Effect of Renal Function on the Pharmacodynamics of Argatroban

Department of Pharmacy, Massachusetts General Hospital, Boston, MA 02114, USA.
Annals of Pharmacotherapy (Impact Factor: 2.06). 01/2004; 38(1):25-9. DOI: 10.1345/aph.1D163
Source: PubMed


Argatroban is a direct thrombin inhibitor used to treat heparin-induced thrombocytopenia (HIT). Argatroban is primarily cleared by hepatic mechanisms, with only small amounts of unchanged drug cleared by the kidneys.
To assess the effects of renal function on argatroban dose and activated partial thromboplastin time (aPTT).
Patients treated with argatroban were identified and prospectively screened. Patients with liver dysfunction were excluded from the analysis. Charts and laboratory data were reviewed daily until a therapeutic aPTT was reached or argatroban was discontinued. Data points collected included age, weight, gender, admitting diagnosis, past medical history, indication for anticoagulation, indication for argatroban, initial dose, goal aPTT, titration instructions, liver function tests, serum creatinine (S(cr)), blood urea nitrogen, and estimated creatinine clearance (Cl(cr)).
A total of 66 patients were evaluated and 44 met criteria for inclusion. Baseline S(cr) was elevated at 1.5 mg/dL (0.9, 2.3; median 25th, 75th percentile), with an estimated Cl(cr) 40 mL/min/1.73 m(2) (26, 74). The median dose of argatroban to reach the predefined therapeutic range was 1 microg/kg/min (0.68, 2), with a corresponding aPTT of 60 seconds (54, 66). After univariate analysis, Cl(cr) significantly predicted the therapeutic dose (coefficient b +/- SE 0.019 +/- 0.004; r(2) 0.35; p < 0.001). Covariates that predicted dose were the presence of HIT (coefficient b +/- SE -0.61 +/- 0.3; p = 0.045), history of myocardial infarction (coefficient b +/- SE -0.74 +/- 0.3; p = 0.02), and an indication for anticoagulation of deep-vein thrombosis/pulmonary embolism (coefficient b +/- SE 0.69 +/- 0.3; p = 0.03).
Estimated Cl(cr) significantly predicted the dose of argatroban needed to reach a therapeutic aPTT.

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    • "In addition, argatroban anticoagulation has been used successfully during renal-replacement therapy in patients with and without HIT [15,16]. However, recent limited data suggested the consideration of kidney function before initiation of argatroban therapy in HIT [13,17,18]. "
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    ABSTRACT: Heparin-induced thrombocytopenia (HIT) is a serious, prothrombotic, immune-mediated adverse reaction triggered by heparin therapy. When HIT is diagnosed or suspected, heparins should be discontinued, and an alternative, fast-acting, parenteral, nonheparin anticoagulation such as argatroban should be initiated. Limited and inconsistent data exist about dosing of argatroban in intensive care unit (ICU) patients with critical illnesses. Retrospective analysis of 12 ICU patients with multiple organ dysfunction syndrome (MODS) treated with argatroban for suspected or diagnosed HIT. The 12 ICU patients with a mean platelet count of 46,000 ± 30,310 had a mean APACHE II score of 26.7 ± 7.8 on ICU admission and a mean SAPS II score of 61.5 ± 16.3 on the first day of argatroban administration. A mean argatroban starting dose of 0.32 ± 0.25 μg/kg/min (min, 0.04; max, 0.83) was used to achieve activated partial thromboplastin times (aPTTs) >60 sec or aPTTs of 1.5 to 3 times the baseline aPTT. Adjustment to aPTT required dose reduction in six (50%) patients. Patients were treated for a mean of 5.5 ± 3.3 days. The final mean dose in these critically ill patients was 0.24 ± 0.16 μg/kg/min, which is about one eighth of the usually recommended dose and even markedly lower than the previously suggested dose for critically ill ICU patients. In all patients, desired levels of anticoagulation were achieved. The mean argatroban dose was significantly lower in patients with hepatic insufficiency compared with patients without hepatic impairment (0.10 ± 0.06 μg/kg/min versus 0.31 ± 0.14 μg/kg/min; P = 0.026). The mean argatroban dose was significantly correlated with serum bilirubin (r = -0.739; P = 0.006). ICU Patients with MODS and HIT can be effectively treated with argatroban. A decrease in the initial dosage is mandatory in this patient population. Further studies are needed to investigate argatroban elimination and dosage adjustments for critically ill patients.
    Full-text · Article · May 2010 · Critical care (London, England)
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    • "Preliminary results of 15 patients with acute stroke enrolled into the argatroban-rTPA study are available (Arpino and Hallisey 2004). In this investigation the dosing of the lower-dose group of the ARGIS-1 study was combined with rTPA lysis. "
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    ABSTRACT: Argatroban is a synthetic direct thrombin inhibitor with a relative short elimination half-life of 45 minutes and elimination which is predominantly performed via hepatic metabolism. Argatroban anticoagulation has been systematically studied in patients exhibiting the heparin-induced thrombocytopenia (HIT)/thrombosis syndrome and demonstrated to be a safe and effective therapy in this indication. Moreover, in smaller studies argatroban has also been assessed in special clinical settings in non-HIT patients. The current review presents the pharmacology of argatroban, data regarding monitoring of the agent, and an overview of the results of the major clinical trials assessing argatroban anticoagulation in HIT patients. Additionally, data from clinical trials with argatroban use outside HIT, in more special indications such as in percutaneous coronary intervention, stroke, renal replacement therapy, and intensive care medicine, are reviewed.
    Full-text · Article · Jul 2007 · Targets & therapy
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    ABSTRACT: The activated partial thromboplastin time (aPTT) is currently the most common test used to measure the anticoagulation intensity of heparins and direct thrombin inhibitors (DTIs). Vitamin K antagonists variably affect aPTT reagents. Interactions between heparin and DTIs occur during concurrent therapy. Three DTIs (lepirudin, argatroban, melagatran) and one unfractionated heparin (liquemin) were added to normal plasma (NP) samples (n = 23) and to vitamin K antagonist plasma (VKAP) samples (n = 23) of patients treated with phenprocoumon. Lepirudin and argatroban were added at concentrations from 300 to 3000 ng/ml, melagatran from 30 to 1000 ng/ml, and unfractionated heparin from 0.016 to 0.48 IU/ml. Wave parameters of clotting time and aPTT ratio curves were evaluated by multivariate analysis for inhibitors, aPTT reagents and NP and VKAP samples. Normal ranges resulting from NP samples were 34.5 +/- 1.0 s with Pathromtin SL and 33.9 +/- 0.8 s with Platelin LS. Normal ranges using VKAP were 52.8 +/- 2.6 s (Pathromtin SL) and 44.2 +/- 1.1 s (Platelin LS) (P < 0.0001). Variance analysis showed that inhibitors, plasmas (NP versus VKAP) and reagents influenced the wave characteristics of aPTT (s) (P < 0.0001) and aPTT ratios (P < 0.0001). Distinct statistical differences between aPTT reagents on one hand and normal versus vitamin K antagonist plasma on the other hand make a comparison of reported aPTT results difficult, especially during overlapping therapy with vitamin K antagonists.
    No preview · Article · Oct 2004 · Blood Coagulation and Fibrinolysis
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