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Ann Thorac Surg 2003;76:273-275
© 2003 The Society of Thoracic Surgeons

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Case report

Bivalrudin use in off-pump myocardial revascularization in patients with heparin-induced thrombocytopenia

^a Department of Cardiovascular Surgery, Orlando, Florida, USA
^b Department of Cardiology, Orlando, Florida, USA
^c Department of Pharmacy, Orlando Regional Medical Center, Orlando, Florida, USA

Accepted for publication January 19, 2003.

^* Address reprint requests to Dr Bott, 217 Hillcrest St, Orlando, FL 32809, USA
e-mail: jbott{at}cvsorlando.com

	Abstract

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With advances in therapy of acute coronary syndromes, repetitive exposure to heparin has become commonplace. Consequently, the incidence of heparin-induced thrombocytopenia has risen. Limited strategies for management exist, and new thrombin inhibitors may provide safe alternatives to heparin. Two patients with documented heparin-induced thrombocytopenia underwent revascularization using a new thrombin inhibitor (Bivalrudin [Angiomax, Medicines Co, Cambridge, MA]) for anticoagulation. Both patients had uneventful perioperative hospitalizations. Thrombin inhibition with Bivalrudin (Angiomax) may provide a safe reliable alternative to heparin use in cardiac surgery.

	Introduction

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The management of patients with heparin-induced thrombocytopenia (HIT) requiring surgical revascularization can be quite challenging. Few alternatives exist for safe, reliable anticoagulation. Experience with low molecular weight heparin preparations demonstrate significant cross reactivity with heparin antibodies. Snake venom derivatives such as Ancrod (Knoll Pharmaceuticals, Whippany, NJ) are difficult to monitor and have long half-lives. Hirudin and its derivatives including Lepirudin (Aventis Pharmaceuticals, Bridgewater, CT) and Argatroban (Glaxo-SmithKline, Research Triangle, NC) are more reliable, but still have long half-lives. A common feature to all the alternatives is an inability to reverse the anticoagulant effect. Recently, a synthetic hirudin analogue (Bivalrudin [Angiomax, Medicines Co, Cambridge, MA]) was released and approved for percutaneous coronary intervention and management of acute coronary syndromes, with its unique feature of a short half-life. We describe the use of Bivalrudin (Angiomax) for anticoagulation in coronary artery bypass in 2 patients with HIT.

	Case reports

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Patient 1
A 57-year-old man presented to an outside hospital with classic anginal symptoms and electrocardiographic evidence of acute inferolateral ischemia. Angiography was performed and stents were deployed with satisfactory results. Heparin was used per standardized protocol during the procedure. The patient was discharged home on plavix (Clopidogrel, Bristol-Myers Squibb, Princeton, NJ) and aspirin.

This patient presented to our facility 5 days later with similar, more intense chest pain. Immediate catheterization demonstrated an occlusion at the area of stent deployment. His admission platelet count was 233,000, and a nadir count of 4,000 was reached less then 24 hours after admission and initiation of heparin. A heparin antibody panel returned positive (enzyme-linked immunosorbent assay). He experienced postinfarction angina, and surgical consultation was obtained.

In view of an active positive heparin antibody, anticoagulation alternatives were explored and Bivalrudin (Angiomax) was selected for its short half-life and ease of monitoring. In preparation for surgery, other thrombin inhibitors and antiplatelet agents were discontinued at midnight. Then a loading dose (0.25 mg/kg) of Bivalrudin (Angiomax) was given. A constant infusion (beginning at 0.55 mg/kg/h) was started with a goal of greater than 200 s on the activated clotting time (ACT). Plans were formulated to perform off-pump revascularization with cardiopulmonary bypass only for unmanageable hemodynamic compromise.

Saphenous vein harvest was uneventful, and the wounds were dry and closed without drains. A routine sternotomy was performed. Additional bolus therapy and infusion adjustments (see Table 1) were necessary to achieve a desired ACT greater than 300 seconds, which, in our experience, is adequate for off-pump revascularization.

Flow-through occluders were used to avoid intracoronary low-flow states and reduce the risk of thrombus formation. A cell saver scavenged shed blood into a citrate-dextrose-phosphate containing reservoir. Clot was noted on several occasions in the pericardial well. The Bivalrudin (Angiomax) infusion was discontinued with the completion of the last proximal.

The patient was taken to the intensive care unit in stable condition on 3 µg per kilogram per minute of dobutamine. Hourly chest tube outputs (mL) measured 40, 80, 95, 65, and 10, and then averaged less than 50 mL per hour over the next 18 hours until they were removed. He was extubated 4 hours after intensive care unit admission. The first postoperative coagulation profile demonstrated an ACT of 115, a prothrombin time of 13.2 seconds (international normalized ratio, 1.3) and a partial thromboplastin time of 31 seconds within 12 postoperative hours. The remainder of his hospitalization was uneventful. He was discharged from the hospital in good condition on postoperative day 4.

Patient 2
A 72-year-old woman was admitted to the hospital with renal colic and urosepsis. Twenty-four hours after admission she had chest pain develop and was diagnosed with an anterior wall non-Q wave myocardial infarction. She was treated with various combinations of medications including both intravenous heparin as well as low molecular weight heparin. A catheterization demonstrated critical left anterior descending coronary artery and right coronary disease not amenable to angioplasty.

The admission platelet count was 208,000, and after 4 days of heparin exposure her nadir reached 62,000. A diagnosis of HIT was confirmed by standard enzyme-linked immunosorbent assay antibody testing. She experienced postinfarction angina and Argatroban (Glaxo-SmithKline, Research Triangle, NC) was initiated. We were called for revascularization.

The perioperative care of patient 2 was conducted in a fashion similar to patient 1. At midnight before her surgery a Bivalrudin (Angiomax) bolus (0.75 mg/kg) was administered with an infusion (1.75 mg/kg/h) at a notably higher dosing regimen compared with patient 1. The initial ACT was 332, and the infusion was reduced by one third (1.15 mg/kg/h) to achieve a desired preoperative ACT of 232 (goal: 200 to 250 seconds).

A three-vessel off-pump revascularization was performed on patient 2 in a manner similar to patient 1. A left internal mammary artery was grafted to the left anterior descending artery with individual saphenous vein grafts to the diagonal and posterior descending artery. We did not adjust the infusion rate of Bivalrudin (Angiomax) established preoperatively, but elected to try bolus therapy (see Table 2).

	Comment

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Heparin-induced thrombocytopenia can be a limb and life-threatening problem occurring in 3% to 5% of patients exposed to unfractionated heparin for greater than 4 days, or sooner if exposure to heparin has occurred in the preceding 3 months [1, 2]. Heparin-induced thrombocytopenia can be further subdivided into HIT-1 and HIT-2, with HIT-1 resulting from platelet sequestration and increased clearance. Heparin-induced thrombocytopenia-2 results from IgG-mediated antibodies to the heparin and platelet factor IV complex. The immune-mediated phenomenon results in thrombotic complications in 30% to 80% of HIT patients [1, 2]. The management of these patients undergoing revascularization is quite problematic. Alternatives to heparin that are reliable, safe, predictable, and reversible do not exist.

Unlike unfractionated heparin, the low molecular weight heparins have a more inhibitory effect on factor Xa, not activated thrombin (IIa) [3]. Furthermore, none of the low molecular weight heparins are reversible and their half-lives range from 2 to 4 hours [3]. Cross reactivity of HIT antibodies may be found in 90% of patients. There is no standard dosing regimen or satisfactory monitoring test to ensure a safe procedure.

Ancrod (Knoll Pharmaceuticals, Whippany, NJ), a glycosylated, fibrinogenolytic serine protease, achieves its anticoagulant effect by degrading fibrinogen and preventing fibrin generation. It can take 12 hours to achieve the appropriate safe levels for revascularization. The half-life is 3 to 5 hours and there are no satisfactory monitoring tests [4].

From a surgical perspective, hirudin and its analogs are the most reliable, safe, and predictable. Unfortunately they also have relatively long half-lives. Naturally occurring hirudin irreversibly binds thrombin. Hirudin is a 65 amino acid protein from the leech Hirudo medicinalis[5]; as a foreign protein it is potentially antigenic. Recombinant hirudin, Lepirudin, has been used successfully for anticoagulation and resembles naturally occurring hirudin with the exception of the 63-Tyrosine molecule [5]. Lepirudin (Aventis Pharmaceuticals, Bridgewater, CT) has a 30- to 60-minute half-life if renal function is normal [6]. Lepirudin is typically monitored by the partial thromboplastin time or Ecarin clotting time. There is no antidote. Because of these characteristics, Lepirudin is less than ideal for anticoagulation during bypass surgery.

Likewise, Argatroban is a competitive direct thrombin inhibitor. It is hepatically metabolized and excreted in the biliary system. Approximately 25% is cleared through the kidneys. The unique disadvantage of Argatroban is a hypercoagulable state induced by abrupt discontinuation of an infusion [7]. Steady state levels can take 1 to 3 hours to reach. Monitoring tests include prothrombin time, partial thromboplastin time, thrombin time, and ACT. The half-life is 30 to 60 minutes and there is no antidote. Similarly, these characteristics are less than ideal for anticoagulation during bypass surgery.

We report the use of Bivalrudin (Angiomax), which possesses the qualities of safety, reliability, and predictability common to the hirudin-type drugs. However, this drug is different because it has a 20- to 30-minute half-life, making it a reasonable substitute for heparin. A postinfusion hypercoagulable state has not been observed. This drug is a specific and reversible direct thrombin inhibitor, and it is deactivated by cleaving the two terminal amino acids. Bivalrudin (Angiomax) is cleared by proteolytic cleavage and renally; therefore, dosing must be adjusted for an abnormal creatinine clearance. The drug is hemodialyzable and can be monitored with prothrombin time, partial thromboplastin time, thrombin time, or ACT. Significant antibody formation has not been documented [8].

Certain precautions are recommended for use during revascularization with Bivalrudin (Angiomax). Vessel occluders or maneuvers that may allow blood stagnation should be avoided, because clots will develop in a relatively short time. Blood should not be allowed to stand inside grafts without frequent flushing. Shed blood should be scavenged immediately. To avoid these premature coagulation problems, a more aggressive dosing regimen may be considered. However, higher doses may offset the time savings intended with the use of Bivalrudin (Angiomax).

In conclusion, we found Bivalrudin (Angiomax) to be a predictable, safe alternative to heparin. The primary advantages of a short half-life and ease of monitoring make this drug an excellent alternative for patients in whom heparin cannot be used. Certainly the best anticoagulant for a patient with HIT requiring revascularization depends on the experience and knowledge of the surgeon, anesthesiologist, and hematologist. It may be advisable to postpone intervention until antibody levels are undetectable and then use unfractionated heparin; however, in those nonelective cases, Bivalrudin (Angiomax) is a viable alternative. The authors acknowledge prospective, randomized trials are needed to carefully document safety and efficacy.

	References

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1. Cancio L.C., Cohen D.J. Heparin-induced thrombocytopenia and thrombosis. J Am Coll Surg 1998;189:76-91.
2. Warkentin T.E., Levine M.N., Hirsh J., et al. Heparin-induced thrombocytopenia in patients treated with low-molecular weight heparin or unfractionated heparin. N Engl J Med 1995;332:1330-1335.[Abstract/Free Full Text]
3. Weitz J.I. Low-molecular weight heparins. N Engl J Med 1997;337:688-698.[Free Full Text]
4. Burkhart W., Smith G.F., Su J.L., Parikh I., LeVine H. Amino acid sequence determination of ancrod, the thrombin-like alpha-fibrogenase from the venom of Akistrodon rhodostoma. FEBS Lett 1992;297:297-301.[Medline]
5. Verstraete M. Recombinant hirudin. Vessels 1995;1:4-14.
6. Koster A., Kuppe H., Hetzer R., Sodian R., Crystal G.J., Mertzlufft F. Emergent cardiopulmonary bypass in five patients with heparin-induced thrombocytopenia type II employing recombinant hirudin. Anesthesiology 1998;89:777-780.[Medline]
7. Gold H.K., et al. Evidence for a rebound coagulation phenomenon after cessation of a 4-hour infusion of a specific thrombin inhibitor in patients with unstable angina pectoris. J Am Coll Cardiol 1993;21:1039-1047.[Abstract]
8. Ben Venue Laboratories package literature for Angiomax, December 2000

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This Article Abstract Full Text (PDF) Correction (v76,p1778) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Jeffrey N. Bott Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bott, J. N. Articles by Krick, S. Search for Related Content PubMed PubMed Citation Articles by Bott, J. N. Articles by Krick, S. Related Collections Extracorporeal circulation