Apixaban is commonly prescribed for the prevention of stroke in patients with non-valvular atrial fibrillation [7]. Patients medicated with apixaban who require emergency surgery face an increased risk of hemorrhagic complications. Andexanet-alfa serves as the antidote to apixaban [10]. In an emergency scenario, this drug can rapidly and almost completely reverse the anticoagulant effects of FXa inhibitors.
However, the effects of andexanet alfa in cardiac surgery and potential interactions with unfractionated heparin are not well-established. Additionally, andexanet-alfa comes at a high cost (US$24,750) [11].
In a cost-utility study aimed at assessing the inherent cost of hemoadsorption in patients treated with ticagrelor, it was found that the use of Cytosorb® could save approximately GBP 4,000 within 30 days. This analysis encompassed the cartridge price, reduced consumption of blood products, and shorter time spent in an emergency surgical environment [5]. Economic factors and ease of use have favoured intraoperative hemoadsorption with Cytosorb® for apixaban elimination in an emergency surgery context [5].
Hemoadsorption with Cytosorb® can be easily integrated into a CPB circuit. In our case, the cartridge was inserted between the recirculation line and the venous reservoir (Fig. 1).
The fundamental principle is that the aspiration line should be connected to a high-pressure area of the circuit (after the arterial pump), and the ejection line should be connected to a low-pressure point in the circuit. This type of connection prevents veno-arterial shunting and gas embolism, allowing for a constant flow in the arterial part of the circuit.
The ideal flow rate through the Cytosorb® cartridge is unknown; however, manufacturers recommend a flow rate between 100-700 ml/min [12]. Recirculation generated through the cartridge should be considered in the blood flow delivered to the patient. As for anticoagulation, it should be mandatory and comprehensive during therapy due to the extensive blood-cartridge contact surface (>40,000m2) [13]. Since this therapy involves an extracorporeal circuit, this point may not be an issue. Nevertheless, it is important to note that partial anticoagulation is likely to result in rapid device thrombosis, greatly limiting its effectiveness [13].
To support our findings, we conducted a brief literature review (up until October 1, 2023) on the PubMed database. Only five articles describing interactions between Cytosorb® and apixaban were identified. The key findings are summarized in Table 2.
The retrieved studies encompassed various designs, including an experimental in vitro investigation and observational cases studies. Notably, an experimental study examined the reduction of apixaban concentration in an in vitro setting using Cytosorb®. Their results revealed a substantial decrease in apixaban levels after 30 minutes of adsorption, suggesting the potential of this device in reducing apixaban concentrations [14] .
Complementing these findings, observational case studies, presented instances of patients, particularly elderly individuals, undergoing emergent surgeries or dialysis while on apixaban therapy [6, 15, 17]. In each case, the utilization of Cytosorb® demonstrated a reduction in apixaban concentration, indicating its potential role in managing anticoagulation during critical interventions.
Furthermore, the case-control study investigated the impact of Cytosorb® on patients undergoing cardiac surgery while on concurrent apixaban therapy. Noteworthy outcomes include a significant reduction in bleeding events, lower postoperative volumes, and decrease requirements for DDAVP in the Cytosorb® group compared to controls. This study suggests a potential benefit of Cytosorb® in improving hemostatic outcomes during cardiac surgery in patients on apixaban [16].
While these findings collectively suggest a positive trend in the use of Cytosorb® in managing apixaban-associated scenarios, it is essential to acknowledge certain limitations within the existing literature, with the majority of studies being case reports. Moreover, the absence of randomized controlled trials introduces uncertainty regarding causality and necessitates caution in interpreting the observational effects.
However, our brief literature review indicates a growing body of evidence suggesting a potential benefit of Cytosorb® in reducing apixaban concentrations and improving hemostasis in patients undergoing surgeries or dialysis while on apixaban therapy.
It is known that the gold standard to measure plasma apixaban concentration, like other drugs, is mass-spectrometry. However, this technique is not viable for real-time use during emergency cardiac surgery. The anti-Xa test is a common method to measure apixaban concentration. Although is it known that during extracorporeal circulation, apixaban levels are not interpretable due to the indirect inhibition of FXa by heparin, with the administration of protamine, the values become valid, as after neutralization of heparin, the test can be interpreted as the apixaban activity.
In our patient, in line with the existing literature, AFXaA also decreased between the beginning and the end of the surgical intervention. A reduction of 63.7% was recorded between the patient’s admission to the operating room (AFXaA=121 ng/l) and admission to the intensive care unit (AFXaA=44 ng/l). This result can be supported by the postoperative 24h chest-tube-drainage, which was only 280 ml.
We also observed an improvement in liver markers (i.e, alkaline phosphatase and GGT) between the two assessment points, which is also supported by published literature [18].
Regarding limitations, it’s important to note that despite the rapid weaning of vasoactive drugs and the small volume recovered by drains, the stabilization of hemodynamics and coagulopathy cannot be solely attributed to the use of Cytosorb®. Aggressive administration of blood products and coagulation factors including fresh plasma, fibrinogen, platelets, prothrombin complex concentrate and recombinant factor VIIa was also necessary.
The measurement of apixaban blood concentration should ideally have been conducted at various stages of the surgery to demonstrate the progressive reduction of this drug during therapy. However, the urgent nature of our case precluded the possibility of conducting this type of analysis.
Another limitation worth noting relates to the monitoring of ACT using the Hemochron system (Hemochron® Signature Elite System, Werfen, Bedford, USA). Although this device provides a quick ACT result in a single measurement, its reliability in assessing the adequacy of heparin anticoagulation monitoring for CPB is questionable. The use of devices like the Hemostasis Management System Plus (HMS®, Medtronic, Minneapolis, USA) with simultaneous dual measurements could address this issue; however, we do not have this equipment in our institution.
It is important to emphasize that, although the emergent nature, as well as the advanced age and health status, of our case may pose challenges for extended follow-up, we recognize the importance of considering the long-term implications of hemoadsorption in future research endeavours.
In conclusion, this case demonstrates that intraoperative hemoadsorption with Cytosorb® may be a safe and feasible approach, increasing the elimination of apixaban in patients undergoing emergency cardiac surgery with CPB, resulting in a reduced risk of hemorrhagic complications.
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