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Ann Thorac Surg 2000;70:873-877
© 2000 The Society of Thoracic Surgeons

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Original articles: cardiovascular

A randomized trial of antithrombin concentrate for treatment of heparin resistance

^a Division of Cardiothoracic Surgery, Columbia University College of Physicians and Surgeons, New York, New York, USA

Address reprint requests to Dr Williams, Division of Cardiothoracic Surgery, Columbia University College of Physicians and Surgeons, 17–401, 630 W 168th St, New York, NY 10032
e-mail: mw365{at}columbia.edu

	Abstract

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Background. Heparin resistance is an important clinical problem traditionally treated with additional heparin or fresh frozen plasma. We undertook a randomized clinical trial to determine if treatment with antithrombin (AT) concentrate is effective for treating this condition.

Methods. Patients requiring cardiopulmonary bypass who were considered to be heparin resistant (activated clotting time < 480 seconds after > 450 IU/kg heparin) were randomized to receive either 1000 U AT or additional heparin.

Results. AT concentrate was effective in 42 of 44 patients (96%) for immediately obtaining a therapeutic activated clotting time. This compared favorably to 28 of 41 patients (68%) treated with additional heparin (p = 0.001). All patients who failed heparin therapy were successfully treated with AT. The patients receiving AT required less time to obtain an adequate ACT but there was no difference in clinical outcomes among the groups. Study patients had deficient AT activity at baseline (56% ± 25%), which improved in those given AT concentrate (75% ± 31% versus 50% ± 23%, p < 0.0005).

Conclusions. Heparin resistance is frequently associated with AT deficiency. Treating this deficiency with AT concentrate is more effective and faster for obtaining adequate anticoagulation than using additional heparin.

	Introduction

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Heparin resistance is an increasingly recognized clinical problem characterized by an inadequate response to high doses of heparin that makes initiation or continuance of cardiopulmonary bypass unsafe [1]. Heparin resistance has various but similar definitions, and for the purpose of this study is defined as an inadequate response after receiving greater than 450 U/kg of heparin. Antithrombin (AT) deficiency is argued to be a primary cause of this condition because the mechanism of action of heparin is through interaction with this molecule. Conventional treatment of heparin resistance includes administering fresh frozen plasma (FFP) as a source of AT, or administering increasingly higher doses of heparin to bind all available AT. FFP can transmit viral infections and its use can result in intraoperative delays while waiting for the product to become available. Additional heparin may prove ineffective if AT is severely deficient and can cause increased bleeding and heparin rebound.

Antithrombin concentrate is purified from heat-treated plasma that is part of the pasteurization process and has not been associated with viral transmission. We investigated the efficacy of AT concentrate in obtaining adequate anticoagulation for heparin-resistant patients requiring cardiopulmonary bypass. To do so, we designed a randomized trial comparing use of AT concentrate versus use of additional heparin in this population.

	Material and methods

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Protocol
All adult patients undergoing a procedure requiring cardiopulmonary bypass from May 1997 to April 1999 were eligible for enrollment. Only patients who were heparin resistant were enrolled in the study. Heparin resistance was defined as an activated clotting time (ACT) less than 480 seconds (or < 600 seconds if using aprotinin) after administering 450 U/kg of heparin. All patients received an initial loading dose of 300 U/kg of heparin, followed by a dose of 150 U/kg. If the clinical scenario required patients to receive cardiopulmonary bypass despite inadequate anticoagulation, they were still eligible for study enrollment (eg, hemodynamic instability). Patients who developed heparin resistance while on cardiopulmonary bypass despite having a prior adequate ACT were not eligible for enrollment. Patients determined to be heparin resistant were randomized to one of two groups. Group one received 1000 U (2 vials) of AT concentrate (Thrombate III, Bayer Pharmaceuticals, West Haven, CT). If the ACT was subtherapeutic after AT administration patients were crossed into the second group and received additional heparin. Conversely, group two received additional doses of heparin until an adequate ACT was obtained. If a total heparin dose of 800 U/kg without an adequate ACT was reached, patients were crossed over into the AT group. All patients received supplemental heparin for the remainder of the cardiopulmonary bypass run as necessary to maintain adequate anticoagulation. Blood samples were obtained at the time of randomization, 30 minutes after entering the study, and at the termination of bypass. These samples were assayed for AT activity levels, thrombin-antithrombin (TAT), and the prothrombin fragment (F1 + 2). To determine if a time advantage existed for one of the treatments, we quantitated the number of cycles involving dosing or redosing the appropriate agent, waiting for equilibration and then running an ACT. The total number of cycles was quantitated starting from study enrollment to obtaining a therapeutic ACT. This calculation is more reliable than actual time between measurements in assessing the time consequences of each treatment. Each dosing cycle represents a minimum of 12 minutes, as it includes administering the appropriate agent, waiting for equilibration, and waiting at least 8 minutes before a therapeutic ACT is returned. Additionally, preoperative demographics were obtained that included preoperative heparin therapy; this was defined as at least 24 hours of intravenous heparin that was not discontinued earlier than 24 hours before surgery. Patients were followed-up for 24 hours after surgery to obtain clinical parameters of bleeding complications, including chest tube output, transfusion requirements, hematocrit, and platelet count. The use of human subjects was approved by the Institutional Review Board of the College of Physicians and Surgeons and the Presbyterian Hospital.

Blood analysis
We performed ACTs using celite tubes and the Hemochron system (International Technodyne, Edison, NJ). TAT and F1 + 2 levels were determined by commercially available enzyme-linked immunosorbent assay (ELISA) kits (Behring Diagnostics GmbH, Marburg, Germany). AT activity levels were determined using an STA Hemostasis Testing System (Diagnostica Stago, Asnieres, France). All protamine doses were determined using a Hepcon system (Medtronic, Minneapolis, MN).

Statistics
Statistical relevance was determined using Student’s t test or Fischer’s exact test where appropriate using either Microsoft Excel (Microsoft Corporation, Redmond, WA) or InStat (GraphPad Software, San Diego, CA) for the Macintosh (Apple Computer, Cupertino, CA). A p value less than 0.05 was considered significant.

	Results

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Population
As seen in Table 1 both groups represented similar populations, without any baseline differences. Table 2 lists the types of procedures performed in each group. In the time period of the study there were 2270 cases on adults requiring cardiopulmonary bypass and 85 (3.7%) of them were found to be heparin resistant.

Analysis of AT activity revealed that 77% of the 61 patients measured were AT deficient at baseline (normal range, 70% to 120%). Patients receiving AT (including cross-over patients) demonstrated a significantly higher AT level at the 30-minute and terminating bypass time points, compared to those who did not (Fig 1).

View larger version (17K): [in this window] [in a new window]   Fig 1. Antithrombin (AT) activity at baseline, 30 minutes after commencing cardiopulmonary bypass (CPB), and at termination of CPB. Both groups had similarly deficient AT activity at baseline but there was a significant rise in activity in the AT concentrate group at the two later time points (p = 0.007 and p = 0.009). (AT = antithrombin; CPB = cardiopulmonary bypass; * denotes statistical significance.)

	Comment

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Antithrombin deficiency as a congenital disorder occurs in only 1 of 3,000 people; however, several additional factors may also lead to acquired AT deficiency including decreased synthesis from liver failure or malnutrition, increased loss of AT from nephrotic syndrome, consumption, or iatrogenic causes [6]. In the cardiac surgery setting the most relevant and common iatrogenic cause is heparin therapy. Administration of heparin will decrease the circulating half-life of AT [7] and is likely the explanation for the higher incidence of heparin resistance in patients previously treated with heparin [8–12]. Other possible culprits include nitroglycerin and oral estrogen [6, 13].

The beneficial effect of FFP in treating heparin resistance is likely explained by its AT content and has prompted use of purified AT concentrate in patients with heparin resistance who required cardiopulmonary bypass [3, 4]. AT has also been used in bypass patients as a method to control and preserve the hemostatic system during bypass outside of the setting of heparin resistance, although this has not been performed on a large scale and strong evidence does not exist regarding its effectiveness [2, 14].

The most significant finding with this study is the high failure rate in the heparin group (32%) compared to the AT group (5%). In all of the heparin failures, administering AT concentrate successfully elevated the ACT to a therapeutic range. Previously at our institution these patients would have received FFP as treatment. The use of FFP, though not studied in this trial, has several disadvantages. First, at our institution, a minimum of 20 minutes is required before the product is available in the room. The AT concentrate is available immediately. Second, FFP carries a risk of viral transmission and allergic reactions. In terms of the AT concentrate, there have been no reports that have confirmed transmission of any virus in clinical studies or during postmarketing surveillance. However, as with any plasma-derived product, one should still maintain caution, as transmission of viral or other pathogenic molecules remains a possibility. Finally, FFP represents a substantial volume load that can be dangerous, especially in patients with congestive heart failure. AT concentrate is only 20 mL.

In this study we have demonstrated advantages of using AT concentrate versus additional heparin in treating heparin resistance. Acquired AT deficiency is a common occurrence among patients with heparin resistance, and a correlation exists between preoperative heparin therapy and the development of heparin resistance. Because the design of this study only evaluated patients with heparin resistance, we are uncertain what percentage of our patients are normally taking preoperative heparin therapy, but we suspect that the 74% receiving this therapy in the study cohort is higher than that of the general population.

The effectiveness of AT was clearly demonstrated by the increased AT activity levels in our patients, accompanied by a resulting appropriate rise in the ACT. This also illustrates that perhaps we are treating a relative heparin insensitivity, as evidenced by a poor ACT response rather than a true heparin resistance. Because these patients are generally AT deficient, they have an altered heparin response curve, which can be restored to normal by repleting their AT.

We were unable to demonstrate an advantage in terms of thrombotic markers, as evidenced by no difference in TAT or F1 + 2 generation; however, these results were skewed by patients entering the trial after cardiopulmonary bypass was initiated and a high cross-over rate between the two groups. In our study we were unable to demonstrate a clinical advantage between any of the groups though follow-up was only for 24 hours. At the doses of AT we used it is unlikely to effect a positive benefit on the hemostatic system outside of its reversal of heparin resistance.

The advantages of a rapid ACT elevation after AT administration must not be overlooked. Potential thrombotic consequences associated with inadequate anticoagulation during cardiopulmonary bypass are avoided, particularly in unstable clinical scenarios mandating emergency cardiopulmonary bypass. Furthermore, additional heparin does not address the underlying problem in AT-deficient patients. Finally, by lowering the total heparin dose one can avoid the theoretical complications of heparin rebound as, over time, heparin becomes unbound from other circulating proteins [15]. This is suggested by a higher postprotamine ACT in the heparin group.

Finally, there is potentially a cost benefit of using AT in appropriately selected patients. Although AT concentrate costs approximately $860/1000 U compared to $144 for 2 units of fresh frozen plasma, the time saved may result in a shorter operating room time. The patients who received additional heparin required almost twice as many dosing cycles as those in the AT group, representing a minimum of 12 minutes of operating room time. In the patients who normally would have required FFP, an additional 20-minute wait was avoided. Thus, in a patient who had one additional dose of heparin and then required FFP followed by a repeat ACT, a minimum wait time of 40 minutes exists. The hospital cost of $1200 for the operating room does not reflect the time lost by the anesthesiologists, perfusionists, nurses, and surgeons. Obviously, this cost is a theoretical advantage and the AT concentrate does represent a real and not insignificant cost to the hospital.

Our dose of 1000 U of AT was derived from past experience and by examining the literature. Most patients responded sufficiently to this dose with a rise in AT activity, even though the rise was not to a normal value. This implies that only small amounts of AT need to be supplemented to achieve this effect. This contrasts to the high doses that are required in other clinical scenarios, including disseminated intravascular coagulation and maintenance of the hemostatic system during bypass. Supplementation of 500 U of AT may have been sufficient in our study, thus reducing the cost of the intervention, though this was not determined.

In conclusion, this study demonstrates that acquired AT deficiency is likely the primary cause of heparin resistance in patients requiring cardiopulmonary bypass. This condition can be managed effectively, safely, and efficiently by administering AT concentrate. It is faster than using only additional heparin and may avoid the use of FFP. No postoperative benefit was identified although an intraoperative time advantage exists. We recommend use of AT concentrate in any heparin-resistant patient and have made it our standard of care.

	Acknowledgments

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This research was funded by a grant from Bayer Pharmaceuticals-Biologics Division. Doctor Matthew R. Williams is supported by National Institutes of Health Training Grant T32-HL07343.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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