Weight-Based Argatroban Dosing Nomogram for Treatment of Heparin-Induced Thrombocytopenia
Weight-Based Argatroban Dosing Nomogram for Treatment of Heparin-Induced Thrombocytopenia
Background: Manufacturer recommendations for argatroban use in the setting of heparin-induced thrombocytopenia (HIT) state that the dosage should be titrated to a goal activated partial thromboplastin time (aPTT) of 1.5-3 times the baseline aPTT. The lack of a clear dosing strategy with argatroban may result in delayed stabilization of aPTT. There are no published nomograms to guide the dosing of argatroban.
Objective: To study the anticoagulant effect and incidence of bleeding and thrombotic events in patients receiving argatroban, with doses determined using a weight-based nomogram.
Methods: Patients with suspected or documented HIT at an 800-bed teaching community hospital were prospectively treated, in a nonrandomized, nonblinded manner, with argatroban; dosage adjustments were made according to 1 of 2 variations of a dosing nomogram: standard or hepatic/critically ill. The primary outcomes were time to aPTT stabilization and percentage of patients whose aPTTs were within the therapeutic range of 45-90 seconds at 6, 12, 24, 48, 72, and 96 hours. Secondary outcomes were the percentage of patients whose aPTTs were subtherapeutic, supratherapeutic, or above the therapeutic threshold of 45 seconds at each time interval; incidence of thrombotic events; number of dosage adjustments to achieve stabilization; and number of major bleeding events.
Results: Fifty-one patients were prospectively treated using the standard (n = 34) and hepatic/critically ill (n = 17) nomograms. Mean time to aPTT stabilization was 16.25 hours with the standard nomogram and 27.05 hours with the hepatic/critically ill nomogram. The percentages of patients with aPTTs within the therapeutic range at each time interval were 82.4%, 82.4%, 88.2%, 96.4%, 100%, and 100% with the standard nomogram and 58.8%, 82.4%, 76.5%, 93.3%, 100%, and 90.9% with the hepatic/critically ill nomogram. There were no thrombotic events after the initiation of argatroban. Three cases of major bleeding occurred.
Conclusions: The nomogram is an effective dosing tool for achieving and maintaining therapeutic levels of anticoagulation.
Heparin-induced thrombocytopenia (HIT) is an antibody-mediated syndrome that occurs in 1-5% of patients treated with unfractionated heparin. Although they are less likely to cause HIT than is unfractionated heparin, low-molecular-weight heparins (LMWHs) also pose a risk for the development of heparin antibodies. HIT results from binding of antibodies (most commonly immunoglobulin G) to a complex of heparin molecules and platelet factor 4. These antibodies promote the activation of platelets and subsequent release of platelet-derived microparticles that are prothrombotic. The particles in turn promote the generation of thrombin and a subsequent hypercoagulable state.
Although HIT can present as an isolated thrombocytopenia, it may be associated with the development of thrombotic events known as heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). While HITTS commonly manifests as venous thromboemboli (VTE), arterial thrombosis resulting in myocardial infarction and ischemic limb damage may occur. Early discontinuation of heparin and initiation of an alternative anticoagulant are necessary for prevention and treatment of HIT and HITTS; however, up to 50% of patients may experience a thrombotic event if untreated after heparin is discontinued. Mortality rates as high as 10-30% are associated with HITTS. Considering these serious sequelae, full-dose anticoagulation must be initiated upon heparin discontinuation. Various drugs, including danaparoid, lepirudin, ancrod, warfarin, fondaparinux, and LMWHs have been evaluated for the treatment of HIT. Each has limitations when used in patients with HIT.
The American College of Chest Physicians recommends danaparoid (grade 1B), lepirudin (grade 1C), argatroban (grade 1C), bivalirudin (grade 2C), or fondaparinux (grade 2C) for patients with strongly suspected or confirmed HIT. Lepirudin, argatroban, and bivalirudin have demonstrated efficacy in reducing thrombotic events associated with HIT and can be used as bridge therapy during transition to oral warfarin therapy. Lepirudin and argatroban have Food and Drug Administration (FDA)-approved indications as alternative anticoagulants in patients with HIT, while bivalirudin is FDA-approved for the treatment of HIT in the setting of percutaneous coronary intervention.
While consensus treatment guidelines recommend the initiation of lepirudin or argatroban when HIT or HITTS is strongly suspected, appropriate dosing adjustments for argatroban have not been substantiated. The FDA-approved dosing for argatroban is 2 µg/kg/min (0.5 µg/kg/min in patients with hepatic impairment), titrated to a target aPTT of 1.5-3 times the baseline level. The rapid achievement of therapeutic anticoagulation levels is crucial, as several studies have demonstrated that suboptimal anticoagulation in the first 48 hours after acute thrombosis is associated with an increased risk of recurrent VTE. The lack of a dosing strategy with argatroban may result in delayed stabilization of therapeutic aPTT levels. To date, there has been no published nomogram to guide the dosing and management of argatroban.
Abstract and Introduction
Abstract
Background: Manufacturer recommendations for argatroban use in the setting of heparin-induced thrombocytopenia (HIT) state that the dosage should be titrated to a goal activated partial thromboplastin time (aPTT) of 1.5-3 times the baseline aPTT. The lack of a clear dosing strategy with argatroban may result in delayed stabilization of aPTT. There are no published nomograms to guide the dosing of argatroban.
Objective: To study the anticoagulant effect and incidence of bleeding and thrombotic events in patients receiving argatroban, with doses determined using a weight-based nomogram.
Methods: Patients with suspected or documented HIT at an 800-bed teaching community hospital were prospectively treated, in a nonrandomized, nonblinded manner, with argatroban; dosage adjustments were made according to 1 of 2 variations of a dosing nomogram: standard or hepatic/critically ill. The primary outcomes were time to aPTT stabilization and percentage of patients whose aPTTs were within the therapeutic range of 45-90 seconds at 6, 12, 24, 48, 72, and 96 hours. Secondary outcomes were the percentage of patients whose aPTTs were subtherapeutic, supratherapeutic, or above the therapeutic threshold of 45 seconds at each time interval; incidence of thrombotic events; number of dosage adjustments to achieve stabilization; and number of major bleeding events.
Results: Fifty-one patients were prospectively treated using the standard (n = 34) and hepatic/critically ill (n = 17) nomograms. Mean time to aPTT stabilization was 16.25 hours with the standard nomogram and 27.05 hours with the hepatic/critically ill nomogram. The percentages of patients with aPTTs within the therapeutic range at each time interval were 82.4%, 82.4%, 88.2%, 96.4%, 100%, and 100% with the standard nomogram and 58.8%, 82.4%, 76.5%, 93.3%, 100%, and 90.9% with the hepatic/critically ill nomogram. There were no thrombotic events after the initiation of argatroban. Three cases of major bleeding occurred.
Conclusions: The nomogram is an effective dosing tool for achieving and maintaining therapeutic levels of anticoagulation.
Introduction
Heparin-induced thrombocytopenia (HIT) is an antibody-mediated syndrome that occurs in 1-5% of patients treated with unfractionated heparin. Although they are less likely to cause HIT than is unfractionated heparin, low-molecular-weight heparins (LMWHs) also pose a risk for the development of heparin antibodies. HIT results from binding of antibodies (most commonly immunoglobulin G) to a complex of heparin molecules and platelet factor 4. These antibodies promote the activation of platelets and subsequent release of platelet-derived microparticles that are prothrombotic. The particles in turn promote the generation of thrombin and a subsequent hypercoagulable state.
Although HIT can present as an isolated thrombocytopenia, it may be associated with the development of thrombotic events known as heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). While HITTS commonly manifests as venous thromboemboli (VTE), arterial thrombosis resulting in myocardial infarction and ischemic limb damage may occur. Early discontinuation of heparin and initiation of an alternative anticoagulant are necessary for prevention and treatment of HIT and HITTS; however, up to 50% of patients may experience a thrombotic event if untreated after heparin is discontinued. Mortality rates as high as 10-30% are associated with HITTS. Considering these serious sequelae, full-dose anticoagulation must be initiated upon heparin discontinuation. Various drugs, including danaparoid, lepirudin, ancrod, warfarin, fondaparinux, and LMWHs have been evaluated for the treatment of HIT. Each has limitations when used in patients with HIT.
The American College of Chest Physicians recommends danaparoid (grade 1B), lepirudin (grade 1C), argatroban (grade 1C), bivalirudin (grade 2C), or fondaparinux (grade 2C) for patients with strongly suspected or confirmed HIT. Lepirudin, argatroban, and bivalirudin have demonstrated efficacy in reducing thrombotic events associated with HIT and can be used as bridge therapy during transition to oral warfarin therapy. Lepirudin and argatroban have Food and Drug Administration (FDA)-approved indications as alternative anticoagulants in patients with HIT, while bivalirudin is FDA-approved for the treatment of HIT in the setting of percutaneous coronary intervention.
While consensus treatment guidelines recommend the initiation of lepirudin or argatroban when HIT or HITTS is strongly suspected, appropriate dosing adjustments for argatroban have not been substantiated. The FDA-approved dosing for argatroban is 2 µg/kg/min (0.5 µg/kg/min in patients with hepatic impairment), titrated to a target aPTT of 1.5-3 times the baseline level. The rapid achievement of therapeutic anticoagulation levels is crucial, as several studies have demonstrated that suboptimal anticoagulation in the first 48 hours after acute thrombosis is associated with an increased risk of recurrent VTE. The lack of a dosing strategy with argatroban may result in delayed stabilization of therapeutic aPTT levels. To date, there has been no published nomogram to guide the dosing and management of argatroban.
