General Information

Heparin is the most commonly used anticoagulant for patients requiring immediate anticoagulation therapy. Heparin-induced thrombocytopenia (HIT) has an immunologic basis and is commonly associated with venous thrombosis. The availability of direct thrombin inhibitors has assisted physicians in managing this disorder.

HIT is an immunoglobulin-mediated adverse drug reaction that is characterized by platelet activation, thrombocytopenia, and a high risk of thrombotic complications among patients receiving or who have recently received heparin. HIT is one of the most important immunologic drug reactions.

Thrombocytopenia is usually mild to moderate, with platelet counts ranging from 20 to 150 x 109/L. Similarly, a fall in platelet count of 50% or more that begins later than 5 days after the start of heparin therapy, but with the platelet count still above the usual threshold for thrombocytopenia (150 x 109/L), should also raise the suspicion of HIT.13 By comparison, thrombocytopenia induced by sulfa drugs and quinine is typically much more severe. (from uspharmacist.com)

Clinical Results

The conclusion that Argatroban is an effective treatment for heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) is based upon the data from a historically controlled efficacy and safety study (Study 1) and a follow-on efficacy and safety study (Study 2). These studies were comparable with regard to study design, study objectives, dosing regimens as well as study outline, conduct, and monitoring.

In these studies, 568 adult patients were treated with Argatroban and 193 adult patients made up the historical control group. Patients were required to have a clinical diagnosis of heparin-induced thrombocytopenia, either without thrombosis (HIT) or with thrombosis (HITTS) and be males or non-pregnant females between the age of 18 and 80 years old.

Patients with documented unexplained aPTT greater than 200% of control at baseline, documented coagulation disorder or bleeding diathesis unrelated to HITTS, a lumbar puncture within the past 7 days or a history of previous aneurysm, hemorrhagic stroke, or recent thrombotic stroke, within the past 6 months, unrelated to HITTS were excluded from these studies.

The primary efficacy analysis was based on a comparison of event rates for a composite endpoint that included death (all causes), amputation (all causes) or new thrombosis during the treatment and follow-up period (study days 0 to 37). Secondary analyses included evaluation of the event rates for the components of the composite endpoint as well as time-to-event analyses.

A categorical analysis showed a significant improvement in the composite outcome in patients with HIT and HITTS treated with Argatroban versus those in the historical control group.

Side Effects

Side effects may include:

Dyspnea

Hypotension

Fever

Diarrhea

Sepsis

Cardiac Arrest

Nausea

Ventricular tachycardia

Pain

Urinary tract infection

Vomiting

Infection

Pneumonia

Atrial fibrillation

Coughing

Abnormal renal function

Abdominal pain

Cerebrovascular disorder

There were hemorrhagic events of both minor and major status in the following areas:

Major:

Gastrointestinal

Genitourinary and hematuria

Decrease hemoglobin/hematocrit

Multisystem hemorrhage and DIC

Limb and BKA stump

Minor:

Gastrointestinal

Genitourinary and hematuria

Decrease in hemoglobin and hematocrit

Groin

Hemoptysis

Brachial

Mechanism of Action

Argatroban is a direct thrombin inhibitor that reversibly binds to the thrombin active site. It does not require the co-factor antithrombin III for antithrombotic activity. Argatroban exerts its anticoagulant effects by inhibiting thrombin-catalyzed or induced reactions, including fibrin formation; activation of coagulation factors V, VIII, and XIII; protein C; and platelet aggregation.

Argatroban is highly selective for thrombin with an inhibitory constant of 0.04 uM. At therapeutic concentrations, argatroban has little or no effect on related serine proteases.

Argatroban is capable of inhibiting the action of both free and clot-associated thrombin. It does not interact with heparin-induced antibodies. (from fda.gov)