Results
Between September 2020 and December 2022, a total of 19 patients (Table
1) were identified as having received apixaban at the time of
transplantation (42% male, median 13.5 years of age). Of those, 13
patients had congenital heart disease, with the remainder having
cardiomyopathy. Sixteen of the 19 patients were listed United Network
for Organ Sharing (UNOS) Status 1A, of which 3 patients were supported
with a HeartMate 3 (HM3, Abbott, Chicago, IL), 2 patients were Status
1B, and 1 patient was Status 2. Fifteen patients were maintained on
inotropic support with milrinone infusions in inpatient and outpatient
settings. For 13 patients, apixaban was administered in 3 patients for
prophylaxis due to history of previous thrombus, 4 patients with severe
ventricular dysfunction with ejection fraction <30%, and 6
patients for the presence of a central venous line in single ventricle
palliation. Therapeutic levels were targeted in 6 patients for active
thrombus treatment or presence of VAD. All patients had normal kidney
function at the time of transplant based on serum blood urea nitrogen
and creatinine levels.
Median length of apixaban therapy prior to transplantation was 114.6
days (Table 2). Dosing ranged from 0.625mg twice daily to 7.5mg twice
daily. In addition, the 3 patients on HM3 VAD and 1 patient with a
bioprosthetic mitral valve received concomitant antiplatelet therapy
with aspirin (ASA). There were no clinically relevant bleeding,
including no major bleeding, or thrombotic events while awaiting
transplant. The median time from last apixaban dose to arrival to the OR
was 23.2 hours. The median apixaban level prior to OR arrival was
37ng/mL, obtained 6.2 hours prior to OR arrival. Apixaban level testing
was not obtained immediately prior to transfer to the OR in 3 patients.
The median chest tube output in the CICU post-operatively was
1.9mL/kg/hr and 1.8mL/kg/hr for the first 2 and 4 post-operative hours
respectively.
In total, 6 patients met our definition for significant post-operative
bleeding, including 1 patient for chest tube output> 10mL/kg/hour for the first two hours, 4 patients
for chest tube output > 5mL/kg/hour over the first 4
hours, and 1 patient requiring re-intervention for hemodynamically
significant bleeding. No patients developed tamponade. All 6 of these
patients had palliated complex congenital heart disease (Table 3) with a
median of 3.5 sternotomies per patient (3, 4.8) and median age of 6.1
years (3.6, 13.1). Additionally, 3 patients had anti-Xa levels
post-operatively <0.2 units/ml, an average of 10 hours after
arrival to the intensive care unit. This confirms no measurable residual
effect of apixaban.
A number of adverse postoperative events deserve further description. As
seen in Table 3, Patient 6 developed severe primary graft dysfunction
requiring extracorporeal membrane oxygenation (ECMO) in the first 12
postoperative hours. This patient was the only to receive a reversal
agent recombinant Factor Xa (andexanet alfa) in addition to protamine,
despite no notable increase in operative bleeding or difficulties
achieving hemostasis. Reason for administration of recombinant Factor Xa
was that it was thought to help establish hemostasis in a patient with
previous sternotomies and it was made readily available for
administration. Notably, pre-operative apixaban level was low at
28.4ng/ml. While on ECMO, patient underwent cardiac catheterization
demonstrating multiple diffuse pulmonary embolism. This patient
developed gross hemolysis, with multi-organ failure and subsequent
redirection of care and death on post-operative day 7. Patient 12
required re-exploration for bleeding after development of acute
postoperative thrombosis in the reconstructed systemic venous system
requiring trans-catheter stent placement near a fresh suture line. It
was thought at the time the significant bleeding was mechanical in
origin post-stent placement, not related to anticoagulation. Patient 14
was managed on HM3 ventricular assist device with apixaban and ASA
prophylaxis pre-transplant without significant complications.
Postoperatively, he was noted to have severe global neurologic injury
unrelated to bleeding or thrombosis and not left to be attributable to
apixaban, resulting in death.