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\begin{document}

\title{Protocol Driven Peri-Procedural Anticoagulation for Left Atrial Ablation}



\author[1]{Christopher Bradley}%
\author[1]{Brian Williamson}%
\author[1]{Julie George}%
\author[1]{David Haines}%
\affil[1]{Beaumont Health System}%


\vspace{-1em}



  
  \date{May 23, 2024}


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\selectlanguage{english}
\begin{abstract}
Introduction: A weight-based heparin dosing policy that adjusted for
pre-procedural oral anticoagulation was implemented to reduce the
likelihood of sub-therapeutic dosing during left atrial catheter
ablation procedures. Our hypothesis was that initiation of the protocol
would result in a greater prevalence of therapeutic Activated Clotting
Time (ACT) values and decreased time to therapeutic ACT during left
atrial ablation procedures. Methods: A departmental protocol was
initiated for which subjects received intravenous unfractionated heparin
(UFH) to achieve and maintain a goal of ACT \textgreater{}300 seconds.
Initial bolus dose was adjusted for pre-procedure oral anticoagulation
and weight as follows: 50 units/kg for those receiving warfarin, 75
units/kg for those not anticoagulated, and 120 units/kg for those on
direct oral anticoagulants. An UFH infusion was initiated at 10\% of the
bolus per hour. An observational study was performed on 100 consecutive
left atrial ablation procedures with usual care, versus 100 with
protocol guided peri-procedural care. Results: When usual care and
protocol guided cohorts were compared, significant findings were limited
to those on pre-procedure direct oral anticoagulant (DOAC). The initial
UFH bolus increased from 97\selectlanguage{ngerman}±29 units/Kg to 113±29 units/Kg
(p\textless{}0.001), the proportion of therapeutic ACT on first draw
after heparin administration increased from 58\% to 77\% (p=0.010), and
the time to therapeutic ACT after UFH administration decreased from
37.8±19.8 minutes to 30.2±16.4 minutes (p=0.032). Conclusion: A
weight-based protocol for peri-procedural UFH administration resulted in
a higher proportion of therapeutic ACT values and decreased the time to
therapeutic ACT for those on pre-procedure DOAC.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Abbreviations}

ACT -- Activated clotting time

BMI -- Body mass index

CAD -- Coronary artery disease

CHF -- Congestive heart failure

DM -- Diabetes Mellitus

DOAC -- Direct oral anticoagulation

GFR -- Glomerular filtration rate

HTN -- Hypertension

LVEF -- Left ventricular ejection fraction

RF- Radiofrequency

UFH -- Unfractionated heparin

\textbf{INTRODUCTION}

Arrhythmia treatment via left atrial ablation procedures is associated
with peri-procedural risk of thromboembolism at a reported rate of
0-7\%.\textsuperscript{1} To mitigate this risk, meticulous
peri-procedural practices should be employed including pre-procedural
imaging to rule out left atrial thrombus, vigilant sheath management,
careful control of radiofrequency (RF) energy, and a strict
peri-procedural anticoagulation strategy. Prior studies have
demonstrated that thrombi can form on sheaths or catheters almost
immediately after transseptal puncture, and peri-procedural
anticoagulation via intravenous heparin can reduce this
risk.\textsuperscript{2,3}A therapeutic Activated Clotting Time (ACT)
goal of \emph{\textgreater{}} 300 seconds should be targeted, as this
value has been associated with reduced thromboembolic complications,
without increased bleeding complications.\textsuperscript{4,5}

Contemporary anticoagulation practices during left atrial catheter
ablation procedures can vary among operators, particularly in regard to
the effect of patient size and peri-procedural oral anticoagulation. To
reduce the likelihood of sub-therapeutic heparin dosing, a weight-based
heparin dosing policy which adjusted for pre-procedural oral
anticoagulation was implemented. We performed an observational quality
improvement study to evaluate whether an implemented protocol would
result in altered dosing practices, a greater prevalence of therapeutic
ACT values, and a decrease in time to therapeutic ACT during left atrial
ablation procedures compared to a retrospective cohort of similar
patients.

\textbf{METHODS}

Study Design

After approval from our Institutional Review Board, data were collected
on all consecutive patients from a single center that underwent left
atrial ablation procedures performed between March
18\textsuperscript{th}, 2018 and December 18\textsuperscript{th}, 2018.
As part of a quality improvement effort to standardize peri-procedural
anticoagulation, a dosing protocol was initiated on August
9\textsuperscript{th}, 2018. Outcomes before (usual care), and after
protocol implementation (protocol guided) were confirmed by chart review
and compared. All patients were evaluated after protocol initiation, and
a retrospective comparison group (usual care) was collected on
consecutive patients preceding protocol initiation. Demographic data,
clinical characteristics and administered medications were recorded, as
well as anticoagulation outcomes and procedural complications. Left
atrial ablation was performed via transseptal access, and UFH was used
for anticoagulation. If patients underwent more than one ablation within
the data collection time period, only the first procedure data were
included to eliminate dosing bias. During the data collection period, a
total of 8 operators performed left atrial ablation procedures.

Peri-Procedural Anticoagulation Protocol

Patients underwent ablation procedures in the left atrium under general
anesthesia using standard techniques. Ablation practices, pre-procedure
oral anticoagulant regimen, and screening of possible drug interactions
were left to the discretion of the treating physician. If used, warfarin
was administered before and after the procedure without interruption. If
patients were receiving DOAC pre-procedure, they were held 0-2 doses
before the procedure. Bolus doses of heparin were administered prior to,
or immediately after transseptal puncture, either initially as one dose,
or a divided dose before and immediately after transseptal access at the
operator's discretion. If the dose was divided, the combined
administered dose was recorded as the bolus amount.

A departmental heparin protocol was initiated for left atrial ablation
procedures based on published weight-based dosing protocols with an
acceptable safety record.\textsuperscript{6} Patients received
intravenous UFH with a goal to achieve and maintain an
ACT\emph{\textgreater{}} 300 seconds. The initial prescribed bolus dose
was: 50 units/kg for patients receiving warfarin, 75 units/kg for
patients not receiving oral anticoagulation, and 120 units/kg for
patients receiving DOACs. An infusion of UFH was initiated at 10\% of
the bolus dose per hour. ACTs were to be drawn and analyzed (Hemochron
Signature Elite, Werfen, Inc., Barcelona, Spain) every 15 minutes until
therapeutic levels are reached. The protocol delineated that the first
ACT was to be drawn 15 minutes after heparin administration. The time to
first therapeutic ACT was measured from time zero to the first
documented therapeutic ACT, where time zero was denoted in two methods;
(A) from initial heparin administration, and (B) from transseptal
puncture. Once a therapeutic ACT was established, repeat ACTs were drawn
a minimum of every 30 minutes. Additional bolus doses and infusion rates
were at the discretion of the operator. Ablation was not to be performed
until a therapeutic ACT had been obtained. The usual care cohort was not
guided by an institutional protocol, thus heparin bolus, infusion, and
pre-procedure oral anticoagulation regimen were left to the discretion
of the operator.

After the procedure was completed, sheaths were removed and hemostasis
obtained by either manual pressure after heparin reversal with
protamine, or figure of eight suture placement.\textsuperscript{7} In
uncomplicated cases, oral anticoagulation was restarted or continued the
evening after the procedure.

Study Endpoints

The endpoints selected to assess anticoagulation success with usual
care, versus a protocol guided approach were: (A) The proportion of
therapeutic ACT's on first draw after heparin administration; (B) Time
to therapeutic ACT after transseptal access; (C) Time to therapeutic ACT
after heparin administered; (D) The proportion of therapeutic ACT during
the case; (E) The proportion of supra-therapeutic ACT during the case,
defined as greater than 400 seconds, and (F) The proportion of
supra-therapeutic ACT's on first draw after heparin administration.

Major complication endpoints were all cause death, major thrombotic
events, and major bleeding events within 30 days of the procedure. Major
thrombotic events included ischemic stroke, transient ischemic attack,
peripheral embolic events, and deep vein thrombosis. Major hemorrhagic
events were those requiring surgical intervention, pericardial effusion
requiring drainage, bleeding resulting in
transfusion\emph{\textgreater{}} 2 units of blood, or fatal bleeding.

Statistical Methods

Cohort characteristics were compared using Pearson chi-square (or
Fisher's exact test where cell counts were small) for categorical data,
presented as frequencies and percentages. Continuous data, presented as
means with standard deviations, were compared using analysis of variance
or Wilcoxon rank sum test. Chi-square was used to compare proportion at
goal on first ACT draw. T-tests were used to analyze weight bolus and
time outcomes. All statistical analyses were conducted using SAS for
Windows 9.4 (Cary, NC). For the analysis of therapeutic and or
supra-therapeutic proportions, we accounted for variable number of ACT
draws per procedure. The number of ACT draws collected ranged from 1 to
14, and consequently the number of therapeutic ACT draws was also
variable. Logistic regression was utilized to analyze the average
success rates between the usual care and protocol guided cohorts, taking
into account the variable number of draws. The odds ratio represents the
increase in odds of achieving a value \emph{\textgreater{}} 300 and
\textgreater{} 400 seconds respectively. For those without pre-procedure
anticoagulation, the weight-based bolus was plotted against first ACT
result. We used a censored regression analysis to account for times
recorded at the Hemochron maximum value of 400 seconds, but were likely
higher.

\textbf{RESULTS}

Baseline characteristics

There were 208 consecutive left atrial ablation cases performed. Two
cases were excluded as there was a contraindication to heparin
administration, with the resultant use of an alternate intravenous
anticoagulant. Another 6 procedures were excluded, as 3 patients had
repeat ablation for which procedures existed in both the usual care and
protocol guided cohorts. After exclusions, 200 patients were analyzed,
100 in each cohort. There was no difference between the usual care and
protocol guided cohorts in regard to demographics, antiplatelet
medications prior to procedure, medical comorbidities, mean glomerular
filtration rate (GFR), and mean left ventricular ejection fraction
(Table 1).

Oral anticoagulant use prior to procedure was similar between the two
cohorts. There were 78 and 77 patients on DOACs in the usual care and
protocol guided arms respectively, with an increase in apixaban (from 49
to 54 patients), and decrease in rivaroxaban (from 27 to 21 patients)
use in the protocol guided cohort. In the usual care cohort there were
12 patients on uninterrupted warfarin, and 10 patients on no oral
anticoagulant prior to procedure. This compared similarly to the
protocol guided cohort as there were 11 patients on uninterrupted
warfarin, and 12 patients on no oral anticoagulant prior to procedure.
The usual care cohort included 15 of the 78 patients (19.2\%) patients
for which their direct oral anticoagulant was held for more than 2 doses
prior to procedure, all of which were on twice daily dosed medications,
and only two patients were interrupted for more than 3 doses. This
compared to 7 out of 77 (9.1\%) in the protocol guided cohort for which
6 patients were on twice daily dosed medications, and only one patient
was interrupted for more than 3 doses.

Procedural Characteristics

The majority of left atrial ablation procedures evaluated were for
treatment of atrial fibrillation. Of the 100 patients in the usual care
ablation cohort, 85 received treatment for atrial fibrillation, 4 for
left sided accessory pathway, and 12 for left atrial tachycardia. Of the
100 patients in the protocol guided ablation cohort, 93 received
treatment for atrial fibrillation, 5 for left sided accessory pathway,
and 2 for left atrial tachycardia.

The average number of ACT's drawn per procedure were similar between
each cohort, as an average of 5.9 \selectlanguage{ngerman}± 2.4 were drawn in the usual care
cohort, as opposed to 5.7 ± 2.4 in the protocol guided cohort. The
average time to ACT after initial heparin bolus was 25 ± 13 minutes in
the usual care, and 25 ± 13 minutes in the protocol guided cohorts.
There was a difference in timing of heparin administered with regard to
transseptal puncture, as heparin was administered prior to transseptal
puncture in the usual care cohort at a lower rate (77\%), compared the
protocol guided arm (94\%). The initial heparin bolus was split (before
and after transseptal puncture) in a high proportion in the usual care
cohort (30\%), when compared to the protocol guided cohort (13\%).

Outcomes

After the peri-procedural heparin protocol was initiated, the initial
weight-based bolus of heparin increased from 97±29 units/Kg to 113±29
units/Kg (p\textless{}0.001). ACT outcomes are shown in Figure 1.
Therapeutic values on first draw increased from 60\% in the usual care
cohort, to 77\% in the protocol guided cohort (Figure 1A, p=0.010). And
there was not a significant increase in supra-therapeutic values on
first ACT value after heparin administration (Figure 1B, 12\% versus
20\%, p=0.123). The total proportion of ACT values in therapeutic range
during the procedure increased from 79\% to 86\% with protocol guidance
(Figure 1C, OR 1.68, 95\% CI 1.24 -- 2.28, p=0.001). Supra-therapeutic
proportions also did not significantly increase between the usual care
and protocol guided cohorts (21\% versus 25\%, Figure 1D, OR 1.26, 95\%
CI 0.89 -- 1.78, p=0.198).

Time to therapeutic ACT decreased after initiation of the heparin
protocol (Figure 2). Time from heparin administration to therapeutic ACT
deceased from 37.3±18.8 minutes with usual care, to 31.1±16.4 minutes in
the protocol guided cohort (p=0.034). Similarly, time from transspetal
access to therapeutic ACT decreased from 30.2±22.3 min with usual care
to 19.8±17.3 in the protocol guided cohort (p=0.001).

There was only one major bleeding or thromboembolic event in either
cohort, which was a pseudoaneurysm formation with concomitant
ipsilateral common femoral vein thrombus identified in the protocol
guided cohort.

Outcomes and Pre-procedure Anticoagulation Regimen

When outcomes were assessed based upon pre-procedure oral anticoagulant
regimen, patients on DOAC demonstrated significant outcome differences
between cohorts. For those on DOAC, the initial weight-based bolus of
heparin increased from 99±25 units/Kg to 118±23 units/Kg
(p\textless{}0.001). Therapeutic values on first draw increased from
58\% to 77\% with protocol guidance (p=0.010). However,
supra-therapeutic values on first ACT draw did significantly increase
from 6\% with usual care, to 18\% in the protocol guided cohort
(p=0.026). Therapeutic proportions increased from 78\% with usual care
to 86\% in the protocol guided cohort (OR 1.89, 95\% CI 1.36 -- 2.64,
p=\textless{}0.001). Supra-therapeutic proportions did not significantly
increase from 18\% with usual care versus 23\% in the protocol guided
cohort (OR 1.44, 95\% CI 0.98 -- 2.13, p=0.067). Time to therapeutic
ACT, when measured after heparin administration, deceased from 38±20
minutes to 30±17 minutes (p=0.032), and time to therapeutic ACT after
transseptal access decreased from 32±23 with usual care to 19±17 minutes
with protocol guidance (p=0.001).

For those patients receiving pre-procedure warfarin, the dose of heparin
administered in the protocol guided cohort was higher (71±39 units/Kg),
than the recommended protocol dose (50 units/Kg) and compared similarly
to the usual cohort 70±36 units/Kg. As a result, the proportion of
therapeutic ACT values on first draw (100\%), and the proportion of
supra-therapeutic (45.5\%) values were higher than any of the other
pre-procedure oral anticoagulant strategies. However lower patient
numbers in this subgroup limited meaningful analysis.

For the patients that received no oral anticoagulant before the
procedure, the average bolus dose in the protocol guided cohort was
higher (116±28 units/Kg) than that recommended by the protocol (75 U/Kg)
and compared similarly to the usual cohort 112±10 units/Kg. Despite this
observation, the proportions of therapeutic ACT values on first draw
remained lower (58 \%) than the overall protocol guided cohort findings
(77\%), and there was no significant change between the usual care and
protocol guided cohorts. This suggests that patients not anticoagulated
pre-procedure may be under dosed by the protocol design. To gain insight
into the proper bolus dosing for this subgroup, we plotted the
weight-based heparin bolus dose versus the first ACT value after
administration, and performed linear regression analysis (Figure 4). As
a result, a weight-based bolus of at least 120 U/Kg may be a more
appropriate for those on no pre-procedure oral anticoagulant, however a
prospective validation of such a weight-based dose is required.

\textbf{DISCUSSION}

A protocol guided approach which accounted for pre-procedure oral
anticoagulation and weight resulted in a higher administered dose,
increased proportion of therapeutic ACT values, and a decreased time to
therapeutic ACT. The findings were driven by a large number of those on
pre-procedure DOAC, which reflects contemporary practice. The complexity
of left atrial ablation procedures requires attention to multiple
variables, and the standardization of peri-procedural anticoagulation by
means of protocol guidance may result in a reduction in untoward
outcomes.

Much attention and investigation has been directed towards the optimal
choice of pre-procedural oral anticoagulation, and whether to proceed
with an interrupted versus uninterrupted strategy. For those randomized
trials which investigated uninterrupted pre-procedure oral anticoagulant
administration during AF ablation, a fixed dose based on sex or weight
was given. These trials did not address both body weight and prior oral
anticoagulation strategy while dosing UFH to achieve a therapeutic
ACT.\textsuperscript{8--12} However, intravenous unfractionated heparin
pharmacokinetics should be considered, as they are dose and weight
dependent. The half-lives of 25, 100, and 400 U/kg UFH are 30, 60, and
150 min, respectively. At lower doses, the infused heparin binds
directly to macrophages and endothelial cells, where it gets
depolymerized. At higher doses, this mechanism becomes
saturated.\textsuperscript{13} Continuous infusion after bolus may allow
for a steady state UFH plasma level, and lead to increased proportion of
therapeutic ACT levels.\textsuperscript{14}

In addition to weight, pre-procedure OAC should be considered given the
preponderance of data indicates that ACT response differs when warfarin
is compared to DOAC therapies.\textsuperscript{4,15} Pre-procedure DOAC
results in larger required weight-based peri-procedural UFH bolus to
achieve a desired ACT of \emph{\textgreater{}} 300
seconds.\textsuperscript{15,16} Additionally, body weight has been
suggested as a predictor of UFH requirement for those who are on
pre-procedure rivaroxaban, during left atrial
ablation.\textsuperscript{17}

To minimize the burden on the operator and decrease the proportion of
sub-therapeutic ACT values, an institutional protocol was initiated with
previously validated safety outcomes.\textsuperscript{6} We leveraged
the temporal initiation of the peri-procedural anticoagulation protocol
to evaluate whether it had an effect on dosing practices, and ACT
outcomes. A~peri-procedural anticoagulation protocol resulted in a
higher dose of heparin administered as the initial bolus~and
improved~ACT outcomes,~primarily~driven by dosage changes~in patients
receiving a pre-procedure DOAC. Those on DOAC (particularly the
Factor~Xa~inhibitors) were the majority of~patients~evaluated,
reflecting~contemporary anticoagulation practices. Heparin under-dosing
in patients receiving DOACs may have been influenced by~the omnipresent
risk of bleeding complications and the lack of an easily obtained
reversal agent for the factor~Xa~inhibitors. The initiation of a
peri-procedural anticoagulation~protocol may have empowered the
operators in the study to administer larger bolus doses of UFH, which
resulted in earlier and increased proportion of therapeutic ACT values.
Sub-therapeutic ACT values have been correlated to silent ischemic
events identified on MRI,\textsuperscript{5} which further highlights
the value of peri-procedural anticoagulation strategies to balance
safety with efficacy.

The small numbers of patients on warfarin limit meaningful conclusion.
Patients receiving warfarin were administered larger bolus dose than
initially recommended by our protocol, resulting in both a high number
of therapeutic and supra-therapeutic ACT values. Patients receiving no
pre-procedure oral anticoagulation received larger doses than the
protocol recommended, yet had lower rates of therapeutic ACTs. The
employed protocol mirrored weight based recommendations based on
previous data with adequate safety profile, for which those on no pre
procedure anticoagulation received a lower heparin bolus than those on
DOAC. Linear regression analysis of these patients revealed that a dose
of at least 120 U/Kg was likely required to achieve an ACT of 300
seconds in half of the patients, however prospective validation is
required before delivering a definitive weight-based recommendation in
those without pre-procedure oral anticoagulant.

Limitations

This study has several limitations. The observational design did not
allow for control of several important variables, in particular the
heparin dose received, which was at physician discretion. In the
protocol guided arm, there was operator adherence to the proposed bolus
in those on pre-procedure DOAC. However, in the protocol guided arm the
average bolus dose administered in those who received pre-procedure
warfarin and no anticoagulant were greater than the protocol recommended
bolus dose. There was an absolute increase of 17\% in the proportion of
heparin given prior to transseptal puncture in the protocol guided
cohort, and an absolute decrease of 17\% in the proportion of heparin
bolus which were split before and after transseptal puncture. The change
in bolus modality and timing may have been an additional effect of the
protocol on physician practice, and certainly affected the reduction in
time from transseptal to therapeutic ACT. However, a reduction in time
to therapeutic ACT persisted when measured from time of heparin
administration Anticoagulant therapy and dosing was prescribed at the
operator's discretion, and not prospectively assigned, possibly
introducing selection bias. Additionally, there is assumption that
patients were adherent to preoperative instructions for managing their
anticoagulant therapy. Finally, the ACT machine did not provide an
absolute value for values over 400, rather a truncated value.

\textbf{CONCLUSION}

A weight-based protocol for peri-procedural heparin administration which
accounted for oral anticoagulation resulted in a higher proportion of
therapeutic ACT, higher administered bolus dose, and decreased the time
to therapeutic ACT for those on pre-procedure DOAC. A weight-base bolus
dosing protocol may serve as a contemporary template for future
peri-procedural anticoagulation strategies during left atrial ablation.

Acknowledgements: The authors would like to thank Divyashree Varma, MD,
Ilana Kutinsky, DO, K. Ching Man, DO, David Nori, MD, Salim Ahmed, MD,
Hazim Al-Ameri, MD, and Nathan Foster, MD for their procedural expertise
and willingness to participate during protocol initiation. Additionally,
we would like to acknowledge Shirley Qu for help in assembling the
database.



\textbf{REFERENCES}

1. Calkins H, Hindricks G, Cappato R, et al. 2017
HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and
surgical ablation of atrial fibrillation. \emph{Hear Rhythm} . Published
online 2017. doi:10.1016/j.hrthm.2017.05.012

2. Asbach S, Biermann J, Bode C, Faber TS. Early heparin administration
reduces risk for left atrial thrombus formation during atrial
fibrillation ablation procedures. \emph{Cardiol Res Pract} . Published
online 2011. doi:10.4061/2011/615087

3. Bruce CJ, Friedman PA, Narayan O, et al. Early heparinization
decreases the incidence of left atrial thrombi detected by intracardiac
echocardiography during radiofrequency ablation for atrial
fibrillation.\emph{J Interv Card Electrophysiol} . Published online
2008. doi:10.1007/s10840-008-9270-x

4. Briceno DF, Villablanca PA, Lupercio F, et al. Clinical impact of
heparin kinetics during catheter ablation of atrial fibrillation:
Meta-analysis and meta-regression. \emph{J Cardiovasc Electrophysiol} .
Published online 2016. doi:10.1111/jce.12975

5. Di Biase L, Gaita F, Toso E, et al. Does periprocedural
anticoagulation management of atrial fibrillation affect the prevalence
of silent thromboembolic lesion detected by diffusion cerebral magnetic
resonance imaging in patients undergoing radiofrequency atrial
fibrillation ablation with o. \emph{Hear Rhythm} . Published online
2014. doi:10.1016/j.hrthm.2014.03.003

6. Armbruster HL, Lindsley JP, Moranville MP, et al. Safety of Novel
Oral Anticoagulants Compared With Uninterrupted Warfarin for Catheter
Ablation of Atrial Fibrillation. \emph{Ann Pharmacother} . Published
online 2015. doi:10.1177/1060028014563950

7. Lakshmanadoss U, Wong WS, Kutinsky I, Khalid MR, Williamson B, Haines
DE. Figure-of-eight suture for venous hemostasis in fully anticoagulated
patients after atrial fibrillation catheter ablation. \emph{Indian
Pacing Electrophysiol J} . Published online 2017.
doi:10.1016/j.ipej.2017.02.003

8. Di Biase L, Burkhardt JD, Santangeli P, et al. Periprocedural stroke
and bleeding complications in patients undergoing catheter ablation of
atrial fibrillation with different anticoagulation nagement results from
the role of coumadin in preventing thromboembolism in atrial
fibrillation (AF) patients u. \emph{Circulation} . Published online
2014. doi:10.1161/CIRCULATIONAHA.113.006426

9. Cappato R, Marchlinski FE, Hohnloser SH, et al. Uninterrupted
rivaroxaban vs. uninterrupted vitamin K antagonists for catheter
ablation in non-valvular atrial fibrillation. \emph{Eur Heart J} .
Published online 2015. doi:10.1093/eurheartj/ehv177

10. Calkins H, Willems S, Gerstenfeld EP, et al. Uninterrupted
dabigatran versus warfarin for ablation in atrial fibrillation. \emph{N
Engl J Med} . Published online 2017. doi:10.1056/NEJMoa1701005

11. Kuwahara T, Abe M, Yamaki M, et al. Apixaban versus Warfarin for the
Prevention of Periprocedural Cerebral Thromboembolism in Atrial
Fibrillation Ablation: Multicenter Prospective Randomized Study. \emph{J
Cardiovasc Electrophysiol} . Published online 2016.
doi:10.1111/jce.12928

12. Hohnloser SH, Camm J, Cappato R, et al. Uninterrupted edoxaban vs.
Vitamin K antagonists for ablation of atrial fibrillation: The
ELIMINATE-AF trial. \emph{Eur Heart J} . Published online 2019.
doi:10.1093/eurheartj/ehz190

13. Hirsh J, Anand SS, Halperin JL, Fuster V. Guide to anticoagulant
therapy: Heparin: A statement for healthcare professionals from the
American Heart Association. \emph{Circulation} . Published online 2001.
doi:10.1161/01.CIR.103.24.2994

14. Kim TS, Kim SH, Kim BK, et al. Randomized Comparison of Continuous
Versus Intermittent Heparin Infusion During Catheter Ablation of
Atrial~Fibrillation. \emph{JACC Clin Electrophysiol} . Published online
2016. doi:10.1016/j.jacep.2015.11.004

15. Konduru S V., Cheema AA, Jones P, Li Y, Ramza B, Wimmer AP.
Differences in intraprocedural ACTs with standardized heparin dosing
during catheter ablation for atrial fibrillation in patients treated
with dabigatran vs. patients on uninterrupted warfarin. \emph{J Interv
Card Electrophysiol} . Published online 2012.
doi:10.1007/s10840-012-9719-9

16. Payne JE, Koerber SM, Bickel T, Ghadban R, Flaker G, Gautam S.
Higher initial weight-based heparin dosing is required with direct oral
anticoagulants during catheter ablation for atrial fibrillation. \emph{J
Interv Card Electrophysiol} . Published online 2019.
doi:10.1007/s10840-019-00579-y

17. Enriquez AD, Churchill T, Gautam S, et al. Determinants of Heparin
Dosing and Complications in Patients Undergoing Left Atrial Ablation on
Uninterrupted Rivaroxaban. \emph{PACE - Pacing Clin Electrophysiol} .
Published online 2017. doi:10.1111/pace.13013

\textbf{FIGURE LEGEND}

\textbf{Figure 1 -} Demonstrated are the ACT outcomes comparing the
usual care, to the protocol guided cohort. Aggregate data includes all
patients regardless of pre-procedure oral anticoagulant. Those on
pre-procedure DOAC, warfarin, and no oral anticoagulant (None) are also
shown. Panel A shows the proportion (\%) of ACT \emph{\textgreater{}}
300 seconds on first draw after the heparin bolus was administered.
Panel B shows the proportion (\%) of ACT \textgreater{}400 seconds on
first draw after the heparin bolus was administered. Panel C shows the
total proportion (\%) of ACT values \emph{\textgreater{}} 300 seconds
during the procedure. Panel D shows the total proportion (\%) of ACT
values \textgreater{}400 seconds during the procedure.

\textbf{Figure 2 -} Demonstrated are the time outcomes to achieved an
ACT \emph{\textgreater{}} 300 seconds, comparing the usual care, to the
protocol guided cohort. Aggregate data includes all patients regardless
of pre-procedure oral anticoagulant. Those on pre-procedure DOAC,
warfarin, and no oral anticoagulant (None) are also shown. Error bars
indicate standard error. Panel A shows the time to an
ACT\emph{\textgreater{}} 300 seconds when measured after Heparin bolus
administered. Panel B shows the time to an ACT \emph{\textgreater{}} 300
seconds when measured after the transseptal puncture was performed.

\textbf{Figure 3 -} Demonstrated are average weight-based bolus
(units/Kg), comparing the usual care, to the protocol guided cohort.
Aggregate data includes all patients regardless of pre-procedure oral
anticoagulant. Those on pre-procedure DOAC, warfarin, and no oral
anticoagulant (None) are also shown. Error bars indicate standard error.

\textbf{Figure 4 --} Data from all patients receiving no pre-procedure
oral anticoagulant are presented, regardless of cohort designation. The
weight-based heparin bolus administered is plotted against the first ACT
value after heparin administration. Blue line represents linear
regression (p=0.011), with a goodness of fit R\textsuperscript{2} value
of 0.297.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Table 1}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Table 1}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Table 1}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Table 1}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Usual Care} \textbf{N=100}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Protocol Guided} \textbf{N=100}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{P value}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Age}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
62.0\selectlanguage{ngerman}±11.2\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
59.5\selectlanguage{ngerman}±10.6\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.122\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Race, n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Caucasian (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
89 (89)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
91 (91)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Black (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
5 (5)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
4 (4)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Asian (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 (2)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (1)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Other (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
4 (4)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
4 (4)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Male, n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
75 (75)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
69 (69)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.345\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{BMI (kg/m\textsuperscript{2})}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
31.0\selectlanguage{ngerman}±5.7\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
31.3\selectlanguage{ngerman}±5.9\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.590\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Antiplatelet, n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Aspirin\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
42 (42)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
42 (42)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Clopidogrel\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
4 (4)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
4 (4)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Comorbidities, n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
CHF\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
18 (18)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
10 (10)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.103\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
DM\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
16 (16)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
13 (13)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.547\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Stroke\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
19 (19)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
12 (12)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.171\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
PAD\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
7 (7)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
5 (5)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.552\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
CAD\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
20 (20)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
15 (15)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.352\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
HTN\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
67 (67)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
66 (66)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.881\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{GFR (mL/min/1.73m2)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
81\selectlanguage{ngerman}±15\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
80\selectlanguage{ngerman}±16\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.559\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{LVEF (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
57\selectlanguage{ngerman}±7\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
58\selectlanguage{ngerman}±9\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.210\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{APPENDIX}

Data sources

A Beaumont Health registry was established to calculate all
demographics, clinical characteristics, comorbid conditions, pertinent
medications, and outcomes of patients who underwent left atrial ablation
procedures. The data from the registry was abstracted through automated
reports generated through a multi-platform database query tool from
Beaumont Health's electronic medical record. Demographics abstracted
from the registry for the purpose of this study were age, sex, race, and
weight. Comorbid conditions abstracted were hypertension, diabetes
mellitus, coronary artery disease, peripheral artery disease, stroke/TIA
history, and congestive heart failure. Laboratory values abstracted were
the peri-procedural race based GFR. The peri-procedural medication
administration record for each patient was abstracted from the registry
and compared with the antiplatelet medications aspirin, clopidogrel,
ticagrelor, prasugrel, and dipyridamole. During the pre-procedure
history and physical, the duration of held oral anticoagulant doses was
documented and collected in the registry.

Data review and collected was performed by a physician trained to
abstract the needed data into SharePoint. Heparin doses and
administration times were obtained by the medical record by review of
the anesthesia procedure log. ACT values and result times were
documented by the electrophysiology laboratory staff, and reviewed in
the medical record. Left ventricular ejection fraction was abstracted
from the electronic medical record after review of the most recent
echocardiogram. All occurrences of major bleeding or thrombotic events
were reviewed and adjudicated by a Board Certified Cardiologist.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1,-A-D/Figure-1,-A-D}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2-A-B/Figure-2-A-B}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3/Figure-3}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-4/Figure-4}

\end{center}
\end{figure}

\textbf{Hosted file}

\verb`Table 1.docx`  available at \url{https://authorea.com/users/350273/articles/475148-protocol-driven-peri-procedural-anticoagulation-for-left-atrial-ablation}

\selectlanguage{english}
\FloatBarrier
\end{document}

