HIT type I is a result of direct heparin-platelet interactions
and is clinically benign.1HIT type II is a severe, immune-
mediated response stimulated by the formation of heparin-
platelet factor 4 complexes.1,2HIT type II is relatively
common, occurring in approximately 1–5% of patients
treated with heparin.1-3If untreated, up to 50% of patients
with HIT type II will develop thromboembolic complica-
tions including limb loss or death.4Treatment of HIT type
eparin-induced thrombocytopenia (HIT) is a potential-
ly life-threatening complication of heparin therapy.
II requires the discontinuation of all forms of heparin and
continuation of anticoagulation. Agents commonly used
inhibit activated thrombin, such as direct thrombin in-
Currently, our institution utilizes 2 DTIs, lepirudin and
argatroban, for the prophylaxis or treatment of thrombosis
in patients with HIT or when HIT and thrombosis syn-
drome (HITTS) is confirmed or suspected. The choice to
use 1 agent over the other is based on pharmacokinetic
properties and practitioner experience. Argatroban is a syn-
thetic DTI approved for prophylaxis or treatment of throm-
bosis in patients with HIT or HITTS. It is administered in-
travenously at an initial recommended rate of 2 µg/kg/min
(actual body weight) and adjusted based on goal activated
partial thromboplastin time (aPTT).6In patients with mod-
The Annals of Pharmacotherapy I
2004 January, Volume 38 I
Effect of Renal Function on the Pharmacodynamics of
Paul A Arpino and Robert K Hallisey
Author information provided at the end of the text.
Dr Hallisey has received consulting fees from Berlex Laboratories
BACKGROUND: 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.
OBJECTIVE: To assess the effects of renal function on argatroban dose and activated partial thromboplastin time (aPTT).
METHODS: 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 (Scr),
blood urea nitrogen, and estimated creatinine clearance (Clcr).
RESULTS: A total of 66 patients were evaluated and 44 met criteria for inclusion. Baseline Scrwas elevated at 1.5 mg/dL (0.9, 2.3;
median 25th, 75th percentile), with an estimated Clcr40 mL/min/1.73 m2(26, 74). The median dose of argatroban to reach the
predefined therapeutic range was 1 µg/kg/min (0.68, 2), with a corresponding aPTT of 60 seconds (54, 66). After univariate
analysis, Clcrsignificantly predicted the therapeutic dose (coefficient b ± SE 0.019 ± 0.004; r20.35; 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).
CONCLUSIONS: Estimated Clcrsignificantly predicted the dose of argatroban needed to reach a therapeutic aPTT.
KEY WORDS: argatroban, heparin-induced thrombocytopenia, renal insufficiency.
Ann Pharmacother 2004;38:25-9.
Published Online, 29 Oct 2003, www.theannals.com, DOI 10.1345/aph.1D163
by guest on October 11, 2013 by guest on October 11, 2013 by guest on October 11, 2013 by guest on October 11, 2013 by guest on October 11, 2013aop.sagepub.comaop.sagepub.comaop.sagepub.com aop.sagepub.comaop.sagepub.comDownloaded from Downloaded from Downloaded from Downloaded from Downloaded from