Author: Dhillon, Sohita

Source: American Journal of Cardiovascular Drugs, Volume 9, Number 4, 1 August 2009 , pp. 261-282(22)

Publisher: Adis International

Abstract:

Abstract Argatroban, a highly selective direct thrombin inhibitor, is indicated for use as an anticoagulant for the treatment and prophylaxis of thrombosis in patients with heparin-induced thrombocytopenia (HIT), and in patients undergoing percutaneous coronary intervention (PCI) who have, or are at risk for, HIT.

Intravenous argatroban improved clinical outcomes and was generally well tolerated in adults with HIT or HIT with thrombosis syndrome (HITTS). In two pivotal, open-label, historically controlled studies in adults with HIT, the incidence of the primary composite endpoint (all-cause death, all-cause amputation, or new thrombosis) was significantly lower in argatroban recipients than in historical controls, and more argatroban recipients than historical controls stayed event-free during the study according to a Kaplan-Meier analysis. In adults with HITTS in these trials, although the incidence of the primary composite endpoint did not differ significantly between argatroban recipients and historical controls, a Kaplan-Meier analysis showed that more patients receiving argatroban than historical controls remained event-free during the study. Major and minor bleeding rates in argatroban recipients were generally similar to those in historical controls in these studies. Argatroban was also an effective anticoagulant in patients with HIT undergoing PCI in three small, uncontrolled trials, pooled data from which showed that most (≥95%) patients achieved a satisfactory outcome of the PCI procedure and adequate anticoagulation (coprimary endpoints). It was generally well tolerated in these patients, with the incidence of major bleeding being ≤1.1%. The efficacy and safety of argatroban in pediatric patients has not been established. However, a small uncontrolled, preliminary study suggests that it may be useful in seriously ill pediatric patients requiring nonheparin anticoagulation. There are no direct head-to-head comparisons of the efficacy and tolerability of argatroban with that of other agents. Nevertheless, available clinical data suggest that argatroban is a valuable treatment option in adult patients with HIT or HITTS and in patients with HIT undergoing PCI, and may be useful for pediatric patients who require nonheparin anticoagulation.

Pharmacological Properties Argatroban is a highly selective direct thrombin inhibitor that rapidly and reversibly binds to the thrombin active site and exerts its anticoagulant effects by inhibiting thrombin-catalyzed or -induced reactions, including fibrin formation, activation of coagulation factors (V, VIII, and XIII), activation of protein C, and platelet aggregation. Argatroban dose-dependently and rapidly increases activated partial thromboplastin times, activated clotting times, prothrombin times, the international normalized ratio (INR), and thrombin times in healthy volunteers and cardiac patients; its anticoagulant effects also dissipate quickly. Anticoagulant properties of argatroban are generally not affected by renal dysfunction, gender, or age. Argatroban does not induce production of anti-argatroban antibodies that could alter its anticoagulant properties.

Plasma concentrations of intravenous argatroban begin to rise soon after initiation of infusion, reach steady-state within 1-3 hours, and are maintained until the infusion is discontinued or the dosage is adjusted. Steady-state plasma concentrations of argatroban are dose-dependent and correlate well with the anticoagulant effects of the drug. Argatroban is largely excreted in the feces, and has a terminal elimination half-life of 39-51 minutes. The pharmacokinetics of argatroban are not affected by renal impairment, gender, or age. Clearance is decreased in patients with hepatic impairment and in seriously ill pediatric patients, and dosage reductions are required in these patients.

Coadministration of argatroban with oral warfarin does not affect the pharmacokinetics of argatroban; however, coadministration of these drugs has a combined effect on the laboratory measurements of INR and prothrombin time, which should be taken into consideration when switching from argatroban to warfarin therapy. Pharmacokinetics of argatroban are unaffected by coadministration of erythromycin, aspirin, acetaminophen, digoxin, or lidocaine.

Therapeutic Efficacy Intravenous argatroban improved clinical outcomes in adult patients with HIT or HITTS. In two nonrandomized, open-label, historically controlled studies in adults with HIT, the incidence of the primary composite endpoint (all-cause death, all-cause amputation, or new thrombosis) was significantly lower in argatroban recipients than in historical controls. In addition, a Kaplan-Meier time-to-event analysis of the primary endpoint showed that more argatroban recipients than historical controls remained event-free during the study period.

Document Type: Research article

Affiliations: 1: Wolters Kluwer Health ∣ Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Philadelphia, Pennsylvania, USA

Publication date: 2009-08-01

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