HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) 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): Cornelius M. Dyke George W. Maier Jerrold H. Levy Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dyke, C. M. Articles by Levy, J. H. Search for Related Content PubMed PubMed Citation Articles by Dyke, C. M. Articles by Levy, J. H. Related Collections Extracorporeal circulation Related Article

Ann Thorac Surg 2005;80:299-303
© 2005 The Society of Thoracic Surgeons

---

New technology

Preemptive Use of Bivalirudin for Urgent On-Pump Coronary Artery Bypass Grafting in Patients With Potential Heparin-Induced Thrombocytopenia

^a Department of Surgery and Anesthesiology, Gaston Memorial Hospital, Gastonia, North Carolina
^b Department of Anesthesia, Deutsches Herzzentrum, Berlin, Germany
^c Department of Cardiothoracic Anesthesiology, Emory University School of Medicine, Atlanta, Georgia

Accepted for publication August 19, 2004.

^_* Address reprint requests to Dr Dyke, Sanger Clinic-Gastonia, Suite 200, 2555 Court Dr, Gastonia, NC 28054 (Email: cdyke{at}sanger-clinic.com).

	Abstract

Top Abstract Introduction Patients and Methods Case Reports Results Comment Summary Disclosures and Freedom of... Disclaimer References

 
PURPOSE: The use of heparin in patients with heparin-induced thrombocytopenia (HIT) may result in severe complications or death. The diagnosis of HIT is frequently uncertain, however. Alternative anticoagulants in at-risk patients undergoing cardiac surgery with cardiopulmonary bypass remain problematic. The novel short-acting, direct-thrombin inhibitor bivalirudin is the only alternative to heparin/protamine being used in elective non-HIT patients during CPB.

DESCRIPTION: Four patients with severe thrombocytopenia after heparin exposure and suspected acute HIT underwent on-pump coronary artery bypass grafting surgery with preemptive use of bivalirudin. A continuous bivalirudin infusion was used during cardiopulmonary bypass, and activated clotting times were used to monitor anticoagulation.

EVALUATION: Anticoagulation with bivalirudin during cardiopulmonary bypass was effective and uncomplicated. Duration of operation was not prolonged, and perioperative blood loss and transfusion rates were acceptable. Activated clotting times were helpful for monitoring anticoagulation in these patients.

CONCLUSIONS: These data provide further evidence of the feasibility of bivalirudin for anticoagulation during on-pump coronary artery bypass graft surgery in urgent clinical situations.

	Introduction

Top Abstract Introduction Patients and Methods Case Reports Results Comment Summary Disclosures and Freedom of... Disclaimer References

 

Drs Dyke, Veale, and Koster disclose that they have a financial relationship with The Medicines Company, Parsippany, NJ.

 

Patients with heparin exposure are at risk for developing heparin-platelet factor 4 (PF4) antibodies. Administration of heparin in the presence of crculating heparin-PF4 antibodies may result in heparin-induced thrombocytopenia (HIT) or the more life-threatening complication of heparin-induced thrombocytopenia thrombosis syndrome (HITTS) [1]. In patients undergoing cardiac surgery, exposure to heparin before operation is commonplace. Screening for circulating heparin-PF4 antibodies is not routine, however, as point-of-care testing is unavailable, creating logistical difficulties with outsourced blood samples and delays in test reporting. Accordingly, HIT-HITTS remains a clinical diagnosis, most frequently manifested by a more than 50% drop in platelet count 3 to 5 days after heparin exposure. With these patients, surgeons are frequently faced with a difficult clinical decision regarding anticoagulation management.

We describe 4 patients requiring urgent coronary revascularization in whom severe thrombocytopenia developed after cardiac catheterization. The decision to proceed with coronary artery bypass graft (CABG) surgery was made without the benefit of heparin-PF4 antibody titers, as the results of the outsourced assays were pending. Bivalirudin, a short-acting thrombin-specific anticoagulant that does not cross-react with heparin-PF4 antibodies, was used for anticoagulation during on-pump CABG surgery.

	Patients and Methods

Top Abstract Introduction Patients and Methods Case Reports Results Comment Summary Disclosures and Freedom of... Disclaimer References

 
The anticoagulation regimen was identical for each patient: a 1.5 mg/kg loading dose of bivalirudin was given through a central venous catheter immediately before aortic cannulation and a continuous infusion of 2.5 mg/kg per hour for the duration of cardiopulmonary bypass (CPB). Activated clotting times (ACT) were measured using a kaolin-based system (Medtronic ACT-II ; Medtronics Inc, Minneapolis, MN) and were monitored throughout bypass. A target ACT of 500 s with a minimum of 450 s was used. Monitoring of ACT was continued through the immediate postoperative period.

Identical priming solutions were used for CPB: 1,500 mL Lactated Ringers solution, 250 mL 10% albumin, 50 mEq sodium bicarbonate, and 25 g mannitol. Bivalirudin, 50 mg, was added to the priming solution. A noncoated hollow fiber membrane oxygenator and noncoated tubing were used. The Quest Blood Cardioplegia delivery system (closed circuit) was used for cardioplegic arrest (Quest Medical Inc, Allen, TX). Normothermic cardiopulmonary bypass was used, and patients were weaned at 37°C. Bivalirudin was used in the cell saving device to avoid clotting (100 mg/L NaCl). Intraoperative details and bleeding and transfusion rates are detailed in Tables 1 and 2.

	Case Reports

Top Abstract Introduction Patients and Methods Case Reports Results Comment Summary Disclosures and Freedom of... Disclaimer References

Case 2
A 51-year-old man presented with a non-ST-segment elevation myocardial infarction. His medical history was significant for ongoing heavy tobacco use, hypertension, dyslipidemia, and chronic bronchitis. Cardiac catheterization revealed three-vessel disease with preserved left ventricular function. Physical examination was unremarkable. Coronary artery bypass graft surgery was recommended but the patient refused and was discharged, returning 10 days later with recurrent angina. Unfractionated heparin and nitroglycerin therapy were begun. Two days after heparin exposure, the patient’s platelet count dropped to 10,000/µL. No thrombotic sequelae were present. Heparin was discontinued and antibody testing performed. Before the results of the heparin-PF4 antibody testing, he had recurrent angina. On-pump CABG surgery was performed using bivalirudin. The left internal mammary artery and three sequential saphenous vein grafts were used. The platelet count postoperatively was 62,000/µL, and one plasmapheresis platelet pack was transfused. No further transfusions were given and recovery was uneventful. He was discharged home on postoperative day 3. The heparin-PF4 antibody assay was negative.

Case 3
A 79-year-old woman presented to the emergency department with a non-ST-segment elevation myocardial infarction. Medical history included hypertension, a 30-pack per year history of cigarette use, metabolic syndrome, lower gastrointestinal bleeding, and emphysema with frequent hospitalizations. Physical examination revealed uncontrolled hypertension, morbid obesity, and amputation of multiple digits. Cardiac catheterization revealed three-vessel coronary artery disease with a 60% ostial left main coronary stenosis. Heparin and eptifibatide infusions were started, and she was referred for CABG surgery. The morning after catheterization, the platelet count fell from 211,000/µL to 78,000/µL. No thrombotic sequelae were present. Heparin and eptifibatide were discontinued, and a bivalirudin infusion was started. Heparin-PF4 antibody titers were sent. Her platelet count gradually increased to 175,000/µL over 4 days, and she remained pain free. On-pump CABG was performed with bivalirudin as the heparin-PF4 assay was pending (subsequently negative). Two units of packed red blood cells were added to the priming solution for preoperative anemia. The left anterior descending artery, the first obtuse marginal artery, and the posterior descending artery were bypassed utilizing the left internal mammary and reversed segments of saphenous vein. Postoperative laboratory studies demonstrated a platelet count of 120,000/µL, a fibrinogen of 161 mg/dL, and a PT/INR of 51 seconds/5.3. Due to significant chest tube output, multiple blood and blood product transfusions were given with satisfactory diminution of her postoperative bleeding. She was extubated on the first postoperative day and transferred to the stepdown unit. Her recovery was complicated by Haemophilus influenza pneumonia requiring intravenous antibiotics. She was discharged to a short-term rehabilitation facility in good condition on postoperative day 14.

Case 4
A 54-year-old man presented to the emergency department with a non-ST-segment elevation myocardial infarction. Medical history included hypertension, dyslipidemia, metabolic syndrome, and morbid obesity. Unfractionated heparin and eptifibatide were initiated on admission, with resolution of his angina. Cardiac catheterization revealed three-vessel coronary artery disease. An intraaortic balloon pump was placed in the catheterization laboratory for recurrent angina, with resolution of his chest pain. Twelve hours after catheterization his platelet count was 15,000/µL (124,000/µL on admission). Heparin antibody titers were sent. Heparin and eptifibatide were discontinued, and a bivalirudin infusion was begun. Recurrent angina developed before the reporting of the heparin-PF4 antibody assay, and the patient was brought to surgery for on-pump CABG using bivalirudin. He underwent CABG with an internal mammary to left anterion descending artery graft and saphenous vein grafts to the first diagonal, first obtuse marginal, and posterior descending arteries. His postoperative course was unremarkable, and he was discharged home on postoperative day 4. The heparin-PF4 antibody assay was negative.

	Results

Top Abstract Introduction Patients and Methods Case Reports Results Comment Summary Disclosures and Freedom of... Disclaimer References

 
All 4 patients had severe thrombocytopenia after exposure to heparin in the emergency department and the cardiac catheterization laboratory. Operative times and pertinent laboratory data are detailed in Table 1. The ACT-II (Medtronics) was used to successfully monitor anticoagulation during cardiopulmonary bypass. (Fig 1). Transfusion requirements are detailed in Table 2.

View larger version (24K): [in this window] [in a new window]   Fig 1. Monitoring of anticoagulation with bivalirudin. Circles = patient 3; diamonds = patient 1; squares = patient 2; triangles = patient 4. (ACT = activated clotting time; CABG = coronary artery bypass graft surgery.)

	Comment

Top Abstract Introduction Patients and Methods Case Reports Results Comment Summary Disclosures and Freedom of... Disclaimer References

Using the dosing protocol outlined above, bivalirudin was successfully used as an anticoagulant during cardiopulmonary bypass with no clot formation during bypass and acceptable bleeding and transfusion rates. In their pilot study, Koster and coworkers [2] used the whole blood ecarin clotting time to monitor anticoagulation during on-pump CABG and demonstrated excellent correlation between the ecarin clotting time and bivalirudin serum levels across a wide dosing range. In this series, anticoagulation monitoring was performed with the kaolin-based activated clotting time (ACT-II, Medtronic). While the ACT correlates less well with bivalirudin serum levels at the higher dosing range, elevations in ACT of 2.5 times baseline have correlated with bivalirudin serum levels suitable for cardiopulmonary bypass (personal communication, The Medicines Company, Parsippany, NJ). In this series, the ACT-II was helpful as a monitor of anticoagulation: a 1.5 mg/kg bolus and 2.5 mg·kg^–1·min^–1 infusion significantly increased the ACT, while the offset of action upon termination of bivalirudin was linear and predictable(Fig 1). Although the ACT is inherently variable, its use as a monitoring test in patients anticoagulated with bivalirudin is likely to continue because ecarin clotting time monitoring equipment is no longer available in the United States.

In all 4 patients in this series, hemostasis was adequate for chest closure approximately 1 hour after cessation of bivalirudin infusion (two half-lives). Total operating times were acceptable (Table 1). In 3 patients, postoperative bleeding and transfusion were unremarkable. Patient 3, however, required significant transfusion(Table 2) for excessive postoperative bleeding likely secondary to a dilutional, factor-deficient coagulopathy. Whether anticoagulation with heparin would have resulted in less transfusion and bleeding is unclear. All patients were discharged in good condition.

Bivalirudin is a direct thrombin inhibitor with a half-life of approximately 25 minutes. It has been demonstrated effective in large trials of patients undergoing percutaneous coronary interventions and is associated with less bleeding than heparin[3]. Successful use during elective off-pump CABG surgery has been reported recently [4]. Although experience with bivalirudin for on-pump cardiac surgery is limited, the dosing as outlined above has been demonstrated to result in bivalirudin serum levels adequate for cardiopulmonary bypass [5]. Although no "antidote" exists for bivalirudin (eg, heparin/protamine), the predominant pathway of elimination is by enzymatic degredation by proteases and by thrombin itself. Approximately 20% of circulating bivalirudin is cleared by the kidneys[6]. This elimination mechanism, largely independent of end-organ function, along with the option of enhanced extracorporeal elimination with modified ultrafiltration, are safety considerations that may render bivalirudin an attractive alternative anticoagulant for patients with suspected (or proven) HIT.

	Summary

Top Abstract Introduction Patients and Methods Case Reports Results Comment Summary Disclosures and Freedom of... Disclaimer References

 
Although limited by the small number of patients, our data provide further evidence for the feasibility of using bivalirudin for on-pump CABG surgery even for patients with preexisting disturbances of the hemostatic system needing urgent cardiac surgery. Anticoagulation monitoring with the ACT-II system was useful and reproducible in these patients, although variability exists. Larger controlled studies are needed for further evaluation of the safety of bivalirudin as a replacement for heparin. Additionally, the frequency of urgent cardiac surgery in clinical practice also highlights the need for a quick and reliable test for HIT antibodies for rational decision making in this potentially high-risk group.

	Disclosures and Freedom of Investigation

Top Abstract Introduction Patients and Methods Case Reports Results Comment Summary Disclosures and Freedom of... Disclaimer References

 
The novel anticoagulant bivalirudin was used in an off-label fashion in this series. No financial support from the manufacturer was used or given. The authors had full control of the design and data detailed in the manuscript. Patient permission for disclosure of clinical information was granted.

	Disclaimer

Top Abstract Introduction Patients and Methods Case Reports Results Comment Summary Disclosures and Freedom of... Disclaimer References

 
The Society of Thoracic Surgeons, the Southern Thoracic Surgical Association, and The Annals of Thoracic Surgery neither endorse nor discourage use of the new technology described in this article.

	References

Top Abstract Introduction Patients and Methods Case Reports Results Comment Summary Disclosures and Freedom of... Disclaimer References

 

1. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia and cardiac surgery Ann Thorac Surg 2003;76:2121-2131.[Abstract/Free Full Text]
2. 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;93:356-359.[Medline]
3. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percoutaneous coronary interventionREPLACE-2 randomized trail. JAMA 2003;289:853-863.[Abstract/Free Full Text]
4. Merry AF, Raudkivi PJ, Middleton NG, et al. Bivalirudin versus heparin and protamine in off-pump coronary artery bypass surgery Ann Thorac Surg 2004;77:925-931.[Abstract/Free Full Text]
5. Koster A, Chew D, Greundel M, Bauer M, Kruppe H, Speiss BD. Bivalirudin monitored with the ecarin clotting time for anticoagulation during cardiopulmonary bypass Anesth Analg 2003;96:383-386.[Abstract/Free Full Text]
6. Reed MD, Bell D. Clinical pharmacology of bivalirudin Pharmacotherapy 2002;22:105S-111S.[Medline]

This article has been cited by other articles:

				J. H. Levy, K. A. Tanaka, and J. M. Bailey Cardiac Surgical Pharmacology Card. Surg. Adult, January 1, 2008; 3(2008): 77 - 110. [Full Text]

				J. H. Levy, K. A. Tanaka, and M. J. Hursting Reducing Thrombotic Complications in the Perioperative Setting: An Update on Heparin-Induced Thrombocytopenia Anesth. Analg., September 1, 2007; 105(3): 570 - 582. [Abstract] [Full Text] [PDF]

				D. C. Kress, S. Aronson, M. L. McDonald, M. I. Malik, A. B. Divgi, A. J. Tector, F. X. Downey III, A. J. Anderson, M. Stone, and C. Clancy Positive Heparin-Platelet Factor 4 Antibody Complex and Cardiac Surgical Outcomes Ann. Thorac. Surg., May 1, 2007; 83(5): 1737 - 1743. [Abstract] [Full Text] [PDF]

				A. Koster, C. M. Dyke, G. Aldea, N. G. Smedira, H. L. McCarthy II, S. Aronson, R. Hetzer, E. Avery, B. Spiess, and A. M. Lincoff 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., February 1, 2007; 83(2): 572 - 577. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) 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): Cornelius M. Dyke George W. Maier Jerrold H. Levy Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dyke, C. M. Articles by Levy, J. H. Search for Related Content PubMed PubMed Citation Articles by Dyke, C. M. Articles by Levy, J. H. Related Collections Extracorporeal circulation Related Article