D. Gortler: Drug Therapy in Carotid Stenting: The Need for More Evidence

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					Vascular, Vol. 16, No. 0, pp. 000–000, 2007. Printed in the USA The International Society for Vascular Surgery # BC Decker Inc. All rights reserved. ISSN: 1708-5381.

DOI: 10.2310/6670.2008.00081


Drug Therapy in Carotid Artery Stenting: The Need for More Evidence
¨ David Gortler*, Felix J.V. Schlosser{, Bart E. Muhs{, Michael A. Nelson, and Alan Dardik{
Carotid artery stenting (CAS) is a widely accepted alternative for patients at high risk for carotid endarterectomy (CEA). However, the role, indications, and evidence for many pharmacologic agents that are used adjunctively in the periprocedural setting have not been established. Several drugs are commonly used before, during, and after CAS, but their uses have not been standardized. Large prospective cohort studies with good validity or randomized trials are needed to demonstrate efficacy, predict outcome, and determine the optimal use of these medications in patients undergoing CAS to improve patient care and obtain optimal outcomes.


Take-home points: (1) dual-antiplatelet therapy (aspirin and clopidogrel) is commonly used for CAS; (2) the most commonly used regimen is aspirin 325 mg and clopidogrel 75 mg per day, but the optimal time of therapy is unknown; and (3) the dose and regimen of other agents used for CAS are not established. Key words: anticoagulants, antiplatelet therapy, carotid artery stenting, carotid endarterectomy, cholesterol, pharmacology

he benefits of combined antiplatelet treatment in coronary artery stenting have been established.1 Studies have shown that dual-antiplatelet therapy such as aspirin and clopidogrel has an advantage over therapy with aspirin alone or aspirin plus warfarin.2 Medical drug treatment is likely beneficial in carotid artery stenting (CAS). However, insight is significantly lacking regarding the effects of medical drug treatment on periprocedural or long-term outcome in patients undergoing CAS. CAS is a widely accepted alternative to carotid endarterectomy (CEA).3–5 The randomized SAPPHIRE trial, which played an important role in the Food and Drug Administration’s approval of CAS, compared CAS with the use of a periprocedural emboliprotection device with CEA


Departments of *Pharmacology and {Surgery, Yale University School of Medicine, New Haven, CT; and the VA Connecticut Healthcare System, West Haven, CT. This material is the result of work partially supported by the National Institutes of Health Career Development Award HL079927/American Vascular Association William J. von Liebig Award, as well as with resources and the use of facilities at the VA Connecticut Healthcare System, West Haven, CT. Correspondence to: Alan Dardik, MD, PhD, Vascular Biology and Therapeutics, Yale University School of Medicine, 10 Amistad Street, Room 437D, Box 208089, New Haven, CT 06520-8089; tel: 203-7372213; fax: 203-737-2290; e-mail:

and showed a 50% reduced risk of a composite of death, stroke, or myocardial infarction within 30 days after the intervention or death or ipsilateral stroke between 31 days and 1 year.6 The 1 year reintervention rate appeared to be 3% after CAS and 7.1% after CEA. The nonrandomized ARCHeR trial also showed that CAS is not inferior to CEA in the treatment of carotid artery disease.7 The authors described good long-term durability after CAS, with a 1year risk of a composite end point including stroke, death, or myocardial infarction of 9.6% after CAS and 14.4% after CEA in high-risk patients. Other trials have suggested that the benefits of CAS compared with CEA were less clear. The randomized SPACE trial found that the risk of ipsilateral ischemic stroke or death from time to randomization to 30 days after the procedure was 6.84% after CAS and 6.34% after 8 <CEA in symptomatic patients. These authors could not significantly prove the noninferiority of CAS and therefore concluded that the widespread use of CAS could not be justified. The French randomized EVA-3S trial was stopped prematurely, after recommendation of the Safety Committee.9 The 30-day risk of stroke or death was significantly higher after CAS than CEA (9.6% versus 3.9%, relative risk 2.5, 95% confidence interval 1.2–5.1). The important differences in =SAPPHIRE and EVA-3S trial may outcomes between the be attributed to several factors. Patients included in the SAPPHIRE trial were at

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higher risk of coronary artery disease, the majority had asymptomatic carotid artery disease (in EVA-3S all patients were symptomatic), emboli protection was used in all patients, stenting time was shorter, and the participating institutions and surgeons had considerably more experience in performing CAS compared with the institutions participating in the EVA-3S trial.6,9–13 Another important difference was that dual-antiplatelet therapy was required in the SAPPHIRE trial and only recommended in the EVA-3S trial. Single-antiplatelet therapy instead of more optimal dual-antiplatelet therapy was subsequently received by 17.1% of the patients in the EVA-3S trial before CAS and 14.6% after CAS. Stroke is an important contributor to the morbidity rates following CAS. Groschel and colleagues reported a 30-day minor stroke risk of 5% after CAS (18t of 327 patients, of whom 17 were ischemic, and 1 had a hemorrhagic stroke).14 Gray and colleagues showed a 30day stroke or death risk of 6.9% after CAS and reported no hemorrhagic strokes in the 581 patients of the ARCHeR trial.7 Risk factors associated with complications after CAS include age,14,15 diabetes,16 symptomatic carotid artery stenosis,14 hypercholesterolemia,17 lack of emboli protection,18 previous stenting, aspirin resistance, and disseminated disease. CAS with the use of an emboli protection device may have similar outcomes compared with CEA,6 but a standardized trial between the two different groups would be necessary to definitively make this assessment. The available studies involved a limited number of patients, and drug therapy19 and the results were not always conclusive.20 de Borst and colleagues showed that CAS can also be performed in patients with recurrent stenosis after CEA and described low complication risks and good long-term protection from stroke after CAS.21 The differences in medical drug treatment in combination with the different outcome results of the SAPPHIRE and EVA-3S randomized trials led to our hypothesis that the risks of complications after CAS are dependent on periprocedural medical drug treatment and that improvements in drug therapy may lead to improved mortality and morbidity results after CAS. This article reviews the available literature on evidence regarding the effects of several pharmacotherapies on prognosis following CAS.

AND (‘‘Carotid Stenosis’’[MeSH Terms] OR ‘‘Carotid Artery Diseases’’[MeSH Terms] OR ‘‘Stents’’[MeSH Terms] OR ‘‘Carotid Artery Thrombosis’’[MeSH Terms] OR ‘‘Carotid Arteries’’[MeSH Terms] OR carotid*) AND (stent[TI] OR stenting[TI] or stents[TI] OR ‘‘stenting’’ [MeSH Terms])), yielding 1627 articles. Selection of Articles All titles and abstracts of these 1,627 articles were read by two independent investigators (F.J.V.S. and D.G.). The following articles were included: (a) randomized trials that evaluated mortality and morbidity results after CAS, (b) articles that described risk factors for complications after CAS, or (c) articles that evaluated the use of medication during or after CAS. Full-text versions were obtained of all articles that matched any of the inclusion criteria. All selected full-text articles were read by two independent investigators (F.J.V.S. and D.G.). No language or publication date restrictions were applied. Reference lists were searched manually to locate additional articles that were relevant for inclusion in our study. The validity of the selected articles was critically appraised according to the Oxford Centre for EvidenceBased Medicine’s levels of evidence.22

Antiplatelet Agents
Aspirin Aspirin was developed into a drug by the Bayer Corporation in 1897.23 Aspirin had been used exclusively as an analgesic until 1971, when it was demonstrated to have several other types of utility, including effectiveness as an anti-inflammatory agent via its inhibition of cyclooxygenase and its ability to prevent platelet adhesion.24 The mechanism of aspirin action includes both central and peripheral mechanisms. The primary mechanism of action is to block the production of prostaglandins in injured peripheral tissues, which accounts for the analgesic effect. In addition, the salicylate and acetate moieties each cross into the brain and spinal cord to inhibit central prostaglandin receptors, preventing activation of these central receptors by diffusible peripheral prostaglandins. Aspirin also inhibits cyclooxygenase within platelets by binding to them in an irreversible fashion. Given that platelets do not have nuclei, they do not have deoxyribonucleic acid (DNA) with which to synthesize cyclooxygenase during their short 8-day life. Therefore, aspirin effectively permanently inhibits platelet function.


Literature Search The MEDLINE database was searched on November 1, 2007. The following search string was used: (caroti*[TIAB]

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However, aspirin only affects one of multiple pathways that regulate coagulation; thus, it is not surprising that aspirin decreases the overall relative risk of thromboembolic stroke by only 20 to 25% and that patients can still suffer from a stroke while taking aspirin.25 The gastrointestinal toxicity of aspirin is typically dose dependent. Given that the dose of aspirin may be given as long-term therapy following CAS, it would only be necessary to give the lowest recommended dose. The lowest recommended dose of aspirin varies depending on the condition being treated (Table 1). It is not known what the lowest recommended dose of aspirin would be to prevent a stroke in patients undergoing CAS. Clopidogrel Clopidogrel’s mechanism of action is selective, irreversible inhibition of adenosine diphosphate–induced platelet aggregation, with no significant effect on thromboxane A2 or prostacyclin synthesis or phospholipase A activity.26–29 Clopidogrel inhibits platelet function by a different mechanism of action than aspirin, and, accordingly, the combination of aspirin and clopidogrel would be expected to provide synergistic platelet inhibition. Clopidogrel is commonly paired with aspirin prior to and following various percutaneous coronary interventions (PCIs). In these studies, dual-antiplatelet therapy was not associated with an untoward number of adverse bleeding events. For example, the PCI-CURE (Clopidogrel in Unstable Angina to prevent Recurrent ischemic Events) study confirmed the benefits of clopidogrel and aspirin therapy seen in the overall CURE study.30 In this study, dualantiplatelet therapy was associated with a minimal (1% increase; p 5 .001) incidence of major bleeding events. A randomized trial by Markus and colleagues showed that a combination therapy of clopidogrel and aspirin
Table 1. Lowest Proven Effective Antithrombotic Dose of Aspirin for Selected Diagnoses25 Diagnosis Chronic stable angina Unstable angina Acute myocardial infarction Transient ischemic attack/stroke Acute ischemic stroke Severe carotid stenosis Atrial fibrillation Polycythemia vera Lowest Effective Daily Aspirin Dose (mg) 75 75 160 50 160 75 325 100

reduced the risk of stroke and transient ischemic attack and reduced asymptomatic embolization when compared with aspirin alone.31 A randomized trial by McKevitt and colleagues compared aspirin and 24-hour heparin with aspirin and clopidogrel for patients undergoing CAS and showed that dual-antiplatelet therapy significantly reduced neurologic outcomes without an additional increase in bleeding complications.32 The neurologic complication rate was 25% in patients treated with aspirin and 24 hours of heparin and 0% in patients treated with aspirin plus clopidogrel (p 5 .02). The 30-day 50% and 100% restenosis rates were 26% and 5%, respectively. The study was ended prematurely owing to the high complication rate in the heparin arm of the study. In CAS, dual-antiplatelet therapy is commonly implemented prior to, during, and following treatment with aspirin and clopidogrel. Studies have shown the benefits of dual-antiplatelet therapy in intracoronary stenting in clinical trials. As is the case with intracoronary stenting, combination therapy with clopidogrel and aspirin may be similarly beneficial following CAS. Despite the fact that dual-antiplatelet therapy has been established in other stenting studies, including CAS trials, a review completed from 2000 to the present shows that it is challenging to find two studies that agree with each other with regard to initial doses, timing of the initial doses, and duration of the drug. Even within recent studies, exact antiplatelet strategies are highly varied. For instance, in the February 2008 CREST lead-in registry data, the doses of clopidogrel and aspirin were chosen at the discretion of the treating physician.33 A review of drugs, doses, and dosing intervals is summarized in Table 2. Following CAS, the optimal duration of clopidogrel therapy has not yet been established, but it is likely that it should not be administered indefinitely. Clopidogrel probably only needs to be given long enough for the stent to be reendothelialized, following which the risk of thrombosis would be diminished and additional therapy would no longer be necessary.34–36 It is tempting to speculate that heparin-bonded stents, or stents that elute clopidrogrel, would require less systemic therapy.

Anticoagulant Agents
Heparin and IIb/IIIa Inhibitors Heparin was first discovered by a second-year medical student in 1916. The ‘‘hep’’ in heparin was named from the liver, from where it was first extracted.37 Heparin is


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Table 2. Dual-Antiplatelet Therapies for Carotid Artery Stenting Carotid Artery Stenting Trial Carotid artery stenting trial in a vascular surgery practice: J Vasc Surg 2002;35:430–4 Yadav et al6 Safety and efficacy of the Perclose suturemediated closure device following carotid artery stenting under clopidogrel platelet blockade: Eur Radiol 2004;14:719–22 International Carotid Stenting Study: protocol for a randomised clinical trial comparing carotid stenting with endarterectomy in symptomatic carotid artery stenosis: Cerebrovasc Dis 2004;18:69–74 Protected carotid stenting in high-risk patients with severe carotid artery stenosis: J Am Coll Cardiol 2006;47:2384–9 Carotid artery stenting in a community setting: experience outside of a clinical trial: Ann Vasc Surg 2003;17:629–34 Carotid artery stenting is associated with increased complications in octogenarians: 30-day stroke and death rates in the CREST lead-in phase: J Vasc Surg 2004;40:1106–11 Hobson et al33 Clopidogrel/ Aspirin Dose Clopidogrel Dosing Interval Aspirin Interval Indefinitely Indefinitely 300 mg for unknown duration Unknown Pre-CEA aspirin use reported in 41% of patients ‘‘The combination of aspirin and clopidogrel is recommended to cover stenting procedures.’’ NOS Notes

75 mg/325 mg ‘‘2–3 days before and 30 days after’’ 75 mg/81 or ‘‘24 hours before and 325 mg 2–4 weeks thereafter’’ 75 mg/500 mg ‘‘At least 4 days before and 30 days after’’ then 300 mg after procedure Unknown/ Unknown unknown


75 mg/81 or 325 mg

(not specified) before and 3 mo after

Unknown if maintenance clopidogrel dose was 150 or 75 mg Unknown if maint 75 mg bid*/ ‘‘Pretreatment’’ (NOS), ‘‘Pretreatment’’ clopidogrel dose was 325–650 mg minimum of 1 mo of (NOS), tmt post minimum of 1 150 or 75 mg or if mo of tmt post aspirin dose was 325 or 650 mg 75 mg/81 mg 3 d before and 3 mo 3 d before and What is the learning curve for carotid artery after indefinitely stenting with neuroprotection? Analysis of following 200 consecutive cases at an academic institution: Pers Vasc Surg Endovasc Ther 2005;17:113–25 Shawl41 75 mg bid*/ 3 (or 5–7) d before and 3 (or 5–7) d Warfarin stopped 4 d 325 mg bid then for 4 wk before to and prior to procedure then indefinitely 75 mg*/ 3–5 d before and and 3–5 d before and Randomized to heparin Wholey et al39 vs heparin plus 325 mg unknown following unknown glycoprotein 11b/111a following inhibitor Bhatt et al19 Unknown/ Heparin or glycoprotein 75 mg*/ None before, 300 mg unknown IIb/IIIa inhibitor was 325 mg load, then 75 mg 3 4 used prior to and wk during the procedure McKevitt et al20 Unknown/ 75–300 mg/ 300 mg 6–12 h, unknown 75 mg 75 mg 2 h before, then 75 mg 3 28 d

75 or 150 mg/ 150 mg 3 2 d when 81 or 325 mg starting, then 4–6 wk or indefinitely 2 d before and 75 mg bid*/ 2 d before and indefinitely 325–650 mg minimum of 2–4 wk or indefinitely following following

(not specified) before and 3 mo after Indefinitely


Not a clinical trial but observed data


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Table 1. Continued Clopidogrel/ Aspirin Dose Clopidogrel Dosing Interval

Carotid Artery Stenting Trial Hofmann et al

Aspirin Interval 2 d before; unknown duration

Notes Negative results with the use of abciximab plus heparin

75 mg/100 mg 2 d before; unknown duration

bid 5 twice daily; CEA 5 carotid endarterectomy; NOS 5 not otherwise specified. *In these trials, provisions were made for a substitution of ticlopidine 250 bid if there was an intolerance to clopidogrel. Ticlopidine has fallen out of favor because it is associated with neutropenia (1–2.4%) and thrombotic thrombocytopenia purpura (1 in 3,000). Unlike clopidogrel, ticlopidine requires twicedaily dosing.

now a very well-established anticoagulant, with its main anticoagulant effect likely mediated by its binding to antithrombin III, accelerating the inhibition of thrombinmediated conversion of fibrinogen to fibrin and preventing additional thrombus accumulation. The precise mechanism by which heparin exerts its anticoagulant action has not been completely elucidated; however, it is widely believed that heparin exerts its effects primarily via the intrinsic clotting cascade and heparin cofactor II.38 Heparin is typically given during the periprocedural period and may be given with or without glycoprotein IIb/ IIIa inhibitors. As a single agent, heparin is usually given as a 5,000- to 8,000-unit bolus. If heparin is given with a IIb/ IIIa inhibitor, the heparin dose is usually halved. The rationale for halving the dose of heparin, and even how this dose was established, is not clear. Two studies examined the combination of IIb/IIIa inhibitors plus heparin in CAS, and both studies had negative outcomes, generally discouraging the use of IIb/ IIIa inhibitors in therapy. One study, which involved a retrospective review of 450 patients who were given either abciximab or eptifibitide periprocedurally, found that the neurologic complications following CAS were more numerous and substantial, thereby discouraging the combination.39 Another study combining only abciximab plus heparin confirmed those findings.40

substitute anticoagulant, such as heparin, in warfarin’s absence. A single study referenced the use of warfarin prior to CAS. The study recommended that warfarin would be stopped and clopidogrel started 4 days prior to CAS.41 This study is included in Table 2. Warfarin is difficult to dose and increases the risk of minor bleeding. Although it is more potent, it has not been shown to have superior outcome data to standard-dose aspirin for preventing stroke in patients undergoing CAS. No other prospective trials exist examining the discontinuation of warfarin in patients undergoing CAS. Given that warfarin is a potent anticoagulant, its routine use might be expected to be associated with a higher number of hemorrhagic adverse events, and its discontinuation would likely be warranted prior to CAS. A 4-day lead discontinuation is plausible based on its 100-hour inhibition of factor II, and the substitution therapy with clopidogrel and aspirin is practical and feasible, but the exact doses and timing of one or more of these platelet inhibitors need to be established. Atropine Atropine is a competitive antagonist of the actions of acetylcholine and other muscarinic agonists. Atropine competes for a common binding site on the muscarinic receptor. The main cardiac effect of atropine is its effect on heart rate. Although the dominant response is tachycardia, the heart rate often decreases transiently with average clinical doses (0.4–0.6 mg). There are little or no accompanying changes in blood pressure or cardiac output.42 Intraprocedural bradycardia (heart rate , 50 bpm) may require vasopressor use, and atropine is often the drug of choice. The cause of the bradycardia is believed to be related to vagal stimulation. The incidence of bradycardia has not been well documented but has been examined in

Warfarin Warfarin is routinely discontinued prior to invasive or surgical procedures, including CAS. The decision to continue to discontinue warfarin is made on a patientby-patient basis and depends, to a large extent, on the indication for its use. Patients using warfarin as an anticoagulant for atrial fibrillation may choose to omit therapy for a few days, whereas patients using warfarin for a mechanical prosthetic valve would likely need a

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smaller studies of just a few hundred participants or less.43,44 These data have shown that a transient bradycardia occurs more frequently in patients with primary carotid artery stenosis relative to redo-CAS patients and that bradycardia occurs more commonly in patients who have had a prior myocardial infarction, independent of age or sex. In contrast, prolonged hypotension requiring vasopressor support has been shown to occur in a minority of patients after CAS, with a relatively higher incidence in older women.45 Some studies involving a very limited number of patients recommend the prophylactic administration of atropine before balloon inflation during CAS to decrease the incidence of intraoperative bradycardia and the potential for cardiac morbidity in primary CAS patients.46 Hemodynamic instability can also include hypotension. This may require intravenous catecholamines (dopamine) to symptomatically treat hypotension in patients undergoing CAS. Unfortunately, the utility of dopamine intraprocedurally is not well described. Statins Two recent articles have shown a likely benefit of statin administration in patients undergoing both PCI generally and CAS in particular. In one cohort study examining CAS, preprocedural statin therapy appeared to reduce the 30-day risk of stroke, myocardial infarction, and death after CAS. The risk of a combined end point, including stroke, myocardial infarction, and death, was 4% in patients using statins versus 15% in nonusers (p , .05).47 A review article examining statin use showed that statins do show multiple beneficial effects in patients undergoing PCIs and percutaneous transluminal coronary angioplasty, but this review also did not standardize the statin used or the length of time.48 In some cases, patients only needed to be on a statin for a few days to be eligible for the trial. It is unknown if there would be any beneficial consequence to taking a statin for only a few days. There may be a difference between the available statins with regard to plaque stabilization, anti-inflammatory action, effect on endothelial function, mechanism of action, and potency. In studies, statin therapy was not standardized with regard to dose or drug, meaning that patients could be on any one of five available statins. The full anti-inflammatory, plaque-stabilizing effect and effect on endothelial function may take weeks or months to manifest. Low-density lipoprotein (LDL) cholesterol is known to have proinflammatory properties, and it is not clear as to

whether the plaque stabilization derived from statin use is directly attributable to a decrease in LDL or if it is a pleiotropic property of the statin itself. Given that several of the statins are structurally distinct, their pleiotropic properties would be expected to differ with regard to plaque stabilization. On the other hand, if LDL lowering is the main cause of plaque stabilization, then the more potent statins would be expected to have the greatest potential for atherosclerotic plaque stabilization.

Other Drugs
This review also included searches for compounds that have been shown to play a role in CEA and could potentially play an ancillary role in CAS. However, a MEDLINE search for CAS articles cross-referenced with dextran, b-blockers, and angiotensin-converting enzyme inhibitors yielded either no results or results that were not relevant to the objectives of this review.

The roleof and indications and evidence for many pharmacologic agents that are used adjunctively to CAS have not been established. Standardization of periprocedural doses and regimens would increase the clinical applicability of data from randomized trials.

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Authors Queries
Journal: Vascular Paper: VAS_2008_00081 Title: Drug Therapy in Carotid Artery Stenting: The Need for More Evidence Dear Author During the preparation of your manuscript for publication, the questions listed below have arisen. Please attend to these matters and return this form with your proof. Many thanks for your assistance RETURN VIA FAX TO BC DECKER PROOFING, CHARLESWORTH CHINA +86 (0) 106779 9806 OR SCAN AND RETURN VIA EMAIL TO




AU: What do you mean by takehome points? Please provide a more appropriate lead-in to this list. AU:You did not make it clear the affiliations. I have tried to indicate this, based on other information received; however, the affiliation that was provided for Nelson doesn’t even appear here, and the affiliation in your address differs from the information in the affil footnote and the other information with which we were provided. Which authors belong to the VA Connecticut Healthcare System? Please clarify for all. AU: In your address, is it Section? Division? AU: I couldn’t tell which heading levels you meant for the drugs. Please check. AU: In Table 2, some of the studies are in your ref list and some aren’t. You need to provide a full reference for each one to appear in the ref list. Then in the table, only the lead author’s name and reference number will appear.


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Status of Drug Therapy for Carotid Stenting



AU: Why is not specified in parens in Table 2, but it doesn’t appear following anything? Please clarify. AU: In Table 2, what is tmt post? AU: In Table 2, what is maint? AU: I know what you mean, but the statement on hep being named from the liver needs to be rephrased. AU: Refs 11 to 13 all have the same title, and are from the same journal, same year, same volume. But their authors are different, and in two cases, the page numbers overlap. Please correct this and make sure that the in-text citations are correct as well. AU: Reference 23 is incomplete. Please advise. AU: Are all of the names in ref 42 editors? It’s difficult to tell given how they are presented. Please clarify, and if you are citing a portion of the book, please provide the title and inclusive pages.

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Description: Several drugs are commonly used before, during, and after CAS, but their uses have not been standardized. Large prospective cohort studies with good validity or randomized trials are needed to demonstrate efficacy, predict outcome, and determine the optimal use of these medications in patients undergoing CAS to improve patient care and obtain optimal outcomes.