Bivalirudin
Bivalirudin
The treatment of patients with acute coronary syndromes has changed dramatically over the last several years. Most patients now undergo some form of percutaneous coronary intervention (PCI), which includes either stent placement or percutaneous transluminal coronary angioplasty (PTCA). Along with new medical interventions for acute coronary syndromes comes the need for new antithrombotic therapies. Combination therapy with antiplatelet agents (aspirin, adenosine diphosphate inhibitors), glycoprotein (GP) IIb-IIIa receptor inhibitors, and anticoagulants (unfractionated heparin or low-molecular-weight heparins) is administered, depending on the type of intervention and severity of the coronary lesion. Bivalirudin is a direct thrombin inhibitor that recently was approved as an alternative to heparin in patients undergoing PTCA. Compared with unfractionated heparin, bivalirudin reduces the rate of death, myocardial infarction, or revascularization, with a concurrent reduction in bleeding. This agent offers promise as a replacement for unfractionated heparin in PCI and is being studied in comparison with unfractionated heparin plus GP IIb-IIIa receptor inhibitors in patients undergoing intracoronary stent placement.
Coronary artery disease affects more than 7 million Americans and accounts for more than 500,000 deaths/year in the United States. Acute coronary syndromes resulting from narrowing or occlusion of a coronary artery include unstable angina, non-ST segment elevation myocardial infarction, and ST segment elevation myocardial infarction. In 1996, unstable angina and non-ST segment elevation myocardial infarction accounted for 1.43 million hospitalizations and ST segment elevation myocardial infarction for 350,000 hospitalizations in the United States. Medical costs associated with managing coronary artery disease are approximately $12,000/patient, or $16 billion/year. These amounts include the cost of percutaneous coronary intervention (PCI), a group of procedures aimed at mechanically improving flow in the affected coronary vessel.
More than 500,000 PCI procedures are performed annually in the United States, greater than 70% of which involve the use of intra-coronary stents. Administration of antithrombotic therapy in the setting of PCI significantly reduces the likelihood of rethrombosis of the culprit coronary artery and/or myocardial infarction. Effective antithrombotic therapy is essential to ensure successful PCI outcomes. The recommended combination of agents includes an oral antiplatelet agent (aspirin in combination with clopidogrel or ticlopidine), a glycoprotein (GP) IIb-IIIa receptor antagonist (abciximab, tirofiban, or eptifibatide), and a systemic anticoagulant (unfractionated heparin or a low-molecular-weight heparin [LMWH]).
Unfractionated heparin has several noteworthy limitations. In addition to binding to anti-thrombin to accelerate its action against factors IIa and Xa, unfractionated heparin binds to plasma proteins, macrophages, and endothelial cells. In addition, the effect of unfractionated heparin is reduced by the presence of platelet factor 4 (heparin cofactor), an acute phase reactant released from activated platelets that is elevated in acute coronary syndromes. These limitations alter its bioavailability and result in a nonlinear pharmacokinetic profile. Dose response is variable and inconsistent, requiring frequent laboratory monitoring of the activated partial thromboplastin time (aPTT) to ensure a therapeutic effect. Although unfractionated heparin is monitored routinely with aPTT, in the setting of PCI, the activated clotting time (ACT) typically is used. The ACT is a point-of-care assay that is used to ensure effective heparin therapy. During PCI, unfractionated heparin is administered by intravenous bolus, and administration is repeated as needed to maintain the ACT at an appropriate level. Finally, unfractionated heparin is associated with a 2-5% frequency of type II heparin-induced thrombocytopenia (HIT), an immune-mediated reaction that leads to platelet aggregation and results in high rates of thrombosis, amputation, and death.
The LMWHs have overcome many of the shortcomings of unfractionated heparin. Like unfractionated heparin, LMWHs induce an anticoagulant effect by accelerating the action of antithrombin against factors IIa and Xa. However, the antifactor Xa:antifactor IIa ratio is much larger for LMWHs than for unfractionated heparin. The LMWHs also offer an improved and more consistent dose response and better bioavailability. They can be dosed subcutaneously once/day or twice/day based on total body weight and do not require routine laboratory monitoring to ensure an appropriate antithrombotic effect. Like unfractionated heparin, LMWHs can cause type II HIT, but in a lower percentage of patients (1-2%). However, LMWHs are contraindicated in patients with HIT because of a high rate of cross-reactivity.
Although unfractionated heparin has been the primary systemic anticoagulant in PCI, enoxaparin has been of interest because of its numerous practical advantages. In a recent registry of patients undergoing elective PCI, 88% of whom received intracoronary stents and all of whom were treated with abciximab and enoxaparin, rates of death, myocardial infarction, and revascularization were similar to those rates seen in other randomized trials of abciximab with unfractionated heparin, as were major bleeding rates. In the setting of unstable angina and non-ST segment elevation myocardial infarction, enoxaparin is more effective than unfractionated heparin in preventing death, myocardial infarction, and revascularization, with a similar risk of major hemorrhage.
Bivalirudin (Angiomax; The Medicines Company, Cambridge, MA) is a direct thrombin inhibitor that recently was approved by the U.S. Food and Drug Administration (FDA) as an alternative to unfractionated heparin in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). Compared with unfractionated heparin, bivalirudin reduces the combined frequency of death, myocardial infarction, or revascularization at 90 days and 6 months, with a significantly lower risk of major hemorrhage. Although its role in contemporary coronary intervention is not yet clearly defined, its potential advantages over unfractionated heparin are intriguing.
The treatment of patients with acute coronary syndromes has changed dramatically over the last several years. Most patients now undergo some form of percutaneous coronary intervention (PCI), which includes either stent placement or percutaneous transluminal coronary angioplasty (PTCA). Along with new medical interventions for acute coronary syndromes comes the need for new antithrombotic therapies. Combination therapy with antiplatelet agents (aspirin, adenosine diphosphate inhibitors), glycoprotein (GP) IIb-IIIa receptor inhibitors, and anticoagulants (unfractionated heparin or low-molecular-weight heparins) is administered, depending on the type of intervention and severity of the coronary lesion. Bivalirudin is a direct thrombin inhibitor that recently was approved as an alternative to heparin in patients undergoing PTCA. Compared with unfractionated heparin, bivalirudin reduces the rate of death, myocardial infarction, or revascularization, with a concurrent reduction in bleeding. This agent offers promise as a replacement for unfractionated heparin in PCI and is being studied in comparison with unfractionated heparin plus GP IIb-IIIa receptor inhibitors in patients undergoing intracoronary stent placement.
Coronary artery disease affects more than 7 million Americans and accounts for more than 500,000 deaths/year in the United States. Acute coronary syndromes resulting from narrowing or occlusion of a coronary artery include unstable angina, non-ST segment elevation myocardial infarction, and ST segment elevation myocardial infarction. In 1996, unstable angina and non-ST segment elevation myocardial infarction accounted for 1.43 million hospitalizations and ST segment elevation myocardial infarction for 350,000 hospitalizations in the United States. Medical costs associated with managing coronary artery disease are approximately $12,000/patient, or $16 billion/year. These amounts include the cost of percutaneous coronary intervention (PCI), a group of procedures aimed at mechanically improving flow in the affected coronary vessel.
More than 500,000 PCI procedures are performed annually in the United States, greater than 70% of which involve the use of intra-coronary stents. Administration of antithrombotic therapy in the setting of PCI significantly reduces the likelihood of rethrombosis of the culprit coronary artery and/or myocardial infarction. Effective antithrombotic therapy is essential to ensure successful PCI outcomes. The recommended combination of agents includes an oral antiplatelet agent (aspirin in combination with clopidogrel or ticlopidine), a glycoprotein (GP) IIb-IIIa receptor antagonist (abciximab, tirofiban, or eptifibatide), and a systemic anticoagulant (unfractionated heparin or a low-molecular-weight heparin [LMWH]).
Unfractionated heparin has several noteworthy limitations. In addition to binding to anti-thrombin to accelerate its action against factors IIa and Xa, unfractionated heparin binds to plasma proteins, macrophages, and endothelial cells. In addition, the effect of unfractionated heparin is reduced by the presence of platelet factor 4 (heparin cofactor), an acute phase reactant released from activated platelets that is elevated in acute coronary syndromes. These limitations alter its bioavailability and result in a nonlinear pharmacokinetic profile. Dose response is variable and inconsistent, requiring frequent laboratory monitoring of the activated partial thromboplastin time (aPTT) to ensure a therapeutic effect. Although unfractionated heparin is monitored routinely with aPTT, in the setting of PCI, the activated clotting time (ACT) typically is used. The ACT is a point-of-care assay that is used to ensure effective heparin therapy. During PCI, unfractionated heparin is administered by intravenous bolus, and administration is repeated as needed to maintain the ACT at an appropriate level. Finally, unfractionated heparin is associated with a 2-5% frequency of type II heparin-induced thrombocytopenia (HIT), an immune-mediated reaction that leads to platelet aggregation and results in high rates of thrombosis, amputation, and death.
The LMWHs have overcome many of the shortcomings of unfractionated heparin. Like unfractionated heparin, LMWHs induce an anticoagulant effect by accelerating the action of antithrombin against factors IIa and Xa. However, the antifactor Xa:antifactor IIa ratio is much larger for LMWHs than for unfractionated heparin. The LMWHs also offer an improved and more consistent dose response and better bioavailability. They can be dosed subcutaneously once/day or twice/day based on total body weight and do not require routine laboratory monitoring to ensure an appropriate antithrombotic effect. Like unfractionated heparin, LMWHs can cause type II HIT, but in a lower percentage of patients (1-2%). However, LMWHs are contraindicated in patients with HIT because of a high rate of cross-reactivity.
Although unfractionated heparin has been the primary systemic anticoagulant in PCI, enoxaparin has been of interest because of its numerous practical advantages. In a recent registry of patients undergoing elective PCI, 88% of whom received intracoronary stents and all of whom were treated with abciximab and enoxaparin, rates of death, myocardial infarction, and revascularization were similar to those rates seen in other randomized trials of abciximab with unfractionated heparin, as were major bleeding rates. In the setting of unstable angina and non-ST segment elevation myocardial infarction, enoxaparin is more effective than unfractionated heparin in preventing death, myocardial infarction, and revascularization, with a similar risk of major hemorrhage.
Bivalirudin (Angiomax; The Medicines Company, Cambridge, MA) is a direct thrombin inhibitor that recently was approved by the U.S. Food and Drug Administration (FDA) as an alternative to unfractionated heparin in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). Compared with unfractionated heparin, bivalirudin reduces the combined frequency of death, myocardial infarction, or revascularization at 90 days and 6 months, with a significantly lower risk of major hemorrhage. Although its role in contemporary coronary intervention is not yet clearly defined, its potential advantages over unfractionated heparin are intriguing.
