ORIGINAL ARTICLE

Gen Thorac Cardiovasc Surg (2011) 59:730–736DOI 10.1007/s11748-011-0825-x

Two-staged treatment strategy in patients with severe carotid or cerebrovascular diseases undergoing coronary artery bypass grafting

Yuki Okamoto, MD · Kenji Minakata, MD, PhD Tomoyuki Yunoki, MD · Masatake Katsu, MD, PhD Shin-ichiro Chino, MD Masahiko Matsumoto, MD, PhD

Abstract

Purpose. There is no clear consensus on how to treat patients undergoing coronary artery bypass grafting (CABG) who have severe concomitant carotid-cerebral artery stenosis. The aim of this study was to evaluate our surgical results in patients with severe carotid and/or cerebrovascular disease undergoing CABG.Methods. Between October 2003 and April 2009, a total of 47 such patients were treated at our institution with the following strategies: (1) protective carotid artery stenting for severe carotid stenosis performed either before (n = 20) or after (n = 5) CABG or (2) a superfi cial temporal artery–middle cerebral artery anastomosis pro-cedure followed by CABG if indicated (n = 4). Off-pump CABG was performed in 75% of the patients. Results. There were no major perioperative strokes or in-hospital deaths; however, three patients had transient ischemic

Received: 12 August 2010 / Accepted: 19 April 2011© The Japanese Association for Thoracic Surgery 2011

attacks and two had minor strokes during the early post-CABG period. All of the patients with postoperative cerebrovascular events had had unilateral carotid artery occlusion. There were no late deaths during the follow-up period (up to 6 years, with a mean of 27 months). However, major adverse cardiocerebrovascular events (MACCE) occurred in seven patients (14.9%). The rates of freedom from MACCE at 1 and 3 years were 92% and 74%, respectively.Conclusion. It appears that our two-staged approach is safe and may reduce the risk of postoperative cerebro-vascular events.

Key words Carotid artery disease · Carotid artery stenting · Coronary artery bypass grafting · Off-pump

Introduction

It is well known that a signifi cant number of patients who require coronary artery bypass grafting (CABG) for severe coronary artery disease have atherosclerotic lesions in other vessels, especially in the carotid or intra-cranial arteries. Indeed, it has been reported that 22% of patients undergoing CABG had carotid artery stenosis involving >50% of the lumen, and 12% of patients had carotid artery stenosis involving >80% of the lumen.1,2 In our institution, carotid artery stenting (CAS), rather than carotid endarterectomy (CEA), has been our fi rst choice for treating signifi cant carotid artery stenosis since 2003. In terms of coronary artery revasculariza-tion, we perform off-pump CABG as our technique of choice if surgical intervention is indicated. The selection and timing of interventions for patients undergoing CABG associated with severe carotid artery stenosis

Y. Okamoto · K. Minakata (*)1 · T. Yunoki · M. Katsu · S. ChinoDivision of Cardiovascular Surgery, Tominaga Hospital, Osaka, Japan

M. MatsumotoSecond Department of Surgery, Yamanashi University Graduate School of Medicine, Yamanashi, Japan

Present address:1Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, JapanTel. +81-75-751-3780; Fax +81-75-751-3098e-mail: minakata@kuhp.kyoto-u.ac.jp

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is still controversial: Some argue for a simultaneous approach, and others argue for staged operations (e.g., with carotid artery fi rst or coronary artery fi rst). The aim of this study was to evaluate the effi cacy of our two-staged approach.

Patient and methods

Patients

Between October 2003 and April 2009, a total of 315 patients underwent CABG at our institution. Of them, 47 patients (15%) were found to have severe carotid artery or cerebrovascular stenosis. It is these patients who form the study cohort for this study. The patients’ demographics and clinical characteristics are summa-rized in Table 1. The mean age was 68.8 ± 7.1 years (range 48–83 years), with men predominating (n = 39). Most of the patients had severe triple-vessel disease with left main stenosis; left ventricular function was relatively preserved, with a mean ejection fraction of 59% ± 13%. In terms of the history of stroke, 53% of patients had had at least one minor stroke, and 34% had had at least one major stroke.

Preoperative screening for carotid artery and cerebrovascular disease

Preoperative carotid artery and cerebral vascular screen-ing was performed for all patients undergoing elective CABG. Screening included carotid artery ultrasonogra-phy (US) and carotid and cerebrovascular magnetic resonance angiography (MRA). The images were evalu-ated by neurovascular radiologists. Multislice computed tomography (CT) with three-dimensional reconstruction or cerebral angiography was performed as necessary.

Signifi cant carotid artery stenosis was defi ned as either >70% reduction of the luminal diameter with symptomatic carotid artery disease or >80% reduction with asymptomatic carotid artery disease. These criteria were based on the North American Symptomatic Carotid Endarterectomy Trial.3 Whenever symptomatic or severe carotid artery stenosis and/or cerebrovascular stenosis were detected, a cerebral blood fl ow study with quantita-tive evaluation of fl ow reserve was performed by single photon emission computed tomography (SPECT). If cerebral blood fl ow and reserve were inadequate, carotid and/or cerebrovascular intervention were then consid-ered. Also, in patients with severe carotid artery stenosis of >90%, prior stroke, or contralateral carotid artery occlusion, even if adequate cerebral blood fl ow and reverse were demonstrated, intervention before CABG was considered.

In this study, preoperative screening revealed unilat-eral carotid artery stenosis in 66% of patients and bilat-eral carotid artery stenosis in 34% of patients. Notably, 32% of patients were found to have unilateral carotid artery occlusion. Cerebrovascular MRA revealed that 34% of patients had intracranial carotid and/or cerebro-vascular stenosis.

CAS procedure

All patients undergoing CAS received single or dual antiplatelet therapy (aspirin, aspirin + clopidogrel, aspirin + cilostazol, or aspirin + ticlopidine) started at least 3 days prior to CAS and continued thereafter. CAS was performed under local anesthesia through a percu-taneous transfemoral artery approach. Self-expanding stents with distal protective devices were used in all patients undergoing CAS in this cohort. After the pro-cedure, a selective thrombin inhibitor, argatroban, was administered intravenously for 5 days in all patients. In cases where CABG was indicated, it was performed an average of 30 days after CAS. Antiplatelet cessation was performed as follows: clopidogrel and ticlopidine were discontinued 7 days prior to CABG, and cilostazol was discontinued 3 days prior to CABG. Aspirin was contin-

Table 1 Patient demographics (n = 47)

Age (years) Mean ± SD 68.8 ± 7.1 Range 48–83Sex Male 38 Female 9Coronary risk factor Hypertension 38 (80.9%) Hyperlipidemia 22 (46.8%) Diabetes mellitus 26 (55.3%) Smoking 18 (38.3%)No. of diseased coronary vessels 1 Vessel 2 (4.3%) 2 Vessels 15 (31.9%) 3 Vessels 27 (57.4%)Left main stenosis 23 (48.9%)LVEF 59% ± 13%OMI 14 (29.8%)History of cerebral infarction Major stroke 16 (34.0%) Minor stroke 25 (53.2%)History of ICH/SAH 2 (4.3%)Carotid artery disease Unilateral 31 (66.0%) Bilateral 16 (34.0%) Unilateral carotid artery occlusion 15 (31.9%) Intracranial artery 16 (34.0%) Vertebral artery 8 (17.0%)

ICH, intracranial hemorrhage; LVEF, left ventricular ejection fraction; OMI, old myocardial infarction; SAH, subarachnoid hemorrhage

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ued before and after the CABG. Intravenous heparin infusion was also given as needed until the day of CABG.

Surgical strategy for CABG complicated with signifi cant carotid artery disease or cerebrovascular disease

A two-staged operation, CAS followed by CABG, was our surgical strategy of choice for CABG patients with signifi cant carotid artery disease or cerebrovascular disease (Fig. 1). Twenty patients underwent this two-staged operation in this order. However, in patients with unstable angina pectoris with poor collateral cerebral blood fl ow and inadequate fl ow reserve or with contra-lateral carotid artery occlusion and prior stroke with adequate cerebral blood fl ow and reserve, we performed CABG fi rst, followed by CAS. Five patients underwent CABG followed by CAS. Four patients underwent CABG followed by superfi cial temporary artery–middle cerebral artery (STA-MCA) anastomosis for occluded carotid artery. Twelve patients underwent only CABG because they were asymptomatic and had adequate fl ow reserve with good collateral circulation. In addition, seven patients who had previously undergone STA-MCA anastomosis for carotid artery occlusion or severe intracranial artery stenosis underwent only CABG. No patients underwent simultaneous CEA and CABG in this series. In all patients, CABG was performed off-pump whenever possible.

Follow-up and study endpoints

The follow-up period ranged from 1 month to 6 years, with a mean of 27 months from the completion of CABG. The primary endpoints of the present study were the incidence of transient ischemic attacks (TIAs), stroke, or death within 30 days of CABG. The secondary endpoint was the incidence of major adverse cardiocerebrovascu-lar events (MACCEs) or death within 30 days of the CABG. MACCE is defi ned as any of the following: myo-cardial infarction, recurrent angina, congestive heart failure, neurological event including major or minor stroke, and intracranial hemorrhage. Neurological events were evaluated upon the appearance of a new intracra-nial lesion on a CT scan or MRI, in addition to neuro-logical symptoms. Major strokes were defi ned as any new neurological defi cit lasting more than 7 days. Minor strokes were defi ned as any new neurological defi cit lasting more than 24 h but less than 7 days. Myocardial infarctions were defi ned based on the presence of a new Q wave on electrocardiography, the appearance of a new wall motion abnormality on echocardiography, creatine kinase levels at least two times the upper limit of the normal range, and an elevated level of MB isoenzyme.

Statistical analysis

Data are presented as the mean ± SD. Categorical vari-ables were analyzed using either the chi-squared test or

Fig. 1 Algorithm for coronary artery bypass grafting (CABG) complicated with severe carotid artery stenosis or cerebrovascular stenosis. CAS, carotid artery stenting; STA-MCA, superfi cial temporary artery–middle cerebral artery

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Fisher’s exact test. The survival curve of “freedom from MACCE” was performed with the Kaplan-Meier method, and the differences of survival curves were ana-lyzed by the log-rank test. P < 0.05 was considered statistically signifi cant. All statistical analyses were per-formed using the JMP 8.0 software package (SAS, Cary, NC, USA).

Results

In patients who underwent a two-staged operation with CAS followed by CABG, there were no cerebrovascular complications after CAS, and no myocardial infarctions before CABG. Intraoperative data are shown in Table 2. Scheduled intraaortic balloon pumping (IABP) was used in seven patients with the aim of achieving hemo-dynamic stability, especially in those with severe left main stenosis. There were no operative or in-hospital deaths. In all, 75% of CABG operations were performed off-pump. Most of the on-pump CABG operations were performed early in the series. The mean number of distal anastomoses was 2.8 ± 0.9 per patient.

The early outcomes of CABG are shown in Table 3. Early complications included three TIAs and two minor strokes. One of these minor strokes occurred in a patient undergoing the two-staged operation with CAS followed by CABG. All of these patients were discharged without neurological sequelae.

During the mid-term follow-up survey, there were no late deaths. However, MACCE occurred in seven patients (14.9%), including three with recurrent angina pectoris (6.4%) and two with minor strokes (4.3%). The Kaplan-Meier survival curve for freedom from MACCE is shown in Fig. 2. The rates of freedom from MACCE at 1 and 3 years were 92% and 74%, respectively. The risk factors for early and late complications are shown in Table 4. The risk factors for TIA were female sex, diabetes mellitus, left main coronary artery stenosis, history of major stroke, and unilateral carotid artery occlusion. The risk factors for minor stroke were

smoking, unilateral carotid artery occlusion, and on-pump CABG. The risk factors for late MACCE were female sex, age >75 years, New York Heart Association (NYHA) functional class III or higher, and depressed left ventricular systolic function (left ventricular ejection fraction <40%).

Discussion

Advantages of CAS for the two-staged operation

The surgical strategy for CABG complicated with sig-nifi cant carotid artery disease or cerebrovascular disease

Table 2 Operative data (n = 47)

Scheduled IABP 7 (14.9%)CABG Off-pump 35 (74.5%) On-pump 12 (25.5%) On-pump beating 2 (4.3%)No. of distal anastomoses/patient 2.8 ± 0.9Combined procedure: aortic valve replacement 1Intraoperative death 0

CABG, coronary artery bypass grafting; IABP, intraaortic balloon pumping

Table 3 Early and late outcomes (n = 47)

Early results Intraoperative stroke 0 Postoperative TIA 3 (6.4%) Postoperative minor stroke 2 (4.3%) Postoperative major stroke 0 Hospital death 0Details of complicated cases Postoperative TIA 3 Prior major stroke 3 Unilateral ICA occlusion 3 Off-pump CABG 2 Postoperative minor stroke 2 Prior minor stroke 2 Unilateral ICA occlusion 2 On-pump CABG 2Late results Angina pectoris 3 (6.4%) Minor stroke 2 (4.3%) Chronic heart failure 1 (2.1%) CSH 1 (2.1%) Death 0

CABG, coronary artery bypass grafting; CSH, chronic subdural hematoma; ICA, internal carotid artery; TIA, transient ischemic attack

Fig. 2 Kaplan-Meier survival curve of “freedom from major adverse cardiocerebrovascular events” (MACCE)

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varies depending on lesion characteristics, the patient’s background, and the presence of other complications. If myocardial ischemia is less of a concern, a two-staged operation with CAS followed by CABG has been our technique of choice because CAS is less invasive and is less likely to cause neurological complications. Also, it causes less hemodynamic compromise than CEA.4,5 Indeed, there were no cerebrovascular complications and no deaths related to CAS in our study. Of course, the results of CAS are best when performed by an expe-rienced operator with established periprocedural mortal-ity and morbidity rates of <4%–6%.6

Problems with the two-staged operation

In patients who undergo a procedure to treat a carotid lesion before undergoing CABG, there is always the risk of myocardial events happening before the CABG is performed. In fact, it has been reported that myocardial infarctions occurred in 5.8% of patients who were treated with a staged operation prior to CABG.7 In our series, there were no such myocardial infarctions, although one patient developed unstable angina with acute pulmonary edema due to overhydration associated with antithrom-bin therapy. This patient subsequently required urgent CABG with IABP support. Thus, it might be useful to consider either a sequential or simultaneous hybrid CAS and CABG procedure to eliminate the risk of myocar-dial events occurring between the two procedures.4,7

This strategy may be one of the most attractive surgi-cal options for CABG complicated with severe carotid artery stenosis, although it is uncertain if this strategy increases the risk of acute thrombosis at the carotid

artery stent site or in more distal arteries due to unstable endothelium following angioplasty. Furthermore, it has been noted that restenosis can occur more frequently during the early postprocedural period following CAS if suffi cient amounts of powerful antiplatelet agents are not given during the CAS procedure [8]. However, it has also been noted that the risk of operative bleeding during or after CABG may increase owing to such intensive dual antiplatelet therapy.8 Because single or dual anti-platelet therapy is recommended over the course of 1 month after CAS, CABG is not usually performed within 30 days of CAS in many institutions so long as the hemodynamic state is stable.8,9

Only one patient (5%) who underwent the two-staged operation had a minor stroke after CABG. However, this minor stroke occurred in the cerebral artery contra-lateral to the one that had undergone CAS. The inci-dence of death due to stroke or the general incidence of any stroke after a two-stage CABG procedure has been reported to be 3.1%–9.6%.10–12 Our results favorably compare with these previous reports. Therefore, our two-staged approach with CAS followed by CABG seems to be safe and valid.

Impact of off-pump technique

It is well known that many cerebrovascular complica-tions associated with CABG are caused by hypotension or hypoperfusion related to the use of cardiopulmonary bypass or embolism due to manipulation of the athero-matous ascending aorta.13,14 Therefore, in the case of CABG complicated with severe carotid artery or cere-brovascular stenosis, off-pump CABG is preferable because it allows pulsatile arterial pressure to be main-tained and can be performed without manipulating the aorta. Indeed, we performed off-pump CABG in seven patients who had previously undergone STA-MCA anastomosis for carotid artery occlusion, and no cere-brovascular events occurred during or after CABG. Of course, even the off-pump technique cannot completely eliminate the risk of stroke. In fact, two patients in this series suffered TIA after off-pump CABG. Both patients were found to have unilateral carotid artery occlusion, and their symptoms seemed to be related to the affected side. Manabe et al. reported that cerebrovascular com-plications were highly associated with the presence of unilateral carotid artery occlusion in patients undergo-ing off-pump CABG.13 In addition to hemodynamic sta-bility, it has been reported that pulsatility generated by IABP may reduce the risk of suboptimal fl ow in severe stenotic carotid/cerebral vessels and/or its collateral cir-culation.15 Indeed, in our study, no cerebral complica-tions occurred in any of the patients who underwent

Table 4 Risk factors for early and late complications

Parameter P

Early results (univariate analysis) Postoperative TIA Sex (female) 0.030 DM on oral medicines 0.034 Left main stenosis 0.034 Prior major stroke 0.029 Carotid artery occlusion 0.007 Postoperative minor stroke Smoking 0.046 Carotid artery occlusion 0.025 On-pump CABG 0.017Late results: MACCE (log-rank test) Sex (female) 0.039 Age (over 75 years) 0.001 NYHA class III or IV 0.049 EF < 40% 0.039

DM, diabetes mellitus; EF, ejection fraction; MACCE, major adverse cardiocerebral event; NYHA, New York Heart Association

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off-pump CABG supported by IABP. When CABG is performed before CAS, off-pump CABG supported by IABP may be a reasonable adjunct for patients with severe carotid artery or cerebrovascular disease.

Late complications and prognosis

There are only a few reports on midterm or long-term results of staged CAS and CABG. Van der Heyden et al. reported that late cerebrovascular complications occurred in only 5.1% of patients who underwent CAS followed by CABG with a 31-month median follow-up, and that 65% of late deaths were caused by cardiac events.11 In the present study, we found that late cere-brovascular complications occurred in 4.3% of patients during the 27-month mean follow-up period. It should be noted that other cardiac events, such as recurrent angina or congestive heart failure, were more common. Overall, MACCE occurred in 14.9% of patients, and the risk factors for those events included female sex, advanced age, advanced NYHA functional class, and depressed left ventricular systolic function. Therefore, to improve long-term survival, strict and careful follow-up by a general practitioner and cardiologist is warranted in patients who have both carotid and coronary disease.

What is the best strategy?

Recently, CAS is being performed more commonly than CEA, especially in high-risk patients with severe coro-nary artery disease.16,17 Also, it is widely known that off-pump CABG most likely decreases the risk of peri-operative stroke in high-risk patients with carotid and cerebrovascular stenosis. Until now, evidence from a randomized controlled trial for staged CAS and CABG has not been presented. In fact, in their systematic review and meta-analysis, Naylor et al. reported that simultane-ous CEA and off-pump CABG may be the best option in patients with both coronary and carotid diseases.8 Because of the lack of data regarding staged CAS and off-pump CABG, they also requested that centers that have performed staged CAS paired with off-pump CABG publish their experiences to further inform the debate. Thus, we have herein reported our results with this technique. We believe that our surgical strategy of staged CAS and off-pump CABG may be the best surgi-cal option to minimize the risk of perioperative stroke.

Study limitations

Several limitations of the present study have to be noted. All of the data were prospectively collected, but this is

obviously a retrospective and nonrandomized study. Therefore, a selection bias may exist, as is usual in such studies. Furthermore, the number of study patients was relatively small.

Conclusions

Our fi ndings indicate that a two-staged operation com-prising CAS followed by CABG is safe and may reduce the rate of postoperative cerebrovascular events. Off-pump CABG is suitable for patients with severe carotid artery stenosis or cerebrovascular disease. Finally, off-pump CABG can be performed with a very low risk of perioperative stroke in patients with prior STA-MCA anastomosis for carotid artery occlusion.

References

1. Ricotta JJ, Faggioli GL, Castilone A, Hassett JM. Risk factors for stroke after cardiac surgery: Buffalo Cardiac-Cerebral Study Group. J Vasc Surg 1995;21:359–63.

2. Schwartz LB, Bridgman AH, Kieffer RW, Wilcox RA, McCann RL, Tawil MP, et al. Asymptomatic carotid artery stenosis and stroke in patients undergoing cardiopulmonary bypass. J Vasc Surg 1995;21:146–53.

3. North American Symptomatic Carotid Endarterectomy Trial. Methods, patient characteristics and progress. Stroke 1991;22:711–20.

4. Versaci F, Reimers B, Del Giudice C, Schofer J, Giacomin A, Saccà S, et al. Simultaneous hybrid revascularization by carotid stenting and coronary artery bypass grafting: the SHARP study. JACC Cardiovasc Interv 2009;2:393–401.

5. Guerra M, Mota JC, Veloso M, Gama V, Vouga L. Combined carotid stenting and urgent coronary artery surgery in unsta-ble angina patients with severe carotid stenosis. Interact Car-diovasc Thorac Surg 2009;9:278–81.

6. Sacco RL, Adams R, Albers G, Alberts MJ, Benavente O, Furie K, et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affi rms the value of this guideline. Circulation 2006;113:e409–9.

7. Versaci F, Del Giudice C, Scafuri A, Zeitani J, Gandini R, Nardi P, et al. Sequential hybrid carotid and coronary artery revascularization: immediate and mid-term results. Ann Thorac Surg 2007;84:1508–13.

8. Naylor AR, Mehta Z, Rothwell PM. A systematic review and meta-analysis of 30-day outcomes following staged carotid artery stenting and coronary bypass. Eur J Vasc Endovasc Surg 2009;37:379–87.

9. Kovacic JC, Roy PR, Baron DW, Muller DW. Staged carotid artery stenting and coronary artery bypass graft surgery: initial results from a single center. Catheter Cardiovasc Interv 2006;67:142–8.

10. Randall MS, McKevitt FM, Cleveland TJ, Gaines PA, Venables GS. Is there any benefi t from staged carotid and

736 Gen Thorac Cardiovasc Surg (2011) 59:730–736

coronary revascularization using carotid stents? A single-cen-ter experience highlights the need for a randomized controlled trial. Stroke 2006;37:435–9.

11. Van der Heyden J, Suttorp MJ, Bal ET, Ernst JM, Ackerstaff RG, Schaap J, et al. Staged carotid angioplasty and stenting followed by cardiac surgery in patients with severe asymptom-atic carotid artery stenosis: early and long-term results. Circu-lation 2007;116:2036–42.

12. Guzman LA, Costa MA, Angiolillo DJ, Zenni M, Wludyka P, Silliman S, et al. A systematic review of outcomes in patients with staged carotid artery stenting and coronary artery bypass graft surgery. Stroke 2008;39:361–5.

13. Manabe S, Shimokawa T, Fukui T, Fumimoto KU, Ozawa N, Seki H, et al. Infl uence of carotid artery stenosis on stroke in patients undergoing off-pump coronary artery bypass graft-ing. Eur J Cardiothorac Surg 2008;34:1005–8.

14. Peel GK, Stamou SC, Dullum MK, Hill PC, Jablonski KA, Bafi AS, et al. Chronologic distribution of stroke after mini-mally invasive versus conventional coronary artery bypass. J Am Coll Cardiol 2004;43:752–6.

15. Schachtrupp A, Wrigge H, Busch T, Buhre W, Weylamd A. Infl uence of intra-aortic balloon pumping oncerebral blood fl ow pattern in patients after cardiac surgery. Eur J Anaesthe-siol 2005;22:165–70.

16. Yadav JS, Wholey MH, Kuntz RE, Fayad P, Katzen BT, Mishkel GJ, et al. Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med 2004;351:1493–501.

17. Gurm HS, Yadav JS, Fayad P, Katzen BT, Mishkel GJ, Bajwa TK, et al. Long-term results of carotid stenting versus endarterectomy in high-risk patients. N Engl J Med 2008;358:1572–9.