The Anticoagulant Therapy With Bivalirudin to Assist in the
The Anticoagulant Therapy With Bivalirudin to Assist in the
Up to 5% of patients given heparin develop heparin-induced thrombocytopenia (HIT). These patients may need anticoagulation for acute coronary syndromes (ACS) or percutaneous coronary intervention (PCI), a clinical challenge given the limited alternatives. In a prospective, open-label study, we evaluated the safety and efficacy of bivalirudin in patients with HIT or HIT with thrombotic syndrome (HITTS) undergoing PCI. Patients aged ≥ 18 years were enrolled in 24 centers in 2 countries. Bivalirudin was given ≥ 5 minutes before PCI (1 mg/kg bolus; 2.5 mg/kg/hour infusion for 4 hours [high-dose group] or 0.75 mg/kg bolus; 1.75 mg/kg/hour infusion [low-dose group]). Clinical and hematological measures were assessed within 24 hours after starting bivalirudin, just before PCI, just before sheath removal, and 48 hours after treatment or at discharge, whichever occurred first. The primary endpoint was major bleeding 48 hours after discontinuation or until discharge, whichever occurred first. From July 1999 to February 2003, 52 patients were recruited. Procedural success (TIMI grade 3 flow and < 50% stenosis) was achieved in 98% of patients, and clinical success (absence of death, emergency bypass surgery, or Q-wave infarction) was achieved in 96%. One high-dose patient who underwent elective bypass surgery had major bleeding (1.9%; 95% CI: 0.05-10.65%), and 7 patients had minor bleeding. No patient had significant thrombocytopenia (platelet count < 50x10/L) after treatment. One patient in the low-dose group died from cardiac arrest ~46 hours after uncomplicated PCI. Bivalirudin appeared safe and provided effective anticoagulation during PCI. These data, and extensive experience with bivalirudin in PCI, support its use in high-risk patients with HIT requiring PCI.
Heparin-induced thrombocytopenia (HIT) is infrequent and often goes unrecognized. It occurs in ~1% to 5% of the patients given unfractionated heparin, about 25-50% of whom will develop HIT with thrombotic syndrome (HITTS). Morbidity and mortality are high, and more than 50% of patients suffering thrombotic complications will die. Patients with recognized HIT may require anticoagulation for acute coronary syndromes (ACS) or percutaneous coronary intervention (PCI), thus presenting a clinical challenge given the limited alternatives for anticoagulation treatment.
The direct thrombin inhibitors provide an attractive alternative for anticoagulation in the settings of ACS and PCI. These agents inhibit thrombin directly, acting to prevent thrombin activation and generation. Bivalirudin, a direct thrombin inhibitor, is a synthetic, 20-amino-acid polypeptide that interacts with both the active site and exosite 1 on thrombin. Once bound to thrombin, the bivalirudin molecule is slowly cleaved by thrombin with consequent recovery of function of the thrombin active site, but competitive inhibition with low-affinity binding to the exosite 1 remains.4 Therefore, bivalirudin has several advantages over heparin, including high specificity and potency for thrombin inhibition, independence from antithrombin for activity, inhibition of both free and clot-bound thrombin, lack of platelet activation, and no association with immune-mediated thrombocytopenia and thrombosis or cross-reactivity with HIT antibodies.
Direct thrombin inhibitors have been studied extensively in non-ST segment elevation ACS, acute ST segment elevation myocardial infarction (MI), and during PCI. While no study has shown superiority of direct thrombin inhibitors in ACS, a systematic overview of trials comparing direct thrombin inhibitors with heparin in ACS showed the superiority of direct thrombin inhibitors in reducing the composite of death or MI, particularly with the bivalent inhibitors (hirudin and bivalirudin) versus univalent inhibitors (argatroban, efegatran, and inogatran). A second systematic overview and a recent trial in contemporary PCI support these finding. The Anticoagulant Therapy with Bivalirudin to Assist in the performance of PCI in patients with heparin-induced Thrombocytopenia (ATBAT) trial was designed to evaluate the safety and efficacy of direct thrombin inhibition with bivalirudin during PCI in patients with HIT or HITTS.
Up to 5% of patients given heparin develop heparin-induced thrombocytopenia (HIT). These patients may need anticoagulation for acute coronary syndromes (ACS) or percutaneous coronary intervention (PCI), a clinical challenge given the limited alternatives. In a prospective, open-label study, we evaluated the safety and efficacy of bivalirudin in patients with HIT or HIT with thrombotic syndrome (HITTS) undergoing PCI. Patients aged ≥ 18 years were enrolled in 24 centers in 2 countries. Bivalirudin was given ≥ 5 minutes before PCI (1 mg/kg bolus; 2.5 mg/kg/hour infusion for 4 hours [high-dose group] or 0.75 mg/kg bolus; 1.75 mg/kg/hour infusion [low-dose group]). Clinical and hematological measures were assessed within 24 hours after starting bivalirudin, just before PCI, just before sheath removal, and 48 hours after treatment or at discharge, whichever occurred first. The primary endpoint was major bleeding 48 hours after discontinuation or until discharge, whichever occurred first. From July 1999 to February 2003, 52 patients were recruited. Procedural success (TIMI grade 3 flow and < 50% stenosis) was achieved in 98% of patients, and clinical success (absence of death, emergency bypass surgery, or Q-wave infarction) was achieved in 96%. One high-dose patient who underwent elective bypass surgery had major bleeding (1.9%; 95% CI: 0.05-10.65%), and 7 patients had minor bleeding. No patient had significant thrombocytopenia (platelet count < 50x10/L) after treatment. One patient in the low-dose group died from cardiac arrest ~46 hours after uncomplicated PCI. Bivalirudin appeared safe and provided effective anticoagulation during PCI. These data, and extensive experience with bivalirudin in PCI, support its use in high-risk patients with HIT requiring PCI.
Heparin-induced thrombocytopenia (HIT) is infrequent and often goes unrecognized. It occurs in ~1% to 5% of the patients given unfractionated heparin, about 25-50% of whom will develop HIT with thrombotic syndrome (HITTS). Morbidity and mortality are high, and more than 50% of patients suffering thrombotic complications will die. Patients with recognized HIT may require anticoagulation for acute coronary syndromes (ACS) or percutaneous coronary intervention (PCI), thus presenting a clinical challenge given the limited alternatives for anticoagulation treatment.
The direct thrombin inhibitors provide an attractive alternative for anticoagulation in the settings of ACS and PCI. These agents inhibit thrombin directly, acting to prevent thrombin activation and generation. Bivalirudin, a direct thrombin inhibitor, is a synthetic, 20-amino-acid polypeptide that interacts with both the active site and exosite 1 on thrombin. Once bound to thrombin, the bivalirudin molecule is slowly cleaved by thrombin with consequent recovery of function of the thrombin active site, but competitive inhibition with low-affinity binding to the exosite 1 remains.4 Therefore, bivalirudin has several advantages over heparin, including high specificity and potency for thrombin inhibition, independence from antithrombin for activity, inhibition of both free and clot-bound thrombin, lack of platelet activation, and no association with immune-mediated thrombocytopenia and thrombosis or cross-reactivity with HIT antibodies.
Direct thrombin inhibitors have been studied extensively in non-ST segment elevation ACS, acute ST segment elevation myocardial infarction (MI), and during PCI. While no study has shown superiority of direct thrombin inhibitors in ACS, a systematic overview of trials comparing direct thrombin inhibitors with heparin in ACS showed the superiority of direct thrombin inhibitors in reducing the composite of death or MI, particularly with the bivalent inhibitors (hirudin and bivalirudin) versus univalent inhibitors (argatroban, efegatran, and inogatran). A second systematic overview and a recent trial in contemporary PCI support these finding. The Anticoagulant Therapy with Bivalirudin to Assist in the performance of PCI in patients with heparin-induced Thrombocytopenia (ATBAT) trial was designed to evaluate the safety and efficacy of direct thrombin inhibition with bivalirudin during PCI in patients with HIT or HITTS.
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