Antiplatelet therapy for the primary and secondary prevention of cerebrovascular events in patients with extracranial carotid artery disease

REVIEW ARTICLE Richard P. Cambria, MD, Section Editor

Antiplatelet therapy for the primary and secondary prevention of cerebrovascular events in patients with extracranial carotid artery disease Thomas J. Kiernan, MD,a Bryan P. Yan, MD,a and Michael R. Jaff, DO,a,b Boston, Mass Cerebrovascular disease is a leading cause of morbidity and mortality in developed countries around the world. In the United States, there are an estimated 700,000 cases of stroke annually (of which over 85% are ischemic), costing an estimated $56.8 billion in associated treatment. Large vessel internal carotid artery stenosis is an important cause of ischemic stroke. Population-based studies have shown that the prevalence of carotid stenosis is ⬃0.5% in the sixth decade of life and increases to ⬃10% in the ninth decade. The majority of patients are asymptomatic. Asymptomatic carotid stenosis with <75% lumen loss carries a stroke risk of 1.3% annually, whereas the combined risk of myocardial ischemia and vascular death is as high as 10%. With diameter stenosis >75%, the combined stroke and transient ischemic attack risk increases to ⬃11% annually, with 75% of events ipsilateral to the affected artery. Other studies have also shown that the risk of stroke increases proportionately to the severity of stenosis. The risk is higher for those patients who are symptomatic. In this review, we will discuss antiplatelet agents to prevent cerebrovascular events in the context of extracranial carotid artery disease. It is beyond the scope of this article to discuss antiplatelet treatment for other etiologies of stroke. ( J Vasc Surg 2009;50:431-9.)

Cerebrovascular disease is a leading cause of morbidity and mortality in developed countries around the world. In the United States, there are an estimated 700 000 cases of stroke annually (of which over 85% are ischemic), costing an estimated $56.8 billion in associated treatment.1 Large vessel internal carotid artery stenosis is an important cause of ischemic stroke. Population-based studies have shown that the prevalence of carotid stenosis is ⬃0.5% in the sixth decade of life and increases to ⬃10% in the ninth decade. The majority of patients are asymptomatic.2-4 Asymptomatic carotid stenosis with ⱕ75% lumen loss carries a stroke risk of 1.3% annually, whereas the combined risk of myocardial ischemia and vascular death is as high as 10%.5 With diameter stenosis ⬎75%, the combined stroke and TIA risk increases to ⬃11% annually, with 75% of events ipsilateral to the affected artery. Other studies have also shown that the risk of stroke increases proportionately to the severity of stenosis.6,7 Currently, the decision to perform prophylactic carotid endarterectomy (CEA) in asymptomatic patients is based mainly on the presence of a hemodynamically significant 60% to 99% internal carotid artery stenosis in relation to the From the Section of Vascular Medicine, Division of Cardiology,a and the Vascular Center,b Massachusetts General Hospital. Competition of interest: MRJ has been paid a consulting fee by Abbott Vascular Devices and is a board member of VIVA Physicians, Inc., a not for profit 501(c)3 organization, www.vivapvd.com. TJK and BPZ have no competing interests to declare. Reprint requests: Michael R. Jaff, DO, Associate Professor of Medicine, Harvard Medical School, Medical Director, Vascular Center, Massachusetts General Hospital, Boston MA 02114 (e-mail: [email protected]). 0741-5214/$36.00 Copyright © 2009 by the Society for Vascular Surgery. doi:10.1016/j.jvs.2009.04.052

normal lumen of the distal internal carotid artery. Compared with best medical treatment alone, this strategy reduces the risk of ipsilateral stroke, as shown by the Veterans Administration (VA) study, the Asymptomatic Carotid Atherosclerosis Study (ACAS), and the Asymptomatic Carotid Surgery Trial (ACST).8-10 The midterm overall risk reduction is minimal, however; the ACAS trial reported that in patients with stenosis ⬎60%, CEA reduced the annual risk of stroke from 2% to 1%, which implies that approximately 20 procedures need to be performed to prevent one stroke in five years. Recently, Nicolaides and colleagues reported on 462 asymptomatic patients with 60% to 99% carotid artery stenosis. The cumulative eventfree rate at eight years was 0.81 (2.4% annual event rate) in the absence of silent cerebral embolic infarcts and 0.63 (4.6% annual event rate) in the 86 patients where they were present (log-rank P ⫽ .032).11 The risk is higher for those patients who are symptomatic. In this review, we will discuss antiplatelet agents to prevent cerebrovascular events in the context of extracranial carotid artery disease. It is beyond the scope of this article to discuss antiplatelet treatment for other etiologies of stroke outside the diagnosis of significant carotid stenosis. ROLE OF ANTIPLATELET THERAPY IN PRIMARY PREVENTION OF STROKE Prevention of a first stroke is the critical strategy to reduce morbidity and mortality associated with cerebrovascular disease. Primary preventive measures are influenced by the patient’s risk factor profile and control of these risks. There has been compelling evidence for more than 30 years 431

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that the control of high blood pressure contributes to the prevention of stroke as well as to the prevention or reduction of other target-organ damage, including congestive heart failure and renal failure.12 A meta-analysis of 18 long-term randomized trials found that both ␤-blocker therapy and treatment with diuretics were effective in preventing stroke.13 Overall, antihypertensive therapy is associated with a 35% to 44% reduction in the incidence of stroke.14 Likewise, statin therapy has been shown to produce consistent benefits in large randomized trials in decreasing stroke risk.15-20 The risk of stroke in diabetic patients with hypertension is increased and blood pressure and blood glucose levels should be controlled. Atrial fibrillation alone is associated with a 3- to 4-fold increased risk of stroke after adjustment for other vascular risk factors.21 For those without prior transient ischemic attack (TIA) or stroke, 2% to 4% per year have an ischemic stroke.22,23 Randomized clinical trials have firmly established the value of antithrombotic therapies for reducing the risk of stroke in patients with atrial fibrillation. Risk is reduced by ⬃60% with adjusted-dose warfarin and by ⬃20% with aspirin.24 Adjusted-dose warfarin reduces stroke by ⬃45% as compared with aspirin.23 Randomized trials have also been conducted comparing a direct thrombin inhibitor to highquality adjusted-dose warfarin in persons with atrial fibrillation, but the U.S. Food and Drug Administration has not approved its use.25,26 The use of aspirin in the primary prevention of major cardiovascular events has been studied in key trials such as the British Doctors’ Trial, the Physicians’ Health Study, the Hypertension Optimal Treatment Study, the Thrombosis Prevention Trial, the Primary Prevention Project, and the Women’s Health Study.27-32 These studies comprised close to 100,000 patients with the results consistently supportive of aspirin as an effective primary preventive agent. In fact, five of the six aforementioned primary prevention trials recruited patients at low-risk for coronary heart disease (CHD) (⬍1% per year), and therefore, relatively few major CVD outcome events were recorded during these studies. Alternatively, aspirin efficacy has been more consistently demonstrated in high-risk patients (eg, those with a history of ischemic stroke, transient ischemic attack, or myocardial infarction). The efficacy of aspirin was proven in the Antithrombotic Trialists’ Collaboration, which studied a total of ⬎200,000 patients enrolled in 287 studies. Two types of studies were included in this meta-analysis: those involving 135,000 patients comparing antiplatelet therapy versus control, and 77,000 patients comparing different antiplatelet regimens.33 Overall, among these high risk patients, antiplatelet therapy reduced the occurrence of any serious vascular event by ⬃25%; non-fatal myocardial infarction was reduced by ⬃30%, non-fatal stroke by ⬃25%, and vascular mortality by ⬃15% (with no apparent adverse effect on total mortality). Aspirin was the most widely studied antiplatelet drug, with doses of 75-150 mg daily at least as effective as higher daily doses. The effects of doses lower than 75 mg daily were less efficacious. Clopidogrel

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reduced serious vascular events by 10% compared with aspirin, which was similar to the 12% reduction observed with ticlopidine. The addition of dipyridamole to aspirin produced no significant further reduction in vascular events compared with aspirin alone. The Women’s Health Study randomized 39,876 initially asymptomatic women aged 45 years of age and older to receive 100 mg of aspirin or placebo on alternate days. Patients were followed for 10 years, with the primary endpoint being a first major vascular event (nonfatal MI, nonfatal stroke, or cardiovascular death).32 Unlike data from prior studies that included mainly men, this study found a nonsignificant 9% reduction (Relative Risk (RR) ⫽ 0.91; 95% Confidence Interval (CI) 0.80 to 1.03; P ⫽ .13) in the combined primary end point among women, but a statistically significant 17% reduction in the risk of stroke (RR ⫽ 0.83; 95% CI 0.69 to 0.99; P ⫽ .04). This was based on a 24% reduction in the risk of ischemic stroke and a nonsignificant increase in the risk of hemorrhagic stroke. The most consistent benefit for aspirin was in women ⱖ65 years of age at study entry, among whom the primary endpoint was significant; risk of major cardiovascular events was reduced by 26% (RR ⫽ 0.74; 95% CI 0.59 to 0.92; P ⫽ .008), including a 30% reduction in the risk of ischemic stroke. The Physicians’ Health Study was a randomized, doubleblind, placebo-controlled trial designed to determine whether low-dose aspirin (325 mg every other day) decreased cardiovascular mortality.28 Among 22,071 participants with a mean follow-up of 60.2 months, there was a 44% relative reduction in the risk of myocardial infarction (RR ⫽ 0.56; 95% CI 0.45 to 0.70; P ⬍ .00001) in the aspirin group (254.8 per 100,000 per year as compared with 439.7 in the placebo group). It is interesting to note that there was a slightly increased risk of stroke among those taking aspirin but this was not statistically significant. This trend was observed primarily in the subgroup with hemorrhagic stroke (RR ⫽ 2.14; 95% CI 0.96 to 4.77; P ⫽ .06). As a result, however, this study did not advocate for aspirin as a primary preventive strategy for stroke. Recently, the U.S. Preventive Services Task Force (USPSTF) published their updated recommendations for the use of aspirin for the prevention of cardiovascular disease statement.34 Having reviewed the available data since 2002, especially the Women’s Health Study (WHS), the USPSTF recommended the use of aspirin for women age 55 to 79 years when the potential benefit of a reduction in ischemic strokes outweighs the potential harm of an increase in gastrointestinal hemorrhage (Class A recommendation). PRIMARY STROKE PREVENTION GUIDELINES Current guideline statements recommend (Class I, Level of Evidence A: Conditions for which there is evidence for and/or general agreement that the procedure or treatment is useful and effective) the use of aspirin for cardiovascular (including but not specific to stroke) prophylaxis among persons whose risk is sufficiently high for the benefits to

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outweigh the risks associated with treatment (a 10-year risk of cardiovascular events of 6% to 10%).35 Aspirin can be useful for prevention of a first stroke among women whose risk is sufficiently high for the benefits to outweigh the risks associated with treatment (Class IIa, Level of Evidence B: The weight of evidence or opinion is in favor of the procedure or treatment). In summary, the weight of evidence from the current guidelines state that all patients with significant carotid artery or peripheral arterial disease should be prescribed aspirin as part of their medical therapy. ROLE OF ANTIPLATELET THERAPY IN SECONDARY PREVENTION OF STROKE Aspirin monotherapy. Follow-up of patients with TIA or stroke has lasted no longer than three to five years to determine the incidence of recurrent stroke, myocardial infarction, and vascular death in modern clinical trials. In one series, the five-year cumulative risk of recurrent stroke was 22.5%. Major determinants of recurrence were advanced age, hemorrhagic stroke, and diabetes mellitus.36 In cohorts from clinical trials, the annual risk of vascular events ranged from 4 to 11%.37,38 The corresponding estimate for population-based studies is 9% per year.39 Follow-up was complete in 2447 (99%) patients. After a mean follow-up of 10.1 years, 1489 (60%) patients had died and 1336 (54%) had had at least one vascular event.40 In patients who have had a previous stroke, there is a significant risk of recurrent stroke. Aspirin remains the cornerstone of antiplatelet therapy for secondary stroke prevention with a 15% to 25% reduction in risk of recurrent stroke.41,42 The Antithrombotic Trialists’ Collaboration meta-analysis indicated that high-dose aspirin (500-1500 mg/day) was no more effective but was associated with more gastrointestinal side-effects than medium (160-325 mg/day) or lower (30-150 mg) doses.33 Clopidogrel monotherapy. The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial compared clopidogrel (75 mg/day) vs. aspirin (325 mg/day) in reducing the risk of ischemic stroke, myocardial infarction, or death among 19,185 patients with symptomatic vascular disease, including recent ischemic stroke.43 Overall, clopidogrel was associated with an 8.7% relative risk reduction (RRR) for ischemic stroke, myocardial infarction, or death compared with aspirin (P ⫽ .043). However, for the 6431 patients enrolled in CAPRIE due to stroke, the benefit of clopidogrel over aspirin was not statistically significant (annual event rate, 7.15% vs. 7.71%; P ⫽ .26). It should be noted that in this post-hoc analysis there was a higher rate of severe gastrointestinal hemorrhage observed in the aspirin group when compared with the clopidogrel group (0.71% vs. 0.49%; P ⬍ .05). Clopidogrel plus aspirin. Combination therapy with clopidogrel plus aspirin (75 mg) was compared with clopidogrel monotherapy in the Management of Atherothrombosis with Clopidogrel in High-risk Patients (MATCH) trial for secondary stroke prevention.44 For the primary end-point of ischemic stroke, myocardial infarction, or cardiovascular death, there was no significant benefit of the

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combination over monotherapy (15.7% vs. 16.7% respectively, P ⫽ NS). In addition, combination therapy was associated with a twofold increase in risk of major bleeding (2% vs. 1%; P ⬍ .001) and threefold increased risk of life-threatening bleeding (3% vs. 1%; P ⬍ .001). This study did not include an aspirin monotherapy group and therefore provided no additional information over CAPRIE as to the advantage of clopidogrel over aspirin. Of the 12,153 patients studied in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial comparing clopidogrel plus aspirin (75-162 mg/day) vs. aspirin alone, there were 4,320 patients enrolled for secondary stroke prevention.45 Overall, the combination regimen did not reduce stroke risk after a median follow-up of 28 months compared with aspirin alone. However, the rate of severe bleeding was higher with combination therapy (1.7% vs. 1.3%; P ⫽ .09). A recent post hoc analysis of data from the CHARISMA trial indicated that daily aspirin doses of 100 mg or greater are not associated with clear benefit and may cause harm compared with lower doses (75-81 mg/d). The rate of severe or life-threatening bleeding was also lowest in patients receiving the lowest baseline doses of aspirin. The overall results suggested that daily aspirin doses no greater than 81 mg optimize efficacy as well as safety in patients receiving aspirin for long-term primary and secondary cardiovascular prevention.46 Aspirin plus extended release dipyridamole (ERDP). In a meta-analysis of 25 trials involving 10,404 patients, aspirin plus dipyridamole was associated with an additional reduction of 6% in the incidence of stroke compared with aspirin alone (11.8% vs. 12.4%, respectively).33 It should be noted that the largest trials with the largest effects used an extended release preparation of dipyridimole. The second European Stroke Prevention Study (ESPS-2) evaluated the efficacy of aspirin plus extendedrelease dipyridamole (ER-DP) in prevention of recurrent stroke.47 The study demonstrated a reduction in risk of stroke by 18.1% with aspirin mono-therapy (P ⫽ .013), 16.3% with ER-DP mono-therapy (P ⬍ .04), and 37.0% with aspirin plus ER-DP (P ⬍ .001) compared with placebo. Aspirin plus ER-DP was twice as effective in stroke prevention as either drug alone (23% RRR vs. aspirin). Bleeding complications were similar between combination therapy (8.7%) and aspirin monotherapy (8.2%). Post hoc analysis of ESPS-2 showed that aspirin plus ER-DP was more effective than aspirin alone in preventing stroke among higher risk patients.48 The aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT) study evaluated aspirin plus ER-DP and ER-DP monotherapy twice daily within six months after TIA or minor stroke.49 At mean follow-up of 3.5 years, primary outcome events (composite of death from all vascular causes, non-fatal stroke, non-fatal myocardial infarction, or major bleeding complication) occurred in 173 (13%) patients on aspirin and dipyridamole and in 216 (16%) on aspirin alone (hazard ratio 0.80, 95% CI 0.66 to 0.98; absolute risk reduction

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1.0% per year, 95% CI 0.1 to 1.8). The absolute risk reduction of 1.0% per year (95% CI 0.1 to 1.8) corresponds with a number of patients needed to treat with the combination regimen instead of with monotherapy to prevent a primary outcome event of 104 (95% CI 55 to 1006) per year, significant but probably not cost effective. Ischemic events were less frequent in the combination group than in the monotherapy group. Aspirin plus ER-DP vs. clopidogrel. In the recently reported Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) Trial, 20,332 patients with a recent (⬍90 days) ischemic stroke were randomized to receive clopidogrel 75 mg per day or the combination of aspirin 25 mg and ER-DP 200 mg twice per day.50,51 After a mean follow-up of 2.5 years, there was no difference in recurrent stroke (9.0% with aspirin plus ER-DP vs. 8.8% for clopidogrel; hazard ratio [HR] 1.01; 95% CI 0.92 to 1.11) or the composite of stroke, myocardial infarction, or vascular death (13.1% aspirin plus ER-DP vs. 13.1% clopidogrel; HR 0.99; 95% CI 0.92 to 1.07).50 Although there were more major hemorrhagic events among the patients taking aspirin plus ER-DP than in those taking clopidogrel alone (4.1% vs. 3.6%; P ⫽ .06), the overall net risk-benefit, as measured by recurrent stroke or major hemorrhagic event, was similar (11.7% for aspirin with ER-DP vs. 11.4% for clopidogrel; HR 1.03; 95% CI 0.95 to 1.11).50 Thus, for patients who have had a stroke and and can tolerate either clopidogrel or aspirin plus ER-DP, there is no need to alter their regimen. SECONDARY STROKE PREVENTION GUIDELINES The current guidelines52,53 have recently been updated based on data from the CHARISMA45 and ESPRIT49 studies, with new recommendations outlined for patients with noncardioembolic ischemic stroke or TIA.54 Aspirin (50-325 mg/d) monotherapy, the combination of aspirin and extended-release dipyridamole, and clopidogrel monotherapy are all acceptable options for initial therapy (Class I, Level of Evidence A) in patients with noncardioembolic ischemic stroke or TIA. The combination of aspirin and extended-release dipyridamole is recommended over aspirin alone (Class I, Level of Evidence B). For patients allergic to aspirin, clopidogrel is a reasonable alternative (Class IIa, Level of Evidence B). The addition of aspirin to clopidogrel increases the risk of hemorrhage. Combination therapy of aspirin and clopidogrel is not routinely recommended for ischemic stroke or TIA patients unless they have a specific indication for this therapy (ie, coronary stent or acute coronary syndrome) (Class III). ANTIPLATELET THERAPY AT THE TIME OF CAROTID REVASCULARIZATION Role of antiplatelet therapy in carotid endarterectomy. Postoperative surgical site thrombosis following carotid endarterectomy (CEA) remains a significant problem in 2% to 3% of patients.55 This may be preceded by embolization, which can be detected by transcranial Dopp-

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ler (TCD) high intensity transient signals (HITS) representing platelet microemboli.56 At the time of CEA, platelets are activated and adhere to the site of CEA. Platelet deposition is significantly reduced in patients receiving preoperative platelet inhibitors.57 Patients receiving preoperative aspirin had fewer postoperative strokes (P ⬍ .001) and showed a trend toward reduced mortality (P ⫽ .11) in a randomized trial.58 A longer-term follow-up study (5.5 years) in CEA patients confirmed the survival benefit of indefinite platelet inhibition with aspirin (P ⬍ .013).59 Intraoperative dextran has been advocated by some to reduce the risk of postoperative stroke. Randomized and observational studies have shown that dextran significantly reduces cerebral embolic signals detected by TCD,60,61 which have been shown to correlate with cerebral infarction.62 Naylor et al60 reported a reduction in stroke from 4% to 0.2% with the use of dextran intraprocedurally. Lennard et al61 began dextran infusions following CEA when patients had more than 25 HITS detected in any 10-minute period by TCD. The embolic signals of all patients were abolished when dextran was started. However, effects of dextran on platelets and the coagulation cascade make heparin reversal especially important to reduce bleeding complications, most notably postoperative cervical incisional hematoma formation. A randomized trial of combined platelet inhibition with aspirin plus clopidogrel versus aspirin alone in patients undergoing CEA showed significant reduction in operative and postoperative cerebral emboli as measured by TCD among those patients receiving combination antiplatelet therapy.63 There was a 10-fold reduction in the relative risk of patients having greater than 20 emboli during the postoperative period (P ⬎ .01). Patients who developed high numbers of emboli in the first one to two hours postoperatively, and were therefore, by definition, at higher risk from stroke,64-67 had platelets that showed a strong response to ADP preoperatively despite the use of a standard 150 mg dose of aspirin in all the patients.68 However, patients receiving aspirin plus clopidogrel had an increased wound closure time (P ⫽ .04), which is an indirect marker of hemostasis. The duration of postoperative combined platelet inhibition depends on other patient co-morbidities. To date, clopidogrel therapy has been used infrequently in patients undergoing CEA. Unlike patients undergoing carotid artery stenting, in which the percutaneous approach allows a maximal loading dose of clopidogrel (300 mg or 600 mg) with minimal risk of bleeding during the procedure, the risk of bleeding is greater in patients undergoing open surgery. Role of antiplatelet therapy in carotid stenting. Intimal injury of the internal carotid artery during percutaneous interventions releases procoagulant tissue factor and exposes collagen and other platelet-adhesive proteins in the subendothelium, thereby triggering formation of a plateletrich thrombus that seals the site of injury. The extent of platelet deposition and thrombus formation is dependent on the degree of vessel wall injury and local shear forces. In

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addition, the presence of distal microemboli after carotid artery intervention is indicative of increased platelet reactivity to ADP and increased systemic inflammation.69,70 The subsequent healing process involves intense cellular (monocyte/macrophage) infiltration of the thrombus along with smooth muscle cell migration and proliferation at the site of injury, resulting in gradual resorption of the thrombus and replacement with neointimal tissue. An excessive healing process, neointimal hyperplasia, leading to in-stent restenosis, is an important late (typically ⬎30 days after stent placement) sequela of stenting. The safety of dual antiplatelet in the context of carotid artery stenosis has already been demonstrated in the Clopidogrel and Aspirin for the Reduction of Emboli in Symptomatic carotid Stenosis (CARESS) study, conducted in 108 symptomatic patients. This study found that treatment with clopidogrel (300 mg loading dose on day 1, 75 mg daily thereafter) and aspirin (75 mg daily) reduced the incidence of silent cerebral microemboli present on TCD by 25% after one day and by 37% after seven days of treatment compared with aspirin alone. Furthermore, dual antiplatelet therapy did not result in an increase in lifethreatening intracranial or major bleeding events.71 Dual antiplatelet therapy has also shown to be associated with a low rate of ischemic events in a single-center carotid stent registry study, which included 162 patients with symptomatic (⬎70% stenosis) or asymptomatic (⬎80% stenosis) carotid artery stenosis who were not appropriate candidates for carotid endarterectomy.72 The overall 30-day rate of ischemic events (death, stroke, TIA, myocardial infarction) was 5.6% in patients who received clopidogrel or ticlopidine plus aspirin. A significant number of patients also received periprocedural glycoprotein (GP) IIb/IIIa inhibitor therapy. No case of stent thrombosis was reported in patients who received clopidogrel or ticlopidine plus aspirin, but one of five patients who did not receive an ADP antagonist did develop in-stent thrombosis. Incidentally, the 30-day rate of ischemic events was much higher in patients who received ticlopidine than those who received clopidogrel (13% vs 4.3%; odds ratio, 5.77; 95% CI 1.45 to 22.91). Dual antiplatelet therapy did not appear to increase the incidence of intracranial hemorrhage. Admittedly, this observation is limited by small sample size. The use of parenteral GPIIb/IIIa inhibitors along with aspirin and an ADP receptor antagonist has been shown to be associated with a low risk for ischemic complications during carotid stenting and with a negligible risk of stent thrombosis during follow-up. Kapadia et al recruited 151 patients deemed to be at high surgical risk, of which 128 received the GPIIb/IIIa inhibitor abciximab 12 hours before stenting.73 All patients subsequently received aspirin and either clopidogrel or ticlopidine after the stenting procedure. The procedural event rate (all events occurring up to hospital discharge) was lower in the abciximabtreated group (1.6%; 1 minor stroke and 1 retinal infarction) compared with the control group (8%; 1 major stroke and 1 neurological death). Furthermore, the number of new periprocedural events occurring in the first 30 days

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after hospital discharge was lower in the abciximab-treated group than the control group (8% versus 4.5%). Other studies have described cases of intracerebral hemorrhage in carotid stent patients who received a GPIIb/IIIa inhibitor.74,75 Kopp et al randomized patients with cerebrovascular disease to either standard antithrombotic therapy (n ⫽ 30) comprising clopidogrel, aspirin, and heparin, or adjunct bolus and 12-hour infusion of abciximab (n ⫽ 20) before CAS. A third cohort of patients was treated with carotid stent and distal embolic filter protection (n ⫽ 30). Adjunctive abciximab did not significantly reduce the incidence of periprocedural ischemic events (10% vs 23%; P ⫽ .2) or the number of ischemic lesions detected by diffusion-weighted MRI (30% vs 47%; P ⫽ .17) compared with standard antithrombotic therapy.76 However, both of these factors were significantly reduced with embolic protection (P ⫽ .023) compared with standard antithrombotic therapy. Nevertheless, TIAs occurred less frequently with abciximab (P ⫽ .05) compared with standard antithrombotic therapy. A retrospective review of 550 patients who underwent carotid angioplasty and stent placement demonstrated that combination therapy with GPIIb/IIIa inhibitors and heparin significantly increased the 30-day incidence of the composite end point of all stroke and neurological death compared with heparin alone (6.6% versus 2.4%; P ⫽ .04).77 However, this was at the expense of an increased number of hemorrhage events in the GPIIb/IIIa inhibitors plus heparin group. Interestingly, Timaran et al recently reported a six-fold increased risk of intracranial hemorrhage (ICH) in patients undergoing carotid stenting as opposed to carotid endarterectomy.78 This retrospective study using the Nationwide Inpatient Sample analyzed 135,903 carotid revascularizations performed in 2005. The vast majority of patients underwent CEA (90.4%), whereas CAS was performed in 13,093 (9.6%) patients. ICH occurred in 19 patients (0.15%) after CAS and in 20 patients (0.016%) after CEA (P ⬍ .001). In-hospital mortality was 12.5% among patients developing ICH (P ⬍ .001). Most centers currently administer dual antiplatelet therapy for up to four weeks after carotid stent placement to protect against subacute stent thrombosis. Prolonged dual antiplatelet therapy may also reduce major ischemic events in patients after carotid stenting but the data for this has been mainly extracted form the coronary artery literature. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial enrolled 12,562 patients with unstable angina or non–ST-segment elevation myocardial infarction (NSTEMI). This study demonstrated that treatment with clopidogrel plus aspirin for up to 12 months following percutaneous coronary intervention (PCI) reduced the relative risk of the composite of cardiovascular death, stroke, or myocardial infarction by 20% and the absolute risk by 2.1% compared with aspirin alone (P ⬍ .001).79 In addition, the Clopidogrel for the Reduction of Events during Observation (CREDO) study, which enrolled 2116 patients after PCI, found that there was a 26.9% relative reduction in the combined risk of death, myocardial infarction, or stroke

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Table. Antiplatelet agents for primary and secondary stroke prevention Indication Primary prevention Secondary prevention

Carotid artery stenting Pre-procedure Post-procedure Maintenance Carotid endarterectomy

Agent

Dose

Mode of action

Aspirin or Clopidogrel Aspirin or Aspirin ⫹ Dipyridimole or Clopidogrel

50-325 mg daily

COX inhibitor

75 mg daily 50-325 mg daily

ADP receptor antagonist

25/200 mg twice daily

Increase cAMP

Aspirin ⫹ Clopidogrel

50-325 mg daily 300 mg loading (6 hours prior) 50-325mg daily 75 mg daily (at least 4 weeks) 50-325 mg daily

Aspirin ⫹ Clopidogrel Aspirin Aspirin or Aspirin ⫹ Clopidogrel

75 mg daily

50-325 mg daily 75 mg daily

COX, Cycloxygenase; ADP, adenosine diphosphatase.

(absolute reduction 3%) with dual antiplatelet therapy for one year compared with aspirin alone (P ⫽ .02).80 It must be stated that the optimal dual antiplatelet regimen for carotid artery stenting has yet to be defined. Kramer and colleagues have performed an analysis of 38 high risk patients that underwent CAS using combination of ASA plus ER-DP. There were no procedure related deaths, stroke, or transient ischemic attacks noted at 24 hours and at 30 days.81 ASA plus ER-DP has previously shown superiority in reducing event rates in patients with acute ischemic neurovascular syndromes with few side effects.47 A head-to-head prospective randomized clinical trial is warranted to provide the optimal dual antiplatelet combination. FUTURE DIRECTIONS Cilostazol. Cilostazol is a phosphodiesterase type III inhibitor that possesses both antiplatelet and vasodilatory effects. Although cilostazol is approved in the United States for treatment of intermittent claudication associated with peripheral artery disease (PAD), its efficacy in secondary stroke prevention related to carotid artery stenosis remains uncertain. This was evaluated in the Cilostazol Stroke Prevention Study, which randomized 1095 Japanese patients with recent stroke or TIA to treatment with cilostazol or placebo. Cilostazol reduced the incidence of secondary stroke by 41.7% compared with placebo (P ⫽ .015). The greatest risk reduction (43.4%) was among patients enrolled after lacunar stroke.82 These clinical benefits were not associated with adverse events relative to placebo. However, despite the magnitude of the observed risk reduction, the lack of an active comparator arm with aspirin makes it difficult to compare the efficacy of cilostazol to that of standard of care.83 Because phosphodiesterase III inhibitors have been shown to cause decreased survival in patients with signifi-

cant congestive heart failure, cilostazol is contraindicated in patients with any degree of congestive heart failure.84 The Cilostazol in Stroke Prevention-2 study is ongoing to determine the efficacy and safety of cilostazol compared with aspirin in secondary stroke prevention. Recent studies have demonstrated benefit of cilostazol in preventing restenosis and need for repeat revascularization following endovascular treatment in both the coronary and peripheral circulations.85,86 The effect of cilostazol after percutaneous or surgical carotid artery revascularization is not known. CONCLUSIONS Primary and secondary prevention of stroke is an important goal for all physicians who care for patients at risk of this potentially devastating event. Stroke related to extracranial carotid artery disease represents a serious manifestation of atherosclerosis among the ever aging population. Appropriate use of antiplatelet agents (Table) in this specific patient cohort, alone or in conjunction with percutaneous or surgical revascularization, is an important therapeutic strategy to prevent stroke. AUTHOR CONTRIBUTIONS Conception and design: MJ Analysis and interpretation: N/A Data collection: N/A Writing the article: MJ, TK, BY Critical revision of the article: MJ Final approval of the article: MJ Statistical analysis: N/A Obtained funding: N/A Overall responsibility: MJ REFERENCES 1. American Heart Association. Heart Disease and Stroke Statistics-2005 Update. Dallas, Tex: American Heart Association; 2005.

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Submitted Mar 7, 2009; accepted Apr 19, 2009.