Enoxaparin versus Unfractionated Heparin in ST-Elevation Myocardial Infarction
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《新英格兰医药杂志》
To the Editor: On behalf of the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment (ExTRACT)–Thrombolysis in Myocardial Infarction (TIMI) 25 Study investigators, Antman et al. (April 6 issue)1 compared the use of seven days of enoxaparin with 48 hours of unfractionated heparin in patients receiving fibrinolysis for ST-elevation myocardial infarction. The longer duration of treatment with enoxaparin was found to be superior to the short course of treatment with unfractionated heparin, although the longer treatment was associated with an increase in major bleeding episodes. One may conclude from this study that enoxaparin provides superior anticoagulation to that of unfractionated heparin, and the authors emphasize this point. However, the results may be fully explained by the fact that both agents provide a similar level of anticoagulation, but extending therapy to seven days provides added protection (but more risk). It is plausible that unfractionated heparin may provide the same improved clinical benefit as enoxaparin if given over a seven-day period, but with a considerably lower risk of major bleeding than that associated with enoxaparin.
Douglas D. DeCarolis, Pharm.D.
Minneapolis Veterans Affairs Medical Center
Minneapolis, MN 55417
douglas.decarolis@med.va.gov
References
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.
To the Editor: The ExTRACT–TIMI investigators reported a 53 percent increase in the rate of serious bleeding (clinically overt bleeding with a drop in hemoglobin of 3 g per deciliter or greater or the need for an equivalent transfusion of packed red cells ) with enoxaparin as compared with unfractionated heparin at 30 days (4.6 percent vs. 3.1 percent; relative risk, 1.47; 95 percent confidence interval, 1.28 to 1.69) and no significant reduction in the rate of deaths (6.9 percent vs. 7.5 percent; relative risk, 0.92; 95 percent confidence interval, 0.84 to 1.02; P=0.11). Deaths attributable to bleeding were not reported separately, but the footnote to Table 3 of the article indicates that 56 deaths were attributable to hemorrhage in the enoxaparin group and 34 deaths were attributable to hemorrhage in the unfractionated heparin group. These figures represent a significant 60 percent increase in the rate of fatal bleeding with enoxaparin as compared with unfractionated heparin (0.55 percent vs. 0.33 percent; relative risk, 1.64; 95 percent confidence interval, 1.07 to 2.51). When deaths attributable to bleeding are excluded from the overall analysis, there is a significant reduction in the rate of death in the enoxaparin group as compared with the unfractionated heparin group (6.4 percent vs. 7.2 percent; relative risk, 0.89; 95 percent confidence interval, 0.80 to 0.98). Taken together with emerging evidence of an adverse effect of serious bleeding on prognosis,1,2 these data underscore the importance of avoiding bleeding in reducing morbidity and mortality.
Peter Sleight, M.D.
University of Oxford
Oxford OX33 1UL, United Kingdom
peter.sleight@attglobal.net
John W. Eikelboom, M.B., B.S.
McMaster University
Hamilton, ON L8L2X2, Canada
Jean-Pierre Bassand, M.D.
University Hospital Jean Minjoz
Besan?on 25030, France
References
Rao SV, O'Grady K, Pieper KS, et al. Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes. Am J Cardiol 2005;96:1200-1206.
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.
The authors reply: DeCarolis questions whether prolonged treatment with unfractionated heparin over a period of seven days might provide the same benefits afforded by seven days of enoxaparin therapy, but with a lower rate of major bleeding. We wish to reiterate a point emphasized in our article — previous work has failed to show that the infusion of unfractionated heparin for more than 48 hours prevents reocclusion of successfully reperfused infarct arteries in patients with ST-elevation myocardial infarction.1 As noted in Table 2 of our article, at 48 hours there was already a 33 percent reduction in the risk of nonfatal myocardial infarction in the enoxaparin group as compared with the unfractionated heparin group (P=0.002); these findings are consistent with those that indicated the superior antithrombotic effect of enoxaparin when there was a direct pharmacologic comparison of the two agents. Finally, prolonged infusion of unfractionated heparin is impractical, is associated with considerable additional cost and an increased risk of heparin-induced thrombocytopenia, and is not recommended by current guidelines.2,3
We agree with DeCarolis and with Sleight et al. that serious bleeding is an undesirable outcome, but we wish to emphasize that efforts to minimize bleeding should not be made at the expense of efficacy. Any evaluation of antithrombotic strategies in patients with ST-elevation myocardial infarction should consider whether efficacy and safety are balanced. As compared with unfractionated heparin, enoxaparin reduced significantly (P<0.001) the risk of both the primary efficacy end point (death or nonfatal myocardial infarction) and the main secondary end point (death, nonfatal myocardial infarction, or urgent revascularization) at 8 days and 30 days. Also, the three prespecified net-clinical-benefit end points (which are composites of efficacy and different aspects of safety) in the ExTRACT–TIMI 25 study all strongly favored the strategy of administering enoxaparin (see Table 4 of our article). Furthermore, the strategy of administering enoxaparin provided seamless antithrombin support not only during the lytic phase of management of ST-elevation myocardial infarction, but also in patients who subsequently underwent percutaneous coronary intervention. By avoiding the need for supplemental anticoagulation with an additional agent in the catheterization laboratory, administration of enoxaparin alone helps to minimize the risk of excess anticoagulation and bleeding during interventional procedures.
Thus, the convenience of the subcutaneous route of administration, more reliable anticoagulation associated with enoxaparin, and the totality of the findings in the ExTRACT–TIMI 25 study lead us to conclude that a strategy of antithrombotic therapy with enoxaparin is preferable to the current strategy of administering unfractionated heparin to patients receiving fibrinolysis for ST-elevation myocardial infarction.
Elliott M. Antman, M.D.
Eugene Braunwald, M.D.
Brigham and Women's Hospital
Boston, MA 02115
eantman@rics.bwh.harvard.edu
References
Thompson PL, Aylward PE, Federman J, et al. A randomized comparison of intravenous heparin with oral aspirin and dipyridamole 24 hours after recombinant tissue-type plasminogen activator for acute myocardial infarction. Circulation 1991;83:1534-1542.
Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995;332:1330-1335.
Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). J Am Coll Cardiol 2004;44:E1-E211.
Douglas D. DeCarolis, Pharm.D.
Minneapolis Veterans Affairs Medical Center
Minneapolis, MN 55417
douglas.decarolis@med.va.gov
References
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.
To the Editor: The ExTRACT–TIMI investigators reported a 53 percent increase in the rate of serious bleeding (clinically overt bleeding with a drop in hemoglobin of 3 g per deciliter or greater or the need for an equivalent transfusion of packed red cells ) with enoxaparin as compared with unfractionated heparin at 30 days (4.6 percent vs. 3.1 percent; relative risk, 1.47; 95 percent confidence interval, 1.28 to 1.69) and no significant reduction in the rate of deaths (6.9 percent vs. 7.5 percent; relative risk, 0.92; 95 percent confidence interval, 0.84 to 1.02; P=0.11). Deaths attributable to bleeding were not reported separately, but the footnote to Table 3 of the article indicates that 56 deaths were attributable to hemorrhage in the enoxaparin group and 34 deaths were attributable to hemorrhage in the unfractionated heparin group. These figures represent a significant 60 percent increase in the rate of fatal bleeding with enoxaparin as compared with unfractionated heparin (0.55 percent vs. 0.33 percent; relative risk, 1.64; 95 percent confidence interval, 1.07 to 2.51). When deaths attributable to bleeding are excluded from the overall analysis, there is a significant reduction in the rate of death in the enoxaparin group as compared with the unfractionated heparin group (6.4 percent vs. 7.2 percent; relative risk, 0.89; 95 percent confidence interval, 0.80 to 0.98). Taken together with emerging evidence of an adverse effect of serious bleeding on prognosis,1,2 these data underscore the importance of avoiding bleeding in reducing morbidity and mortality.
Peter Sleight, M.D.
University of Oxford
Oxford OX33 1UL, United Kingdom
peter.sleight@attglobal.net
John W. Eikelboom, M.B., B.S.
McMaster University
Hamilton, ON L8L2X2, Canada
Jean-Pierre Bassand, M.D.
University Hospital Jean Minjoz
Besan?on 25030, France
References
Rao SV, O'Grady K, Pieper KS, et al. Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes. Am J Cardiol 2005;96:1200-1206.
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.
The authors reply: DeCarolis questions whether prolonged treatment with unfractionated heparin over a period of seven days might provide the same benefits afforded by seven days of enoxaparin therapy, but with a lower rate of major bleeding. We wish to reiterate a point emphasized in our article — previous work has failed to show that the infusion of unfractionated heparin for more than 48 hours prevents reocclusion of successfully reperfused infarct arteries in patients with ST-elevation myocardial infarction.1 As noted in Table 2 of our article, at 48 hours there was already a 33 percent reduction in the risk of nonfatal myocardial infarction in the enoxaparin group as compared with the unfractionated heparin group (P=0.002); these findings are consistent with those that indicated the superior antithrombotic effect of enoxaparin when there was a direct pharmacologic comparison of the two agents. Finally, prolonged infusion of unfractionated heparin is impractical, is associated with considerable additional cost and an increased risk of heparin-induced thrombocytopenia, and is not recommended by current guidelines.2,3
We agree with DeCarolis and with Sleight et al. that serious bleeding is an undesirable outcome, but we wish to emphasize that efforts to minimize bleeding should not be made at the expense of efficacy. Any evaluation of antithrombotic strategies in patients with ST-elevation myocardial infarction should consider whether efficacy and safety are balanced. As compared with unfractionated heparin, enoxaparin reduced significantly (P<0.001) the risk of both the primary efficacy end point (death or nonfatal myocardial infarction) and the main secondary end point (death, nonfatal myocardial infarction, or urgent revascularization) at 8 days and 30 days. Also, the three prespecified net-clinical-benefit end points (which are composites of efficacy and different aspects of safety) in the ExTRACT–TIMI 25 study all strongly favored the strategy of administering enoxaparin (see Table 4 of our article). Furthermore, the strategy of administering enoxaparin provided seamless antithrombin support not only during the lytic phase of management of ST-elevation myocardial infarction, but also in patients who subsequently underwent percutaneous coronary intervention. By avoiding the need for supplemental anticoagulation with an additional agent in the catheterization laboratory, administration of enoxaparin alone helps to minimize the risk of excess anticoagulation and bleeding during interventional procedures.
Thus, the convenience of the subcutaneous route of administration, more reliable anticoagulation associated with enoxaparin, and the totality of the findings in the ExTRACT–TIMI 25 study lead us to conclude that a strategy of antithrombotic therapy with enoxaparin is preferable to the current strategy of administering unfractionated heparin to patients receiving fibrinolysis for ST-elevation myocardial infarction.
Elliott M. Antman, M.D.
Eugene Braunwald, M.D.
Brigham and Women's Hospital
Boston, MA 02115
eantman@rics.bwh.harvard.edu
References
Thompson PL, Aylward PE, Federman J, et al. A randomized comparison of intravenous heparin with oral aspirin and dipyridamole 24 hours after recombinant tissue-type plasminogen activator for acute myocardial infarction. Circulation 1991;83:1534-1542.
Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995;332:1330-1335.
Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). J Am Coll Cardiol 2004;44:E1-E211.