Fondaparinux versus Enoxaparin in Acute Coronary Syndromes
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《新英格兰医药杂志》
To the Editor: The authors of the Fifth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS-5) study (April 6 issue)1 point out that despite the presence or absence of administration of unfractionated heparin, bleeding rates were significantly lower with fondaparinux than with enoxaparin in patients with acute coronary syndromes. However, the authors do not fully evaluate the significant difference between patients who received unfractionated heparin after randomization in the enoxaparin group and those who did so in the fondaparinux group (31.2 percent and 22.0 percent, respectively; P<0.001) (Table 1 in the article).
Of the patients who underwent percutaneous coronary intervention (PCI), 55.5 percent of those in the enoxaparin group and 20.8 percent of those in the fondaparinux group received unfractionated heparin. Notably, the rate of major bleeding at nine days among patients undergoing percutaneous coronary intervention was 5.1 percent for patients in the enoxaparin group and 2.3 percent in the fondaparinux group. By comparison, in the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (also known as SYNERGY) trial, among patients receiving enoxaparin, the rate of major bleeding, defined according to Thrombolysis in Myocardial Infarction (TIMI) criteria, that was not related to coronary-artery bypass grafting was 2.4 percent, and according to the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (also known as GUSTO) criteria, the rate of severe bleeding was 2.7 percent.2 Although the authors of the OASIS-5 study give a P value of less than 0.001 for the comparison of rates of bleeding between groups, regardless of the presence or absence of heparin therapy during PCI, a more complete evaluation is needed. Given the significant difference between groups in the number of patients who were treated with unfractionated heparin, the authors should present the relative risk of bleeding in each group stratified according to the use of unfractionated heparin during PCI and provide an interaction term.3
David T. Majure, M.D., M.P.H.
Johns Hopkins School of Medicine
Baltimore, MD 21287
dmajure@jhmi.edu
Scott K. Aberegg, M.D., M.P.H.
Ohio State University College of Medicine and Public Health
Columbus, OH 43210
References
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.
Ferguson JJ, Califf RM, Antman EM, et al. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA 2004;292:45-54.
Lagakos SW. The challenge of subgroup analyses -- reporting without distorting. N Engl J Med 2006;354:1667-1669.
The authors reply: Majure and Aberegg highlight the important finding in our study that patients receiving fondaparinux had a lower rate of bleeding than those receiving enoxaparin, regardless of whether they received unfractionated heparin before randomization. The use of a post-randomization variable for subgroup analyses, such as the subsequent use of unfractionated heparin, as Majure and Aberegg suggest, is hazardous, since the similarity of the patients being compared can no longer be guaranteed. Nevertheless, Table 1 demonstrates that among patients undergoing PCI in the hospital, the rate of severe bleeding (as defined by criteria similar to the TIMI major criteria) was consistently lower with fondaparinux than with enoxaparin in all subgroups, including patients who did not receive unfractionated heparin after randomization, patients for whom unfractionated heparin was intended according to the protocol in the enoxaparin group (as compared with the equivalent patients in the fondaparinux group who received placebo), and patients who received open-label unfractionated heparin in both groups. The findings show that fondaparinux is safer than enoxaparin, regardless of whether unfractionated heparin is administered.
Table 1. Severe Bleeding among Patients Undergoing PCI within the First Nine Days after Randomization.
Salim Yusuf, D.Phil., M.B., B.S.
McMaster University
Hamilton, ON L8L 2X2, Canada
Christopher B. Granger, M.D.
Duke University
Durham, NC 27708
Shamir R. Mehta, M.D.
McMaster University
Hamilton, ON L8L 2X2, Canada
Of the patients who underwent percutaneous coronary intervention (PCI), 55.5 percent of those in the enoxaparin group and 20.8 percent of those in the fondaparinux group received unfractionated heparin. Notably, the rate of major bleeding at nine days among patients undergoing percutaneous coronary intervention was 5.1 percent for patients in the enoxaparin group and 2.3 percent in the fondaparinux group. By comparison, in the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (also known as SYNERGY) trial, among patients receiving enoxaparin, the rate of major bleeding, defined according to Thrombolysis in Myocardial Infarction (TIMI) criteria, that was not related to coronary-artery bypass grafting was 2.4 percent, and according to the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (also known as GUSTO) criteria, the rate of severe bleeding was 2.7 percent.2 Although the authors of the OASIS-5 study give a P value of less than 0.001 for the comparison of rates of bleeding between groups, regardless of the presence or absence of heparin therapy during PCI, a more complete evaluation is needed. Given the significant difference between groups in the number of patients who were treated with unfractionated heparin, the authors should present the relative risk of bleeding in each group stratified according to the use of unfractionated heparin during PCI and provide an interaction term.3
David T. Majure, M.D., M.P.H.
Johns Hopkins School of Medicine
Baltimore, MD 21287
dmajure@jhmi.edu
Scott K. Aberegg, M.D., M.P.H.
Ohio State University College of Medicine and Public Health
Columbus, OH 43210
References
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.
Ferguson JJ, Califf RM, Antman EM, et al. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA 2004;292:45-54.
Lagakos SW. The challenge of subgroup analyses -- reporting without distorting. N Engl J Med 2006;354:1667-1669.
The authors reply: Majure and Aberegg highlight the important finding in our study that patients receiving fondaparinux had a lower rate of bleeding than those receiving enoxaparin, regardless of whether they received unfractionated heparin before randomization. The use of a post-randomization variable for subgroup analyses, such as the subsequent use of unfractionated heparin, as Majure and Aberegg suggest, is hazardous, since the similarity of the patients being compared can no longer be guaranteed. Nevertheless, Table 1 demonstrates that among patients undergoing PCI in the hospital, the rate of severe bleeding (as defined by criteria similar to the TIMI major criteria) was consistently lower with fondaparinux than with enoxaparin in all subgroups, including patients who did not receive unfractionated heparin after randomization, patients for whom unfractionated heparin was intended according to the protocol in the enoxaparin group (as compared with the equivalent patients in the fondaparinux group who received placebo), and patients who received open-label unfractionated heparin in both groups. The findings show that fondaparinux is safer than enoxaparin, regardless of whether unfractionated heparin is administered.
Table 1. Severe Bleeding among Patients Undergoing PCI within the First Nine Days after Randomization.
Salim Yusuf, D.Phil., M.B., B.S.
McMaster University
Hamilton, ON L8L 2X2, Canada
Christopher B. Granger, M.D.
Duke University
Durham, NC 27708
Shamir R. Mehta, M.D.
McMaster University
Hamilton, ON L8L 2X2, Canada