\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,english]{babel}



\usepackage{float}








\begin{document}

\title{Long term use of donepezil and QTc prolongation}



\author[1]{Jason Kho}%
\author[2]{Adam Ioannou}%
\author[1]{Amit Mandal}%
\author[1]{Andrew Cox}%
\author[1]{Ashraf Nasim}%
\author[1]{Sofia Metaxa}%
\author[1]{Constantinos Missouris}%
\affil[1]{Wexham Park Hospital}%
\affil[2]{Royal Free London NHS Foundation Trust}%


\vspace{-1em}



  
  \date{June 17, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Background and Purpose: The neurocognitive benefits of donepezil are
well recognised, but the potential side effects on cardiac conduction
remain unclear. Our objectives are to investigate whether long-term
donepezil therapy is associated with electrocardiographic (ECG) changes
and in particular to assess its effects on the QT interval. Experimental
approach: We conducted a single centre retrospective analysis of
patients admitted to our institution on donepezil therapy over a
12-month period. 59 patients were identified as suitable for analysis.
An admission resting 12-lead ECG was obtained and compared to their ECG
prior to commencement of donepezil therapy to assess for any significant
difference in ECG parameters. Key Results: Donepezil significantly
prolonged the PR (P=0.04), QRS (P=0.04) and QT (P=0.002) intervals. The
increase in QT intervals remained significant on correction for heart
rate; resulting in 8 (13.6\%) patients developing high arrhythmogenic
risk based on assessment using QT nomogram plots. Concomitant use of
tricyclic antidepressants was associated with significant QT
prolongation, while use of rate limiting calcium channel blockers was
associated with significant PR prolongation, and beta-blockers with
reduction in heart rate. Conclusion and Implications: Our results
clearly demonstrate that long-term use of donepezil results in
prolongation of the QT interval. We suggest ECG evaluation should take
place before and after donepezil initiation, and clinicians should be
even more vigilant in those prescribed tricyclic antidepressants.%
\end{abstract}%



\sloppy


\textbf{Long term use of donepezil and QTc prolongation}

Jason Kho\textsuperscript{1}, Adam Ioannou\textsuperscript{2}, Amit K J
Mandal\textsuperscript{1}, Andrew Cox\textsuperscript{1}, Ashraf
Nasim\textsuperscript{1}, Sofia Metaxa\textsuperscript{1}, Constantinos
G Missouris\textsuperscript{1, 3}

\textsuperscript{1}Wexham Park Hospital, Frimley Health NHS Foundation
Trust, UK

\textsuperscript{2}Royal Free Hospital, Royal Free London NHS Foundation
Trust, UK

\textsuperscript{3}University of Cyprus Medical School, Nicosia, Cyprus

\emph{Corresponding Author}

Prof Constantinos G Missouris, MD, FRCP

Department of Cardiology and Internal Medicine

Wexham Park Hospital

Frimley health NHS Foundation Trust

Wexham Street, Slough UK

Telephone: 01753633000

E-mail: dinos.missouris@nhs.net

Abstract: 221 words

Manuscript: 2532 words

\emph{Funding:} The authors received no specific funding for this work.

\emph{Disclosures} : No potential conflict of interest was reported by
the authors.

\emph{Author Contributions} \textbf{:} All authors confirm that they
contributed to the design and implementation of the research, to the
analysis of the results and to the writing of the manuscript.

\emph{Acknowledgements:} This work was aided and supported by the
Pharmacy Department of Wexham Park Hospital, Frimley Health NHS
Foundation Trust, United Kingdom.

\emph{Abstract}

\textbf{Background and Purpose:}

The neurocognitive benefits of donepezil are well recognised, but the
potential side effects on cardiac conduction remain unclear. Our
objectives are to investigate whether long-term donepezil therapy is
associated with electrocardiographic (ECG) changes and in particular to
assess its effects on the QT interval.

\textbf{Experimental approach:}

We conducted a single centre retrospective analysis of patients admitted
to our institution on donepezil therapy over a 12-month period. 59
patients were identified as suitable for analysis. An admission resting
12-lead ECG was obtained and compared to their ECG prior to commencement
of donepezil therapy to assess for any significant difference in ECG
parameters.

\textbf{Key Results:}

Donepezil significantly prolonged the PR (P=0.04), QRS (P=0.04) and QT
(P=0.002) intervals. The increase in QT intervals remained significant
on correction for heart rate; resulting in 8 (13.6\%) patients
developing high arrhythmogenic risk based on assessment using QT
nomogram plots. Concomitant use of tricyclic antidepressants was
associated with significant QT prolongation, while use of rate limiting
calcium channel blockers was associated with significant PR
prolongation, and beta-blockers with reduction in heart rate.

\textbf{Conclusion and Implications:}

Our results clearly demonstrate that long-term use of donepezil results
in prolongation of the QT interval. We suggest ECG evaluation should
take place before and after donepezil initiation, and clinicians should
be even more vigilant in those prescribed tricyclic antidepressants.

\emph{Keywords:} Cardiac pharmacology, pharmacodynamics, ageing/aging,
donepezil, electrocardiography, cardiac arrhythmias, cholinesterase
inhibitors

\emph{Introduction}

Donepezil is an acetylcholinesterase inhibitor primarily used to treat
mild to moderate Alzheimer's dementia (AD). While the neurocognitive
benefits of donepezil are well documented, its adverse affects on
cardiac conduction remain unclear. Several case studies have reported QT
prolongation and subsequent Torsades de Pointes (TdP) associated with
donepezil use in patients with AD (Kitt \& Irons et al., 2015; Mandal \&
Khan et al., 2019; Malik \& Hamid et al., 2019; Takaya \& Okamoto et
al., 2009) while others have reported bradycardia and PR prolongation,
resulting in subsequent medication cessation (Bordier \& Garrigue et
al., 2003; Hernandez \& Farwell et al., 2009). Smaller scale studies to
date have shown that donepezil is relatively safe to use in the older
population. Common parasympathetic side-effects have been associated
with its use, but importantly these small-scale observational studies
have not reported any sinister cardiac conduction abnormalities such as
significant QT prolongation, subsequent arrhythmia or syncopal episodes
(Bordier \& Garrigue et al., 2006; Igeta \& Suzuki et al., 2014; Wang \&
Wu et al., 2018).

The British National Formulary (BNF, 2020) describes bradycardia as an
uncommon side-effect and cardiac conduction disorders to be a rare, or
very rare side effect of donepezil. First-degree atrioventricular (AV)
block and supraventricular tachycardia were reported to be infrequent
side-effects by the United States Food and Drug Administration (FDA,
2020). Physicians are advised to practise caution when prescribing
donepezil in patients with cardiac conduction disorders, but despite
these warnings there remains on-going debate as to whether a resting
12-lead electrocardiogram (ECG) is required prior to initiation of
donepezil therapy (Rowland \& Rigby et al., 2007).

The primary objective of our study is to investigate whether ECG changes
are associated with donepezil therapy and in particular assess its
effects on the QT interval. We also aim to evaluate whether gender,
treatment duration, donepezil dose or concomitant use of medications are
associated with conduction abnormalities and QT prolongation in patients
prescribed donepezil therapy.

\emph{Methods}

We carried out a retrospective analysis of all acute admissions of
patients on donepezil treatment to our institution between March 2019 --
March 2020. An admission resting 12-lead ECG was obtained and compared
to their ECG prior to commencement of donepezil therapy. All data were
collected from our local hospital electronic care record and memory
clinic database. Patient characteristics and demographics were recorded,
including indications for donepezil, comorbidities and left ventricular
function (assessed using the Simpson's biplane method on images obtained
from a recent transthoracic echocardiogram). Baseline serum electrolytes
(magnesium, adjusted calcium and potassium) and thyroid status were
noted. Medications with potential side-effects on cardiac conduction or
known to cause electrolyte disturbances, including beta-blockers,
levothyroxine, rate-limiting calcium-channel blockers, diuretics,
digoxin, tricyclic antidepressants, antipsychotics and selective
serotonin reuptake inhibitor (SSRI)/selective serotonin noradrenaline
reuptake inhibitor (SNRI) antidepressants were all recorded. In
addition, the duration of donepezil therapy was established and rounded
off to the nearest year.

Exclusion criteria included recent initiation of donepezil therapy
(\textless{}6 months), patients with electrolyte disturbances or
deranged thyroid function on admission, patients with a paced rhythm on
ECG and those patients in whom an ECG prior to commencement of therapy
could not be obtained.

\textbf{Measuring Electrocardiographic Parameters}

All patients underwent a 12-lead resting ECG using a 25mm/second paper
speed and standardised at 0.1mV/mm. The patient's heart rhythm was
analysed by a cardiology registrar or consultant. Heart rate (HR), PR
and QRS intervals were calculated automatically by the ECG apparatus.
The QT interval was measured from multiple leads (chest leads V3-V6 and
lead II) and the median QT was calculated. Due to the discrepancies in
formulae used for correcting QT intervals; all four commonly used
formulae (Bazett, Fredericia, Framingham and Hodges) were included. The
QT intervals were plotted on a QT nomogram (a plot of uncorrected QT
interval against heart rate) to predict arrhythmogenic risk (Chan \&
Isbister et al., 2007).

\textbf{Ethics}

This survey was approved by the trust audit department with reference
CB582. As a registry report using clinically collected, non-identifiable
data, this work does not fall under the remit of National Health Service
Research Ethics Committees.

\textbf{Data and Statistical Analysis}

Data was analysed with SPSS Version 26 software. Continuous variables
were expressed as mean \selectlanguage{ngerman}± standard deviation and categorical variables
were summarised as frequencies and percentages. Normality of all
continuous variables was tested with the Kolmogorov-Smirnov test. Since
the variables were not normally distributed, the Wilcoxon signed rank
test was used to compare the mean in all ECG parameters while the
Mann-Whitney U test was used to compare the changes in ECG parameters
between gender and donepezil doses. We performed point-biserial
correlations to assess whether cardiac comorbidities and concurrent use
of medications alongside donepezil were associated with changes in ECG
parameters. The Kruskal Wallis test was used to evaluate whether any
changes in ECG parameters were associated with duration of donepezil
treatment. Statistical significance was defined as P-value
\textless{}0.05. Our data and statistical analysis are compliant with
the recommendations on experimental design and analysis in pharmacology
(Curtis \& Alexander et al., 2018).

\emph{Results}

We identified 59 patients that were suitable for inclusion in our study.
Their baseline demographics and characteristics are summarised in Table
1. Analysis of a resting 12-lead ECG prior to commencing donepezil
treatment was compared to the ECG obtained during their most recent
acute hospital admission and demonstrated evidence of significant
prolongation of the PR, QRS and QT intervals (Table 2). The QT corrected
using Bazett, Fredericia, Framingham and Hodges formulae were also
compared, and all confirmed significant QT prolongation during donepezil
therapy. Analysis using the QT nomogram revealed that 8 (13.6\%)
patients (3 male and 5 female) went from low arrhythmogenic risk to high
while on donepezil therapy (Figure 1). No significant change in mean HR
was noted; although one patient had donepezil ceased on admission due to
bradycardia and intermittent complete heart block. Cessation of
donepezil resulted in normalisation of this patient's heart rate and
resolution of their heart block.

Assessment of the effect of donepezil on ECG parameters demonstrated
that males experienced a significantly greater increase in their
corrected QT intervals compared to females (Table 3). There were no
significant differences in all ECG parameters when comparing donepezil
doses (Table 4). Although there was a significant difference in QT
interval between the different treatment duration groups, no significant
difference was found once QT intervals were corrected. Duration of
donepezil therapy did not affect the HR, PR interval or QRS interval
(Table 5).

Point-biserial correlation found that concomitant use of rate-limiting
calcium channel blockers was associated with significant PR prolongation
(\emph{r} \textsubscript{pb} = 0.314, P=0.030), while beta-blockers in
combination with donepezil were found to significantly reduce the HR
(\emph{r} \textsubscript{pb} =0.256, P=0.050). All corrected QT
intervals whilst on donepezil were significantly prolonged by the use of
tricyclic antidepressants (QTcB: \emph{r} \textsubscript{pb} = 0.344,
P=0.008, QTcFred: \emph{r} \textsubscript{pb} = 0.382, P=0.003,
QTcFram:\emph{r} \textsubscript{pb} = 0.379, P=0.003, QTcH:\emph{r}
\textsubscript{pb} = 0.352, P=0.006). There was no significant
correlation between cardiac comorbidities and changes in ECG parameters.

\emph{Discussion and Conclusions}

Our study clearly demonstrated that the use of donepezil for more than a
year significantly prolongs the PR, QRS and QT intervals. Male patients
had a significantly greater prolongation of their QTc interval compared
to females, and concomitant use of tricyclic antidepressants
significantly increased the risk of QT interval prolongation, while no
dose or treatment duration related differences were found.

The QT interval is an electrocardiographic representation of the time
taken for depolarisation and repolarisation of the ventricles. Measuring
the QT interval and understanding its significance can be difficult
since it is influenced by multiple factors including heart rate and
disease-associated ECG changes. The use of corrected QT intervals is
more useful in the clinical setting, but the applicability of each
formula remains debatable because of over or under correction at
extremes of heart rate (Roden, 2008).

A prolonged QT interval has been used as a surrogate marker for
predicting subsequent risk of ventricular arrhythmias. However, its
significance varies between individuals and is affected by multiple
factors including medications, underlying heart rhythm, asystolic pauses
and genetics. Furthermore, the relationship between the QT interval and
risk of TdP is non-linear. It should therefore be interpreted with
caution and not in isolation, with consideration of the aforementioned
confounding patient characteristics (Roden, 2008). Despite the above
caveats, the risk of ventricular arrhythmias and increased cardiac
morbidity and mortality in the presence of a prolonged QT interval are
well established. Although its consequences may be unpredictable, QT
prolongation does frequently lead to adverse outcomes (Kitt et al.,
2015; Mandal et al., 2019; Roden, 2008; Malik \& Batchvarov, 2000).

Our study confirmed that the use of donepezil for duration of at least 1
year was associated with a significant increase in the QT intervals.
Donepezil enhances the cholinergic function of the brain while also
causing undesired systemic cholinergic side-effects, with
gastrointestinal disturbances such as nausea, vomiting and diarrhoea
being the most common. The adverse effects on the heart are
unpredictable. The heart is an organ rich in cholinesterase enzymes
(ChE). Inhibition of these enzymes leads to increased acetylcholine,
which deactivates the membrane bound voltage-gated calcium channels.
Phase two of the cardiac action potential is also known as the plateau
phase, which is defined by the membrane potential remaining constant due
to the concurrent influx of calcium ions and efflux of potassium ions.
Donepezil may delay this phase by increasing cardiomyocyte acetylcholine
levels, hence deactivating the voltage-gated calcium channels, while
simultaneously causing direct inhibition of delayed rectifier potassium
channels. This results in QT interval prolongation and a subsequent
increased risk of ventricular arrhythmias (Takaya et al., 2009; Malik \&
Batchvarov, 2000; Li \& Cheng et al., 2017; Isik \& Bozoglu et al.,
2012).

Most studies to date have evaluated ECG changes in patients taking
donepezil for up to four months. Significant prolongation of the PR
interval is a common finding, with no associated change in the QT
interval (Igeta et al., 2014; Wang et al., 2018; Rabkin \& Cheng et al.,
2016). We postulate that a longer duration of donepezil therapy may be
necessary to demonstrate a significant QT interval prolongation, as
found in our study. This finding raises concerns since the adverse
effects of QT prolongation and subsequent TdP have only been previously
identified in case studies, resulting in the risk being underestimated
by clinicians (Kitt et al., 2015; Mandal et al., 2019). Furthermore, it
is known that the QT interval increases with age and this may exacerbate
the risk of ventricular arrhythmias in an older population (Rabkin et
al., 2016). This risk may be further amplified by polypharmacy,
electrolyte derangements and concurrent cardiac comorbidities or
conduction disorders.

Female gender has been reported in literature to be an independent risk
factor for QT prolongation, due to their greater baseline QT interval
and oestrogen mediated gender differences in the expression of cardiac
delayed rectifier potassium channels (Rabkin, 2015). Interestingly our
study demonstrated that male patients experienced a significantly
greater prolongation of their corrected QT interval compared to females.
While females tend to show a longer QT interval at younger ages, gender
differences decrease with age due to males having a more pronounced
age-related increase in their QT interval (Rabkin, 2015). This is
observed within our cohort with both older males and females having a
similar QT interval prior to commencing donepezil therapy (Table 3).

A possible explanation is that male patients have a greater sensitivity
to the increase in cardiac acetylcholine levels caused by donepezil,
which results in a greater prolongation of the QT interval (Takaya et
al., 2009). Naturally there is an increase in vagal tone and
acetylcholine release when patients undergo a carotid sinus massage.
Male patients exhibit an increased sensitivity to carotid sinus massage
and have an increased prevalence of carotid sinus disease, which could
theoretically be due to an underlying oversensitivity to acetylcholine
(Tan \& Newton et al., 2009; Kumar \& Thomas et al., 2003; Kerr \&
Pearce et al., 2006). Further evidence of this is that male patients are
less responsive to muscarinic receptor antagonists such as atropine
(Tsutsui \& Falcão et al., 2007). This mechanism may explain why male
patients exhibit a greater prolongation of the corrected QT interval
compared to females, but our results would require confirmation in a
larger study.

Another manifestation of the increase in vagal tone caused by donepezil
is prolonged PR and QRS intervals, as seen in our study population (Sato
\& Urbano et al., 2010). Underlying cardiac conduction disease and the
concomitant use of commonly prescribed negatively chronotropic
medications could exacerbate this further. We demonstrated that
concurrent use of rate limiting calcium channel blockers and
beta-blockers in those on donepezil therapy were associated with
significant PR prolongation and a reduction in heart rate respectively.
One patient in our study population developed symptomatic bradycardia
requiring admission. Cessation of donepezil therapy reversed the
bradycardia and resulted in normalisation of heart rate. Previous
studies have similarly reported hospitalisation for donepezil associated
bradycardia, with a proportion of patients developing syncope and
irreversible heart block requiring permanent pacemaker implantation.
Careful consideration must be taken when initiating donepezil in
patients already prescribed negatively chronotropic medications (Bordier
et al., 2003; Hernandez et al., 2009; Park-Wyllie \& Mamdani et al.,
2009).

Our study did not demonstrate a correlation between the duration of
donepezil therapy and further QT prolongation (Table 5), but its
prolonged use theoretically carries an increased risk of ventricular
arrhythmias. The neurocognitive benefits of donepezil are most
pronounced in the initial months of treatment and continue for up to two
years. Following two years of treatment, the overall benefit of
donepezil remains unclear (Courtney \& Farrell et al., 2004). We noted
that several of our patients had extended donepezil therapy for longer
than the beneficial 2-year treatment period. We therefore suggest that
such patients should be reassessed at this point and termination of
treatment with donepezil should be considered if the risks of adverse
events are deemed to outweigh any clear neurocognitive benefit.

We recognise the limitation of our study as a single centre study in an
acute hospital setting with a predominantly Caucasian population, which
may limit the generalizability of our results to other hospitals or
community settings. We also recognise that ECG recordings took place
during acute hospital admissions and the parameters measured may have
been affected by confounding factors such as a concurrent acute illness
e.g. infection. Our results were based on resting 12-lead ECGs before
and during donepezil treatment, and despite providing valuable
information they are only a snapshot of the patient's cardiac conduction
and may not be representative of their predominant rhythm. A Holter
monitor would provide a more reliable assessment of cardiac conduction
abnormalities and would also capture intermittent arrhythmias. Therefore
a larger prospective study with prolonged cardiac monitoring and longer
follow-up period would be of interest.

In conclusion, the results demonstrate that donepezil therapy results in
a significant prolongation in the PR and QT intervals. Therefore, we
urge clinicians to exercise caution and pharmacovigilance when
prescribing donepezil, particularly in patients with pre-existing
cardiac comorbidities or among those already prescribed medications
known to cause QT prolongation such as tricyclic antidepressants. We
suggest a resting 12-lead ECG should take place before and after
donepezil initiation and where there is suspicion of QT prolongation,
utilisation of a QT nomogram can reliably assess arrhythmogenic risk.

\emph{Summary}

\textbf{What is already known}

\begin{itemize}
\tightlist
\item
  Case studies have reported QT prolongation and subsequent Torsades de
  Pointes associated with donepezil use.
\item
  Cardiac conduction disturbances are considered to be rare side-effects
  of donepezil.
\end{itemize}

\textbf{What this study adds}

Donepezil prolongs QTc intervals, a surrogate marker for predicting
subsequent risk of ventricular arrhythmias.

\textbf{Clinical significance}

ECG evaluation should take place before and after the initiation of
donepezil therapy.

\emph{References}

Bordier, P., Garrigue, S., Barold, S. S., Bressolles, N., Lanusse, S.,
\& Clementy, J. (2003). Significance of syncope in patients with
alzheimer's disease treated with cholinesterase
inhibitors.\emph{~Europace : European Pacing, Arrhythmias, and Cardiac
Electrophysiology : Journal of the Working Groups on Cardiac Pacing,
Arrhythmias, and Cardiac Cellular Electrophysiology of the European
Society of Cardiology,~5} (4), 429-431.
doi:10.1016/s1099-5129(03)00080-1 {[}doi{]}

Bordier, P., Garrigue, S., Lanusse, S., Margaine, J., Robert, F.,
Gencel, L., \& Lafitte, A. (2006). Cardiovascular effects and risk of
syncope related to donepezil in patients with alzheimer's
disease.\emph{~CNS Drugs,~20} (5), 411-417. doi:2055 {[}pii{]}

Chan, A., Isbister, G. K., Kirkpatrick, C. M., \& Dufful, S. B. (2007).
Drug-induced QT prolongation and torsades de pointes: Evaluation of a QT
nomogram.\emph{~QJM : Monthly Journal of the Association of
Physicians,~100} (10), 609-615. doi:hcm072 {[}pii{]}

Courtney, C., Farrell, D., Gray, R., Hills, R., Lynch, L., Sellwood, E.,
. . . AD2000 Collaborative Group. (2004). Long-term donepezil treatment
in 565 patients with alzheimer's disease (AD2000): Randomised
double-blind trial.\emph{~Lancet (London, England),~363} (9427),
2105-2115. doi:10.1016/S0140-6736(04)16499-4 {[}doi{]}

Curtis, M. J., Alexander, S., Cirino, G., Docherty, J. R., George, C.
H., Giembycz, M. A., . . . Ahluwalia, A. (2018). Experimental design and
analysis and their reporting II: Updated and simplified guidance for
authors and peer reviewers.\emph{~British Journal of Pharmacology,~175}
(7), 987-993. doi:10.1111/bph.14153

Hernandez, R. K., Farwell, W., Cantor, M. D., \& Lawler, E. V. (2009).
Cholinesterase inhibitors and incidence of bradycardia in patients with
dementia in the veterans affairs new england healthcare
system.\emph{Journal of the American Geriatrics Society,~57} (11),
1997-2003. doi:10.1111/j.1532-5415.2009.02488.x {[}doi{]}

Igeta, H., Suzuki, Y., Tajiri, M., \& Someya, T. (2014). Cardiovascular
pharmacodynamics of donepezil hydrochloride on the PR and QT intervals
in patients with dementia.\emph{~Human Psychopharmacology,~29} (3),
292-294. doi:10.1002/hup.2398 {[}doi{]}

Isik, A. T., Bozoglu, E., Yay, A., Soysal, P., \& Ateskan, U. (2012).
Which cholinesterase inhibitor is the safest for the heart in elderly
patients with alzheimer's disease?\emph{~American Journal of Alzheimer's
Disease and Other Dementias,~27} (3), 171-174.
doi:10.1177/1533317512442999 {[}doi{]}

Kerr, S. R., Pearce, M. S., Brayne, C., Davis, R. J., \& Kenny, R. A.
(2006). Carotid sinus hypersensitivity in asymptomatic older persons:
Implications for diagnosis of syncope and falls.\emph{~Archives of
Internal Medicine,~166} (5), 515-520. doi:166/5/515 {[}pii{]}

Kumar, N. P., Thomas, A., Mudd, P., Morris, R. O., \& Masud, T. (2003).
The usefulness of carotid sinus massage in different patient
groups.\emph{~Age and Ageing,~32} (6), 666-669.
doi:10.1093/ageing/afg114 {[}doi{]}

Li, K., Cheng, N., \& Li, X. T. (2017). Inhibitory effects of
cholinesterase inhibitor donepezil on the Kv1.5 potassium
channel.\emph{~Scientific Reports,~7} , 41509. doi:10.1038/srep41509
{[}doi{]}

Malik, B. H., Hamid, P., Khan, S., Gupta, D., \& Islam, M. (2019).
Correlation between donepezil and QTc prolongation and torsades de
pointes: A very rare phenomenon.\emph{~Cureus,~11} (12), e6451.
doi:10.7759/cureus.6451 {[}doi{]}

Malik, M., \& Batchvarov, V. N. (2000). Measurement, interpretation and
clinical potential of QT dispersion.\emph{~Journal of the American
College of Cardiology,~36} (6), 1749-1766. doi:S0735-1097(00)00962-1
{[}pii{]}

Mandal, A. K. J., Khan, U. F., \& Missouris, C. G. (2019). Ventricular
tachycardia in a patient with sigmoid volvulus on treatment with
donepezil.\emph{~Clinical Toxicology (Philadelphia, Pa.),~57} (12),
1157-1159. doi:10.1080/15563650.2019.1588288 {[}doi{]}

Park-Wyllie, L. Y., Mamdani, M. M., Li, P., Gill, S. S., Laupacis, A.,
\& Juurlink, D. N. (2009). Cholinesterase inhibitors and hospitalization
for bradycardia: A population-based study.\emph{~PLoS Medicine,~6} (9),
e1000157. doi:10.1371/journal.pmed.1000157 {[}doi{]}

Rabkin, S. W. (2015). Impact of age and sex on QT prolongation in
patients receiving psychotropics.\emph{~Canadian Journal of
Psychiatry.Revue Canadienne De Psychiatrie,~60} (5), 206-214.
doi:cjp-2015-vol60-may-206-214 {[}pii{]}

Rabkin, S. W., Cheng, X. J., \& Thompson, D. J. (2016). Detailed
analysis of the impact of age on the QT interval.\emph{~Journal of
Geriatric Cardiology : JGC,~13} (9), 740-748. doi:jgc-13-09-740
{[}pii{]}

Roden, D. M. (2008). Keep the QT interval: It is a reliable predictor of
ventricular arrhythmias.\emph{~Heart Rhythm,~5} (8), 1213-1215.
doi:10.1016/j.hrthm.2008.05.008 {[}doi{]}

Sato, K., Urbano, R., Yu, C., Yamasaki, F., Sato, T., Jordan, J., . . .
Diedrich, A. (2010). The effect of donepezil treatment on cardiovascular
mortality.\emph{~Clinical Pharmacology and Therapeutics,~88} (3),
335-338. doi:10.1038/clpt.2010.98 {[}doi{]}

Takaya, T., Okamoto, M., Yodoi, K., Hata, K., Kijima, Y., Nakajima, H.,
. . . Kawashima, S. (2009). Torsades de pointes with QT prolongation
related to donepezil use.\emph{~Journal of Cardiology,~54} (3), 507-511.
doi:10.1016/j.jjcc.2009.03.011 {[}doi{]}

Tan, M. P., Newton, J. L., Reeve, P., Murray, A., Chadwick, T. J., \&
Parry, S. W. (2009). Results of carotid sinus massage in a tertiary
referral unit--is carotid sinus syndrome still relevant?\emph{~Age and
Ageing,~38} (6), 680-686. doi:10.1093/ageing/afp160 {[}doi{]}

Tsutsui, J. M., Falcao, S. N., Dourado, P. M., Lima, M. F., Alves, A.
A., Guerra, V. C., . . . Mathias, W. (2007). Gender differences in
chronotropic and hemodynamic responses during dobutamine-atropine stress
echocardiography.\emph{~Echocardiography (Mount Kisco, N.Y.),~24} (8),
843-850. doi:ECHO487 {[}pii{]}

United States Food and Drug Administration. (2012). Aricept (donepezil
hydrochloride). Retrieved
from~https://www.accessdata.fda.gov/drugsatfda\_docs/label/2012/020690s035,021720s008,022568s005lbl.pdf

Wang, D., Wu, Y., Wang, A., Chen, Y., Zhang, T., \& Hu, N. (2018).
Electrocardiogram changes of donepezil administration in elderly
patients with ischemic heart disease.\emph{~Cardiology Research and
Practice,~2018} , 9141320. doi:10.1155/2018/9141320 {[}doi{]}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1-QT-nomogram-plots-comparison/Figure-1-QT-nomogram-plots-comparison}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Table-1/Table-1}

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

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

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

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Table-5/Table-5}

\end{center}
\end{figure}

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

