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Ann Thorac Surg 2007;84:836-839
© 2007 The Society of Thoracic Surgeons
a Department of Cardiovascular and Thoracic Surgery, Gaston Memorial Hospital, Gastonia, North Carolina
b Department of Cardiac Surgery, Washington State University, Seattle, Washington
c Department of Anesthesia, Deutsches Herzzentrum Berlin, Berlin, Germany
d Department of Cardiothoracic Surgery, The Cleveland Clinic Foundation, Cleveland, Ohio
e Department of Cardiac Anesthesia, Massachusetts General Hospital, Boston, Massachusetts
f Department of Anesthesia, Duke University Medical Center, Durham, North Carolina
g Department of Cardiac Surgery and Cardiothoracic Anesthesia, Virginia Commonwealth University, Richmond, Virginia
h Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio
Accepted for publication April 2, 2007.
* Address correspondence to Dr Dyke, Gaston Memorial Hospital, 2555 Court Drive, Suite 200, Gastonia, NC 28054 (Email: dykec{at}gmh.org).
| Drs Dyke, Koster, Spiess, Lincoff, Aldea, and Aronson disclose that they have a financial relationship with The Medicines Company.
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Abstract |
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Methods: In a prospective, open-label, multicenter study, fifty-one patients with documented anti-PF4/H antibodies and (or) HIT/TS underwent OPCAB with bivalirudin anticoagulation (0.75 mg/kg IV bolus, 1.75 mg/kg/hour infusion). Procedural success (absence of death, Q-wave myocardial infarction, repeat revascularization, and stroke), bleeding, and transfusion at day seven/discharge, thirty days, and twelve weeks were assessed.
Results: Thirty-five patients (67%) were included with positive anti-PF4/H antibodies and no thrombocytopenia or thrombosis, eleven patients (22%) had thrombocytopenia, and five patients had clinical HIT/TS (10%). Procedural success at seven days/discharge was achieved in forty-seven patients (92%), while procedural success at thirty days and twelve weeks was 88%. There were no deaths. Chest tube output over the first twenty-four hours was 936 ± 525 mL and twenty-five patients received a red blood cell transfusion during their hospitalization. Two patients required reexploration for persistent postoperative hemorrhage.
Conclusions: Bivalirudin was an effective alternative anticoagulant for patients with HIT/TS or circulating anti-PF4/H antibodies undergoing OPCAB, with high rates of procedural success and an acceptable incidence of bleeding or transfusions.
Heparin-induced thrombocytopenia or thrombotic syndrome (HIT/TS) results in an intense prothrombotic state manifested by devastating thromboembolic complications. Anticoagulation for patients with HIT/TS requires an alternative to heparin, and while alternative anticoagulants have been approved for patients treated medically, none of these agents is approved for use during cardiac surgery. Additionally, anecdotal experience with alterative anticoagulants for patients with HIT/TS has been associated with bleeding complications.
In an effort to minimize the intensity of anticoagulation when using heparin alternatives, surgeons may choose to avoid cardiopulmonary bypass and utilize off-pump surgical techniques. Whether this approach is appropriate for patients with antiplatelet factor four-heparin (anti-PF4/H) antibodies or HIT/TS is unknown. To date only a limited number of protocols are described for anticoagulation patients with HIT/TS during surgery [1] and no clinical trials exist for patients undergoing off-pump coronary artery bypass (OPCAB). The Coronary Artery Bypass HIT/TS On and Off Safety and Efficacy (CHOOSE-OFF) trial was designed to evaluate anticoagulation with bivalirudin for patients with anti-PF4/H antibodies and confirmed or prior HIT/TS undergoing OPCAB.
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Material and Methods |
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Inclusion and Exclusion Criteria
Patients were at least 18 years of age and scheduled for off-pump coronary artery bypass. All enrolling sites had approval from the local Institutional Review Board and informed consent was obtained from all patients prior to enrollment. Patients with severe renal dysfunction, severe left ventricular dysfunction (ejection fraction less than 30%), or recent stroke (within the prior six months) were excluded.
Diagnosis of HIT/TS
Patients with HIT/TS or at risk for HIT/TS were enrolled in the trial. Patients with confirmed HIT/TS exhibited serologic and clinical evidence of the disease at the time of enrollment. Patients with suspected HIT/TS were defined as patients with circulating anti-PF4/H antibodies anytime before surgery, a platelet count decline of more than 50% baseline within two weeks of surgery, or a history of previous HIT/TS.
Clinical Endpoints
The primary study endpoint was in-hospital procedural success, defined as the absence of death, myocardial infarction, stroke, or repeat revascularization by postoperative day seven or hospital discharge, whichever occurred first. The secondary study endpoints included procedural success at thirty days and twelve weeks postoperatively. Perioperative blood loss, transfusion requirements, and bleeding events were recorded through postoperative day seven or hospital discharge, whichever occurred first. Transfusion decisions were determined by institutional practices. Postoperative myocardial infarction was defined by the development of new electrocardiographic Q-waves or elevation of creatine kinase-myocardial band isoenzyme more than ten times the upper limit of normal. All myocardial infarctions were adjudicated by an independent and blinded clinical events committee prior to statistical analysis. Postoperative bleeding was quantified as mediastinal chest tube output at two and twenty-four hours. Major bleeding was defined as any intracranial or intraocular hemorrhage, retroperitoneal or gastrointestinal bleeding, or persistent hemorrhage after surgery requiring reexploration.
Anticoagulation Protocol
Intraoperative anticoagulation was dosed according to the Evaluation of Patients during Coronary Artery Bypass Graft Operation: Linking Utilization of Bivalirudin to Improved Outcomes and New Anticoagulant Strategies (EVOLUTION-OFF) trial protocol [3]. A bivalirudin bolus dose of 0.75 mg/kg was initiated at the surgeons request with a continuous infusion of 1.75 mg/kg/hour. The target activated clotting time (ACT) was greater than 300 seconds with the frequency of monitoring according to institutional practice. All ACT values were obtained using devices that were appropriately quality-controlled based on institutional standards (or using Clinical Laboratory Improvement Amendment compliant protocols), but the manufacturer of the ACT device was not prespecified. Because of the reliable pharmacokinetic profile of bivalirudin, additional bolus doses or infusion titration was discouraged. Cessation of the infusion was recommended at the time of the last proximal anastomosis, although the timing was at the discretion of the surgeon-anesthesiologist. During the procedure, care was taken to avoid stasis within the surgical field and bypass conduits.
Statistical Analysis
Descriptive statistical analysis (mean, median, standard deviation, range, percentage) was performed upon the protocol-specified safety population (all patients who received bivalirudin). No attempt was made to compare outcomes between groups and no comparative statistical techniques were used.
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Results |
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Comment |
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In the CHOOSE-OFF trial, monitoring anticoagulation with currently available ACT systems was effective and consistent with earlier trials (Table 4) [10, 11]. The primary endpoint of procedural success was achieved in 92% of patients upon discharge and no deaths occurred within the twelve week follow-up period (Table 5). The incidence of myocardial infarction and stroke was also low (Table 5). These data suggest that a 0.75 mg/kg bolus and 1.75 mg/kg infusion of bivalirudin provides adequate anticoagulation for patients with HIT/TS undergoing OPCAB. In a prior single-center trial in patients without HIT/TS or anti-PF4/H antibodies patients anticoagulated with bivalirudin had fewer graft thromboses than patients anticoagulated with heparin [9]. While the incidence of perioperative myocardial infarction was low in CHOOSE-OFF, no comment can be made regarding graft patency.
Bleeding has been problematic for patients undergoing cardiac surgery with alternative anticoagulants. In CHOOSE-OFF, early and late postoperative chest tube output was not excessive (Table 6), likely due to the rapid metabolism of bivalirudin. Transfusion requirements were also reasonable (Table 5) and similar to the rates in the EVOLUTION-OFF trial [10].
This dataset has several limitations. Concurrent randomization and comparison to heparin or an alternative anticoagulant was not done. However, no standard alternative anticoagulation regimen exists for patients with HIT/TS or at risk for HIT/TS. Individual surgeon experience with alternative anticoagulants is also low and may lead to variable transfusion practices. Finally, the diagnosis of HIT/TS requires a combination of laboratory and clinical data [10] and the recognition of HIT/TS between practice groups and regions is variable, making prospective patient recruitment difficult. Despite these limitations, the CHOOSE-OFF trial represents the largest series of OPCAB patients with HIT/TS or anti-PF4/H antibodies to be studied using an alternative anticoagulant.
These data suggest that bivalirudin is an effective anticoagulant for patients with anti-PF4/H antibodies or HIT/TS undergoing OPCAB. Together with the CHOOSE-ON trial, these data suggest that patients with anti-PF4/H antibodies or HIT/TS may be treated with bivalirudin regardless of the decision to utilize cardiopulmonary bypass. As the recognition of HIT/TS increases, the number of patients who undergo cardiac surgery with bivalirudin is expected to increase.
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Related Article
This article has been cited by other articles:
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  A Koster, S Buz, T Krabatsch, R Yeter, and R Hetzer Bivalirudin anticoagulation during cardiac surgery: a single-center experience in 141 patients Perfusion, January 1, 2009; 24(1): 7 - 11. [Abstract] [PDF]
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 Q. A Czosnowski, S. W Finks, and K. C Rogers Bivalirudin for Patients with Heparin-Induced Thrombocytopenia Undergoing Cardiovascular Surgery Ann. Pharmacother., September 1, 2008; 42(9): 1304 - 1309. [Abstract] [Full Text] [PDF]
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 T. E. Warkentin, A. Greinacher, A. Koster, and A. M. Lincoff Treatment and Prevention of Heparin-Induced Thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 340S - 380S. [Abstract] [Full Text] [PDF]
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 A. F. Merry Invited commentary Ann. Thorac. Surg., September 1, 2007; 84(3): 840 - 840. [Full Text] [PDF]
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