Combining Enoxaparin and Glycoprotein IIb/IIIa Antagonists
Combining Enoxaparin and Glycoprotein IIb/IIIa Antagonists
Background: In high-risk patients with acute coronary syndromes (ACS), there have been concerns relating to the safety of using low molecular weight heparins (LMWH) in combination with a glycoprotein (GP) IIb/IIIa antagonist, and the continued use of LMWH in patients brought to the cardiac catheterization laboratory for percutaneous coronary intervention (PCI).
Methods: The National Investigators Collaborating on Enoxaparin-3 (NICE-3) study was an open-label observational study of enoxaparin in combination with any 1 of 3 available GP IIb/IIIa antagonists in patients presenting with non-ST elevation ACS. The primary end point was the incidence of major bleeding not related to coronary artery bypass graft (CABG) surgery. Data were also recorded on the incidence of death, myocardial infarction (MI), and urgent revascularization for repeat ischemia.
Results: A total of 671 patients with validated data were treated with enoxaparin; 628 of these patients also received a GP IIb/IIIa antagonist (tirofiban, n = 229; eptifibatide, n = 272; abciximab, n = 127); 283 of 628 underwent percutaneous coronary intervention (PCI). The 30-day incidence of non-CABG major bleeding was 1.9%, and was not significantly higher than a prespecified historical control rate of 2.0%. Outcome events included death (1.0% at hospital discharge and 1.6% at 30 days), MI (3.5% and 5.1%, respectively), and urgent revascularization (2.7% and 6.8%, respectively).
Conclusions: The safety of enoxaparin plus a GP IIb/IIIa antagonist was comparable to that of unfractionated heparin plus a GP IIb/IIIa antagonist, as reported in other recent major trials. Patients undergoing PCI can be safely managed with enoxaparin and a GP IIb/IIIa antagonist, without supplemental use of unfractionated heparin.
In a prespecified meta-analysis of the ESSENCE and TIMI-11B trials, 2 large clinical studies comparing the low molecular weight heparin (LMWH) enoxaparin with unfractionated heparin (UFH) in patients with unstable angina (UA) and/or non-Q-wave myocardial infarction (NQWMI), enoxaparin was superior to UFH in reducing the composite incidence of death and nonfatal MI. At 1-year follow-up in the ESSENCE population, the superiority of enoxaparin over UFH was maintained, with significant reductions in both the triple ischemic end point of death/MI/recurrent angina (P = .022) and the need for diagnostic catheterization and coronary revascularization (P = .002). In addition, subcutaneous enoxaparin has been shown to be more cost-effective than intravenous UFH in the management of patients with acute coronary syndromes (ACS).
However, with recent parallel advances in the management of ACS, 2 important issues emerge regarding the use of LMWH in higher-risk patients. First, because higher-risk patients may be more likely to receive GP IIb/IIIa antagonists, questions arise about the safety (primarily with regard to bleeding) of combining LMWH and GP IIb/IIIa antagonists. Second, because higher-risk patients are also more likely to be brought to the catheterization laboratory for possible percutaneous coronary intervention (PCI), there are concerns about the feasibility and safety of using LMWH (which, unlike UFH, is not monitored and adjusted using traditional coagulation tests such as aPTTs and ACTs) for anticoagulation in invasively managed patients.
These concerns prompted implementation of a series of independent observational studies collectively known as the National Investigators Collaborating on Enoxaparin (NICE) studies. The first of these studies, NICE-1 and NICE-4, demonstrated the safety of a single intravenous bolus of enoxaparin, alone (NICE-1) or in combination with the GP IIb/IIIa antagonist abciximab (NICE-4), as procedural anticoagulation for patients undergoing PCI.
These preliminary studies did not, however, address some of the broader issues concerning the use of LMWH in patients with ACS, particularly issues related to bringing patients who are already on LMWH therapy forward to the catheterization laboratory for PCI. The NICE-3 study was designed to examine the safety and efficacy of a strategy involving the combined use of enoxaparin and any 1 of the 3 commercially available GP IIb/IIIa antagonists in patients with ACS, and to determine the feasibility and safety of bringing patients who had already received subcutaneous enoxaparin to the catheterization laboratory for coronary intervention, if necessary, without the supplemental use of UFH.
Background: In high-risk patients with acute coronary syndromes (ACS), there have been concerns relating to the safety of using low molecular weight heparins (LMWH) in combination with a glycoprotein (GP) IIb/IIIa antagonist, and the continued use of LMWH in patients brought to the cardiac catheterization laboratory for percutaneous coronary intervention (PCI).
Methods: The National Investigators Collaborating on Enoxaparin-3 (NICE-3) study was an open-label observational study of enoxaparin in combination with any 1 of 3 available GP IIb/IIIa antagonists in patients presenting with non-ST elevation ACS. The primary end point was the incidence of major bleeding not related to coronary artery bypass graft (CABG) surgery. Data were also recorded on the incidence of death, myocardial infarction (MI), and urgent revascularization for repeat ischemia.
Results: A total of 671 patients with validated data were treated with enoxaparin; 628 of these patients also received a GP IIb/IIIa antagonist (tirofiban, n = 229; eptifibatide, n = 272; abciximab, n = 127); 283 of 628 underwent percutaneous coronary intervention (PCI). The 30-day incidence of non-CABG major bleeding was 1.9%, and was not significantly higher than a prespecified historical control rate of 2.0%. Outcome events included death (1.0% at hospital discharge and 1.6% at 30 days), MI (3.5% and 5.1%, respectively), and urgent revascularization (2.7% and 6.8%, respectively).
Conclusions: The safety of enoxaparin plus a GP IIb/IIIa antagonist was comparable to that of unfractionated heparin plus a GP IIb/IIIa antagonist, as reported in other recent major trials. Patients undergoing PCI can be safely managed with enoxaparin and a GP IIb/IIIa antagonist, without supplemental use of unfractionated heparin.
In a prespecified meta-analysis of the ESSENCE and TIMI-11B trials, 2 large clinical studies comparing the low molecular weight heparin (LMWH) enoxaparin with unfractionated heparin (UFH) in patients with unstable angina (UA) and/or non-Q-wave myocardial infarction (NQWMI), enoxaparin was superior to UFH in reducing the composite incidence of death and nonfatal MI. At 1-year follow-up in the ESSENCE population, the superiority of enoxaparin over UFH was maintained, with significant reductions in both the triple ischemic end point of death/MI/recurrent angina (P = .022) and the need for diagnostic catheterization and coronary revascularization (P = .002). In addition, subcutaneous enoxaparin has been shown to be more cost-effective than intravenous UFH in the management of patients with acute coronary syndromes (ACS).
However, with recent parallel advances in the management of ACS, 2 important issues emerge regarding the use of LMWH in higher-risk patients. First, because higher-risk patients may be more likely to receive GP IIb/IIIa antagonists, questions arise about the safety (primarily with regard to bleeding) of combining LMWH and GP IIb/IIIa antagonists. Second, because higher-risk patients are also more likely to be brought to the catheterization laboratory for possible percutaneous coronary intervention (PCI), there are concerns about the feasibility and safety of using LMWH (which, unlike UFH, is not monitored and adjusted using traditional coagulation tests such as aPTTs and ACTs) for anticoagulation in invasively managed patients.
These concerns prompted implementation of a series of independent observational studies collectively known as the National Investigators Collaborating on Enoxaparin (NICE) studies. The first of these studies, NICE-1 and NICE-4, demonstrated the safety of a single intravenous bolus of enoxaparin, alone (NICE-1) or in combination with the GP IIb/IIIa antagonist abciximab (NICE-4), as procedural anticoagulation for patients undergoing PCI.
These preliminary studies did not, however, address some of the broader issues concerning the use of LMWH in patients with ACS, particularly issues related to bringing patients who are already on LMWH therapy forward to the catheterization laboratory for PCI. The NICE-3 study was designed to examine the safety and efficacy of a strategy involving the combined use of enoxaparin and any 1 of the 3 commercially available GP IIb/IIIa antagonists in patients with ACS, and to determine the feasibility and safety of bringing patients who had already received subcutaneous enoxaparin to the catheterization laboratory for coronary intervention, if necessary, without the supplemental use of UFH.
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