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Argatroban

A Review of its Use in the Management of Heparin-Induced Thrombocytopenia

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Summary

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. 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 indicated that more patients receiving argatroban than historical controls remained event-free during the study period. Additionally, post hoc analyses of the two pivotal trials showed that argatroban therapy reduced the incidence of thrombotic outcomes and the risk of new stroke in patients with HIT or HITTS, and was beneficial in several subgroups of patients, such as patients who developed HIT after heparin therapy for coronary artery disease, acutely ill patients, and those with hepatic impairment.

Intravenous argatroban is also an effective anticoagulant in 91 patients with HIT undergoing PCI in three uncontrolled trials. A pooled analysis of data from these trials showed that a satisfactory outcome of the PCI procedure was attained in ≥95% and adequate anticoagulation during the procedure was achieved by ≥97.7% of patients undergoing PCI (subjectively assessed coprimary endpoints).

The efficacy of argatroban in pediatric patients has not been established. A small, preliminary, multicenter, uncontrolled study in 18 seriously ill pediatric patients (aged ≤16 years) requiring nonheparin anticoagulation showed that five patients experienced a new thrombotic event and one patient experienced a thromboembolic complication during argatroban treatment and follow-up (total 30-day period) [coprimary endpoints], suggesting that argatroban may be a useful anticoagulant in these patients.

Tolerability

Argatroban was generally well tolerated in patients with HIT or HITTS. As with other anticoagulants, a major concern with argatroban is the risk of bleeding. A pooled analysis of data from the two pivotal, historically controlled trials showed that major bleeding rates in argatroban recipients were generally similar to the rates in historical controls (5.3% vs 6.7%). Minor bleeding rates in argatroban recipients in the two trials were also not significantly different from the rates in historical controls (≤42% vs 41%). The most frequent treatment-emergent major or minor bleeding events were gastrointestinal bleeding, and genitourinary bleeding and hematuria; two fatal bleeding events were reported in argatroban recipients, one in each pivotal trial. The most common nonhemorrhagic treatment-emergent adverse events in these patients were dyspnea, hypotension, and fever.

A pooled analysis of three uncontrolled trials showed that major bleeding rates were also low (≤1.1%) in adults with HIT who received argatroban treatment during PCI; minor bleeding events occurred in ≤32% of these patients. Retroperitoneal and gastrointestinal bleeding were the two treatment-emergent major bleeding adverse events reported, each occurring in 0.9% of patients; groin bleeding or hematoma were the most frequent minor bleeding events, occurring in 3.6% and 2.6% of patients. Chest pain and hypotension were the most common nonhemorrhagic treatment-emergent adverse events in these patients. Serious treatment-emergent nonhemorrhagic adverse events occurred in 20% of patients with HIT undergoing PCI and included myocardial infarction (4 events), myocardial ischemia (2 events), coronary occlusion (2 events), coronary thrombosis (2 events), and angina pectoris (2 events).

Argatroban treatment was also associated with symptomatic or asymptomatic intracranial bleeding events in ≥4.3% of patients in populations other than those with HIT or HITTS (those with acute myocardial infarction also receiving thrombolytic therapy and in patients with acute stroke within 12 hours before argatroban therapy).

The safety of argatroban in pediatric patients has not been established. In the small, preliminary, uncontrolled study in 18 seriously ill pediatric patients who required nonheparin anticoagulation, two fatal major bleeding events were reported during treatment and follow-up (total 30-day period); the most frequent treatment-emergent nonhemorrhagic adverse events in these patients were constipation, hypokalemia, and hypotension.

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  1. Wolters Kluwer Health ∣ Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand

    Sohita Dhillon

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Additional information

Various sections of the manuscript reviewed by: N.S. Kleiman, The Methodist DeBakey Heart and Vascular Center, The Methodist Hospital, Houston, Texas, USA; L. Rice, Weill Cornell Medical College, The Methodist Hospital, Houston, Texas, USA; J.E. Rodgers, Eshelman School of Pharmacy, Division of Pharmacotherapy, University of North Carolina, Chapel Hill, North Carolina, USA; J.M. Walenga, Loyola University Chicago, Cardiovascular Institute, Stritch School of Medicine, Maywood, Illinois, USA; D.E. Wallis, Midwest Heart Specialists, Downers Grove, Illinois, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘argatroban’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search term was ‘argatroban’. Searches were last updated 17 June 2009.

Selection: Studies in patients with heparin-induced thrombocytopenia who received argatroban. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Argatroban, direct thrombin inhibitor, heparin-induced thrombocytopenia, heparin-induced thrombocytopenia and thrombosis syndrome, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

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Dhillon, S. Argatroban. Am J Cardiovasc Drugs 9, 261–282 (2009). https://doi.org/10.2165/1120090-000000000-00000

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