Evaluation and management of plaque protrusion or thrombus following carotid artery stenting.

Carotid artery stenting (CAS) has become a common treatment for carotid artery stenosis. However, complications, such as an ischemic event, can occur with CAS during intra- and post-operative periods. Among these ischemic complications, plaque protrusion into the stent and thrombus on the stent have occurred after CAS. We retrospectively evaluated the temporal profile and treatment options for these complications in 32 consecutive cases who underwent CAS at our hospital between April 2009 and December 2011. The cases were evaluated pre-operatively for risk factors, as well as the plaque morphology and characteristics using computed tomographic angiography (CTA), ultrasound (US), and magnetic resonance imaging (MRI). Post-operatively, lesions were examined by CTA and/or US within 1 week of CAS. As a result, among the 32 cases, 8 experienced plaque protrusions or thrombus, which were treated with medication (anti-platelet and/or anti-coagulation reinforcement). In 7 of these 8 cases, the plaque protrusion or thrombus was stabilized with medication alone. However, the remaining case showed growth and migration of the plaque protrusion or thrombus when treated with medication alone, and therefore, required further endovascular treatment. We identified that a history of symptomatic cerebral infarction and plaques with ulceration were risk factors for plaque protrusion or thrombus formation after CAS, and pre dilatation can decrease the risk of these complications. Medication was effective in most cases of plaque protrusion or thrombus; however, further endovascular treatment was required when medication alone was unsuccessful.

Introduction

Carotid artery stenting (CAS) has become a common treatment for internal carotid artery (ICA) stenosis. Even though embolic protection devices have been developed to reduce the occurrence of intraoperative ischemic events, plaque protrusion or thrombus can still occur during the subacute phase following CAS.[1,2)] Because of the risk of these embolic complications,[1,3,4)] it is important to identify the risk factors of plaque protrusion and thrombus and an adequate treatment. Several devices or techniques, such as magnetic resonance imaging (MRI) plaque imaging,[5–7)] intravascular ultrasound (IVUS),[8)] and computed tomographic angiography (CTA), can be used to evaluate the characteristics of the plaque. In this study, we evaluated the medical risk factors and plaque characteristics that affect the occurrence of plaque protrusion or thrombus in our patients.

Materials and Methods

We retrospectively examined 32 consecutive cases who underwent CAS at our hospital between April 2009 and December 2011. Among these patients, we identified symptomatic ICA stenosis over 60% and asymptomatic ICA stenosis over 80%. Cases with ICA dissection were excluded from the analysis.

We selected patients requiring CAS for post-ischemic heart disease, a high risk of general anesthesia, and the high position of the CCA-ICA bifurcation. All 32 cases included carotid lesions and were evaluated both pre- and post-operatively with CTA, ultrasound (US), and MRI plaque imaging (black-blood imaging), in addition to digital subtraction angiography (DSA). Post-operative CTA and US were routinely performed, but DSA exams were not mandatory. CTA was performed using a multi-slice CT scanner (Aquilion, Toshiba Medical Systems, Otawara, Tochigi). MRI plaque imaging was performed on a 1.5 T MRI scanner (Intera Achieva, Phillips Medical Systems) using neck three-dimensional time-of-flight (3D TOF) magnetic resonance angiography (MRA) and T1-weighted and T2-weighted black-blood imaging. Aspirin (100 mg) and clopidogrel (75 mg) were given orally for 5 days before the procedure. Most of the cases (30/32) were treated via the trans-femoral artery; 2 cases were treated via direct carotid artery puncture through a small cervical incision. A bolus injection of heparin (5,000 U) was administered immediately after the sheath was implanted in the artery. During the procedure, the activated clotting time was between 250 s and 350 s. We used Optimo (Tokai Medical Products) and Brite Tip (Cordis) as guiding catheters; Guardwire (Medtronic AVE), Angioguard XP (Cordis), and EZ Filter (Boston Scientific) as distal protection devices; Jackal RX (Kaneka Medical) and Submarine (Medtronic AVE) as pre and post dilatation balloons; and Precise (Cordis; n = 30) and Wallstent (Boston Scientific; n = 2) as stents. The Brite Tip catheters were used when we could not deploy the Optimo catheters at common carotid artery. We performed pre-dilatation when the smallest diameter of the lesion was less than 2 mm and performed post-dilatation when the smallest diameter of the lesion was less than 3 mm after stent deployment. The selection of the distal protection device and balloon depended on period. The selection of stent depended on the surgeon’s preference. The patients were administered heparin (10,000 U/24 h) after the procedure. IVUS (Volcano) was performed regularly after stent deployment. Plaque protrusion and/or thrombus were defined as CTA or US evidence of adhesion of some components within the stent. We compared patients who were occurred plaque protrusion or thrombus formation with the patients who were not occurred any complications. The following nine factors were compared: age, hypertension, diabetes mellitus, hyperlipidemia, symptomatic (this means the patient have a past history of symptomatic cerebral infarction), pre-dilatation, post-dilatation, ulcer, and MRI plaque imaging positive. MRI plaque imaging positive was defined as the plaque having higher signal intensity than that of the sternocleidomastoid. We compared all nine factors using a χ2 test and some factors which have tendency or significantly differ by χ2 test (p-value < 0.1) were taken for multivariate logistic regression analysis. All of the statistical analyses were performed with StatMate5 software.

Results

The characteristics of these 32 cases are shown in Table 1. Among them, eight showed plaque protrusions or thrombus, who were treated with intensive anti-platelet and/or anti-coagulation therapies. Seven cases showed remission of the plaque protrusions or thrombus with medication alone (Fig. 1); however, one case did not respond to medication and required further endovascular therapy (Fig. 2). According to χ2 test, symptomatic and ulcer are significant risk factors for plaque protrusion or thrombus following CAS. MRI plaque imaging positive tended to show plaque protrusions or thrombus. In contrast, pre-dilatation tended to decrease the risk of plaque protrusions or thrombus (Table 1). Multivariate logistic regression analysis also revealed that symptomatic and ulcer tended to cause plaque protrusion or thrombus. However, despite the high odds ratios, no significant difference was observed (Table 2).

Table 1

Patient characteristics (32 patients)

Characteristic	Plaque protrusion or thrombus positive (n = 8)	Plaque protrusion or thrombus negative (n = 24)	χ square test p-value
Age (years)	77.9	77.7	(NS)
Hypertension	5 (62.5%)	17 (70.8%)	0.7
Diabetes mellitus	2 (25%)	9 (37.5%)	0.5
Hyperlipidemia	2 (25%)	7 (29.1%)	0.8
Symptomatic	7 (87.5%)	9 (37.5%)	0.01
Pre-dilatation	3 (37.5%)	17 (70.8%)	0.09
Post-dilatation	4 (50%)	12 (50%)	1.0
Ulcer	7 (87.5%)	9 (37.5%)	0.01
MRI plaque image positive	7 (87.5%)	13 (54.2%)	0.09

MRI: magnetic resonance imaging.

Fig. 1.

(Case 8). Images of representative case of medically treatable plaque protrusion or thrombus. A: CTA on the 2nd day after CAS, the arrow shows plaque protrusion or thrombus in the stent. B: CTA on the 6th day, arrowhead shows plaque protrusion or thrombus got small. C: DSA before CAS. D: DSA after CAS. CAS: carotid artery stenting, CTA: computed tomographic angiography, DSA: digital subtraction angiography.

Fig. 2.

(Case 7). Images of representative case of plaque protrusion or thrombus that required further endovascular therapy. A: CTA on the 5th day after CAS. B: CTA on the 9th day after CAS. C: Intravascular ultrasound before the treatment of plaque protrusion or thrombus, asterisk shows plaque protrusion or thrombus. D: Intravascular ultrasound after the treatment of plaque protrusion or thrombus. E: DSA before the 1st CAS. F: DSA after the 1st CAS. G: DSA before the 2nd CAS. H: DSA after the 2nd CAS. CAS: carotid artery stenting, CTA: computed tomographic angiography, DSA: digital subtraction angiography.

Table 2

Multivariate logistic regression analysis

Characteristics	p-value	Odds ratio	95% CI lower	95% CI upper
Symptomatic	0.052	12.86	0.976	169.4
Pre-dilatation	0.259	0.267	0.026	2.654
Ulcer	0.072	10.81	0.807	144.8
MRI plaque image positive	0.169	6.841	0.439	106.4

CI: confidence interval, MRI: magnetic resonance imaging.

Table 3 shows all characteristics of patients with plaque protrusion or thrombus. Echogenicity in this table categorize three groups. “Low” is lower echogenicity than intima, “iso” means equivalent, and “mixed” means nonhomogeneous. Table 4 shows the treatment procedures for plaque protrusion or thrombus. In most of the cases, we added cilostazol as a third anti-platelet therapy and continued anti-coagulation therapy with heparin. The plaque protrusions or thrombus were reduced in seven cases with medication alone; only one case required further endovascular treatment with balloon dilatation and stent deployment.

Table 3

Characteristics of plaque protrusion or thrombus positive cases

Case	Echogenicity	Pre-dilatation	Post-dilatation	Ulcer	MRI plaque image positive
1	Low	−	−→ +	+	+
2	Iso	+	−→ +	+	+
3	No data	−	−→ +	+	+
4	Mixed	−	+	−	−
5	Low	−	−	+	+
6	Mixed	+	−→ +	+	+
7	Mixed	−	+	+	+
8	Low	−	−→ +	+	+

MRI: magnetic resonance imaging.

Table 4

Treatment procedures for plaque protrusion or thrombus

Case	Aspirin	Clopidogrel	Cilostazol	Post-op heparin	Others	Outcome
1	+	+	−→ +	−	Argatroban, edaravone	Minor stroke
2	+	+	−→ +	−
3	+	+	−→ +	−
4	+	+	+	+
5	+	+	−	+	Post-dilatation
6	+	+	−→ +	−
7	+	+	+	+		Re-CAS
8	+	+	−→ +	+

CAS: carotid artery stenting, Post-op: post-operation, +: drug used, −: drug not used.

Discussion

Plaque protrusion is one type of ischemic event that can follow CAS,[1,3,4)] yet its mechanism and treatment remain unclear. At the same time, although the mechanisms of thrombus formation on stents are known, the risk factors and the treatment have not been established. To clarify these issues, and to reduce the risk of peri-operative embolic complications, we evaluated their risk factors and interventional techniques. We found that symptomatic tended to be an independent risk factor for plaque protrusions or thrombus after CAS. Symptomatic plaque was also indicated as a thrombo-embolic risk factor in CAS during the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) study.[9)] In that study, the characteristics of carotid plaque were pre-operatively evaluated using CTA, MRI, and US. CTA was used to evaluate the morphology of plaques and associated ulceration. In other studies, MRI and US have been used to investigate the pathological mechanisms of plaque progression.[5–7,10,11)] We consider that the complications following CAS depend on the characteristics of the plaque. Carotid plaque is classified into three components: calcified, fibrous, and lipid rich, which are often mixed.[12–14)] The lipid rich plaque is the most highly vulnerable, and shows low echogenicity on US and a high intensity of T1WI black blood (T1BB) imaging.[12–14)] Although the differences were not statistically significant in the present study, the ratio of showing high intensity of T1BB in the plaque protrusion or thrombus positive group was higher than that in the negative group. These data suggest that plaques with a higher intensity of T1BB are more likely to progress plaque protrusion or thrombus formation following CAS. The Imaging in Carotid Angioplasty and Risk of Stroke (ICAROS) study showed that plaques with low echogenicity were a risk factor for endovascular treatment.[15)] As for the US data in our cases, the ratio of low echoic plaque in the plaque protrusion or thrombus positive group (3/8) was higher than that in the negative group (2/19). Because there were data defects, we could not statistically analyze the US data.

Plaques with ulceration were also associated with a high risk of complications following CAS in this study. Plaques with ulceration are a plausible risk factor for stroke because they are highly vulnerable.[10)] Although prestent balloon dilatation does not decrease peri-operative ischemic events overall, this study suggests that pre-dilatation tended to decrease the risk of plaque protrusion or thrombus. It is assumed that pre-dilatation and aspiration can decrease plaque volume, particularly the soft tissues in the plaque that is fragmented by pre-dilatation. Therefore, following pre-dilatation, the ratio of plaque protrusion or thrombus tends to be low.

In the previously reported cases, plaque protrusion has been treated by surgical removal,[1,3)] and additional endovascular therapy,[16)] despite intensive anti-thrombotic therapy.[1)] In the present study, we reinforced anti-platelet and/or anti-coagulation therapy after plaque protrusion or thrombus was detected. Seven cases improved with medication alone, whereas one case continued to deteriorate with medication (case 2) and required further endovascular therapy to eliminate the plaque protrusion or thrombus. Thus, medical treatment alone was effective for the majority of cases of plaque protrusions or thrombus. We recommend that reinforcement of anti-platelet and/or anti-coagulation therapy should be the first line of treatment for plaque protrusion or thrombus. In this study, we performed endovascular therapy for one case that did not respond to medical therapy.[16)]

In most of our cases, we used the Precise stent, which is an open-cell stent. Although closed-cell stents are considered suitable for vulnerable plaque,[17)] some reports have shown no difference between open-cell and closed-cell stents in terms of embolic complications[18,19)] and plaque protrusion.2) However, this matter remains controversial and further studies with larger samples are needed to compare these stents prospectively.

Another particularly concerning issue is accurate diagnosis of plaque protrusion. Okahara et al.[2)] reported that a low density area on CTA could be assumed to be a plaque protrusion, but that it may have had some thrombus components. We consider US/IVUS findings to be helpful in distinguishing a thrombus from a plaque protrusion within the stent. In this study, we defined plaque protrusion or thrombus as adhesion of intra-stent components on CTA or US. Post-operative US was unable to assess the echogenicity of the lesion correctly because of the acoustic shadow produced by the stents and could only assess whether an intra-stent lesion was present. Therefore, it is not possible to define whether the lesions were plaque protrusion only or were thrombus only. We speculate that the risk of thrombus formation after CAS is high when the plaque protrusion exists, because the plaque itself can cause a thrombus. Based on this speculation, we consider that the risk for plaque protrusion is associated with the risk of thrombus after CAS.

From a clinical viewpoint, once a plaque protrusion is detected, if it was thrombus in fact, several US examinations must be performed to monitor the size and volume of the stent over time. In our cases, the plaque protrusion or thrombus make changes in 1 week after it detected, so if there is no remission of the plaque protrusion or thrombus with intensive medication therapy for 1 week, we must consider endovascular or surgical treatments to prevent ischemic complications.

Conclusion

Ulcers and symptomatic stroke were putative risk factors for plaque protrusion and thrombus in this study. In addition, we found that pre-dilatation might reduce the risks of these complications. Although intensive medical therapy was generally effective after the complications were diagnosed, further endovascular treatment might be required in some medication-refractory cases.