Argatroban Anticoagulation in Intensive Care Patients: Effects of Heart Failure and Multiple Organ System Failure

Abstract

We retrospectively evaluated argatroban dosing patterns, clinical outcomes, and the effects of heart failure and multiple organ system failure on dosing requirements in 65 adult, intensive care patients administered argatroban anticoagulation for clinically suspected heparin-induced thrombocytopenia (n=56) or history of heparin-induced thrombocytopenia (n=9). Argatroban was initiated then titrated to achieve target activated partial thromboplastin times 1.5 to 3 times normal control (ie, 42-84 seconds). Overall, argatroban was initiated at 1.14+/-0.62 microg/kg/min (mean+/-SD) and administered for 11.4+/-9.5 days, with comparable dosing patterns between patients with suspected, versus previous, heparin-induced thrombocytopenia. Sixty-four (98.5%) patients achieved target activated partial thromboplastin times, typically following no or one dose adjustment. Therapeutic doses were lower in patients with, versus without, heart failure (0.58+/-0.28 vs 0.97+/-0.6 microg/kg/min, P= .042) and decreased as the number of failed organ systems increased from 1 to 2 to =3 (1.10+/-0.67 vs 0.87+/-0.47 vs 0.58+/-0.47 microg/kg/min, P= .008). From argatroban initiation until patient discharge or death, 11 (16.9%) patients (3 off argatroban) developed thromboembolic complications; 14 (21.5%) died (11 off argatroban, 7 from multiple organ system failure); and 1 (1.5%) required amputation. Nine patients (13.8%) experienced bleeding, none fatal. This experience suggests that argatroban administered at approximately 1 micro/kg/min provides adequate levels of anticoagulation in many intensive care unit patients with suspected or previous heparin-induced thrombocytopenia. Reduced doses are needed when heart failure or multiple organ system failure is present.

Clinical Experience with Argatroban for Heparin-Induced Thrombocytopenia in a Large Teaching Hospital

“…Liver failure was present in 3.1% of the patients in that study. 29 In the study reported here, critically ill patients had initial doses of 0.5 to 5 µg/kg per minute and required the greatest number of dosage reductions, relative to patients with hepatic or renal dysfunction or acute cardiac disease. These results are consistent with reports of lower dosing of argatroban for critically ill patients.…”

“…Small studies and case series of 4 to 65 patients have reported maintenance doses of 0.125 to 0.91 µg/kg per minute. 17,18,20,29 Conversely, initial infusions of 1.5 to 2 µg/kg per minute in these patients have resulted in supratherapeutic aPTTs and bleeding. 17,18 One group of authors suggested that passive hepatic congestion, accumulation of metabolites, and/or interactions with multiple medications used in the ICU may justify lower dose requirements.…”

“…17,18 One group of authors suggested that passive hepatic congestion, accumulation of metabolites, and/or interactions with multiple medications used in the ICU may justify lower dose requirements. 20 In a retrospective study of 65 ICU patients, 29 it was noted that significantly lower doses were required to achieve therapeutic aPTT as the number of failed organ systems increased from 1 (n = 26; 1.1 µg/kg per minute) to 2 (n = 26; 0.87 µg/kg per minute) to 3 (n = 13; 0.58 µg/kg per minute) (p = 0.008). Liver failure was present in 3.1% of the patients in that study.…”

Pharmacology of argatroban

“…The impact of heart failure and multiple organ system failure on argatroban dosing was evaluated retrospectively in intensive care patients receiving argatroban therapy owing to a suspicion or history of HIT [26]. A reduced dose of argatroban (~1 µg/kg/min) was shown to provide adequate anticoagulation in intensive care patients.…”

Impact of renal function on argatroban therapy during percutaneous coronary intervention

“…In the prospective studies from which the analysis population was identified, patients with hepatic dysfunction were excluded and ejection fractions were not recorded. At the levels of anticoagulation used in the non-interventional setting, argatroban dose requirements are reduced in patients with hepatic dysfunction [6,30] or conditions such as heart failure or multiple organ system failure that may indirectly affect hepatic function via decreased perfusion [1,31]. It is possible that such morbidities may have contributed to the supratherapeutic ACTs observed in some argatroban-treated patients during PCI, although this remains to be evaluated.…”