Bivalirudin Anticoagulation for Cardiopulmonary Bypass
Abstract: The standard agent used for systemic anticoagulation during cardiopulmonary bypass is heparin. Alternative methods of anticoagulation are required for patients with heparin hypersensitivity. We present the case of a patient with heparin hypersensitivity who was anticoagulated with bivalirudin during cardiopulmonary bypass for coronary artery bypass grafting. This presented unusual challenges surrounding the monitoring of anticoagulation and the method of myocardial protection.
Heparin remains the gold standard for anticoagulation during cardiopulmonary bypass (CPB) because of its rapid onset of action, reliable effect, low cost, and reversibility. However, hypersensitivity to heparin poses substantial challenges for cardiac surgical interventions. An alternative approach for hypersensitive patients who need coronary artery bypass grafting (CABG) is off-pump coronary artery bypass (OPCAB); nevertheless, a reserve strategy needs to be in place, in case hemodynamic instability during OPCAB should necessitate the institution of CPB.
Alternatives to heparin are ancrod,1,2 danaproid,3 lepirudin,4 argatroban,5 platelet IIb/IIIa inhibitor (trifiban),6 and prostacyclin.7 All of these drugs have been used, but they have limitations. A recent alternative, bivalirudin, is a direct thrombin inhibitor with rapid anticoagulative effect; excreted renally, bivalirudin has a short half-life. To date, bivalirudin is licensed for use only in percutaneous coronary interventions (PCI),8 and only a few published reports exist for its use in CPB in patients with heparin-induced thrombocytopenia.7,9,10 We describe a case of a patient with heparin hypersensitivity who required CABG using bivalirudin anticoagulation.
Case Report : A 42-year-old man who was a smoker with a 6-month history of exertional angina presented with acute inferolateral myocardial infarction associated with ventricular fibrillatory arrest. The patient was successfully resuscitated, and his thrombi were lysed with streptokinase. Coronary catheterization showed an occluded posterior descending branch of the right coronary artery, an occluded left anterior descending artery, and severely narrowed intermediate and diagonal arteries. There was moderate left ventricular systolic dysfunction on transthoracic echocardiography. The patient’s medical history included asthma, hypertension, and morbid obesity (100 kg; body mass index, 39.1 kg/m2). During hospitalization, he developed an abdominal eczematous rash at the site of low-molecular-weight heparin (LMWH) injection. Dermatological consultation and subsequent skin biopsies confirmed hypersensitivity to LMWH. The rash did not improve when unfractionated heparin was tried. Discontinuation of heparin resulted in a gradual resolution of the skin reaction. Preoperatively, the patient had normal liver and renal function and normal hemoglobin and platelet values. He remained as an inpatient until surgery.
Surgery was undertaken 9 weeks after the myocardial infarction. In view of the patient’s coronary anatomy and ventricular function, we elected to undertake CABG with CPB, rather than use the OPCAB approach. Anticoagulation monitoring was undertaken by measuring activated clotting time (ACT), activated partial thromboplastin time ratio (aPTTR), and international normalized ratio (INR), and by obtaining a thromboelastogram (TEG). The baseline measurements during anesthetic induction were: ACT, 122 (Fig. 1); aPTTR, 1.46 (Fig. 2); INR, 1.1 (Fig. 2); and a normal TEG (Figs. 3 and 4). All of the above measurements were taken before, during, and after the bivalirudin infusion, at specific time intervals.
Bivalirudin (Angiomax®, The Medicines Company; Parsippany, NJ) was started as a bolus dose and infusion while we prepared for CPB. Published data suggested that a bolus of 1 mg/kg would result in an ACT of approximately 350 sec. Our ACT target for initiation of CPB was derived from previous reports10 and was ACT >400 sec and <500 sec, to avoid either clot formation in the CPB circuit or excessive anticoagulation. Initially, 100 mg (1 mg/kg) of bivalirudin bolus and an infusion of 2.5 mg/kg per hr was given. This resulted in an ACT of 291, an aPTTR of 4.52, and an INR of 3.4. A repeat bolus of 50 mg (0.5 mg/kg) and an increase in the infusion rate to 5 mg/kg per hr resulted in a rise in the ACT to 322; in the aPTTR, to 4.98; and in the INR, to 4.2. A further bolus of 100 mg (1 mg/kg) was given, and the infusion was continued at 5 mg/kg per hr. Repeat measurements were: ACT, 362; aPTTR, >5; and INR, 5.4. A final bolus of 100 mg (1 mg/kg) with the same rate of infusion (5 mg/kg per hr) increased the ACT to 426 and the INR to 8.52, and left the aPTTR at >5. We initiated CPB and continued the bivalirudin infusion at 5 mg/kg per hr. The ACT during the 61 min on CPB ranged between 404 and 462 sec.
Myocardial protection was undertaken using the cross-clamp fibrillation technique, in order to avoid a protracted period of cross-clamping and intravascular stasis. Four bypass grafts were performed (left internal mammary artery to the left anterior descending artery, and vein grafts to the diagonal, intermediate, and posterior descending arteries). The CPB time was 61 min. The patient was then weaned from CPB using low-dose dopamine support. In the post-CPB period, bivalirudin was reversed spontaneously by renal excretion. The ACT values declined from 404 to 270 one hr after termination of the infusion and, 2 hr afterwards, to 207. At the same points in time, the aPTTR declined from >5 to 4.7 and 2.78, and the INR fell from 7.46 to 3.2 and 2.4. During this period, the patient was transfused with 1 unit of platelets for persistent mediastinal oozing. Satisfactory hemostasis was achieved, and the operation was completed 2 hr after the end of CPB. During the early postoperative phase, there was a progressive normalization of the anticoagulation values (Figs. 1–4), and no substantial mediastinal bleeding was observed. The patient was discharged 7 days postoperatively with no morbidity.
Discussion: Delayed-type hypersensitivity reactions to subcutaneously injected unfractionated heparin or LMWH are relatively common. Particularly, extensive cross-reactivity between different heparins and heparinoids often occurs. It presents as eczema-like, infiltrated plaques at injection sites. The pathogenesis of heparin hypersensitivity is not fully understood. Heparin may act as a hapten by binding to dermal or subcutaneous structural proteins. Although intravenous administration of heparin may be tolerated, susceptible patients are at risk of developing a systemic reaction. It is therefore preferable to use alternative methods of anticoagulation when CPB is required.
Bivalirudin is a relatively new alternative anticoagulant. It is a semi-synthetic, specific, and reversible direct thrombin inhibitor.8 The active substance is a synthetic, 20-amino-acid peptide. Bivalirudin directly inhibits thrombin by specifically binding both to the catalytic site and to the anion-binding exosite of circulating and clot-bound thrombin. Bivalirudin does not bind to plasma proteins (other than thrombin) or to red blood cells. In vitro studies have found bivalirudin to inhibit both soluble (free) and clot-bound thrombin, which is not neutralized by products of the platelet release reaction. Bivalirudin prolongs the activated partial thromboplastin time, thrombin time, and prothrombin time of normal human plasma in a concentration-dependent manner.
Bivalirudin is cleared from plasma by a combination of renal mechanisms and proteolytic cleavage, with a half-life of approximately 25 min in patients with normal renal function. The disposition of bivalirudin was studied in PCI patients with mild, moderate, and severe renal impairment.7,11 Drug elimination was related to the glomerular filtration rate. Total body clearance was similar for patients with normal renal function and with mild renal impairment (60–89 mL/min). Clearance was reduced by approximately 20% in patients with moderate and severe renal impairment and by approximately 80% in dialysis-dependent patients.7,11 Bivalirudin should therefore be used with caution in the presence of renal dysfunction in order to avoid protracted postsurgical bleeding.
In our patient, 3 intravenous boli of bivalirudin and an infusion rate of 5 mg/kg per hr were required to achieve an ACT of above 400 sec. Although the recommended infusion rate is 2.5 mg/kg per hr for PCI, the dose requirement is patient-dependent and needs to be tailored to the anticoagulative response. We elected to monitor the anticoagulant status using both laboratory-based (aPTTR and INR) and operating-room-based (ACT and TEG) tests. All measured values showed similar responses to changes in bivalirudin administration. The TEG was used because it is a useful adjunct to monitor whole blood clotting and fibrinolysis and because it can provide rapid bedside information on the coagulation status (Figs. 3 and 4). The “R” value is the clotting or “reaction” time, and it indicates factor deficiency or thrombocytopenia; the “K,” or clot-formation time, depends upon fibrinogen and platelets. The alpha angle (measure of rate of clot formation by TEG) is abnormal in the presence of clotting-factor deficiencies, platelet dysfunction, thrombocytopenia, and hypofibrinogenemia; the maximum amplitude of the TEG is affected by platelet function and number and by fibrinogen.12 The case that we report here shows that TEG can be used in conjunction with ACT to monitor anticoagulation with bivalirudin in a predictable manner.
The main clinical drawback of bivalirudin is that it has no known antidote. Excessive bleeding is the main risk from this drug, although it may be hemodialyzed out of the circulation in patients with renal failure. In addition, because of the relatively short half-life of bivalirudin, we elected to avoid a protracted period of coronary stasis, by using a cross-clamp fibrillation technique for myocardial preservation, as opposed to the intermittent administration of cold-blood cardioplegic solution. Alternative strategies include continuous retrograde administration and frequent intermittent antegrade administration of cardioplegic solution, although occluded vessels rely initially on a collateral supply.
Moreover, clot formation in the CPB circuit shortly after discontinuation of CPB has been described.10 Therefore, after discontinuation of CPB and decannulation, we reconnected the circuit and continued circulating fluid through the pump-oxygenator, with ongoing infusion of bivalirudin into this circuit. This ensured the availability of the CPB circuit in case the patient became hemodynamically unstable.
Finally, the interaction of aprotinin and bivalirudin is unknown. Bivalirudin is a thrombin inhibitor, which is a serine protease, and aprotinin is a nonspecific serine protease inhibitor.13 In our patient, we elected not to use aprotinin, although it would usually be part of our CPB protocol. Top Conclusion Our case shows that bivalirudin can be used safely for CPB, and its anticoagulant effect monitored, with the aid of currently available laboratory- and operating-room-based tests of anticoagulation.
References:
Demers C, Ginsberg JS, Brill-Edwards P, Panju A, Warkentin TE, Anderson DR, et al. Rapid anticoagulation using ancrod for heparin-induced thrombocytopenia. Blood 1991;78:2194–7. [PubMed].
Cole CW, Fournier LM, Bormanis J. Heparin-associated thrombocytopenia and thrombosis: optimal therapy with ancrod. Can J Surg 1990;33:207–10. [PubMed].
Fernandes P, Mayer R, MacDonald JL, Cleland AG, Hay-McKay C. Use of danaparoid sodium (Orgaran) as an alternative to heparin sodium during cardiopulmonary bypass: a clinical evaluation of six cases. Perfusion 2000;15:531–9. [PubMed].
Riess FC, Kormann J, Poetzsch B. Recombinant hirudin as anticoagulant during cardiopulmonary bypass. Anesthesiology 2000;93:1551–2. [PubMed].
Swan SK, Hursting MJ. The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction. Pharmacotherapy 2000;20:318–29. [PubMed].
Koster A, Kukucka M, Bach F, Meyer O, Fischer T, Mertzlufft F, et al. Anticoagulation during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II and renal impairment using heparin and the platelet glycoprotein IIb-IIIa antagonist tirofiban. Anesthesiology 2001;94:245–51. [PubMed].
Maraganore JM, Adelman BA. Hirulog: a direct thrombin inhibitor for management of acute coronary syndromes. Coron Artery Dis 1996;7:438–48. [PubMed].
Vasquez JC, Vichiendilokkul A, Mahmood S, Baciewicz FA Jr. Anticoagulation with bivalirudin during cardiopulmonary bypass in cardiac surgery. Ann Thorac Surg 2002;74:2177–9. [PubMed].
Gordon G, Rastegar H, Schumann R, Deiss-Shrem J, Denman W. Successful use of bivalirudin for cardiopulmonary bypass in a patient with heparin-induced thrombocytopenia. J Cardiothorac Vasc Anesth 2003;17:632–5. [PubMed].
Clayton SB, Acsell JR, Crumbley AJ 3rd, Uber WE. Cardiopulmonary bypass with bivalirudin in type II heparin-induced thrombocytopenia. Ann Thorac Surg 2004;78:2167–9. [PubMed].
Gaigl Z, Pfeuffer P, Raith P, Brocker EB, Trautmann A. Tolerance to intravenous heparin in patients with delayed-type hypersensitivity to heparins: a prospective study. Br J Haematol 2005;128:389–92. [PubMed].
Jappe U, Juschka U, Kuner N, Hausen BM, Krohn K. Fondaparinux: a suitable alternative in cases of delayed-type allergy to heparins and semisynthetic heparinoids? A study of 7 cases. Contact Dermatitis 2004;51:67–72. [PubMed].
Robson R. The use of bivalirudin in patients with renal impairment. J Invasive Cardiol 2000;12 Suppl F:33F-6.
