Antiplatelet Therapy for Ischemic Heart Disease
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《新英格兰医药杂志》
Rupture or injury of an atherosclerotic coronary arterial plaque — as occurs spontaneously in patients with an acute coronary syndrome or as the result of a percutaneous coronary intervention — serves as a nidus for platelet aggregation and thrombus formation, which, in turn, may cause myocardial infarction or death. Activation of the platelet-surface glycoprotein IIb/IIIa receptor is the final common pathway in the process leading to platelet aggregation and, eventually, thrombus formation. When this receptor is activated, circulating fibrinogen binds to it and cross-links with adjacent platelets to create a platelet–fibrinogen matrix. Since platelets have a pivotal role in the pathogenesis of thrombosis after plaque rupture, it is not surprising that various antiplatelet agents (aspirin, the thienopyridines, and the glycoprotein IIb/IIIa inhibitors) have proved to be effective in reducing the incidence of adverse events that are associated with plaque rupture. The antiplatelet agents differ in their modes of action, antiplatelet potency, onsets of action, costs, and the specific circumstances and temporal framework in which they should be used.
Aspirin blocks the conversion of arachidonic acid to thromboxane in the platelet. Since it inhibits only one pathway by which platelet activation and aggregation occur (other agonists can directly stimulate the glycoprotein IIb/IIIa receptor, for example, thereby bypassing the arachidonic acid–thromboxane pathway), it is a relatively weak antiplatelet agent. Its full effects are manifested within 30 minutes after the ingestion of 162 to 325 mg, after which they persist for the life of the platelet. It is by far the least expensive of all antiplatelet agents, costing only pennies per day. Unless a contraindication exists, aspirin should be given to all patients with acute coronary syndromes and to all those undergoing percutaneous coronary intervention. Subsequently, it should be continued indefinitely (Table 1).
Table 1. Recommended Antiplatelet Therapy in Patients with an Acute Coronary Syndrome and in Those Undergoing a Percutaneous Coronary Intervention (PCI).
The thienopyridines ticlopidine and clopidogrel inhibit adenosine diphosphate (ADP) receptor–mediated platelet activation; they are more potent platelet inhibitors than aspirin. Clopidogrel is preferred, since in rare cases ticlopidine causes thrombocytopenic purpura and neutropenia. Maximal inhibition of ADP-induced platelet aggregation occurs three to five days after the initiation of a standard dose (75 mg daily), but within four to six hours after the administration of a larger loading dose (300 to 600 mg).1 In patients with an acute coronary syndrome, the administration of aspirin and clopidogrel for up to nine months was more effective than aspirin alone in reducing the combined incidence of death from cardiovascular causes, myocardial infarction, or stroke.2 Unfortunately, patients receiving both agents had an increased risk of bleeding. Of particular concern was the fact that those who received aspirin and clopidogrel during the five days before coronary-artery bypass grafting were more likely than those receiving aspirin alone to have major bleeding and to require transfusions, reoperation, or both. Therefore, although some physicians give clopidogrel to all patients with acute coronary syndromes, others delay such treatment until the results of coronary angiography are known and confirm that bypass grafting is not necessary. If clopidogrel is administered before coronary angiography and bypass grafting becomes the preferred management strategy, the drug should be discontinued five to seven days before surgery.
In the patient undergoing percutaneous coronary intervention, the administration of aspirin and clopidogrel reduces the risk of vessel thrombosis, as compared with aspirin alone.3 Until recently, clopidogrel was continued after percutaneous intervention only until the endothelial integrity of the injured arterial segment was thought to have been restored (four weeks after balloon angioplasty or the placement of a bare-metal stent, four to eight weeks after the deployment of a drug-eluting stent, and six months after brachytherapy). However, recent studies3,4 have shown that the administration of aspirin and clopidogrel for 9 to 12 months after such a procedure further reduces the incidence of major adverse cardiovascular events (death, myocardial infarction, or stroke) without increasing the risk of bleeding, as compared with aspirin alone. The aspirin–clopidogrel combination was effective only if 300 mg of clopidogrel was administered at least six hours before the procedure.4 Thus, in all patients undergoing percutaneous coronary intervention, a loading dose of clopidogrel (300 to 600 mg) should be given at least four to six hours before the procedure, after which a maintenance dose (75 mg daily) should be continued for at least 9 to 12 months. Clopidogrel costs about $4 per day (Table 1).
The glycoprotein IIb/IIIa inhibitors abciximab, eptifibatide, and tirofiban are the most potent and expensive antiplatelet agents, costing $600 to $1,800 per infusion. They are administered concomitantly with aspirin and heparin. Their antiplatelet effects are maximal within minutes after the initial intravenous bolus. In patients with acute coronary syndromes, tirofiban or eptifibatide reduces the incidence of subsequent myocardial infarction and the need for coronary revascularization.5,6 Patients considered to be at high risk (i.e., those with elevated serum troponin concentrations, ischemic ST-segment abnormalities, or ongoing ischemia) who undergo percutaneous intervention within one to two days after hospitalization appear to obtain the most benefit from them. In these patients, tirofiban or eptifibatide is infused for a total of 48 to 72 hours or until 12 to 24 hours after the procedure (Table 1).7
Many patients with unstable angina are referred promptly for diagnostic coronary angiography before the initiation of treatment with a glycoprotein IIb/IIIa inhibitor. In these patients, the results of angiography may suggest that percutaneous coronary intervention is appropriate, and the decision is made to proceed with it immediately. In this situation, an infusion of abciximab or eptifibatide before the procedure and for 12 to 24 hours thereafter reduces the incidence of procedure-associated myocardial infarction or vessel occlusion requiring urgent, repeated revascularization.8,9 Retrospective analyses of these studies suggested that patients who were pretreated with aspirin and clopidogrel derived no additional benefit from a glycoprotein IIb/IIIa inhibitor. Since aspirin and clopidogrel are much less expensive than the glycoprotein IIb/IIIa inhibitors, whether glycoprotein IIb/IIIa inhibitors are beneficial in all patients receiving aspirin and clopidogrel is a matter of intense interest. In this regard, the study by Kastrati et al.10 that is reported in this issue of the Journal showed that abciximab did not reduce the incidence of ischemic complications in patients at low or intermediate risk who were undergoing elective stent placement after pretreatment with aspirin and a 600-mg loading dose of clopidogrel. Furthermore, those receiving aspirin and clopidogrel without abciximab were less likely than those receiving all three agents to have thrombocytopenia and to require transfusions.
Two points should be emphasized with respect to the study by Kastrati et al.10 First, patients considered to be at high risk (those with acute coronary syndromes, recent myocardial infarction, bypass-graft stenoses, chronically occluded coronary arteries, or angiographically visible intracoronary thrombus) were not enrolled; thus, the conclusions of this study may not be applicable to such patients. In the United States, as many as two thirds of those who undergo percutaneous coronary intervention are considered to be at high risk. In these patients, abciximab has been shown to reduce the incidence of procedure-related ischemic events.8 Second, in the study by Kastrati et al., patients received a loading dose of clopidogrel a median of 7.4 hours before stent placement, with 75 percent of them receiving it at least 4 hours beforehand. In the United States, where stenting often is performed immediately after diagnostic angiography, the need for a four-to-six-hour wait between the administration of clopidogrel and percutaneous intervention may create logistical problems. In previous studies of high-risk patients, a combination of aspirin and clopidogrel was more effective than aspirin alone only if clopidogrel was administered at least six hours before the procedure; a 300-mg loading dose given three to six hours before the procedure was not beneficial.4
What then, can we learn from the study by Kastrati et al.? In patients undergoing percutaneous coronary intervention (as well as those with acute coronary syndromes), the decision regarding which antiplatelet agent or agents to administer should be based on clinical and angiographic variables. Patients who are believed to be at low risk for an ischemic complication should receive only aspirin and clopidogrel. In such patients, a glycoprotein IIb/IIIa inhibitor, although more potent, does not provide additional benefit. This is good news for both patients and hospitals: patients can receive treatment with an oral antiplatelet regimen that is associated with a lower risk of bleeding, and hospitals can dispense a therapy that is much less expensive. In contrast, high-risk patients should receive all three agents.
Source Information
From the Department of Internal Medicine, Cardiovascular Division, University of Texas Southwestern Medical Center, Dallas.
References
Helft G, Osende JI, Worthley SG, et al. Acute antithrombotic effect of a front-loaded regimen of clopidogrel in patients with atherosclerosis on aspirin. Arterioscler Thromb Vasc Biol 2000;20:2316-2321.
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.
Mehta SR, Yusuf S, Peters RJ, et al. 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.
Steinhubl SR, Berger PB, Mann JT III, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288:2411-2420.
The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998;339:436-443.
The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med 1998;338:1488-1497.
Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet 2002;359:189-198.
The EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Lancet 1998;352:87-92.
O'Shea JC, Hafley GE, Greenberg S, et al. Platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in coronary stent intervention: the ESPRIT trial: a randomized controlled trial. JAMA 2001;285:2468-2473.
Kastrati A, Mehilli J, Schühlen H, et al. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004;350:232-238.
Related Letters:
Antiplatelet Therapy for Ischemic Heart Disease
Steimle A. E., Lange R. A., Hillis L. D.
Extract | Full Text | PDF
N Engl J Med 2004; 350:2101-2102, May 13, 2004. Correspondence(Richard A. Lange, M.D., a)
Aspirin blocks the conversion of arachidonic acid to thromboxane in the platelet. Since it inhibits only one pathway by which platelet activation and aggregation occur (other agonists can directly stimulate the glycoprotein IIb/IIIa receptor, for example, thereby bypassing the arachidonic acid–thromboxane pathway), it is a relatively weak antiplatelet agent. Its full effects are manifested within 30 minutes after the ingestion of 162 to 325 mg, after which they persist for the life of the platelet. It is by far the least expensive of all antiplatelet agents, costing only pennies per day. Unless a contraindication exists, aspirin should be given to all patients with acute coronary syndromes and to all those undergoing percutaneous coronary intervention. Subsequently, it should be continued indefinitely (Table 1).
Table 1. Recommended Antiplatelet Therapy in Patients with an Acute Coronary Syndrome and in Those Undergoing a Percutaneous Coronary Intervention (PCI).
The thienopyridines ticlopidine and clopidogrel inhibit adenosine diphosphate (ADP) receptor–mediated platelet activation; they are more potent platelet inhibitors than aspirin. Clopidogrel is preferred, since in rare cases ticlopidine causes thrombocytopenic purpura and neutropenia. Maximal inhibition of ADP-induced platelet aggregation occurs three to five days after the initiation of a standard dose (75 mg daily), but within four to six hours after the administration of a larger loading dose (300 to 600 mg).1 In patients with an acute coronary syndrome, the administration of aspirin and clopidogrel for up to nine months was more effective than aspirin alone in reducing the combined incidence of death from cardiovascular causes, myocardial infarction, or stroke.2 Unfortunately, patients receiving both agents had an increased risk of bleeding. Of particular concern was the fact that those who received aspirin and clopidogrel during the five days before coronary-artery bypass grafting were more likely than those receiving aspirin alone to have major bleeding and to require transfusions, reoperation, or both. Therefore, although some physicians give clopidogrel to all patients with acute coronary syndromes, others delay such treatment until the results of coronary angiography are known and confirm that bypass grafting is not necessary. If clopidogrel is administered before coronary angiography and bypass grafting becomes the preferred management strategy, the drug should be discontinued five to seven days before surgery.
In the patient undergoing percutaneous coronary intervention, the administration of aspirin and clopidogrel reduces the risk of vessel thrombosis, as compared with aspirin alone.3 Until recently, clopidogrel was continued after percutaneous intervention only until the endothelial integrity of the injured arterial segment was thought to have been restored (four weeks after balloon angioplasty or the placement of a bare-metal stent, four to eight weeks after the deployment of a drug-eluting stent, and six months after brachytherapy). However, recent studies3,4 have shown that the administration of aspirin and clopidogrel for 9 to 12 months after such a procedure further reduces the incidence of major adverse cardiovascular events (death, myocardial infarction, or stroke) without increasing the risk of bleeding, as compared with aspirin alone. The aspirin–clopidogrel combination was effective only if 300 mg of clopidogrel was administered at least six hours before the procedure.4 Thus, in all patients undergoing percutaneous coronary intervention, a loading dose of clopidogrel (300 to 600 mg) should be given at least four to six hours before the procedure, after which a maintenance dose (75 mg daily) should be continued for at least 9 to 12 months. Clopidogrel costs about $4 per day (Table 1).
The glycoprotein IIb/IIIa inhibitors abciximab, eptifibatide, and tirofiban are the most potent and expensive antiplatelet agents, costing $600 to $1,800 per infusion. They are administered concomitantly with aspirin and heparin. Their antiplatelet effects are maximal within minutes after the initial intravenous bolus. In patients with acute coronary syndromes, tirofiban or eptifibatide reduces the incidence of subsequent myocardial infarction and the need for coronary revascularization.5,6 Patients considered to be at high risk (i.e., those with elevated serum troponin concentrations, ischemic ST-segment abnormalities, or ongoing ischemia) who undergo percutaneous intervention within one to two days after hospitalization appear to obtain the most benefit from them. In these patients, tirofiban or eptifibatide is infused for a total of 48 to 72 hours or until 12 to 24 hours after the procedure (Table 1).7
Many patients with unstable angina are referred promptly for diagnostic coronary angiography before the initiation of treatment with a glycoprotein IIb/IIIa inhibitor. In these patients, the results of angiography may suggest that percutaneous coronary intervention is appropriate, and the decision is made to proceed with it immediately. In this situation, an infusion of abciximab or eptifibatide before the procedure and for 12 to 24 hours thereafter reduces the incidence of procedure-associated myocardial infarction or vessel occlusion requiring urgent, repeated revascularization.8,9 Retrospective analyses of these studies suggested that patients who were pretreated with aspirin and clopidogrel derived no additional benefit from a glycoprotein IIb/IIIa inhibitor. Since aspirin and clopidogrel are much less expensive than the glycoprotein IIb/IIIa inhibitors, whether glycoprotein IIb/IIIa inhibitors are beneficial in all patients receiving aspirin and clopidogrel is a matter of intense interest. In this regard, the study by Kastrati et al.10 that is reported in this issue of the Journal showed that abciximab did not reduce the incidence of ischemic complications in patients at low or intermediate risk who were undergoing elective stent placement after pretreatment with aspirin and a 600-mg loading dose of clopidogrel. Furthermore, those receiving aspirin and clopidogrel without abciximab were less likely than those receiving all three agents to have thrombocytopenia and to require transfusions.
Two points should be emphasized with respect to the study by Kastrati et al.10 First, patients considered to be at high risk (those with acute coronary syndromes, recent myocardial infarction, bypass-graft stenoses, chronically occluded coronary arteries, or angiographically visible intracoronary thrombus) were not enrolled; thus, the conclusions of this study may not be applicable to such patients. In the United States, as many as two thirds of those who undergo percutaneous coronary intervention are considered to be at high risk. In these patients, abciximab has been shown to reduce the incidence of procedure-related ischemic events.8 Second, in the study by Kastrati et al., patients received a loading dose of clopidogrel a median of 7.4 hours before stent placement, with 75 percent of them receiving it at least 4 hours beforehand. In the United States, where stenting often is performed immediately after diagnostic angiography, the need for a four-to-six-hour wait between the administration of clopidogrel and percutaneous intervention may create logistical problems. In previous studies of high-risk patients, a combination of aspirin and clopidogrel was more effective than aspirin alone only if clopidogrel was administered at least six hours before the procedure; a 300-mg loading dose given three to six hours before the procedure was not beneficial.4
What then, can we learn from the study by Kastrati et al.? In patients undergoing percutaneous coronary intervention (as well as those with acute coronary syndromes), the decision regarding which antiplatelet agent or agents to administer should be based on clinical and angiographic variables. Patients who are believed to be at low risk for an ischemic complication should receive only aspirin and clopidogrel. In such patients, a glycoprotein IIb/IIIa inhibitor, although more potent, does not provide additional benefit. This is good news for both patients and hospitals: patients can receive treatment with an oral antiplatelet regimen that is associated with a lower risk of bleeding, and hospitals can dispense a therapy that is much less expensive. In contrast, high-risk patients should receive all three agents.
Source Information
From the Department of Internal Medicine, Cardiovascular Division, University of Texas Southwestern Medical Center, Dallas.
References
Helft G, Osende JI, Worthley SG, et al. Acute antithrombotic effect of a front-loaded regimen of clopidogrel in patients with atherosclerosis on aspirin. Arterioscler Thromb Vasc Biol 2000;20:2316-2321.
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.
Mehta SR, Yusuf S, Peters RJ, et al. 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.
Steinhubl SR, Berger PB, Mann JT III, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288:2411-2420.
The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998;339:436-443.
The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med 1998;338:1488-1497.
Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet 2002;359:189-198.
The EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Lancet 1998;352:87-92.
O'Shea JC, Hafley GE, Greenberg S, et al. Platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in coronary stent intervention: the ESPRIT trial: a randomized controlled trial. JAMA 2001;285:2468-2473.
Kastrati A, Mehilli J, Schühlen H, et al. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004;350:232-238.
Related Letters:
Antiplatelet Therapy for Ischemic Heart Disease
Steimle A. E., Lange R. A., Hillis L. D.
Extract | Full Text | PDF
N Engl J Med 2004; 350:2101-2102, May 13, 2004. Correspondence(Richard A. Lange, M.D., a)