It is well established that intracranial artery stenosis is an independent risk factor for ischemic stroke. In China, intracranial artery stenosis has a high incidence and a wide patient population. Endovascular interventional techniques have been increasingly used in the treatment of intracranial stenosis, and this new means of treating cerebrovascular disease is one of the current hot spots in neurological research, but there are still many questions about its effectiveness and safety that need to be faced. Shi Jin, Department of Neurology, Air Force General Hospital
1. Risks after intracranial cerebral artery stenosis
Unlike other malignant diseases, the risk after cerebral artery stenosis has its uncertainty. The mechanisms that cause stroke after atherosclerotic stenosis of intracranial arteries are: (1) low perfusion; (2) thrombosis due to plaque rupture, internal bleeding or plaque enlargement at the stenosis site, resulting in vascular occlusion; (3) distal embolism due to thrombus dislodgement; and (4) occlusion of the penetrating vessels at the stenosis site. The degree of arterial stenosis is associated with the risk of ischemic stroke, and some studies suggest that the risk of ischemic cerebrovascular disease increases by 26% for every 10% increase in intracranial arterial stenosis. An early prospective study on stenosis of the intracranial segment of the internal carotid artery showed that the 2-year recurrence rate in patients with cerebral ischemia under medical treatment was 38.2%, including stroke in 13.7% of cases and transient ischemic attack in 24.5% [1].The results of the WASID trial in 2005 showed that despite treatment with standardized antiplatelet aggregation and other drugs, the mean follow-up symptomatic intracranial artery Severe stenosis (stenosis of 70% to 99%) in patients for 1.8 years, the recurrence rate of stroke was still more than 22.1%, and the annual incidence of ischemic stroke in the stenotic area was 12%, and when the stenosis was ≥70%, the annual incidence of stroke was 18% [2]. The newly published SAMMPRIS study showed that 12.2% of patients with severe stenosis of the intracranial arteries also had stroke within 1 year despite regular medical treatment [3]. Therefore, it is necessary to explore further treatment for intracranial artery stenosis.
2. Limitations of endovascular stenting for intracranial artery stenosis
Due to the anatomical characteristics of intracranial vessels such as tortuous shape, lack of obvious muscular tissue and lack of strong supporting tissue around the vessels, brain tissue is easily damaged after ischemia and recovery after lesion is poor. This means that the vascular pathway is the roadblock that must be crossed before interventional therapy can be performed today. Currently, stenting can be performed only in the intracranial segment of the internal carotid artery, the M1 segment of the middle cerebral artery (mostly in front of the bifurcation, with a few cases reaching the M2-3 segment), the intracranial segment of the vertebral artery and the basilar artery, with some cases reported in the P1 segment of the posterior cerebral artery [4,5]. When stenting is performed, proximal vessels are less difficult than distal vessels; stenoses in small lumen arteries are more likely to form restenosis or occlusion after stenting, and stenting of vessels less than 2 mm in diameter is generally not performed at present due to material factors; vascular lesions with few penetrating branches, non-bifurcated and non-angled may have better results, and there is no good clinical evidence regarding which vessel will have better results with stenting. There is no good clinical evidence to confirm this.
Endovascular stenting is not indicated for atopic or nonatopic inflammatory vascular lesions, especially for active inflammatory lesions. Atherosclerotic stenosis is currently the most common lesion treated with stenting, but there are no studies to determine whether either stable or nonstable plaques should be stented, or perhaps we cannot yet clearly determine the nature of the plaque. There is evidence that the incidence of stroke in the second year of symptomatic intracranial artery stenosis is significantly lower than in the first year; therefore, there is a lack of strong evidence whether stenting is needed for a patient with already long-standing intracranial artery stenosis.
3. Types of stents for interventional treatment of intracranial artery stenosis
Although simple balloon dilation has a high throughput for tortuous vessels and no foreign body is retained in the vessel, it has many drawbacks, including intimal injury and entrapment of the artery, acute vascular occlusion, elastic retraction of the vessel preventing effective dilation of the canal diameter, and restenosis, etc. In 1999, Connors performed slow dilation with a smaller diameter balloon, which reduced complications but did not completely relieve the stenosis [6 ], an idea sometimes adopted by neurointerventionalists, but clinical evidence of effectiveness was lacking. When Gomez et al. first reported the successful placement of l coronary stents in the middle cerebral artery stenosis in 2000 [7 ], the development of intracranial artery stenting has been rapidly changing with the advancement of material technology, and the results of the development of intracranial artery stenting technology in China in the last decade are more than world-renowned, and these stents include: balloon stents, drug-coated stents, and self-expanding stents.
3.1 Balloon stents
In 2004, a study on stenting of intracranial and extracranial symptomatic atherosclerotic lesions reported that 43 cases of intracranial arterial stenosis with more than 50% stenosis were treated with balloon stent (NEUROLINK System), with a technical success rate of 95% and a stroke rate of 6.6% at 30 d and 1 year after surgery, respectively. In 2009, Miao reported a technical success rate of 96.46% in 113 patients with symptomatic middle cerebral artery stenosis treated with balloon-expandable stents, with a perioperative mortality and stroke rate of 4.42%. Jiang et al. treated 46 patients with intracranial artery stenosis of ≥50% stenosis with Apollo stent, 6.5% had a minor stroke within 30 days and the annual ischemic endpoint event rate was 4.3%, while 28% of patients experienced restenosis. stenosis, and the authors concluded that its efficacy was superior to that of aspirin drug therapy [10]. Although the SFDA approved the Apollo stent for cerebrovascular disease in China, there are still many critical issues that remain unresolved with balloon-expandable stents, such as: (1) high restenosis rate; (2) relatively poor flexibility of balloon-expandable stents, which sometimes cannot reach the stenosis site through intracranial tortuous vessels; (3) possible arterial rupture during balloon expansion; (4) acute intra-stent thrombosis; and (5) occlusion of the stent-site penetrating artery. .
3.2 Drug-coated stents
Faced with the high incidence of restenosis during intracranial artery stenting, some domestic and foreign neurointerventionalists have applied drug-coated stents used in coronary arteries to the treatment of cerebral artery stenosis and obtained certain efficacy [11,12]. The mechanical properties of drug-coated stents are the same as those of balloon stents, but with a major breakthrough in materials, which coat the stents with immunosuppressive or cytotoxic drugs and release drugs with inhibitory cell proliferation (rapamycin and paclitaxel, etc.) after stent placement to prevent restenosis. Although the use of drug-coated stents in coronary arteries has gained recognition, there are differences in tissue structure between intracranial arteries and coronary arteries, the drug toxicity of drug-coated stents on cerebrovascular and neurological tissues is unclear, the effects of delayed intimalization and other effects on cerebrovascular vessels, the prognosis of cerebrovascular disease from the use of dual antiplatelet drugs for a longer period of time, etc. need to be further investigated.
3.3 Self-expanding stents
The Wingspan system uses a balloon with a slightly smaller diameter than the target vessel to complete subfull dilation followed by placement of a self-expanding stent that is slightly thicker than the target vessel. The Wingspan study conducted in 2005 was a prospective study based on 45 patients with medically ineffective intracranial artery stenosis, with only 1 unsuccessful procedure and a perioperative stroke and mortality rate of 4.4% and a 1-year postoperative mortality and ipsilateral stroke incidence of 9.3% [5], for which the system was approved by the US FDA for the treatment of cranial artery stenosis. A subsequent multicenter treatment study included 78 cases with 82 stenoses, and while maintaining a high success rate (98.8%) with 4 perioperative deaths and 1 intracranial hemorrhage, the authors concluded that its safety was still acceptable [13]. The Wingspan prospective cohort study was also performed in China, where 100 patients with symptomatic intracranial atherosclerotic stenosis (≥70% stenosis) within 90 days were enrolled with a technical success rate of 99% and a mean follow-up of 1.8 years, with 9 patients presenting with a primary endpoint event, 5 of which occurred within 30 d and 4 subsequently, with an annual stroke rate considered by the authors to be lower than the WASID incidence of aspirin treatment in similar patients in the study (7.3% vs. 18%, P<0.05) [14]. Although the dedicated intracranial stent Wingspan stent has been widely used in clinical practice, its restenosis rate is significantly higher than that of ball expansion stents [15]. Currently, patients with severe stenosis of intracranial arteries are mainly treated with selective intracranial stenting. Meta-analysis showed that the restenosis rate was higher with the Wingspan stent than with the ball-expandable stent, but there was no significant difference in recurrent stroke events between the two [16], which may be a result of time to establish compensation of the collateral circulation for chronic stenosis after stenting.
At a time when stenting for intracranial artery stenosis is looking bright, the recently published multicenter study of SAMMPRIS with a larger sample has yielded completely different results. This study involved 50 centers and enrolled 451 patients who had a TIA or mini-stroke within the past 30 d and had a major intracranial artery diameter stenosis rate of 70% to 99%. 224 versus 227 patients were randomized to Wingspan stenting system versus aggressive pharmacologic therapy, respectively. The study was terminated early because stroke and mortality within 30 days was 14.7% in the stent group (10.2% ischemic stroke, 4.5% cerebral hemorrhage) compared with 5.8% in the control group, with twice the expected number of adverse events [3]. The publication of this result called into question the effectiveness and safety of stenting for intracranial arterial stenosis. However, flaws in the design of this study have also been raised, such as the fact that the study included patients with a mean time to stroke onset of only 7 days, which is shorter than WASID (mean 30 days), poor stability of the intracranial vessels early after an ischemic event, more prone to recurrence, and more prone to intracranial hemorrhage after stenting; the inclusion of patients did not distinguish between subtypes of stroke, and 28 patients with penetrating artery syndrome were enrolled, which affected the results; the inclusion of treated vessels with diameters of 2 to 4.5 mm, with a greater likelihood of restenosis and occlusion in vessels less than 2.5 mm in diameter; technical factors of surgical manipulation in the trial could not be ignored, with 75% of events occurring within 24 hours of the procedure, including four cases of subarachnoid hemorrhage due to guidewire penetration of the vessel and five cases of cerebral hemorrhage [17].
The advantages of the Wingspana stent system over balloon stents are reflected in better flexibility, easy access to the target vessel, stent coated with a hydrophilic layer reducing damage to the intima, and pre-satisfactory balloon subdilation reducing vessel rupture.
Cases of Neuroform self-expanding stents designed for aneurysms to treat intracranial artery stenosis have also been reported [18], Neuroform has good ease of passage, the stent mesh is large but its support is low, its efficacy needs further confirmation.
4. Antiplatelet medication for intracranial artery stenting
Antiplatelet drug therapy is needed before and after intracranial artery stenting, how long this time is and how large the dose is, there are no large-scale clinical trials to illustrate this, but there are some common understanding of some basic points, including: ① antiplatelet therapy must be enhanced during the perioperative period of cerebral artery stenting, ② the preparation of enhanced antiplatelet drug therapy must be carried out before surgery for 3-5 days in general, and must be continued after surgery for for more than 1 to 3 months, and (iii) the current commonly used drug is aspirin in combination with clobigrel [19].
5. The current basic view of stenting for intracranial artery stenosis
Based on past studies, in 2009, the American Heart Association (AHA) recommended that balloon dilatation angioplasty and/or stenting may be considered in patients with symptomatic intracranial artery stenosis with >70% stenosis, even under optimal conservative medical treatment [20]. Our guidelines for interventional treatment of intracranial artery stenosis, published at the end of 2011, state that balloon angioplasty and/or stenting may be considered in patients with symptomatic intracranial artery stenosis for which pharmacological treatment has failed [21].
Many issues remain to be resolved regarding stenting for symptomatic intracranial artery stenosis, including: (i) stenting is aimed at stroke prevention, and no trial has yet met the statistical sample size requirements for ischemic stroke prophylaxis trials, let alone double-blind controls; (ii) stenting cannot yet be performed in patients with all types of vascular pathways because of the anatomical characteristics of the cerebral vasculature, and operators are not yet even (3) the longer-term effects of stenting need to be further observed; (4) not all stenoses are associated with stroke, and it is unclear which stenoses are malignant and urgently require stenting. The safety, efficacy and wide applicability of stenting need to be further improved, especially the high restenosis rate deserves attention.
Intracranial artery stenosis is highly risky, and endovascular stenting is still an important therapeutic tool under the current unsatisfactory effect of drug therapy. With the emergence of more scientific evaluation methods and improvements in materials and technology, endovascular stenting shows good prospects as an emerging treatment method that has emerged in the last decade or so.
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