3. Management:
Several recommendations can be made concerning the acute management of coagulopathy in patients undergoing emergent cardiac surgical intervention depending on the anticoagulant and are summarized in (Table 2).
1-Activated oral charcoal is given if DOAC was last ingested within 2-4 hours.
2-Vitamin K (5-10 mg IV) is administered for VKA reversal; however, its effect may be too slow for emergent surgery.20
3-Non-specific prohemostatic agents can be used including four-factor prothrombin complex concentrate (4F-PCC) with a recommended dose of 25-50 IU/kg. Four-factor PCC was found to be close to 70% effective in achieving hemostasis in patients with major bleeding.21,22 In a review by Goldstein et al, 4F-PCC was superior to FFP for rapid INR reversal and effective hemostasis in patients requiring VKA reversal for urgent surgical procedures (most were non-cardiac).23 One study reported 40 patients on oral VKA, mainly for AF, who underwent urgent cardiac surgery and were randomized to FFP and PCC. Patients received, pre cardiopulmonary bypass (CPB), either 2 units of FFP or half of the calculated PCC dose. Post-bypass, they received 2 more units of FFP or the second half of PCC dose. It was noted that reversal with PCC was faster and bleeding was less compared to FFP.24
4- Three-factor PCC has less concentration of factor VII compared to 4F- PCC and can be used for reversal of VKA. Both 4F-PCC and 3F-PCC do not require large volumes to be administered, an advantage in patients with heart failure and fluid overload.
5-Antifibrinolytic agents such as aminocaproic acid and tranexamic acid are frequently used even in elective cases. They exert their effect by inhibiting plasminogen activators and to a lesser degree through antiplasmin activity, thereby minimizing the untoward effects of fibrinolysis seen with CPB and challenging an already attenuated hematologic profile.25
6-Two specific DOAC reversal agents (antidotes) have been approved by the US Food and Drug administration (FDA): idarucizumab for reversal of dabigatran and andexanet alfa for reversal of apixaban, edoxaban and rivaroxaban.26 Dosing is typically based on predicted concentration of the anticoagulant depending on its dose and last time of ingestion.
Idarucizumab was studied in patients with dabigatran–associated bleeding (REVERSE-AD trial). Most common sites of bleeding were gastrointestinal and intracranial. Median time to achieve hemostasis was 2.5 hours and there was no correlation with drug levels. None underwent CPB and several patients suffered thromboembolic events, 50% of which occurred within 5 days.27 In a multicenter experience in Spain, Idarucizumab was used in 56 heart transplant patients, 7.5% required reoperations for bleeding and 66% were transfused with blood products.28
The use of andexanet alfa (a recombinant modified factor Xa protein) as an antidote was reported on 352 patients on factor Xa inhibitors who had major bleeding (64% intracranial and 26% gastrointestinal). It markedly reduced anti-factor Xa activity with good or excellent hemostatic effects in 82% patients.29 In one prospective study of 66 patients on factor Xa inhibitors and presenting with major bleeding, reversal was effective in 68%, ineffective in 32% and 8% suffered a major thromboembolic event.30
These drugs are costly and have a short half-life that may result in anticoagulant rebound when infusion is stopped. On the other hand, specifically andexanet alfa, can bind to heparin-antithrombin complexes precluding therapeutic activated clotting time (ACT) necessary for CPB (heparin resistance) and should be used with caution.31–33 It is worthwhile reporting on a potential promising universal antidote (ciraparantag) to all DOACs that binds to the anticoagulants via noncovalent hydrogen bonds, but is still under investigation and not available for commercial use34 (Table 3).
7-Hemodialysis (HD) is thought not to be very beneficial with regards to urgent reversal as most DOACs, including rivaroxaban and apixaban, are highly protein bound. Although edoxaban is relatively low protein bound, it is not well cleared by HD. Betrixiban is 60% protein bound, but there is paucity of data demonstrating the effectiveness of dialysis in clearing the drug. Dabigatran is 35% protein bound and HD has been proposed as a possible treatment strategy in patients with major bleeding. Published reports have shown that 4-hours of HD can reduce the plasma concentration of dabigatran by up to 68%, with a recent meta-analysis suggesting HD may be of some benefit in patients requiring urgent reversal.35
8-Antiplatelet medications: Aspirin irreversibly acetylates a serine residue of cyclooxygenase 1, which ultimately decreases the synthesis and release of the platelet-activating molecule thromboxane A2 (TxA2). The aspirin effect is permanent and lasts for the lifespan of the circulating platelet (7-10 days).36 In was noted that there was no increased risk of mortality or bleeding among patients undergoing coronary artery bypass grafting (CABG) perioperatively taking ASA compared with placebo, but it was associated with increased transfusion requirements.37,38 Oral P2Y12 receptor antagonists, such as clopidogrel, prasugrel and ticagrelor, can be more problematic given their more potent antiplatelet effect. Like aspirin, the thienopyridine P2Y12 receptor antagonists clopidogrel and prasugrel covalently modify the receptor and the antiplatelet effect lasts for the lifespan of the platelet. Ticagrelor; however, is a non-thienopyridine P2Y12 receptor antagonist and its antiplatelet effect lasts for approximately 4 days. In patients undergoing urgent CABG with prior ticagrelor administration, serial platelet aggregometry revealed a return to normal platelet function within 3-days.39
The intraoperative use of Cytosorb adsorption, previously used in septic patients, was tested in Europe on 55 patients who were on ticagrelor or rivaroxaban and required emergency cardiac surgery, mostly CABG. The Cytosorb adsorpter is included in the CPB circuit between the oxygenator and the venous reservoir. The filter is made of biocompatible porous beads capable of removing substances based on pore capture and surface adsorption. It was effective in reducing bleeding complications with the majority of patients not requiring transfusions and none required re-exploration (compared to 37.5% in the non-Cytosorb group).40 The FDA has issued an Emergency Use Authorization for the use of Cytosorb to treat COVID-19 patients and respiratory failure; however, further testing to corroborate the findings in the European study and determine its effect on other substrates such as albumin and antibiotics will be important.