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Carotid Artery In-Stent Restenosis after Carotid Artery Stenting
Stroke is the leading cause of long-term disability and the third leading cause of death after cardiac- and cancer-related deaths. In 2004, the prevalence of stroke was estimated to be 5.7 million (2.4 million males, 3.3 million females). Every year, there are approximately 500,000 new and 200,000 recurrent strokes. Overall, 87% of all strokes are ischemic and 13% are hemorrhagic. Although the stroke-related death rate fell from 20.4% to 6.7% in recent years, it still accounts for 1 in every 16 deaths. The major cause of stroke is large-vessel atherosclerosis (accounting for one-third of all strokes), with the highest risk associated with stenosis of the internal carotid arteries (ICA). It may account for up to 20% of ischemic cerebrovascular events, and it is one of the treatable causes of initial (5–12% of all new strokes amenable for revascularization) and recurrent strokes.1,2 Major risk factors for the development of carotid artery disease include hypertension, diabetes, hypercholesterolemia, tobacco use and family history. Stroke risk factors include prior stroke, older age, family history of stroke, alcoholism, male sex, hypertension, cigarette smoking, hypercholesterolemia, diabetes, cocaine or other amphetamine use, hypercoagulability, atrial fibrillation and the presence of intracranial aneurysms. Research has demonstrated that abstinence from smoking, low body mass index, moderate alcohol consumption, regular exercise and healthy diet have reduced total and ischemic strokes, but not hemorrhagic strokes.
The most common site of cerebrovascular atherosclerotic disease is the carotid bifurcation extending into the ICA, where atherosclerotic ulceration leads to distal embolization. Carotid bruit on physical examination generally warrants further testing. The clinical symptoms may consist of head, neck and retroorbital pain, new-onset Horner’s syndrome, contralateral sensorimotor or cognitive deficits and unilateral visual disturbances. Patients with temporary retinal or hemispheric neurologic deficits should be screened for extracranial carotid disease. Other than this, asymptomatic patients over the age of 65, patients with left main coronary stenosis, peripheral arterial disease, history of smoking, history of transient ischemic attacks/stroke or carotid bruit should also be screened prior to coronary artery bypass surgery (CABG).
From a historical perspective, the initial trials, such as the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Surgery Trial (ESCT), have shown benefit of carotid endarterectomy over medical therapy in reducing subsequent strokes and/or death in patients with symptomatic carotid artery disease.3,4 Although the Asymptomatic Carotid Atherosclerosis Study (ACAS) and the Asymptomatic Carotid Surgery Trials (ACST) showed a reduction in stroke and/or death rates in asymptomatic patients with carotid artery disease,5,6 the benefit of carotid endarterectomy over medical management has been less impressive in asymptomatic patients than in symptomatic patients. More recently, the Carotid and Vertebral Transluminal Angioplasty Study (CAVATAS) and the Stenting and Angioplasty Protection for Patients with High-Risk Endarterectomy (SAPPHIRE) trials have revealed noninferiority of carotid artery stenting over surgery.7,8
Carotid artery stenting (CAS) has been demonstrated to be technically feasible and safe in high-risk patients, with current data indicating clinical noninferiority with respect to endarterectomy. At present, carotid artery stent placement has been approved as a less invasive alternative treatment to carotid endarterectomy (CEA) in high-risk patients with symptomatic high-grade carotid artery stenosis. It is clear that carotid stenting will continue to be performed at increasing rates as indications expand. Therefore, it is anticipated that there will be a corresponding increase in the number of carotid in-stent restenosis cases, a sequela of this procedure, which may affect outcomes and require repeat interventions. In several studies, the carotid artery in-stent restenosis rate has been evaluated and reported as 2.27% at 6 months and 3.36% at 12 months, with stent deformation observed in 2.5% of the cases after CAS.9 Although this is a relatively small number, its consequence in terms of morbidity and mortality related to repeat interventions warrants some attention.
The restenosis rates after CEA appear to be about five- to ten-fold higher compared to CAS. Fibromuscular (myointimal) hyperplasia in early recurrent cases and atherosclerotic degeneration in later cases have been reported as the underlying pathology in post-CEA patients.10 The clinical course is relatively benign in the early cases, whereas the later cases need further attention and intervention. Repeat surgery for carotid artery restenosis has a higher complication rate than primary CEA. Considerable controversy still exists regarding the clinical significance, natural history, threshold for management and appropriate intervention for recurrent carotid stenosis and carotid in-stent restenosis after endarterectomy and stenting, respectively.11,12
The classic risk group for developing carotid restenosis after CEA has been noted to have increased atherosclerotic risk factors including family history of CAD, smoking, gender, age, hyperlipidemia, diabetes mellitus, presence of CAD, bilateral carotid artery stenosis, thrombosis at the site of CEA, and the type of surgery.
Duplex ultrasound (DUS) is the primary means of surveillance utilized as an initial screening tool after carotid endarterectomy and also post carotid artery stenting to assess for carotid artery patency. Like every noninvasive imaging modality, ultrasound has its limitations in carotid artery imaging. These include a high carotid bifurcation, a long (> 3 cm) ICA plaque or high-grade stenosis, calcification shadows and acoustic artifacts, short neck, presence of tortuosity and nearcomplete occlusion. Furthermore, it is believed that the deployment of a stent changes the compliance and blood-flow velocities, altering biomechanical properties of the artery, all of which make it difficult to utilize the standard velocity criteria in the diagnosis of carotid in-stent restenosis.13
In cases of indeterminate or suboptimal DUS examination, computed tomographic angiography (CTA) has been recommended as a useful imaging modality because of its ability to image tortuous vessels, short necks, high bifurcations and densely calcified carotid plaques. An alternative to CTA, magnetic resonance angiography (MRA) has also been utilized, though its use in the evaluation of in-stent restenosis is hampered by radiofrequency-shifting artifact caused by the metallic composition of the stent (nitinol and tantalum alloy cause less artifact than cobalt and stainless steel stents). In addition, at least one study showed superiority of CTA imaging with nitinol and cobalt stents, and MRA imaging with tantalum stents. Since most carotid stents are either nitinol or stainless steel, CTA may be of some advantage over MRA at this time. Each imaging modality has its own advantages and disadvantages over another imaging modality. Among these, CTA and MRA offer the advantage of assessing the extent of ischemic events and excluding intracranial pathologies prior to endovascular therapy. Carotid angiography, although invasive, may provide useful information where other imaging modalities have difficulties and limitations, and is the confirmed gold standard test for carotid in-stent restenosis.
In this article, we report a single-center experience of carotid in-stent restenosis in a total of 278 patients. Our database was searched for carotid artery disease or CAS patients. The records were further reviewed in terms of patient outcomes, repeat interventions and the specific diagnosis of carotid in-stent restenosis.
From December 2001 to December 2007, angioplasty and stenting were performed on 313 carotid lesions in 278 patients, with an overall success rate of 99% and a complication rate (all stroke, all MI and death at 30 days) of 3.2%. It is the intent of this article to report and discuss in-stent restenosis noted during follow up. Restenosis was defined as a > 50% visual stenosis by carotid DUS, confirmed by carotid angiography. A variety of stents were utilized during this study period and include the following: Precise™ (Cordis Corp., Miami Lakes, Florida) (186), Xact (Abbott Vascular Devices, Redwood City, California) (99), Medtronic (Medtronic, Inc., Minneapolis, Minnesota) (34), Acculink™ (Abbott Vascular) (11), Protégé® (ev3, Inc., Plymouth, Minnesota) (6), Genesis (Cordis) (3), SMART™ (Cordis) (2), and Assurant (Medtronic) (1).
Only 4 patients were identified with instent restenosis, with an additional patient (total of 5) who was considered a treatment failure (Patient #5). Three of these patients had de novo lesions and developed carotid in-stent restenosis after CAS for native carotid artery lesions. The other 2 patients (including the treatment failure patient) were noted to have carotid restenosis secondary to post-CEA, which was treated percutaneously, and later developed carotid in-stent restenosis (these were actually re-restenoses in post-CEA and post-CAS patients). Embolic protection devices were used in all of the patients discussed here and are further reviewed in terms of patient characteristics, repeat intervention and outcomes.
Patient 1. This patient was a 61-year-old male with a history of hypertension, hyperlipidemia, a family history of premature coronary artery disease (CAD), former tobacco use, and cerebrovascular accident (CVA). He was scheduled to undergo cerebral angiography because of amaurosis fugax, and an abnormal carotid duplex study, and developed acute coronary syndrome just prior to his carotid angiogram. In 2002, the patient underwent coronary angiography which showed multivessel CAD. His carotid examination at the same time showed 50% distal left common carotid artery, and 95% left ICA stenosis that was treated with angioplasty and stenting (10 x 30 mm Precise stent), and was postdilated down to 40% residual stenosis (this residual also takes the plaque prolapse into account, which was noted at the end of the case). There also appeared to be plaque prolapse, which was noted in the final images. CABG was performed 48 hours later without any incident. The patient was noted to have increased Doppler velocities approximately 1 year later in a follow-up duplex study, for which he was re-studied and found to have 53% in-stent restenosis that was medically managed. His carotid duplex study from 2006 demonstrated a peak velocity of 162 cm/second (consistent with 20–39% in-stent restenosis).
Patient 2. A 79-year-old female with a history of CAD, prior CABG, prior aortic valve replacement, hypertension, hypothyroidism, hyperlipidemia, obesity and atrial fibrillation was experiencing transient ischemic attack (TIA) symptoms and was found to have an abnormal carotid bruit on ultrasound. She underwent cerebral angiography, which showed bilateral carotid artery disease. In 2002, the patient underwent percutaneous transluminal angioplasty (PTA) and stenting (8 x 30 mm Precise stent) and postdilatation of the 80% stenosis in the right ICA, leaving 15% residual disease. One month later, she underwent successful angioplasty and stenting of the left ICA. Three years later, the patient experienced similar TIA symptoms for which another duplex ultrasound was ordered, showing increased Doppler velocities. Repeat angiographic evaluation revealed 95% in-stent restenosis of the right ICA for which the patient underwent repeat PTA, stenting (9 x 30 mm Acculink) and postdilatation.
Patient 3. An 85-year-old female with a history of CAD, atrial fibrillation and hypertension was experiencing recurrent TIAs. Her duplex ultrasound was abnormal, and carotid angiography revealed 95% right ICA stenosis with diffuse distal disease. The patient underwent predilatation, stent placement (8 x 40 mm Medtronic self-expanding stent) and postdilatation, achieving < 10% residual stenosis. However, distal flow was limited due to diffuse distal disease. Follow-up studies at 30 days, 6 months and 1 year revealed a patent stent. A repeat carotid duplex study was performed 18 months later and showed total occlusion, which was confirmed by MRA. Carotid angiography was not performed because of her age.
Patient 4. A 75-year-old female with a history of hypertension, hyperlipidemia and degenerative joint disease had previously demonstrated bilateral carotid artery disease (remote silent occlusion of the right ICA and critical left ICA disease). She underwent CEA in 2001, followed by repeat CEA with patch angioplasty in 2002 to treat restenosis. Several weeks after her CEA, the patient developed left hemispheric TIA symptoms for which she underwent carotid angiography that showed complete occlusion of the right ICA and 99% restenosis of the left ICA. PTA was performed using predilatation and deployment of two 7 x 30 mm Medtronic stents, followed by postdilatation, achieving 35% residual stenosis. Another 10 x 40 mm Medtronic stent was deployed for a mid-left CCA lesion in 2003. On her follow-up examination in 2004, she underwent repeat angiography because of an abnormal duplex study, which showed 50% residual stenosis. Medical management was recommended since she was asymptomatic. In 2006, duplex ultrasound revealed a peak systolic velocity of 95 cm/second and she remained asymptomatic.
Patient 5. A 57-year-old male with a history of CAD, peripheral vascular disease, diabetes, aortic stenosis, hypertension and hyperlipidemia underwent bilateral CEA 12 years previously. He had an abnormal Doppler ultrasound examination, which led to carotid angiography, showing 80% stenosis of the right carotid artery, which was hemodynamically significant, but asymptomatic. The patient underwent predilatation and stenting (8 x 40 mm Medtronic stent), followed by postdilatation of this lesion, achieving 50% residual stenosis. Since there was a suboptimal outcome to start with, it was considered a treatment failure. Subsequently, the patient developed 50% and 98% in-stent restenosis for which he underwent repeat percutaneous interventions.
Discussion
Carotid in-stent restenosis is one of the potential longterm sequela following CAS. Although it is not as prevalent as in the in the coronary bed, there is a great deal of debate in the medical community on how it should be managed. In a series of 301 post-CEA patients, the incidence of carotid restenosis was found to be 31%, with a 10% regression rate (some of these lesions regress over time) at 7 years and a prevalence of 21% in the surgical cohorts.14 Other than the CAVATAS trial, most registries report less carotid in-stent restenosis with post-CAS than carotid restenosis with post- CEA in surgical cohorts.
In our series, if the surgical patients are excluded, the incidence of carotid in-stent restenosis is reported as 3 (a total of 5 patients) in 278 patients. Apart from traditional risk factors, most of the in-stent restenosis cases had suboptimal results and undilatable lesions. Postprocedural residual lesion/stenosis appears to have the greatest effect on outcomes. At least 50% of our patients also had aortic stenosis and/or atrial fibrillation. There was no gender difference. The subset of patients presenting with surgical restenosis in post- CEA tended to have a stubborn recurrent clinical course, even though they were subsequently retreated percutaneously.
In our series, although post-CAS/post-CEA carotid instent restenosis was observed with Precise and/or Medtronic stents, this may be partly due to selection bias and other confounding variables and should be further looked into in large, randomized trials. Nevertheless, patients who have a previous history of restenosis may also have a higher risk of recurrence, even though they underwent percutaneous intervention.
Possible treatment options include medical management (“watchful waiting”), balloon angioplasty (including cutting balloon and plain-old balloon angioplasty) and/or stenting or repeat surgery. Currently, there is no large, randomized trial underway to identify the best approach in these patients.
Medical management (watchful waiting) was one of the modalities that was suggested, especially in post-CEA patients, since repeat CEA has been noted to produce less-than-impressive results. Therefore, some authors recommend that the treatment should be considered in symptomatic patients only, and/or in those with > 80% restenosis, especially in atherosclerotic degenerative lesions.15,16
The percutaneous approach is still one of the most acceptable methods of treatment in this patient population.17,18 Comorbidity of aortic stenosis/carotid artery disease and restenosis appears to be an undesirable combination and not likely well tolerated (especially in the presence of atrial fibrillation) with a percutaneous approach, as CAS may lower blood pressure substantially and/or chronically in some patient populations. Careful case selection for CAS is warranted, especially in patients who are not candidates for aortic valve surgery to treat severe aortic stenosis. It is equally important to maintain optimum medical therapy with statins and antiplatelet agents in patients with carotid artery in-stent restenosis. For patients in whom there are questions about the nature of the stenosis, IVUS guidance may help to differentiate between rare cases of restenosis from thrombus formation and/or plaque prolapse at the stent site.
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