13.1 Goals

1. 
   

   Critically analyze the literature on medical management of symptomatic intracranial atherosclerotic disease.

   
   
2. 
   

   Review relevant trials on endovascular treatment of symptomatic intracranial atherosclerotic disease.

   
   
3. 
   

   Highlight key issues in endovascular therapy, periprocedural management, and follow-up after intracranial angioplasty and stenting.

13.2 Case Example

13.2.1 History of Present Illness

A 75-year-old patient complained of recurrent episodes of left-sided weakness and speech disturbance. Magnetic resonance (MR) imaging showed acute infarcts in the left cerebellar hemisphere, right pons, and left occipital lobe (Fig. 13.1a, b). A basilar artery stenosis was detected on MR angiography (Fig. 13.1c). Best medical treatment was initiated including dual antiplatelet treatment with acetylsalicylic acid (ASA) and clopidogrel, atorvastatin at 80 mg daily, and an optimization of antihypertensive medication. One month later, the patient experienced palpitations and was diagnosed with atrial fibrillation. The treating cardiologist performed cardioversion and replaced the dual antiplatelet treatment with rivaroxaban without any other change of medication.

Another month later, episodes of speech disturbance and perioral paresthesia occurred. These episodes were interpreted as brainstem transient ischemic attack (TIA), but MR imaging did not show any new infarcts or stenosis progression. ASA was added to rivaroxaban. A few weeks later, atrial fibrillation relapsed. The patient was readmitted and treated with amiodarone. During the course of the hospital stay, the patient experienced two more episodes of speech disturbance. This time MR imaging revealed a new pontine infarction. Since all infarcts and the TIA were in the territory of the basilar artery, it was assumed that a large artery atherosclerosis was the cause rather than atrial fibrillation. After interdisciplinary discussion with the neurologist, neuroradiologist, and cardiologist, endovascular therapy was regarded as the only treatment option left and the patient gave informed consent after careful consideration. During prepro-cedural medical work-up, a slight drop in hemoglobin was recognized. In view of the extensive postprocedural anticoagulation required, an endoscopy was performed. An angio-dysplasia was found in the colon and coagulated.

Past Medical History: hypertension, hyperlipidemia, heterozygous factor-V-Leiden mutation with previous deep vein thrombosis, impaired glucose tolerance, atrial fibrillation (CHA2DS2-VASC 5).

Past surgical history: Previous bilateral cataract surgery. Family history: Answered negative to family history of stroke.

Social history: Answered negative to being a former or current smoker.

Review of systems: As per the above.

Neurological examination: Unremarkable.

Imaging studies: As described above.

13.3 Case Summary

1. 
   

   What is the recommended anticoagulation/antithrombotic treatment in patients with symptomatic intracranial atherosclerosis?

   
   

   The first attempt to clarify the uncertainty about the optimal antithrombotic therapy in patients with symptomatic intracranial atherosclerosis was the “Warfarin and Aspirin for Symptomatic Intracranial Stenosis (WASID)” trial. ¹ The trial was terminated early since the use of warfarin was associated with an increased mortality and major bleeding risk without any benefit in terms of stroke prevention. The increased risk of major hemorrhage was largely triggered by excess international normalized ratio (INR) values and low values were associated with an increased risk of stroke. Out of range INR was not infrequent within the trial. Novel anticoagulants (NOACs) are more suitable in this aspect and have proven to be superior to warfarin in terms of safety and efficacy in patients with cardioembolic stroke. Therefore, they might play a future role in the treatment of patients with symptomatic intracranial atherosclerosis. The “Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis (SAMMPRIS)” trial compared stenting with aggressive medical management to aggressive medical management alone for the treatment of high-grade symptomatic intracranial stenosis. ^{2 , 3} The likelihood of a primary end-point event in the noninterventional arm of the trial was only 5.8% at 30 days and much lower than expected. Dual antiplatelet treatment with ASA and clopidogrel during the first 3 months after randomization was an essential component of medical therapy.

   
   

   The superiority of dual antiplatelet treatment compared to ASA alone to prevent recurrence of cerebral ischemia without an increased risk of hemorrhage was demonstrated in the “Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE)” trial. ⁴ A CHANCE subgroup analysis focusing on patients with intracranial atherosclerosis showed only a trend for improved outcome with dual antiplatelet therapy. ⁵ This may be attributable to the very common phenomenon of “clopidogrel resistance,” which is caused by the inability to convert the prodrug clopidogrel into the active form via the CYP2C19 enzyme. An additional subgroup analysis showed that the benefit of dual antiplatelet therapy was not present in carriers of CYP2C19 loss-of-function alleles but was highly significant in noncar-riers. ⁶ Ticagrelor has the same mode of action as clopidogrel but does not require enzymatic conversion. Therefore, it will likely overcome the issue of clopidogrel resistance. The safety and efficacy of ticagrelor in patients with intracranial large artery atherosclerosis has not been investigated yet.

   
   
2. 
   

   What are the most important adjunctive components of medical therapy in symptomatic intracranial atherosclerosis? The medical treatment arm of the SAMMPRIS trial showed the most favorable clinical results in patients with symptomatic intracranial atherosclerosis so far. ³ Therefore, medical therapy in the real-world setting should ideally be aligned to the trial guidelines. Specific risk factor targets were as follows ⁷ : systolic blood pressure < 140 mm Hg (< 130 mm Hg if diabetic), LDL cholesterol < 70 mg/dL, non-HDL lipoprotein < 100 mg/dL, HbAlc< 7%, smoking cessation, weight management (for initial BMI of 25-27 kg/m ² : target BMK25 kg/m ² ; for initial BMI > 27 kg/m ² : target 10% weight loss), physical activity: > 30 min of moderate exercise > 3 times per week. The effectiveness of the components of risk factor management in the medical arm of SAMMPRIS was validated in a subgroup analysis. Interestingly, physical activity was the strongest predictor for favorable outcome. ⁸

   
   
3. 
   

   What is the risk of endovascular therapy compared to medical management in intracranial atherosclerotic disease? Endovascular therapy was compared to best medical management in two prospective randomized trials. The leading trial was SAMMPRIS, which compared the clinical outcomes of patients with high-grade (> 70% degree of stenosis), symptomatic intracranial stenosis receiving stent-angioplasty with the self-expanding Wingspan device in conjunction with aggressive medical management versus aggressive medical management alone. ^{2 , 3} The “Vitesse Stent Ischemic Therapy (VISSIT)” trial followed using the balloon-expandable Pharos Vitesse stent as the study device in the endovascular treatment arm. ⁹ SAMMPRIS was halted after randomization of 451 patients due to safety concerns and VISSIT was stopped after the publication of the initial results from SAMMPRIS.

   
   

   In both trials, the probability of a primary end-point event was higher in the endovascular treatment arm as compared to medical treatment alone. The primary end point in SAMMPRIS was any of the following: stroke or death within 30 days after enrollment, ischemic stroke in the territory of the qualifying artery beyond 30 days of enrollment, or stroke or death within 30 days after a revascularization procedure of the qualifying lesion during follow-up. During a median follow-up of 32.4 months, 34 (15%) of 227 patients in the medical group and 52 (23%) of 224 patients in the stenting group had a primary end-point event (p = 0.0252). The primary end point of VISSIT was a composite of stroke in the same territory within 12 months of randomization or a TIA in the same territory from day 2 through month 12 postrandomization. The 1-year primary outcome occurred in more patients in the stent group 21 (36.2%) of 58 versus the medical group 8 (15.1%) of 53 (p = 0.02). Under the premises of these studies stent-angioplasty was inferior compared to medical management alone in the treatment of symptomatic intracranial large artery disease. The negative trial results were mainly driven by high procedure-related event rates. In SAMMPRIS, two-thirds of procedure-related events were ischemic and one-third were hemorrhagic. ¹⁰ Basilar artery stenosis, diabetes, and old age were predictors of procedural ischemic events and perforator stroke was the most critical issue. A higher grade of stenosis, a lower modified Rankin score, and a clopidogrel load associated with an activated clotting time above the target range predicted procedural hemorrhage. Delayed hemorrhage turned out to be the major contributor.

   
   

   It is worth noting that patients with unstable clinical symptoms were excluded in both trials. Therefore, the results cannot be transferred to acute stroke treatment.

   
   
4. 
   

   What is the rationale for endovascular treatment of symptomatic intracranial atherosclerotic disease?

   
   

   Extensive subgroup analyses have been performed from the SAMMPRIS data to identify subgroups which would potentially benefit from endovascular therapy. Subgroup analyses have included the following (underlined representing prespecified subgroups): patients on and off antithrombotic therapy at the time of the qualifying event (QE), age < 60 versus > 60, gender, black or white racial background, vascular risk factors (hypertension, lipid disorder, diabetes, smoking), location of the stenosis (internal carotid artery, middle cerebral artery, vertebral artery, basilar artery), anterior versus posterior circulation, percent stenosis (< 80% vs. > 80%), type of QE (stroke vs. TIA), days to enrollment (< 7 days vs. > 7 days), old infarcts in the territory, proton pump inhibitors at QE, and hypoperfusion symptoms. ^{11 , 12} None of the above revealed an advantage of stent-angioplasty over medical treatment.

   
   

   Both SAMMPRIS and VISSIT have been criticized in many ways, including the treatment being confined to a specific device, the development of devices for this purpose still being at an early stage, inadequate operator experience, patient selection issues, and a low enrollment rate. Nevertheless, from an evidence-based perspective, stent-angioplasty of intracranial atherosclerotic disease is a compassionate treatment and must be confined to a small patient group with recurrent cerebral ischemia despite having optimized medical management.

   
   

   New prospective randomized trials with more advanced devices and techniques demonstrating a clinical benefit of intracranial stent-angioplasty are required to establish the stenting of intracranial stenosis as a standard treatment. For balloon angioplasty alone, scientific data are sparse and no meaningful prospective randomized trials exist. An early meta-analysis dated 2009 suggested that rates of recurrent stroke and restenosis are higher following balloon angioplasty compared to stent-assisted treatment. ¹³ Two more recent case series suggest that angioplasty alone may carry a lower procedural risk compared to stent-angioplasty. ^{14 , 15} From a practical point of view, balloon angioplasty alone is frequently associated with dissection and/or elastic recoil and does not result in reliable treatment results.

   
   
5. 
   

   What is the ideal endovascular treatment strategy?

   
   

   Intracranial stenting can be performed with either self-expanding or balloon-expandable stents. Since SAMMPRIS was conducted with a self-expanding stent and VISSIT with a balloon-expandable stent and both failed to prove superiority of endovascular therapy, no general recommendation can be given. The choice of the device must be made individually and is triggered by vascular anatomy, location of stenosis, and operator preference. In general, balloon-expandable stents are stiffer and lesion access may be hampered in tortuous anatomy. This may be the reason for the relatively low technical success rate in the VISSIT trial (54%). If vessel anatomy is appropriate, using balloon-expandable stents is more convenient as it is generally a one-step procedure. With a self-expanding stent, while nearly every lesion of a major intracranial artery is accessible, this is at the expense of it being a multiple step procedure and requiring at least one exchange maneuver. High rates of restenosis are described for both types of stents. ^{9 , 16} Drug-eluting devices may overcome this issue, but currently none have been approved for intracranial stenting. ¹⁷

   
   
6. 
   

   What is the recommended postprocedural management and follow-up after endovascular treatment of intracranial atherosclerotic disease?

   
   

   Delayed hemorrhage was a major issue in SAMMPRIS, and therefore, postprocedural intensive care is recommended to ensure optimal blood pressure management and clinical observation. There is no general rule for how long dual antiplatelet medication should be taken. In SAMMPRIS and VIS-SIT, clopidogrel was added to ASA for 3 months, which appears reasonable but may vary with other devices and the morphological result of the procedure. With bare metal stents, the rate of restenosis generally exceeds 20% and restenosis is associated with new ischemic symptoms. ¹⁸ Therefore, a systematic follow-up regimen should be established.