\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{A mysterious resistance to acenocoumarol!~~~~~~~~~~~~}



\author[1]{Ines Souilem}%
\author[1]{Imen Aouinti}%
\author[1]{Ahmed Zaiem}%
\author[1]{Ons Charfi}%
\author[1]{Widd Kaabi}%
\author[1]{Sarrah Kastalli}%
\author[1]{Riadh Daghfous}%
\author[1]{Ghozlane Lakhoua}%
\author[1]{Sihem El Aidli}%
\affil[1]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 15, 2024}


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





\selectlanguage{english}
\begin{abstract}
Acenocoumarol is the most widely prescribed vitamin K antagonist (VKA)
to prevent and treat thromboembolic disorders. It keeps a major place in
many indications despite the introduction of new direct oral
anticoagulants (DOACs). However, a narrow therapeutic range, an
intra-individual variability and drug interactions may lead to serious
adverse drug reactions. ~Sometimes, a genetic or acquired resistance to
this drug may lead to a risky situation. Hopefully, resistance to
acenocoumarol is a very rare phenomen.

Here in we present an unsusual case of a suspected resistance to
acenocoumarol. This case was notified to the Tunisian National Center of
Pharmacovigilance on October 2017 and registered under the number
\textbf{} 2449/2017.

A 67-year-old patient with hypertension, diabetes, and coronary disease
was treated with captopril, atenolol, atorvastatin, and salicylic acid.
In 2017, acenocoumarol treatment was introduced. At biological control,
the prothrombin time (PT) was 100\%. The doses of acenocoumarol were
raised progressively with iterative controls of PT. PT was always 100\%
even when acenocoumarol reached the dose of 2 g/day. A resistance to
acenocoumarol was suspected. The patient was referred to
pharmacovigilance department for case analysis. During the patient
interview, we discover that the patient was confusing acenocoumarol with
atenolol. In fact, when his doctor was increasing the doses of
acenocoumarol, the patient increased her intake of atenolol believing
that it was acenocoumarol.

A resistance to acenocoumarol was eliminated in this patient since she
had never taken the drug. We highlight through this case the importance
of patient's interview. Explaining the indications and the potential
adverse events of the drug to patients taking VKA is crucial to ensure a
better efficiency of treatment without increasing the risk of bleeding
complication.%
\end{abstract}%



\sloppy




Keywords: vitamin K antagonist, anticoagulant, acenocoumarol,
resistance, pharmacovigilance.

\par\null

Introduction:

Acenocoumarol is the most widely prescribed vitamin K antagonist (VKA)
to prevent and treat thromboembolic disorders. It keeps a major place in
many indications despite the introduction of new direct oral
anticoagulants (DOACs). However, a narrow therapeutic range, an
intra-individual variability and drug interactions may lead to serious
adverse drug reactions. ~Sometimes, a genetic or acquired resistance to
this drug may lead to a risky situation. Hopefully, resistance to
acenocoumarol is a very rare phenomen.

Here in we present an unsusual case of a suspected resistance to
acenocoumarol. This case was notified to the Tunisian Center of
Pharmacovigilance on October 2017 and registered under the number
\textbf{} 2449/2017. It was analyzed according to the French updated
method for the causality assessment of adverse drug reactions {[}1,2{]}.

\textbf{Case report}

A 67-year-old patient with hypertension, diabetes, and coronary disease
was treated with captopril, atenolol, atorvastatin, and salicylic acid.
In 2017, acenocoumarol treatment was introduced. At biological control,
the prothrombin time (PT) was 100\%. The doses of acenocoumarol were
raised progressively with iterative controls of PT. PT was always 100\%
even when acenocoumarol reached the dose of 2 g/day. A resistance to
acenocoumarol was suspected. The patient was referred to
pharmacovigilance department for case analysis. During the patient
interview, it was found that the patient was confusing acenocoumarol
with atenolol. In fact, when his doctor was increasing the doses of
acenocoumarol, the patient increased her intake of atenolol believing
that it was acenocoumarol. The patient had never taken acenocoumarol.

\textbf{Discussion:}

The prescription of acenocoumarol must be monitored by the
``International Normalized Ratio'' (INR) to adjust the posology, achieve
the desired levels of anticoagulation capable of preventing
thromboembolic events without increasing the risk of bleeding
complications. The management of these complications remains a major
challenge regarding their potential severity. In fact, an INR below 1.7
has been associated with a doubling of stroke risk, whereas an INR above
3.0 doubles the risk of major hemorrhage{[}3{]}.

Despite a well-defined target range of INR for various indications and
close monitoring of patients, large fluctuations in anticoagulant
control are frequently noticed. In this regard, poor patient's adherence
is the first cause of a floating INR. A good INR monitoring can be
obtained via patients' behavior control. For example, patients with
better knowledge and higher medication adherence are more likely to have
good INR control {[}4{]}. Otherwise, the requirement of acenocoumarol's
therapy is particularly frequent in older patients. In a prospective
collaborative study, Palareti et al found that 30\% of patients starting
an anticoagulant treatment were 70 years and older{[}5{]}. The lack of
knowledge about treatment in population of elderly subjects can severely
affect patients' INR control. Actually, multiple comorbidities,
polypharmacy, history of hypertension, insufficient social support,
decreased access to care and reduced functional status are to blame
{[}3,6{]}. Furthermore, cognitive impairment is thought by many
physicians to be a contraindication for anticoagulant treatment{[}6{]}.

Consistent with a previous Tunisian study, a~moderate negative
correlation was found between patients' knowledge of VKA therapy ~and
age{[}7{]}. Elderly patients and patients with lower education were more
likely to have poor knowledge of the treatment. Most of this study's
patients were unable to indicate the consequences that may occur if VKA
dosing is insufficient or if they do not take their medication. Only
one-third of the study patients were aware of the importance of VKA
therapy monitoring and one-fifth knew how VKA treatment should be
monitored. This lack of knowledge may be due to the fact that over
one-third of the patients were illiterate{[}7{]}. Yet, other
investigators reported similar findings among patients with a higher
level of education{[}4{]}. These results suggested that these patients
may require special consideration. Innovative and patient-targeted
educational programs and improvement of the physician-patient
communication are needed regardless of education~level. That kind of
attitude may improve patients' knowledge, drug compliance, and adherence
to medical advice.

In our case, thanks to a meticulous interview, we discovered that this
67-year old patient was confusing acenocoumarol with atenolol. This
emphasize that a premature diagnosis of resistance should be avoided.
Actually, true resistance to acenocoumarol, which is genetic, is
extremely rare{[}8{]}. It is attributed to the presence of enzymes or
receptor sites with altered affinity for vitamin K or the drug{[}9{]}.
This sort of resistance is constantly primary and its diagnosis is
complex because a highly detailed genetic study must be conducted.
Absence of drug intake, a high vitamin K intake, drug interaction,
malabsorption or increased destruction/metabolism of the drug may be
sometimes mistakenly considered as a resistance situation.

\textbf{Conclusion}

A resistance to acenocoumarol was eliminated in this patient since she
had never taken the drug. We highlight through this case the importance
of patient's interview. Thus, a proper communication between patients
and healthcare providers is essential. Explaining the indications and
the potential adverse events of the drug to patients taking VKA is
crucial to ensure a better efficiency of treatment without increasing
the risk of bleeding complication.

~

\textbf{References:}

~

1.~~~~~~ Miremont-Salam\selectlanguage{ngerman}é G, Théophile H, Haramburu F, Bégaud B.
Causality assessment in pharmacovigilance: The French method and its
successive updates. Therapies.2016;71:179\selectlanguage{english}-86.

2.~~~~~~ Montastruc JL. Pharmacovigilance and drug safety: Fair
prescribing and clinical research. Therapies.2022;77:261\selectlanguage{english}-3.

3.~~~~~~ Newman DH, Zhitomirsky I. The Prevalence of Nontherapeutic and
Dangerous International Normalized Ratios Among Patients Receiving
Warfarin in the Emergency Department. Ann Emerg Med.2006;48:182-189.e1.

4.~~~~~~ McCabe PJ, Schad S, Hampton A, Holland DE. Knowledge and
self-management behaviors of patients with recently detected atrial
fibrillation. Heart Lung.2008;37:79\selectlanguage{english}-90.

5.~~~~~~ Palareti G, Leali N, Coccheri S, Poggi M, Manotti C, D'Angelo
A, et al. Bleeding complications of oral anticoagulant treatment: an
inception-cohort, prospective collaborative study (ISCOAT). The
Lancet.1996;348:423\selectlanguage{english}-8.

6.~~~~~~ Kagansky N, Knobler H, Rimon E, Ozer Z, Levy S. Safety of
Anticoagulation Therapy in Well-informed Older Patients. Arch Intern
Med. 2004;164:2044.

7.~~~~~~ Jeddou KB, Abbassi A, M'barka FB, Bedoui Y, Boukhris I, Baccar
H, et al. Evaluation of anticoagulant therapy management in a teaching
hospital in Tunisia: information and education for vitamin k antagonist
newly treated patients need to be improved. Int J Pharm
Pract.2021;29:389\selectlanguage{english}-93.

8.~~~~~~ Batisse A, Helft G. Resistance aux anticoagulants oraux -
Resistance to anticoagulants. M ISE AU POINT.

9.~~~~~~ Wolff FA de, Cate JW ten. Transient Acquired Resistance to the
Coumarin Anticoagulants Phenprocoumon and Acenocoumarol. Scand J
Haematol. 2009;23:437\selectlanguage{english}-41.

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

