Argatroban

Mechanism of Action

Argatroban is a synthetic compound based on the structure of L- arginine. It is a direct thrombin inhibitor that binds reversibly to the active site of thrombin and inhibits its downstream action. In contrast, indirect thrombin inhibitors like heparin exert their anticoagulant effect via activation of antithrombin.[6]

Thrombin (clotting factor IIa) is a serine protease that has a central role in coagulation. It is the final enzyme in the coagulation cascade that, upon activation from prothrombin, converts fibrinogen to fibrin, activates procoagulant factors V, VIII, XI, and XIII, and activates platelets.

Univalent DTIs like argatroban and melagatran bind only at the active site of thrombin, whereas bivalent DTIs like hirudin and bivalirudin bind to two sites of thrombin: the active site and exosite I, a positively charged region in the thrombin molecule, which is also a recognition site for many physiologic substrates like fibrinogen, protein C, factor V and thrombomodulin (thrombin receptor in endothelial cells).[9]

Unlike heparin, which acts only on soluble thrombin, argatroban acts on both soluble and clot-bound thrombin because of its low molecular weight. It shows linear pharmacokinetic properties after starting an intravenous infusion. The drug concentration and anticoagulant effects attain steady-state levels 1 to 3 hours after the start of infusion. Since it acts on the final step of coagulation, most of the parameters of coagulation, eg, activated partial thromboplastin time (aPTT), activated clotting time (ACT), prothrombin time (PT), the international normalized ratio(INR), and thrombin time (TT) are prolonged rapidly and in a dose-dependent manner. The elimination half-life of argatroban is 39 to 51 minutes. This short half-life is desirable, given the risk of potential bleeding and the lack of a specific antidote. Anticoagulant effects gradually decline and reach the pretreatment level within 2 to 4 hours after stopping the infusion. However, in patients with impaired hepatic function, it may take 6 to 20 hours for its effects to wear off.[6]

Argatroban is metabolized primarily by hydroxylation and aromatization via cytochrome P450 enzymes and excreted mainly via feces. However, significant drug interactions have not occurred with CYP3A4/5 inhibitors like erythromycin, digoxin, and acetaminophen.[10]

Often in patients with HIT, long-term anticoagulation with oral warfarin is needed. When transitioning from argatroban to warfarin, INR may be elevated due to the additive effects of both drugs. In the absence of clear guidelines, the supratherapeutic level of INR>5 during such transition and overlap has no association with an increased risk of bleeding.[11] Warfarin therapy should not start unless the platelet count has recovered above 150,000/mm³ and the patient is on therapeutic anticoagulation with non-heparin anticoagulants like argatroban. As a general rule, warfarin and argatroban should overlap for at least five days before discontinuing argatroban and continuing with warfarin monotherapy.

Administration

Argatroban is available as an intravenous solution of 1 mg/ml.

Heparin-induced thrombocytopenia: Discontinue heparin and obtain baseline aPTT. For adult patients, the recommended dose is 2 mcg/kg/min, administered as a continuous intravenous infusion. Lower doses are used in critically ill patients, e.g., patients with multiorgan failure or severe anasarca. In a study by Beiderlinden M., et al. performed on 24 critically ill patients with multiorgan dysfunction syndrome (MODS) and HIT, argatroban infusion of 2 mcg/kg/min for 4 hours resulted in excessive anticoagulation and even resulted in bleeding complications in three patients but with infusion at starting dose of 0.2 mcg/kg/min, sufficient anticoagulation was achieved with no bleeding complications.[12]

Monitoring: Monitor aPTT (target range of 1.5 to 3 times of initial baseline, not to exceed 100 seconds). 

Dosage adjustment: Adjust the dose (not to exceed 10 mcg/kg/min) to maintain aPTT in the target range.

Percutaneous coronary intervention: Administer a bolus of 350 mcg/kg over 3 to 5 minutes and start an infusion at the rate of 25 mcg/kg/min.

Check an activated clotting time (ACT) 5 to 10 minutes after completing the bolus dose.

If the ACT > 300 seconds: Proceed with the PCI.

If the ACT < 300 seconds: Administer an additional intravenous bolus dose of 150 mcg/kg, increase the infusion dose to 30 mcg/kg/min, and check the ACT 5 to 10 minutes later.

If the ACT> 450 seconds: Decrease the infusion rate to 15 mcg/kg/min and check the ACT 5 to 10 minutes later.

Titration of the dose should continue until ACT is in the therapeutic range (between 300 and 450 seconds).[6]

Argatroban use requires caution in patients with hepatic dysfunction, especially in patients with total serum bilirubin >1.5 mg/dl. In such patients, a lower dose should be used (starting infusion rate from 0.5 mcg/kg/min).[6][13] However, no dosage adjustment is necessary for patients with renal dysfunction.[10][3]

Adverse Effects

The most common adverse effect of argatroban, as with other anticoagulants, is bleeding, which can manifest as gastrointestinal, genitourinary, intracranial, retroperitoneal bleeding, hemoptysis, and other minor bleedings.[14] Non-hemorrhagic complications include hypotension, dyspnea, fever, sepsis, and cardiac arrest. When used in PCI, chest pain, back pain, nausea, vomiting, hypotension, and headache can occur.[10]

Contraindications

Argatroban, like other anticoagulants, is contraindicated in overt bleeding.[6]

When argatroban is used in patients with increased bleeding risk like severe hypertension, after major surgery, immediately following lumbar puncture, spinal anesthesia, particular caution, and vigilance are necessary.

Avoid argatroban in patients with a history of hypersensitivity to it or any of its components in the dosage form.

Monitoring

In patients with HIT, aPTT is commonly useful for monitoring argatroban therapy. Clinicians should obtain a baseline aPTT, and the initial dosing should be adjusted to obtain a steady-state aPTT of 1.5 to 3 times baseline (not to exceed 100 seconds). The aPTT should also be obtained 2 hours after the initiation of therapy and after any change in dosage.[6][15]

In the PCI setting, where a higher argatroban dose is used, activated clotting time (ACT) is used to monitor therapy.

Toxicity

The toxicity of argatroban from supratherapeutic dosage is related to its anticoagulant effect. There is no antidote to reverse its actions.[16] In case of overdose, stop the drug and initiate appropriate transfusion therapy, eg, fresh frozen plasma.[17] Patients with hepatic dysfunction are particularly susceptible to the excessive anticoagulant effect of argatroban due to reduced clearance. In such patients, the reversal of its effect takes a longer time.

Enhancing Healthcare Team Outcomes

Heparin products see frequent use in hospitals, including line flushes, catheters, to DVT prophylaxis in patients with prolonged hospitalization. It is reasonable to obtain platelet counts after heparin therapy. Any fall in platelet count requires evaluation, and a 4T score (degree of thrombocytopenia, timing relative to heparin exposure, presence of thrombosis, and other causes for thrombocytopenia) should be calculated if HIT is suspected. Clinicians, pharmacists, and nurses should be aware of HIT pathology. Argatroban is indicated only in Type II HIT, not in Type I. Type I HIT can be differentiated from Type II by a milder drop in platelet count, earlier onset of thrombocytopenia, and absence of antibodies. Since argatroban is expensive and can have potential bleeding complications, it is necessary to ensure its use is in the correct clinical scenario. Patients on argatroban therapy should have frequent monitoring of aPTT or ACT, and any signs suggestive of bleeding or fall in hemoglobin should be promptly reported to the healthcare team so that the clinician can promptly discontinue argatroban and initiate transfusion therapy.