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As the safety and effectiveness of urgent carotid artery stenting (CAS) for neurologically progressing patients remain controversial, we retrospectively analyzed the outcome of urgent CAS based on the patients’ pathophysiological condition and neuroimaging findings. We divided 71 patients who underwent CAS within 14 days of stroke onset into two groups. Group 1 (n = 35) was comprised of patients with progressing neurologic signs and a reversible ischemic penumbra on magnetic resonance images (MRI). They were treated by urgent CAS. Group 2 (n = 36) was neurologically stable and underwent prophylactic CAS. In all patients we recorded the National Institutes of Health Stroke Scale (NIHSS) score and the modified Rankin scale (mRS). Urgent CAS resulted in significant improvement in the NIHSS score, when compared before and after CAS in group 1 (5.3 ± 4.3, P < 0.01). The rate of good outcomes (mRS 0–2 at 3 months post-CAS) was 48.6% in group 1, and 75% in group 2. The cumulative incidence of ipsilateral stroke between 31 days and 1 year was 5.9% in group 1, and 0% in group 2. The procedural complication rate was similar in both groups (group 1: 5.7%, n = 2; group 2: 5.6%, n = 2). No patient suffered a symptomatic intracerebral hemorrhage. When the pathophysiological status and neuroimaging findings are used to determine patient eligibility for urgent CAS, this treatment improve neurologic outcome and can be performed as safely as prophylactic CAS in our cohort of patients with acute ischemic stroke.
Approximately, 30% of patients with symptomatic moderate to severe carotid artery stenosis suffered neurological deterioration within 2 weeks of stroke onset; in most, it occurred within the first 2 days.1,2) While some meta-analysis claimed that the greatest benefit is obtained when carotid endarterectomy (CEA) is performed within 2 weeks of a stable transient ischemic attack (TIA) or minor stroke, patients with progressing neurologic signs were excluded in those study.3,4) The optimal timing for urgent revascularization in patients with neurologically progressing and unstable internal carotid artery (ICA) stenosis remains controversial.
Patients with evolving stroke are at higher operative risk from urgent CEA than patients with stable symptoms,5–7) The incidence of perioperative stroke or death was significantly higher in patients undergoing urgent than non-urgent CEA (14% vs 4%).8) Although the higher operative risk of urgent CEA, early revascularization in the severe ICA stenosis has the potential to prevent clinical deterioration and improve the symptoms of progressing stroke. This may also apply to carotid artery stenting (CAS). From the stand point view of early restoration of the cerebral blood flow, urgent CAS might be the best option for emergency revascularization. Their pathophysiological status, e.g. the severity of neurological findings, their systemic condition, hemodynamic insufficiency, carotid plaque vulnerability, and antiplatelet count, dictates the appropriate timing of CAS in neurologically progressing patients.
We retrospectively evaluated the feasibility, effectiveness, and safety of urgent CAS in patients with neurologically progressing ICA stenosis who underwent CAS within 14 days of stroke onset. We divided our 71 patients into two groups based on their neurological status and neuroradiological findings and assessed their treatment outcomes.
Between January 2008 and April 2014, 393 consecutive patients with cervical carotid artery stenosis underwent CAS or CEA at our three stroke centers; 162 were symptomatic and treated by CAS. Of these, 71 who presented with acute ischemic stroke and underwent CAS within 14 days of stroke onset were reviewed. The patients who underwent both thrombectomy and urgent CAS for internal carotid artery occlusion (ICO) or tandem occlusion were excluded from our cohort study. Use of carotid stents in patients with ischemic stroke was approved by the Ethics Committees of the participating institutions, and patient or proxy informed consent was obtained before initiation of the procedure.
We divided the 71 symptomatic carotid artery stenosis patients into two groups based on their preoperative pathophysiological status and neuroimaging findings. Group 1 (n = 35) patients underwent urgent CAS within 14 days after stroke onset. Their neurological symptoms were moderate to serious at the time of admission or mild but worsened despite aggressive medical therapy, indicating that progressing stroke or evolution to stroke was underway. Urgent CAS was performed immediately after admission or neurologically worsened point. Group 1 consisted of neurologically progressing and unstable patients in whom a diffusion-weighted imaging (DWI)/perfusion-weighted imaging (PWI) mismatch and a DWI/clinical mismatch (National Institutes of Health Stroke Scale (NIHSS) ≥ 6 and DWI-Alberta Stroke Programme Early CT Score (ASPECTS) ≥ 6) was observed on magnetic imaging (MRI) studies. Patients with crescendo TIA (n = 2) were also included in group 1. In group 2 (n = 36) we performed prophylactic CAS 48 hr to 14 days post-onset. These patients were neurologically stable and treated medically. At our institutions CEA is the first-line choice in neurologically stable patients without high-risk factors for CEA that identified by SAPPHIRE trial.9) The treatment in group 2 patients was mainly based on inclusion criteria of SAPPHIRE trial9) or their wishes. However in this study, all the patients suffered from progressing stroke or evolution to stroke have been treated with urgent CAS.
The treatment of patients in our stroke database was based on their clinical presentation and imaging findings. Unless contraindicated, MRI is our first-line diagnostic tool in stroke patients. Their neurological and systemic status is assessed and plaque imaging studies are performed after admission. CAS was performed in patients without hemorrhagic transformation, defined as the new appearance of low-intensity lesions on follow-up -weighted images. Patients were initially treated by infusion- and antiplatelet therapy (75 mg clopidgrel and 200 mg aspirin). We administered 300 mg clopidgrel and 300 mg aspirin as a loading dose to patients underwent urgent CAS within 48 hr after onset; the others received 75 mg clopidgrel and 200 mg aspirin per day before surgery.
All procedures were performed by an experienced neurointerventionist using a biplane angiography system. First, the femoral artery was punctured under local anesthesia and a femoral sheath was placed. Heparin was administered and the activated clotting time was maintained at more than 250 sec. In all patients with internal carotid artery stenosis, an embolic protection device (Filter Wire EZ, Spider, Percusurge, Protégé) was introduced; in most instances we performed pre- and post-dilation. A self-expandable stent (Precise, Carotid Wallstent) was advanced to cover the stenosis. The devices were chosen by the surgeon. After CAS, dual antiplatelet therapy was continued for at least a month; single antiplatelet treatment was administered during the follow-up period.
All patients were assessed clinically at the time of admission and immediately before- and 7 days after surgery using the NIHSS score. Neurological improvement was defined as a 4-point improvement in the NIHSS score. Treatment outcomes were assessed in-hospital or by a telephone interview conducted 3 months and 1 year post-CAS and recorded based on the mRS. The incidence of ipsilateral stroke was assessed within 31 days to 1 year after the procedure.
Analysis was performed using SPSS. Categorical variables were compared using the Fisher exact test, continuous variables were compared using analysis of variance and expressed as the mean ± standard deviation (SD). Differences of P < 0.05 were considered statistically significant.
CAS for symptomatic ICA stenosis was performed within 14 days after onset in 71 patients; 35 (49.3%) were assigned to group 1 and 36 (50.7%) to group 2. Their demographic and clinical data are shown in Table 1.
In group 1 patients, 14.3% underwent the intravenous infusion of recombinant tissue plasminogen activator. Their mean NIHSS score at the time of admission was statistically higher (5.1 ± 3.9, median 4, range 0–12) than group 2 (3.2 ± 3.2, median 3, range 0–12) (P < 0.05). The mean number of days from the first attack to CAS in group 1 was statistically shorter (3.4 ± 4.3) than in group 2 (7.4 ± 3.3) (P < 0.001). The clinical outcomes in all patient groups are shown in Table 2.
Stent insertion was successful in all 71 patients; procedural complications were encountered in 4 (5.6%). They included cerebral infarction (n = 1 in group 1), 3 patients suffered central retinal artery occlusion (n = 1 in group 1, n = 2 in group 2). There was no significant difference in the rate of procedural complications among the two groups. No patient developed a symptomatic intracerebral hemorrhage. The mean NIHSS score of all patients before treatment and 7 days post-CAS was 6.6 ± 5.6 (median 6, range 0–26) and 3.3 ± 3.8 (median 4, range 0–18), respectively. In-hospital neurological improvement (improvement of more than four points in the NIHSS score) was observed in 21 of 35 group 1- (60.0%) and 6 of 36 group 2 patients (16.7%). The NIHSS score recorded at 7 days post-CAS was significantly improved compared to immediately before-CAS in group 1 (5.2 ± 4.3, P < 0.01) (Fig. 1).
The rate of good outcomes (mRS 0-2 at 3 months post-CAS) was 48.6% in group 1 and 75% in group 2. Two of our 71 patients died (2.3%) within 1 year after treatment; one group 2 patient had carcinomatous peritonitis and the other, a group 1 patient, had esophageal carcinoma. The incidence of ipsilateral stroke within 31days to 1year was 5.9% in group 1 and 0% in group 2.
According to Bond et al.,7) the risk for stroke and death was the same in patients with stable symptoms who underwent early (< 3–6 weeks) or late (> 3–6 weeks) CEA although urgent CEA in patients with evolving symptoms carried a much higher risk. Others5,6) suggested that the risk was high in patients with unstable symptoms treated by urgent CEA and Brandl et al.10) found that their risk was similar to that of patients with stable symptoms. The number of patients in those studies was too small to draw conclusions about the efficacy and safety of urgent CEA.
Shahdi et al.11) reported that urgent aggressive, best medical therapy may reduce the risk of early recurrent stroke in patients awaiting CEA. They suggested that its higher procedural risks may argue against urgent revascularization surgery soon after symptom onset and recommended delaying surgery. Nevertheless, despite best medical therapy, we have encountered rapid neurological deterioration in patients with acute symptomatic ICA stenosis and in that subpopulation, urgent revascularization may be the best treatment option.
The optimal timing of urgent CAS in patients with neurologically progressing and unstable ICA stenosis also remains controversial. Wach et al.12) reported that the risk of CAS performed within 2 days of the insult is not greater than when the procedure is carried out up to 90 days later. Jonsson et al.13) found that urgent CAS did not increase the peri-procedural risk. Nonetheless, CAS may be unsafe in patients with evolving symptoms who are suspected of harboring fragile carotid plaques. At our institutions, the procedural complication rate was not different between urgent and prophylactic CAS group.
Urgent CAS was performed in patients of group 1 with neurologically progressing and unstable symptoms whose MRI studies revealed a DWI/PWI- and a DWI/clinical mismatch. Urgent CAS was performed not only to prevent recurrent stroke but also to obtain neurological improvement. Some studies have reported efficacy of urgent CAS of ICA occlusion or high-grade stenosis in acute stroke.14–19) But most of the studies involved only the patients with ICA occlusion. Imai et al. reported 17 patients with ICA occlusion (n = 4) or high-grade stenosis (n = 13) underwent urgent CAS. Urgent CAS resulted in significant improvement in the NIHSS score, when compared before and after urgent CAS (median NIHSS scores before urgent CAS and at 7 days were 12 and 5).14) In our study, of the 35 group 1 patients, 21 (60.0%) improved by ≥ 4 NIHSS points during hospitalization. Urgent CAS returned the neurological status to the pre-degradation state in patients with evolving stroke (Fig. 1). However, despite marked neurological improvement and the low complication rate, more than half of patients in group 1 showed moderate disability (modified Raskin scale (mRS) ≥ 3) after three months. We attribute the poorer outcomes in that group to the greater severity of their neurological symptoms. As for prevention of recurrent stroke, annual rate of ipsilateral stroke in group 1 (5.9%) and group 2 (0%) was acceptable when compared to recent study.9)
Urgent CAS should be considered in patients with crescendo TIAs and in patients who are neurologically unstable or fluctuating because they may rapidly progress to complete stroke and deteriorating neurological symptoms. Urgent CAS can be expected to improve fluctuating conditions by increasing the cerebral blood flow and by covering vulnerable carotid plaques with a stent.
The neurological symptoms were mild and stable in our group 2 patients. Medical therapy effectively prevented early recurrent stroke and urgent revascularization was not required. According to Brott et al.20) the perioperative stroke rate in patients with symptomatic ICA stenosis was higher for CAS than CEA, and the perioperative myocardial infarction rate was higher for CEA than CAS. In patients with symptomatic ICA stenosis, CEA is our first-line treatment except in emergency situations; patients with high-risk factors for CEA that identified by SAPPHIRE trial9) are subjected to CAS. Although the majority of our group 2 patients had risk factors for CEA, prophylactic CAS was safely performed and their prognosis was good.
Some of the concerns about antiplatelet medication exist in urgent CAS. Insufficient efficacy of antiplatelet medication may cause acute stent thrombosis. Antiplatelet-related symptomatic intracranial hemorrhage may result in a further deterioration of neurological status after revascularization. The incidence rate of symptomatic intracranial hemorrhage was from 0% to 18% in other studies on acute CAS.12,14,16–19) No patients suffered symptomatic intracranial hemorrhage in our urgent CAS group. Bazan et al.21) reported that thrombolysis followed by urgent CAS was not associated with an increased risk of symptomatic intracranial hemorrhage in select patients with minor to moderate ischemic stroke. Most of our group 1 patients manifested moderate to serious neurological symptoms; MRI studies showed a DWI/PWI- and a DWI/clinical mismatch without hemorrhagic transformation, defined as low-intensity lesions on -weighted images. Evaluation of the extension of the ischemic lesion and of tissue at risk of hemorrhage on MRI scans, including diffusion-, perfusion-, and -weighted images, is important for avoiding post-procedural hemorrhagic complications. Strict blood pressure control in the intensive stroke care unit may also help to avoid symptomatic intracranial hemorrhage.
We retrospectively analyzed 71 patients who underwent CAS within 14 days after stroke onset and assessed their treatment outcomes and procedural complications from the standpoint of not only the time elapsed since onset but also their pathophysiological status. Our findings indicate that urgent CAS is effective and safe in carefully selected patients with neurologically progressing symptoms and unstable ICA stenosis. The rate of procedural complications was not higher in patients with unstable- than in those with stable symptoms. Careful patient selection and preoperative MRI studies contributed to our relatively low complication rate.
Our study has some limitations. It was retrospective and the number of patients was small, we did not include a group exposed to conservative treatment, and our study lacked a core lab control for the imaging evaluations. Further evaluation of this treatment strategy is underway.
Conflicts of Interest Disclosure
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this article. All authors have registered online Self-reported COI Disclosure Statement Forms through the website for The Japan Neurosurgical Society members.
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.