With the introduction of modern devices for vacuum assisted positioning of the beating heart, stabilizers and coronary artery shunts, coronary artery bypass grafting (CABG) without cardiopulmonary bypass (CPB), so called ‘off-pump’ CABG (OPCAB surgery) has developed into a standard technique in contemporary cardiac surgery [1,2]. However, despite this sophisticated technical support providing excellent conditions for the surgeon, there is still an ongoing debate about patient selection and, in particular, about whether the quality of the coronary anastomoses constructed during OPCAB surgery can be as good as with conventional ‘on-pump’ CABG on the resting heart [3,4]. Most of the investigations are limited in scope, and the strategies of surgical performance, anticoagulation and perfusion technique vary considerably, so the results of a single center study do not have general applicability. However, a recent investigation in OPCAB surgery patients, comparing heparin anticoagulation and protamine reversal with bivalirudin anticoagulation, a short acting direct thrombin inhibitor, demonstrated increased graft patency in the bivalirudin treated patients . The results of this study demonstrate for the first time that graft patency may not only be attributed to the technical quality of the coronary anastomoses but also depends on the anticoagulation strategy. The aim of the current review is to describe the influence of OPCAB surgery on hemostatic activation and to review the literature with regard to perioperative anticoagulation protocols in OPCAB surgery.
Hemostatic activation during OPCAB surgery
Surgical trauma results in the releases of tissue factor and thereby activates the coagulation system. If CPB is used, high dose anticoagulation is necessary to avoid thrombosis of the CPB system. However, despite this potent anticoagulation the contact of the blood with the large non-endothelial surfaces of CPB results in further hemostatic activation and progressive consumption of procoagulants . The contact of platelets with the CPB surfaces not only leads to activation and consumption of platelets, but also appears to induce a mechanical alteration which finally leads to the ‘platelet defect’ of CPB . As a result of this activation and progressive impairment of the coagulation system, hemorrhagic complications may occur and the avoidance of these complications is a central topic in contemporary cardiovascular surgery with CPB. As during OPCAB surgery the use of CPB is avoided, it can be assumed that the effect of the operation on the hemostatic system is less pronounced, and activation of the coagulation system may result in a more ‘prothrombotic’ state after heparin reversal. Over recent years a large number of studies have been performed to assess the impact of OPCAB surgery on hemostatic activation. Unfortunately the results of these investigations are inhomogeneous, probably due to the often limited number of patients and variations in heparin/protamine management. While some authors concluded that OPCAB surgery is associated with increased procoagulant activity, increased platelet aggregation and reduced fibrinolytic activity, others could not confirm these results [8-12]. Nevertheless, it appears that the ‘perioperative trauma’ of the hemostatic system is not as pronounced as following CPB surgery, and that the system, and particularly the platelets, is better preserved. As a result, there may be an increased risk of early thrombotic complications when compared to on-pump CABG.
Perioperative anticoagulation management: current US and European practice
While during on-pump cardiac surgery a target activated clotting time (ACT) value of 400-480 is generally accepted, to date no standardized target ACT value for OPCAB surgery has been established. However, not only ACT targets and heparin management are not standardized during OPCAB surgery; there are also no standards with regard to the amount of protamine administration after the grafting procedure or the use of antiplatelet agents before and after surgery.
Two recent investigations, one from the United States of America and Canada and one from Europe, elaborated the differences in current OPCAB anticoagulation management via a questionnaire. These two studies, evaluating standards of 304 US/Canadian centers and 26 European centers, demonstrated substantial differences among OPCAB surgeons with regard to anticoagulation management, which will be outlined in the following [13,14].
Pre- and postoperative antiplatelet therapy
There is evidence, that preoperative treatment with antiplatelet agents such as aspirin or clopidrogel is associated with an increase in perioperative blood loss, thus leading to strategies to stop therapy with these agents 5-7 days prior to surgery. However, this practice may be associated with an increased risk of myocardial event during this time. Due to the fact that during OPCAB surgery the hemostatic systems appears to be less affected than with CPB surgery bleeding does not play such a central role. Moreover, as in the immediate postoperative period the coagulation system, and particularly the platelets, appear to be better preserved, immediate postoperative re-institution of antiplatelet therapy may be a strategy to reduce early graft thrombosis.
Comparing the situation in US/Canada and Europe, there seems to be a clear trend in the US/Canada to stop antiplatelet therapy before surgery (Table 1) while in Europe only approximately 50% of institutions stop antiplatelet therapy beforehand. However, immediately postoperatively there is a clear predominance of early start of antiplatelet therapy in both continents (Table 1).
Target ACT values and heparin management
Target levels for ACT values and corresponding heparin management strategies are presented in Table 2. In the US/Canadian centers there is an obvious trend towards higher target ACT values and heparin dosages. However, these basic data show that, apart from major differences in detail, an ACT value of > 300 seconds is accepted by approximately 80% of US/Canadian surgeons and 60% of European surgeons. Even given the large variation commercially available heparins, the inter-individual variability of the effect of heparins on the ACT, and large differences in coagulation activation and ‘clot detection’ of currently used ACT systems, this target ACT corresponds to a heparin dose of approximately 150-300 IU/kg.
Degree of heparin reversal via protamine
Similar to differences in anticoagulation during the procedure, the reversal of heparin anticoagulation via protamine is characterized by substantial differences (Table 2). While approximately 50% of institutions reverse heparin anticoagulation completely, the other 50% prefer partial reversal of the anticoagulant effect.
Perioperative anticoagulation management: practice in OPCAB/graft patency trials and surveys
Since OPCAB surgery gained an emerging role, numerous trials have assessed graft patency following OPCAB surgery in comparison to conventional on-pump surgery. As the publications from these specialized centers might reflect the standard of anticoagulation management in the ‘scientific’ and specialized OPCAB centers, anticoagulation practice was also reviewed from this source [15-19]. The incorporated studies were the basis of a current review about this problem . Additionally, information is added from studies focusing on anticoagulation problems and large case/experience series of leading single institutions [5,20-23]. The information is presented in Table 3. These data again confirm that contemporary OPCAB surgery is performed without any clear standardized anticoagulation management protocols. A heparin dose of 150 IU/kg and target ACT value of 300 seconds appear to be accepted by most institutions and there seems to be a trend towards complete reversal of heparin anticoagulation with protamine. Information with regard to pre- and postoperative antiplatelet therapy is rather scant. The fact that only in a few of these trials detailed information is provided on all aspects of perioperative anticoagulation management signals, that even in the contemporary scientific world this central aspect of patient management is widely ignored.
Limitations of current heparin/protamine management in OPCAB surgery
The ACT is still the standard assay to monitor the effect of heparin anticoagulation. As this test is designed to evaluate the inhibition of contact activation, it is suitable for monitoring anticoagulation during CPB in order to avoid pump thrombosis. During OPCAB surgery hemostatic activation has to be predominately attributed to tissue factor activation, thus limiting the potential value of currently used ACT systems. A small study comparing heparin management according to the ACT with results obtained with the HEPCON HMS™ (Medtronic, Minneapolis, Minnesota USA), a device which is based on the measurement and maintenance of individually determined heparin levels, showed an underestimation of the heparin demand when monitoring was only by the ACT . Similar to the situation in on-pump surgery the ACT does not correlate to heparin levels and more generally affects the status of the coagulation system.
The strategy to only partially reverse heparin anticoagulation via protamine may reflect the recognition of a possible procoagulant condition in the early postoperative period following OPCAB surgery and potential risk of early graft occlusion . However in a recent investigation with partial reversal with only 50% of the calculated protamine dose, due to significant decrease of heparin levels, in most patients ACT returned to baseline values . Measuring and maintaining heparin levels during the grafting procedure with systems like the Hepcon HMS™ may help to provide adequate anticoagulation during the procedure and determine the necessary amount of protamine for calculated partial reversal of the heparin effect.
There are only few data available regarding the use of alternative anticoagulants to unfractionated heparin during OPCAB surgery. In one small prospective randomized trial Carrier et al. evaluated anticoagulation with danaparoid sodium in comparison to heparin/protamine . Danaparoid is a low molecular heparinoid which inhibits thrombin generation via activity inhibition of the activation of coagulation factor X. The pharmacokinetics of danaparoid sodium are characterized by a long elimination half-life and renal excretion. Currently used ACT assays do not correlate with danaparoid levels or anticoagulation and no antidote is available. In this study 71 patients were randomized to either a single bolus of 40 IU/kg of danaparoid or 1 mg/kg of heparin (target ACT, protamine?). Clinical outcomes in the two treatment groups were almost comparable, but there was a marked trend towards increased blood loss and transfusion demands in danaparoid treated patients.
Bivalirudin is a bivalent reversible thrombin inhibitor. The half-life is approximately 25 minutes and elimination predominately independent of the function of a single organ system. No antidote is available. Bivalirudin has been intensively studied during percutaneous coronary intervention (PCI) [28,29].
The dosing protocols used during OPCAB surgery are identical to those during PCI with a bolus of 0.75 mg/kg and a continuous infusion of 0.175/mg/kg/h during the grafting procedure. During OPCAB surgery bivalirudin has been assessed in two controlled randomized investigations of which the results have been published. In a single center investigation with 100 patients comparing bivalirudin with heparin/protamine, bleeding and transfusion rates were comparable between the groups while however there was improved graft patency in bivalirudin treated patients . The second investigation was the multicenter, controlled randomized EVOLUTION OFF study. In this investigation, in which patients were randomized 2:1 to either bivalirudin anticoagulation or heparin/protamine, safety and efficacy data were almost comparable in the two treatment groups . In both trials monitoring was performed using current ACT systems. Similar to PCI, an ACT value of > 300 seconds was defined as the target value. Analysis of bivalirudin pharmacokinetics and ACT measurements resulted in predictable and effective bivalirudin concentrations during the procedure and a good correlation of bivalirudin plasma levels to ACT values .
Conclusions and perspectives
Viewing the data currently available in literature shows that anticoagulation management is performed without any internationally accepted standard and, due to this and the lack of adequately powered studies, there is few information about the effects of OPCAB surgery on hemostatic activation in the immediate perioperative period.
It appears that a target ACT value of > 300 seconds is accepted by a majority of centers and that there is a trend to only partially reverse the heparin anticoagulant effect via protamine in order to prevent early graft thrombosis. Moreover, early institution of antiplatelet therapy seems to be accepted in most centers and to be associated with improved patient outcome [32,33]. However, currently used ACT assays, apart from the fact that these tests are intended to monitor inhibition of contact activation and not inhibition of tissue factor induced hemostatic activation, do not correlate with heparin concentrations. Employment of devices which measure heparin levels and therefore allow a better calculated partial reversal of heparin effect via protamine may be interesting in this regard.
Although limited to two modest studies, bivalirudin appears to be an interesting option for the future. Bivalirudin provides rapid potent anticoagulation and the short initial half-life of 25 minutes reduces the risk of excessive hemorrhage, while the longer terminal half-life provides longer lasting anticoagulation and may thereby prevent early graft thrombosis . However, larger controlled clinical trials are necessary to further define the safety and efficacy of bivalirudin during OPCAB surgery.
Financial support and conflict of interest: none.
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