Therapy for Patients with Acute Coronary Syndromes — New Opportunities
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《新英格兰医药杂志》
Acute coronary syndromes, defined as myocardial infarction with ST-segment elevation, myocardial infarction without ST-segment elevation, and unstable angina, share a common pathophysiology: atherosclerotic plaque rupture, erosion, or both with superimposed intracoronary thrombosis, commonly known as atherothrombosis.1 Two large randomized trials reported in this issue of the Journal2,3 address the evolving use of antithrombotic agents for these syndromes; a third trial has been published recently.4
Table 1 places these trials in the context of existing practice guidelines for antithrombotic agents. The oldest antithrombotic agent is unfractionated heparin. Although treatment with unfractionated heparin is generally indicated for 24 to 48 hours in myocardial infarction with ST-segment elevation, the evidence supporting its use is limited. An overview of six small randomized trials revealed similar rates of death, recurrent ischemia, and reinfarction with and without unfractionated heparin.5 Furthermore, unfractionated heparin has many well-recognized disadvantages, including the need for frequent monitoring, a risk of thrombocytopenia, and an increased risk of bleeding.5
Table 1. Guideline-Based Recommendations for Antithrombotic Therapy.
In contrast, low-molecular-weight heparins have a more predictable anticoagulant effect; in addition, there is no need for laboratory monitoring, rates of thrombocytopenia are lower, and administration can be performed by subcutaneous injection. Although low-molecular-weight heparins are generally indicated in myocardial infarction without ST-segment elevation or unstable angina, the limited evidence regarding their use in myocardial infarction with ST-segment elevation is conflicting. Prehospital administration of enoxaparin, as compared with unfractionated heparin, caused an increase in intracranial hemorrhage among elderly patients.6
In this issue of the Journal, Antman et al. report on the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment (ExTRACT)–Thrombolysis in Myocardial Infarction (TIMI) 25 trial,2 in which enoxaparin was compared with unfractionated heparin in 20,506 patients who had myocardial infarction with ST-segment elevation and who were scheduled to receive fibrinolytic therapy. Administration of unfractionated heparin was continued for 48 hours. In contrast, treatment with enoxaparin was continued throughout hospitalization. Thus, the trial compared treatment regimens and was not a head-to-head comparison of the two agents. There was a significant, absolute reduction of 2.1 percentage points in the primary end point (death or nonfatal myocardial infarction) at 30 days with enoxaparin as compared with unfractionated heparin, but an excess in major bleeding of 0.7 percentage point. The number needed to treat with enoxaparin, as compared with unfractionated heparin, would be about 50 to prevent one death or nonfatal myocardial infarction, but at a cost of one major bleeding event for about every 150 patients treated. The longer period of administration of enoxaparin may in part account for both the reduction in cardiac events and the increase in bleeding.
These positive results may also in part reflect the exclusion of men with a creatinine level of greater than 2.5 mg per deciliter (220 μmol per liter) and women with a creatinine level of greater than 2.0 mg per deciliter (177 μmol per liter) and the careful adjustment of the enoxaparin dose according to the patient's age and renal function. Dose adjustment may lead to more problems in clinical practice, where excess dosing7 with existing, simpler regimens is already common and is associated with adverse outcomes. The higher cost of enoxaparin remains a concern, although prior studies have found it to be cost-effective.
Fondaparinux is a synthetic pentasaccharide that selectively inhibits factor Xa. Fondaparinux can be administered daily without laboratory monitoring. In small dose-ranging studies, a low dose of fondaparinux (2.5 mg) had similar efficacy to higher doses of fondaparinux and the standard dose of enoxaparin, with a similar or lower risk of bleeding. In this issue of the Journal, Yusuf et al. report on the Fifth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS-5) trial, in which fondaparinux was compared with enoxaparin in 20,078 patients with acute coronary syndromes.3 Patients with a creatinine level of at least 3 mg per deciliter (265 μmol per liter) were excluded. The mean duration of therapy with the two drugs was similar, permitting a direct comparison. The trial successfully demonstrated the noninferiority of fondaparinux as compared with enoxaparin with respect to the primary efficacy end point of death, myocardial infarction, or refractory ischemia at nine days (5.8 percent vs. 5.7 percent, respectively). The rate of the primary safety end point, major bleeding at nine days, was significantly lower with fondaparinux than with enoxaparin (2.2 percent vs. 4.1 percent). Mortality at 30 days (2.9 percent vs. 3.5 percent) and at 180 days (5.8 percent vs. 6.5 percent) was also significantly lower with fondaparinux; 61 of the 64 excess deaths with enoxaparin were associated with either major or minor bleeding. Treatment of about 150 patients with fondaparinux rather than enoxaparin would result in three fewer bleeding events and one fewer death at 180 days. The noninferiority of fondaparinux with respect to the primary efficacy outcome and the superiority of fondaparinux with respect to major bleeding were also demonstrated in the subgroup of 7932 patients who underwent percutaneous coronary intervention. The specific anti–factor Xa activity of fondaparinux, as compared with the antithrombin and anti–factor Xa effect of enoxaparin, may in part be responsible for its safer profile. Fondaparinux inhibits factor Xa within the clot, preventing thrombus progression and thus enhancing effectiveness, but does not inhibit platelet function, thus enhancing safety.
Supporting the evolving role of fondaparinux in acute coronary syndromes, Yusuf et al. have also reported data from the OASIS-6 trial, in which fondaparinux was compared with a control in 12,902 patients who had myocardial infarction with ST-segment elevation and who presented relatively late (a median of 4.8 hours after the onset of chest pain).4 The control group included 3221 patients treated with unfractionated heparin on the basis of the investigator's judgment. The rate of the primary end point of death or reinfarction at 30 days was significantly lower in the fondaparinux group, as was the rate of death at 30 days. However, there was no benefit with fondaparinux among the 3789 patients who underwent primary percutaneous coronary intervention. There was a trend (P=0.12) toward fewer major bleeding events among the patients who received fondaparinux.
Only a minority of the patients in ExTRACT–TIMI 25 and OASIS-6 received clopidogrel, since these trials were designed and performed before the publication of a very large trial8 that reported a significant, 0.6 percentage point absolute decrease in mortality with clopidogrel, without any increase in major bleeding. The evaluation of enoxaparin and fondaparinux as compared with clopidogrel will require further study.
What are the implications of these three major studies? First, these large randomized studies demonstrate the superiority of newer antithrombotic agents in the management of acute coronary syndromes. They provide important new evidence for consideration in the next updates or revisions of the existing guidelines. Second, these studies demonstrate the critical importance of bleeding and its attendant risks; the previous focus on efficacy and ischemic complications needs to be balanced by recognition of the risks associated with bleeding. Extension of these results to clinical practice will require careful selection of patients, indications, and dosages to minimize bleeding. For example, these trials do not apply to patients with moderate or severe chronic renal disease, who are less likely to receive recommended therapies and who are at greater risk for bleeding and death than are patients without moderate or severe chronic renal disease.9 Finally, the potential benefits of the newer antithrombotic agents will be realized only if they are administered along with the other therapies recommended by the guidelines, particularly reperfusion therapy for myocardial infarction with ST-segment elevation. There is evidence from registry data that 25 to 30 percent of eligible patients with the latter condition never receive fibrinolytic therapy and never undergo early percutaneous coronary intervention10 and that the guidelines for myocardial infarction with ST-segment elevation and for myocardial infarction without ST-segment elevation or unstable angina are followed inconsistently. The question is whether the results in the highly selected patient populations in these three controlled trials can be matched in the real-world treatment of acute coronary syndromes.
Dr. Fuster reports being chairman of the GlaxoSmithKline Research and Education Foundation for Cardiovascular Disease. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Mayo Clinic College of Medicine, Rochester, Minn. (R.J.G.); and Mt. Sinai School of Medicine, New York (V.F.).
This article was published at www.nejm.org on March 14, 2006.
References
Fuster V, Moreno PR, Fayad ZA, Corti R, Badimon JS. Atherothrombosis and high-risk plaque: part I: evolving concepts. J Am Coll Cardiol 2005;46:937-954.
Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med 2006;354:1477-1488.
The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 2006;354:1464-1476.
Yusuf S, Mehta SR, Chrolavicius S, et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction. JAMA 2006;295:E1-E12.
Mahaffey KW, Granger CB, Collins R, et al. Overview of randomized trials of intravenous heparin in patients with acute myocardial infarction treated with thrombolytic therapy. Am J Cardiol 1996;77:551-556.
Wallentin L, Goldstein P, Armstrong PW, et al. Efficacy and safety of tenecteplase in combination with the low-molecular-weight heparin enoxaparin or unfractionated heparin in the prehospital setting: the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 PLUS randomized trial in acute myocardial infarction. Circulation 2003;108:135-142.
Alexander KP, Chen AY, Roe MT, et al. Excess dosing of antiplatelet and antithrombin agents in the treatment of non-ST-segment elevation acute coronary syndromes. JAMA 2005;294:3108-16.
Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005;366:1607-1621.
Han JH, Chandra A, Mulgund J, et al. Chronic kidney disease in patients with non-ST-segment elevation acute coronary syndromes. Am J Med 2006;119:248-254.
Eagle KA, Goodman SG, Avezum A, Budaj A, Sullivan CM, Lopez-Sendon J. Practice variation and missed opportunities for reperfusion in ST-segment-elevation myocardial infarction: findings from the Global Registry of Acute Coronary Events (GRACE). Lancet 2002;359:373-377.(Raymond J. Gibbons, M.D.,)
Table 1 places these trials in the context of existing practice guidelines for antithrombotic agents. The oldest antithrombotic agent is unfractionated heparin. Although treatment with unfractionated heparin is generally indicated for 24 to 48 hours in myocardial infarction with ST-segment elevation, the evidence supporting its use is limited. An overview of six small randomized trials revealed similar rates of death, recurrent ischemia, and reinfarction with and without unfractionated heparin.5 Furthermore, unfractionated heparin has many well-recognized disadvantages, including the need for frequent monitoring, a risk of thrombocytopenia, and an increased risk of bleeding.5
Table 1. Guideline-Based Recommendations for Antithrombotic Therapy.
In contrast, low-molecular-weight heparins have a more predictable anticoagulant effect; in addition, there is no need for laboratory monitoring, rates of thrombocytopenia are lower, and administration can be performed by subcutaneous injection. Although low-molecular-weight heparins are generally indicated in myocardial infarction without ST-segment elevation or unstable angina, the limited evidence regarding their use in myocardial infarction with ST-segment elevation is conflicting. Prehospital administration of enoxaparin, as compared with unfractionated heparin, caused an increase in intracranial hemorrhage among elderly patients.6
In this issue of the Journal, Antman et al. report on the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment (ExTRACT)–Thrombolysis in Myocardial Infarction (TIMI) 25 trial,2 in which enoxaparin was compared with unfractionated heparin in 20,506 patients who had myocardial infarction with ST-segment elevation and who were scheduled to receive fibrinolytic therapy. Administration of unfractionated heparin was continued for 48 hours. In contrast, treatment with enoxaparin was continued throughout hospitalization. Thus, the trial compared treatment regimens and was not a head-to-head comparison of the two agents. There was a significant, absolute reduction of 2.1 percentage points in the primary end point (death or nonfatal myocardial infarction) at 30 days with enoxaparin as compared with unfractionated heparin, but an excess in major bleeding of 0.7 percentage point. The number needed to treat with enoxaparin, as compared with unfractionated heparin, would be about 50 to prevent one death or nonfatal myocardial infarction, but at a cost of one major bleeding event for about every 150 patients treated. The longer period of administration of enoxaparin may in part account for both the reduction in cardiac events and the increase in bleeding.
These positive results may also in part reflect the exclusion of men with a creatinine level of greater than 2.5 mg per deciliter (220 μmol per liter) and women with a creatinine level of greater than 2.0 mg per deciliter (177 μmol per liter) and the careful adjustment of the enoxaparin dose according to the patient's age and renal function. Dose adjustment may lead to more problems in clinical practice, where excess dosing7 with existing, simpler regimens is already common and is associated with adverse outcomes. The higher cost of enoxaparin remains a concern, although prior studies have found it to be cost-effective.
Fondaparinux is a synthetic pentasaccharide that selectively inhibits factor Xa. Fondaparinux can be administered daily without laboratory monitoring. In small dose-ranging studies, a low dose of fondaparinux (2.5 mg) had similar efficacy to higher doses of fondaparinux and the standard dose of enoxaparin, with a similar or lower risk of bleeding. In this issue of the Journal, Yusuf et al. report on the Fifth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS-5) trial, in which fondaparinux was compared with enoxaparin in 20,078 patients with acute coronary syndromes.3 Patients with a creatinine level of at least 3 mg per deciliter (265 μmol per liter) were excluded. The mean duration of therapy with the two drugs was similar, permitting a direct comparison. The trial successfully demonstrated the noninferiority of fondaparinux as compared with enoxaparin with respect to the primary efficacy end point of death, myocardial infarction, or refractory ischemia at nine days (5.8 percent vs. 5.7 percent, respectively). The rate of the primary safety end point, major bleeding at nine days, was significantly lower with fondaparinux than with enoxaparin (2.2 percent vs. 4.1 percent). Mortality at 30 days (2.9 percent vs. 3.5 percent) and at 180 days (5.8 percent vs. 6.5 percent) was also significantly lower with fondaparinux; 61 of the 64 excess deaths with enoxaparin were associated with either major or minor bleeding. Treatment of about 150 patients with fondaparinux rather than enoxaparin would result in three fewer bleeding events and one fewer death at 180 days. The noninferiority of fondaparinux with respect to the primary efficacy outcome and the superiority of fondaparinux with respect to major bleeding were also demonstrated in the subgroup of 7932 patients who underwent percutaneous coronary intervention. The specific anti–factor Xa activity of fondaparinux, as compared with the antithrombin and anti–factor Xa effect of enoxaparin, may in part be responsible for its safer profile. Fondaparinux inhibits factor Xa within the clot, preventing thrombus progression and thus enhancing effectiveness, but does not inhibit platelet function, thus enhancing safety.
Supporting the evolving role of fondaparinux in acute coronary syndromes, Yusuf et al. have also reported data from the OASIS-6 trial, in which fondaparinux was compared with a control in 12,902 patients who had myocardial infarction with ST-segment elevation and who presented relatively late (a median of 4.8 hours after the onset of chest pain).4 The control group included 3221 patients treated with unfractionated heparin on the basis of the investigator's judgment. The rate of the primary end point of death or reinfarction at 30 days was significantly lower in the fondaparinux group, as was the rate of death at 30 days. However, there was no benefit with fondaparinux among the 3789 patients who underwent primary percutaneous coronary intervention. There was a trend (P=0.12) toward fewer major bleeding events among the patients who received fondaparinux.
Only a minority of the patients in ExTRACT–TIMI 25 and OASIS-6 received clopidogrel, since these trials were designed and performed before the publication of a very large trial8 that reported a significant, 0.6 percentage point absolute decrease in mortality with clopidogrel, without any increase in major bleeding. The evaluation of enoxaparin and fondaparinux as compared with clopidogrel will require further study.
What are the implications of these three major studies? First, these large randomized studies demonstrate the superiority of newer antithrombotic agents in the management of acute coronary syndromes. They provide important new evidence for consideration in the next updates or revisions of the existing guidelines. Second, these studies demonstrate the critical importance of bleeding and its attendant risks; the previous focus on efficacy and ischemic complications needs to be balanced by recognition of the risks associated with bleeding. Extension of these results to clinical practice will require careful selection of patients, indications, and dosages to minimize bleeding. For example, these trials do not apply to patients with moderate or severe chronic renal disease, who are less likely to receive recommended therapies and who are at greater risk for bleeding and death than are patients without moderate or severe chronic renal disease.9 Finally, the potential benefits of the newer antithrombotic agents will be realized only if they are administered along with the other therapies recommended by the guidelines, particularly reperfusion therapy for myocardial infarction with ST-segment elevation. There is evidence from registry data that 25 to 30 percent of eligible patients with the latter condition never receive fibrinolytic therapy and never undergo early percutaneous coronary intervention10 and that the guidelines for myocardial infarction with ST-segment elevation and for myocardial infarction without ST-segment elevation or unstable angina are followed inconsistently. The question is whether the results in the highly selected patient populations in these three controlled trials can be matched in the real-world treatment of acute coronary syndromes.
Dr. Fuster reports being chairman of the GlaxoSmithKline Research and Education Foundation for Cardiovascular Disease. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Mayo Clinic College of Medicine, Rochester, Minn. (R.J.G.); and Mt. Sinai School of Medicine, New York (V.F.).
This article was published at www.nejm.org on March 14, 2006.
References
Fuster V, Moreno PR, Fayad ZA, Corti R, Badimon JS. Atherothrombosis and high-risk plaque: part I: evolving concepts. J Am Coll Cardiol 2005;46:937-954.
Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med 2006;354:1477-1488.
The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 2006;354:1464-1476.
Yusuf S, Mehta SR, Chrolavicius S, et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction. JAMA 2006;295:E1-E12.
Mahaffey KW, Granger CB, Collins R, et al. Overview of randomized trials of intravenous heparin in patients with acute myocardial infarction treated with thrombolytic therapy. Am J Cardiol 1996;77:551-556.
Wallentin L, Goldstein P, Armstrong PW, et al. Efficacy and safety of tenecteplase in combination with the low-molecular-weight heparin enoxaparin or unfractionated heparin in the prehospital setting: the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 PLUS randomized trial in acute myocardial infarction. Circulation 2003;108:135-142.
Alexander KP, Chen AY, Roe MT, et al. Excess dosing of antiplatelet and antithrombin agents in the treatment of non-ST-segment elevation acute coronary syndromes. JAMA 2005;294:3108-16.
Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005;366:1607-1621.
Han JH, Chandra A, Mulgund J, et al. Chronic kidney disease in patients with non-ST-segment elevation acute coronary syndromes. Am J Med 2006;119:248-254.
Eagle KA, Goodman SG, Avezum A, Budaj A, Sullivan CM, Lopez-Sendon J. Practice variation and missed opportunities for reperfusion in ST-segment-elevation myocardial infarction: findings from the Global Registry of Acute Coronary Events (GRACE). Lancet 2002;359:373-377.(Raymond J. Gibbons, M.D.,)