title: Effect of renal function on argatroban therapy in heparin-induced thrombocytopenia.
abstract: BACKGROUND
  Argatroban is considered to be an alternative anticoagulant of choice in patients with heparin-induced thrombocytopenia (HIT) and renal impairment. The recommended initial dose in HIT is 2 microg/kg/min (0.5 microg/kg/min in hepatic impairment), adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline. Although argatroban is predominantly hepatically metabolized with minimal renal clearance, recent limited data have suggested that a patient's renal function should also be considered when initiating argatroban therapy for HIT. We retrospectively evaluated the effect of renal function on argatroban therapy in HIT patients with normal hepatic function, with the goal of refining dosing guidance, if needed.
  
  
  METHODS
  From case records of previous prospective studies of argatroban in clinically diagnosed HIT, we identified patients who had baseline laboratory data on liver and renal function. Individuals with abnormal hepatic function (serum total bilirubin > 1.5 mg/dl or ALT or AST > 100 U/l) were excluded. Patients were stratified according to their estimated creatinine clearance (CL(cr)): normal or mild impairment (CL(cr) > 60 ml/min), moderate impairment (CL(cr) 30-60 ml/min), or severe impairment (CL(cr) < 30 ml/min). Argatroban doses, aPTTs, and clinical outcomes were summarized overall and by group. By-patient relationships between CL(cr) and dose or aPTT during therapy were explored using regression analyses.
  
  
  RESULTS
  The analysis population included 260 patients with normal to mild (n = 144), moderate (n = 80), or severe (n = 36) renal impairment. Argatroban was initiated at a mean infusion dose of 1.8 +/- 0.7 microg/kg/min (overall), titrated to achieve aPTTs 1.5-3 times baseline. Among renal function groups, no significant differences occurred in argatroban dose during therapy (overall value, 1.9 +/- 1.1 microg/kg/min), duration of therapy (7 +/- 6 days), or aPTTs (63 +/- 17 s). Regression analyses showed a 0.1 microg/kg/min increase in dose (r2 = 0.02) for each 30 ml/min increase in CL(cr). Within a 37 day follow-up, 46 (17.7%) patients died, most often when severe renal impairment was present. New thrombosis (11.5% overall) and major bleeding (5.0%) did not differ among groups.
  
  
  CONCLUSIONS
  In this large cohort of HIT patients with normal hepatic function and varying levels of renal function, argatroban administered in accordance with current recommendations provided adequate levels of anticoagulation and was well tolerated. Altered renal function did not clinically significantly affect argatroban doses, aPTT responses, or rates of thrombosis or bleeding. These findings further support argatroban as an alternative anticoagulant of choice, without need for initial dose adjustment, in most patients with HIT and renal impairment.
  
  
  CONCLUSIONS
  We retrospectively evaluated the effect of renal function on argatroban therapy in HIT patients with normal hepatic function, with the goal of refining current dosing guidance, if needed. From previous prospective studies of argatroban in HIT, we identified 260 patients with clinically diagnosed HIT, normal hepatic function, and varying degrees of renal function. Among patients whose renal function was normal or mildly impaired (estimated creatinine clearance, CL(cr) > 60 ml/min); moderately impaired (CL(cr) 30-60 ml/min), or severely impaired (CL(cr) < 30 ml/min), no significant differences occurred in the argatroban dose, aPTT response, duration of therapy, or rates of thrombosis or major bleeding. By regression analysis, there was a clinically insignificant 0.1 microg/kg/min increase in dose for each 30 ml/min increase in CL(cr). Overall, argatroban administered in accordance with current recommendations provided adequate levels of anticoagulation and was well tolerated, supporting its use as an alternative anticoagulant of choice, without need for initial dose adjustment, in most patients with HIT and renal impairment.
authors.affiliation: Florida Hospital, Orlando, FL, USA.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Guzzi
authors.forename: David A
authors.initials: DA
authors.lastname: McCollum
authors.forename: Marcie J
authors.initials: MJ
authors.lastname: Hursting
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000009:adverse effects* / Q000627:therapeutic use; D001120:Arginine / Q000031:analogs & derivatives; D015331:Cohort Studies; D003404:Creatinine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006493:Heparin / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D007674:Kidney Diseases / Q000150:complications*; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D010314:Partial Thromboplastin Time; D010875:Pipecolic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D012189:Retrospective Studies; D013449:Sulfonamides; D013921:Thrombocytopenia / Q000139:chemically induced*
chemical_list: D000925:Anticoagulants; D010875:Pipecolic Acids; D010975:Platelet Aggregation Inhibitors; D013449:Sulfonamides; D006493:Heparin; D001120:Arginine; D003404:Creatinine; C031942:argatroban