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.