-resolution cross-sectional imaging, neurologists and neurosurgeons could only establish the location of strokes on the basis of clinicopathological correlation. Little was known about the pathophysiology of stroke for much of the 20th century, with in situ thrombosis being the presumed etiology for most ischemic strokes.² The recognition of thromboembolic phenomena to the brain originating from the carotid artery and the description of lacunar syndromes allowed the development of strategies for stroke prevention.^3,⁴ However, therapies for acute stroke were not developed until the latter part of the 20th century.

Initial attempts to use systemic thrombolytic agents were complicated by the propensity of ischemic brain tissue to hemorrhage. Uncertainty about the optimal doses of thrombolytic medications, the window of time for intervention, and the identification of patients at high risk of developing complications from treatment proved challenging in developing safe and effective treatments for acute stroke.

The first three trials evaluating the use of intravenous streptokinase for the treatment of acute stroke were terminated prematurely due to an increase in mortality rate, primarily related to the hemorrhagic conversion of ischemic infarcts.^5,⁶ The European Cooperative Acute Stroke Study (ECASS),⁷ which tested recombinant tissue plasminogen activator (r-tPA) at a dose of 1.1 mg/kg, demonstrated no overall benefit to the use of intravenous (IV) r-tPA for the treatment of acute stroke. Subgroup analysis, however, revealed significant improvement after IV t-PA administration in patients with moderate to severe stroke without extended signs of infarction on CT. This study showed the therapeutic potential for thrombolytic agents in the treatment of acute stroke while underscoring the need to refine indications and contraindications for therapy.

The first trial to demonstrate significant clinical benefit for intravenous r-tPA with an acceptable risk of intracranial hemorrhage was the National Institute of Neurological Diseases and Stroke (NINDS) study.⁸ The NINDS study used a lower dose of intravenous r-tPA (0.9 mg/kg), which was administered within 3 hours of stroke onset. The results of the NINDS study led to the approval of intravenous r-tPA by the United States Food and Drug Administration (FDA) for use in acute stroke within 3 hours of onset of stroke symptoms. The safety and efficacy of the 3-hour therapeutic window was confirmed by the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) trial.⁹ The ATLANTIS trial also failed to demonstrate benefit to patients who received r-tPA in a 3- to 5-hour window.

Numerous studies have subsequently demonstrated the efficacy of intravenous r-tPA when given within the 3-hour window.¹⁰^–¹² Although the use of IV r-tPA was initially controversial, it has now been endorsed as class IA level of evidence by the major national guidelines development organizations.¹³ Pooled results from the six major randomized, placebo-controlled IV r-tPA stroke trials^8,^9,¹⁴ (ATLANTIS I & II, ECASS I & II, and NINDS I & II) included 2775 patients who were treated with IV r-tPA or a placebo. Treatment up to 3 hours after symptom onset benefitted patients, and findings suggested a benefit in treatment beyond 3 hours in certain subsets of patients. The ECASS III trial demonstrated the benefit of IV r-tPA in the 3.5- to 4-hour window in a more select group of patients.¹⁵

Recanalization rates, which are related to the diameter of the affected vessel, range from 20% for the ICA to 50% for occlusion of a distal branch of the MCA.¹⁶ Ischemic stroke related to large vessel (i.e., >2 mm) occlusion carries a high risk of mortality (53% to 92%) and severe morbidity.^17,¹⁸ The presence of a hyperdense MCA sign on CT in the presence of a moderate stroke (National Institute of Health Stroke Scale [NIHSS] stroke score of >10) portends a less favorable therapeutic outcome with IV r-tPA. This finding suggests that large proximal clots are resistant to IV r-tPA.¹⁹ Endovascular therapies for acute stroke, particularly those related to large vessel occlusion, may overcome some limitations of systemic thrombolysis by providing superior recanalization rates in large vessel occlusions, reducing the incidence of intracranial hemorrhage, and expanding the therapeutic window.

Recanalization strategies

Recanalization aims to restore antegrade blood flow by removing or dissolving occlusive thrombus, thereby allowing reperfusion of the ischemic penumbra, the functionally impaired but still viable brain tissue. Endovascular techniques for recanalization include mechanical thrombectomy, chemical thrombolysis, stenting (either temporary or permanent), or a combination thereof (Figure 20–1).

Figure 20–1 Posteroanterior projection of left internal carotid artery (ICA) injection before (A) and after (B) mechanical thrombectomy and direct intra-arterial infusion of plasminogen activator. The previously occluded M2 branch opacifies, indicating restoration of blood flow.

(Used with permission from Barrow Neurological Institute.)

The rationale for restoring antegrade flow as rapidly as possible after stroke is intuitive. The aphorism “time is brain” accurately reflects the ephemeral nature of the ischemic penumbra and underscores the importance of rapid restoration of blood flow. The ultimate outcome of stroke is not solely dependent on the time of occlusion of the target vessel. It also depends on a number of factors and their complex degree of interactions. These factors include the site of arterial occlusion, the extent of the core of infarction, the size of the ischemic penumbra, the quality and quantity of collateral arterial supply, and the integrity of the blood-brain barrier (BBB). However, on an epidemiological level, a number of studies have documented the correlation between radiographic recanalization and improved clinical outcome as well as the critical role of rapid restoration of flow.²⁰

Intracranial hemorrhage (ICH) remains the most common and dangerous complication of recanalization. Most postrecanalization ICH occurs within the core of infarcted brain tissue, suggesting that ischemia and disruption of the BBB play a major role in its pathogenesis.

Intra-Arterial Thrombolysis

Intra-arterial recanalization is occasionally used as a primary treatment modality in patients in whom IV r-tPA is contraindicated or patients who fail to demonstrate clinical improvement after administration of IV r-tPA. Primary intra-arterial thrombolysis can benefit clinical outcomes of patients who receive treatment 3 to 6 hours after symptom onset.^21,²² Compared to systemic IV thrombolysis, intra-arterial thrombolysis offers several theoretical advantages. Coaxial microcatheter techniques allow superselective access to the occluded vessel, thereby allowing infusion of thrombolytic agents directly into the thrombus. By infusing thrombolytic agents directly at the site of the thrombus, a smaller dose of fibrinolytic agent can result in more complete recanalization compared to systemic administration. Theoretically, rates of complications from systemic fibrinolysis such as ICH should be reduced.

The first generation of fibrinolytic agents consists of plasminogen activators. These drugs work by converting an inactive proenzyme, plasminogen, into the active form, plasmin. Plasmin degrades fibrinogen and fibrin (monomers and cross-linked) leading to clot dissolution. The plasminogen activators vary in terms of their stability and selectivity for fibrin. Urokinase and streptokinase are nonfibrin-selective agents and carry the risk of systemic hypofibrinogenemia. These drugs have a narrow therapeutic window and are no longer routinely used for intra-arterial thrombolysis since thrombolytic agents with higher selectivity for fibrin were adopted.

Alteplase (r-tPA) is a glycoprotein serine protease produced by recombinant DNA technology. It has a higher affinity and selectivity for fibrin than urokinase and streptokinase, and its use is associated with a lower rate of systemic complications than the first-generation plasminogen activators. Drawbacks to r-tPA include reduced clot penetration due to its high affinity for surface fibrin and its short half-life. Investigational trials are underway to evaluate the clinical utility of modified plasminogen activators (Reteplase, Tenecteplase, Desmoteplase) and direct fibrinolytics (Ancrod, Microplasmin, Alfimeprase) for use in intra-arterial thrombolysis.

Intra-Arterial Thrombolysis Technical Comments

Intra-arterial thrombolysis is rarely used as monotherapy for acute stroke at our institution. In general, if a patient is a candidate for an invasive stroke therapy, intra-arterial thrombosis may be employed as an adjunct to mechanical thrombolysis. The decision to use plasminogen activators is largely subjective, but the interventionalist must consider the likelihood of potentiating a hemorrhagic conversion of the infarcted brain parenchyma.

Transfemoral arterial access followed by guide catheter placement into the parent brachiocephalic artery of the target vessel is the most common approach to gain access to the lesion. Superselective microcatheter placement using standard digital subtraction roadmapping and over-the-wire navigation is then employed to position the microcatheter near the thrombus.

If used, the dose of r-tPA is low, on the order of 3 to 10 mg, and can be infused through the guide catheter or microcatheter. Abciximab is occasionally used, typically in the setting of stent placement or hyperacute thrombosis (i.e., recognition of an intraprocedural thrombotic branch occlusion or acute in-stent thrombosis).

Mechanical Thrombectomy

Ischemic stroke involving large vessel occlusions is especially morbid, and a good neurological outcome from such an event depends on rapid recanalization. The observation that clots in large intracranial vessels is relatively resistant to dissolution from intravenous plasminogen activators provides the rationale for developing endovascular techniques for revascularization. All mechanical thrombectomy devices are delivered by endovascular access and approach the lesion from the proximal/antegrade direction. The Food and Drug Administration (FDA) has approved two mechanical thrombectomy devices for the treatment of acute stroke: the Merci Retrieval System (Concentric Medical, Inc., Mountain View, CA) and the Penumbra System (PS; Penumbra, Alameda, CA). Both devices are approved for use within 8 hours of the onset of symptoms.

All patients qualified for endovascular thrombolysis are treated under general anesthesia at our institution. The use of general anesthesia in acute stroke is not universal; however, our experience suggests that the elimination of patient movement afforded by general anesthesia reduces the technical difficulty of the procedure and ultimately is safer for the patient. Transfemoral arterial access is typically employed; however, the access site selected is ultimately guided by the most favorable guide catheter stabilization needed for treatment. A baseline activating clotting time (ACT) is obtained, and the patient is heparinized to achieve an ACT between 250 to 300 seconds after arterial access is obtained.

Merci Retrieval System

The Merci Retrieval System was approved by the FDA in 2004 for the treatment of acute stroke due to thromboembolic occlusion of the intracranial vertebral artery, basilar artery, intracranial ICA, or M1 division of the MCA. The Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial was a prospective, nonrandomized, single-arm, multicenter trial that investigated the use of a novel mechanical thrombectomy device in patients with occluded large intracranial vessels within 8 hours of the onset of stroke symptoms.²³ The primary endpoint of the trial was radiographic recanalization of the target vessel with a low rate of serious adverse events. The trial enrolled 151 patients and demonstrated recanalization rates of 48% with a complication rate of 7.1%. Morbidity and mortality rates were lower in patients who demonstrated radiographic recanalization.

The Merci Retrieval System consists of the Merci Retriever, the Merci Balloon Guide Catheter (BGC), and the Merci microcatheter through which the actual retrieval device is deployed (Figure 20–2). The BGC is a 9-French catheter with a large 2.1-mm lumen and a balloon located at the distal tip. The Merci Retriever itself consists of a tapered wire with five helical loops of decreasing diameter (from 2.8 to 1.1 mm) at the distal end. The loops are constructed from memory-shaped nitinol (nickel titanium) and therefore exploit the superelastic properties of this alloy. Once the microcatheter is advanced distal to the clot, the Merci Retriever is advanced through the microcatheter in its straight configuration. Once deployed, the retriever reforms into its pre-established helical shape thereby ensnaring the thrombus. During this procedure, the balloon at the tip of the BGC (usually located in the common carotid artery or ICA) is inflated to minimize distal flow. A complete description of the technique can be found in the original description of the MERCI Phase I Study.²⁴

Figure 20–2 The various components of the Merci Retrieval System. A, Balloon Guide Catheter. B, Distal access catheter. C, Merci Retriever (V series).

(Used with permission from Concentric Medical, Inc.)

On the basis of the results of the MERCI trial, the Merci Retrieval System was approved by the FDA for use in the treatment of acute stroke up to 8 hours after symptom onset. The approval of this device without a randomized trial has drawn some criticism, most notably due to the apparent increase in deaths associated with its use compared to the Prolyse in Acute Cerebral Thromboembolism (PROACT II—an earlier study evaluating the use of intra-arterial prourokinase) from 27% to 44%.^25,²⁶ However, the MERCI investigators argued that the presence of a higher percentage of distal ICA and basilar artery occlusions may have biased their results toward worse outcomes. The discrepancies in clinical outcomes underscore the need to accurately identify which patients are most likely to benefit from aggressive intervention.

Merci System Technical Comments

After conventional catheter angiography is performed, an 8- or 9-French Merci balloon-guided (Concentric Medical, Inc., Mountain View, CA) catheter is placed in the proximal ICA (for the anterior circulation) and the subclavian or vertebral artery (for the posterior circulation). With the balloon of the guide catheter deflated, an over-the-wire microcatheter with 0.014-inch microguidewire is navigated through the thrombus. The guidewire is then exchanged for the Merci Retriever. Up to four distal loops of the retriever are deployed distal to the thrombus. With the balloon inflated to arrest proximal flow (to minimize the risk of distal embolization), the microcatheter and the retriever are retracted to engage the clot. The proximal loops of the retriever are further deployed by gentle retraction of the microcatheter. While aspirating with a syringe on the BGC, the microcatheter and retriever are slowly withdrawn into the lumen of the guide catheter. The balloon is deflated and the thrombus is examined. Multiple passes with the retriever (as many as six passes) can be performed if the initial attempt is unsuccessful. If unsuccessful (less than thrombolysis in myocardial infarction [TIMI] grade 2 after six attempts or unable to access distal thrombus), intra-arterial tPA can be given (up to 24 mg) through the microcatheter. Postprocedural CT of the head is obtained to evaluate for intracerebral hemorrhage and the need for further management. In general, heparinization is neither reversed nor continued immediately after the procedure.

Penumbra System

The Penumbra System (PS) is a suction-based embolectomy device designed to reduce clot burden in large-vessel occlusive disease. It received FDA approval in 2008 for the treatment of acute stroke up to 8 hours after the onset of symptoms. The FDA approval was based on positive results from Phase I and II trials evaluating the safety and efficacy of the PS used for the treatment of acute stroke. The Phase II trial was a prospective, nonrandomized, single-arm, multicenter trial that enrolled patients with stroke related to an acute, large vessel occlusion that had failed to improve after treatment with IV r-tPA or patients who were not eligible to receive IV r-tPA. Like the MERCI trial, primary endpoints for the study were revascularization of the target vessel (TIMI grade 2 or 3) and the incidence of serious procedural events. Although the study lacked sufficient power to permit analysis of clinical outcomes, the authors relied on previous studies that correlated recanalization to clinical improvement. The Phase II trial investigators reported a favorable outcome (defined as 4-point improvement on the NIHSS) at discharge or on the 30-day modified Rankin Scale (mRS) of 2 or less in 41.6% of patients.

The PS is composed of three main components: a reperfusion catheter, a separator, and a thrombus removal ring (Figure 20–3). For aspiration, the reperfusion catheter is used coaxially with the separator while attached to an aspiration (suction) source to separate the thrombus from the vessel wall. If residual thrombus is still present after revascularization with aspiration, the thrombus removal ring can be used to directly engage and remove the residual thrombus. A complete description of the device and its use can be found in the original trial.²⁷

Figure 20–3 Penumbra reperfusion catheters and separators. The catheters are available with inner diameters of 0.026’ (0.66 mm), 0.032’ (0.81 mm), 0.041’ (1.04 mm), and 0.054’ (1.37 mm, not pictured). The corresponding separators are available with outer diameters of 0.022’ (0.56 mm), 0.028’ (0.71 mm), 0.035’ (0.89 mm), and 0.045’ (1.14 mm, not pictured).

(Used with permission from Penumbra, Inc.)

Penumbra System Technical Comments

Again, the site of arterial access is selected on the basis of establishing stable guide catheter placement, typically through the femoral artery. A baseline ACT is obtained and the patient is given IV heparin to maintain an ACT of 250 to 300 seconds after arterial access is established.

All mechanical thrombolysis with the Penumbra System (Penumbra, Inc., Alameda, CA) is performed through a 6-French guide catheter after conventional catheter angiography is performed. Depending on the location of the thrombus, the appropriate size of the Penumbra reperfusion catheter is chosen and navigated to the proximal end of the thrombus over a 0.014-inch guide wire. Once the target lesion is reached, the guide wire is exchanged for the same size separator. With the reperfusion catheter connected to an aspiration pump that generates a vacuum of 20 mm Hg, the separator is advanced and withdrawn into the reperfusion catheter for continuous aspiration-thrombolysis process. After multiple passes with the separator, angiography is performed to evaluate the degree of recanalization. For persistent thrombus, intra-arterial tPA can be given locally to soften the thrombus and potentially increase the efficacy of the thrombolysis. Recanalization is considered successful if TIMI grade 2 to 3 is achieved. In most cases, heparinization is neither reversed nor continued after the procedure.

Early recanalization and reperfusion have been identified as good prognostic indicators in a number of clinical trials. However, the lack of contemporaneous controls in these studies precludes the conclusion that thrombectomy definitively improves stroke outcomes. Randomized controlled trials evaluating the clinical benefit and cost-effectiveness of these invasive treatment modalities will help answer these questions and are underway.^28,²⁹ The Phenox CRC Mechanical Thrombectomy Device (Phenox, Bochum, Germany) and the Catch Mechanical Thrombus Retriever (Balt, Montmorency, France) are approved for use in Europe.

Frequently, mechanical thrombectomy is used in conjunction with chemical thrombolysis to restore flow. Adjuvant intra-arterial thrombolysis has been evaluated in Phase I and II trials,³⁰ and randomized trials are ongoing.²⁸

Drawbacks to intra-arterial thrombolysis include the invasiveness of the procedure, antecedent intubation, admission to an intensive care unit, and the expense of maintaining the constant availability of a dedicated interventional team. In 2007, a meta-analysis evaluating uncontrolled cohort studies of intra-arterial thrombolysis with a model predicting outcome without the use of intra-arterial thrombolysis failed to demonstrate clinical benefit. This finding indicates that more work remains to be done to identify the patients who will most benefit from aggressive intervention.

AngioJet Catheter

The AngioJet (Possis Medical, Inc., Minneapolis, MN) thrombectomy catheter uses high-pressure, pulsatile saline to fragment and aspirate clot into the lumen of the catheter. The AngioJet is used primarily in peripheral and interventional cardiac procedures, but successful intracranial use has been reported.^31,³² This device could be considered for off-label use in patients with large clot burden.

Stenting for Acute Stroke

Several case reports involving the use of self-expanding stents in the setting of recalcitrant thromboses led to interest in evaluating the use of stents for the treatment of acute stroke. The Stent-Assisted Recanalization in Acute Ischemic Stroke (SARIS) trial was a prospective, single-arm trial to evaluate intracranial stenting as a first-line intra-arterial acute stroke treatment.³³ Primary outcome measures were safety, which is defined by the occurrence of symptomatic (>4 point worsening on the NIHSS or neurological decline in the presence of intracranial hemorrhage) or asymptomatic intracranial hemorrhage, or neurological deterioration and evidence of recanalization (evaluated by the TIMI score of the target vessel). In this small investigational study, results were encouraging and the authors recommended further analysis to evaluate the utility of intra-arterial stenting as a primary treatment modality for acute stroke.

Clinical trials

At the time of this writing, several clinical trials are ongoing to evaluate new techniques for endovascular treatment of acute stroke. The Magnetic Resonance and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) trial randomizes patients to mechanical thrombectomy with the Merci System or to maximize medical therapy after MR or CT perfusion imaging. The MR RESCUE trial is the first trial to attempt to identify patients likely to benefit from aggressive intervention on the basis of objective, radiographic findings. The Interventional Management of Stroke Trial III (IMS-III) randomizes patients to a group receiving IV r-tPA or to a group receiving combined IV/intra-arterial r-tPA. Patients randomized to the combined IV/intra-arterial group will undergo mechanical thrombectomy (Merci Retriever, PS, or EKOS Micro-Infusion Catheter), intra-arterial r-tPA (maximum dose 22 mg), or both.

Endovascular Revascularization Techniques for Intracranial Stenosis

Large vessel atherosclerotic disease is a significant cause of intracranial ischemic events, accounting for about 10% of strokes. Important demographic disparities have been identified as well; African Americans, Asians, and Latinos are more likely to suffer from stroke related to intracranial stenosis than Caucasians, who tend to suffer from extracranial stenoses.³⁴

The Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) Trial demonstrated that certain subgroups of patients remain at a high risk of developing a stroke despite adequate medical therapy.³⁵ The WASID trial and the smaller Groupe d’ Étude des Sténoses Intra-Crâniennes Athéromateuses symptomatiques (GESICA) both identified subgroups of patients with intracranial stenosis who are at high risk of suffering from stroke. The WASID trial studies found that the 1- and 2-year risk of stroke in patients with 50% to 69% stenosis was 6% and 10%, respectively. However, in patients with 70% to 99% stenosis, the 1- and 2-year risk rose to 18% and 20%, respectively. The GESICA trial did not quantify the degree of stenosis but identified patients with hemodynamic features (i.e., symptoms exacerbated by physical activity, change in body position, or the addition or increase in an antihypertensive medication) that increased the risk of developing recurrent vascular events.

Since its initial description by Dotter and Judkins in 1964, percutaneous transluminal angioplasty (PTA) has been used successfully to treat peripheral and coronary arterial disease.³⁶ Initially, coronary angioplasty balloons were used off-label to perform intracranial PTA alone. As balloon-mounted stents became the mainstay of endoluminal treatment of coronary artery disease, these devices were adopted for the treatment of intracranial atherosclerotic disease. Technological modifications were necessary to allow navigation of the more tortuous intracranial circulation with more flexible catheters and improved stent delivery systems. Initial attempts at treatment of intracranial atherosclerotic disease with stenting resulted in acceptable periprocedural rates of morbidity and mortality, but with relatively high rates of technical failure.

Initial reports of high complication rates (vessel dissection, distal embolization, vasospasm, and arterial thrombosis)³⁷ were probably related to inadequate technology. Angioplasty with modern over-the-wire microcatheter-guided balloons alone appears to compare favorably to medical therapy alone,³⁸ but is associated with higher restenosis rates than modern intracranial stenting (50% compared to 7.5%).³⁹

The findings of the WASID trial that identified patients who remain at high risk of stroke despite adequate medical therapy occurred in the same year (2005) that the FDA granted a humanitarian device exemption for the Wingspan stent system (Boston Scientific, Fremont, CA). The periprocedural rates of stroke associated with the Wingspan stent were relatively low and led to widespread adoption of this technology by neurointerventionalists. At present, stenting for the treatment of intracranial atherosclerosis is reserved for patients with severe disease who have failed maximal medical therapy.

Based on the data collected from single-arm stenting trials and registries, it is probable that stenting has the potential to be an effective technique for reducing the risk of stroke in selected patients with intracranial atherosclerotic disease. The risk-benefit profile is most favorable for individuals with more than 70% stenosis of a large intracranial vessel. A number of clinical trials attempting to demonstrate this assumption are ongoing.

Stenting versus Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) is a randomized, controlled trial funded by the National Institutes of Health (NIH). This trial was designed to compare the Wingspan stent and Gateway balloon systems with maximal medical therapy in patients with intracranial stenosis of 70% or more with a qualifying event (stroke or transient ischemic attack) within 30 days. The Micrus Endovascular Corporation (San Jose, CA) has initiated a smaller, randomized, controlled trial comparing the Vitesse Pharos stent to medical therapy in patients with high-grade intracranial stenosis.

Complications

Major cerebrovascular complications related to angioplasty and stenting of intracranial vessels are related primarily to vessel rupture and thromboembolic phenomena. The Wingspan Intracranial Stent Registry Study Group identified possible risk factors for major complications due to angioplasty and stenting in patients with posterior circulation stenosis, low-volume centers, stenting within 10 days of a qualifying event, or stroke as a qualifying event.⁴⁰

Restenosis represents a major source of long-term failure of endoluminal stent therapy. Restenosis occurs as a result of the elastic recoil of the vessel, neointimal hyperplasia, and vascular remodeling. In-stent stenosis occurs in approximately one third of patients who receive the Wingspan stent ⁴¹ and is most common in the anterior circulation, particularly in the supraclinoid ICA segment.⁴² Revascularization by angioplasty with or without stenting in patients with restenosis is safe and effective in approximately 50% of patients with in-stent stenosis, although the durability of this therapy is unknown.⁴³

At this time, the hypothesis that angioplasty and stenting for nonacute intracranial stenotic lesions is a safe and effective treatment for the reduction of stroke risk in a select group of patients is supported by class IV data. However, the degree of risk reduction for stroke that this treatment imparts is unknown.

Intracranial Stenting Technical Comments

Several standard procedural protocols are used at our institution for endovascular revascularization for cranial ischemic pathologies. All patients undergoing angioplasty and stenting as an elective procedure are given dual antiplatelet therapy for 3 days consisting of aspirin (325–350 mg/day orally) and either ticlopidine (Ticlid; Roche Pharmaceuticals, Nutley, NJ) (250 mg orally twice a day) or clopidogrel (Plavix; Bristol-Myers Squibb/Sanofi Pharmaceuticals, New York) (75 mg/day orally). In urgent situations requiring endovascular interventions, patients are given a loading dose of aspirin (650 mg) and clopidogrel (450 mg). Intraprocedural functional assays are tested to verify individual responsiveness to aspirin, clopidogrel, and abciximab, and doses of dual antiplatelet regimen may be readjusted postprocedurally. The dual antiplatelet regimen is maintained until follow-up angiography is obtained (3 to 6 months). Clopidogrel is discontinued if no in-stent restenosis is demonstrated on follow-up angiography. Aspirin is continued indefinitely unless contraindicated.

All patients are placed under general anesthesia for percutaneous transluminal angioplasty and stenting (PTAS) treatment of intracranial stenoses using the Wingspan system (Figure 20–4). Intraoperative neurophysiological monitorings (somatosensory evoked potential and electroencephalography) are used throughout the procedure. Arterial access is typically achieved through the common femoral artery. In rare instances, other arterial sites such as transradial, transbrachial, or direct carotid puncture are required. Heparinization is instituted with the goal of activated coagulation times between 250 and 300 seconds after arterial access is achieved. All interventions are performed through a 6-French system guide catheter.

Figure 20–4 The Gateway balloon and Wingspan intracranial stent.

(Used with permission from Boston Scientific.)

After conventional catheter-based angiography, a microcatheter is navigated across the target lesion over a 0.014-inch guidewire. The microcatheter is then exchanged over a 0.014-inch exchange microguidewire for a Gateway angioplasty balloon and advanced across the stenotic lesion. The balloon diameter and length are sized to 80% of the normal parent vessel diameter and matched to the length of the lesion, respectively. Angioplasty is typically performed with a slow, graded inflation of the balloon to a pressure of between six and 12 atmospheres for approximately 120 seconds. After angioplasty, the balloon is removed and conventional angiography is repeated.

Next, the Wingspan delivery system is prepared and advanced over the exchange wire across the target lesion. The stent diameter is sized to exceed the diameter of the normal parent vessel by 0.5 to 1.0 mm. The stent length is selected to equal or exceed the length of the angioplasty balloon. In addition, the stent length is selected to completely cover the entire diseased segment and to allow the proximal end of the stent to be positioned so as not to preclude future endovascular access into the stented segment. The diameter of the stenotic lesion is measured using biplanar angiography and compared with a reference diameter of the normal vessel (usually proximal to the lesion), according to the technique used in the WASID study. Angiography is performed after the stent is deployed (Figure 20–5). Post-stenting angioplasty may be required if residual stenosis is present. Heparinization is typically neither reversed nor continued postoperatively.

Figure 20–5 Posteroanterior angiogram of left ICA injection demonstrating high-grade, flow-limiting stenosis of the ICA terminus and M1 segment of the MCA (A) before and (B) after Wingspan stent placement and angioplasty with the Gateway balloon.

(Used with permission from Barrow Neurological Institute.)

Extracranial carotid stenosis

Occlusive disease of the extracranial ICA is assumed to be the cause of one-fourth of all strokes.⁴⁴ Based on numerous randomized trials, carotid artery endarterectomy (CEA) reduces the risk of stroke in patients with moderate (>50%) symptomatic or severe (>60%) asymptomatic carotid stenosis.^45,⁴⁶ CEA is considered to be the best surgical treatment for carotid atherosclerotic disease, and CEA has subsequently become one of the most commonly performed surgical procedures in the United States. Certain groups of patients, however, are at high risk for complications related to CEA. Anatomic considerations (high carotid bifurcations, prior CEA, radiation-induced stenosis) can increase the technical difficulty of the operation. Patients with a history of myocardial infarction, angina, or hypertension are at increased risk of sustaining procedure-related complications. The benefits of CEA are lost if the 30-day rate of stroke or death exceeds 6% for symptomatic stenosis or 3% for asymptomatic stenosis.

Carotid artery stenting had emerged as a less invasive and effective alternative to CEA. Several randomized controlled trials comparing CEA with carotid artery stenting have yielded conflicting results. While some studies have demonstrated that carotid artery stenting was not inferior to CEA,^47,⁴⁸ others have concluded that carotid artery stenting was inferior to CEA.⁴⁹ Meta-analysis and pooled risk estimates resulted in wide confidence intervals, making generalizations based on these studies very difficult.

At present, the relative benefits in reducing stroke, morbidity, and mortality between CEA and carotid artery stenting in conventional-risk patients are unknown. The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) is designed to answer these questions by randomizing conventional-risk patients with either symptomatic (≥50% by angiography or ≥70% by ultrasound) or asymptomatic (≥60% by angiography or ≥70% by ultrasound) extracranial stenosis to either carotid artery stenting or CEA. The investigational devices used are the RX Acculink stent and the RX Accunet embolic protection system (Abbott Vascular, Santa Clara, CA). The primary endpoints of CREST are stroke, myocardial infarction, all causes of mortality during a 30-day periprocedural period, and ipsilateral stroke over the 4-year follow-up period. CREST established equivalent safety profiles for endarterectomy and stenting. In terms of periprocedural complications within the first 30 days of treatment, 2.3% of endarterectomy patients suffered a stroke compared to 4.1% of stenting patients. Myocardial infarction, however, occured more frequently in patients undergoing endarterectomy (2.3%) than stenting (1.1%). The cumulative total of these adverse outcomes produced a statistically equivalent safety profile for the two procedures.

Strong evidence recommends carotid artery stenting for treating specific subsets of patients, including restenosis after CEA, radiation-induced stenosis, those with anatomically high lesions, and those at high risk for undergoing general anesthesia.^50,⁵¹

Extracranial Carotid Stenting Technical Comments

At our institution, we prefer to perform carotid artery stenting under conscious sedation with the supervision of an anesthesiologist for hemodynamic control and comfort. Patients who undergo carotid artery stenting are typically high-risk patients for general anesthesia. Conscious sedation allows continuous neurological examination during the procedure.

The arterial access site is guided by the most favorable guide catheter stabilization needed for treatment. A baseline ACT is obtained, and the patient is heparinized to achieve an ACT between 250 and 300 prior to accessing across the stenosis. For transfemoral approach, a 5-French diagnostic catheter in coaxial fashion with a 6-French shuttle catheter is then used to selectively catheterize the targeted lesion. Opposite oblique and lateral angiograms of the carotid stenosis are obtained to minimize overlapping between the branches of the external carotid artery and the targeted stenosis in the ICA. A preprocedural angiogram of the ipsilateral anterior circulation is also performed as a baseline for postprocedural comparison. The following measurements are calculated on the carotid angiogram: (1) diameter and percentage of the stenosis, (2) normal proximal and distal carotid artery, and (3) length of the lesion. We also evaluate the carotid angiogram under subtracted condition to determine the stenosis in relation to the cervical bony anatomy on the lateral angiography.

All carotid artery stenting performed at our practice is executed on a monorail system with a distal protection device (DPD) (Figure 20–6). The monorail guidewire with the DPD is navigated gently across the stenosis. The DPD is deployed in the distal ICA but may require more proximal deployment if the vessel is extremely tortuous to navigate. Prestenting angioplasty with an undersize, noncompliant balloon may be required if the lesion is severely stenotic. Before angioplasty, we notify the anesthesiologist of potential vasovagal response associated with angioplasty. The vasovagal response can be dramatic, sometimes resulting in hemodynamically significant bradycardia or even asystole.⁵² Occasionally, the anesthesiologist may elect to pretreat the patient with an anticholinergic agent to blunt the vasovagal reflex.