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\begin{document}

\title{Effect of outcome measures on the apparent efficacy of ablation for
atrial fibrillation: Why ``success'' is an inappropriate term}



\author[1]{Nick Jackson}%
\author[2]{Ehsan Mahmoodi}%
\author[1]{James Leitch}%
\author[1]{Malcolm Barlow}%
\author[1]{Allan Davies}%
\author[1]{Nicholas Collins}%
\author[2]{Lucy Leigh}%
\author[2]{Christopher Oldmeadow}%
\author[1]{Andrew Boyle}%
\affil[1]{John Hunter Hospital}%
\affil[2]{The University of Newcastle}%


\vspace{-1em}



  
  \date{May 08, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
INTRODUCTION: Different endpoint criteria, different durations of follow
up and the completeness of follow up can dramatically affect the
perceived benefits of Atrial Fibrillation (AF) ablation. METHODS: We
defined three endpoints for recurrence of AF post ablation in a cohort
of 200 patients with symptomatic AF, refractory to antiarrhythmic drugs
(AADs). A ``Strict Endpoint'' where patients were considered to have a
recurrence with any symptomatic or documented recurrence for [?]30 seconds
with no blanking period, and off their AADs, a ``Liberal Endpoint''
where only documented recurrences after the blanking period, either on
or off AADs were counted, and ``Liberal Endpoint + Redo'' which was the
same as the Liberal endpoint but allowing for 1 redo ablation or 1
cardioversion (DCCV) during follow up. We also surveyed 50 patients on
the waiting list for an AF ablation and asked them key questions
regarding what they would consider to be a successful result for them.
RESULTS: Freedom from recurrence of atrial tachyarrhythmias (AT) at 5
years was 62\% for the strict endpoint, 73\% for the liberal endpoint,
and 80\% for the liberal endpoint + redo group (p\textless{}0.001). Of
the 50 patients surveyed awaiting AF ablation, 70\% said they would
still consider the procedure a success if it required one repeat
ablation or one DCCV (p=0.004), and 76\% would be accepting of one or
two recurrences during follow-up (p\textless{}0.001). CONCLUSION: In
this study the most important predictor of AT recurrence following AF
ablation was the criteria used to define recurrence.%
\end{abstract}%



\sloppy


\textbf{Introduction:}

The outcome of ablation for atrial fibrillation (AF) is often described
in terms of success or failure, perhaps owing to the legacy from trials
of surgical and then catheter-based ablation for pre-excitation. The
paradigm of a ``successful or unsuccessful'' procedure for
Wolf-Parkinson-White Syndrome is quite reasonable but much less so for
more complex acquired conditions such as AF or ventricular tachycardia.
These are chronic medical conditions influenced by many factors over
time, quite apart from the technical aspects of an index procedure
itself.

The principles of actuarial follow-up to measure efficacy for procedures
such as coronary artery bypass surgery (CABG) have been well described
for many years\textsuperscript{1} and consequently the efficacy of CABG
is almost never described in terms of success or failure (or for that
matter labelled as definitive or curative). Efficacy is dependent on a
combination of factors including the hazard ratio for recurrence (based
on clinical factors), data handling (should a survival or an event count
model be used), censoring and most importantly follow-up duration and
completeness. Ultimately efficacy is mostly a combination of the hazard
ratio and the duration of follow-up and reducing this to success or
failure is misleading. The nomenclature used in patient discussions can
have a strong influence on the decisions patients make about their
treatment so we should use terms that accurately reflect the data rather
than emotive nomenclature such as success and failure.

The aim of this paper is to discuss how different patient populations
and different criteria for the endpoint of the study can dramatically
affect the perceived benefits and the outcomes in AF ablation trials. In
this way we use our own previously published cohort of patients
undergoing AF ablation to show how different the outcomes can appear
with the same results and discuss what the patients themselves consider
to be a successful outcome.

\textbf{Methods:}

Ethics for this study were obtained from the Hunter Research Ethics
Committee (authorization number: AU201905-14). In order to perform this
study, we analysed our cohort of 200 patients with symptomatic
paroxysmal or persistent AF who had undergone an index cryoballoon
ablation between the years of 2013 and 2016. This was a reanalysis of
the study by Davies et al.\textsuperscript{2} `Long term follow up of
pulmonary vein isolation following cryoballoon ablation'.

All patients had symptomatic, paroxysmal or persistent AF and had failed
treatment with at least one AAD. Patients were reviewed routinely at 3
months with a Holter monitor and a clinic visit. Then at 6, 12 and 24
months with electrocardiograms and clinic visits. The follow up beyond
this was at the discretion of the treating cardiologist. Patients were
contacted at least twice by phone (beyond 24 months and again at the end
of the follow up period) and all correspondence was reviewed from the
local area electronic health record and the patient's treating
cardiologist and general practitioner. Wherever a patient had symptoms
consistent with recurrence further ECGs/telemetry were used to attempt
to document this recurrence.

From this cohort we defined three different end points for ablation
success in order to show how different the outcomes may seem despite the
same procedures being performed on the same group of patients. For the
Strict Outcome endpoint, we used the most strict criteria to define a
successful outcome. For this endpoint a patient was deemed to have a
recurrence if they had [?]30 seconds of symptomatic or asymptomatic atrial
tachyarrhythmia, they were not allowed to be on any antiarrhythmic drugs
beyond three months after ablation (recurrences during the usual 3 month
blanking period were also counted) and patients were followed for 5
years. For the Liberal Outcome endpoint patients had to have a
documented recurrence, were allowed a 3-month blanking period and were
also allowed to be on antiarrhythmic medications during follow up. The
Liberal Outcome + Redo endpoint was the same as the Liberal Outcome
endpoint, however, they were allowed one repeat procedure
(radiofrequency ablation) or one DCCV during their follow up as well.
The Liberal Outcome and the Liberal Outcome + Redo endpoints were both
evaluated for the success rates at 1 and 5 years.

The Strict Outcome endpoint was defined based on 2018 HRS consensus
guidelines for follow up of patients in clinical trials with AF
ablation\textsuperscript{3}, however, we removed the blanking period as
from a patient perspective a recurrence of AF is the same for them
whether it occurs prior to 3 months or after. To come up with the
criteria for the Liberal Outcome and the Liberal Outcome + Redo
endpoints we surveyed 50 patients on the waiting list for an AF ablation
and asked them key questions regarding what they would consider to be a
successful result for them (see Tables 2 and 3). From the point of view
of these questions, patients were then further divided into those with
high burden of AF ([?] weekly symptoms from AF) or a low burden of AF
(less than weekly).

\textbf{Primary Endpoint:}

The primary endpoint of the study was freedom from recurrence of
symptomatic atrial tachyarrhythmia following pulmonary vein isolation
according to the three endpoints as defined above. For the Strict
Outcome endpoint any patient with symptoms beyond 30 seconds consistent
with a recurrence was considered to have met this endpoint for the
study.

\textbf{Statistical Analysis:}

All continuous variables are displayed as mean and standard deviation,
and the categorical variables as count and percentage. Kaplan-Meier
survival curves with an overall 5 years survival were used to depict
time to recurrence of AF as per 3 different recurrence criteria. Frailty
Cox Proportional Hazards models, using a gamma distribution for the
shared frailty, were utilised to estimate pairwise Hazard Ratios between
the three groups, and Cox PH regression models (with a gamma frailty)
were utilised to determine the association between any of the predictors
and the hazard of AF recurrence following AF ablation for all three
endpoints. Student's t test or Mann-Whitney U test were used to compare
the continuous variables based on the distribution, and the Chi squared
test was used to compare categorical variables. All statistical analyses
were programmed using R and SAS V9.4.

\textbf{Results:}

The baseline characteristics of the 200 patients undergoing cryoballoon
ablation for drug refractory symptomatic atrial fibrillation are shown
in Table 1.

Of the 50 consecutive patients who were interviewed as to what they
would consider to be a successful outcome from ablation following
pulmonary vein isolation, 26 patients (52\%) were considered high burden
of symptoms and 24 low burden (48\%). The answers to the questions
regarding patient expectations are shown in Tables 2 and 3. There were
no statistically significant differences between the expectations of the
outcome following AF ablation in the high versus low symptom burden
groups.

The different endpoints used for freedom from recurrence of atrial
tachyarrhythmias had a significant impact on outcome. Freedom from
recurrence of atrial tachyarrhythmias as one year was 62\% with Strict
Outcomes, 87\% with Liberal Outcomes and 90\% with Liberal Outcomes +
Redo (Frailty p-value\textless{}0.005). Freedom from recurrence of
atrial tachyarrhythmias at five years was 62\% with Strict Outcomes,
73\% with Liberal Outcomes and 80\% with Liberal Outcomes + Redo
(Frailty p-value\textless{}0.001). Kaplan Meier survival curves for
freedom from atrial tachyarrhythmia recurrence are shown in Figures 1
and 2. When performing pairwise comparisons between all three different
endpoints, there was a statistically significant difference between the
rates of atrial tachyarrhythmia free survival for all three different
endpoints (Table 4).

The results of the adjusted frailty Cox PH regression model are reported
in Table 5. The only significant predictor of freedom from atrial
tachyarrhythmia recurrence in this model was the three different ways in
which the endpoint was defined.

\textbf{Discussion:}

In this study the freedom from atrial tachyarrhythmia recurrence
following pulmonary vein isolation ranged from 90\% at 1 year (Liberal
Outcomes + Redo) to 62\% at five years (Strict Outcomes) according to
the duration of follow up and how strict the criteria were for
recurrence during that time period. In our Cox proportional hazards
model the only significant predictors of freedom from AF were how the
endpoint of recurrence was defined and not traditionally recognised
predictors of success such as type of AF, age or LA size. Furthermore,
when we surveyed 50 patients with AF who were awaiting pulmonary vein
isolation we found that the majority of them would still consider
ablation successful if it had to be repeated once (70\%), if one DCCV
was required following ablation (70\%), or if they had just one or two
recurrences of AF following their ablation procedure (76\%). However,
the majority (68\%) of patients expected to be completely off AADs.

This study shows how subjective the notion of success can be following a
procedure such as AF ablation and raises the important point of
primarily considering the patients perspective when determining success
or not. The HRS consensus statement for follow up of trials on AF
ablation recommend the strict criteria of freedom from recurrence of any
atrial tachyarrhythmia ([?]30 seconds) beyond a three month blanking
period, off antiarrhythmic medications and with at least 3 monthly 24
hour Holter monitoring\textsuperscript{3}. These criteria are important
as they provide a consistent end point to allow for some comparison of
different trials on different populations and with different techniques.
Furthermore, more strict criteria ([?]30 sec of atrial tachyarrhythmia)
will generally mean a greater number of patients reach the study
endpoint and increases the statistical power of the studies. For this
reason, it is important to keep this clear definition, but at the same
time discuss what this means in clinical practice. For example, many
patients may consider a one-year measure of efficacy too short or feel
misled if one-year freedom from recurrence is described as a success
rate.

In the 2009 meta-analysis of trials of AF ablation versus AAD therapy
the 1-year freedom from recurrence of atrial fibrillation ranged from
57\% (over 2,800 patients) with a single procedure to 71\% with multiple
procedures (over 3,481 patients) and 77\% with multiple procedures on
AADs\textsuperscript{4}. Freedom from recurrent AF at one year on AADs
alone in this meta-analysis was 52\%\textsuperscript{4}. In these
studies, the frequency and duration of Holter monitoring is less
important since the aim is to compare two different treatments. It is
more important that it is equivalent in each arm and sufficient to
detect the expected differences in efficacy between the two groups.
These trials primarily used ECGs at 3 monthly follow up visits to look
for AF recurrence, with Holter or event monitors used in fewer than half
of the ablation studies and fewer than a quarter of the AAD studies.
These trials established the fact that PVI was superior to AAD therapy
in reducing the time to recurrent AF in patients who had already failed
an AAD. More recent trials, however, have used implantable cardiac
monitors to determine exactly what the recurrence rates of AF are after
ablation.

The Circa-dose study\textsuperscript{5} highlighted the importance of
monitoring in defining PVI success by showing that following cryoballoon
or radiofrequency PVI, the freedom from any symptomatic recurrence of
atrial tachyarrhythmia was 73-79\%, however, the freedom from any
recurrence [?]30 seconds of atrial tachyarrhythmia as detected by ILR was
52-54\%.\textsuperscript{5} This finding raises the question of the
impact of a placebo affect from ablation therapy but also questions the
clinical relevance of very short duration episodes of AF that are not
symptomatic. Further to this, in a study by Steinberg et
al.\textsuperscript{6} prospectively looking at episodes of pacemaker
detected AF they found that shorter index episodes of AF (\textless{}3.8
hours duration) did not predict recurrence of clinically meaningful AF
episodes over the subsequent 3.7 year duration of the study.

The results of the Circa-dose study\textsuperscript{5} could be
interpreted to say that AF ablation was unsuccessful in up to 48\% of
patients at 1 year following an AF ablation. However, both the
Circa-dose\textsuperscript{5} and the Close to
Cure\textsuperscript{7}studies also compared the mean burden of AF on
ILR prior to and following ablation and this showed a 98-100\% mean
reduction in AF burden with ablation. Prior to ablation, however,
patients were in AF for a median of 1.5-4\% of the time and following
ablation they were is AF for a median of 0.00\% of the time. In the
CAPTAF study\textsuperscript{8} which included patients with persistent
AF as well, the median burden of AF was reduced from 24.9\% to 5.5\%
with AF ablation (78\% reduction). Median burden reduction speaks to the
strong efficacy of PVI for reducing the burden of AF in individual
patients. In the Close to Cure study\textsuperscript{7} almost all
patients had a lower burden of AF following ablation and even those
patients with some residual AF still reported improved QoL scores on the
basis of this reduced AF burden. The authors of this study point out
that AF burden may be a more meaningful endpoint for AF studies as AF
burden correlates with symptoms and risk of stroke and heart
failure\textsuperscript{9-11}. Since QoL improves in patients post
ablation who are free from or have reduced AF
burden\textsuperscript{12,13} this may be a more representative endpoint
than simply a survival analysis that sensors patients after a single
brief recurrence.

AF ablation trials have long used a 3-month blanking period following
ablation before counting recurrent episodes towards the trial endpoint.
This is chiefly since AF ablation may lead to inflammation, transient
autonomic imbalance or delayed lesion maturation and a period of time
for atrial remodelling may also be important in success following
ablation\textsuperscript{14,15}. Some trials have even allowed redo
procedures within this blanking period, suggesting some early recurrence
is due to pulmonary vein reconnection\textsuperscript{16,17}. Whilst
this 3-month blanking period may more fairly show the efficacy of AF
ablation when assessed by time to first recurrence, from a patient's
perspective, if they have a recurrence, require a cardioversion or a
repeat procedure it is irrelevant at what time this occurs. Furthermore,
some studies have suggested that recurrences beyond a 1-month blanking
period are predictive of recurrence\textsuperscript{18} and this may be
different for different PVI techniques\textsuperscript{19}. For this
reason assessing burden pre and post ablation without a 3-month blanking
period may give a more accurate assessment of clinical efficacy since a
patient with a low burden of paroxysmal AF pre ablation, who has a
significant `flare up' in their AF symptoms in the first three months
following ablation may not consider their procedure a success.

A number of clinical factors have long been known to influence the
success of AF ablation. The most important of these may be the presence
of persistent AF, female sex, renal dysfunction, low ejection fraction,
advanced age and larger left atrial size\textsuperscript{20-23}. These
factors have been incorporated into various scores such as the APPLE,
ATLAS, DR-FLASH and MB-LATER scores that could give a patient a
percentage likelihood that they would be free from any AF at one year
between 19\% to 71\%. Although these scores were developed to predict
recurrence at difference time points and despite both the APPLE and
MB-LATER scores being the only ones validated in external cohorts, both
these scores still had modest predictive capacity on ROC analysis (AUC
0.64 and 0.65 for APPLE and MB LATER respectively)\textsuperscript{24}.
The number of different scores developed, however, demonstrates the
differences in predictive variables in different populations and these
predictions have wide confidence intervals for individual cases.
Furthermore these scores do not take into account other potentially
important factors such as the experience of the
operator\textsuperscript{25} or the willingness of the patient to
address modifiable risk factors around the time of and following
ablation\textsuperscript{26}.

The success of AF ablation is further dependent upon the indication for
which the ablation is being performed. Much of the discussion to this
point has focussed on AF ablation to reduce symptoms directly related to
episodes of AF, however, a number of randomised controlled trials have
shown an improvement in ejection fraction and/or a reduction in
mortality in patients with severe systolic impairment and
AF\textsuperscript{27,28,29,30}. In the largest of these RCTs the
CASTLE-AF\textsuperscript{27} study the NNT to save one life was 8.6. In
these studies looking at ablation to treat heart failure, patients have
primarily had implantable defibrillators and these have shown a
substantial reduction in the burden of AF despite the presence of
structural heart disease. In these studies, low residual burdens of AF
were still associated with improved heart failure outcomes. These
patients were also much more commonly continued on AADs beyond a
three-month blanking period, their AF was more commonly persistent or
chronic persistent and they were less likely to be aware of individual
episodes of AF. For these reasons the success of an AF ablation here
cannot be assessed in terms of conventional endpoints but rather from
heart failure endpoints.

\textbf{Limitations:}

In our cohort we primarily assessed the recurrence of AF by the presence
of symptoms and our rates of AF recurrence would have been higher with
more frequent monitoring or implantable loop recorders. The purpose of
this study, however, was not to precisely define the incidence of
recurrent AF following ablation but to demonstrate how reliant the
success rates of AF ablation procedures are upon study design.

\textbf{Conclusion:}

In this study the most important predictor of atrial fibrillation
recurrence following ablation was the criteria used to define recurrence
(duration of follow up, the presence of a blanking period and whether
AADs were allowed or not). We showed that the majority of patients still
considered AF ablation a successful treatment if they had up to two
recurrences of AF, one repeat procedure or one DCCV. This study
highlights the complexity in understanding the `success' of a procedure
such as AF ablation and emphasizes the importance of a patient centred
prospective.

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Table 1. Baseline characteristics (total number=200)\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Variable & Number\tabularnewline
\midrule
\endhead
Age, mean (SD) & 61.7 (10)\tabularnewline
Female sex, number (\%) & 76 (38)\tabularnewline
Left atrial dimension, mm, mean (SD) & 40.5 (6.6)\tabularnewline
Left ventricle ejection fraction (\%), mean (SD) & 61.3
(8.8)\tabularnewline
Paroxysmal AF, number (\%) & 138 (69)\tabularnewline
Persistent AF, number (\%) & 61 (31)\tabularnewline
Symptom duration (months) & 36 (23-60)\tabularnewline
Congestive cardiac failure, number (\%) & 27 (14)\tabularnewline
Diabetes mellitus, number (\%) & 15 (7.5)\tabularnewline
Hypertension, number (\%) & 106 (53)\tabularnewline
Stroke/TIA, number (\%) & 8 (4)\tabularnewline
Pre-Ablation Anti-arrhythmic drugs &\tabularnewline
Class Ic (Flecainide), number (\%) & 56 (28.8\%)\tabularnewline
Class III (Sotalol or Amiodarone), number (\%) & 134
(67.7\%)\tabularnewline
Oral Anticoagulation & 180 (90\%)\tabularnewline
\bottomrule
\end{longtable}

Table 2. The Results of 50 patents with AF awaiting ablation who were
surveyed at to what they would consider acceptable in relation to
outcomes from the procedure.

AAD = Antiarrhythmic drugs. DCCV =Direct current cardioversion.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
QUESTION\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Yes, Count (\%)\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
No, Count (\%)\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
P-Value\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
High burden versus low burden AF. (High: weekly 1, Low \textless{}weekly
0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
26 (52)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
24 (48)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.77\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Would you consider having just one or two recurrences a good
outcome?\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
38 (76)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
12 (24)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Would you be accepting one repeat procedure or one DCCV?\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
35 (70)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
15 (30)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.004\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Would you consider having half the amount of AF you previously had as a
Successful procedure/good outcome? (half the duration and/or half the
number of episodes)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
35 (70)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
15 (30)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.004\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Would you expect to be completely off AADs?\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
34 (68)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
16 (32)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.01\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Table 3. The Results of 50 patents with AF awaiting ablation who were
surveyed as to what they would consider acceptable in relation to
outcomes from the procedure.

AAD = Antiarrhythmic drugs. DCCV = Direct current cardioversion.\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\textbf{QUESTION} & \textbf{Response} & \textbf{High Burden (N = 26)} &
\textbf{Low Burden (N = 24)} & \textbf{Chi-square
P-value}\tabularnewline
Q1 - would you consider having just one or two recurrences a good
outcome? & No & 6 (23.1) & 6 (25.0) & 0.87\tabularnewline
& Yes & 20 (76.9) & 18 (75.0) & .\tabularnewline
Q2 - Would you be accepting of one repeat procedure or one DCCV? & No &
7 (26.9) & 8 (33.3) & 0.62\tabularnewline
& Yes & 19 (73.1) & 16 (66.7) & .\tabularnewline
Q3 - Would you consider halving the duration/number of AF a
successful/good outcome? & No & 9 (34.6) & 6 (25.0) &
0.45\tabularnewline
& Yes & 17 (65.4) & 18 (75.0) & .\tabularnewline
Q4 - Would you expect to be completely off AADs? & No & 9 (34.6) & 7
(29.2) & 0.67\tabularnewline
& Yes & 17 (65.4) & 17 (70.8) & .\tabularnewline
\bottomrule
\end{longtable}

Figure 1 shows the survival free from AT recurrence according to the
three specified endpoints of Strict Outcome, Liberal Outcome and Liberal
Outcomes + Redo out to one year.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure 2 shows the survival free from AT recurrence according to the
three specified endpoints of Strict Outcome, Liberal Outcome and Liberal
Outcomes + Redo out to five years.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Table 4. shows the pairwise comparisons between each of the defined end
point groups.\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\textbf{Comparison} & \textbf{HR (95\% CI)} &
\textbf{P-value}\tabularnewline
Group 3 (Loose + redo) vs 2 (Loose) & 0.53 (0.34, 0.82) &
\textless{}0.01\tabularnewline
Group 3 (Loose + redo) vs 1 (Strict) & 0.31 (0.20, 0.48) &
\textless{}0.01\tabularnewline
Group 2 (Loose) vs 1 (Strict) & 0.59 (0.41, 0.85) &
\textless{}0.01\tabularnewline
\bottomrule
\end{longtable}

Table 5. shows Hazard Ratios from Univariable Cox Proportional Hazards
Models\^{}, and multivariable Frailty Cox Proportional Hazards
Regression Model\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
& & \textbf{Univariable} & \textbf{Univariable} & \textbf{Multivariable}
& \textbf{Multivariable}\tabularnewline
\textbf{Variable} & & \textbf{HR (95\% CI)} & \textbf{P-value} &
\textbf{HR (95\% CI)} & \textbf{P-value}\tabularnewline
Group & Liberal +Redo vs Strict & 0.31 (0.20, 0.48) & \textless{}.0001 &
0.35 (0.22, 0.56) & \textless{}0.001\tabularnewline
& Liberal vs Strict & 0.59 (0.41, 0.85) & 0.004 & 0.65 (0.43, 0.97) &
0.034\tabularnewline
& Liberal + Redo vs Liberal & 0.53 (0.34, 0.82) & 0.004 & 0.57 (0.35,
0.91) & 0.02\tabularnewline
Age & & 1.03 (0.99, 1.06) & 0.12 & 1.03 (0.97, 1.10) &
0.33\tabularnewline
LA Dimension & & 1.00 (0.95, 1.05) & 0.97 & 0.97 (0.86, 1.09) &
0.61\tabularnewline
LVEF & & 1.00 (0.97, 1.04) & 0.86 & 0.99 (0.90, 1.09) &
0.87\tabularnewline
Sex & Female & 2.42 (1.29, 4.53) & 0.005 & 3.10 (0.78,12.26) &
0.10\tabularnewline
AF Type & paroxysmal & 0.60 (0.32, 1.14) & 0.11 & 0.56 (0.13, 2.45) &
0.44\tabularnewline
Hypertension & Yes & 1.36 (0.72, 2.56) & 0.33 & 2.07 (0.58, 7.33) &
0.26\tabularnewline
Diabetes Mellitus & Yes & 0.30 (0.04, 2.19) & 0.23 & 1.09 (0.09,13.89) &
0.94\tabularnewline
\bottomrule
\end{longtable}

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

