- Email: [email protected]
Preemptive Use of Bivalirudin for Urgent On-Pump Coronary Artery Bypass Grafting in Patients With Potential Heparin-Induced Thrombocytopenia
NEW TECHNOLOGY
Preemptive Use of Bivalirudin for Urgent On-Pump Coronary Artery Bypass Grafting in Patients With Potential Heparin-Induced Thrombocytopenia
Departments of Surgery and Anesthesiology, Gaston Memorial Hospital, Gastonia, North Carolina, Department of Anesthesia, Deutsches Herzzentrum, Berlin, Germany, and Cardiothoracic Anesthesiology, Emory University School of Medicine, Atlanta, Georgia
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. (Ann Thorac Surg 2005;80:299 –303) © 2005 by The Society of Thoracic Surgeons
P
atients with heparin exposure are at risk for developing heparin-platelet factor 4 (PF4) antibodies. Administration of heparin in the presence of circulating 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
Accepted for publication Aug 19, 2004. Address reprint requests to Dr Dyke, Sanger Clinic-Gastonia, Suite 200, 2555 Court Dr, Gastonia, NC 28054; e-mail: [email protected].
© 2005 by The Society of Thoracic Surgeons Published by Elsevier Inc
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.
Drs Dyke, Veale, and Koster disclose that they have a financial relationship with The Medicines Company, Parsippany, NJ. 0003-4975/05/$30.00 doi:10.1016/j.athoracsur.2004.08.037
NEW TECHNOLOGY
Cornelius M. Dyke, MD, Andreas Koster, MD, James J. Veale, CCP, George W. Maier, MD, Thomas McNiff, MD, and Jerrold H. Levy, MD
Ann Thorac Surg 2005;80:299 –303
14.1 15.2 12.4 13.8 13.9 ⫾ 1.5 149,000 62,000 120,000 80,000 102,750 ⫾ 39,220 146,000 82,000 174,000 187,000 147,500 ⫾ 46,936 28,000 10,000 78,000 15,000 32,750 ⫾ 31,105 220,000 212,000 211,000 124,000 191,750 ⫾ 45,345 CPB ⫽ cardiopulmonary bypass.
52 77 52 114 73.6 ⫾ 29.3
Cross-Clamp Time (min)
1 2 3 4 Mean ⫾ SD
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 dis-
Patient No.
Case 2
Skin-toSkin Time (min)
A 47-year-old man presented with unstable angina of 2 months’ duration. Risk factors for coronary artery disease included hypertension and hyperlipidemia. Coronary angiography revealed a 70% left main coronary artery stenosis with normal ventricular function. Heparin and eptifibatide infusions were begun in the catheterization suite. Twelve hours after catheterization, the patient had a platelet count of 28,000/L without thrombotic sequelae. Heparin antibody titers were sent, and the surgery was delayed. With the antibody titers were still pending, a recurrent episode of angina developed in the patient, and the decision was made to proceed with CABG using bivalirudin. The left anterior and obtuse marginal arteries were grafted with the left internal mammary and saphenous veins. The patient was weaned from CPB uneventfully. A total of 2 U packed red blood cells were transfused during hospitalization. The postoperative course was unremarkable, and he was discharged home on the third postoperative day. The assay for heparin-PF4 antibodies was negative.
Presenting Platelet Count (per L)
Case 1
341 218 173 272 251 ⫾ 72.4
Preoperative Hemoglobin (per L) Postoperative Platelet Count (per L) Nadir Platelet Count (per L)
Immediate Preoperative Platelet Count (per L)
Case Reports
Table 1. Intraoperative Details
NEW TECHNOLOGY
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.
47 45 26 67 46.3 ⫾ 16.7
Postoperative Hemoglobin (per L)
Patients and Methods
11.3 11.7 9.6 10.6 10.8 ⫾ 0.9
NEW TECHNOLOGY DYKE ET AL ANTICOAGULATION WITH BIVALIRUDIN
CPB Time (min)
300
Ann Thorac Surg 2005;80:299 –303
NEW TECHNOLOGY DYKE ET AL ANTICOAGULATION WITH BIVALIRUDIN
301
Table 2. Chest Tube Output and Transfusions Chest Tube 8 Hours (mL)
Chest Tube Total (mL)
PRBC (Units)
Platelets (Units)
FFP (Units)
470 220 1510 242 610 ⫾ 610
1,260 820 2,670 1,415 1,415 ⫾ 857
2 0 8 3 3.3 ⫾ 3.4
0 10 20 0 7.5 ⫾ 9.8
0 0 8 0 2.0 ⫾ 4.0
FFP ⫽ fresh frozen plasma;
PRBC ⫽ packed red blood cells.
charged, 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/L. 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/L, 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 30pack 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/L to 78,000/L. 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/L 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/L, 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 postoper-
ative 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/L (124,000/L 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 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.
Comment Cardiac surgeons are commonly faced with a difficult management choice when patients present with angina and thrombocytopenia develops during hospitalization. Whereas HIT usually presents days after heparin exposure, the etiology of thrombocytopenia in a patient with an acute coronary syndrome can be difficult to diagnose,
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Patient 1 Patient 2 Patient 3 Patient 4 Mean ⫾ SD
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NEW TECHNOLOGY DYKE ET AL ANTICOAGULATION WITH BIVALIRUDIN
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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.)
as many patients have had numerous hospitalizations or procedures. Detection of circulating heparin-PF4 antibodies can be cumbersome as well, as rapid point-of-care testing is unavailable and outsourcing of the blood sample is frequently necessary. Heparin reexposure in the presence of circulating heparin-PF4 antibodies can result in significant and life-threatening complications [1]. In the present series, the use of glycoprotein IIb/IIIa inhibitors and intraaortic balloon pump counterpulsation were likely causes for the observed thrombocytopenia; however, recurrent ischemia precluded waiting until the heparin-PF4 antibody titer ruled out HIT. To avoid the potentially devastating consequences of HIT in patients after cardiac surgery, bivalirudin was chosen preemptively as the alternative anticoagulant, as recent data have demonstrated its feasibility for anticoagulation during on-pump bypass grafting in non-HIT patients. 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
Ann Thorac Surg 2005;80:299 –303
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 halflife 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 onpump 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 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 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.
Ann Thorac Surg 2005;80:299 –303
1. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia and cardiac surgery. Ann Thorac Surg 2003;76: 2121–31. 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 –9. 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 intervention: REPLACE-2 randomized trail. JAMA 2003;289:853– 63. 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;77:925–31.
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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– 6. 6. Reed MD, Bell D. Clinical pharmacology of bivalirudin. Pharmacotherapy 2002;22:105S–111S.
Disclaimer 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.
INVITED COMMENTARY Heparin-induced thrombocytopenia (HIT) is a potential life threatening complication of heparin therapy, in particular unfractitionated heparin. Heparin is the mainstay of anticoagulation used for cardiopulmonary bypass thanks to its ease of use, rapid monitoring, short half-life, reversibility, and low cost. As many as 50% of patients have measurable heparin-platelet factor 4 antibody titers develop after cardiac surgery using unfractitionated heparin, but only 1% to 3% have observed HIT (a clinicopathologic diagnosis based on clinical findings, fall in platelet count, and measurable heparin-platelet factor 4 antibodies) develop after cardiac surgery. Early reexposure to heparin in established HIT is a serious risk. Alternative anticoagulants (such as bivalirudin, which is a direct thrombin inhibitor) have been marketed as alternatives to heparin anticoagulation and have a role in cardiac surgery in proven or suspected HIT. The author outlines their experience in four cases of suspected HIT, based on a fall in platelet count after heparin administration at cardiac catheterization. Experience with bivalirudin in cardiac surgery is limited, and although the authors have demonstrated that in certain cases it can be used relatively safely, there are important issues to note with its use. Bivalirudin interacts reversibly with thrombin; its halflife is 25 minutes and it requires continuous infusion. Frequent intraoperative monitoring with ecarin clotting time is required, and adjustments are made according to individual patient nomograms. The effect on intraoperative blood loss is not well described. Cessation of the infusion before the end of bypass requires careful planning. Patient temperature at this time is also critical in determining the time taken for the infusion to be enzymatically eliminated and for adequate hemostasis return.
© 2005 by The Society of Thoracic Surgeons Published by Elsevier Inc
The author has highlighted their use of bivalirudin in these select cases. Heparin-induced thrombocytopenia was not proven, and it is important to remember that there are other important causes of thrombocytopenia, such as glycoprotein IIb/IIIa inhibitors and hemodilution, which may have contributed in the studied cases. The thrombotic risk associated with HIT is not confined to the intraoperative period, and both preoperative and postoperative anticoagulation with alternative anticoagulants must be carefully planned. Patients should be screened for thrombotic complications. Use of bivalirudin should be limited to proven cases or where there is a high degree of suspicion. Heparin therapy currently remains the safest and most proven method of anticoagulation in patients without acute HIT and HIT ⬎ 100 days previously. When HIT is suspected and timely antibody titer is not available, alternative anticoagulant therapy, such as bivaliruidin, may be used with attention paid to the previously raised issues. Simon C. Moten, MD Brian Buxton, FRACS Cardiothoracic Surgery Brody School of Medicine East Carolina University Greenville, NC 27858 e-mail: [email protected] Department of Cardiac Surgery Austin Hospital HSB-5, Studley Rd Heidelberg, Melbourne, Victoria, Australia 3084 e-mail: [email protected]
0003-4975/05/$30.00 doi:10.1016/j.athoracsur.2004.11.003
NEW TECHNOLOGY
References
NEW TECHNOLOGY DYKE ET AL ANTICOAGULATION WITH BIVALIRUDIN
Preemptive Use of Bivalirudin for Urgent On-Pump Coronary Artery Bypass Grafting in Patients With Potential Heparin-Induced Thrombocytopenia
Departments of Surgery and Anesthesiology, Gaston Memorial Hospital, Gastonia, North Carolina, Department of Anesthesia, Deutsches Herzzentrum, Berlin, Germany, and Cardiothoracic Anesthesiology, Emory University School of Medicine, Atlanta, Georgia
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. (Ann Thorac Surg 2005;80:299 –303) © 2005 by The Society of Thoracic Surgeons
P
atients with heparin exposure are at risk for developing heparin-platelet factor 4 (PF4) antibodies. Administration of heparin in the presence of circulating 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
Accepted for publication Aug 19, 2004. Address reprint requests to Dr Dyke, Sanger Clinic-Gastonia, Suite 200, 2555 Court Dr, Gastonia, NC 28054; e-mail: [email protected].
© 2005 by The Society of Thoracic Surgeons Published by Elsevier Inc
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.
Drs Dyke, Veale, and Koster disclose that they have a financial relationship with The Medicines Company, Parsippany, NJ. 0003-4975/05/$30.00 doi:10.1016/j.athoracsur.2004.08.037
NEW TECHNOLOGY
Cornelius M. Dyke, MD, Andreas Koster, MD, James J. Veale, CCP, George W. Maier, MD, Thomas McNiff, MD, and Jerrold H. Levy, MD
Ann Thorac Surg 2005;80:299 –303
14.1 15.2 12.4 13.8 13.9 ⫾ 1.5 149,000 62,000 120,000 80,000 102,750 ⫾ 39,220 146,000 82,000 174,000 187,000 147,500 ⫾ 46,936 28,000 10,000 78,000 15,000 32,750 ⫾ 31,105 220,000 212,000 211,000 124,000 191,750 ⫾ 45,345 CPB ⫽ cardiopulmonary bypass.
52 77 52 114 73.6 ⫾ 29.3
Cross-Clamp Time (min)
1 2 3 4 Mean ⫾ SD
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 dis-
Patient No.
Case 2
Skin-toSkin Time (min)
A 47-year-old man presented with unstable angina of 2 months’ duration. Risk factors for coronary artery disease included hypertension and hyperlipidemia. Coronary angiography revealed a 70% left main coronary artery stenosis with normal ventricular function. Heparin and eptifibatide infusions were begun in the catheterization suite. Twelve hours after catheterization, the patient had a platelet count of 28,000/L without thrombotic sequelae. Heparin antibody titers were sent, and the surgery was delayed. With the antibody titers were still pending, a recurrent episode of angina developed in the patient, and the decision was made to proceed with CABG using bivalirudin. The left anterior and obtuse marginal arteries were grafted with the left internal mammary and saphenous veins. The patient was weaned from CPB uneventfully. A total of 2 U packed red blood cells were transfused during hospitalization. The postoperative course was unremarkable, and he was discharged home on the third postoperative day. The assay for heparin-PF4 antibodies was negative.
Presenting Platelet Count (per L)
Case 1
341 218 173 272 251 ⫾ 72.4
Preoperative Hemoglobin (per L) Postoperative Platelet Count (per L) Nadir Platelet Count (per L)
Immediate Preoperative Platelet Count (per L)
Case Reports
Table 1. Intraoperative Details
NEW TECHNOLOGY
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.
47 45 26 67 46.3 ⫾ 16.7
Postoperative Hemoglobin (per L)
Patients and Methods
11.3 11.7 9.6 10.6 10.8 ⫾ 0.9
NEW TECHNOLOGY DYKE ET AL ANTICOAGULATION WITH BIVALIRUDIN
CPB Time (min)
300
Ann Thorac Surg 2005;80:299 –303
NEW TECHNOLOGY DYKE ET AL ANTICOAGULATION WITH BIVALIRUDIN
301
Table 2. Chest Tube Output and Transfusions Chest Tube 8 Hours (mL)
Chest Tube Total (mL)
PRBC (Units)
Platelets (Units)
FFP (Units)
470 220 1510 242 610 ⫾ 610
1,260 820 2,670 1,415 1,415 ⫾ 857
2 0 8 3 3.3 ⫾ 3.4
0 10 20 0 7.5 ⫾ 9.8
0 0 8 0 2.0 ⫾ 4.0
FFP ⫽ fresh frozen plasma;
PRBC ⫽ packed red blood cells.
charged, 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/L. 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/L, 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 30pack 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/L to 78,000/L. 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/L 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/L, 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 postoper-
ative 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/L (124,000/L 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 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.
Comment Cardiac surgeons are commonly faced with a difficult management choice when patients present with angina and thrombocytopenia develops during hospitalization. Whereas HIT usually presents days after heparin exposure, the etiology of thrombocytopenia in a patient with an acute coronary syndrome can be difficult to diagnose,
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Patient 1 Patient 2 Patient 3 Patient 4 Mean ⫾ SD
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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.)
as many patients have had numerous hospitalizations or procedures. Detection of circulating heparin-PF4 antibodies can be cumbersome as well, as rapid point-of-care testing is unavailable and outsourcing of the blood sample is frequently necessary. Heparin reexposure in the presence of circulating heparin-PF4 antibodies can result in significant and life-threatening complications [1]. In the present series, the use of glycoprotein IIb/IIIa inhibitors and intraaortic balloon pump counterpulsation were likely causes for the observed thrombocytopenia; however, recurrent ischemia precluded waiting until the heparin-PF4 antibody titer ruled out HIT. To avoid the potentially devastating consequences of HIT in patients after cardiac surgery, bivalirudin was chosen preemptively as the alternative anticoagulant, as recent data have demonstrated its feasibility for anticoagulation during on-pump bypass grafting in non-HIT patients. 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
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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 halflife 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 onpump 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 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 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.
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1. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia and cardiac surgery. Ann Thorac Surg 2003;76: 2121–31. 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 –9. 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 intervention: REPLACE-2 randomized trail. JAMA 2003;289:853– 63. 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;77:925–31.
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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– 6. 6. Reed MD, Bell D. Clinical pharmacology of bivalirudin. Pharmacotherapy 2002;22:105S–111S.
Disclaimer 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.
INVITED COMMENTARY Heparin-induced thrombocytopenia (HIT) is a potential life threatening complication of heparin therapy, in particular unfractitionated heparin. Heparin is the mainstay of anticoagulation used for cardiopulmonary bypass thanks to its ease of use, rapid monitoring, short half-life, reversibility, and low cost. As many as 50% of patients have measurable heparin-platelet factor 4 antibody titers develop after cardiac surgery using unfractitionated heparin, but only 1% to 3% have observed HIT (a clinicopathologic diagnosis based on clinical findings, fall in platelet count, and measurable heparin-platelet factor 4 antibodies) develop after cardiac surgery. Early reexposure to heparin in established HIT is a serious risk. Alternative anticoagulants (such as bivalirudin, which is a direct thrombin inhibitor) have been marketed as alternatives to heparin anticoagulation and have a role in cardiac surgery in proven or suspected HIT. The author outlines their experience in four cases of suspected HIT, based on a fall in platelet count after heparin administration at cardiac catheterization. Experience with bivalirudin in cardiac surgery is limited, and although the authors have demonstrated that in certain cases it can be used relatively safely, there are important issues to note with its use. Bivalirudin interacts reversibly with thrombin; its halflife is 25 minutes and it requires continuous infusion. Frequent intraoperative monitoring with ecarin clotting time is required, and adjustments are made according to individual patient nomograms. The effect on intraoperative blood loss is not well described. Cessation of the infusion before the end of bypass requires careful planning. Patient temperature at this time is also critical in determining the time taken for the infusion to be enzymatically eliminated and for adequate hemostasis return.
© 2005 by The Society of Thoracic Surgeons Published by Elsevier Inc
The author has highlighted their use of bivalirudin in these select cases. Heparin-induced thrombocytopenia was not proven, and it is important to remember that there are other important causes of thrombocytopenia, such as glycoprotein IIb/IIIa inhibitors and hemodilution, which may have contributed in the studied cases. The thrombotic risk associated with HIT is not confined to the intraoperative period, and both preoperative and postoperative anticoagulation with alternative anticoagulants must be carefully planned. Patients should be screened for thrombotic complications. Use of bivalirudin should be limited to proven cases or where there is a high degree of suspicion. Heparin therapy currently remains the safest and most proven method of anticoagulation in patients without acute HIT and HIT ⬎ 100 days previously. When HIT is suspected and timely antibody titer is not available, alternative anticoagulant therapy, such as bivaliruidin, may be used with attention paid to the previously raised issues. Simon C. Moten, MD Brian Buxton, FRACS Cardiothoracic Surgery Brody School of Medicine East Carolina University Greenville, NC 27858 e-mail: [email protected] Department of Cardiac Surgery Austin Hospital HSB-5, Studley Rd Heidelberg, Melbourne, Victoria, Australia 3084 e-mail: [email protected]
0003-4975/05/$30.00 doi:10.1016/j.athoracsur.2004.11.003
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References
NEW TECHNOLOGY DYKE ET AL ANTICOAGULATION WITH BIVALIRUDIN