Bivalirudin is approved for iv administration only and dosing regimens for patients undergoing PCI (including patients with HIT) are well established. There are no well established dosing guidelines for other indications (Dager and White, 2002), although dosing regimens for certain indications have been reported. In three patients with venous and arterial thrombosis treated with bivalirudin for HIT, Chamberlin and associates (1994) used doses ranging from 0.05 to 0.20mg/kg/h. Their goal was to maintain a therapeutic aPTT greater than 50 s. Bufton and coworkers (2002a) used an average dose of 0.27mg/kg/h in one patient who received bivalirudin for over 2 mo while Berilgen et al. (2003) initiated therapy at a mean dose of 0.16mg/kg/h in 15 suspected HIT patients maintaining a mean dose of 0.11 mg/kg/h. All patients achieved a therapeutic aPTT within 24 h.

Francis and colleagues (2004) have used bivalirudin in patients with both clinically suspected and confirmed HIT. Initial infusion rates ranged from 0.15 to 0.20 mg/kg/h and their target aPTT was a 1.5- to 2.5-fold prolongation of the baseline aPTT value. Ramirez et al. (2005) reported doses ranging from 0.03 to 0.2 mg/kg/h in 42 patients, many with multiorgan failure who were clinically suspected of, or had a history of, HIT. More recently, Kiser and Fish (2006) reported mean bivalirudin doses for critically ill patients with hepatic and renal dysfunction, including 10 patients receiving continuous venovenous hemofiltration (CVVH) with or without dialysis. They recommended doses of 0.14 mg/kg/h for patients with hepatic dysfunction, 0.03 to 0.05 mg/kg/h in those with renal or combined renal/hepatic dysfunction, and 0.03 to 0.04 mg/kg/h in patients receiving CVVH. Finally, Dang et al. (2006), reviewing their experience with 24 patients who received bivalirudin for confirmed or presumed HIT, found doses ranged from 0.10 to 0.17mg/kg/h.

Based on these studies, a reasonable regimen might be to start at 0.10 to 0.15mg/kg/h (no initial bolus) for non-interventional procedures, with subsequent adjustments according to aPTT. However in patients with renal or hepatic dysfunction (or both), much lower doses are advised.

For HIT patients undergoing PCI, the dose initially recommended in the "Anticoagulant Therapy with Bivalirudin to Assist in the Performance of Percutaneous Coronary Intervention in Patients with Heparin-induced Thrombocytopenia" (ATBAT) trial was a bolus of 1.0 mg/kg followed by an infusion of 2.5mg/kg/h for 4 h. This dose was later changed to a bolus of 0.75 mg/kg followed by a 1.75mg/kg/h infusion over 4 h, based on data from the Comparison of Abciximab Complications with Hirulog Ischemic Events Trial (CACHET) and Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events Trial (REPLACE-1) trials (Mahaffey, 2001; Lincoff et al., 2002a).

Bivalirudin is approved for PTCA in patients with unstable angina The current recommended dose for patients with (near) normal renal function is a bolus of 0.75 mg/kg followed immediately by a continuous infusion at 1.75 mg/ kg/h for the duration of the procedure (Sciulli and Mauro, 2002; The Medicines Company, 2005). The bolus is given just prior to angioplasty. Continuation of the infusion for up to 4 h after the procedure is optional, at the discretion of the physician. After completing the 4 h infusion, additional bivalirudin may be given at a rate of 0.20 mg/kg/h for up to 20 h.

Bivalirudin infusion may need to be reduced in patients with moderate to severe renal impairment (GFR < 30 mL/min) (Robson et al., 2002, The Medicines Company, 2005), e.g., to 1.0 mg/kg/h (for GFR < 30 mL/min). In dialysis-dependent patients the dose is reduced to 0.25 mg/kg/h and ideally should be given when the patient is off dialysis (Sciulli and Mauro, 2002; The Medicines Company, 2005) (Table 1).

Allie et al. (2003) used doses similar to the modified ATBAT trial dose for percutaneous transluminal angioplasty (PTA) of the renal and iliac arteries. Following a 0.75 mg/kg iv bolus, bivalirudin was subsequently given by infusion (1.75 mg/kg/h) until completion of the procedure. Similar bivalirudin doses were also used by Shammas and colleagues (2003) in a single-center experience, by Allie et al. (2004) in The Angiomax Peripheral Procedure Registry Of Vascular Events (APPROVE) Trial involving patients undergoing intervention for renal, iliac, and femoral vessels and by Katzen and colleagues (2005) in patients who underwent peripheral interventions of the lower extremities (iliac, femoropopliteal, or distal), and carotids, vertebrals, renal, aorta, and subclavian vessels. Of note, bivalirudin is not FDA approved for any of these indications.

For cardiac surgery using cardiopulmonary bypass (CPB), i.e., on-pump surgery, about two- to threefold greater levels of anticoagulation are required, compared with OPCAB. (For details regarding these protocols, including important technical considerations for the cardiac surgeon and cardiac anesthesiologist, see Chapter 19; see also Warkentin and Greinacher, 2003; Warkentin and Koster, 2005.)

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