Current Perspectives on Carotid Revascularization Among Patients Who Need Cardiac Surgery

ABSTRACT: Carotid stenosis is often present in patients who need cardiac surgery and is predictive of post-operative stroke. A strategy of combined carotid endarterectomy and cardiac surgery had been adopted in the past. Staged carotid artery stenting prior to cardiac surgery is a less invasive alternative and seems to be associated with a lower incidence of stroke and myocardial infarction as compared to the combined surgical approach. This article provides a systemic review of the management of patients with concomitant carotid and cardiac disease requiring cardiac surgical procedure, and will discuss some management issues related to carotid stenting in this group of patients. Based on the available data, it is perhaps time to revise our practice guidelines by replacing the combined surgical strategy with the staged carotid stenting and cardiac surgery approach.

J INVASIVE CARDIOL 2010;22:386–390

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Perioperative stroke during cardiac surgery. Perioperative stroke is one of the most devastating complications of cardiac surgery (CSurg). It is second to a low cardiac output state as a cause of post-operative mortality.¹ Stroke could be the result of: (i) aortic atheroembolization during manipulation of the aorta; (ii) cardiac embolization in the presence of poor left ventricular function, recent myocardial infarction (MI), chronic atrial fibrillation or severe mitral annulus calcification; or (iii) severe carotid stenosis.^2,3 Severe carotid disease is found in 6–12% of patients undergoing coronary bypass surgery.^4,5 The risk of perioperative stroke increases from 3 Patients who had history of neurological events and carotid occlusion were found to have a 28-fold increased risk of post-operative ipsilateral stroke following CSurg, when compared with those without carotid stenosis.⁶ The presence of occlusive carotid disease and an incomplete Circle of Willis perhaps represent those with the highest risk of stroke. Elderly age, female gender, left main coronary disease, cigarette smoking, peripheral artery disease and prior transient ischemic attacks, are the major predictive factors for obstructive carotid disease, and hence the practice guidelines have recommended carotid screening prior to CSurg among patients with these risk factors.²Rationale for carotid revascularization prior to cardiac surgery. Few data are available to guide the management of patients who have severe carotid disease and require CSurg. While intuitively most physicians would agree that symptomatic extracranial carotid artery disease should undergo carotid artery stenting (CAS) prior to CSurg based on the result of the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) study,^7,8 consensus has not been reached about the management of severe asymptomatic unilateral or bilateral carotid artery stenosis. Systemic hypotension during cardiopulmonary bypass or during the recovery phase could result in cerebral hypoperfusion and stroke in the presence of untreated severe carotid artery stenosis.⁹ On the other hand, three randomized control trials that enrolled a total of 2,400 asymptomatic patients with severe carotid artery disease have consistently shown that carotid revascularization could roughly halve the risk of stroke at 5 years.^10–12 The current practice guidelines, therefore, have stated that carotid endarterectomy (CEA) should be used to treat patients who have asymptomatic severe (i.e., > 80% stenosis) carotid artery stenosis, provided that the perioperative risk can be kept at 5 years.¹³ Since the latter criterion is anticipated in patients undergoing CSurg, it would be reasonable to perform carotid revascularization prior to, or at the same time as heart surgery. The current practice guidelines consider staged or combined CEA and CSurg to have a Class IIa indication (Level C evidence) for treating concomitant severe symptomatic or asymptomatic carotid disease in patients who need CSurg.² While there is no randomized trial to support the relative merit of combined surgery versus heart surgery alone, the combined strategy has been adopted in clinical practice for more than a decade, with cerebral revascularization preceding, or taking place concurrently, with heart surgery. Nevertheless, we should keep in mind that since severe carotid stenosis was suggested to be related to post-operative stroke in ~40% of cases,⁵ one would think that carotid revascularization might reduce, but not eliminate, the risk of post-operative stroke among these patients. Indeed, a portion of post-operative stroke after combined CEA/CSurg could occur on the contralateral side of the carotid revascularization.¹⁴Problems associated with staged or combined CEA and cardiac surgery. While staged or combined CEA and CSurg was recommended in the 2004 practice guidelines with the idea of reducing post-operative stroke,² combined surgery remains a challenge both during the operation and in the post-operative phase because it requires prolonged operative time and general anesthesia. Carotid sinus manipulation during CEA could result in parasympathetic response, persistent vasodilation and reduced coronary perfusion, which could theoretically result in myocardial ischemia and deter post-operative left ventricular recovery. Higher doses of vasopressors and longer course of intensive care unit stay and hospitalization have been associated with combined CEA/CSurg cases as compared to CSurg alone.^15,16 From the cerebrovascular perspective, carotid revascularization could result in cerebral hyperperfusion, which is an infrequent but potentially devastating complication of the procedure.^17,18 Patients with cerebral hyperperfusion syndrome could manifest with headache, lethargy, non-localizing neurological signs or symptoms (facial numbness, motor weakness or paresthesia in the extremities) and seizure; intracranial bleeding could occur in the extreme scenario.^17–19 It could occur even in the presence of relatively “normal” systemic blood pressure after carotid revascularization. Cerebral hyperperfusion syndrome is related to the lack of autoregulation of the intracranial cerebral arteries seen within the first few days after revascularization as a result of chronically maximal vasodilation due to severe internal carotid artery stenosis.²⁰ This condition requires early identification and prompt management by lowering blood pressure.²¹ Neurological assessment and blood pressure lowering are often problematic early after CSurg, in which ventilation for > 24 hours and hemodynamic fluctuation are often the case, and the diagnosis and treatment of cerebral hyperperfusion syndrome could be delayed if it does occur. Several large registries of combined CEA/CSurg have been published in the past two decades, and they reported post-operative stroke and MI rates at 1.0–11.1% and 0–12.6%, respectively (Table 1).^22–34 Intracranial bleeding was reported in 2.2% of patients in one large series.²² Although they all concluded that combined CEA/CSurg was relatively safe and was an “acceptable” strategy, these were largely single-center retrospective reports with or without a control group for comparison, and were conducted without an independent neurologist’s adjudication and routine cardiac biomarkers assessment, which could lead to underreporting of the events. In a retrospective review of a large Medicare database, the perioperative death and non-fatal stroke rates of combined CEA/CSurg in the real-world community-based practice were found to be 6.6% and 11.1%, respectively.¹⁴ In a meta-analysis that included nearly 9,000 synchronous (staged or combined) surgical procedures,³⁵ the composite risk of death, stroke and MI was highest among patients undergoing combined CEA/CSurg (11.5%), while staged CEA and CSurg had the highest risk of MI (6.5%), and reversed staged procedures (i.e., CSurg followed by CEA) were associated with the highest risk of ipsilateral stroke (5.8%). Although this type of analysis might be hampered by selection bias, these complication rates did not appear to be significantly lower than those of CSurg alone when compared to historical control,^5,36 and would be perhaps considered high by today’s standard. The outcomes did not seem to be improved with off-pump coronary bypass techniques.²⁹Staged carotid artery stenting and cardiac surgery. CAS has been accepted as an alternative for CEA, and is the preferred revascularization modality in the high surgical-risk population, including those who are waiting for heart surgery.^7,8,37 Ziada et al compared the results of 56 consecutive patients who underwent staged CAS/CSurg with 111 patients who underwent combined CEA/CSurg during the period 1997–2002 at the Cleveland Clinic.²⁶ Patients who underwent CAS/CSurg had higher baseline cardiovascular risks (e.g., more patients with poor left ventricular function, symptomatic carotid disease, re-do CSurg or unstable angina), and yet the 30-day risk of death, stroke and MI were lower in the CAS/CSurg group than the CEA/CSurg group (death 5.4% vs. 7.2%; stroke 1.8% vs. 9.0%; MI 3.3% vs. 12.6%). Van der Heyden et al published the largest single-center experience of staged CAS and CSurg (total 356 patients) during the period of 1997–2005.³⁸ Embolic protection devices were used in 40% of the patients and 6% underwent staged bilateral CAS. The incidence of death, stroke and MI within 30 days after CSurg were 13/356 (3.7%), 4/356 (1.1%, including 3 cases which occurred after CSurg), and 7/354 (2.0%, including 5 cases which occurred after CSurg), respectively. During a mean 31 months of follow up, neurological death and non-fatal ipsilateral major stroke were both at 1.1%, and repeat angioplasty for restenosis was needed in only 2 patients. Timaran et al summarized the results of 27,084 patients who underwent carotid revascularization and coronary bypass surgeries in the United States during the years 2000–2004.³⁹ Staged CAS/CSurg was used in only 3.3% of the patients and the rest (96.7%) were treated by a CEA/CSurg strategy, reflecting the fact that CAS was available only in experienced centers that were involved in the high surgical-risk CAS registries or trials during the study period. Overall, the CAS/CSurg group had a lower stroke rate and combined stroke/death rates than the CEA/CSurg group (2.4% vs. 3.9% and 6.9% vs. 8.6%, respectively; p 40–44 and they all seemed to show more favorable results when compared to the historical controls (CEA/CSurg or CSurg alone). However, a definitive conclusion could not be drawn because different definitions for stroke and MI and different times for endpoint assessment were used across various studies, and randomized data are still lacking. Performance of CAS. Central to the strategy of staged CAS and CSurg is the performance of CAS. The extraordinarily poor outcomes seen in the CAS group in the Endarterectomy Versus Stenting in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial and the International Carotid Stent Study (ICSS) as compared to those in Carotid Revascularization Endarterectomy versus Stent Trial (CREST) highlight the importance of the interventionist’s experience in performing CAS.^45–47 The procedure should only be performed by operators who can maintain a perioprocedural risk of death/stroke 13,48 As most of the patients under discussion are asymptomatic from a neurological point of view, it would be devastating for a patient to suffer from a permanent neurological complication from CAS before even getting to CSurg. Therefore, one may demand only the most experienced interventionists who could maintain an even lower periprocedural risk (e.g., 17 Cardiovascular units with telemetry monitors and nursing staff who are familiar with hemodynamic assessment are suitable places to provide post-procedural care. Antiplatelet regimen following CAS and time to cardiac surgery. Thirty days of dual antiplatelet therapy has been part of the routine practice after CAS based on our experience in percutaneous coronary intervention.⁴⁹ However, the efficacy of clopidogrel after CAS has not been firmly established in a randomized, controlled clinical study. McKevitt et al reported less risks of bleeding and neurological complications with combined clopidogrel and aspirin as compared to aspirin and 24-hour unfractionated heparin infusion,⁵⁰ but in this study the poor outcomes in the control arm were largely related to an increased bleeding rate with heparin infusion, and the benefit of dual antiplatelet therapy versus aspirin alone was still not established. Carotid stent thrombosis related to the lack of clopidogrel has not been reported in the medical literature at the time of this writing. Theoretically, stent thrombosis is less likely to occur after CAS than after coronary angioplasty due to the high-flow state and large luminal diameter of the carotid artery. On the other hand, clopidogrel use within 5 days prior to CSurg has been consistently shown to be associated with ~30% excess in major bleeding and transfusion rates in a clinical trial and in routine practice,^51,52 without affecting the mortality rate. It has been recommended that clopidogrel be discontinued 5 days prior to elective CSurg, while aspirin should be continued. Importantly, delaying heart surgery after CAS could lead to cardiac deaths.^26,38,43 Therefore, the risk of post-operative bleeding and increased blood transfusion related to dual antiplatelet therapy needs to balance against the risk of delaying CSurg. To try to reduce the risk of post-operative bleeding associated with clopidogrel and to minimize the risk of a myocardial event related to surgical delay, Versaci and coworkers in Italy and Germany reported a strategy of CAS followed by immediate CSurg on the same day.⁴⁴ In this series, a loading dose of clopidogrel was given after CSurg when the risk of bleeding was deemed minimal. Thirty-day neurologist-adjudicated events of death/stroke/MI occurred in 4% of the patients. The same strategy was used by another group in Argentina and they achieved similar results.⁴² Although the authors concluded that these results were acceptable, broad dissemination of this strategy may be difficult due to the logistical challenges in coordinating the two procedures simultaneously between the catheterization laboratory and the operating room on the same day, and hybrid operating rooms are not available in every hospital. In addition, management of cerebral hyperperfusion syndrome, femoral access complication, acute nephropathy due to contrast and bypass pump and the impact of a lack of dual antiplatelet therapy during CAS remain some of the outstanding issues with this one-day strategy. Based on the available data, it would be reasonable for patients with unstable angina, recent acute coronary syndrome or heart failure to undergo CSurg as early as 1–2 days after CAS, since the risk of cardiac decompensation or mortality in this population probably outweighs the bleeding risk related to antiplatelet therapy. Continuation of clopidogrel after CAS in these patients would be at the discretion of the operators. Other patients who have stable cardiac disease and require elective CSurg may delay the surgery until 3 weeks after CAS and clopidogrel has been stopped for 5 days. This strategy has been used in some centers, including ours.^38,40Conclusions and current perspectives. Based on what we have observed over the last 25 years, the following conclusions can be made. Firstly, obstructive internal carotid artery disease is predictive of ischemic stroke after CSurg. The risk is highest with bilateral occlusive carotid disease, followed by unilateral occlusive disease with or without contralateral disease, bilateral severe disease and unilateral obstructive disease. Secondly, the strategy of staged or combined CEA/CSurg does not appear to lower the overall risk of death, stroke or MI when compared with CSurg alone, largely related to the longer operative time and numerous challenges during the post-operative period. Thirdly, CAS prior to CSurg is less invasive, and the outcomes in the published reports have been satisfactory. Adoption of this strategy should be limited to centers where experienced interventionists are available. The risk of delaying heart surgery must be balanced against the benefit of clopidogrel after CAS. For patients with recent cardiac destabilization, it is probably advisable to proceed with CSurg as early as possible, with or without concomitant clopidogrel use, while elective CSurg could be delayed by 3 weeks after CAS and clopidogrel is stopped. Ideally, a randomized clinical trial should be carried out to test the CAS/CSurg strategy against CSurg alone. However, such a trial will unlikely be conducted due to the relatively low number of these cases (~1% of all CSurg cases), the need for large sample sizes, the lack of equipoise among practitioners, and the lack of interest from the funding agencies or device companies. However, based on what we have learned, it is reasonable to revise our practice guidelines by replacing a combined CEA/CSurg strategy with a staged CAS/CSurg strategy, provided experienced operators are available in an institution. Acknowledgement. The author appreciates Dr. Shahzad Karim, Cardiac Surgeon at Royal Columbian Hospital, British Columbia, for his review of this article.

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From the Department of Cardiac Services, Royal Columbian Hospital, New Westminster; Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. The author reports no conflict of interest regarding the content herein. Manuscript submitted April 12, 2010, provisional acceptance given April 14, 2010, final version accepted April 20, 2010. Address for correspondence: Dr. Albert W. Chan, 301 E. Columbia Street, Suite 206, New Westminster, BC, V3L 3W5. Canada. E-mail: albertwchan@shaw.ca