masthead


Frequently Asked Questions

Is bivalirudin an option for treating heparin-induced thrombocytopenia in patients not undergoing a percutaneous coronary intervention?

Introduction
Heparin-induced thrombocytopenia (HIT) is a serious and potentially fatal immune-mediated thrombogenic complication that is associated with both unfractionated heparin (UFH) and low molecular weight heparin (LMWH).1 Early recognition and treatment are essential in preventing morbidity (thrombosis, limb loss) and mortality. Direct thrombin inhibitors such as lepirudin and argatroban are Food and Drug Administration (FDA) labeled for the management of HIT; however, both agents have potential drawbacks with their use. Argatroban requires a dosage adjustment in hepatic insufficiency and increases the International Normalized Ratio (INR) when used with warfarin. The dose of lepirudin should be adjusted in renal insufficiency, and it may precipitate antibody formation. Bivalirudin is FDA-labeled for anticoagulation during percutaneous transluminal coronary angioplasty (PTCA), for anticoagulation during percutaneous coronary intervention (PCI) with provisional use of a glycoprotein IIb/IIIa antagonist, and for anticoagulation in patients with or at risk of HIT or HIT with thrombus syndrome (HITTS) undergoing PCI.2 Of note, bilvalirudin is also approved in Canada for patients with, or at risk of HIT or HITTS undergoing cardiac surgery.3 Its short half-life (25 minutes), minor renal excretion (20%), and predictable response are potential advantages when used in a critically ill patient.4,5

Supporting Literature
The recently published 8th edition of the American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines recommend using non-heparin anticoagulants (danaparoid, lepirudin, argatroban, fondaparinux, or bivalirudin) in place of UFH or LMWH in patients with suspected or confirmed HIT.3 For patients with acute HIT requiring cardiac surgery, the guidelines recommend delaying surgery until HIT has resolved and antibodies are negative. If surgery cannot be postponed, bivalirudin is then preferred for intraoperative anticoagulation if cardiac surgery and anesthesiology techniques have been adapted for its use. Bivalirudin, argatroban, lepirudin, or danaparoid are also recommended as alternatives to heparin preparations for patients with acute HIT who undergo PCI.

Until recently, most of the evidence to support using bivalirudin in cardiac surgery patients with HIT had been limited to case reports, retrospective case series, and small studies.6-10 Recently, an open-label, multicenter trial (CHOOSE-ON) prospectively enrolled 50 patients with confirmed or suspected HIT and/or antiplatelet factor 4/heparin antibodies who were undergoing coronary artery bypass grafting (CABG).11 Patients on cardiopulmonary bypass received bivalirudin 1 mg/kg bolus with a 50 mg bolus added to the priming solution of cardiopulmonary bypass followed by an infusion of 2.5 mg/kg/hour. Additional 0.1 to 0.5 mg/kg boluses were allowed in order to maintain the activated clotting time (ACT) >2.5 times its baseline value. In-hospital acute procedural success was the primary end point and was defined as the absence of death, Q-wave myocardial infarction, repeat operation for coronary revascularization, and stroke 7 days after the surgery or hospital discharge, whichever occurred first. The secondary endpoints mirrored the primary endpoints but were assessed 30 days and 12 weeks after surgery. Safety was specifically measured as perioperative blood loss, transfusions, and the incidence of major bleeding events. The primary endpoint was achieved in 94% of patients, and the success rates at 30 days and 12 weeks were 86% and 82%, respectively. Blood loss was 998  524 mL twenty-four hours after surgery, and 84% of patients required a blood transfusion. Ten patients with moderate renal insufficiency had results similar to the overall group. Despite the limitation of an open-label design, the authors concluded that bivalirudin has the potential to be a first-line treatment in patients with HIT who require alternative anticoagulation during cardiac surgery.

The CHOOSE-OFF trial evaluated 51 patients with HIT, HITTS or antiplatelet factor 4/heparin antibodies who were undergoing off-pump CABG.12 The primary and secondary endpoints in this prospective, open-label, multicenter study were identical to the CHOOSE-ON trial. Patients received bivalirudin at a dose of 0.75 mg/kg IV bolus followed by 1.75 mg/kg/hour to maintain the ACT >300 seconds. Procedural success was 92% at day 7 and 88% at both day 30 and week 12. Intraoperative blood loss was 936  525 mL, and 83% of patients required a transfusion. Based on the results of this trial and the CHOOSE-ON trial, the authors concluded that patients with HIT/HITTS can utilize bivalirudin regardless of whether cardiopulmonary bypass is used or not during CABG.

Case reports have also described successful use of bivalirudin in patients with HIT undergoing extracorporeal membrane oxygenation, cardiac valve replacement, heart transplantation, and carotid endarterectomy.13-17 Prospective, randomized trials with each of these clinical scenarios are currently lacking.

Dang and colleagues conducted a retrospective chart review to compare the efficacy, safety, and cost of therapy with argatroban, lepirudin, and bivalirudin in managing patients with HIT.18 Patients who received a direct thrombin inhibitor for PCI were excluded from analysis. The presence of HIT was determined by clinical history and laboratory determinations. The primary endpoint was the time to reach goal activated partial thromboplastin time (aPTT). A variety of secondary outcomes were evaluated including proportion of aPTT measurements per patient that were therapeutic, subtherapeutic, or supratherapeutic, laboratory and drug costs, duration of therapy, clinical outcomes (death, amputations, new thromboembolic events), and safety.

A total of 42 patients were enrolled, of who 13 received argatroban, 24 received bivalirudin, and 5 received lepirudin.18 Several of the patients had renal dysfunction, hepatic dysfunction, or both. The bivalirudin group had the highest incidence of dual renal/hepatic dysfunction at baseline (12 [50%] of 24). The authors reported the average (range) initial, lowest, and highest doses for each direct thrombin inhibitor. For argatroban the initial dosing was 2 mcg/kg/minute (0.5 to 20), the lowest dose was 1 mcg/kg/minute (0.05 to 3), and the highest dose was 2 mcg/kg/minute (1.25 to 20). Values for bivalirudin were 0.1 mg/kg/hour (0.03 to 0.8), 0.08 mg/kg/hour (0.004 to 0.8), and 0.17 mg/kg/hour (0.031 to 0.95), respectively. Average doses for lepirudin were 0.075 mg/kg/hour (0.045 to 0.14), 0.04 mg/kg/hour (0.025 to 0.086), and 0.1 mg/kg/hour (0.045 to 0.16), respectively.

No significant difference was found among groups for the time to reach therapeutic aPTT (14 hours, 8.5 hours, and 24 hours for argatroban, bivalirudin, and lepirudin, respectively, p=0.124).18 The average length of therapy was 15.7 days for argatroban, 7.1 days for bivalirudin, and 5.2 days for lepirudin. No significant difference was found in the percentage of patients with therapeutic, subtherapeutic, or supratherapeutic aPTTs among groups. The average percentage of therapeutic aPTTs per patient was 62% with argatroban, 57% with bivalirudin, and 29% with lepirudin (p=0.062). Clinical outcomes were similar among groups, and the incidence of major bleeding was higher with argatroban (8 [62%] of 13) and bivalirudin (14 [58%]) as compared to lepirudin (1 [20%], p=not reported). Laboratory costs were similar, but average drug cost (based on average wholesale price) per day was less with bivalirudin ($533) as compared to argatroban ($884) and lepirudin ($1759). Based on the similar results for the 3 direct thrombin inhibitors, the authors concluded that bivalirudin was appropriate for the management of HIT at their institution. In addition, it was the least costly option of the agents reviewed.

Conclusions
Based on its favorable pharmacokinetic profile, positive results of recent clinical trials, and the most recent ACCP recommendations, bivalirudin appears to be an acceptable alternative for general use as an anticoagulant in patients with HIT.

References

  1. Dager WE, Dougherty JA, Nguyen PH, Militello MA, Smythe MA. Heparin-induced thrombocytopenia: treatment options and special considerations. Pharmacotherapy. 2007;27(4):564-587.
  2. Warkentin TE, Greinacher A, Koster A, Lincoff AM. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(suppl 6):340-380.
  3. Angiomax [package insert]. Bedford, OH: BenVenue Laboratories; 2005.
  4. Seybert AL, Coons JC, Zerumsky K. Treatment of heparin-induced thrombocytopenia: is there a role for bivalirudin? Pharmacotherapy. 2006;26(2):229-241.
  5. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia and cardiac surgery. Ann Thorac Surg. 2003;76(2):2121-2131.
  6. Bott JB, Reddy K, Krick S. Bivalrudin use in off-pump myocardial revascularization in patients with heparin-induced thrombocytopenia. Ann Thorac Surg. 2003;76(1):273-275.
  7. Davis Z, Anderson R, Short D, Garber D, Valgiusti A. Favorable outcome with bivalirudin anticoagulation during cardiopulmonary bypass. Ann Thorac Surg. 2002;74(6):2177-2179.
  8. Koster A, Spiess B, Chew DP, et al. Effectiveness of bivalirudin as a replacement for heparin during cardiopulmonary bypass in patients undergoing coronary artery bypass grafting. Am J Cardiol. 2004;93(3):356-359.
  9. Clayton SB, Ascell JR, Crumbley AJ, Shackelford AG, Uber WE. Cardiopulmonary bypass with bivalirudin in type II heparin-induced thrombocytopenia. Ann Thorac Surg. 2004;78(6):2167-2169.
  10. Dyke CM, Koster A, Veale J, Maier GW, McNiff T, Levy JH. Preemptive use of bivalirudin for urgent on-pump coronary artery bypass grafting in patients with potential heparin-induced thrombocytopenia. Ann Thorac Surg. 2005;80(1):299-303.
  11. Koster A, Dyke CM, Aldea G, et al. Bivalirudin during cardiopulmonary bypass in patients with previous or acute heparin-induced thrombocytopenia and heparin antibodies: results of the CHOOSE-ON trial. Ann Thorac Surg. 2007;83(2):572-577.
  12. Dyke CM, Aldea G, Koster A, et al. Off-pump coronary artery bypass with bivalirudin for patients with heparin-induced thrombocytopenia or antiplatelet factor four/heparin antibodies. Ann Thorac Surg. 2007;84(3):836-840.
  13. Stratmann G, deSilva AM, Tseng EE, et al. Reversal of direct thrombin inhibition after cardiomyopulmonary bypass in a patient with heparin-induced thrombocytopenia. Anesth Analg. 2004;98(6):1635-1639.
  14. Finks SW. Bivalirudin use in carotid endarterectomy in a patient with heparin-induced thrombocytopenia. Ann Pharmacother. 2006;40(2):340-343.
  15. Davis Z, Anderson R, Short D, Garber D, Valgiusti A. Favorable outcome with bivalirudin anticoagulation during cardiopulmonary bypass. Ann Thorac Surg. 2003;75(1):264-265.
  16. Koster A, Weng Y, Bottcher W, Gromann T, Kuppe H, Hetzer R. Successful use of bivalirudin as anticoagulant for EMCO in a patient with acute HIT. Ann Thorac Surg. 2007;83(5):1865-1867.
  17. Vasquez JC, Vichiendilokkul A, Mahmood S, Baciewicz FA. Anticoagulation with bivalirudin during cardiopulmonary bypass in cardiac surgery. Ann Thorac Surg. 2002;74(6):2177-2179.
  18. Dang CH, Durkalski VL, Nappi JM. Evaluation of treatment with direct thrombin inhibitors in patients with heparin-induced thrombocytopenia. Pharmacotherapy. 2006;(4):461-468.