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Argatroban therapy in heparin-induced thrombocytopenia Expert Rev. Clin. Pharmacol. 1(3), 357–367 (2008)

Lawrence Rice† and Marcie J Hursting †

Author for correspondence The Methodist Hospital; Cornell Weill Medical College, 6550 Fannin, Suite 1001, Houston, TX 77030, USA Tel.: +1 713 441 5900 Fax: +1 713 793 7065 [email protected]

Argatroban is a direct thrombin inhibitor approved for anticoagulation in heparin-induced thrombocytopenia (HIT; in several countries) and in patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI; in the USA). HIT is a relatively common extreme prothrombotic condition. When HIT is reasonably suspected, an alternative anticoagulant should be promptly initiated. In historical controlled studies, argatroban reduced new thrombosis, mortality from thrombosis and the composite of death, amputation or thrombosis, without increasing bleeding. With intravenous infusion, advantages include short half-life, easy monitoring and elimination primarily by hepatobiliary (rather than renal) means. In patients undergoing PCI, argatroban with or without glycoprotein IIb/IIIa inhibition leads to high rates of procedural success with low bleeding risk. Herein we review argatroban therapy for HIT and for PCI. KEYWORDS: argatroban • direct thrombin inhibition • heparin-induced thrombocytopenia • percutaneous coronary intervention • thrombosis

Argatroban (Argatroban, GlaxoSmithKline, Research Triangle Park, NC, USA; Novastan®, Argatra® and Arganova ®, Mitsubishi Tanabe Pharma Corporation, Osaka, Japan) is a parenteral direct thrombin inhibitor (DTI). Among other indications worldwide, argatroban is approved in North America and various European countries as an anticoagulant for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT), and in the USA during percutaneous coronary intervention (PCI) in patients with or at risk of HIT (TABLE 1). We review the pharmacology of argatroban and its efficacy and safety in HIT in both noninterventional and interventional settings. Heparin-induced thrombocytopenia is a prothrombotic disorder affecting 0.5–5% of heparin-treated patients [1,2]. In the USA, this amounts to more than 100,000 new patients annually [3]. The pathophysiology is based on antibodies formed against heparin-platelet factor 4 complexes that induce platelet activation and procoagulant microparticle release [4] ; thrombocytopenia, thrombin generation and extreme hypercoagulability ensue. Venous or arterial thromboses develop in 38–76% of patients who do not receive an www.expert-reviews.com

10.1586/17512433.1.3.357

effective alternative anticoagulant, 10% resulting in limb amputation, and mortality in 20–30% within a month [5]. Heparin-induced thrombocytopenia should be suspected whenever the platelet count decreases by 50%, or new thrombosis occurs, 4–14 days after heparin initiation (sooner if there has been recent heparin exposure) [6,7,101]. Other causes of thrombocytopenia should be excluded. Guidelines for treatment, available from the American College of Chest Physicians (ACCP), British Committee for Standards in Hematology and the US National Comprehensive Cancer Network (NCCN), all closely agree [6,7,101]. When there is reasonable clinical suspicion of HIT, heparin should be stopped and a fast-acting, nonheparin anticoagulant initiated without delay. Therapy may be reconsidered once laboratory results are known and the post-test probability of HIT is determined [7,101]. The DTIs argatroban, lepirudin and bivalirudin, and the heparinoid danaparoid have been recommended as alternative anticoagulants [6,7,101]. Warfarin alone can worsen thrombotic tendencies acutely and should be initiated only after nonheparin anticoagulation is adequate and platelets have recovered [6,7,101]. According to the NCCN guidelines, anticoagulation should continue for 1 month if there is no

© 2008 Expert Reviews Ltd

ISSN 1751-2433

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Rice & Hursting

thrombosis [11]. The overall rate of major bleeding in the studies was 17.6% [11]. Lepirudin has a relatively narrow therapeutic window, and the activated partial thromboplastin time (aPTT) should be maintained lower than 65 s to reduce bleeding risk [12]. Lepirudin is associated with frequent formation of antihirudin antibodies; these uncommonly retard drug clearance causing supratherapeutic levels [13]. Anaphylactic reactions to lepirudin may occur, especially on re-exposure; elimination of the bolus dose may reduce the incidence or severity of the reaction [14]. Bivalirudin-enabled PCI was evaluated in an open-label study of 52 HIT patients and is well studied in non-HIT patients undergoing PCI [15,16]. In open-label studies in Market overview patients with or at risk of HIT undergoing coronary artery The approved indications for argatroban are stated above, as are bypass surgery, bivalirudin anticoagulation was associated with recommendations for initiation of therapy from consensus high rates of procedural success and an acceptable incidence of guidelines and an estimate of the magnitude of the HIT prob- bleeding [17,18]. There are reports of successful off-label use of lem. Since heparin use is ubiquitous, iatrogenic thrombo- bivalirudin therapy for HIT outside interventional or surgical cytopenia is very common (particularly in intensive care units settings [19–21], although controlled prospective studies have not and after heart surgery), in addition, commonly used antibody been conducted. tests may frequently produce ‘false-positive’ results; therefore, Danaparoid (unavailable in the USA) is approved for HIT suspicions of HIT and indications for therapy arise more often in the EU, Australia and Canada. In a randomized controlled than the irrefutable full-blown HIT syndrome [8–10]. study of 42 patients with HIT, danaparoid (plus warfarin) Among alternative anticoagulants that could be used for therapy, versus dextran 70 (plus warfarin) resulted in complete HIT, lepirudin is the other agent approved in the USA (and clinical recovery of 56%, versus 14%, of thromboembolic various European countries). Bivalirudin is approved in the events, and no patient had major bleeding [22]. Danaparoid USA for use in patients with or at risk of HIT undergoing PCI. may crossreact with HIT antibodies, and this may be one reaNo other DTI has been evaluated in HIT. son for treatment failures [23]. In a report of 1478 danaparoid In historical controlled studies in HIT, lepirudin reduced the courses for HIT, rates of new thrombosis, major bleeding and composite primary end point of new thrombosis, limb amputa- clinically significant crossreactivity were 9.7, 8.1 and 3.2%, tion and death, with the benefit primarily on reduction of new respectively [24]. Fondaparinux, a selective factor Xa inhibitor, has been used successfully for HIT, but Table 1. Regulatory status of argatroban use in heparin-induced published data are limited [25,26]. In one thrombocytopenia, effective October 2007 *. reported case, fondaparinux appeared to Country Anticoagulation in Anticoagulation in patients with or cause a syndrome resembling HIT [27]. patients with HIT at risk of HIT during PCI An important distinguishing feature among these anticoagulants is their primary Austria Approved route of elimination. Lepirudin, fondaCanada Approved parinux and danaparoid are primarily cleared renally; bivalirudin is cleared by renal and Denmark Approved enzymatic mechanisms; and argatroban is Germany Approved predominantly hepatically metabolized.

thrombosis (or other indication to continue) but longer if thrombosis is present [101]. However, the optimum duration of anticoagulant therapy remains to be established prospectively. Future avoidance of heparin, when possible, is advised for patients with previous HIT, especially if HIT occurred within the past 3 months [6,7]. The availability of alternative anticoagulants provides viable alternatives to heparin for most situations, although cardiac surgery may sometimes be an exception where the unique advantages of unfractionated heparin on pump may outweigh risks of re-exposure [6,7].

Iceland

Approved

Italy

Under review

Japan

Under review

Netherlands

Approved

Norway

Approved

USA

Approved

Sweden

Approved

*

Introduction to argatroban Chemistry

Approved

Argatroban is also approved for use in nonlacunar stroke in Japan and South Korea; chronic arterial occlusion in Japan, South Korea and China; and hemodialysis in patients with antithrombin deficiency in Japan. HIT: Heparin-induced thrombocytopenia; PCI: Percutaneous coronary intervention.

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Argatroban, or 1-[5-[(aminoiminomethyl)amino]-1-oxo-2-[[(1,2,3,4-tetrahydro-3-methyl-8-quinolinyl)sulfonyl]amino]pentyl]-4-methyl-2piperidinecarboxylic acid monohydrate, is a synthetic molecule (molecular weight: 526.66) derived from L-arginine. The molecular formula is C23H36N6O5S•H2O.

Expert Rev. Clin. Pharmacol. 1(3), (2008)

Argatroban therapy in heparin-induced thrombocytopenia

Pharmacodynamics

Argatroban binds reversibly, specifically and without a cofactor to the thrombin catalytic site (Ki = 0.04 µmol/l), exerting anticoagulant effects by inhibiting thrombin-mediated reactions, including fibrin formation, activation of factors V, VIII and XIII, and platelet aggregation. Monitoring employs a routine aPTT or, during PCI, activated clotting time (ACT). The EC50 for argatroban is approximately 1.5–2.0 µg/ml for the aPTT [28] and 1.9 µg/ml for the ACT [29]. Argatroban, in a concentrationdependent fashion, also affects the prothrombin time (PT), thrombin time, ecarin clotting time (EC50 ∼0.5–0.6 µg/ml), and extrinsic coagulation activity assay (half maximal inhibitory concentration 1 µg/ml) [28,30,31]. Pharmacokinetics & metabolism

Steady-state volume of distribution is 174 ml/kg; 54% is serum protein bound. Systemic clearance is approximately 5.1 ml/min/kg. Argatroban is hepatically metabolized, primarily excreted in feces. The elimination half-life is 39–51 min in healthy subjects. Moderate hepatic impairment (defined as a Child–Pugh score > 6) decreases argatroban clearance approximately fourfold and prolongs the elimination half-life approximately threefold [32]. A need for reduced doses is also documented in patients with hepatic impairment, as assessed using hepatic function tests, particularly serum total bilirubin [33]. Decreased clearance is suspected with poor cardiac output, fluid overload and/or hepatic congestion, even with normal liver function tests [34–36]. There are no effects of age, gender, race or renal function on argatroban pharmacokinetics [29,32,37,38]. In clinical studies to date, dialytic clearance is less than 23% [37,38]. It is possible, however, that clearance may be increased with adaptation of dialytic technique, and in vitro data indicate that sieving coefficients of approximately 0.5 can be achieved with some membranes [39]. Plasma argatroban levels and anticoagulant effects are measurable upon initiation. Steady-state drug levels occur after 1–3 h of continuous infusion, increase with dose up to 40 µg/kg/min, correlate well with anticoagulant effects and are maintained until infusion adjustment. After drug cessation, levels and anticoagulant effects return to baseline, typically within 2–4 h [32]. Anticoagulant effects may take longer to normalize if hepatic impairment or conditions indirectly affecting hepatic function (e.g., poor cardiac output) are present [32–36]. Clinical efficacy Prophylaxis or treatment of thrombosis in HIT Phase II/III studies & their combined analyses

Two prospective, multicenter, historical controlled, similarly designed studies (Argatroban-911 and Argatroban-915) evaluated argatroban for thromboprophylaxis or treatment of adults with clinically diagnosed HIT [40,41]. Patients were stratified to study arms of HIT (without thrombosis) or HIT

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with thrombosis. Patients with previous HIT requiring anticoagulation were also eligible. Argatroban 2 µg/kg/min (reduced in hepatic impairment), adjusted to achieve aPTTs 1.5–3-times baseline, was administered for 6 days (mean) to 304 and 418 patients in the respective studies. Outcomes were compared with 193 historical controls administered no DTI. In each study, argatroban reduced the primary composite end point of all-cause death, all-cause amputation or new thrombosis within 37 days (Argatroban-911: 25.6 vs 38.8%; p = 0.014; Argatroban-915: 28.0 vs 38.8%; p = 0.04). In HIT with thrombosis, the composite end point occurred in 56.5% of controls and 43.8% of treated patients (p = 0.13) in Argatroban-911 and 41.5% (p = 0.07) in Argatroban-915. Time-to-event analyses of the composite end point favored argatroban in each study arm and each study. Therapeutic aPTTs occurred typically within 4–5 h. Thrombocytopenia resolved more rapidly in argatrobantreated patients. These benefits occurred without increased bleeding (see section on bleeding). Argatroban particularly reduced new thrombosis. A combined study analysis using the primary thrombotic composite end point of death due to thrombosis, amputation secondary to HIT-associated thrombosis or new thrombosis within 37 days, found argatroban reduced the risk of the thrombotic composite end point, as well as new thrombosis and death due to thrombosis (TABLE 2) [42]. These studies included 36 nonthrombocytopenic patients with previous HIT who required anticoagulation [43]. Argatroban 2.0 µg/kg/min (median dose) was administered typically for 4 days, to 12 patients on multiple occasions. All achieved therapeutic aPTTs, and none had bleeding, new thromboembolic complications or adverse treatment effects. In other combined analyses of the historical controlled studies, argatroban reduced new stroke and stroke-related mortality (without increasing intracranial hemorrhage) in HIT [44] and reduced new thrombosis (without increasing bleeding) in HIT with coronary artery disease [45], acute illness [46] or hepatic impairment [33]. Argatroban provided effective anticoagulation in HIT with renal impairment or failure [47,48], and in HIT following heparin exposure for venous thromboembolism [49], hemodialysis [50] or line flushing [51]. Dosing considerations

The US FDA-approved argatroban dose for prophylaxis or treatment of thrombosis in HIT is 2 µg/kg/min (0.5 µg/kg/min in hepatic impairment), adjusted to achieve aPTTs 1.5–3-times baseline. However, this dose appears to be excessive for many patients, based on single-center experiential reports of 25 or more patients [23,52–54] and analyses of a 118patient, multicenter registry [55,56]. These show that mean or median doses of 0.5–1.2 µg/kg/min achieve target aPTTs. Reduced initial doses are particularly prudent in conditions associated with poor cardiac output, fluid overload, hepatic congestion, multiple organ dysfunction, anasarca and following cardiovascular surgery [33–36,57–62]. Although some studies indicate that no initial dose adjustment is needed solely for

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Table 2. Combined analysis of Phase II/III multicenter, historical controlled studies of argatroban anticoagulation in heparin-induced thrombocytopenia*. Outcome

HIT

HIT with thrombosis

Argatroban (n = 321)

Control (n = 139)

p-value‡

Argatroban (n = 376)

Control (n = 46)

p-value‡

Thrombotic composite end point§

9

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Argatroban therapy in heparin-induced thrombocytopenia.

Argatroban is a direct thrombin inhibitor approved for anticoagulation in heparin-induced thrombocytopenia (HIT; in several countries) and in patients...
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