Low Risk of Intracerebral Hemorrhage with Adjunctive IIb/IIIa Inhibitors in Ad Hoc Carotid Artery Stenting

Abstract

Objective. We assessed the risk of intracerebral hemorrhage (ICH) in patients who underwent carotid artery stenting (CAS) and received glycoprotein IIb/IIIa inhibition as adjunctive antiplatelet therapy. Background. Despite smaller studies to the contrary, we report a negligible risk of ICH with adjunctive glycoprotein IIb/IIIa inhibitor use in CAS. Methods. We reviewed 573 consecutive patients who underwent ad hoc CAS at Baptist Medical Center-Princeton, Birmingham, Alabama between August 1999 and August 2009. Of these, 538 patients were administered a glycoprotein IIb/IIIa inhibitor (eptifibatide, n=536, abciximab, n=2) as adjunctive antiplatelet therapy. Results. Most patients were asymptomatic with positive atherosclerotic risk factors of: hypertension, coronary artery disease, hyperlipidemia, and history of smoking. The overall procedural success rate was 99.3% and an embolic protection device was used in 95.2% of cases. Mean stenosis of primary lesion was 85.6% pre-procedure and 4.8% post-procedure. There was one (0.2%) case of intracerebral hemorrhage. The patient was a 70-year-old Caucasian male with 99.9% stenosis of the ipsilateral right internal carotid artery who was symptomatic from multiple recurrent TIAs with a history of multiple ischemic strokes and extensive comorbidities. Antithrombotic therapy consisted of aspirin, clopidogrel, bivalirudin, and adjunctive use of a single bolus of eptifibatide. Approximately 30 minutes post-procedure, a CT showed the patient suffered a massive ipsilateral intracranial hemorrhage. Other complications in the series included death (0.9%), ischemic stroke (1.1%), TIA (0.9%), and access site bleeding (3.0%). Conclusion. Adjunctive use of the glycoprotein IIb/IIIa inhibitor eptifibatide in ad hoc CAS does not increase the risk of intracerebral hemorrhage.

VASCULAR DISEASE MANAGEMENT 2011;8(12):E203–E206

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Introduction

Carotid artery stenting (CAS) is a therapeutic alternative to carotid endarterectomy (CEA).¹ Antithrombotic therapy is an essential adjunct to the carotid stent technique and consists of both periprocedural anticoagulation and preprocedural platelet inhibition with aspirin and thienopyridines, typically clopidogrel.² The pharmacokinetic profile of thienopyridines requires several hours to several days to achieve adequate platelet inhibition.³ Thus, ad hoc carotid intervention with this approach would leave the platelets fully functional during the period of the carotid artery stent procedure when thromboembolic risk is greatest.⁴ Much of the literature on the use of glycoprotein IIb/IIIa inhibitors in CAS suggests their use is contraindicated due to an increase in complications, especially intracerebral hemorrhage (ICH).^5–8 To optimize platelet inhibition during ad hoc carotid intervention, we initiated the practice of bolus glycoprotein IIb/IIIa inhibition regardless of prior antiplatelet treatments. Here we report the safety of this approach in the largest single operator series of glycoprotein IIb/IIIa inhibitors in CAS.

Methods

Patients. Between August 1999 and August 2009, 573 patients were diagnosed with severe carotid occlusive disease at Baptist Medical Center–Princeton (BPH) and underwent CAS at the same institution. Of these, 538 patients received adjunctive glycoprotein IIb/IIIa therapy and comprise the cohort of this paper. Patients were eligible if they had neurological symptoms and >50% stenosis or no symptoms and >80% stenosis. The majority of patients were asymptomatic (69.5%) and all patients had evidence of high-risk clinical features. All interventions were performed by a single operator.

Technique. After noninvasive imaging revealed severe occlusive disease, 4-vessel cerebral angiography was performed and carotid intervention immediately followed. The carotid stenting procedure was performed as previously described.9 Various cerebral protection devices (RX Accunet, n=313 [Guidant Corp.], FilterWire EZ, n=110 [Boston Scientific Corp.], Emboshield, n=4 [Abbott Laboratories], Angioguard, n=84 [Cordis Corp.], Spider, n=1 [ev3 Endovascular]) and stents (Rx Acculink, n=349 [Guidant], Dynalink, n=91 [Guidant], Omnilink, n=5 [Guidant], Conformex, n=8 [CR Bard], Vivexx, n=1 [Bard], Smart, n=3 [Cordis], Multi-Link Vision, n=1 [Abbott], Express, n=1 [Boston Scientific], Genesis, n=1 [Cordis], Precise, n=78 [Cordis]) were used. The initial 9 cases were performed without cerebral protection. After November 2001, cerebral protection devices were used in all but 17 cases, where unfavorable anatomy precluded their delivery. Access site closure devices were used for the majority of the patients.

All patients received glycoprotein IIb/IIIa inhibitor antiplatelet therapy of either eptifibatide or abciximab. Eptifibatide was administered either as a single bolus, a single bolus with infusion, or a double bolus. Abciximab was administered only as a single bolus. The dosing rationale for bolus, rather than infusion, was to inhibit platelet aggregation only during the procedure, when the risk of thromboembolic risk is greatest. Patients typically received anticoagulant therapy of a single bolus plus infusion of bivalirudin. A minority of those also received low-dose heparin. Prior to May 2003, all patients were administered only heparin for anticoagulation.

The average time from arterial insertion of the carotid sheath to removal for all patients was 39 minutes (±14). After the procedure, patients were observed in a post-interventional unit and blood pressure was monitored noninvasively. Vasopressor or antihypertensive agents were used for hemodynamic stability at the discretion of the operator. Serial hematologic testing was performed routinely. A detailed neurological exam was performed pre- and post-intervention. At the onset of neurological symptoms, including headache, a stat computed tomography (CT) brain scan and an independent neurological consult were obtained.

Data Collection. A retrospective chart review was conducted on 573 consecutive patients who underwent CAS using glycoprotein IIb/IIIa inhibitors at Baptist Princeton between August 1999 and August 2009. Demographic characteristics, symptomatic status, angiographic data, procedural details, antithrombotic use, hemodynamic data, and periprocedural events, including ICH, were recorded.

Statistics. Data are given as mean ± standard deviation (SD) and counts (percent).

Results

Patient demographics. Patient characteristics are summarized in Table 1. The majority of patients were asymptomatic but with positive atherosclerotic risk factors of: hypertension, coronary artery disease, hyperlipidemia, and history of smoking.

Angiographic and procedural results. The overall procedural success rate was 99.3%. The mean time of procedure was 39 minutes ± 14. Embolic protection device was used in 95.2% of cases. Mean stenosis of primary lesion was 85.6% ± 8.4% pre-procedure and 4.8% ± 8.9% post-procedure. There was contralateral disease in 470 patients with a mean of 37.9% ± 26.7%. The mean post-procedure BPM was 135/70. There were incidences of non-hemorrhagic complications including ischemic stroke (1.1%), transient ischemic attack (TIA) (0.9%), ventricular arrhythmias (0.4%), and death (0.9%). Two deaths were due to complications post-coronary artery bypass graft (CABG) and one was due to ventricular tachycardia. Non-cerebral bleeding complications were limited to access site bleeding in 3% of patients.

There was one incidence of intracerebral hemorrhage in the cohort (0.2%). This patient was a 70-year-old Caucasian male who was symptomatic from multiple recurrent TIAs with extensive morbidities including: diabetes mellitus, hypertension, chronic obstructive pulmonary disease (COPD), hyperlipidemia, and coronary artery disease (CAD). Notably, he experienced multiple ischemic events in the 5 years prior to the procedure, including a lacunar infarct in 2002, a left occipital stroke in 2004, and multiple incidences of left leg weakness thought to be attributed to TIAs in the days to weeks prior to the procedure. A 4-vessel angiogram identified 99.9% stenosis of the right internal carotid artery, 25%-50% stenosis of the contralateral internal carotid artery, and 50%-75% stenosis of the distal vertebral artery. Bivalirudin was administered in a single bolus (0.75 mg/kg) and infusion (1.75 mg/kg/hr). Antithrombotic therapy consisted of 325 mg aspirin, 600 mg clopidogrel, and adjunctive use of a single bolus (180 mcg/kg) of eptifibatide. A right carotid artery stent was successfully deployed and the final result showed minor irregularity. The patient exhibited signs of altered consciousness approximately 30 minutes post-procedure and a CT showed a massive ipsilateral intracranial hemorrhage (Figure 1). 

Discussion

CAS was initiated in the early 1990s as a minimally invasive alternative to carotid endarterectomy¹⁰ and was approved in 2004 by the FDA for use in symptomatic patients deemed high-risk for CEA.¹¹ Studies have been published comparing the two modalities and CEA remains the “gold standard” due in part to its reported lower rates of stroke, bleeding and death.¹² A complication associated with particularly high mortality in carotid revascularization of either type is intracerebral hemorrhage. Incidences of ICH in CEA have been reported in multiple studies to be between 0.4% and 0.6%^13–18 and range from 0.7% up to 5%^17,18 for CAS.

Adjunctive glycoprotein IIb/IIIa use in CAS has been thought to increase the risk of ICH.^5,6,7,8 Wholey et al reviewed 550 patients who underwent CAS with either heparin and a glycoprotein IIb/IIIa inhibitor or heparin alone and found 3 ICH (1.4%) in the glycoprotein IIb/IIIa inhibitor group (216 patients) and none in the heparin-only group (334 patients). All patients received aspirin and a thienopyridine (ticlopidine or clopidogrel) 3-5 days prior to the procedure. Eptifibatide was administered in 80% of the glycoprotein IIb/IIIa group, as either a 135 mcg/kg bolus or bolus plus 0.5 mcg/kg/min infusion. Abciximab was used in 41 cases, either as a 0.25 mcg/kg bolus or bolus and 10 mcg/min infusion. A single patient who suffered an ICH received eptifibatide and 2 received abciximab. The dosing regimen in these patients is unknown. The increased incidence of catastrophic bleeding, in part, led Wholey et al to discourage glycoprotein IIb/IIIa inhibitor use in CAS. Smaller studies by Hofmann et al, Quereshi at al, and Chan et al report a combined 1.9% incidence of ICH in CAS with adjunctive eptifibatide or abciximab use, compared to no ICH complications in their control groups.^6,7,8

Glycoprotein IIb/IIIa inhibitor use has also been associated with increased bleeding in the treatment of patients with acute ischemic stroke. The AbESTT-II trial demonstrated a statistically significant increased rate of fatal and symptomatic ICH compared to placebo among patients presenting within 5 hours of stroke onset or within 3 hours of awakening with signs of stroke. Patients in each of these cohorts received a bolus followed by 12-hour infusion of abciximab.

Our single-operator experience in 538 patients at BPH over a 10-year period contradicts the aforementioned studies. We demonstrate a far lower incidence of ICH with adjunctive glycoprotein IIb/IIIa use compared to antiplatelet therapy of aspirin and thienopyridines alone. Our ICH rate of 0.2% is more comparable to the 0.12%-0.15% ICH rate^20,21 associated with glycoprotein IIb/IIIa use in percutaneous coronary intervention than in carotid revascularization by CEA or CAS. The sole ICH in our study was in a patient with multiple prior ischemic events, including crescendo TIAs occurring days prior to admission and ipsilateral 99.9% stenosis. The patient did not undergo pre-procedure imaging, but the possibility of hemorrhagic conversion of a prior stroke is significant. His history and near occlusion of the ICA are confounding factors that made him high-risk for either ischemic or hemorrhagic stroke independent of antithrombotic therapy. The answer for the difference in our results compared to prior studies is undetermined. We postulate that the relevant variables include differences in patient populations, periprocedural antithrombotic therapy, stenting technique, and operator experience.

The patients in our study share similar demographics and risk factors to CAS studies that show very different results. Our cohort was comprised of consecutive patients insofar as our retrospective review allowed. The specific antithrombotic regimen utilized in our study has not been reported to our knowledge and could offer some explanation of our results. In the above CAS studies, all patients were pretreated with aspirin and thienopyridines 2-5 days prior to procedure whereas our cohort received ad hoc intervention and received 325 mg of aspirin and 600 mg of clopidogrel during the procedure. We relied almost exclusively on eptifibatide as the adjunctive agent and bivalirudin as the primary anticoagulant. Other studies report a more balanced mix of eptifibatide and abciximab and utilize heparin rather than bivalirudin. There is also an important difference in glycoprotein IIb/IIIa administration in our study. In all but a few (n=7) cases where we added a short duration eptifibatide infusion or second bolus, we utilized only a single bolus of glycoprotein IIb/IIIa inhibitor to match platelet inhibition with time of procedure and minimize the risk of hemorrhage. A single bolus plus infusion, sometimes up to 24 hours, is common in other studies. Lastly, there exists variability in case volume and stenting technique that invariably occurs among different operators.

We initiated the practice of ad hoc carotid stenting to offer high-risk patients with cardiovascular disease an effective therapeutic alternative to CEA while minimizing hospital and recovery time. In this setting, the ability to inhibit platelet formation rapidly is vital in reducing the likelihood of a thromboembolic event. Among glycoprotein IIb/IIIa inhibitors, eptifibatide is best suited for ad hoc intervention due to its quick onset of platelet inhibition and short half-life. Platelet inhibition has already reached 84.8% (±12.1%)²² 10 minutes after single bolus administration. With an average time of 39 minutes for procedure in the cohort, maximal platelet inhibition has been achieved prior to the time where risk of thrombus/thromboembolus is the greatest. Eptifibatide’s short half-life means that platelet aggregation, and therefore risk of hemorrhage, has returned to normal within 2-4 hours of bolus administration.²³ Adjunctive use of glycoprotein IIb/IIIa inhibitors enables ad hoc CAS without the need for pretreatment with aspirin and clopidogrel.

Ad hoc intervention is well-understood and commonplace in percutaneous coronary intervention where it is associated with low dye-induced nephropathy and a decrease in vascular complications without sacrificing procedural success or compromising patient safety.^24,25 Fewer hospital visits minimizes the occurrence of hospital or procedure-related complications, including ischemic stroke as a consequence of catheter or wire manipulation of the aortic arch.²⁶ It also reduces any personal or professional burdens that may exist for the patient related to their admission.

Study limitations. This study is a retrospective review and is underpowered to find statistically significant differences between the sole patient with intracerebral hemorrhage and the rest of the cohort. Only patients with neurological symptoms identified by the operator received brain imaging. Thus, the true number of complications may be understated. Our reported complications are in-hospital only and may understate the actual number of adverse events. Since only one patient was given abciximab, the incidence of intracerebral hemorrhage we report should not be considered applicable to all glycoprotein IIb/IIIa inhibitors.

Study strengths. Strengths of our study include that it is a large single-operator series with a high procedural success rate over 10 years and a low overall rate of ICH, stroke, and death.

Conclusion

We believe the benefits of ad hoc carotid intervention combined with the low risk of intracerebral bleeding in our large patient population make a compelling case for adjunctive glycoprotein IIb/IIIa inhibitor use in this modality of carotid artery intervention.

References

1. Lal BK, Hobson RW 2nd. Treatment of carotid disease: stenting or surgery? Curr Neurol Neurosci Rep. 2007 Jan;7(1):49-53.
2. Silva JA, White CJ. Adjunctive pharmacologic treatment for elective stenting of the extracranial carotid arteries. Int J Cardiovasc Intervent. 2001 Sep;4(3):141-144.
3. Nikhil JY, Radhakrishnan S, Paradiso-Hardy FL, Cohen EA. Clopidogrel in interventional cardiology: questions answered and questions remaining. Can J Cardiol. 2002 Jul;18(7):739-748.
4. Bachman F, Savcic M, Hauert J, Geudelin B, Kleffer G, Carlou R. Rapid onset of inhibition of ADP-induced platelet aggregation by a loading dose of clopidogrel [Abstract]. Eur Heart J. 1996;17:263.
5. Wholey MH, Wholey MH, Eles G, et al. Evaluation of glycoprotein IIb/IIIa inhibitors in carotid angioplasty and stenting. J Endovasc Ther. 2003 Feb;10(1):33-41.
6. Hofmann R, Kerschner K, Steinwender C, Kypta A, Bibl D, Leisch F. Abciximab bolus injection does not reduce cerebral ischemic complications of elective carotid artery stenting: a randomized study. Stroke. 2002 Mar;33(3):725-727.
7. Qureshi AI, Suri MF, Ali Z, et al. Carotid angioplasty and stent placement: a prospective analysis of perioperative complications and impact of intravenously administered abciximab. Neurosurgery. 2002 Mar;50(3):466-473; discussion 473-475.
8. Chan AW, Yadav JS, Bhatt DL, et al. Comparison of the safety and efficacy of emboli prevention devices versus platelet glycoprotein IIb/IIIa inhibition during carotid stenting. Am J Cardiol. 2005 Mar 15;95(6):791-795.
9. Bates ER, Babb JD, Casey DE Jr, et al; for the American College of Cardiology Foundation; American Society of Interventional & Therapeutic Neuroradiology; Society for Cardiovascular Angiography and Interventions; Society for Vascular Medicine and Biology; Society of Interventional Radiology. ACCF/SCAI/SVMB/SIR/ASITN 2007 clinical expert consensus document on carotid stenting: A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2007 Jan;49(1);126-170.
10. McPhee JT, Hill JS, Ciocca RG, Messina LM, Eslami MH. Carotid endarterectomy was performed with lower stroke and death rates than carotid artery stenting in the United States in 2003 and 2004. J Vasc Surg. 2007 Dec;46(6):1112-1118. 
11. U.S. Department of Health and Human Services, Food and Drug Administration. ACCULINK review. Available at: https://www.fda.gov/cdrh/pdf4/p040012a.pdf.292:847-51.
12. Mas JL, Chatellier G, Beyssen B, et al; for the EVA-3S Investigators. Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. N Engl J Med. 2006 Oct;355(16):1660-1671.
13. Piepgras DG, Morgan MK, Sundt TM Jr, Yanagihara T, Mussman LM. Intracerebral hemorrhage after carotid endarterectomy. J Neurosurg. 1988 (Apr);68(4):532-536.
14. Pomposelli FB, Lamparello PJ, Riles TS, Craighead CC, Giangola G, Imparato AM. Intracranial hemorrhage after carotid endarterectomy. J Vasc Surg. 1988 Feb;7(2):248-255.
15. Hafner DH, Smith RB 3rd, King OW, et al. Massive intracerebral hemorrhage following carotid endarterectomy. Arch Surg. 1987 Mar;122(3):305-307.
16. Solomon RA, Loftus CM, Quest DO, Correll JW. Incidence and etiology of intracerebral hemorrhage following carotid endarterectomy. J Neurosurg. 1986 Jan;64(1):29-34.
17. Ogasawara K, Sakai N, Kuroiwa T, et al; for the Japanese Society for Treatment at Neck in Cerebrovascular Disease Study Group. Intracranial hemorrhage associated with cerebral hyperperfusion syndrome following carotid endarterectomy and carotid artery stenting: retrospective review of 4494 patients. J Neurosurg. 2007 Dec;107(6):1130-1136.
18. Qureshi AI. Adjunctive use of platelet glycoprotein IIb/IIIa inhibitors for carotid angioplasty and stent placement: time to say goodbye? J Endovasc Ther. 2003 Feb;10(1):42-44.
19. Abou-Chebl A, Yadav JS, Reginelli JP, Bajzer C, Bhatt D, Krieger DW. Intracranial hemorrhage and hyperperfusion syndrome following carotid artery stenting; risk factors, prevention, and treatment. J Am Coll Cardiol. 2004 May;43(9):1596-1601.
20. Akkerhuis KM, Deckers JW, Lincoff AM, et al. Risk of stroke associated with abciximab among patients undergoing percutaneous coronary intervention. JAMA. 2001 Jul;286(1):78-82.
21. Memon MA, Blankenship JC, Wood GC, Frey CM, Menapace FJ. Incidence of intracranial hemorrhage complicating treatment with glycoprotein IIb/IIIa receptor inhibitors: a pooled analysis of major clinical trials. Am J Med. 2000 Aug;109(3):213-217.
22. Mardikar HM, Hiremath MS, Moliterno DJ, et al. Optimal platelet inhibition in patients undergoing PCI: data from the Multicenter Registry of High-Risk Percutaneous Coronary Intervention and Adequate Platelet Inhibition (MR PCI) study. Am Heart J. 2007 Aug;154(2)344.e1-344.e5.
23. Scarborough RM. Development of eptifibatide. Am Heart J. 1999 Dec;138(6 Pt 1):1093-1104.
24. Varani E, Balducelli M, Lucchi GR, Vecchi G, Maresta A. Ad-hoc coronary angioplasty: organizational model, clinical results and costs. Ital Heart J Suppl. 2002 Jun;3(6):630-637.
25. Shubrooks SJ Jr, Malenka DJ, Piper WD, et al. Safety and efficacy of percutaneous interventions performed immediately after diagnostic catheterization in northern New England and comparison with similar procedures performed later. Am J Cardiol. 2000 Jul 1:86(1):41-45.
26. Keeley EC, Grines CL. Scraping of aortic debris by coronary guiding catheters: a prospective evaluation of 1,000 cases. J Am Coll Cardiol. 1998 Dec;32(7):1861-1865.

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From the ¹University of Alabama School of Medicine, Birmingham, Alabama, ²Cardiology PC, Princeton Baptist Medical Center, Birmingham, Alabama, and ³East Carolina University Brody School of Medicine, Greenville, North Carolina.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted May 30, 2011, provisional acceptance given June 20, 2011, final version accepted August 16, 2011.
Corresponding author: Mr. Hugh B. Milteer, Jr, BA, MBA, University of Alabama School of Medicine, 2912 Virginia Road, Birmingham, Alabama, 35223. Email: milteer@gmail.com