Carotid Artery Stenting in High-Risk Patients: Midterm Mortality Analysis
Article Outline
Carotid artery interventions are predicated on early and late survival to prevent ischemic strokes. The technical feasibility of carotid artery stenting (CAS) has been established. Short-term results have been conflicting. Despite this, many practices have adopted CAS as an alterative to carotid endarterectomy in high-risk patients. Long-term protective benefits, however, are less established in high-risk patients. Midterm results following CAS in our high-risk protocol were analyzed to determine specific and all-cause mortality rates (beyond 30 days). We retrospectively evaluated a prospective carotid artery stent registry from October 2003 to February 2006. Demographics, high-risk indication, presence of carotid symptoms, prior history of cancer, periprocedural success, complications, as well as follow-up including readmission rate as well as specific etiology of death were recorded. Fifty patients with critical carotid stenosis (mean stenosis 90%) underwent CAS. This cohort met high-risk criteria due to physiologic reasons in 26 patients and anatomic factors in 22 cases. Two patients met both criteria. Indications were symptomatic disease in 14 (30%) and asymptomatic in 36 cases. The overall 30-day stroke, myocardial infarction, and death rate was 2%. No minor or major strokes were recorded within 30 days postprocedure. Overall average follow-up was 11-28 months. Stroke-free survival was 94% for all patients. Overall 1-year survival was 75% for all patients, significantly higher for the asymptomatic group (88%) (p < 0.01). Late mortality after 30 days was 11 cases (22%) at an average of 9 months post-CAS, ranging 3-13 months. No late mortality was due to ischemic stroke. Specific etiologies of mortality included end-stage cardiac disease (n = 1), recurrent or metastatic cancer (n = 2), acute cardiac event (n = 1), infectious complications (n = 3), and other (n = 3). Only symptomatic indication was predictive of late mortality. Clinicians may continue to cautiously offer CAS to asymptomatic high-risk patients given their anticipated longevity. Symptomatic patients, despite poor midterm survival, do achieve freedom from neurologic death following CAS.
Introduction
The natural history of surgical treatment of high-grade symptomatic carotid stenosis shows an excellent neurologic protection compared to medical treatment.1 In the asymptomatic subset, stroke prevention was also validated, but its benefits are more dependent on long-term survival.2 Protected carotid artery stenting (CAS) is considered by many the treatment of choice in high-risk patients based on a single randomized control trial.3 Data from multiple high-risk registries have been presented, though not published in peer-reviewed articles, but have only evaluated periprocedural issues (within 30 days) and concentrated mainly on safety end points.
Despite Food and Drug Administration approval of dedicated CAS systems, clinical reimbursement of CAS is limited to high-risk symptomatic patients. The rationale for this may be the perception that high-risk asymptomatic patients may not experience stroke prevention due to an anticipated limited life span. This study evaluates all-cause and specific late mortality (beyond 30 days) in high-risk patients undergoing CAS.
Methods
Review of a prospectively maintained “high-risk” carotid artery stent registry identified 50 consecutive patients from October 2003 to February 2006 at the Loma Linda Veterans Affairs Medical Center. Selection and allocation to the high-risk category was based on established protocol (Table I). Patients were separated into anatomic high-risk and physiologic high-risk groups based upon accepted criteria.
Table I. Categories of high risk
| Anatomic | High or tandem lesion |
| Previous CEA with recurrent stenosis | |
| Previous radical neck dissection or radiation therapy to neck | |
| Physiologic | Congestive heart failure (class III/IV) or LVEF <30% |
| Open heart surgery required within 6 weeks | |
| Recent MI (>24 hr and <4 weeks) | |
| Unstable angina (CCS class III/IV) | |
| Severe pulmonary disease (O2-dependent) | |
| Unfit for surgery per vascular surgeon consensus |
Briefly, our technique includes preprocedural combination antiplatelet therapy and magnetic resonance angiography of the aortic arch, extracranial carotid, and intracerebral circulation. The percutaneous femoral approach is preferred, and selective placement of a 6F guide sheath on the targeted common carotid artery (CCA) after activated clotting time was over 250 sec. Angiographic confirmation of the internal carotid stenosis precedes crossing of the lesion with a filter protective device (Filterwire from Boston Scientific, Natick, MA; Emboshield from Abbott Vascular, Redwood City, CA). Pharmacologic management of hemodynamics was tailored to patient response to predilatation of the lesion. Stents used included Precise, Precise Rx (Cordis Endovascular, Indianapolis, IN), and X-act (Abbott Vascular). Postdilatation was followed by angiographic evaluation and retrieval of the protective device.
Data were collected in accordance with the Society of Vascular Surgery Database on Carotid Artery Stenting. Main outcomes measured included late (beyond 30 days) all-cause and specific mortality. Other outcomes included late neurologic event rate. Duplex ultrasound was obtained at 1, 6, and 12 months and yearly thereafter. Neurologic follow-up was performed by clinical evaluation for the first 12 months. After that, telephone contact was made with a preset questionnaire, and if any neurologic event or complaint occurred or an increased velocity was noted on duplex ultrasound, a direct clinical encounter was scheduled. Mortality data were gathered using the Decedent Affairs Office of the Veterans Administration.
Clinical data were exported into a statistical software program (SPSS for Windows v.10; SPSS, Chicago, IL) and evaluated using Student's t-test, chi-squared analysis, and univariate/multivariate logistic regression analysis. Survival analysis was performed using Kaplan-Meier and Cox regression analyses. p < 0.05 was considered statistically significant.
Results
Fifty high-risk patients (48 males, 2 females) underwent CAS with attempted carotid protection in all cases. Atherosclerotic risk factors included hypertension in 64%, dyslipidemia in 66%, diabetes in 44%, and active tobacco abuse in 24%. Patients had a remote history of ischemic cerebrovascular events in 18%, coronary artery disease in 46%, and symptomatic peripheral arterial disease in 20%. Mean age was 70 years (range 54-84). Ten patients were over 80 years of age.
Twenty-six patients underwent CAS due to physiologic risk: ten due to severe heart failure, eight due to active coronary heart disease, four were unfit for surgery (severe myasthenia gravis in two, severe Parkinson's in two), two required urgent cardiac surgery due to severe aortic stenosis, and two had severe chronic obstructive lung disease. A total of 22 patients were deemed anatomic high risk: eight due to prior radiation to the neck due to ear, nose, and throat (ENT) cancer; six due to evidence of tandem or high lesions of the internal carotid artery (ICA); and six due to restenosis after carotid endarterectomy (CEA). In two instances patients met both physiologic and anatomic criteria and were included in the physiologic group for analysis.
Recent ischemic stroke in six cases and eight transient ischemic attacks were recorded prior to surgery (symptomatic group 30%). Thirty-six patients (70%) had no recorded neurologic events within 6 months of CAS (asymptomatic group). There was no difference in the distribution of high-risk criteria between these two groups.
Intraprocedural complications included one episode of hypotension that required pharmacologic support, one case of vasospasm, slow flow due to debris in one case, and inability to pass the filter protection device in one case. No periprocedural stroke was observed.
Early complications (<30 days) included hypotension in eight cases (16%), hypertension in one (2%), transient contrast nephropathy without need for dialysis in one (2%), mild reperfusion headache in one (2%), and access site bleeding in one (2%). There was a single mortality due to sudden cardiac arrest while waiting for aortic valvular repair on postprocedure day 29. This patient had a transient ischemic attack (TIA) 8 hr after uneventful CAS that extended his hospitalization and sustained ST-elevation myocardial infarction (MI) on postprocedure day 3. The overall stroke/TIA/MI/death rate was 2% (Table II).
Table II. Early (<30 days) complications
| Complications | Number of cases |
|---|---|
| TIA/MI/death | 1 (2%) |
| Stroke | 0 (0%) |
| Hypotension | 8 (16%) |
| Hypertension | 1 (2%) |
| Contrast nephropathy | 1 (2%) |
| Reperfusion (headache) | 1 (2%) |
Late ipsilateral neurologic events (Table III) were recorded in three cases (6%) (one asymptomatic and two symptomatic patients) at a mean of 4 months post-CAS. One patient suffered profound hypotension due to severe epistaxis (radiation mucositis) that required surgical control of the airway and packing. This patient recovered from anesthesia with a moderate right hemispheric stroke. Duplex ultrasound interrogation showed a thrombosed stent. Another patient had a left hemispheric stroke 3 months after CAS and recovered without deficits. The last patient had a right retinal stroke that resolved without visual disturbances. Both of these patients had patent carotid stents by ultrasound (peak systolic velocity [PSV] ICA 44 cm/sec, CCA 52 cm/sec, ICA/CCA ratio 0.8; PSV ICA 36 cm/sec, CCA 48 cm/sec, ICA/CCA ratio 0.7, respectively). There were no contralateral ischemic neurologic complications. A single patient (2%) had gastrointestinal bleeding post-CAS that did not require transfusion.
Table III. Late complications
| Event (n = 3) | Stent status | Mechanism | Time to event (months) |
|---|---|---|---|
| Right hemispheric CVA | Thrombosed | Bleeding/hypotension | 3 |
| Left hemispheric CVA | Patent; PSV ICA 44 cm/sec, CCA 52 cm/sec, ICA/CCA ratio 0.8 | Aortic arch atheroma | 2 |
| Left retinal CVA | Patent; PSV ICA 36 cm/sec, CCA 48 cm/sec, ICA/CCA ratio 0.7 | Unknown | 6 |
Freedom from stroke was 93% at 1 year. No difference was observed when the symptomatic versus asymptomatic groups were compared (log rank 0.03, p > 0.05, standard error [SE] = 4) (Fig. 1). Overall, 1-year survival was 75%. There was a significant difference in survival noted when the symptomatic versus symptomatic groups were compared (88% vs. 51%) at 1 year (log rank 6.33, p < 0.01, SE = 5) (Fig. 2).
Fig. 1
Freedom from stroke curves. (Left) Asymptomatic and symptomatic carotid stenoses are compared. Log rank 0.03 (p > 0.05). (Right) Overall stroke-free event rate. SE <10% for entire plot.
Fig. 2
Kaplan-Meier curves for event-free survival after CAS, symptomatic versus asymptomatic. Log rank 6.33 (p < 0.01). SE <10% for entire plot.
A total of 11 deaths were recorded (22%) at a mean of 9 months (range 3-15) postprocedure. Specific analysis showed that two patients died due to cardiac events (end-stage cardiac heart disease and fatal MI). Three patients died from cancer (two unrelated and one recurrent ENT carcinoma). Three patients died from pulmonary disease, and three other patients died from complications following acute hospitalization that required surgical procedures unrelated to the CAS (Table IV).
Table IV. Mortality analysis
| Group (n = 3) | Number | Specific cause | Time to event from CAS (months) |
|---|---|---|---|
| Cardiac | 2 | 1 End-stage cardiac disease | 5 |
| 1 MI | 15 | ||
| Cancer | 3 | 2 ENT-related | 2.7 |
| 1 Not ENT-related | 6 | ||
| Infectious | 3 | 3 Pneumonia | 3, 9, 10 |
| Other | 3 | 1 Acute limb ischemia | 11 |
| 1 Colon obstruction | 6 | ||
| 1 Acute cholecystitis | 10 |
Neither age, high-risk type, prior cancer history, presence of peripheral arterial disease, intraprocedural issues, early complications, nor occurrence of late neurologic complications were predictive of late mortality. Symptomatic indication for CAS was the only variable predictive of late mortality (p < 0.01) validated by multivariable regression.
Discussion
CEA in the prevention of recurrent ischemic stroke is firmly established based on the results of the North American Symptomatic Carotid Endarterectomy Trial (NASCET).1 These results are unquestionable in patients with >69% ICA stenosis, predicated on the high recurrence rate of stroke in patients assigned to medical therapy at 24 months. Superiority was observed as early as 3 months post-CEA. Extrapolating, longevity does not play a major role in neurologic protection. Long-term efficacy was also established.2
The Asymptomatic Carotid Atherosclerosis Study (ACAS) 3 and Asymptomatic Carotid Surgery Trial (ACST) trial,4 given a CEA complication rate <3%, have also shown a benefit of a 50% relative risk reduction of an ipsilateral stroke over 5 years in asymptomatic patients, making CEA a warranted primary preventive option. A prerequisite for benefiting is long-term survival. Since the so-called high-risk patients were excluded from the large randomized trials, guidelines for treatment of this subset are still controversial. The Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial5 is the only published level I trial that compares these two modalities in the high-risk setting, concluding noninferiority for CAS. Other randomized comparisons between CEA and CAS have excluded high-risk patients.6, 7
The current reimbursement policy for the Centers for Medicare and Medicaid Services for CAS includes high-risk, symptomatic patients. Exclusion of asymptomatic patients may be in part due to the perception of anticipated limited life span. This study was undertaken to evaluate midterm all-cause mortality in high-risk patients.
Asymptomatic patients represented 70% of the treated patients, which parallels most North American practices.8 Our early (<30 days) complications are within those described in the published literature.9, 10, 11 Our late freedom from stroke was not different between the symptomatic and asymptomatic cohorts. This observation was also validated by others.12
Overall 1-year survival was 75%, with a significant difference between asymptomatic (88%) and symptomatic (51%) patients (p < 0.01) (Fig. 2). This has been validated in the randomized trials as well.13 No significant differences were observed between asymptomatic and symptomatic patients regarding high-risk distribution, age, prior cancer history, presence of peripheral arterial disease, intraprocedural issues, early complications, or late neurologic complications.
Although the all-cause analysis post-CAS (Table IV) does not support a direct correlation with prior recent stroke and death, the decreased functional reserve in an already poor physiologic patient likely plays a role.
Major limitations of our study are the small sample of patients as well as the follow-up for the asymptomatic group being less than 5 years. Only with longer follow-up will the role of CAS in asymptomatic high-risk patients be clarified. Controversy will remain on what to do with this subset, and longer follow-up is warranted; however, CAS in asymptomatic high-risk patients should not be bluntly disregarded.
In conclusion, in our experience with CAS, symptomatic high-risk patients have an increased midterm mortality that is not associated with ischemic neurologic events. The protective role of CAS in this setting remains to be determined.
References
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- . Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med. 1998;339:1415–1425
- . Endarterectomy for asymptomatic carotid artery stenosis. JAMA. 1995;273:1421–1428
- . Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomized control trial. Lancet. 2004;363:1491–1502
- Protected carotid artery stenting versus endarterectomy in high risk patients. N Engl J Med. 2004;351:1493–1501
- Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. N Engl J Med. 2006;355:1660–1671
- 30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial. Lancet. 2006;368:1239–1247Erratum in Lancet 2006;368:1238
- Carotid endarterectomy in SAPPHIRE-eligible high risk patients: implications for selecting patients for carotid angioplasty and stenting. J Vasc Surg. 2004;39:958–966
- Carotid artery stenting. Analysis of data for 105 patients at high risk. J Vasc Surg. 2003;37:1234
- Protected carotid stenting in high risk patients with severe carotid artery stenosis. J Am Coll Cardiol. 2006;47:2384–2389
- Treatment of asymptomatic carotid disease: similar early outcomes after carotid stenting for high risk patients and endarterectomy for standard-risk patients. J Vasc Surg. 2006;43:953–958
- Patients subgroups in the randomized SAPPHIRE study of carotid stenting with distal protection versus endarterectomy. Stroke. 2006;37:620
- A systematic comparison of the risk of stroke and death for symptomatic and asymptomatic stenosis. Stroke. 1996;27:266
Presented at the Twenty-fourth Annual Meeting of the Southern California Vascular Society, Temecula, CA, May 6, 2006.
PII: S0890-5096(07)00301-9
doi:10.1016/j.avsg.2007.08.001
© 2008 Annals of Vascular Surgery Inc. Published by Elsevier Inc All rights reserved.
