Argatroban Dosage in Critically Ill Patients with HIT.

Abstract

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.

Argatroban Therapy for Heparin-Induced Thrombocytopenia in Acutely Ill Patients

“…This remains to be investigated further. Other reports suggest that a reduced initial dose, such as that recommended for patients with hepatic impairment (0.5 μg/kg/min), may be appropriate in critically ill patients who have multisystem organ failure (20) or who have decreased liver perfusion such as may occur following cardiothoracic surgery (21).…”

Effects of Critical Illness and Organ Failure on Therapeutic Argatroban Dosage Requirements in Patients with Suspected or Confirmed Heparin-Induced Thrombocytopenia

“…The overall distribution of therapeutic argatroban dosages among our critically ill patients correlates with those described in previous case reports 11 -13,22 and studies. 14,15 Collectively, these data strongly suggest that critically ill patients require argatroban dosages well below those designated in current FDA-approved labeling. Prior to our findings, however, limited data were available to guide argatroban dosage decisions in patients with nonhepatic organ failure.…”

“…RÉSULTATS: Cinquante-trois patients ont été inclus dans l'étude (34 patients en état critique et 19 patients en état non-critique). Les patients critiques avaient un score médian pour l'échelle d'APACHE II (17 [12][13][14][15][16][17][18][19][20][21] comparativement 10 [3.25-17.75]; p = 0.007) et de 11 (7)(8)(9)(10)(11)(12)(13) comparativement à 2 (0-2.75); p < 0.001 pour le score de SOFA. Les patients en état critique ont reçu en moyenne une posologie moins élevée d'argatroban (0.6 ± 0.5 vs 1.4 ± 0.9 µg/kg/min; p < 0.001).…”

Heparin‐Induced Thrombocytopenia: Treatment Options and Special Considerations

“…Other investigators have also reported low mean infusion rates for argatroban in patients with renal insufficiency. 123,124 Most of the available pharmacokinetic and pharmacodynamic data suggest that argatroban is not removed during hemodialysis. 125,126 However, one report noted a 20% increase in the systemic clearance of argatroban during intermittent hemodialysis in patients without HIT.…”