Bivalirudin in Percutaneous Coronary Intervention
Bivalirudin in Percutaneous Coronary Intervention
The chemistry and pharmacology, pharmacokinetics, pharmacodynamics, adverse effects, drug interactions, dosing and administration, and pharmacoeconomics of bivalirudin are reviewed; clinical trials of bivalirudin s application in percutaneous coronary intervention (PCI) are also discussed.
Bivalirudin is a direct thrombin inhibitor approved for use in PCI. It reversibly binds to thrombin s catalytic site and substrate recognition site and blocks both circulating and fibrin-bound thrombin. Peak concentrations occur in less than 5 minutes after bolus-dose administration, and its half-life is approximately 25 minutes. It is primarily eliminated renally, and dosage reduction may be required in patients with severe renal dysfunction. Two clinical trials have demonstrated that bivalirudin is at least as effective as unfractionated heparin (UFH) in preventing ischemic complications in PCI. Other trials have shown that bivalirudin has beneficial ischemic and hemorrhagic outcomes in a more modern PCI setting (i.e., intracoronary stent placement, clopidogrel, and glycoprotein IIb/IIIa-receptor inhibitors). Bivalirudin combined with provisional glycoprotein IIb/IIIa inhibitors was noninferior to UFH with planned glycoprotein IIb/ IIIa inhibitors and superior to UFH alone with respect to ischemic and hemorrhagic endpoints in PCI. Major bleeding with bivalirudin has occurred in approximately 3% of patients in clinical trials, and it is not known to have any interactions with the cyto-chrome P-450 isoenzyme system. The acquisition cost of bivalirudin in one study was less than the combination of UFH and glycoprotein IIb/IIIa inhibitors.
Bivalirudin combined with provisional glycoprotein IIb/IIIa inhibitors appears to be an acceptable alternative to the standard of care and is superior to UFH alone in PCI.
In medical centers with established cardiac catheterization laboratories, percutaneous coronary intervention (PCI), including percutaneous coronary angioplasty with or without intracoronary stent placement, is a safe and effective treatment for patients with acute coronary syndrome (ACS). In the United States PCI procedures and patients increased 262% and 260% from 1987 to 2000, respectively. A recent meta-analysis comparing PCI with thrombolysis in patients with ST-segment elevation myocardial infarction (STEMI) showed that PCI may be superior for preventing combined adverse outcomes over both the short (4-6 weeks) and long (6-18 months) terms. Also, there is growing evidence that transferring a patient to a tertiary care center for PCI is a reasonable alternative to on-site thrombolysis for STEMI patients at small community hospitals.
Recent investigation has more clearly defined the importance of thrombin in the clotting cascade. Thrombin has several mechanisms that influence clot formation, which ultimately leads to complications related to ACS. Thrombin's actions include (1) cleaving fibrinogen to form fibrin, an important component of blood clots, (2) increasing coagulation factor XIII, which increases fibrin strand cross-linking, a process that enhances the integrity of the fibrin clot, (3) increasing the levels of coagulation factors V and VIII, which promote thrombin's own formation, and (4) stimulating platelet activation and aggregation. Therefore, thrombin inhibition is an important treatment for patients with ACS, regardless of whether PCI is used.
Antithrombotic drug strategies used in the PCI setting include traditional indirect thrombin inhibitors (unfractionated heparin [UFH], low-molecular-weight heparins [LMWHs]) and, most recently, direct thrombin inhibitors. It is important to note that other drug therapies used in PCI include antiplatelet agents such as aspirin, clopidogrel, and glycoprotein IIb/IIIa-receptor inhibitors. Because of the limitations of indirect thrombin inhibitors (e.g., the potential for varied anticoagulant response and resistance to fibrin-bound thrombin and platelet-bound factor Xa), newer pharmacologic strategies are being investigated to minimize thrombosis and the risk of bleeding in the expanding PCI arena.
Bivalirudin (Angiomax, The Medicines Company), which received Food and Drug Administration (FDA)-approved labeling in December 2000 for use in patients with un-stable angina (UA) undergoing PCI, has been the most extensively studied direct thrombin inhibitor for this indication. Studies have demonstrated greater reductions in ischemic outcomes with bivalirudin than UFH and corresponding significant reductions in bleeding complications. However, most of the clinical data supporting bivalirudin in PCI were not in a contemporary setting (e.g., did not include intracoro-nary stent placement, aspirin, clopidogrel, and glycoprotein IIb/IIIa inhibitors), until the recently reported Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 data showed bivalirudin to be noninferior to the combination of UFH and glycoprotein IIb/IIIa inhibitors and superior to UFH in preventing the complications associated with PCI.
This article summarizes bivalirudin's chemistry and pharmacology, pharmacokinetics, pharmacodynamics, clinical trials, adverse effects, drug interactions, dosing and administration, and pharmacoeconomics. This review focuses on bivalirudin's application in PCI and briefly discusses its use in non-STEMI and STEMI.
The chemistry and pharmacology, pharmacokinetics, pharmacodynamics, adverse effects, drug interactions, dosing and administration, and pharmacoeconomics of bivalirudin are reviewed; clinical trials of bivalirudin s application in percutaneous coronary intervention (PCI) are also discussed.
Bivalirudin is a direct thrombin inhibitor approved for use in PCI. It reversibly binds to thrombin s catalytic site and substrate recognition site and blocks both circulating and fibrin-bound thrombin. Peak concentrations occur in less than 5 minutes after bolus-dose administration, and its half-life is approximately 25 minutes. It is primarily eliminated renally, and dosage reduction may be required in patients with severe renal dysfunction. Two clinical trials have demonstrated that bivalirudin is at least as effective as unfractionated heparin (UFH) in preventing ischemic complications in PCI. Other trials have shown that bivalirudin has beneficial ischemic and hemorrhagic outcomes in a more modern PCI setting (i.e., intracoronary stent placement, clopidogrel, and glycoprotein IIb/IIIa-receptor inhibitors). Bivalirudin combined with provisional glycoprotein IIb/IIIa inhibitors was noninferior to UFH with planned glycoprotein IIb/ IIIa inhibitors and superior to UFH alone with respect to ischemic and hemorrhagic endpoints in PCI. Major bleeding with bivalirudin has occurred in approximately 3% of patients in clinical trials, and it is not known to have any interactions with the cyto-chrome P-450 isoenzyme system. The acquisition cost of bivalirudin in one study was less than the combination of UFH and glycoprotein IIb/IIIa inhibitors.
Bivalirudin combined with provisional glycoprotein IIb/IIIa inhibitors appears to be an acceptable alternative to the standard of care and is superior to UFH alone in PCI.
In medical centers with established cardiac catheterization laboratories, percutaneous coronary intervention (PCI), including percutaneous coronary angioplasty with or without intracoronary stent placement, is a safe and effective treatment for patients with acute coronary syndrome (ACS). In the United States PCI procedures and patients increased 262% and 260% from 1987 to 2000, respectively. A recent meta-analysis comparing PCI with thrombolysis in patients with ST-segment elevation myocardial infarction (STEMI) showed that PCI may be superior for preventing combined adverse outcomes over both the short (4-6 weeks) and long (6-18 months) terms. Also, there is growing evidence that transferring a patient to a tertiary care center for PCI is a reasonable alternative to on-site thrombolysis for STEMI patients at small community hospitals.
Recent investigation has more clearly defined the importance of thrombin in the clotting cascade. Thrombin has several mechanisms that influence clot formation, which ultimately leads to complications related to ACS. Thrombin's actions include (1) cleaving fibrinogen to form fibrin, an important component of blood clots, (2) increasing coagulation factor XIII, which increases fibrin strand cross-linking, a process that enhances the integrity of the fibrin clot, (3) increasing the levels of coagulation factors V and VIII, which promote thrombin's own formation, and (4) stimulating platelet activation and aggregation. Therefore, thrombin inhibition is an important treatment for patients with ACS, regardless of whether PCI is used.
Antithrombotic drug strategies used in the PCI setting include traditional indirect thrombin inhibitors (unfractionated heparin [UFH], low-molecular-weight heparins [LMWHs]) and, most recently, direct thrombin inhibitors. It is important to note that other drug therapies used in PCI include antiplatelet agents such as aspirin, clopidogrel, and glycoprotein IIb/IIIa-receptor inhibitors. Because of the limitations of indirect thrombin inhibitors (e.g., the potential for varied anticoagulant response and resistance to fibrin-bound thrombin and platelet-bound factor Xa), newer pharmacologic strategies are being investigated to minimize thrombosis and the risk of bleeding in the expanding PCI arena.
Bivalirudin (Angiomax, The Medicines Company), which received Food and Drug Administration (FDA)-approved labeling in December 2000 for use in patients with un-stable angina (UA) undergoing PCI, has been the most extensively studied direct thrombin inhibitor for this indication. Studies have demonstrated greater reductions in ischemic outcomes with bivalirudin than UFH and corresponding significant reductions in bleeding complications. However, most of the clinical data supporting bivalirudin in PCI were not in a contemporary setting (e.g., did not include intracoro-nary stent placement, aspirin, clopidogrel, and glycoprotein IIb/IIIa inhibitors), until the recently reported Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 data showed bivalirudin to be noninferior to the combination of UFH and glycoprotein IIb/IIIa inhibitors and superior to UFH in preventing the complications associated with PCI.
This article summarizes bivalirudin's chemistry and pharmacology, pharmacokinetics, pharmacodynamics, clinical trials, adverse effects, drug interactions, dosing and administration, and pharmacoeconomics. This review focuses on bivalirudin's application in PCI and briefly discusses its use in non-STEMI and STEMI.
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