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Ann Thorac Surg 2006;81:104-111
© 2006 The Society of Thoracic Surgeons
a Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland
b Department of Radiology, University of Maryland School of Medicine, Baltimore, Maryland
c Department of Clinical Effectiveness, University of Maryland School of Medicine, Baltimore, Maryland
d Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland
e Chronolog Corp, Havertown, Pennsylvania
f Sinai Center for Thrombosis Research, Baltimore, Maryland
Accepted for publication May 10, 2005.
* Address correspondence to Dr Poston, Division of Cardiac Surgery, N4W94 22 S Greene St, Baltimore, MD 21201 (Email: rposton{at}smail.umaryland.edu).
Presented at the Forty-first Annual Meeting of The Society of Thoracic Surgeons, Tampa, FL, Jan 24–26, 2005.
| Ms Avari discloses a financial relationship with Chronolog, Corp.
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Abstract |
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METHODS: Sixty patients were randomly assigned to full-dose aprotinin or placebo. Heparin was titrated to a kaolin-based activated clotting time of greater than 300 seconds. Exclusionary criteria included creatinine greater than 2 mg/dL, conversion to on-pump CABG, and preoperative GPIIb/IIIa inhibition. Hematologic assessments were obtained preoperatively, at the end of surgery, and on days 1 and 3: mean platelet volume, thrombin generation (prothrombin fragment 1.2 assay), and aspirin resistance using a modified thrombelastography, whole blood aggregometry, 11-dehydro-thromboxane B2 levels, and flow cytometry. Thrombotic events were defined as postoperative myocardial infarction by electrocardiography or elevated troponin I, clinical stroke by examination and head computed tomography, and bypass graft failure by multichannel computed tomography angiography on day 5.
RESULTS: Aprotinin was associated with a significant reduction in intraoperative and postoperative blood loss compared with placebo but had no effect on transfusion rates. Patients treated with aprotinin had significantly fewer thrombotic events (3% versus 23%, p < 0.05, Fisher's exact test) and less postoperative aspirin resistance (20% versus 46%, respectively, p < 0.05, Fisher's exact test). Postoperative prothrombin fragment 1.2 level was reduced by aprotinin use.
CONCLUSIONS: Aprotinin reduced perioperative bleeding after OPCABG. Preserved aspirin sensitivity in the aprotinin group may explain the observed reduction in thrombotic events and might be related to the suppression of perioperative and transmyocardial thrombin formation.
Aprotinin (Trasylol; Bayer Pharmaceuticals Corp, West Haven, CT) reduces the need for blood transfusions and preserves platelet function in patients undergoing cardiopulmonary bypass (CBP) [1, 2]. Similarly, off-pump coronary artery bypass graft surgery (OPCABG) is also associated with reduced transfusions and improved hemostatic function as compared with on-pump CABG [3–5]. Aprotinin use has been widely avoided during OPCABG based on the concern of provoking hypercoagulability [6]. The lack of an established in vitro assay of hypercoagulability hinders critical evaluation of OPCABG, aprotinin therapy, and the risk of de novo thrombotic events. Despite the known benefit of aspirin therapy for early saphenous vein graft (SVG) failure [7], insufficient inhibition of in vitro platelet function, or acetylsalicylic acid (aspirin) resistance (ASA-R), is seen in nearly 50% of patients on an aspirin regimen after cardiac surgery [8, 9]. As ASA-R is associated with an increased risk of SVG failure after OPCABG [8], this endpoint could provide a surrogate for monitoring for hypercoagulability in this setting.
A recent randomized trial showed a favorable effect of aprotinin on bleeding after OPCABG [10]. Unfortunately, anatomic SVG patency was not assessed in this cohort, as early graft failure, often clinically silent [2], can have long-term consequences. In the current study, postoperative computed tomography (CT) imaging of bypass SVG patency and serial assessment of hematologic function were performed. We hypothesized that this comprehensive study design would allow us to better assess any possible discrete consequences of aprotinin therapy in OPCABG.
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Patients and Methods |
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Treatments
A modified full-dose regimen was used: 10,000 kallikrein inhibiting units (KIU) intravenous test dose (or saline placebo), 2 million KIU aprotinin through a central line before sternotomy, and 500,000 KIU/h until the end of the operation. Study drug or saline placebo was delivered to operating room in unlabeled bottles to maintain the blinding. Heparin dose was calculated by protamine titration using the HMS heparin assay (0.0 to 2.5 mg/kg [cat. no. 30407; Medtronic, Minneapolis, Minnesota]) to maintain levels greater than 2 µg/mL and a kaolin-based activated clotting time greater than 300 seconds. The heparin effect was partially reversed by administering half the dose of protamine calculated by the HMS device. The algorithm for intraoperative and postoperative blood product transfusions was based on thrombelastography analysis, as described [11]. All patients received preoperative and postoperative aspirin (325 mg orally each morning and within 6 hours after intensive care unit arrival) as the sole platelet inhibitor. Compliance was documented by patient questioning and examining medication administration records. Glucose levels were maintained at less than 150 mg/dL in the intensive care unit using insulin infusion. Given an association with ASA-R and direct effects on thromboxane production, nonsteroidal anti-inflammatory drugs were prohibited until hospital discharge.
Surgery and Perioperative Management
Four surgeons experienced in OPCABG enrolled patients. Internal mammary conduits were used in all patients. Saphenous veins were harvested using an endoscopic or open approach and stored in heparinized blood until use. The distal anastomosis was facilitated with suction-based devices (Medtronic). Enrolled patients converted to on-pump CABG (n = 9) were excluded from analysis. The volume retrieved intraoperatively by a cell salvage device (Haemonetics, Braintree, Massachusetts) and amount of postoperative shed blood after 24 hours was measured. Chest drain red blood cell volume was calculated at 24 hours by the hematocrit of contents in the chest drainage system (Atrium Medical Corp, Hudson, New Hampshire) multiplied by total volume [12]. Patients were excluded from the study if reoperation for bleeding due to a "surgical" source was required (n = 1). Intensive care unit and hospital discharge criteria followed closely monitored protocols.
Saphenous Vein Graft Quality Assurance
Intraoperatively, flow and pulsatility index (maximum-minimum/mean blood flow) were assessed in each SVG using a transit-time techniques (Medistim, Minneapolis, Minnesota). Saphenous vein grafts with flow that remained less than 10 cc/min and pulsatility index greater than 5 despite revision were excluded from analysis (n = 2). Endothelial integrity was analyzed in surplus portions of each SVG. A segment was frozen in cutting compound, and 5-µm sections were stained with monoclonal antibody against the endothelial marker, CD31 (R&D System, Minneapolis, MN). Percentage endothelial integrity was calculated by image analysis software (Bioquant Nova Prime; BIOQUANT Image Analysis Corp, Nashville, TN).
Assays for Coagulation
All coagulation and platelet function testing were performed on citrated blood samples drawn at four time points: before skin incision, postoperatively after protamine, and the mornings of postoperative days 1 and 3. International normalized ratio, partial thromboplastin time, fibrinogen, and quantitative d-dimer were performed by the clinical laboratory. Prothrombin fragment F1.2, released when thrombin is generated from prothrombin, was assessed in platelet-poor plasma using a commercially available enzyme-linked immunosorbent assay kit (Enzygnost F1.2 Micro; Dade-Behring, Deerfield, IL). The percent perioperative difference was calculated as follows: (preoperative F1.2 – postoperative F1.2) / preoperative F1.2 x 100. In a subset of patients (n = 20), coronary sinus samples were obtained at the completion of the grafting procedure by direct puncture using a 21G needle to determine the percent transmyocardial difference: (coronary sinus F1.2 – aortic F1.2) / coronary sinus F1.2 x 100.
Assays for Platelet Function/Aspirin Resistance
Platelet count and mean platelet volume were measured on EDTA blood samples using an automated hematology analyzer. The diagnosis of ASA-R was based on positive findings consistent with this diagnosis on at least two of the three following assays at any time point: for the first assay, thrombelastography (Haemoscope, Niles, Illinois), reptilase plus factor XIIIa was added to heparinized blood samples in cups within the analyzer (thrombelastography). Maximum amplitude (MA) of the thrombelastography trace was assayed with (MAAA) and without (MA0) the addition of arachidonic acid (AA), 0.5 mM. A standard kaolin-activated thrombelastography assay was used to compare thrombin-mediated platelet activation (MAThr). Aspirin resistance was determined as more than 50% platelet response to arachidonic acid (AA) according to a normalized formula: ([MAAA-MA0]/[MAThr-MAO])· 100 [13]. For the second assay, whole blood aggregometry (Chronolog, Hawerton, Pennsylvania), impedance change (
) was assessed in whole blood 6 minutes after 1 µg/mL and 5 µg/mL collagen. The ASA-R was defined as: %low/high = 1 mcg collagen/5 mcg collagen*100 greater than 50% [14]. For the third assay, 11-dehydro-thromboxane B2 levels, platelet-poor serum was assayed for 11-dehydro-thromboxane B2 levels using enzyme-linked immunosorbent assay (Assay Designs, Ann Arbor, Michigan), and ASA-R defined as a 25% rise from baseline serum levels.
In a subgroup of patients with and without ASA-R, the diagnosis was confirmed using whole blood flow cytometry (Becton-Dickinson FACScan) as follows: blood was incubated for 2 minutes with or without arachidonic acid (1.0 mM) and for 20 minutes with saturating concentrations of fluorescently labeled antibodies against a standard platelet receptor (CD41a; BD Pharmingen, San Jose, CA) and P-selectin (CD62P; BD Pharmingen). Samples were fixed overnight with 1% paraformaldehyde and stored at 4°C until analysis by fluorescence-activated cell sorter. The ASA-R was verified by a 50% increase in P-selectin expression after arachidonic acid [15].
Postoperative Follow-Up of Thrombotic Events
Stroke was determined by focal neurologic deficit on daily physical examinations and confirmed by head CT examination. Deep venous thrombosis was assessed by a duplex examination of the lower extremity venous system on day 5. Noninvasive, 16 detector row CT angiography with retrospective electrocardiography gating was obtained on day 5 and at midterm follow-up (10 to 20 months) to assess SVG patency. "Patent" was defined as any flow through the graft regardless of stenosis, and "nonpatent" if a stump or no flow was observed by CT angiography. Postoperative myocardial infarction was defined by a fivefold rise in cardiac troponin I or new Q waves at 4, 12, or 72 hours on electrocardiography [16]. After excluding patients with preoperative and postoperative myocardial infarction, data on plasma cardiac troponin I levels were further analyzed by calculating the area under the concentration–time curve by the trapezoidal method.
Data Management
Patient demographics, preoperative risk factors and medications, intraoperative variables such as conduit and target size and postoperative clinical outcomes were prospectively recorded onto Teleform case report forms (TELEform Elite; Cardiff Software, Vista, California) and electronically imported into a predesigned relational database (Integrated Research Information System, University of Maryland). Laboratory results were automatically captured through a database interface with the University's Clinical Data Repository.
Statistical Methods
The primary endpoint of this trial was the effect of aprotinin on blood loss at 24 hours. Assuming an impact of aprotinin that is similar to prior reports [14, 17], 30 patients per group provides 80% power to detect a difference at p = 0.05.
Secondary endpoints were (1) the number of patients that reached a composite endpoint of arterial thrombotic events during the initial hospitalization (SVG thrombosis, myocardial infarction, stroke); (2) the incidence of ASA-R determined on serial testing; (3) risk of deep venous thrombosis/pulmonary embolism; and (4) cost analysis. Unless specified, comparisons were done by analysis of variance with subsequent pairwise comparisons according to Duncan's multiple range test. Kaplan-Meier curves showing freedom from SVG failure at midterm follow-up were compared using a log-rank test. A p value less than 0.05 was considered significant. Statistical analysis was performed using InStat with the assistance of a statistician. The sponsors of this trial assisted in study design but played no role in the collection, analysis, and interpretation of data.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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No significant differences between aprotinin and placebo groups were observed for demographics, preoperative risk factors, and medications. Intraoperative data such as conduit flow and endothelial integrity, vein diameter, and target size and quality, need for intra-aortic balloon pump, and inotropic requirements were also similar.
Bleeding and Transfusions
Aprotinin significantly reduced the volume of bleeding seen intraoperatively (Fig 1A) and the percent of surgical fields classified as "dry" at chest closure (69.0% versus 29%, aprotinin versus placebo, p = 0.001). At 24 hours, red blood cell volume (namely, chest drain volume multiplied by hematocrit of drainage contents) was significantly reduced by aprotinin (77.8 ± 84 cc for aprotinin versus 185.6 ± 128 cc for placebo, p = 0.007; Fig 1B). A trend toward a reduction in the percent of patients transfused with RBC was suggested in the aprotinin group (p = 0.07; Table 1).
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Although incidence of ASA-R was similar at baseline (3% both groups), patients treated with aprotinin were significantly less likely to acquire ASA-R compared with placebo (20% versus 47%, p = 0.045; Fig 3). Patients with ASA-R according to both thrombelastography and whole blood aggregometry demonstrated a significant increase in perioperative thromboxane B2 production compared with patients found to have a preserved aspirin response (61% ± 14% versus 10% ± 15% perioperative change, p = 0.009). Nine cases classified as ASA-R by both thrombelastography and whole blood aggregometry and 11 thought to be aspirin sensitive were analyzed further by flow cytometry. A more than 25% increase in P-selectin expression in response to arachidonic acid was seen in 7 of 9 patients though to have ASA-R. None of 11 with preserved aspirin responsiveness by the other assays showed this change in P-selectin. Therefore, ASA-R was reduced by aprotinin according to all four assays (Fig 4). Five of 20 patients (25%) with ASA-R exhibited a postoperative thrombotic event compared with 2 of 40 patients maintaining aspirin sensitivity (5%, p = 0.03).
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Comment |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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After intensive study, the safety and efficacy of aprotinin during on-pump CABG has been well established [2], but a complete understanding of its mechanism remains elusive. Its hemostatic benefit is believed to be derived from its ability to block multiple derangements in coagulation induced during cardiac surgery. On the other hand, the antithrombotic mechanism of aprotinin is most likely focused on the blockade of thrombin formation and its receptor on platelets, protease-activated receptor 1 [18]. In our study and in others, aprotinin has been shown to reduce the level of F1.2 [19], a marker of thrombin formation and proven risk factor for SVG thrombosis [20]. While cardiopulmonary bypass is the culprit for thrombin formation during conventional surgery, the SVG itself may be a major source during OPCAB. We found less than 50% endothelial coverage in a majority of veins used for bypass grafting in this study. This procurement-related injury exposes tissue factor found in the subendothelial layer, leading to thrombin generation and an increased risk of SVG thrombosis [21]. Thrombin activates platelets within the SVG which, in turn, provide a thrombogenic surface for further thrombin formation, creating a syngergistic feedback loop [22]. The reduced difference in F1.2 across the coronary circulation after grafting in the aprotinin group suggests that this is a therapy that might interrupt this process.
Aspirin use after CABG is appropriately widespread owing to its favorable therapeutic window [23]. Monotherapy with ASA remains a standard of care despite increasing recognition of the clinical importance of ASA-R [15] and availability of agents to more effectively inhibit platelet function in this context [24]. The mechanism of how platelets develop ASA-R postoperatively, and how aprotinin may prevent it, is poorly understood. Aspirin resistance is unusual before cardiac surgery but is acquired in as many as 50% of cases postoperatively [9]. Thrombin generated during surgery can activate the platelet despite effective blockade of the thromboxane pathway, thereby creating an apparent ASA-R. Alternatively, the prevention of ASA-R by aprotinin may simply be due to reduced bleeding [1] and preservation of functional, aspirinated platelets [18]. That reduces the need for replacement by new, aspirin-naïve platelets capable of thromboxane formation within the once-daily dosing interval of aspirin [9]. Bleeding was reduced by aprotinin in our study, but postoperative mean platelet volume, an accepted marker for the formation of new platelets [25], was not different in the aprotinin versus placebo groups, suggesting that platelet turnover did not affect our results. We interpret our data to support the hypothesis that a reduction in thrombin formation and activity by aprotinin represents the principal mechanism through which this agent preserves the aspirin response.
Potential disadvantages of aprotinin during OPCABG were increased rates of deep vein thrombosis and hospital costs, which both approached statistical significance. Although aprotinin has not been found to increase deep vein thrombosis in high-risk patients [26] or costs [27] in prior reports, these issues deserve further study. Of note, downstream healthcare costs, such as those attributed to ASA-R, were not included in this analysis.
This study had several limitations. First, the best diagnostic test for ASA-R remains uncertain. We addressed this problem by considering the diagnosis of ASA-R established only if findings were compatible in two of three separate assays performed in all patients. The strong correlation of these assays with flow cytometry, a more established method for quantifying platelet activation, justifies confidence regarding our diagnostic criteria. Second, an intraoperative target of activated clotting time greater than 350 seconds (instead of 300 seconds) during OPCABG is frequently recommended based on the inverse relationship of heparin levels to systemic thrombin formation seen during on-pump CABG [28]. No relationship of heparin levels to systemic or transmyocardial thrombin generation was observed in our study. Intraoperative exposure of blood to the mediastinum may further exacerbate thrombin formation [29]. However, blood was washed by a cell salvage device, which minimizes patient exposure to plasma components in salvaged blood [30]. Therefore, the contribution of the mediastinum to thrombin formation in our patients was likely minor. Finally, clopidogrel after OPCABG may eliminate the importance of ASA-R [24]. However, its role in the management of patients after OPCABG is controversial [31]. On the basis of these limitations, while mechanistically consistent and statistically compelling, our findings should be considered only hypothesis generating pending prospective confirmation.
In conclusion, aprotinin administration was associated with a reduced incidence of new ASA-R after OPCABG, potentially mediated by a reduction in thrombin formation. These data provide clinical support to the growing body of experimental evidence that aprotinin demonstrates both hemostatic and antithrombotic effects [18], and is likely to prove a valuable therapeutic adjunct to promote conduit patency after OPCABG, as it has for blood loss associated with this and other cardiac surgical procedures.
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Discussion |
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DR POSTON: It is a full dose of aprotinin, which is basically identical to the way it is described for on-pump except you don't have 2 million units in the pump. You end up using a little bit less total aprotinin, but it is a 2 million load and then 500 KIUs per hour until case completion. And then with regard to us changing our management, we don't use routinely aprotinin in off-pump. I think you can certainly based on these data feel more justified to use it in cases about which you are concerned. I know patients who are on preoperative Plavix or other antiplatelets for whom you might like to use it to help reduce the bleeding effects. It certainly can be done without any concern about provoking thrombotic events, which is what people had been concerned about with aprotinin in off-pump previously. But we haven't changed our policy of routinely using aprotinin off-pump, based mostly on cost. It is about $1,000 a course.
DR BEN P. BIDSTRUP (Tugun, Queensland, Australia): I enjoyed this paper. I think you have produced a wealth of information that is going to be very important to us. Quigley and colleagues, using thrombelastography, and we also showed some years ago, that platelets weren't apparently as inhibited post-OPCABG compared with on-pump surgery (Quigley RL et al. Heart Surg Forum 2003;6:94; and Bidstrup BP et al. Heart Surg Forum 2003;6;286). This you have confirmed in this study. You noted that 20% of patients seemed to be resistant to aspirin even in the aprotinin-treated group. Did you look at preoperative aspirin resistance to identify that section of the population that are normally aspirin resistant and would that perhaps influence you in terms of giving other antiplatelet agents such as clopidogrel postoperatively?
DR POSTON: Thank you very much for your questions. I certainly appreciate your experience on this topic. The definition of aspirin resistance hasn't reached a standard yet. There is no specific test that has been well established and proven a track record with an in vitro result which correlates with clinical events, which is what we really need, and so the incidence of aspirin resistance varies according to the test that you are talking about. We defined aspirin resistance as meeting the definition of both the thrombelastography and whole blood aggregrometry, in other words, having to meet both of those tests, the criteria according to both those tests. So it only occurred in 5% of our patients, 3 of the 60 study patients.
With regard to Plavix and the use of that after off-pump surgery, I know it is used a lot, with the thought that it might help improve graft patency. I like the idea of using aprotinin to improve graft patency because it doesn't affect bleeding and in fact reduces bleeding while potentially improving the aspirin benefits that you get. The problem with Plavix is that you have to give it in a loading dose for it to be effective. I think that graft thrombosis occurs within minutes of perfusion, and if you wait, there have been studies showing that if you don't give aspirin until postoperative day 3 or 4 that it doesn't have the efficacy that it does if you give it within 6 hours postoperatively. And so by giving Plavix at a 75 mg dose, until the Plavix effect takes, it can take a week or two. And so it is like giving a patient a placebo unless you also give aspirin at the same time.
I think without loading Plavix, then it is probably not a very effective strategy, and if you do load Plavix, then you are kind of flying without a seat belt because you have got all this Plavix in the system. Unlike aspirin, aspirin is safe, because you give it and 20 minutes later it is out of the bloodstream, whereas Plavix is going to be around for 8 to 12 hours. So if the patient does happen to bleed immediately postoperative, then even if you give new platelets, platelet transfusions, the Plavix is going to bind those, and you are really going to be in trouble. It is hard to beat the therapeutic window and safety of aspirin, and I think it would be difficult to change off of that too easily.
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J. H. Levy and S. Force Invited commentary Ann. Thorac. Surg., September 1, 2007; 84(3): 986 - 987. [Full Text] [PDF]
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R. Poston and O. Toshinaga Reply Ann. Thorac. Surg., November 1, 2006; 82(5): 1951 - 1952. [Full Text] [PDF]
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