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J Thorac Cardiovasc Surg 2005;130:107-113
© 2005 The American Association for Thoracic Surgery
Cardiopulmonary Support and Physiology |
a Departments of Anesthesiology and Cardiothoracic Surgery, St Louis, Mo
k Departments of Anesthesiology, Surgery, Pathology, and Immunology, Washington University School of Medicine, St Louis, Mo
b Department of Anesthesiology, Emory University School of Medicine, and the Division of Cardiothoracic Anesthesiology and Critical Care, Emory Healthcare, Atlanta, Ga
c Department of Anesthesiology, Westfalische Wilhelms-Universiteit, Münster, Klinik für Anasthesiologie, Münster, Germany
d Department of Anaesthesia, St Thomas’ Hospital, London, United Kingdom
e Department of Anaesthesia, Papworth Hospital, Cambridge, United Kingdom
f Department of Anesthesiology, Universitäts-Klinikum Großhadern, Institut für Anästhesiologie, Munich, Germany
g Department of Anesthesiology, Ruprecht-Karls-Universiteit, Heidelberg, Germany
h Department of Anesthesiology, Klinikum der Universiteit Regensburg, Regensburg, Germany
i Clinical Research, GTC Biotherapeutics, Inc, Framingham, Mass
j Eli Lilly & Co, Lilly Corporate Center, Indianapolis, Ind.
Received for publication August 2, 2004; revisions received September 26, 2004; accepted for publication October 6, 2004. * Address for reprints: M. S. Avidan, MBBCh, Department of Anesthesiology, Box 8054, Washington University School of Medicine, 660 South Euclid, St Louis, MO 63110 (Email: avidanm{at}msnotes.wustl.edu).
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Abstract |
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METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study in heparin-resistant patients undergoing elective cardiac surgery. Patients were considered heparin resistant if the activated clotting time was less than 480 seconds after 400 U/kg heparin. Fifty-two heparin-resistant patients were randomized into 2 cohorts. One cohort received a single bolus (75 U/kg) of recombinant human antithrombin III (n = 28), and the other, the placebo group (n = 24), received a normal saline bolus. If the activated clotting time remained less than 480 seconds, this was defined as treatment failure, and 2 units of fresh frozen plasma were transfused. Patients were monitored for adverse events during hospitalization.
RESULTS: Six (21%) of the patients in the recombinant human antithrombin III group received fresh frozen plasma transfusions compared with 22 (92%) of the placebo-treated patients (P < .001). Two units of fresh frozen plasma did not restore heparin responsiveness. There was no increased incidence of adverse events associated with recombinant human antithrombin III administration. Postoperative 24-hour chest tube bleeding was not different in the 2 groups. Surrogate measures of hemostatic activation suggested that there was less activation of the hemostatic system during cardiopulmonary bypass in the recombinant human antithrombin III group.
CONCLUSION: Treatment with recombinant human antithrombin III in a dose of 75 U/kg is effective in restoring heparin responsiveness and promoting therapeutic anticoagulation for cardiopulmonary bypass in the majority of heparin-resistant patients. Two units of fresh frozen plasma were insufficient to restore heparin responsiveness. There was no apparent increase in bleeding associated with recombinant human antithrombin III.
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Introduction |
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but historically, values of less than 300 seconds were associated with grossly visible clots in the bypass circuit. In a 1000-member survey of the Society of Cardiovascular Anesthesiology and American Society of Extracorporeal Circulation, the target ACT used by 82% of responders was 400 to 480 seconds or longer, with an additional 4.5% targeting an even higher ACT.
2
Heparin resistance can be defined as the failure to achieve the desired ACT after a standard dose of heparin (300–400 U/kg).
2
Failure to achieve an acceptable ACT for CPB is usually managed by additional heparin administration. Less frequently, fresh frozen plasma (FFP) is administered in an attempt to restore heparin responsiveness. Investigators have found the incidence of heparin resistance among patients undergoing cardiac surgery to vary between 4% and 13%, depending on the target ACT and heparin dose required and on whether patients have recently received heparin.
3,4
Lower ATIII levels are associated with a decreased heparin dose response (HDR), as measured by the ACT.
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ATIII supplementation has been used to improve the ACT response to heparin
6
and is associated with better thrombin inhibition.
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Initial studies suggest that recombinant human ATIII (rhATIII) is effective in restoring heparin responsiveness in patients with heparin resistance.
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A previous study established that single dosing with 75 U/kg or more of rhATIII resulted in plasma ATIII levels approximating 100% activity that were maintained throughout CPB.
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FFP is readily available at most institutions and has been effectively used as an exogenous source of ATIII to restore heparin responsiveness.
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FFP as a source of ATIII is one of the medically accepted treatments for heparin resistance. FFP, however, is not an innocuous intervention and carries the risk of several complications, including viral infections and allergic reactions. It is also possible that FFP increases ATIII concentrations only when large volumes (>2 L) are administered. The current study was therefore designed to assess the efficacy and safety of rhATIII for improving heparin responsiveness in heparin-resistant patients undergoing elective cardiac surgery involving CPB, thereby avoiding the need for FFP. The trial also aimed to assess whether rhATIII at a dose of 75 U/kg increases plasma ATIII activity and inhibits thrombin and fibrinolytic activity more effectively than 2 units of FFP.
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Methods |
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Study Design
This multicenter, randomized, double-blind, placebo-controlled rhATIII efficacy study included patients at 6 European study centers undergoing first-time elective coronary artery bypass surgery requiring CPB. This population was chosen because FFP is sometimes administered as a source of ATIII to facilitate heparin anticoagulation in heparin-resistant patients before or during CPB.
8
Patients 18 to 85 years of age scheduled for elective cardiac surgery and requiring CPB were included in the study. No patients received aprotinin or any other antifibrinolytic agent. The bypass circuits were not heparin coated, systems were open, cardiotomy suction was used, and patients were cooled to 32°C. Patients who had a baseline HDR slope of 80 seconds or less with the Hepcon Hemostasis Management System (Medtronics, Minneapolis, Minn) were eligible. In addition, patients who had received intravenous heparin before surgical intervention, regardless of the HDR slope, were also eligible. Patients were excluded who had recently received or were receiving one or more of the following medications: warfarin (within 3 days); streptokinase; tissue plasminogen activator; abciximab, eptifibatide, or tirofiban; or clopidogrel. Also excluded were patients with preexisting coagulopathy defined as a history of bleeding problems or a laboratory history of a bleeding disorder.
Patients were considered heparin resistant if their ACT was less than 480 seconds (ACT II, Medtronics) 5 minutes after receiving a heparin dose of 300 U/kg, followed by an additional 100 U/kg (total heparin dose, 400 U/kg). Heparin-resistant patients were randomized into one of the 2 treatment groups. One group received a single-bolus 75 U/kg intravenous injection of rhATIII, and the other received a single-bolus intravenous injection of a normal saline placebo. If after the randomized bolus the ACT remained less than 480 seconds, this was defined as treatment failure, and 2 units of FFP were transfused. Additional heparin was administered during CPB as guided by the automated protamine titration method (Hepcon, Medtronics) and ACT values. Reversal of heparin with protamine after CPB was per institutional protocol.
Blood for measurement of hematologic parameters was obtained just before study drug administration (0 minutes), at 30 minutes after the initiation of CPB, and just before heparin reversal with protamine. These parameters included Kaolin ACT without heparinase and plasma ATIII activity levels. The ACT II (Automated Coagulation Timer, Medtronics) device was used for measuring the ACT during the treatment period. ACTrac (Medtronics), an electronic calibration device, was used in conjunction with the ACT II device to insure that evaluation values by using Hepcon (Medtronics), and study values with ACT II were consistent between the 2 devices. Additional blood was obtained at baseline and 4 weeks postoperatively to monitor serum samples for antibody formation to rhATIII.
All adverse events occurring from the time of study drug administration until hospital discharge and during the 4-week postoperative follow-up period were recorded. Blood and blood components transfused in the perioperative period were recorded. Postoperative blood loss through chest tube drainage was also recorded. Four weeks postoperatively, a blood sample for rhATIII was obtained, and a postoperative review for serious adverse events was performed.
The study’s primary efficacy end point was whether rhATIII restores heparin responsiveness. Patients who met the requirement for FFP but did not receive FFP were included in the analysis of patients who received FFP (ie, intention to treat). Secondary end points were comparisons between study groups of ACT values and plasma ATIII activity levels in the peri-CPB period. Other secondary evaluations included the inhibition of thrombin activity, as measured by changes in levels of fibrin monomer, the inhibition of fibrinolysis as measured by changes in D-dimer levels, and the changes in plasma ATIII activity levels at 2 time points: 30 minutes after initiation of CPB and before protamine administration.
Study Medications
RhATIII, manufactured by GTC Biotherapeutics (Framingham, Mass), was supplied in clear, glass, single-dose 20-mL vials and was refrigerated at 2°C to 8°C until reconstitution. The institutional research pharmacist at each study site prepared all study materials and was the only person at the site who knew the treatment assignment. Normal saline, indistinguishable from the reconstituted rhATIII at the designated concentration, served as the placebo control.
Statistics
It was anticipated that up to 500 patients would have to be screened and consented to identify 52 eligible patients. With 24 patients in each group, there would be 80% power to detect a 40% absolute reduction (65% vs 25%) in the proportion of patients requiring FFP. A total of 52 randomized patients, 26 in each treatment group, was recommended for the trial to account for a dropout rate of approximately 10%. The primary end point of the study was the comparison of the proportion of patients in each treatment group requiring the infusion of FFP after administration of study medication but before initiation of CPB.
The primary efficacy analysis, the difference between the proportions of patients requiring FFP in each treatment group, was assessed by using the Pearson 
2 test or the Barnard unconditional exact test, depending on the data distribution. Differences in the treatment effect on the odds of requiring FFP were assessed by using logistic regression. Odds ratios comparing treatment groups and 95% confidence intervals were calculated if indicated.
The secondary efficacy end points, ACT values, and plasma AT activity, were examined at 2 time points: 30 minutes after initiation of CPB and before protamine administration. Differences between the group means were assessed at each time point by analysis of variance. Cohort differences in change from baseline (time 0) in levels of fibrin monomer, D-dimer, and plasma ATIII at 30 minutes after CPB initiation and before protamine were assessed with an analysis of variance model or rank sum test, depending on data distribution. Two additional parameters, indicators of thrombin activation that were recognized as useful but were evaluated after completion of the study, were measured at baseline (time 0), at 30 minutes after initiation of CPB, and at the preprotamine time point in retained plasma samples. These included prothrombin fragment 1.2 and thrombin-antithrombin complex. Although not prospectively defined, evaluation of these parameters was performed under blinded conditions.
The significance of shifts in safety parameters was evaluated within each group by the McNemar test for binary variables and the generalized McNemar test for more than 2 categories. The difference between proportions of patients experiencing other safety-related events (ie, rehospitalization, incidence of red blood cell transfusion, platelet transfusion, additional blood product transfusion, duration of surgical intensive care unit stay, duration of hospitalization, 30-day incidence of rehospitalization, myocardial infarction, stroke, or death) were assessed by the Barnard unconditional exact test.
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Results |
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In the intraoperative period, during which FFP administration was guided by study protocol, 6 (21%) of 28 of patients in the rhATIII group received FFP compared with 22 (92%) of 24 patients in the placebo group (P < .001). This primary end point was similarly distributed across study centers for both treatment groups. In the 24-hour postoperative period, blood and blood component administration was guided by clinician discretion. There was no significant difference in the FFP, packed red blood cell, or platelet administration between the 2 groups in the 24-hour postoperative period. There was no significant difference between the groups in 24-hour postoperative bleeding.
ATIII activity was low at baseline in both groups and not significantly different in the 2 groups. In the rhATIII group, ATIII activity increased to within the normal range during CPB. In the placebo group, ATIII activity decreased even lower than it had been at baseline during CPB (Figure 1).
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The ACT was significantly increased in the rhATIII group compared with that in the placebo group after rhATIII administration and during CPB (P < .001, Figure 3).
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Discussion |
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The concept that ATIII deficiency is an important cause of heparin resistance in patients undergoing cardiac surgery was supported by the study data. Patients in the placebo group had a mean baseline ATIII activity of 61% (normal, 70%-130%). Furthermore, CPB-associated hemodilution induced a further decrease in ATIII activity to a mean of 42% activity in placebo-treated patients. In this group ATIII activity remained abnormally low throughout CPB. Importantly, despite the additional heparin the patients in the placebo group received, the ACTs remained low during CPB compared with those in patients in the rhATIII group (Figure 3). Administering additional heparin is not without potential complications, including increased bleeding and heparin rebound in the postoperative period. Administration of 75 U/kg rhATIII restored the mean plasma ATIII activity to greater than 100% activity despite hemodilution during CPB and maintained mean ATIII activity within normal physiologic range throughout CPB. This finding supports the chosen dose of rhATIII (75 U/kg). The large disparity in maximum ATIII plasma activity levels between the 2 groups demonstrates that administration of 2 units of FFP is not effective for normalizing plasma ATIII activity. Administration of rhATIII at a dose of 75 U/kg was well tolerated by heparin-resistant patients undergoing CPB. There was no difference in the incidence of serious adverse events or the incidence of clinically significant abnormal laboratory parameters between the 2 treatment groups. Importantly, rhATIII administration in this setting was not associated with increased intraoperative or postoperative blood loss. FFP was administered empirically to patients who were bleeding postoperatively, including to patients who had received rhATIII. This approach, however, has fallen out of favor on the basis of studies that demonstrate that prophylactic FFP
13
and platelet
14
administration do not decrease bleeding. Postoperative transfusion of blood and blood components was similar in the 2 groups.
During CPB, blood and the artificial surface of the bypass circuit come into contact, providing a powerful stimulus to activate the hemostatic system. Subsequently, tissue factor and tissue plasminogen activator are retransfused to the patient through cardiotomy suction, resulting in systemic activation of the hemostatic system.
2
Without anticoagulation, clots can form in the bypass circuit and might result in circuit occlusion or intracardiac thrombosis.
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In addition, with subtherapeutic anticoagulation, hemostatic system activation through thrombin and plasmin results in depletion of factors and platelets because of inadequate suppression of a disseminated intravascular coagulation-like consumptive state. To prevent these events, heparin is used to promote the action of ATIII in the blood, thereby reducing thrombin generation, thrombin activity, and fibrin generation extracorporeally and systemically. Therefore, heparin resistance might lead to inadequate anticoagulation during CPB and potentially lead to an increase in bleeding, thrombotic complications, or both.
Although gross clot formation in the extracorporeal circuit rarely occurs, activation of the hemostatic system still has important clinical implications. CPB activation of the hemostatic system has been implicated in the generation of cerebral microemboli, one of the proposed causes of stroke, and neurologic deficit often observed after CPB.
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Similarly, intraoperative coronary,
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pulmonary intracardiac,
18
and CPB circuit thromboses have all been described during cardiac surgery. Postoperative bleeding might result from platelet and labile coagulation factor consumption caused by thrombin activity during CPB.
2
Judging from surrogate markers, the results from this study are strongly suggestive that there was less hemostatic system activation in the group that received rhATIII. There was less activation of markers of both thrombin (eg, prothrombin fragments 1.2 and thrombin antithrombin complexes) and fibrinolytic activity (eg, D-dimer). Heparin-resistant patients might be at risk for the consequences of inadequate anticoagulation during CPB. Previous studies have demonstrated that more pronounced anticoagulation with heparin can reduce transfusion requirements
19
and preserve the hemostatic system.
20
Studies have demonstrated that ATIII supplementation can attenuate thrombin and fibrinolytic activity.
7
This suppression of thrombin and fibrinolytic activity, both of which usually increase during CPB, might represent better inhibition of hemostatic activation than that achieved with heparin alone.
7
The problem with detecting rare clinical events is that large numbers of patients are needed to detect these. For example, if giving rhATIII would result in a decrease in thrombotic complications in heparin-resistant patients from 10% to 5%, 433 patients would be required in each group (power, 80%; P = .05) to detect this. Assuming a 13% incidence of heparin resistance, 6662 patients (866/6662 [13%]) would have to be recruited to such a study. It is for this reason that we looked at surrogate markers.
This is the second randomized, double-blind, placebo-controlled trial that has demonstrated that rhATIII is effective in the management of heparin resistance in patients undergoing cardiac surgery with CPB.
21
There was a suggestion in the other study that rhATIII might be associated with increased postoperative bleeding.
21
There was no increase in postoperative bleeding with rhATIII in the present study. Heparin resistance was caused by ATIII deficiency in the majority of cases because the ACT was prolonged to the therapeutic range (>480 seconds) in 79% of patients after rhATIII administration. Administration of 75 U/kg rhATIII restored ATIII activity to within the normal range, which led to improved heparin responsiveness, adequate anticoagulation for CPB, and avoidance of FFP administration in the majority of cases. In contrast, ATIII activity decreased further from baseline in placebo-treated patients and required FFP treatment and additional heparin administration to obtain adequate anticoagulation before CPB initiation. Two units of FFP did not restore ATIII activity to the normal range.
In summary, the present study demonstrated that 75 U/kg rhATIII can be administered to heparin-resistant patients undergoing CPB and effectively restores heparin responsiveness in the vast majority of cases. There was strong evidence that rhATIII administration decreased hemostatic system activation during CPB. In addition, this prospective trial demonstrates that rhATIII administration for management of heparin resistance might substantially reduce exposure to FFP.
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Acknowledgments |
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Footnotes |
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This article has been cited by other articles:
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  J. M. Rodriguez-Lopez, E. del Barrio, F. S. Lozano, and C. Muriel Does Preoperative Level of Antithrombin III Predict Heparin Resistance During Extracorporeal Circulation? Anesth. Analg., October 1, 2008; 107(4): 1444 - 1445. [Full Text] [PDF]
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 B. D. Spiess Treating Heparin Resistance With Antithrombin or Fresh Frozen Plasma Ann. Thorac. Surg., June 1, 2008; 85(6): 2153 - 2160. [Abstract] [Full Text] [PDF]
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 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]
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 S. T. Morozowich, B. S. Donahue, and I. J. Welsby Genetics of coagulation: considerations for cardiac surgery. Seminars in Cardiothoracic and Vascular Anesthesia, December 1, 2006; 10(4): 297 - 313. [Abstract] [PDF]
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N. A. Guzzetta, B. E. Miller, K. Todd, F. Szlam, R. H. Moore, K. K. Brosius, E. C. Wilson, A. M. Cohen, and S. R. Tosone Clinical Measures of Heparin's Effect and Thrombin Inhibitor Levels in Pediatric Patients with Congenital Heart Disease Anesth. Analg., November 1, 2006; 103(5): 1131 - 1138. [Abstract] [Full Text] [PDF]
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