Argatroban –This direct thrombin inhibitor is finding increasing use during vascular surgery and transplant surgery in patients in whom heparin is contraindicated. It is also indicated for prophylaxis or treatment of thrombosis in patients with HITT or for patients undergoing percutaneous coronary intervention. This drug (as are the two below) belongs to a group that interacts with free or clot-bound thrombin. In so doing it inhibits the conversion of fibrinogen to fibrin. There is no pharmacologic reversal in the case of drug overdose (this is true for all direct thrombin inhibiters). This drug, as well as the other direct thrombin inhibitors, is difficult to titrate. Changes in liver function can produce radical changes in drug requirement. Argatroban is the drug of choice in patients with severely impaired renal function as it is eliminated mostly by the liver. The half life is 30 – 51 minutes but this can increase to more than 3 hours in patients with hepatic impairment. The major risk of this drug is hemorrhage. Each 2.5 ml vial contains 250 mg of drug. Mix with 250 ml saline for a final concentration of 1 mg/ml. For heparin induced thrombocytopenia the initial infusion rate is 2 mcg/kg/min. This should be adjusted so that the aPTT is 1.5 – 3.0 times the initial baseline value. Infusions without a bolus reach steady state in 1 – 3 hours. The dose should not exceed 10 mcg/kg/min. For percutaneous coronary intervention the initial dose is 25 mcg/kg/min along with a bolus of 350 mcg/kg given over 5 minutes. The ACT should be checked after 5 minutes and the procedure can start if the ACT is greater than 300 sec. I could find no suggested dosing for vascular surgery or renal transplantation. However Hallman et al described the use of argatroban during carotid endarterectomy. They used a bolus of 150 mcg/kg followed by an infusion of 5 mcg/kg/min. This dose regimen provided adequate anticoagulation (ACT > 200s) by 10 minutes after the bolus dose (the drug may have acted faster but this was the first post administration sample reported by Hallman et al). Proper use of this drug in the operating room requires ACT testing before starting the drug and at appropriate intervals. Considering the risk of this drug I would suggest having a second person confirm the correctness of each step of preparation and the infusion settings. Do not use this drug based only on the information presented here, read package insert first. I would also suggest consulting with someone experienced in this drug’s use. Ref: Hallman SE et al: The use of argatroban for carotid endarterectomy in heparin-induced thrombocytopenia. Anesth Analg 2005;100:946-8
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Bivalirudin –This direct thrombin inhibitor is also seeing increased use when heparin is not an option. It is being used during percutaneous transluminal coronary angioplasty (PTCA), percutaneous coronary intervention (PCI) and cardiopulmonary bypass when heparin is contraindicated. In patients with renal impairment a reduced dose is required. No dosage adjustment is required with hepatic impairment. The elimination half life is 25 minutes in pts with normal renal function. The elimination half life can increase to as much as 3.5 hours in dialysis dependent patients. For patients undergoing PTCA or PCI the initial bolus is 0.75 mg/kg followed by an infusion of 1.75 mg/kg/h. APTT or ACT should be used to titrate the dosage. When used during bypass special precautions must be taken to prevent blood stagnation in the circuit. The drug comes as a powder (250 mg). It should be reconstituted into 5 ml of sterile water for injection; gently swirl to dissolve. Dilute to 500 ml for a final concentration of 0.5 mg/ml. Proper use of this drug in the operating room requires ACT testing before starting the drug and at appropriate intervals. Considering the risk of this drug I would suggest having a second person confirm the correctness of each step of preparation and the infusion settings. Do not use this drug based only on the information presented here, read the package insert first. I would also suggest consulting with someone experienced in this drug’s use.
Lepirudin –The attending in the UPENN CTICU use this drug exclusively unless there is significant kidney dysfunction. I am told that they use aPTT monitoring as often as q2 hours, particularly if they suspect worsening renal function. A suggested initial infusion is 0.15 mg/kg/h for pts up to 110 kg. The target is an aPTT range of 1.5 – 2.5 times normal. This drug can also be used as an IV push and there is some data on SQ use. The elimination half life is 1.3 hours and its route of elimination is via the kidney. Antibodies may develop during lepirudin therapy and fatal anaphylactic reactions have been reported in patients re-exposed in a second or subsequent treatment course. For infusion use a final concentration or 0.2 or 0.4 mg/ml. Lepirudin can be diluted with 5% dextrose in water, or normal saline. Reconstitut 2 vials (50 mg each) using 1 ml of sterile water for injection or 0.9% sodium chloride for injection for each vial. The contents of both vials should then be transferred to either a 500 ml or 250 ml bag for infusion. Proper use of this drug in the operating room requires ACT testing before starting the drug and at appropriate intervals. Considering the risk of this drug I would suggest having a second person confirm the correctness of each step of preparation and the infusion settings. Do not use this drug based only on the information presented here, read the package insert first. I would also suggest consulting with someone experienced in this drug’s use.
Acknowledgements: Yianni Augoustides and Jiri Horak from the UPENN Department of Anesthesiology and Critical Care and Gene Gibson from Pharmacy made critical contributions to this discussion of rFVIIa and heparin alternatives. This section could not have been written without their help. I also received helpful advice from Barbara Konkle, M.D., Professor of Medicine, Department of Hematology, Oncology Division and Brain Birmingham from the Pharmacy’s anticoagulation service. However I am responsible for any errors in this presentation.
David S. Smith, M.D., Ph.D.
Argatroban –This direct thrombin inhibitor is finding increasing use during vascular surgery and transplant surgery in patients in whom heparin is contraindicated. It is also indicated for prophylaxis or treatment of thrombosis in patients with HITT or for patients undergoing percutaneous coronary intervention. This drug (as are the two below) belongs to a group that interacts with free or clot-bound thrombin. In so doing it inhibits the conversion of fibrinogen to fibrin. There is no pharmacologic reversal in the case of drug overdose (this is true for all direct thrombin inhibiters). This drug, as well as the other direct thrombin inhibitors, is difficult to titrate. Changes in liver function can produce radical changes in drug requirement. Argatroban is the drug of choice in patients with severely impaired renal function as it is eliminated mostly by the liver. The half life is 30 – 51 minutes but this can increase to more than 3 hours in patients with hepatic impairment. The major risk of this drug is hemorrhage. Each 2.5 ml vial contains 250 mg of drug. Mix with 250 ml saline for a final concentration of 1 mg/ml. For heparin induced thrombocytopenia the initial infusion rate is 2 mcg/kg/min. This should be adjusted so that the aPTT is 1.5 – 3.0 times the initial baseline value. Infusions without a bolus reach steady state in 1 – 3 hours. The dose should not exceed 10 mcg/kg/min. For percutaneous coronary intervention the initial dose is 25 mcg/kg/min along with a bolus of 350 mcg/kg given over 5 minutes. The ACT should be checked after 5 minutes and the procedure can start if the ACT is greater than 300 sec. I could find no suggested dosing for vascular surgery or renal transplantation. However Hallman et al described the use of argatroban during carotid endarterectomy. They used a bolus of 150 mcg/kg followed by an infusion of 5 mcg/kg/min. This dose regimen provided adequate anticoagulation (ACT > 200s) by 10 minutes after the bolus dose (the drug may have acted faster but this was the first post administration sample reported by Hallman et al). Proper use of this drug in the operating room requires ACT testing before starting the drug and at appropriate intervals. Considering the risk of this drug I would suggest having a second person confirm the correctness of each step of preparation and the infusion settings. Do not use this drug based only on the information presented here, read package insert first. I would also suggest consulting with someone experienced in this drug’s use. Ref: Hallman SE et al: The use of argatroban for carotid endarterectomy in heparin-induced thrombocytopenia. Anesth Analg 2005;100:946-8 <?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" />
Bivalirudin –This direct thrombin inhibitor is also seeing increased use when heparin is not an option. It is being used during percutaneous transluminal coronary angioplasty (PTCA), percutaneous coronary intervention (PCI) and cardiopulmonary bypass when heparin is contraindicated. In patients with renal impairment a reduced dose is required. No dosage adjustment is required with hepatic impairment. The elimination half life is 25 minutes in pts with normal renal function. The elimination half life can increase to as much as 3.5 hours in dialysis dependent patients. For patients undergoing PTCA or PCI the initial bolus is 0.75 mg/kg followed by an infusion of 1.75 mg/kg/h. APTT or ACT should be used to titrate the dosage. When used during bypass special precautions must be taken to prevent blood stagnation in the circuit. The drug comes as a powder (250 mg). It should be reconstituted into 5 ml of sterile water for injection; gently swirl to dissolve. Dilute to 500 ml for a final concentration of 0.5 mg/ml. Proper use of this drug in the operating room requires ACT testing before starting the drug and at appropriate intervals. Considering the risk of this drug I would suggest having a second person confirm the correctness of each step of preparation and the infusion settings. Do not use this drug based only on the information presented here, read the package insert first. I would also suggest consulting with someone experienced in this drug’s use.
Lepirudin –The attending in the UPENN CTICU use this drug exclusively unless there is significant kidney dysfunction. I am told that they use aPTT monitoring as often as q2 hours, particularly if they suspect worsening renal function. A suggested initial infusion is 0.15 mg/kg/h for pts up to 110 kg. The target is an aPTT range of 1.5 – 2.5 times normal. This drug can also be used as an IV push and there is some data on SQ use. The elimination half life is 1.3 hours and its route of elimination is via the kidney. Antibodies may develop during lepirudin therapy and fatal anaphylactic reactions have been reported in patients re-exposed in a second or subsequent treatment course. For infusion use a final concentration or 0.2 or 0.4 mg/ml. Lepirudin can be diluted with 5% dextrose in water, or normal saline. Reconstitut 2 vials (50 mg each) using 1 ml of sterile water for injection or 0.9% sodium chloride for injection for each vial. The contents of both vials should then be transferred to either a 500 ml or 250 ml bag for infusion. Proper use of this drug in the operating room requires ACT testing before starting the drug and at appropriate intervals. Considering the risk of this drug I would suggest having a second person confirm the correctness of each step of preparation and the infusion settings. Do not use this drug based only on the information presented here, read the package insert first. I would also suggest consulting with someone experienced in this drug’s use.
Acknowledgements: Yianni Augoustides and Jiri Horak from the UPENN Department of Anesthesiology and Critical Care and Gene Gibson from Pharmacy made critical contributions to this discussion of rFVIIa and heparin alternatives. This section could not have been written without their help. I also received helpful advice from Barbara Konkle, M.D., Professor of Medicine, Department of Hematology, Oncology Division and Brain Birmingham from the Pharmacy’s anticoagulation service. However I am responsible for any errors in this presentation.
David S. Smith, M.D., Ph.D.