Dual Antiplatelet Therapy with Clopidogrel and Aspirin After Carotid Artery Stenting

Percutaneous carotid artery stenting is increasingly being used for the treatment of carotid artery stenosis, particularly in patients who are not candidates for surgical endarterectomy.1–3 In addition, it is currently being investigated as an alternative to surgery in randomized clinical trials such as Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) and Carotid Revascularization Endarterectomy versus Stent Trial (CREST). Carotid stenting is thought to be superior to balloon angioplasty.4,5 Accumulating evidence from multiple centers supports the utility of carotid stenting.6 Accordingly, virtually all carotid lesions treated percutaneously are presently being stented. Platelet-rich thrombus formation in response to stenting is common.7 Previous studies have shown the importance of antiplatelet therapy after intracoronary stenting. In particular, the superiority of dual antiplatelet therapy with aspirin and adenosine diphosphate (ADP)-receptor blockade over aspirin alone or aspirin plus warfarin has been conclusively demonstrated in numerous trials.8–12 Furthermore, clopidogrel plus aspirin appears superior in safety to ticlopidine plus aspirin.13,14 Indeed, clopidogrel may even be more efficacious than ticlopidine.15 As with coronary artery stenting, activation and embolization of platelets occurs with carotid artery stenting.16,17 Despite the larger size of the carotid arteries, stent thrombosis can still occur. We sought to evaluate whether clopidogrel plus aspirin would be efficacious in reducing stent thrombosis in patients undergoing carotid artery stenting. Since this patient population also included those with prior cerebrovascular events, the possibility of intracerebral bleeding was of particular concern with potent dual antiplatelet therapy, and we therefore also sought to examine the safety of 30 days of clopidogrel and aspirin in these patients with cerebrovascular disease. METHODS Study population. Patients with severe symptomatic (> 70% stenosis) or asymptomatic (> 80% stenosis) carotid artery stenosis who were not candidates for surgical endarterectomy were enrolled prospectively in a single-center registry between February 1998 and February 2000. All patients were assessed by an experienced vascular surgeon who deemed that they were not suitable for surgery due to significant comorbidities or due to technical factors, such as prior neck surgery or irradiation. Informed consent was obtained from all patients. Antithrombotic therapy. All patients received 325 mg of aspirin and 50 U/kg of intravenous heparin, with additional heparin administered to achieve an activated clotting time of approximately 250 seconds (or greater than 300 seconds if no glycoprotein (GP) IIb/IIIa inhibitor was used). In addition, 82% received abciximab bolus (0.25 mg/kg) and infusion (0.125 µg/kg/minute). If patients were not already on clopidogrel, they received 300 mg immediately after the procedure and 75 mg/day for 4 weeks. Patients not already on ticlopidine received a 500 mg loading dose immediately after the procedure and then 250 mg twice daily for 2–4 weeks. Statistical analysis. All statistical calculations were performed using Statistica 5.0 software (Statsoft, Inc., Tulsa, Oklahoma). Periprocedural (within 24 hours) and 30-day rates of death, stroke, transient ischemic attack (TIA) and myocardial infarction were determined and expressed as percentages. The cause of death was ascertained in all cases by detailed chart review (2 patients had autopsies). Rates of stent thrombosis and intracranial hemorrhage were also determined. RESULTS Baseline characteristics. The baseline characteristics of the 162 patients in the registry are shown in Table 1. Five patients who did not receive any thienopyridine were excluded from this analysis, since they received only eptifibatide until undergoing urgent coronary artery bypass grafting. The average age was 70.3 years. Sixty-five percent were males. The majority (59%) had symptomatic carotid artery stenosis. There was a high prevalence of cardiovascular co-morbidities. The anatomic characteristics of the treated lesions are shown in Table 2. A significant proportion received concomitant GP IIb/IIIa inhibition. Periprocedural results. There was one stroke (the patient ultimately suffered an intracranial hemorrhage and died after urokinase treatment) and one retinal infarct in the patients receiving clopidogrel. In the ticlopidine group, there were 2 major periprocedural strokes; one resulted in contralateral hemiparesis with only partial recovery by 7 days and the other resulted in contralateral upper extremity sensory loss that persisted beyond 7 days. Thirty-day results. In the clopidogrel-treated patients, there were two additional deaths (from myocardial infarction). There were no additional major or minor strokes. No cases of stent thrombosis occurred. In the ticlopidine group, there was one additional death (the exact cause could not be determined) and no stent thrombosis. The only patient with stent thrombosis in this registry did not receive aspirin or a thienopyridine (but did receive eptifibatide), since she was going for urgent cardiac surgery. The event rate at 30 days was 5.6% in the patients who received thienopyridines. The cumulative 30-day event rate was higher for the ticlopidine group than the clopidogrel group (13% vs. 4.3%, respectively; p = 0.01; odds ratio, 5.77; 95% confidence interval, 1.45–22.91) (Table 3). DISCUSSION The present study is the first detailed report of dual antiplatelet therapy with clopidogrel plus aspirin after carotid artery stenting. There were no cases of stent thrombosis in this series. The 30-day rate of ischemic events (death, stroke, TIA, myocardial infarction) was very low at 5.6%. The rate in those treated specifically with clopidogrel was 4.3%. This rate compares favorably with the results of surgical endarterectomy, although the patients included in this registry were all at much higher risk than in the carotid endarterectomy trials, and would have been excluded from those trials.18–20 Of course, there were no cases of cranial nerve palsies or surgical wound infections in the patients in this series. Importantly, the incidence of intracranial hemorrhage was not increased. Thus, dual therapy with clopidogrel plus aspirin for a 30-day period appears both efficacious and safe, and likely enhanced the results obtained with carotid artery stenting in a high-risk population. Interestingly, one out of five patients not receiving an ADP antagonist did have stent thrombosis. A recent report described catastrophic outcomes in patients undergoing noncardiac surgery when antiplatelet therapy was prematurely stopped after intracoronary stenting.21 Likely, surgery increases hypercoagulability and increases the risk of stent thrombosis when antiplatelet therapy has been withdrawn. Stent endothelialization is a gradual process that takes at least 28 days.22,23 More recent reports suggest that complete stent endothelialization occurs at a median of 96 days.7 Thus, long-term antiplatelet therapy is particularly suitable for patients receiving stents. Also, clopidogrel after carotid endarterectomy may have merit. In addition, patients with carotid artery stenosis are at risk for cerebrovascular events due to factors other than the treated carotid stenosis.24 Furthermore, atherosclerotic involvement of other arterial beds is common in patients with carotid artery stenosis, expanding the possible benefits of antiplatelet therapy.25,26 Clopidogrel has been shown to be more efficacious than aspirin in the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study in reducing adverse ischemic events, including stroke and TIA.27 This benefit of clopidogrel over aspirin is amplified in higher-risk subgroups.28–30 Thus, it is probable that the combination of clopidogrel plus aspirin would have even greater efficacy in reducing recurrent cerebral ischemia in patients with carotid artery stenosis. ADP receptor blockade provides platelet inhibition via a pathway separate from aspirin’s effects on thromboxane. In addition, there is a cohort of patients who appear to be aspirin resistant, displaying minimal antiplatelet effect after receiving aspirin.31–33 Furthermore, platelet activation, as assessed by measurement of p-selectin, and fibrinogen binding to the glycoprotein IIb/IIIa receptor are more greatly reduced with the combination of ADP blockade and aspirin than either agent alone.34 ADP antagonism plus aspirin has been studied extensively in the setting of intracoronary stent deployment. Several randomized studies have established the superiority of ticlopidine plus aspirin over aspirin alone or aspirin plus warfarin.8,10,35 A recent meta-analysis showed that clopidogrel plus aspirin was superior to ticlopidine plus aspirin after coronary stent deployment.15 This finding may be due in part to the faster onset of action of clopidogrel compared with ticlopidine. The superior efficacy of clopidogrel is in addition to the better safety profile and tolerability compared with ticlopidine seen in randomized comparisons.36 Thus, after coronary artery stenting, clopidogrel with aspirin is the standard of care, creating a logical basis for this form of dual antiplatelet therapy after carotid artery stenting. Studies are underway that are examining the value of long-term therapy with clopidogrel plus aspirin. The Clopidogrel for Reduction of Events During Observation (CREDO) study is examining dual therapy for a year versus a month in patients who have received intracoronary stents, while the Management of Atherothrombosis with Clopidogrel in High-risk Patients (MATCH) study will examine dual therapy in high-risk patients who have had a recent ischemic stroke or transient ischemic attack. Ongoing collection of registry data at several centers will confirm the importance of therapy with clopidogrel plus aspirin.37 However, future randomized studies should determine whether long-term combination antiplatelet therapy with clopidogrel and aspirin is warranted after carotid artery stenting. Study limitations. This study represents the experience of a single center, and the results seen with carotid stenting are not necessarily generalizable to other settings. As is inherent to registry studies, there is no control arm that did not receive antiplatelet therapy. However, we felt that we could not withhold antiplatelet therapy from carotid stent patients, especially given the established value of antiplatelet therapy in the coronary stent literature. There may be value in starting therapy a few days prior to carotid artery stenting. In this series, if patients were not already on clopidogrel, a 300 mg loading dose was given. Thus, the relative importance of a loading dose versus a period of pre-treatment could not be ascertained from this data set. The duration of therapy may have differed with some ticlopidine patients receiving only two weeks of therapy. Concomitant GP IIb/IIIa inhibitors were used in the majority of patients in this series, although there is no consensus on the role of these agents in carotid stenting. While this study confirms the safety of such potent antiplatelet blockade via multiple pathways, it is not possible to differentiate the beneficial effects of clopidogrel from any independent effect of intravenous antiplatelet therapy. There were imbalances in baseline characteristics between the clopidogrel and ticlopidine groups. Due to few events in either group and the relatively small ticlopidine group, it was not possible to perform a multivariate analysis. Potentially, the fact that many patients received clopidogrel before the procedure, while the ticlopidine patients received the drug after the procedure, could have in part accounted for clopidogrel’s superiority over ticlopidine. CONCLUSION Dual antiplatelet therapy with clopidogrel and aspirin is associated with a low rate of recurrent ischemic events after carotid artery stenting. Even in this population that included patients with prior cerebrovascular events, potent antiplatelet therapy seems to be safe. Clopidogrel and aspirin given for a period of 30 days after carotid stenting appears to be a reasonable strategy to decrease ischemic outcomes. Future studies will need to delineate the value of more prolonged periods of therapy. Acknowledgment. The authors would like to thank Cindie Davidson for editorial assistance.

1. Yadav JS, Roubin GS, Iyer S, et al. Elective stenting of the extracranial carotid arteries. Circulation 1997;95:376–381. 2. Yadav JS, Roubin GS, King P, et al. Angioplasty and stenting for restenosis after carotid endarterectomy. Initial experience. Stroke 1996;27:2075–2079. 3. Wholey MH, Wholey M, Mathias K, et al. Global experience in cervical carotid artery stent placement. Cathet Cardiovasc Intervent 2000;50:160–167. 4. Qureshi AI, Luft AR, Sharma M, et al. Prevention and treatment of thromboembolic and ischemic complications associated with endovascular procedures: Part II — Clinical aspects and recommendations. Neurosurgery 2000;46:1360–1375. 5. Sivaguru A, Venables GS, Beard JD, Gaines PA. European carotid angioplasty trial. J Endovasc Surg 1996;3:16–20. 6. Shawl F, Kadro W, Domanski MJ, et al. Safety and efficacy of elective carotid artery stenting in high-risk patients. J Am Coll Cardiol 2000;35:1721–1728. 7. Grewe PH, Deneke T, Machraoui A, et al. Acute and chronic tissue response to coronary stent implantation: Pathologic findings in human specimen. J Am Coll Cardiol 2000;35:157–163. 8. Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic drug regimens after coronary artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998;339:1665–1671. 9. Schomig A, Neumann FJ, Walter H, et al. Coronary stent placement in patients with acute myocardial infarction: Comparison of clinical and angiographic outcome after randomization to antiplatelet or anticoagulant therapy. J Am Coll Cardiol 1997;29:28–34. 10. Bertrand ME, Legrand V, Boland J, et al. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (FANTASTIC) Study. Circulation 1998;98:1597–1603. 11. Goods CM, al-Shaiba KF, Liu MW, et al. Comparison of aspirin alone versus aspirin plus ticlopidine after coronary artery stenting. Am J Cardiol 1996;78:1042–1044. 12. Goods CM, Liu MW, Iyer SS, et al. A cost analysis of coronary stenting without anticoagulation versus stenting with anticoagulation using warfarin. Am J Cardiol 1996;78:334–336. 13. Berger PB, Bellot V, Melby S, et al. Clopidogrel versus ticlopidine for coronary stents. J Am Coll Cardiol 1999;33:34A. 14. Moussa I, Oetgen M, Roubin G, et al. Effectiveness of clopidogrel and aspirin versus ticlopidine and aspirin in preventing stent thrombosis after coronary stent implantation. Circulation 1999;99:2364–2366. 15. Bhatt DL, Bertrand ME, Berger PB, et al. Meta-analysis of randomized and registry comparisons of ticlopidine with clopidogrel after stenting. J Am Coll Cardiol 2002;(in press). 16. Topol EJ, Yadav JS. Recognition of the importance of embolization in atherosclerotic vascular disease. Circulation 2000;101:570–580. 17. Jordan WD Jr., Voellinger DC, Doblar DD, et al. Microemboli detected by transradial Doppler monitoring in patients during carotid angioplasty versus carotid endarterectomy. Cardiovasc Surg 1999;7:33–38. 18. The North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991;325:445–453. 19. The Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995;273:1421–1428. 20. The ECST Investigators. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: Final results of the MRC European Carotid Surgery Trial. Lancet 1998;351:1379–1387. 21. Kaluza GL, Joseph J, Lee JR, et al. Catastrophic outcomes of noncardiac surgery soon after coronary stenting. J Am Coll Cardiol 2000;35:1288–1294. 22. Van Belle E, Tio FO, Couffinhal T, et al. Stent endothelialization. Time course, impact of local catheter delivery, feasibility of recombinant protein administration, and response to cytokine expedition. Circulation 1997;95:438–448. 23. Verheye S, Salame MY, Robinson KA, et al. Short- and long-term histopathologic evaluation of stenting using a self-expanding nitinol stent in pig carotid and iliac arteries. Cathet Cardiovasc Intervent 1999;48:316–323. 24. Barnett HJ, Gunton RW, Eliasziw M, et al. Causes and severity of ischemic stroke in patients with internal carotid artery stenosis. JAMA 2000;283:1429–1436. 25. Bhatt DL, Topol EJ. Antiplatelet and anticoagulant therapy in the secondary prevention of ischemic heart disease. Med Clin North Am 2000;84:163–179. 26. Bhatt DL, Hirsch AT, Ringleb PA, et al. Reduction in the need for hospitalization for recurrent ischemic events and bleeding with clopidogrel instead of aspirin. Am Heart J 2000;140:67–73. 27. CAPRIE Steering Committee. A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329–1339. 28. Bhatt DL, Marso SP, Hirsch AT, et al. Superiority of clopidogrel versus aspirin in patients with a history of diabetes mellitus. J Am Coll Cardiol 2000;35(Suppl A):409. 29. Bhatt DL, Foody JM, Hirsch AT, et al. Complementary, additive benefit of clopidogrel and lipid-lowering therapy in patients with atherosclerosis. J Am Coll Cardiol 2000;35(Suppl A):326. 30. Bhatt DL, Hirsch AT, Chew DP, et al. Superiority of clopidogrel versus aspirin in patients with prior cardiac surgery. Circulation 2001;103:363–368. 31. Helgason CM, Tortorice KL, Winkler SR, et al. Aspirin response and failure in cerebral infarction. Stroke 1993;24:345–350. 32. Helgason CM, Bolin KM, Hoff JA, et al. Development of aspirin resistance in persons with previous ischemic stroke. Stroke 1994;25:2331–2336. 33. Poggio ED, Kottke-Marchant K, Welsh PA, et al. The prevalence of aspirin resistance in cardiac patients as measured by platelet aggregation and the PFA-100. J Am Coll Cardiol 1999;33:254A. 34. Rupprecht HJ, Darius H, Borkowski U, et al. Comparison of antiplatelet effects of aspirin, ticlopidine or their combination after stent implantation. Circulation 1998;97:1046–1052. 35. Urban P, Macaya C, Rupprecht HJ, et al. Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: The multicenter aspirin and ticlopidine trial after intracoronary stenting (MATTIS). Circulation 1998;98:2126–2132. 36. Bertrand ME, Rupprecht HJ, Urban P, et al. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin after coronary stenting: The clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 2000;102:624–629. 37. Moussa I, New G, Al-Moubarak N, et al. Clopidogrel may enhance the clinical efficacy of carotid artery stent implantation: The EMILY Registry. Eur Heart J 2000;21:320. 38. Qureshi AI, Suri MF, Khan J, et al. Abciximab as an adjunct to high-risk carotid or vertebrobasilar angioplasty: Preliminary experience. Neurosurgery 2000;46:1316–1324.