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Keywords:

  • heparin-induced thrombocytopenia;
  • HIT;
  • bivalirudin;
  • direct thrombin inhibitor;
  • kidney dysfunction;
  • thrombosis;
  • adverse drug reaction

Study Objectives. To evaluate steady-state bivalirudin dosing requirements in patients with a wide range of kidney function who were being treated for heparin-induced thrombocytopenia (HIT)-related disorders.

Design. Retrospective medical record review.

Setting. Academic medical center.

Patients. Sixty-four adults with varying degrees of renal function who were receiving bivalirudin for at least 48 hours for HIT-related disorders between March 2007 and May 2010.

Measurements and Main Results. Steady-state conditions were defined as a constant bivalirudin infusion dose for at least 12 hours, with serum creatinine concentration varying less than 20% for 48 hours (for patients not receiving renal replacement therapy) and at least two therapeutic activated partial thromboplastin time (aPTT) values (60–80 sec). Patients were assigned to five groups based on Cockcroft-Gault-estimated creatinine clearance (Clcr) of less than 30, 30–60, or greater than 60 ml/minute, or by type of renal replacement therapy—intermittent hemodialysis or continuous venovenous hemofiltration (CVVH). For Clcr greater than 60 ml/minute, the median bivalirudin dose was 0.15 mg/kg/hour (interquartile range [IQR] 0.11–0.15 mg/kg/hr), which was greater than median doses for Clcr 30–60 ml/minute (0.10 mg/kg/hr, IQR 0.06–0.13 mg/kg/hr, p=0.004), Clcr less than 30 ml/minute (0.08 mg/kg/hr, IQR 0.04–0.1 mg/kg/hr, p=0.001), CVVH (0.06 mg/kg/hr, IQR 0.03–0.10 mg/kg/hr, p=0.046), and hemodialysis (0.04 mg/kg/hr, IQR 0.03–0.05 mg/kg/hr, p=0.0001). Bivalirudin doses correlated with Clcr (Spearman r = 0.58, p<0.01). The median aPTT value of 70 seconds (IQR 63–74 sec) was similar in all groups. Thrombosis was present before bivalirudin therapy in 18 (28%) of 64 patients, and two patients (3%) developed thromboemboli during bivalirudin therapy. Clinically significant bleeding related to bivalirudin and leading to discontinuation of bivalirudin occurred in four patients (6%). The median international normalized ratio increased from 1.5 (IQR 1.3–1.7) before bivalirudin therapy to 1.9 (IQR 1.8–2.1) during bivalirudin therapy (p=0.002) in 11 patients who were not receiving warfarin.

Conclusion. Bivalirudin dosing requirements increased with increasing Clcr values. The high degree of variability suggests that dosing in individual patients will require careful titration to achieve adequate anticoagulation.