Optimized Combination of Antiplatelet Treatment and Anticoagulation for Percutaneous Coronary <br />
Intervention: The Final Word is

The term acute coronary syndromes (ACS) comprise a continuum of diseases of various risks and severities including unstable angina pectoris, non-Q and Q-wave myocardial infarction (MI) and sudden death.1 These conditions share a similar pathologic pattern of intracoronary plaque rupture leading to formation of a platelet thrombus with either partial or complete coronary occlusion. Unstable angina and non-Q wave myocardial infarction are due to platelet thrombi that are often less stable and cause a smaller amount of ischemia than the occlusive thrombi that cause Q-wave myocardial infarction. The thrombi associated with Q-wave myocardial infarction are characterized by relatively higher levels of fibrin in comparison to the other ACS.(1) It has been suggested that the higher content of fibrin present in the thrombi of Q-wave infarctions represent a higher degree of activation of the coagulation cascade in these patients. In the last decade, we have seen not only an evolution in our understanding of the basic mechanisms underlying ACS, but also in the development of potent antiplatelet agents. One of the most significant advances has been the development of platelet glycoprotein (GP) IIb/IIIa receptor inhibitors. A large series of randomized, controlled clinical trials of these agents has shown a significant reduction in ischemic events not only in patients with ACS, but also in patients who undergo elective percutaneous coronary intervention (PCI). The first GP IIb/IIIa receptor antagonist to be used in the United States in patients undergoing PCI was abciximab (ReoPro, Centocor, Malvern, Pennsylvania and Eli Lilly, Indianapolis, Indiana). Treatment with abciximab during PCI has shown in various clinical trials a significant reduction in the incidence of ischemic events during PCI. Four years later, two other drugs entered the market: eptifibatide (Integrilin, COR Therapeutics, South San Francisco, California and Schering-Plough, Kenilworth, New Jersey) and tirofiban (Aggrastat, Merck, West Point, Pennsylvania). These two drugs have a much shorter half-life than abciximab (2–3 hours), a greater selectivity for the IIb/IIIa receptor complex and when administered with heparin and aspirin have reduced the incidence of ischemic events in patients with ACS. From these two drugs, only eptifibatide achieved a treatment benefit equal with that seen with abciximab in patients undergoing PCI, regardless of the use of a loading dose of a thienopyridine.(2) Ticlopidine and clopidogrel are thienopyridine derivatives with potent antiplatelet action that inhibit adenosine diphosphate-induced platelet aggregation, thereby reducing the expression of several platelet surface signaling and adhesion molecules. In patients with ACS who undergo PCI with stenting, the combination of one of these drugs with aspirin, which blocks the thromboxane-mediated pathway, has an additive effect and reduces the incidence of thrombotic stent occlusion as well as myocardial infarction, cardiovascular death or urgent target vessel revascularization.(3) Clopidogrel, in combination with aspirin, has become the standard treatment for patients who undergo PCI with stenting, due to its better safety and efficacy profile. Antithrombotic therapy is an important component of the pharmacological arsenal available for the anticoagulation management of patients with ACS or for patients who undergo PCI. Although enoxaparin, a low molecular weight heparin, has shown to be superior to unfractionated heparin in patients presenting with unstable angina or non-Q wave MI, its role in patients who require coronary catheterization has been less clear. Limited data are available on the efficacy and safety of low molecular weight heparin during catheterization, although some studies suggest that they might be superior to unfractionated heparin because of the more predictable kinetics, less potential for platelet activation and better bioavailability. Prior studies. A recently published study by Collet et al. has shown that PCI can safely be performed with subcutaneous enoxaparin in patients with ACS, without the need for additional anticoagulation or monitoring.(4) Enoxaparin is one of several low molecular weight heparins, which are obtained by depolymerization of unfractionated heparin. Enoxaparin has been approved in the United States for the prevention of deep vein thrombosis in patients undergoing abdominal and orthopedic surgery who are at risk for thromboembolic complications and for the prevention of ischemic complications of unstable angina and non-Q wave myocardial infarction, when administered concurrently with aspirin. While enoxaparin has an established role in patients presenting with ACS, it is not currently utilized in patients undergoing percutaneous coronary interventions on a routine manner. The NICE 1 pilot trial and the NICE 1 study randomly assigned patients to either 10,000 U of unfractionated heparin plus supplements to reach a target activated clotting time (ACT) > 300 seconds versus enoxaparin 1 mg/kg intravenous bolus immediately prior to PCI. These studies suggested that intravenous enoxaparin is a safe and effective anticoagulation during PCI.(5) The NICE 4 trial provided the first large scale experience with the combination of aspirin, oral thienopyridine (either ticlopidine or clopidogrel), enoxaparin (0.75 mg/kg intravenous bolus) and the GP IIb/IIIa abciximab during PCI.(6) The primary endpoint was the incidence of major and minor bleeding complications and blood product transfusion. Secondary endpoints were death, MI, urgent revascularization and CK-MB release in-hospital and at 30 days post-procedure. Major bleeding complications and transfusion were not frequent and did not increase due to the administration of abciximab (Figure 1). The incidence of clinical events during the index hospitalization and at 30-day follow-up was low and is shown in Figure 2. This study provided evidence that the use of a thienopyridine, enoxaparin and concomitant abciximab therapy in patients undergoing PCI provides safe and effective anticoagulation and is associated with a low incidence of bleeding and peri-procedural ischemic complications. These results were very similar to previous studies with GP IIb/IIIa inhibitors and unfractionated heparin. Unfortunately, neither one of these studies was randomized, did not use different dose regimens of enoxaparin and apply only to the combination of enoxaparin and abciximab and may not be extrapolated to other drugs.(6) In this issue of the Journal, Miller et al.(7) assess the safety and feasibility of the concomitant administration of aspirin, a loading dose of clopidogrel (300 mg), enoxaparin (0.5 mg/kg IV) and a double-bolus plus infusion regimen (“front-loaded”) of eptifibatide in 198 patients with ACS who underwent PCI. Procedural success was high, with a minimal incidence of peri-procedural bleeding complications. Only one patient required repeat manual compression at the access site due to bleeding. None of the 198 patients had life-threatening bleeding episodes, bleeding requiring surgical intervention, hemorrhagic stroke, access site hematoma, thrombocytopenia or required blood transfusion. Access site minor ecchymosis was seen in 21% of the patients. Furthermore, during the 30-day follow-up, there were no cases of death, acute vessel thrombosis or target vessel revascularization. Only one patient required re-intervention of a non-target vessel. It is important to note that due to skin rash, five patients required discontinuation of clopidogrel. While these data support the proposed strategy, the study is limited by the non-randomized design of the study with lack of an appropriate control group, by the small number of patients. The routine use of stents in combination with potent antiplatelet and antithrombotic therapy have already dramatically reduced the incidence of events in patients who undergo PCI; therefore, the sample size in this study may be too small to detect the desired effect (a type II or b error). A more definitive answer will be provided when the results of the NICE-5 Trial become available. This is a prospective, randomized, open-label, multicenter study in patients presenting with ACS undergoing a planned invasive treatment strategy. Patients will be randomized to either unfractionated heparin or enoxaparin and will receive concomitant anti-platelet therapy with a glycoprotein IIb/IIIa inhibitor. A total of approximately 8,000 patients will be enrolled. The primary objective will be to observe the composite endpoint of death and nonfatal myocardial infarction in the first 30 days after randomization. The primary safety endpoint will be the incidence of major hemorrhage during the index hospitalization. In conclusion, the current study by Miller et al.7 has shown excellent results with a strategy using enoxaparin, in addition to eptifibatide and clopidogrel during PCI. While this approach may have the potential advantage over the current strategy, its role will be determined by future randomized studies that are under way today.

1. Rentrop P. Thrombi in acute coronary syndromes. Revisited and revised. Circulation 2000;101:1619–1626. 2. Tcheng JE, Strony J, Lorenz TJ, O’Shea JC. ESPRIT in context: Pharmacology matters! Eur Heart J 2001;22:1965–1967. 3. Mehta SR, Yusuf S, Peters RJ, et al., and 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;358:527–533. 4. Collet JP, Montalescot G, Lison L, et al. Percutaneous coronary intervention after subcutaneous enoxaparin pretreatment in patients with unstable angina pectoris. Circulation 2001;103:658–663. 5. Young JJ, Kereiakes DJ, Grines CL, for the National Investigators Collaborating on Enoxaparin (NICE) Investigators. Low-molecular-weight heparin therapy in percutaneous coronary intervention: The NICE 1 and NICE 4 Trials. J Invas Cardiol 2000;12(Suppl E):E14–E18. 6. Kereiakes DJ, Grines C, Fry E, et al., for the National Investigators Collaborating on Enoxaparin (NICE) Investigators. Enoxaparin and abciximab adjunctive pharmacotherapy during percutaneous coronary intervention. J Invas Cardiol 2001;13:272–278. 7. Miller L, Gupta A, Bertolet BD. Use of clopidogrel loading, enoxaparin, and double bolus eptifibatide in the stetting of early percutaneous coronary intervention for acute coronary syndromes. J Invas Cardiol 2002;14:247–250.