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\begin{document}

\title{Antithrombotic Therapy After Cardiac Surgery: Role of Different Oral
Anticoagulants}



\author[1]{Vincenzo Caruso}%
\author[2]{Robert Leatherby}%
\author[3]{Muhammad Usman Shah}%
\author[3]{Sudhir Bhusari}%
\author[3]{Arvind Singh}%
\author[3]{Hasnat Khan}%
\affil[1]{Guy's and Saint Thomas' Hospitals NHS Trust}%
\affil[2]{Wythenshawe Hospital}%
\affil[3]{Basildon and Thurrock University Hospitals NHS Foundation Trust}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\selectlanguage{english}
\begin{abstract}
Background and aim of the study: Aim of this study is to compare the
incidence of postoperative bleeding events, identified as pericardial
effusion, for those patients undergoing cardiac surgery and discharged
on vitamin K antagonist (VKA) versus those discharged on NOACs. Methods:
This was a retrospective observational cohort study; from July 2017 to
July 2019, all the patients who underwent any cardiac surgical procedure
and discharged on any oral anticoagulant, were rolled in the study. The
study variables and setting followed the STROBE checklist. The final
cohort was constituted by 382 patients (mean age 70\selectlanguage{ngerman}±11.2 years);
260(68.1\%) patients were discharged on VKA and 122(31.9\%) were
discharged on NOACs. The primary end point was the incidence of major
postoperative bleeding, defined as pericardial effusion requiring
surgical re-exploration. The key secondary composite end point was the
late re-admission for pericardial effusion. Results: The overall
incidence of in-hospital immediate bleeding events, with need of
re-exploration for pericardial effusion, was 4.7\% (n=18). The incidence
of re-admission for pericardial effusion was 3.1\% (n=12). Eight of
those patients had surgical re-exploration: four patients were
discharged on NOACs and the remnant four ones were discharged on VKA. No
significant relationships were observed between the different oral
anticoagulants and the incidence of pericardial effusion, at any time.
No ischemic and thromboembolic events were recorded. Conclusions: The
use of non-vitamin K antagonist oral anticoagulant, in post cardiac
surgery patients, does not increase the incidence of major bleeding
events, intended as immediate or late pericardial effusion.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy




\textbf{INTRODUCTION}

The novel non-vitamin K antagonist oral anticoagulant (NOACs) are now
widely accepted as valid alternative of vitamin K antagonist (VKA) in
the treatment of non-valvular atrial fibrillation and deep venous
thrombosis\textsuperscript{1-2}. Recently, subgroup analyses of
randomized trial support initial evidence of the use of NOACs in
patients with valvular AF, if not associated with degenerative mitral
stenosis, or after three months post bio-prosthesis
replacement\textsuperscript{3}.

Their role after cardiac surgery still represents a challenge choice for
the heart team in regards of the risks of bleedings events; objective of
this study is to compare the incidence of pericardial effusion in
patients started on oral anticoagulant after cardiac surgery, to assess
if their use is safe and reproducible.

\textbf{MATERIALS AND METHODS}

\textbf{Data source}

From July 2017 to July 2019, data from a single institution were
collected in an open, double arm, retroprospective manner. The final
database was constituted by pre-operative demographic variable,
intra-operative interventional data and post-operative measurements.

Only the patients who underwent cardiac surgery and discharged with oral
anticoagulant were rolled in the study; patients with preexisting
bleeding disorders were excluded. Pre-operative use of any oral
anticoagulant did not constitute an exclusion criteria. All major,
elective, cardiac surgical procedures were considered; patients who
underwent urgent or emergency operation were excluded from the study.

The VKA included exclusively warfarin. The NOACs used were dabigatran,
rivaroxaban and apixaban.

Reasons for antithrombotic treatment at discharge were atrial
fibrillation, deep venous thrombosis, atrial myxoma and left ventricular
thrombus.

A bleeding event was defined as evidence of pericardial effusion, with
or without need of surgical intervention. The incidence of pleural
effusion, cerebral and abdominal hemorrhagic events were recorded but
not reported as not primary outcomes of the present study.

All the ischemic or thromboembolic events were collected and reported.
As ischemic event it was considered the incidence of cerebrovascular
events, bowel ischemia, lower limb ischemia or myocardial infarction. A
thromboembolic event was defined as incidence of deep venous thrombosis,
pulmonary embolism, cerebral infarct or systemic venous thrombosis.

The primary end point was the incidence of immediate postoperative
bleeding, defined as pericardial effusion requiring intra-hospital
re-exploration. This term was used to define any pericardial drainage
performed before discharge; this was then differentiated as early, if
within the first 72 hours from surgery, or late, if after 72 hours.

The key secondary composite end point was the late re-admission for
pericardial effusion, with or without need of surgical drainage.

\textbf{Statistical analysis}

The SPSS\selectlanguage{ngerman}\textsuperscript{®} software, version 26.0 (IBM Corporation,
Armonk, New York), was used for statistical analysis. Continuous
variables are presented as mean ± standard deviation, and categorical
variables are presented as absolute numbers and/or percentages.

A linear regression was used to assess statistically significant between
continuous variable, while a chi square test and logistic regression was
used for categorical variables. For all tests, a \emph{p} -value
\textless{}0.05 was considered statistically significant.

\textbf{RESULTS}

The final cohort was constituted by 382 adult patients; of those
patients, 260(68.1\%) were discharged on VKA and 122(31.9\%) were
discharged on NOACs.

Pre-operative use of oral anticoagulant was recorded in 193 patients
(73.2\%) for chronic AF, previous mechanical valve or deep venous
thrombosis (Table 1).

In the overall cohort no ischemic or thromboembolic event were recorded
both in the immediate post-operative course, both at median follow-up.
The median length of stay was 9.5 days (IQR: 7-14). There was no
intra-hospital mortality and all the patients were alive at the
follow-up (median 23.9 months, IQR:18-30).

\textbf{Covariates analysis:}

The main reason for anticoagulation, in the overall cohort, was AF
(n=308, 80.6\%).

In the VKA's group, warfarin was started for AF in 192 patients(73\%);
111(57\%) of those patients had chronic AF and they were on
anticoagulation prior to surgery, either with Warfarin (n=98, 89\%) or
NOACs(n=13, 11\%).

In the NOACs'cohort, anticoagulation was required in 116 patients (95\%)
for AF. NOACs was used de novo in 49 patients (42\%), while sixty-two of
those patients (57\%) were on NOACs prior to surgery.

All the patients with a mechanical valve were started on Warfarin at
postoperative day two (n=62, 23\%).

Warfarin was used, with a limited three months length, in six patients
(4\%) with left ventricular thrombus and atrial myxoma.

\textbf{Intra-hospital re-exploration}

The overall rate of intra-hospital re-exploration, for all causes -
pericardial effusion, delayed sternal closure, graft failure or cardiac
arrest - was 6.5\% (n=25).

In this cohort, the incidence of pericardial effusion, was 72\%(n=18).
Ten patients(55\%) returned in theatre within the first 72 hours from
surgery. In these cases, no significant relationships were observed
between the incidence of re-exploration and pre-operative use of
anticoagulants (\emph{p} =.150; Odd Ratio: 0.52(0.2-1.2); NOACs: n=2,
1.9\%, ; Warfarin: n=1, 0.9\%).

Nine patients required re-exploration after 72 hours (mean
post-operative day of 11.8±4.3). Warfarin was already started for seven
patients with a median value of INR of 1.8 (IQR: 1.2-2.6). Higher the
INR, bigger was the effusion drained (median:800mls, IQR: 400-1250), but
this was not statistically significant (\emph{r} =0.37,
R\textsuperscript{2}=0.13 \emph{p} =0.368, n=9).

Major aortic surgery was statistically related to a higher incidence of
re-exploration when compared with the other surgical procedures
(\emph{p} =.011; Odd Ratio: 3.4(1.3-8.4), (Table 2).

\textbf{Re-admission}

The incidence of re-admission for pericardial effusion was 3.1\% (n=12)
at a median of 11 days(IQR: 7.5-99). All the patients expect four
(NOACs=3, 27\%; Warfarin=1, 9\%), underwent surgical drainage. Four of
those patients were discharged on NOACs (Apixaban=2, 25\%,
Rivaroxaban=2, 25\%).

In the NOACs group the median effusion drained was 650mls (IQR:
525-775). In the Warfarin group, the median INR was 2.2 (IQR: 1.7-3.4).
Also, in this case, a higher INR was associated with a bigger effusion
(median:800mls, IQR: 750-1100), but this was not statistically
significant (\emph{r} =0.8, R\textsuperscript{2}=0.65 \emph{p} =.192,
n=4).

\textbf{CONCLUSION}

Different studies have showed the safety of NOACs as alternative to
warfarin in the treatment of AF and deep venous
thrombosis\textsuperscript{1-3}. The updated guidelines on the
management of atrial fibrillation now recommends the new oral
anticoagulants (NOACs) as the preferred anticoagulant to warfarin,
unless patients have moderate to severe mitral stenosis or they have an
artificial heart valve\textsuperscript{4}. Their use after cardiac
surgery seems to be safe as showed by a retrospective study that
evaluated the length of stay, the post-operative bleeding and the cost
of the therapy\textsuperscript{5}.

This retrospective study evaluates the incidence of post-operative
pericardial effusion as a measure of bleeding event. No statistical
differences were observed in the two cohorts examined, with an incidence
similar between NOACs and Warfarin; despite the pre-operative use of
NOACs seems to increase the incidence of early re-exploration, this was
not statistically significant. A strong association was instead noted
between pericardial effusion and type of surgery. More interestingly, it
was observed that a high value of INR correlated with the effusion
drained; plus, almost all the patients re-admitted and on Warfarin,
required a surgical re-exploration.

In term of re-admission, after initial discharge, this was similar
between NOACs and warfarin, with no significant differences.

At the end, from this retrospective study, appears that the use of NOACs
in post cardiac surgery, appeared to be a safe and valid alternative to
warfarin, in term of incidence of pericardial effusion and need of
surgical drainage.

In patients undergoing surgery for valvular disease, expect in those
with mechanical valve, the use of NOACs appears safe as immediate
treatment.

This study has some limits: the overall cohort is small with a prevalent
warfarin group; second, the incidence of thromboembolic events and/or
other hemorrhagic events, was not considered as primary outcome.

Despite this, at follow-up, none of the patients in the study showed
significant complications, redo-surgery for graft or valve failure
and/or mortality.

\textbf{ACKNOWLEDGEMENTS}

No acknowledgements

\textbf{CONFLICT OF INTEREST}

None

\textbf{AUTHOR CONTRIBUTION:}

Dr Caruso: partecipate in concept and design, analysis and
interpretation, writing the article, critical revision of the article,
final approval of the article, data collection, statistical expertise,
literature search.

Dr Leatherby: partecipate in concept and design, analysis and
interpretation, writing the article, critical revision of the article,
final approval of the article, data collection.

Dr Shah: partecipate in concept and design, analysis and interpretation,
writing the article, critical revision of the article, final approval of
the article, data collection.

Mr Bhusari: partecipate in concept and design, analysis and
interpretation, critical revision of the article, final approval of the
article.

Mr Singh: partecipate in concept and design, analysis and
interpretation, critical revision of the article, final approval of the
article.

Mr Khan: partecipate in concept and design, analysis and interpretation,
critical revision of the article, final approval of the article.

\textbf{REFERENCES}

1. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al.. The
ROCKET AF Steering Committee . Rivaroxaban versus warfarin in
nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883--891

2. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H,
et al. Dabigatran versus warfarin in the treatment of acute venous
thromboembolism. N Engl J Med 2009; 361: 2342--2352.

3. Avezum A, Lopes RD, Schulte PJ, Lanas F, Gersh BJ, Hanna M, et al.
Apixaban in comparison with warfarin in patients with atrial
fibrillation and Valvular heart disease: findings from the Apixaban for
reduction in stroke and other Thromboembolic events in atrial
fibrillation (ARISTOTLE) trial. Circulation. 2015;132(8):624--32

4. Craig T. January, et al. 2019 AHA/ACC/HRS Focused Update of the 2014
AHA/ACC/HRS Guideline for the Management of Patients with Atrial
Fibrillation: A Report of the American College of Cardiology/American
Heart Association Task Force on Clinical Practice Guidelines and the
Heart Rhythm Society in Collaboration with the Society of Thoracic
Surgeons. Circulation. 2019;140:e125--e151

5. Anderson E., Johnke K., Leedhal D., Glogoza M., Newman R., Dyke C.
Novel oral anticoagulants vs warfarin for the management of
postoperative atrial fibrillation: clinical outcomes and cost analysis.
J. Am Surg. 2015; 210(6):1095-1103.

\textbf{Table Legend:}

\textbf{TABLE 1:} Baseline characteristics, preoperative medications and
cardiac surgical procedure.

\textbf{TABLE 2:} Univariate analysis of risk factors: Surgery and
re-exploration for pericardial effusion.

\textbf{TABLE 1:} Baseline characteristics, preoperative medications and
cardiac surgical procedure.\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
covariates\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
vka (N=260)\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
noac (N=122)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Age (years)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
68.1\selectlanguage{ngerman}±12.1\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
74.1\selectlanguage{ngerman}±7.9\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Gender (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
87 (33.4)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
32 (26.2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Preoperative Anticoagulant (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
120 (46.1)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
73 (59.8))\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Warfarin (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
98 (81)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
4 (5)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
NOAC (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
22 (19)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
69 (95)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Anti-platelets (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
84 (32)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
41 (33)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
CABG alone\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
92\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
41\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
AVR/AVR+CABG Tissue AVR Mechanical AVR\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
139 (96/43) 88 51\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
49 (31/18) 49 0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
MVR/MVR+CABG MV Repair Tissue MVR Mechanical MVR\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
80 (70/10) 46 24 10\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
43 (34/9) 34 9 0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
MVR +/- TVR\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
3 (Repair)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
4 (Repair)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Major Aortic Surgery\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
48\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
3\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Other Surgery\textsuperscript{*}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
9\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
4\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Redo\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
14\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
3\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\emph{Legends: CABG= Coronary artery by-pass graft; AVR= Aortic valve
replacement; MVR= Mitral valve repair/replacement; TVR= Tricuspid valve
repair/replacement.}

\emph{\textsuperscript{*}Other Surgery= Ventricular septal defect
closure, Pericardiectomy, Morrow's procedure.}

\textbf{TABLE 2:} Univariate analysis of risk factors: Surgery and
re-exploration for pericardial effusion.\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
covariates & \emph{p} value & \emph{Odd ratio(95\% CI)}\tabularnewline
\midrule
\endhead
CABG alone & .527 & 0.7(0.3-1.6)\tabularnewline
AVR/AVR+CABG & .150 & 1.9(0.8-4.4)\tabularnewline
MVR/MVR+CABG & .825 & 0.8(0.3-1.9)\tabularnewline
MVR +/- TVR & .112 & 2.3(0.8-4.4)\tabularnewline
Major Aortic Surgery & .011 & 3.4(1.3-8.4)\tabularnewline
\bottomrule
\end{longtable}

\emph{Legends: CABG= Coronary artery by-pass graft; AVR= Aortic valve
replacement; MVR= Mitral valve repair/replacement; TVR= Tricuspid valve
repair/replacement.}

\textbf{Hosted file}

\verb`TABLE 1.docx`  available at \url{https://authorea.com/users/325508/articles/465457-antithrombotic-therapy-after-cardiac-surgery-role-of-different-oral-anticoagulants}

\textbf{Hosted file}

\verb`TABLE 2.docx`  available at \url{https://authorea.com/users/325508/articles/465457-antithrombotic-therapy-after-cardiac-surgery-role-of-different-oral-anticoagulants}

\selectlanguage{english}
\FloatBarrier
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