Short- and long-term oral antiplatelet therapy in acute coronary syndromes and percutaneous coronary intervention
Shamir R. Mehta, MD, FACC*,* and
Salim Yusuf, DPhil, FACC*
* Division of Cardiology, McMaster University and the Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada
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Figure 1 Platelet activation is an important early step in the pathophysiology of atherothrombosis. Platelet activation involves: 1) a shape change in which the platelet membrane surface area is greatly increased; 2) the secretion of pro-inflammatory, prothrombotic, adhesive, and chemotactic mediators (release reaction), that propagate, amplify, and sustain the atherothrombotic process; and 3) the activation of the glycoprotein (GP) IIb/IIIa receptor from its inactive form. Multiple agonists including thromboxane A2 (TXA2), adenosine diphosphate (ADP), thrombin, serotonin, epinephrine, and collagen, can activate the platelet and thus contribute toward establishing the environmental conditions necessary for atherothrombosis to occur. Aspirin inhibits the production of thromboxane A2 by its effect on the enzyme cyclooxygenase (COX) 1. The ADP receptor antagonists clopidogrel and ticlopidine prevent the binding of ADP to its receptor. The effect of combining aspirin and clopidogrel is synergistic in preventing platelet aggregation. Antithrombins such as unfractionated or low-molecular-weight heparin, hirudin, or bivalirudin are important in interfering with both thrombin-induced platelet activation and coagulation. The GP IIb/IIIa receptor antagonists act at a later step in the process by preventing fibrinogen mediated cross-linking of platelets, which have already become activated. ATP = adenosine triphosphate; PAI = plasminogen activator inhibitor; PDGF = platelet-derived growth factor; vWF = von Willebrand factor.
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Figure 2 First co-primary outcome in Clopidogrel in Unstable angina to prevent Recurrent ischaemic Events (CURE). Cardiovascular death, myocardial infarction, or stroke from randomization up to one year of follow-up (mean nine months). ASA = acetylsalicylic acid. The CURE 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. Adapted with permission 2002. © 2002 Massachusetts Medical Society. All rights reserved.
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Figure 3 Percutaneous Coronary Intervention-Clopidogrel in Unstable angina to prevent Recurrent ischaemic Events (PCI CURE) trial: overall long-term results from randomization up to one year: cardiovascular death or myocardial infarction. A = median time to PCI; B = 30 days after PCI. ASA = acetylsalicylic acid; PCI = percutaneous coronary intervention. Reprinted with permission from Elsevier Science (The Lancet 2001;358:527–33).
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Figure 4 Effects of pretreatment with clopidogrel compared with placebo in stented patients (excludes those receiving open-label thienopyridine before percutaneous coronary intervention [PCI]). All patients received open-label clopidogrel or ticlopidine for a median of 30 days after PCI. Day 0 is the day of PCI. Reprinted with permission from Elsevier Science (The Lancet 2002;359:169).
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Figure 5 Cardiovascular (CV) death or MI in Percutaneous Coronary Intervention-Clopidogrel in Unstable angina to prevent Recurrent ischaemic Events (PCI CURE): consistent benefits of clopidogrel at all non-overlapping time points. MI = myocardial infarction; RRR = relative risk ratio.
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Figure 6 Excess mortality with oral glycoprotein IIb/IIIa antagonists. All trials demonstrate a consistent increase in total mortality. p = 0.5888 Breslow-Day heterogeneity. CI = confidence interval; EXCITE = Evaluation of oral Xemilofiban In controlling Thrombotic Events trial; OPUS = Optimal angioplasty and primary stenting trial; SYMPHONY = Sibrafiban vs. aspirin to Yield Maximum Protection from ischemic Heart events pOst acute coroNary sYndromes. Chew DP, Bhatt DL, Sapp S, Topol EJ. Increased mortality with oral platelet glycoprotein IIb/IIIa antagonists: a meta-analysis of phase III multicenter randomized trials. Circulation 2001;103:201–6. Reproduced with permissions from Lippincott, Williams and Wilkins.
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