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Department of Cardiothoracic Surgery, Lankenau Hospital, Wynnewood, Pennsylvania
Accepted for publication January 28, 2008.
* Address correspondence to Dr Samuels, Lankenau Hospital, Department of Cardiothoracic Surgery, MSB Suite 280, 100 Lancaster Ave, Wynnewood, PA 19096 (Email: samuelsl{at}mlhs.org).
| Dr Samuels discloses that he has a financial relationship with Abiomed, Inc, and Thoratec, Inc.
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Abstract |
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Methods: This is a retrospective review of all Abiomed (BVS5000, AB5000) and Thoratec (PVAD and IVAD) ventricular assist devices from May 2003 through May 2006 at a single institution. Postoperatively, patients received either heparin or argatroban as their anticoagulant. Patients in whom heparin-induced thrombocytopenia was suspected or confirmed were converted from heparin to argatroban.
Results: There were 33 Abiomed and Thoratec ventricular assist devices implanted. Thirteen patients received heparin as their primary postoperative anticoagulant; 8 of the 13 were converted to argatroban as a secondary anticoagulant (hep-arg), and 5 patients remained with heparin as their only anticoagulant. Twenty patients received argatroban as their primary and only postoperative anticoagulant. Thrombocytopenia occurred in 26 patients (79%) overall, 16 (80%) with argatroban only, 6 (75%) with hep-arg, and 4 (80%) with heparin only. Thromboembolic events occurred in 5 patients (15%) overall, 3 (15%) with argatroban only, 1 (13%) with hep-arg, and 1 (20%) with heparin only. Postoperative bleeding requiring reexploration occurred in 5 patients overall (15%), 1 with argatroban only (5%), 3 (38%) with hep-arg, and 1 (20%) with heparin only. Enzyme-linked immunosorbent assay heparin-induced thrombocytopenia tests were positive in 7 patients overall (21%), 5 (25%) with argatroban only, 2 (25%) with hep-arg, and 0 (0%) with heparin only.
Conclusions: Argatroban is a comparable primary or secondary anticoagulant to heparin postoperatively in patients receiving ventricular assist devices.
Postoperative anticoagulation is necessary for all ventricular assist devices (VADs) with the exception of the HeartMate XVE (Thoratec Inc, Pleasonton, CA). As such, bleeding and thromboembolic complications are among the major adverse events of this therapy. In addition to these specific VAD-related concerns is the increasing incidence and prevalence of heparin-induced thrombocytopenia (HIT) as a result of the more frequent exposure to heparin during diagnostic and therapeutic procedures [1]. In response to this, alternatives to heparin have been used in HIT-positive patients when the diagnosis has been suspected or confirmed. Argatroban (GlaxoSmithKline, Brentford, London, UK), a direct thrombin inhibitor, is fully approved for the treatment of HIT and has been used in a variety of settings in general cardiac surgery [2, 3]. The purpose of this report is to describe our experience with the use of argatroban as a primary or secondary postoperative intravenous anticoagulant after VAD placement.
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Material and Methods |
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There were 47 VADs implanted, 13 of which were HeartMate XVE types. Because the HeartMate XVE does not require intravenous anticoagulation postoperatively, patents receiving this device were excluded from the study. Thus, 33 VADs requiring postoperatively intravenous anticoagulation—Abiomed (BVS5000 and AB5000; Abiomed, Inc, Danvers, MA) and Thoratec (PVAD and IVAD; Thoratec Inc) VADs—were included.
The criteria for VAD implantation was acute cardiac failure despite maximal medical therapy (eg, intraaortic balloon pump and inotropic drugs) or acute decompensation of chronic heart failure. The end points were bridge to recovery with VAD removal or bridge to transplantation.
All implants were performed with heparin as the intraoperative anticoagulant. The heparin was bovine and the dosing was 3 mg/kg. After the VAD implant, the heparin was reversed with protamine sulfate to restore the activated clotting time to baseline. Postoperatively, patients received either heparin or argatroban as their primary anticoagulant. The standard argatroban concentration consisted of 250 mg in 250 mL of normal saline solution; the standard heparin concentration consisted of 25,000 units in 250 mL of 5% dextrose in water.
The decision to use heparin or argatroban was based on a chronologic change in the anticoagulation protocol—from May 2003 through June 2004, all patients were initiated on heparin as their primary postoperative anticoagulant. From July 2004 through May 2006, all patients were initiated on argatroban as their primary postoperative anticoagulant. Patients in the former group who received heparin as their primary postoperative anticoagulant were converted to argatroban as a secondary postoperative anticoagulant if there was concern for HIT. The criteria for converting from heparin to argatroban included a drop in the absolute platelet count by 50% or more, clinical stigmata or HIT, an HIT-positive assay, or persistent heparin resistance. The serologic HIT testing included both serotonin C 14 release assay and the enzyme-linked immunosorbent assay detection of antibodies to the platelet factor 4 (PF4)/PVS complex. We did not perform preoperative HIT assays. Serologic HIT interpretation was considered positive if the serotonin C 14 release assay value was greater than 20% serotonin released and the enzyme-linked immunosorbent assay results demonstrated an optical density value greater than 0.41.
Postoperatively, all patients were initiated with intravenous anticoagulation within 12 to 24 hours after entry to the intensive care unit. The partial thromboplastin time was measured every 6 hours until a steady state of 60 to 90 seconds was established, after which daily partial thromboplastin times were obtained. Neither heparin nor argatroban was initiated with a bolus. Instead, a maintenance infusion was started in the following manner: heparin at 1,000 U/h titrated up or down by 100 U until the desired range was achieved; argatroban at 1.0 µg · kg–1 · min–1 (normal liver function) or 0.5 µg · kg–1 · min–1 (abnormal liver function) titrated up or down by 0.1 µg/kg until the desired range (partial thromboplastin time 60 to 90 seconds) was achieved. Antiplatelet therapy with aspirin (81 mg) was introduced when the absolute platelet count exceeded 100,000 K/UL. Neither platelet aggregometry nor thromboelastography measurements were made.
Comparison was made between heparin only, argatroban only, and heparin/argatroban (hep-arg) patients with regard to clinical and hematologic outcomes. After this determination, a statistical test for dependence was run. Because of the small sample size, both 
2 and G distributions were not considered. Alternatively, Fisher exact tests were run comparing the independence of argatroban to all other methods sampled (Table 1). Platelet counts, thromboembolic events, postoperative bleeding and blood transfusion requirements, and HIT assay positivity were examined. A positive decrease in platelet count was defined as a 50% reduction from the baseline value. An HIT-positive assay was defined as both serotonin C 14 release assay and enzyme-linked immunosorbent assay positivity. By definition, patients who were maintained on heparin throughout their course were HIT negative. Postoperative bleeding was defined as the need to return to the operating room for bleeding.
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Results |
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Comment |
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Heparin, the most used anticoagulant in the world, introduces another serious complication: HIT. In 25% to 50% of patients undergoing open heart surgery with cardiopulmonary bypass, heparin-dependent antibodies are observed. In approximately 1% to 3% of these patients, HIT will occur—and in about 50% of these cases, a thrombosis will happen [4]. Interestingly, the prevalence of heparin/platelet factor 4 (HPF4) antibodies before and after cardiac surgery demonstrated a fivefold increase after the procedure (4.3% to 22.4%) [5]. And in a study examining the prevalence of HPF4 antibodies in patients with heparin-coated and uncoated VADs, the formation of HPF4 antibodies was observed in 73% (40 of 55) of the cases with 88% (35 of 40) of the antibodies existing before surgery [6]. The presence of HPF4 antibody, however, does not necessarily translate into the HIT syndrome. In the study by Everett and colleagues [5], 2 of 8 patients (25%) with both thrombocytopenia and positive antibody suffered a thromboembolic event.
In response to the concern for the development of antibodies and HIT, alternatives to heparin have been used in cardiac surgery [7]. Many heparin alternatives have been discovered and used clinically, including the snake venom ancrod [8], the low molecular weight heparin danaparoid [9], and the GIIb/IIIa inhibitors [10]. However, among the more commonly used heparin alternatives in cardiology and cardiac surgery are the direct thrombin inhibitors [11]. Recombinant and synthetic forms of hirudin have been developed, including Angiomax (The Medicines Company, Parsippany, NJ) and Refludan (Berlex Laboratories, Inc, Wayne, NJ). These drugs have been particularly useful in patients with heparin antibodies undergoing cardiac surgical procedures [12, 13].
The literature on the use of argatroban, a synthetic direct thrombin inhibitor derived from L-arginine, as an alternative to heparin is limited in cardiac surgery [2, 3, 14] and virtually absent in the field of VAD procedures with the exception of experimental animal models and pediatric cases with extracorporeal membrane oxygenation [15–17]. Argatroban has recently been evaluated in a multicenter European trial (ARG-E03) in which open-label argatroban as a replacement for heparin was used in patients with a history of HIT or suspected HIT in cardiovascular surgery [18]. Twenty patients were enrolled and 14 patients qualified for the study. The study methods were as follows: anticoagulation during cardiopulmonary bypass was conducted with heparin and tirofiban (Aggrastat; Merck and Company, Inc, Whitehouse Station, NJ), a GIIb/IIIa inhibitor, and postoperative argatroban anticoagulation with a target activated partial thromboplastin time of 50 to 70 seconds. The clinical course of 13 patients was unremarkable with a mean postoperative blood loss of 765 ± 623 mL at 24 hours; 1 patient had excessive bleeding requiring discontinuation of the argatroban with cessation of the bleeding and no need for surgical exploration. Other investigators have had less favorable experiences with argatroban in cardiac surgical procedures, suggesting that argatroban may be insufficient in providing adequate anticoagulation with thrombosis or too sufficient in maintaining anticoagulation with resultant bleeding [19–21].
Our experience with argatroban was strictly postoperative. The desire to use argatroban was born out of the need for an alternative intravenous anticoagulant in VAD patients who demonstrated either clinical or hematologic concerns for HIT while on heparin. Based on our initial favorable experience with conversion from heparin to argatroban, we sought to determine whether argatroban could be used as the primary postoperative anticoagulant. The logic was to determine whether we could avoid the use of heparin postoperatively to reduce the risk of HIT and to use an agent (eg, argatroban) that would treat HIT if the substrate (ie, antibody) was present for HIT to occur. Our results showed that the effectiveness of argatroban as a postoperative anticoagulant in VAD patients was similar to heparin from a thromboembolic perspective with less observed postoperative bleeding. We did not find any specific correlation between the thromboembolic event and the type of VAD. Nor did we find a good explanation for why there was less observed bleeding with argatroban instead of heparin. The statistical analysis of the data was of no value in discerning any significant differences between heparin and argatroban as it pertained to outcomes. Although a trend toward less bleeding was observed in the argatroban subgroup, it is our opinion that this finding is not real because the number of study subjects is too small and bleeding in VAD patients too complex. It should be pointed out, though, that we did modify (reduce) the dosage of argatroban for patients with abnormal liver function tests. This may explain our observation that we did not experience such profound bleeding with argatroban as had been the case in the past when the dosage was not adjusted for liver function abnormalities. We maintained the partial thromboplastin time between 60 and 90 seconds without difficulty and in no instance did we have to discontinue the argatroban infusion because of coagulopathy. Instead, postoperative bleeds that required surgical intervention were related to technical issues.
In summary, argatroban serves as an adequate postoperative anticoagulant in patients receiving VADs and can be used either primarily or secondarily to heparin. The next logical step is a prospective randomized trial.
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Related Article
This article has been cited by other articles:
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  T. E. Warkentin, A. Greinacher, and A. Koster Heparin-induced thrombocytopenia in patients with ventricular assist devices: are new prevention strategies required? Ann. Thorac. Surg., May 1, 2009; 87(5): 1633 - 1640. [Abstract] [Full Text] [PDF]
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J. Butterworth Invited Commentary Ann. Thorac. Surg., May 1, 2008; 85(5): 1655 - 1655. [Full Text] [PDF]
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