Discussion
In this retrospective analysis, we demonstrate that the use of apixaban
for prophylactic and therapeutic indications can be safe and effective
in patients awaiting heart transplantation. We report no significant
preoperative bleeding or thrombotic complications while receiving
apixaban therapy. Postoperatively the rate of major bleeding was
comparable to that previous reported, given patient complexity and
likely unrelated to our anticoagulation strategy. The benefit of DOAC
therapy includes reliability, predictability, ease of oral
administration and the need for less frequent monitoring. In total,
apixaban therapy accounted for 2 178 patient days in our patient
population, all of whom would have otherwise received twice daily LMWH
injections, or associated rigorous monitoring and dosing parameters of
vitamin K antagonists.
Apixaban levels are not routinely recommended for monitoring therapy in
adult patients. However, given the lack of apixaban data in pediatrics,
and our use of apixaban in a high-risk population, intermittent
monitoring may help guide management and reduce the risk of
complications from bleeding or thrombosis while receiving apixaban. Most
importantly, baseline peak and random apixaban levels allow for
assessment of drug clearance prior to invasive procedures, such as heart
transplantation. Drug monitoring is also beneficial for identifying
causality in situations with significant post-operative bleeding. While
our center can receive same day results for apixaban levels, we do
realize that is not an option at all institutions. The described
prophylactic and therapeutic apixaban levels have been demonstrated to
have appropriate efficacy, safety, and low events rates in an analysis
219 pediatric patients from our institution [16], along with a large
meta-analysis in adults [17]. It has been demonstrated that
chromogenic anti-factor Xa assay calibrated with heparin standards shows
a correlation between apixaban levels and LMWH levels [18]. These
previously described findings correlate with our experience as well,
with goal LMWH of greater than 1.5units/mL suggesting appropriate
apixaban anticoagulation.
We acknowledge the seemingly high percentage of significant
post-operative bleeding. Unfortunately, there is no standard definition
of what should be considered significant postoperative bleeding in
patients requiring cardiopulmonary bypass. The limited pediatric
literature available is applicable to infants under the age of 1 year,
where the author also highlights the discrepancy in definitions used for
other studies [19]. Looking at the rates of significant
post-operative bleeding, our rate of 32% appears to correlate with what
has been described from previously published studies in pediatric
patients requiring cardiopulmonary bypass, with incidence ranging from
21.5% to 42% [20-24]. These studies all utilize different values
based on chest tube output in the intensive care unit for their
definition of significant bleeding. We utilized a more stringent
definition of significant bleeding in our study. If we were to utilize
the definitions described in the above studies, our rate of significant
bleeding would range from 10.5% to 32%. Additionally, these patients
have a high prevalence of previous sternotomies, presence of cyanosis,
and hemodilution from cardiopulmonary bypass [25].
We do acknowledge that this lack of a formal definition is a limitation
to our retrospective analysis given the subjectivity of formulating our
own definition. This definition was determined in discussion with a
multidisciplinary team including cardiac anesthesiologists, cardiac
surgeons, transplant cardiologists and cardiac intensivists at our
institution. Further analysis shows that in 3 of the 5 patients defined
as having significant post-operative bleeding by chest tube output,
anti-Xa heparin levels obtained within the first 18 hours
post-operatively were under 0.2units/mL. This further supports the idea
that, in those patients, there was little to no appreciable apixaban
effect remaining post-operatively, based on available serum testing.
After extensive institutional review, we did not attribute any of the
mortalities described to the use of apixaban pre-transplant. As
described, one patient, later noted to have pulmonary emboli while on
ECMO, received recombinant Factor Xa prophylactically early in our use
of apixaban. Given this potential complication we advise against empiric
use of recombinant Factor Xa in the absence of life threatening
bleeding, as reversal can be a potential trigger of thrombosis. Data
from a recent meta-analysis on reflex thrombosis secondary to reversal
showed a rate of thromboembolism after utilization of andexanet alfa of
10.7% [26], making this a well-described and not insignificant
complication. No other patients required recombinant Factor Xa.
We recognize there are several limitations to our study, including the
previously mentioned lack of definition for post-operative bleeding, as
well as potential inability to monitor apixaban levels promptly. Lastly,
our single center cohort was small, retrospective and descriptive in
nature. We hope that our experience can lead to randomized controlled
studies comparing apixaban use to the more traditional anticoagulants.
Conflict of Interest: The authors have no disclosures to
report.
Funding: Supported by the Grousbeck Fazzalari Fund for
Cardiology Research and the Furber Advanced Cardiac Therapies Fellowship
Fund
Acknowledgements: None