Argatroban Dosage in Critically Ill Patients with HIT.

Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin therapy that can result in significant morbidity and mortality. Immediate discontinuation of heparin followed by the administration of a direct thrombin inhibitor (DTI) is the standard of care. There are two DTIs approved by the FDA for this indication, argatroban and lepirudin. Argatroban is metabolized in the liver by hydroxylation and aromatization and requires dosage adjustment in patients with moderate hepatic impairment defined as a Child-Pugh score >6. The normal recommended starting dose of 2 mcg/kg/min is reduced to 0.5 mcg/kg/min in these patients.

Objective: Our clinical observation was that the recommended starting doses of argatroban in the ICU resulted in elevated activated partial thromboplastin time (aPTT) values that persisted for a prolonged time. This may result in a higher bleeding risk and delay life-saving invasive procedures especially in the absence of an antidote. Therefore, our objective is to show that critically ill patients without significant liver disease require a lower dosage of argatroban than recommended in the manufacturer’s prescribing information and to identify factors that may affect this recommendation.

Materials and Method: Retrospective chart review of patients admitted to a medical or surgical intensive care unit (ICU), diagnosed with HIT who received argatroban for more than 24 hours. SPSS version 11.5 was used for data analysis.

Results: 65 patients (37 men) were analyzed. The mean age was 65.8 years. 43% had abnormal liver function tests (LFT’s) defined as ALT>50 or bilirubin >1.5 (100% of the patients had a normal baseline INR), 24.6% had acute renal failure (ARF) and 36.9% were septic. 40% had one organ system failure (OSF), 40% had two and 20% three. The diagnosis of ARF, sepsis and the number of OSF was based on the ICU physician’s documentation and the patient’s active problem list. Excluding 3 patients with a history of liver disease (1) or acute liver decompensation (2), the mean argatroban dose for our ICU patients was 0.91 mcg/kg/min. Patients with ARF (n=16/65) required a significantly lower dose (0.65 mcg/kg/min, p=0.044), as did patients with sepsis (0.70 mcg/kg/min, p=0.03, n=24/65). Even in patients with normal LFT’s, dosage requirements were lower ranging from 1.2 mcg/kg/min with one OSF to 0.52 mcg/kg/min with three OSF (p=0.009).

Discussion: Factors other than pre-existing liver disease appear to affect the dosage of argatroban in critically ill patients with HIT. Our mean dose to achieve a therapeutic aPTT was 0.91 mcg/kg/min with even lower doses in patients with ARF, sepsis or more than one OSF. This may be explained by the influence of ARF, sepsis, or OSF on argatroban metabolism by the liver that is not necessarily reflected in ALT, bilirubin, or even INR measurements. This metabolic effect may be due to passive hepatic congestion, accumulation of certain metabolites or interaction with the multiple medications used in these patients. Consideration should be given to initiate argatroban at a lower dosage in the critically ill patient.