Safety and efficacy of carotid angioplasty and stenting for radiation-associated carotid artery stenosis

Article Outline

• Abstract
• Methods
  • Preoperative patient characteristics
  • Procedures
  • Perioperative endpoints
  • Captured particulate data
  • Statistical analysis
• Results
  • Preoperative characteristics
  • Perioperative endpoints
  • Captured particulate data
• Discussion
• Conclusion
• Author contributions
• References
• Copyright

Introduction

Prior neck irradiation may induce atherosclerosis in the carotid artery and is considered an indication for carotid angioplasty and stenting (CAS). This study sought to evaluate the effect of neck radiation therapy (XRT) on the rate of restenosis and embolic potential in patients undergoing CAS.

Methods

Two hundred ten CAS procedures were performed on 193 patients (XRT [N = 28], non-XRT [N = 182]). Mean follow-up was 347 ± 339 days (median, 305 days; range, 16-1354 days). Duplex velocity criteria for restenosis after CAS were: >50% restenosis (peak systolic velocity [PSV] > 125 cm/sec, end diastolic velocity [EDV] 40-99 cm/sec, and internal carotid artery to common carotid artery systolic ratio [ICA/CCA] > 2.0); >70% restenosis (PSV>230 cm/sec, EDV>100 cm/sec, and ICA/CCA ratio >4.0). Restenosis >70% was confirmed by digital subtraction angiography. Additional endpoints included groin hematoma, groin pseudoaneurysm, myocardial infarction, stroke, mortality, and the combined myocardial infarction/stroke/mortality rate. Captured particulate data was obtained from microporous filters used during CAS. Nineteen XRT and 128 non-XRT consecutive filters were analyzed. Photomicroscopy was performed along three axes for each filter, and the quantity and size of the captured particles were analyzed using video image analysis software.

Results

There were more men (XRT: 85.7% vs. non-XRT: 52.8%, P < .001) and prior surgical neck dissections in the XRT patients (XRT: 82.1% vs. non-XRT: 4.7%, P < .001). Pre-procedural stenosis did not differ significantly betweeen the two groups (XRT: 86.5% ± 8.9% [range, 70%-99%] vs. non-XRT: 85.5% ± 8.7% [range 70%-99%], P = NS). Perioperative outcomes, including the composite 30 day stroke/myocardial infarction/mortality rate did not differ significantly between the two groups (XRT: 0% vs. non-XRT: 3.2%, P = NS). Twelve-month freedom from restenosis rates did not differ significantly at the 50% threshold (XRT: 95.5% vs. non-XRT: 90.3%, P = NS) or at the 70% threshold (XRT: 95.5% vs. non-XRT: 96.5%, P = NS). Target lesion revascularization did not differ significantly (XRT: 0% vs. non-XRT: 0.5%, P = NS). Photomicroscopy demonstrated a trend towards increased particle number and size in the XRT filters, however the results did not achieve statistical significance: particle number (XRT: 9.8 ± 8.4 vs. non-XRT: 9.6 ± 11.7, P = NS), %patients with particle size >1000 μm (XRT: 47.4% vs. non-XRT: 30.5%, P = NS).

Conclusions

This study suggests that the durability of CAS and the characteristics of captured embolic particles are not altered by a history of neck XRT. This supports the safety and efficacy of CAS for the treatment of patients with a history of neck XRT. Prior neck XRT may predispose the patient to the de novo development of stenoses at locations that were not previously treated.

Extracranial carotid artery occlusive disease is a significant risk factor for stroke. Level I evidence demonstrates that treatment for carotid artery occlusive disease using carotid endarterectomy (CEA) results in durable freedom from stroke in symptomatic and asymptomatic patients.¹, ², ³, ⁴, ⁵ In addition, emerging evidence is demonstrating that endovascular treatment using carotid angioplasty and stenting (CAS) with embolic protection may be beneficial in specific subgroups of patients with carotid artery occlusive disease.⁶, ⁷ CAS is thought to be beneficial in patients who are at increased risk for developing complications when treated using standard CEA, including patients with a history of neck radiation therapy (XRT).⁸

Patients who undergo treatment for neck malignancies frequently exhibit scarring, distorted neck anatomy, and impaired wound healing due to prior surgical neck dissection and radiation injury sequelae. In vitro and rodent models have demonstrated that XRT promotes the development of atherosclerosis.⁹, ¹⁰ In humans, this has been hypothesized to result in increased carotid stenosis and restenosis rates following surgical or endovascular therapy.¹¹, ¹², ¹³ Due to the absence of a neck incision, the diminished risk for cranial nerve injury, and the remote location of percutaneous intervention, CAS is suited for the treatment of patients with a history of neck XRT.

CAS may result in the emoblization of atherosclerotic particulate debris.¹⁴ As a corollary, the addition of embolic protection devices to the procedure has been demonstrated to decrease the risk for stroke.¹⁵ In addition, embolic protection devices enable the analysis of the captured embolic particles. This study sought to evaluate the effect of a history of neck XRT on restenosis rates and on embolic potential in patients treated using CAS.

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Methods 

This study was a retrospective review of a prospectively maintained database of a consecutive unselected group of patients who underwent carotid angioplasty and stenting. Data was collected from April 2003 to August 2008. The internal review board and the ethics committee approved the study protocol.

Preoperative patient characteristics 

Two hundred ten CAS procedures were performed on 193 patients. The mean follow-up interval was 347 ± 339 days (median, 305 days; range, 16-1354 days). The patients were initially selected for treatment using CAS based on clinical variables that placed them at increased risk for complications from standard carotid endarterectomy, including restenosis after prior CEA, a history of neck XRT, neck dissection for cancer therapy, contralateral carotid artery occlusion, and increased cardiopulmonary risk.¹⁶, ¹⁷ In this study, the patients were stratified according to whether they exhibited a history of neck XRT (N = 28) or no XRT (N = 182). Patients underwent neck XRT as neoadjuvant or adjuvant treatment for neck malignancy. The preoperative percentage stenosis was determined using North American Symptomatic Carotid Endarterectomy (NASCET) criteria.

Procedures 

All procedures were performed by vascular surgeons in an operating room angiography suite using a fixed imaging system (Siemens AG, Munich, Germany) or using portable fluoroscopy (GE-OEC, Salt Lake City, Utah). All procedures were performed using local anesthetic without sedation and through femoral access. The embolic protection devices used included: Accunet (Abbott Laboratories, Chicago, Ill), Angioguard (Cordis Corporation, Miami Lakes, Fla), Emboshield (Abbott Laboratories), EPI FilterWire (Boston Scientific Corp, Natick, Mass), PercuSurge (Medtronic, Santa Rosa, Calif), and SpiderFX (EV3 Inc, Plymouth, Minn) (Tables Ia and Ib). The proportion of each emoblic protection device did not vary between the XRT and non-XRT groups. Perioperative anticoagulation consisted of Aspirin 81 mg or 325 mg by mouth daily, which was started 72 hours preoperatively and continued for four weeks postoperatively; Clopidogrel 75 mg by mouth daily, which was started five days preoperatively and continued for four weeks postoperatively; and intraoperative heparinization which was used with a goal activated clotting time of 250-350 seconds.

Table Ia. Embolic protection devices used for the study population

non-XRT, No prior history of neck irradiation; XRT, prior history of neck irradiation.

Table Ib. Embolic protection devices used for the captured embolic particles analysis

non-XRT, No prior history of neck irradiation; XRT, prior history of neck irradiation.

Accunet (Abbott Laboratories, Chicago, Ill), Angioguard (Cordis Corporation, Miami Lakes, Fla), Emboshield (Abbott Laboratories), EPI FilterWire (Boston Scientific Corp, Natick, Mass), PercuSurge (Medtronic, Santa Rosa, Calif), and SpiderFX (EV3 Inc, Plymouth, Minn).

Perioperative endpoints 

Postoperative follow-up consisted of an independent neurological assessment including a National Institutes of Health Stroke Scale (NIHSS) assessment by a neurologist or a NIHSS-certified provider. Each postoperative stroke was confirmed and documented by a neurologist. Patients were evaluated postoperatively at one, three, six, nine, and 12 months and annually thereafter. Carotid artery duplex studies were performed on each follow-up visit. Duplex velocities were used to evaluate restenosis according to the following criteria: >50% restenosis required a peak systolic velocity (PSV) > 125 cm/sec, an end diastolic velocity (EDV) 40-99 cm/sec, or an internal carotid artery to common carotid artery systolic velocity ratio (ICA/CCA) > 2.0; > 70% restenosis required a PSV > 230 cm/sec, EDV > 100 cm/sec, or ICA/CCA ratio > 4.0. Greater than 70% restenosis was confirmed using digital subtraction angiography.¹⁸

The primary endpoints evaluated included: stroke; myocardial infarction, which was diagnosed by cardiac enzyme elevation and electrocardiogram changes; mortality; and the combined stroke, myocardial infarction, and mortality rate. Secondary endpoints included > 50% restenosis, > 70% restenosis, access site hematoma, and access site pseudoaneurysms. The primary and secondary endpoints were evaluated at 30 days with the exception of > 50% restenosis and > 70% restenosis, which were evaluated up until the most recent follow-up.

Captured particulate data 

Captured particulate data were obtained from formalin-preserved microporous embolic protection filters that were used during CAS. Nineteen consecutive XRT and 128 consecutive non-XRT filters were analyzed. The embolic protection devices evaluated in this study (N = 147) were unselected, although they included only those devices that were filters (Tables Ia and Ib). There was no significant difference in the distribution of filter types analyzed between the XRT and the non-XRT groups. There were no significant differences in preoperative characteristics between the entire population studied and the population that underwent filter analysis.

In-situ filter thrombosis was minimized with the use of systemic anticoagulation during the procedure. Upon completion of the procedure, the external surface of each filter was wiped with a sterile gauze moistened with normal saline. Saline was then instilled into the filter and wicked through the microporous membrane using a dry gauze applied to the external surface of the filter. The filter was then fixed in 10% neutral buffered formalin (EMD Chemicals Inc., Gibbstown, NJ) solution for 24 hours. The captured particles were analyzed using photomicroscopy. Each filter was analyzed along three perpendicular axes, and the captured particles were analyzed using a computerized video image analyzer. The total number of particles and the greatest length of each particle were recorded. The greatest length was used to represent particle size due to heterogeneity in particle shape.

Statistical analysis 

Discrete variables were compared using Fisher's exact test. Normally distributed continuous variables were compared using two-tailed, unpaired Student's t tests. All values were represented as a mean ± standard deviation, where applicable. Restenosis rates were evaluated using Kaplan-Meier life-table analyses and compared using log-rank analyses. P < .05 was considered statistically significant. The statistical software used was SPSS version 15.0 for Windows (Microsoft, Chicago, Ill).

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Results 

Preoperative characteristics 

Following stratification of the total number of procedures performed in patients with a history of neck XRT and those without a history of neck XRT, there was a greater percentage of men in the XRT group (XRT: 85.7% vs. non-XRT: 52.8%, P < .001) (Table II). The mean age and the percentage of right-sided interventions did not differ significantly between the two groups.

Table II. Preoperative characteristics of the total population following stratification into XRT and non-XRT patients

	Percentage
Characteristic	XRT N = 28	Non-XRT N = 182	P value
Demographics
Age (mean ± standard deviation)	69.3±7.3	72.1±9.2	.14
Gender (percent men)	85.7	52.8	<.001
Interval follow-up	314.9±339.8	352.8±335.8	.66
Preoperative symptoms
Any symptoms	34.6	34.3	1.00
Transient ischemic attack	25.9	17.2	.29
Stroke	14.8	12.9	.76
Amaurosis fugax	7.4	7.3	1.00
Lesions
Preoperative percent stenosis	84.5±12.6	86.8±8.3	.35
Side (percent right)	53.6	50.8	.84
Contralateral occlusion	30.0	14.8	.11
Preoperative cardiac history
Congestive heart failure	3.7	14.1	.21
Coronary artery disease	40.7	57.9	.10
Myocardial infarction	14.8	23.4	.46
Preoperative non-cardiac history
Neck dissection for cancer	82.1	4.7	<.001
Chronic obstructive pulmonary disease	7.4	17.0	.26
Chronic renal insufficiency	14.8	10.5	.51
Diabetes	18.5	30.4	.26
End-stage renal disease	0.0	0.6	1.00
Hyperlipidemia	59.3	69.2	.37
Hypertension	59.3	87.9	<.001
Peripheral vascular disease	11.1	25.3	.14
Tobacco	78.3	67.9	.47

non-XRT, No prior history of neck irradiation; XRT, prior history of neck irradiation.

Evaluation of preoperative symptomatology demonstrated that there was no significant difference in patients who presented with symptomatic carotid artery stenosis (XRT: 34.6% vs. non-XRT: 34.3%, P = NS). Additional stratification into patients who presented with transient ischemic attack, stroke, or amaurosis fugax also failed to demonstrate significant differences between the XRT and non-XRT groups. The degree of preoperative stenosis also did not differ significantly between the two groups.

Evaluation of the preoperative cardiac history did not differ significantly between the XRT and non-XRT groups. In addition, preoperative coronary artery disease, congestive heart failure, and myocardial infarction did not differ significantly between the two groups.

Evaluation of the preoperative non-cardiac history demonstrated that a greater percentage of patients in the XRT group presented with his history of prior neck dissection for cancer (XRT: 82.1% vs. non-XRT: 4.7%, P < .001). In addition, a greater percentage of patients in the non-XRT group presented with hypertension (XRT: 59.3% vs. non-XRT: 87.9, P < .001). Additional preoperative variables that did not differ significantly between the two groups included chronic obstructive pulmonary disease, chronic renal insufficiency, diabetes, end-stage renal disease, hyperlipidemia, peripheral vascular disease, and tobacco use.

Perioperative endpoints 

The restenosis and perioperative complication rates did not differ significantly between the XRT and non-XRT groups (Table III). Twelve-month freedom from restenosis rates did not differ significantly at the 50% threshold (XRT: 95.5% vs. non-XRT: 90.3%, P = NS) or at the 70% threshold (XRT: 95.5% vs. non-XRT: 96.5%, P = NS). In the XRT group, the affected patient developed restenosis at a site separate from that which was treated originally. The restenosis occurred distal on the ICA. In addition, twelve-month target lesion revascularization rates did not differ significantly (XRT: 0% vs. non-XRT: 0.5%, P = NS). Perioperative outcomes, including the combined 30 day stroke, myocardial infarction, and mortality rate did not differ significantly between the two groups (XRT: 0% vs. non-XRT: 3.2%, P = NS).

Table III. Perioperative endpoints

	Percentage
Characteristic	XRT N = 19	Non-XRT N = 128	P value
Freedom from restenosis at 12 months
> 50%	95.5	90.3	.70
> 70%	95.5	96.5	.58
Complications
Hematoma	5.3	4.4	1.00
Pseudoaneurysm	0	0.7	1.00
Myocardial infarction	0	0.6	1.00
Stroke	0	1.9	1.00
Mortality	0	0.7	1.00
Myocardial infarction/stroke/mortality	0	3.2	1.00

non-XRT, No prior history of neck irradiation; XRT, prior history of neck irradiation.

Captured particulate data 

Photomicroscopy demonstrated that the percentage of patients with embolic debris did not differ significantly between the XRT and non-XRT groups (Table IV). In addition, the mean particles per filter and the percentage of filters with particles in the 200-500 μm, 500-1000 μm, and > 1000 μm ranges did not differ significantly between the XRT and non-XRT groups.

Table IV. Captured particulate

	Percent with embolic debris	Percent patients 200-500 μm	Percent patients 500-1000 μm	Percent patients >1000 μm	Mean number of particles
XRT (N = 19)	84.2	73.4	63.2	47.4	9.8±8.4
Non-XRT (N = 128)	80.5	70.3	58.6	30.5	9.6±11.7
P Value	1.00	1.00	.81	.19	.95

non-XRT, No prior history of neck irradiation; XRT, prior history of neck irradiation.

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Discussion 

CAS may be beneficial for the treatment of carotid artery occlusive disease in those patients who are at increased risk for complications following standard carotid endarterectomy. In particular, patients with a history of neck XRT are thought to derive benefit from CAS due to the absence of a neck incision, the avoidance of possible cranial nerve injury due to the increased difficulty of dissection, and the avoidance of wound healing complications in an irradiated field, particularly in the presence of a tracheal stoma.⁸

Neck XRT may contribute to increased complication rates through multiple mechanisms. In vitro and rodent models demonstrate that radiation induces a proinflammatory and prothrombotic phenotype within atherosclerotic plaque.¹⁰ Hypercholesterolemic ApoE(−/−) mice subject to fractionated radiation exhibit accelerated development of macrophage rich, pro-inflammatory atherosclerotic lesions, which are also prone to hemorrhage.¹⁰, ¹⁹ In addition, ionizing radiation may also result in foam cell formation within atherosclerotic plaque.²⁰

Clinically, rates of carotid restonsis following CEA or CAS are thought to be increased in patients with a history of cervical irradation. One study reported a significant rate of late reinterventions that occurred three to four years following CAS in patients with a history of cervical XRT.²¹ In a similar study of patients with a history of radiation arteritis who were treated using CAS, an increased rate of late asymptomatic occlusions was observed.²² In one retrospective review, the mean interval between radiation exposure and stroke was 8.5 years.²³ In addition to altering atherosclerotic plaque biology, radiation therapy may contribute to wound healing complications due to ischemic changes that result from obliterative endarteritis and due to scar tissue formation.²⁴ Lastly, cervical irradiation in this study was used exclusively in patients with cervical malignancies, the majority of whom also required neck dissection. This might also contribute to the increased difficulty of subsequent neck dissection.

Atherosclerotic embolic particles are released during CAS. This has been demonstrated previously using multiple modalities. Transcranial doppler demonstrates that atherosclerotic particles are embolized to the distal vasculature even in the presence of an embolic protection device.²⁵ Postprocedural magnetic resonance imaging studies suggest the presence of new focal ischemic deficits in up to 43% to 78% of patients who undergo CAS.²⁶, ²⁷ This has been borne out clinically with the demonstration of improved outcomes in patients treated using embolic protection devices.⁷, ⁸

Analysis of captured embolic debris may be used as a clinically significant proxy for evaluating changes in atherosclerotic plaque biology. For example, the presence of preoperative symptomatology is associated with an increase in the number and size of captured embolic particles.¹⁴ This finding is consistent with the increased friability of plaque and the increased risk of neurologic sequelae that are observed in symptomatic patients.

This study compared patients with and without a history of neck XRT. In addition, the embolic protection devices were analyzed using photomicroscopy in order to characterize the captured emoblic particles. Periopertive outcomes including > 50% restenosis, > 70% restenosis, vascular access site complications, stroke, myocardial infarction, mortality, and the combined stroke, myocardial infarction and mortality rates were low and did not differ significantly between the XRT and non-XRT patients. In addition, characterization of the captured embolic particles did not reveal any significant differences between the XRT and non-XRT patients. The failure to demonstrate differences in restenosis rates and in the characteristics of captured embolic debris suggests that the safety and durability of CAS for the treatment of patients with a history of neck irradiation is similar to that of CAS for the treatment of primary atherosclerotic lesions.

This study has the limitation that it is a retrospective review, which lacks a formal randomization process. In addition, there is a significant discrepancy in the patient sample sizes when comparing patients with and without a history of neck XRT. This is predictable, since only a small percentage of patients undergoing CAS have a history of neck XRT for the treatment of cancer. Nevertheless, the majority of preoperative characteristics did not differ significantly between the two groups. The incidence of hypertension was increased in the non-XRT group, and the percentage of men was increased in the XRT group. Hypertension may be a confounding variable, since it has been shown to correlate with atherosclerotic burden.²⁸ The difference in gender might potentially complicate interpretation of the data in this study. The predominance in men is predictable due to the male predominance of head and neck cancers.²⁹ However, recent studies have failed to demonstrate a gender effect with regards to carotid stenosis or restenosis rates.³⁰, ³¹ The preoperative characteristic in this study that correlates most strongly with a history of neck XRT is prior neck dissection for surgery. The neck dissections for cancer treatment in this study did not involve carotid artery manipulation. Therefore, the results of this study are predicated on the assumption that prior neck XRT plays the greatest potential role in altering plaque pathobiology.

Although this study has a mean follow-up of approximately one year, other studies report a significant rate of late reintervention following cervical XRT. This is thought to occur three to four years following CAS.²¹ The development of de novo stenoses at locations that were not previously treated was observed in this study and might be a potential explanation for the need for secondary intervention. Further study is required to evaluate this hypothesis.

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Conclusion 

This study demonstrates that, on mid-term follow-up, the durability of CAS and the characteristics of captured embolic particles are not altered by a history of neck XRT. This supports the safety and efficacy of CAS for the treatment of patients with a history of neck XRT. Additional studies are required to confirm that these results are durable on long-term follow-up.

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Author contributions 

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