Aspirin Plus Clopidogrel for Everyone: Panacea Comes True in the 21st Century

Antiplatelet therapy is of seminal importance for the prevention of arterial thrombosis. Aspirin is the prototype agent, but the evolution of therapeutic agents has led to the thienopyridines. The first thienopyridine, ticlopidine, was used for years by neurologists for the prevention of stroke, before cardiologists understood how powerful its combination with aspirin might be for the prevention of subacute stent thrombosis. Following a promising initial experience, a formal randomized trial unequivocally proved that the combination of the two agents was superior to aspirin alone and to aspirin plus warfarin.1 Accordingly, the use of ticlopidine plus aspirin rose dramatically, in parallel to the number of coronary stent implantation procedures. This extended use of ticlopidine also made apparent a few dangerous side effects of the drug initially thought to be very remote and unlikely: neutropenia, thrombocytopenia and thrombotic thrombocytopenic purpura, best known as TTP.2 In the meantime, the newer thienopyridine clopidogrel was developed and was shown to be superior to aspirin in a head-to-head trial comparing the efficacy of the two agents in preventing cardiovascular death.3 The remarkable finding was in the side effect profile of this new agent: it was even lower than with aspirin. Subsequently, several studies reported on the more favorable profile of clopidogrel, rather than ticlopidine therapy for prevention of coronary stent thrombosis. Although thrombosis itself was not examined in most studies, they all revealed enhanced tolerability and lower side effects with clopidogrel with rather similar ischemic event rates between the 2 agents. Therefore, due mainly to its favorable side effect profile, clopidogrel has largely replaced ticlopidine as the preferred agent for prevention of coronary stent thrombosis in combination with aspirin. Prolonged use of this “golden” combination regimen has recently been shown to offer significant clinical benefits to patients with acute coronary syndromes whether they are treated with coronary stent implantation or not.4,5 As stent implantation has been expanding to other vascular territories outside the heart, prevention of subacute stent thrombosis has been mainly extrapolated from the coronary experience. This is because: 1) there are sound data from the cardiology literature, and many cardiologists are involved with endovascular stent implantation; 2) stent thrombosis is very rare, even with suboptimal therapies, and new studies in each vascular bed treated with stents would require a very large number of patients; and 3) patients are able to tolerate the aspirin plus clopidogrel regimen for the month following the stent procedure. This issue of the Journal contains a study on the use of aspirin plus clopidogrel after carotid artery stenting.6 It is not surprising that very few events See Bhatt et al. on pages 767–771 occurred after the procedure. In fact, events occurred only around the time of the procedure, and were either hemorrhagic (seldom) or embolic. I do not see how either type may have been affected by the oral combination antiplatelet therapy used. First, the hemorrhagic events might be related to hyperperfusion syndrome after carotid revascularization or to the use of intravenous heparin plus platelet glycoprotein IIb/IIIa inhibitors. Second, the embolic events are typical of carotid revascularization procedures, and they decrease: 1) with experience (learning curve); 2) with less hemodynamic fluctuation after stent implantation; and 3) with use of distal embolic protection devices.7–9 The timing of these embolic events is usually during or right after the procedure; at this point, most patients have only received the first dose of clopidogrel or ticlopidine. It is hard for me to believe that a single dose of any agent can prevent these events. Rather, improved procedural technique was employed in the clopidogrel group, which was treated later than the ticlopidine group, based on the availability of the two agents in the United States. Regardless of the reason, there was no stent thrombosis, and the current approach of carotid stenting with adjunctive therapy with aspirin plus clopidogrel emerges as a very successful one; this combination antiplatelet regimen should be used as the true cardiovascular therapeutic panacea of the 21st century!

1. 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. 2. Bennett CL, Kiss JE, Weinberg PD, et al. Thrombotic thrombocytopenic purpura after stenting and ticlopidine. Lancet 1998;352:1036–1037. 3. CAPRIE Steering Committee. A randomized, blinded trial of clopidogrel versus aspirin in patients at risk of ischemic events. Lancet 1996;348:1329–1339. 4. Yusuf S, Zhao F, Mehta SR, et al., for the Clopidogrel in Unstable angina to prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494–502. 5. Mehta SR, Yusuf S, Peters RJ, et al., for the Clopidogrel in Unstable angina to prevent Recurrent Events Trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: The PCI-CURE study. Lancet 2001;358:520–526. 6. Bhatt DL, Kapadia SR, Bajzer CT, et al. Dual antiplatelet therapy with clopidogrel and aspirin after carotid artery stenting. J Invas Cardiol 2001;13:767–771. 7. Roubin GS, New G, Iyer SS, et al. Immediate and late clinical outcomes of carotid artery stenting in patients with symptomatic and asymptomatic carotid artery stenosis: A 5-year prospective analysis. Circulation 2001;103:532–537. 8. Dangas G, Laird JR Jr., Satler LF, et al. Postprocedural hypotension after carotid artery stent placement: Predictors and short- and long-term clinical outcomes. Radiology 2000;215:677–683. 9. Al-Mubarak N, Roubin GS, Vitek JJ, et al. Effect of the distal-balloon protection system on microembolization during carotid stenting. Circulation 2001;104:1999–2002.