Membres du jury
Monsieur le Professeur GARNIER François | Président Monsieur le Docteur BRANGIER Antoine | Directeur Monsieur le Professeur AUBE Christophe | Membre Monsieur le Professeur LAGARCE Frédéric | Membre Monsieur le Docteur LABRIFFE Matthieu | Membre Monsieur le Professeur ANNWEILER Cédric | Invité
Soutenue publiquement le :
2019-2020
THÈSE
pour le
DIPLÔME D’ÉTAT DE DOCTEUR EN MÉDECINE
Qualification en MEDECINE GÉNÉRALE
Fardeau de calcifications intracrâniennes sous anti-vitamine K ou anticoagulant oral direct : une étude exposés-non exposés chez la personne
âgée
Intracranial calcifications under vitamin K antagonists or direct oral anticoagulants: an exposed-
unexposed study in older adults
ANNWEILER Gaëlle
Née le 22 Avril 1986 à Saumur (49)
Sous la direction de M. BRANGIER Antoine
ENGAGEMENT DE NON PLAGIAT
Je, soussigné(e) ANNWEILER Gaëlle
déclare être pleinement conscient(e) que le plagiat de documents ou d’une partie d’un document publiée sur toutes formes de support, y compris l’internet, constitue une violation des droits d’auteur ainsi qu’une fraude caractérisée.
En conséquence, je m’engage à citer toutes les sources que j’ai utilisées pour écrire ce rapport ou mémoire.
signé par l'étudiante le 24/01/2020
LISTE DES ENSEIGNANTS DE LA FACULTÉ DE SANTÉ D’ANGERS
Doyen de la Faculté : Pr Nicolas Lerolle
Vice-Doyen de la Faculté et directeur du département de pharmacie : Pr Frédéric Lagarce
Directeur du département de médecine : Pr Cédric Annweiler
PROFESSEURS DES UNIVERSITÉSABRAHAM Pierre Physiologie Médecine
ANNWEILER Cédric Gériatrie et biologie du
vieillissement Médecine
ASFAR Pierre Réanimation Médecine
AUBE Christophe Radiologie et imagerie
médicale Médecine
AUGUSTO Jean-François Néphrologie Médecine
BAUFRETON Christophe Chirurgie thoracique et
cardiovasculaire Médecine BENOIT Jean-Pierre Pharmacotechnie Pharmacie BEYDON Laurent Anesthésiologie-réanimation Médecine
BIGOT Pierre Urologie Médecine
BONNEAU Dominique Génétique Médecine
BOUCHARA Jean-Philippe Parasitologie et mycologie Médecine
BOUVARD Béatrice Rhumatologie Médecine
BOURSIER Jérôme Gastroentérologie ;
hépatologie Médecine
BRIET Marie Pharmacologie Médecine
CAILLIEZ Eric Médecine générale Médecine
CALES Paul Gastroentérologe ; hépatologie Médecine CAMPONE Mario Cancérologie ; radiothérapie Médecine CAROLI-BOSC François-xavier Gastroentérologie ;
hépatologie Médecine
CHAPPARD Daniel Cytologie, embryologie et
cytogénétique Médecine
CONNAN Laurent Médecine générale Médecine
COUTANT Régis Pédiatrie Médecine
CUSTAUD Marc-Antoine Physiologie Médecine
DE CASABIANCA Catherine Médecine Générale Médecine DESCAMPS Philippe Gynécologie-obstétrique Médecine D’ESCATHA Alexis Médecine et santé au Travail Médecine DINOMAIS Mickaël Médecine physique et de
réadaptation Médecine
DIQUET Bertrand Pharmacologie Médecine
DUCANCELLE Alexandra Bactériologie-virologie ;
hygiène hospitalière Médecine DUVAL Olivier Chimie thérapeutique Pharmacie
DUVERGER Philippe Pédopsychiatrie Médecine
EVEILLARD Mathieu Bactériologie-virologie Pharmacie FAURE Sébastien Pharmacologie physiologie Pharmacie
FOURNIER Henri-Dominique Anatomie Médecine
FURBER Alain Cardiologie Médecine
GAGNADOUX Frédéric Pneumologie Médecine
GARNIER François Médecine générale Médecine
GASCOIN Géraldine Pédiatrie Médecine
GOHIER Bénédicte Psychiatrie d'adultes Médecine GUARDIOLA Philippe Hématologie ; transfusion Médecine
GUILET David Chimie analytique Pharmacie
HAMY Antoine Chirurgie générale Médecine
HENNI Samir Chirurgie Vasculaire, médecine
vasculaire Médecine
HUNAULT-BERGER Mathilde Hématologie ; transfusion Médecine IFRAH Norbert Hématologie ; transfusion Médecine
JEANNIN Pascale Immunologie Médecine
KEMPF Marie Bactériologie-virologie ;
hygiène hospitalière Médecine LACCOURREYE Laurent Oto-rhino-laryngologie Médecine
LAGARCE Frédéric Biopharmacie Pharmacie
LARCHER Gérald Biochimie et biologie
moléculaires Pharmacie
LASOCKI Sigismond
LEGENDRE Guillaume Anesthésiologie-réanimation
Gynécologie-obstétrique Médecine Médecine
LEGRAND Erick Rhumatologie Médecine
LERMITE Emilie Chirurgie générale Médecine
LEROLLE Nicolas Médecine Intensive-
Réanimation Médecine
LUNEL-FABIANI Françoise Bactériologie-virologie ;
hygiène hospitalière Médecine MARCHAIS Véronique Bactériologie-virologie Pharmacie MARTIN Ludovic Dermato-vénéréologie Médecine MAY-PANLOUP Pascale Biologie et médecine du
développement et De la reproduction
Médecine
MENEI Philippe Neurochirurgie Médecine
MERCAT Alain Réanimation Médecine
MERCIER Philippe Anatomie Médecine
PAPON Nicolas Parasitologie et mycologie
médicale Pharmacie
PASSIRANI Catherine Chimie générale Pharmacie
PELLIER Isabelle Pédiatrie Médecine
PETIT Audrey Médecine et Santé au Travail Médecine
PICQUET Jean Chirurgie vasculaire ;
médecine vasculaire Médecine PODEVIN Guillaume Chirurgie infantile Médecine
PROCACCIO Vincent Génétique Médecine
PRUNIER Delphine Biochimie et Biologie
Moléculaire Médecine
PRUNIER Fabrice Cardiologie Médecine
REYNIER Pascal Biochimie et biologie
moléculaire Médecine
RICHARD Isabelle Médecine physique et de
réadaptation Médecine
RICHOMME Pascal Pharmacognosie Pharmacie
RODIEN Patrice Endocrinologie, diabète et
maladies métaboliques Médecine ROQUELAURE Yves Médecine et santé au travail Médecine ROUGE-MAILLART Clotilde Médecine légale et droit de la
santé Médecine
ROUSSEAU Audrey Anatomie et cytologie
pathologiques Médecine
ROUSSEAU Pascal Chirurgie plastique,
reconstructrice et esthétique Médecine ROUSSELET Marie-Christine Anatomie et cytologie
pathologiques Médecine
ROY Pierre-Marie Thérapeutique Médecine
SAULNIER Patrick Biophysique et biostatistique Pharmacie
SERAPHIN Denis Chimie organique Pharmacie
TRZEPIZUR Wojciech Pneumologie Médecine
UGO Valérie Hématologie ; transfusion Médecine
URBAN Thierry Pneumologie Médecine
VAN BOGAERT Patrick Pédiatrie Médecine
VENIER-JULIENNE Marie-Claire Pharmacotechnie Pharmacie
VERNY Christophe Neurologie Médecine
WILLOTEAUX Serge Radiologie et imagerie
médicale Médecine
MAÎTRES DE CONFÉRENCES
ANGOULVANT Cécile Médecine Générale Médecine
BAGLIN Isabelle Chimie thérapeutique Pharmacie BASTIAT Guillaume Biophysique et biostatistique Pharmacie
BEAUVILLAIN Céline Immunologie Médecine
BELONCLE François Réanimation Médecine
BENOIT Jacqueline Pharmacologie Pharmacie
BIERE Loïc Cardiologie Médecine
BLANCHET Odile Hématologie ; transfusion Médecine
BOISARD Séverine Chimie analytique Pharmacie
CAPITAIN Olivier Cancérologie ; radiothérapie Médecine
CASSEREAU Julien Neurologie Médecine
CHAO DE LA BARCA Juan-Manuel Médecine
CHEVALIER Sylvie Biologie cellulaire Médecine
CLERE Nicolas Pharmacologie / physiologie Pharmacie
COLIN Estelle Génétique Médecine
DERBRE Séverine Pharmacognosie Pharmacie
DESHAYES Caroline Bactériologie virologie Pharmacie
FERRE Marc Biologie moléculaire Médecine
FORTRAT Jacques-Olivier Physiologie Médecine
HAMEL Jean-François Biostatistiques, informatique médicale Médicale HELESBEUX Jean-Jacques Chimie organique Pharmacie
HINDRE François Biophysique Médecine
KHIATI Salim Biochimie et biologie moléculaire Médecine JOUSSET-THULLIER Nathalie Médecine légale et droit de la santé Médecine JUDALET-ILLAND Ghislaine Médecine Générale Médecine KUN-DARBOIS Daniel Chirurgie Maxillo-Faciale et
Stomatologie Médecine
LACOEUILLE Franck Biophysique et médecine nucléaire Médecine
LEBDAI Souhil Urologie Médecine
LANDREAU Anne Botanique/ Mycologie Pharmacie
LEBDAI Souhil Urologie Médecine
LEGEAY Samuel Pharmacocinétique Pharmacie
LE RAY-RICHOMME Anne-
Marie Pharmacognosie Pharmacie
LEPELTIER Elise Chimie générale Pharmacie
LETOURNEL Franck Biologie cellulaire Médecine
LIBOUBAN Hélène Histologie Médecine
LUQUE PAZ Damien Hématologie; Transfusion Médecine MABILLEAU Guillaume Histologie, embryologie et
cytogénétique Médecine
MALLET Sabine Chimie Analytique Pharmacie
MAROT Agnès Parasitologie et mycologie médicale Pharmacie
MESLIER Nicole Physiologie Médecine
MOUILLIE Jean-Marc Philosophie Médecine
NAIL BILLAUD Sandrine Immunologie Pharmacie
PAILHORIES Hélène Bactériologie-virologie Médecine
PAPON Xavier Anatomie Médecine
PASCO-PAPON Anne Radiologie et imagerie médicale Médecine
PECH Brigitte Pharmacotechnie Pharmacie
PENCHAUD Anne-Laurence Sociologie Médecine
PIHET Marc Parasitologie et mycologie Médecine
PY Thibaut Médecine Générale Médecine
RAMOND-ROQUIN Aline Médecine Générale Médecine RINEAU Emmanuel Anesthésiologie réanimation Médecine
RIOU Jérémie Biostatistiques Pharmacie
ROGER Emilie Pharmacotechnie Pharmacie
SAVARY Camille Pharmacologie-Toxicologie Pharmacie SCHMITT Françoise Chirurgie infantile Médecine
SCHINKOWITZ Andréas Pharmacognosie Pharmacie
SPIESSER-ROBELET
Laurence Pharmacie Clinique et Education
Thérapeutique Pharmacie
TANGUY-SCHMIDT Aline TESSIER-CAZENEUVE Christine
Hématologie ; transfusion
Médecine Générale Médecine
Médecine
VENARA Aurélien Chirurgie générale Médecine
VIAULT Guillaume Chimie organique Pharmacie
PROFESSEURS EMERITES
Philippe MERCIER Neurochirurgie Médecine
Dominique CHABASSE Parasitologie et Médecine Tropicale Médecine
Jean-François SUBRA Néphrologie Médecine
AUTRES ENSEIGNANTS
AUTRET Erwan Anglais Médecine
BARBEROUSSE Michel Informatique Médecine
BRUNOIS-DEBU Isabelle Anglais Pharmacie
CHIKH Yamina Économie-Gestion Médecine
FISBACH Martine Anglais Médecine
O’SULLIVAN Kayleigh Anglais Médecine
Mise à jour au 09/12/2019
SERMENT D’HIPPOCRATE
« Au moment d’être admise à exercer la médecine, je promets et je jure d’être fidèle aux lois de l’honneur et de la probité. Mon premier souci sera de rétablir, de préserver ou de promouvoir la santé dans tous ses éléments, physiques et mentaux, individuels et sociaux.
Je respecterai toutes les personnes, leur autonomie et leur volonté, sans aucune discrimination selon leur état ou leurs convictions. J’interviendrai pour les protéger si elles sont affaiblies, vulnérables ou menacées dans leur intégrité ou leur dignité. Même sous la contrainte, je ne ferai pas usage de mes connaissances contre les lois de l’humanité.
J’informerai les patients des décisions envisagées, de leurs raisons et de leurs conséquences. Je ne tromperai jamais leur confiance et n’exploiterai pas le pouvoir hérité des circonstances pour forcer les consciences. Je donnerai mes soins à l’indigent et à quiconque me les demandera. Je ne me laisserai pas influencer par la soif du gain ou la recherche de la gloire.
Admise dans l’intimité des personnes, je tairai les secrets qui me seront confiés. Reçue à l’intérieur des maisons, je respecterai les secrets des foyers et ma conduite ne servira pas à corrompre les mœurs. Je ferai tout pour soulager les souffrances. Je ne prolongerai pas abusivement les agonies. Je ne provoquerai jamais la mort délibérément.
Je préserverai l’indépendance nécessaire à l’accomplissement de ma mission. Je n’entreprendrai rien qui dépasse mes compétences. Je les entretiendrai et les perfectionnerai pour assurer au mieux les services qui me seront demandés.
J’apporterai mon aide à mes confrères ainsi qu’à leurs familles dans l’adversité.
Que les hommes et mes confrères m’accordent leur estime si je suis fidèle à mes promesses
; que je sois déshonorée et méprisée si j’y manque ».
RE M E RC IE M E N TS
A monsieur le Professeur GARNIER, merci d’avoir accepté de présider mon jury de thèse et m’avoir fait bénéficier tout au long de mon cursus étudiant de votre expérience humaine de généraliste engagé (je ne vis plus chez ma mère !).A monsieur le Docteur Antoine BRANGIER, merci d’avoir accepté de diriger mon travail de thèse. Ton soutien et ta réflexion sur ce sujet m’ont été d’une aide précieuse. Surtout, un grand merci pour ta rigueur de clinicien qui m’inspire au quotidien.
A monsieur le Professeur LAGARCE, merci d’apporter ton expertise de pharmacien à ce jury de thèse, même si la lecture de ces quelques pages ne saurait égaler un bon roman de SF !
A monsieur le Professeur AUBE, vous me faites l’honneur d’apporter votre expérience à la critique de ce travail, merci pour votre temps et votre bienveillance.
A monsieur le Professeur ANNWEILER, merci de m’avoir encouragée à faire médecine (c’est gagné !), de m’avoir soutenue dans mon parcours de bébé gériatre (c’est presque gagné !) et d’avoir cru encore plus fort que moi qu’un jour, je serai un super docteur (ça reste à voir !).
A monsieur le Docteur LABRIFFE, merci de ton soutien précieux et de ton expertise indispensable pour l’analyse des données d’imagerie, et d’avoir créé (rien que ça !) un score de fardeau de calcification pour les besoins de la thèse.
RE M E R CI E M E N T S
hh
Tous les MERCI du monde ne suffiraient pas, Maman, Papa, pour tout ce que vous avez fait pour moi.
Pour m’avoir toujours poussée à croire en mes rêves, à avoir la force de les entreprendre, la ténacité de les accomplir et l’insolence de rêver plus grand encore. Je vous aime.
A mon petit frère, mon poupon (que j’ai mordé), mon copain de jeux, de bêtises, d’école, mon co-listier, mon dépanneur, ma roue de secours, ma baby-sitter, mon déménageur, mon éternel co-étudiant… Avec qui vais-je faire la course aux diplômes maintenant qu’on a tous les deux terminé ?? <3
A mes grands-parents, pour votre soutien réconfortant à toute épreuve et l’image de la famille que vous portez. Votre maison est une grande Arche de Noé, et ce n’est sûrement pas étranger à mon besoin d’aider les gens ! (Et mamie, j’ai réalisé mon premier rêve de petite fille, je suis docteur ! Pour la Ferrari rouge, j’ai juste choisi la mauvaise spécialité !)
A ma belle-famille, Marc, Josiane, Thierry, Déborah et les garçons, merci pour votre affection et votre bienveillance. Bientôt un nouveau docteur dans la famille… les prochains seront dans 20 ans !
A mon trinôme d’externat et d’internat, Marie et Shirley, avec qui j’ai passé de nombreuses heures les fesses sur une chaise de la BU, bu des litres de café, posé des centaines de questions incongrues (c’est quel stade de la classification du cancer de l’auriculaire quand la tumeur dépasse 2,3cm ?), stressé pour des dizaines d’examens, deux concours (et autant d’attentes de publications de résultats), pour ENFIN trinquer après cette thèse ! On se fait Hypokhâgne après ?
A mes co-internes de DESC avec qui je suis devenue un #GériatreAngevin en passant de supers semaines de vacances séminaires. Vous êtes au top (sauf toi Pierre évidemment).
A tous mes chefs de gériatrie, Leila, Anaïs, Cédric ;), Jean, Antoine, Guillaume, Hélène & Hélène, Gonzague, Jocelyne, merci d’avoir pris de votre temps pour m’apprendre TOUT ce que je sais aujourd’hui sur cette belle spécialité, et l’état d’esprit qui va avec ! Je suis très fière de rejoindre le clan.
A mes MGSU, Camille, Bernard et Philippe, merci de m’avoir fait partager votre quotidien et vos difficultés de généralistes passionnés. J’ai appris avec vous à m’éloigner un peu de l’Evidence-Based Medicine pour découvrir qu’il y avait autant de façon de pratiquer la médecine que de médecins (je cherche encore un peu la mienne…).
A mes derniers chefs en date, Charline et Arnaud, et à l’équipe du MIP, merci pour votre accompagnement bienveillant et votre bonne humeur. J’espère pouvoir bientôt écrire à vos côtés une nouvelle page de ma vie professionnelle.
A l’équipe du CeRAL, sans qui tous ces jolis chiffres n’auraient aucun sens… Vous êtes de magiciens ! A toutes les équipes soignantes que j’ai eu la chance de croiser durant mon internat, qui ont rattrapé mes boulettes, soufflé des idées brillantes ou partagé des situations difficiles. Vous avez toute mon admiration et ma reconnaissance, au quotidien !
A mes enfants, mes soleils, Faustine et Émile. Vous avez rendu mes études de médecine tellement plus supportables (quoique légèrement plus acrobatiques). Ne lisez pas ce travail, il sera sûrement obsolète quand vous saurez lire et vous aurez bien mieux à faire ! Peu importe la voie que vous choisirez, pourvu que ce soit celle qui vous fasse vibrer. Je vous aime inconditionnellement « jusqu’aux étoiles » ! ;) A mon mari. Mon meilleur supporter. Merci de ton soutien indéfectible pour ce travail, pour ces études, et pour tout le reste. Merci pour ta sérénité à toute épreuve et ta patience face à ma procrastination maladive (Gaëlle, c’est dans une semaine/demain/ce soir/dans une heure la deadline pour les soumissions/le permis d’imprimer/les inscriptions au DU/les courses…). Merci d’être toujours là pour moi.
Merci pour ton amour sans bornes et pour l’importance que tu me donnes. Tu fais de ma vie un festival (techno évidemment !). Je t’aime.
PLAN
ABBREVIATIONS LIST - LISTE DES ABREVIATIONS ... 1
INTRODUCTION - INTRODUCTION ... 2
METHODS - MATERIELS ET METHODES ... 3
RESULTS - RESULTATS ... 6
DISCUSSION - DISCUSSION ... 7
REFERENCES - BIBLIOGRAPHIE ... 10
ANNEXE : ARTICLE PUBLIE ... 18
Liste des abréviations
VIKING VItamin K Inhibition and NeurocoGnition VKA Vitamin K Antagonists
DOA Direct Oral Anticoagulant FAB Frontal Assessment Battery
CT scan Computerized Tomography scanner eGFR Estimated Glomerular Filtration Rate MGP Matrix Gla Protein
INR International Normalized ratio
1. INTRODUCTION
Vitamin K antagonists (VKAs) are commonly used for the prophylaxis and treatment of thromboembolic events, especially in older adults [1]. Unlike direct oral anticoagulants (DOAs), which mechanisms do not interfere with the cycle of vitamin K, VKAs are inhibitors of the enzymatic conversion of inactive vitamin K epoxide to its reduced active form, thus resulting in a relative state of vitamin K deficiency [1]. Importantly, neurocognitive disorders have been reported among VKA users compared to those using no blood-thinning drugs [2-4]. The use of VKA was associated with impaired cognitive performance as a whole in previous studies [2,3], specifically with a decline of executive functions in longitudinal studies [4]. These associations were independent of the condition warranting the use of anticoagulation, notably the history of atrial fibrillation [2-4]. Thus the most likely explanation was based on the decreased bioavailability of the active form of vitamin K under VKA [5,6]. In fact, the use of VKA in animals has been associated with cognitive impairment and a dysregulation of the synthesis of sphingolipids, a constituent of the myelin sheath and neuronal membrane [6], and a reduction of the biological activation of the vitamin K-dependent proteins involved in neuronal physiology and survival [5]. Such changes may account for the onset of pathological morphological brain changes in VKA users [7,8].
Of note, the regular use of VKA has also been associated with the onset of vascular and extra-vascular calcifications, including in the coronary arteries or the tracheobronchial tree [9].
As intracranial calcifications could in turn lead to neurocognitive disorders [10], we hypothesized that the subcortical executive dysfunction that was observed in older VKA users may have resulted at least in part from a greater burden of intracranial calcifications depending on their quantity, size, confluence and location. The objective of this case-control study was to determine whether the regular use of VKA in older adults was associated with an increased burden of intracranial calcifications compared to the use of direct oral anticoagulant (DOA), as a comparator not interfering with the vitamin K cycle.
2. METHODS
2.1 Participants
We conducted the ‘VItamin K Inhibition and NeurocoGnition’ (VIKING) study, a case-control study with a 1:1 ratio. Cases were 19 consecutive patients aged 70 years and older using VKA in the Department of Geriatric Medicine of the University Hospital of Angers, France. Nineteen controls using a DOA matched on age (± 5 years), gender and indication for anticoagulation (i.e., atrial fibrillation versus venous thromboembolism or mechanical valve) were selected from other patients in the same Department between 1 January 2015 and 1 June 2017. Diads were screened using the computerized registry of Angers University Hospital, and finally included in the analysis after manual review of medical records by one author (PM). Diads were included in the analysis if i) both cases and controls used the anticoagulant for more than 3 months at the time of the inclusion, and ii) both cases and controls underwent a computed tomography of the brain at the time of the inclusion. Main exclusion criteria were severe kidney failure defined as creatinine clearance <30mL/min according to Cockcroft-Gault formula, history of any acute medical illness in the preceding 3 months, poor vision, inability to understand or answer the study questionnaires, and refusal to participate in research.
2.2 Anticoagulants
The regular use of VKA (i.e., warfarin, acenocoumarol or fluindione) and DOA (i.e., apixaban, dabigatran, rivaroxaban) was noted from family physician prescriptions and sought by questioning the patients and relatives. The length of use above 3 months and the reason for treatment were checked and collected in a standardized manner from the family physician interview.
2.3 CT scan procedure
Images were acquired on CT scanner at the University Hospital of Angers, France, using a standardized CT protocol. CT is very sensitive for detection and localization of intracranial calcifications [11]. The burden of intracranial calcifications was visually graded by an experienced neuroradiologist (ML) from 0 (no burden) to 1 (light burden), 2 (moderate burden) and ultimately 3 (high burden) according to a clinical reading combining the quantity, the size, the
intensity and the confluence of calcifications across the brain, without knowledge of any clinical information including participants' age, gender, prior imaging findings or anticoagulants used.
The following locations were distinguished: carotid siphons (i.e., intracranial internal carotids), internal carotids in their horizontal intra-petrous segment, intracranial fourth segment of the vertebral arteries, basilar artery, choroid plexus, pallidum (i.e., internal parts of lentiform nucleus), falx cerebri, calcifications in the immediate vicinity of veins or venous plexus, and others (i.e., rare or unusual locations of intracranial calcification). The sum of all site-specific calcification burdens was calculated to approximate a global burden of intracranial calcifications.
2.4 Covariables
Age, gender, frontal assessment battery (FAB) score, hypertension, dyslipidemia, carotid artery stenosis, kidney failure, and indications for anticoagulation were used as potential confounders in our analysis. The FAB score was used to assess the performance of the executive functions (total score range: 0-18, best), with good to excellent reliability and validity [12].
History of hypertension, dyslipidaemia and carotid artery stenosis was sought from the family physician correspondence and the patient's file, and by questioning the patient or relatives. The indication for anticoagulation (i.e., atrial fibrillation, venous thromboembolism or mechanical valve) was also sought by questioning the patients, the family physicians and the patients' files.
Finally, serum concentration of creatinine was determined using automated standard laboratory methods at the University Hospital of Angers, France. Estimated glomerular filtration rate (eGFR) was calculated using the Cockcroft-Gault formula ([(140 – age years) x weight kg / creatinine µmol/L] x1.04 for females, and x1.25 for males). Kidney failure was defined as eGFR ≤ 60 mL/min.
2.5 Statistical analysis
Firstly, the participants’ characteristics were summarized using medians [interquartile range, IQR] or frequencies and percentages, as appropriate. Univariate comparisons between 19 cases using VKA and 19 controls using DOA were performed using the Chi-square test Fisher exact test or the Mann-Whitney U test, as appropriate. Secondly, multiple linear regression
studied potential confounders. Finally, a Pearson correlation matrix was used to determine which site-specific burdens of intracranial calcifications were specifically linked to the use of VKA in the studied sample. P-values less than 0.05 were considered significant. All statistics were performed using SPSS (version 19.0; SPSS, Inc., Chicago, IL).
2.6 Ethics
The study was conducted in accordance with the ethical standards set forth in the Helsinki Declaration (1983). Ethics approval was obtained from the Ethics Board of the University Hospital of Angers, France (2017). Informed consent was obtained at enrolment according to protocols approved by the local institutional review board.
3. RESULTS
Nineteen cases using VKA (median age [IQR], 84 years [7]; 10 females; median all-site calcification burden, 10 [7]) and 19 controls using DOA (84 years [7]; 10 females; median all- site calcification burden, 8 [2]) were recruited. The vast majority (94.7%) received anticoagulation due to a history of atrial fibrillation, with no difference between cases using VKA and matched controls using DOA. Univariate comparisons between cases and controls showed no differences in the calcification burden across all studied locations, except in the falx cerebri (median, 2 [1] among VKA users versus 1 [2] among DOA users, P=0.025) (Table 1).
Table 2 shows multiple linear regressions between the regular use of anticoagulant and the global burden of intracranial calcifications. Using VKA was associated with a greater burden (fully adjusted β=1.56, P=0.049) compared to DOA used as a reference in the model (β=1). The advance in age was also associated with a greater burden of intracranial calcifications.
Table 3 reports the correlations between the use of VKA and the burden of intracranial calcifications by site. Using VKA correlated positively with the burden of falcian calcifications (r=0.41 with P=0.011). Figure 1 shows CT scan transverse image from one representative participant using VKA, with calcifications in the frontal part of the falx cerebri marked by arrows.
No correlation was found with the other locations (Table 3).
4. DISCUSSION
The main finding of this case-control study is that, irrespective of all measured potential confounders, the regular use of VKA was associated with a greater burden of intracranial calcifications compared to the use of DOA, specifically in the falx cerebri. In contrast, no correlations were found with the other locations. These findings may provide insight into the pathophysiology of neurocognitive disorders met among older adults using VKA.
Several lines of epidemiological evidence argue for an involvement of VKA in brain health.
Some morphological changes of the brain are notably reported under VKA in prior literature. For instance, it is long known that newborns exposed in utero to warfarin or other coumarin derivatives exhibit abnormalities of the central nervous system [13]. Also in older adults, smaller whole-brain volume has been reported among those taking VKA regulary compared to those taking no anticoagulant [7]. Specifically, the exposure to VKA correlated in another study with focal atrophies within the frontal lobes [8]. All these previous studies have yet addressed the brain changes only in terms of cerebral atrophy. Thus, the present study provides additional and novel evidence by exploring for the first time to our knowledge the possibility that the use of VKA may increase the risk of intracranial calcifications, with potential adverse consequences on neurocognition. Interestingly, the location of the calcifications found mainly in the frontal part of the falx cerebri is consistent with previous psychometric findings since the frontal-subcortical circuits, which support the executive functions, are nearby and could thus be altered by the mass effect of calcifications. Of note, our results are also consistent with previous studies reporting greater risks of vascular and extra-vascular calcifications among people with chronic vitamin K deficiency [9]. For instance, patients with chronic kidney disease suffer from extensive vascular calcifications resulting in excessive mortality [14]. The use of VKA has been associated with an increase in systemic calcification, including in the coronary and peripheral vasculature [9]. In one study, the Agatston score of coronary calcifications correlated positively with the duration of exposure to VKA [15]. In another study, the group treated with warfarin developed calcified vessels on mammograms at a rate 50% greater than age and diabetes status-matched controls [16]. For patients who were treated for more than 5 years with warfarin, the prevalence of vascular calcification increased to nearly 75% [16]. Finally, treatment with warfarin has also
been linked to calcification in the tracheobronchial tree among patients lacking other traditional risk factors for calcification [17], stressing that both vascular and extra-vascular calcifications may occur in patients under VKA.
The mechanisms linking VKAs to calcification has been the matter of extensive research over the past decade. The main explanation relies on the matrix gamma-carboxyglutamate Gla protein (MGP), a highly insoluble protein synthesized by vascular smooth muscle cells, which prevents calcification at the cellular level [18]. To become active, MGP undergoes a post- translational modification, i.e. carboxylation reaction, which requires vitamin K as a cofactor.
Thus, in the setting of vitamin K deficiency, MGP cannot be converted to its active form [9]. As an illustration, homozygous MGP-deficient mice exhibited widespread calcification of the carotid arteries, aorta, celiac axis, renal arteries, and iliac arteries [19]. Similarly, rats treated with warfarin at high doses for long periods of time developed calcifications in multiple tissues [20].
Also, in otherwise healthy humans, poor vitamin K status as measured by MGP assays was linked to higher rates of vascular calcification [21]. In contrast, Schurgers et al. administered vitamin K in a rat model that prevented and even reversed vascular calcification [22]. Taken together, these studies suggest that chronic vitamin K deficiency due to VKA fails to activate MGP and may lead to systemic calcifications, including in the brain with plausible subsequent neurocognitive risk.
The strengths of the present study include i) the originality of the research question on drugs widely used in clinical routine, ii) the detailed description of the participants’ characteristics allowing the use of multiple regression models to measure adjusted associations, and iii) the standardized collection of data from a single research center. Regardless, a number of limitations also existed. First, the observational case-control design of our study is less robust than a prospective longitudinal cohort study and prevents any causal inference because temporality cannot be demonstrated. Secondly, the limited size of the studied sample may have exposed to lack of statistical power with the risk of missing significant differences. Moreover participants were recruited from one single geriatric ward, which potentially limits generalization of our results to other settings, and it is also possible that the relatively poor state of health may have
although we were able to control for important characteristics that could modify the associations, residual potential confounders might still be present such as the serum phylloquinone concentration, the history of international normalized ratio (INR) or the use of drugs that interfere with calcifications. Despite these limitations, we were able to report among older adults an increased burden of intracranial calcifications under VKA. Further prospective observational cohorts and randomized clinical trials, preferentially on a variety of adult populations, are needed to clarify whether those using VKA are more likely to experience intracranial calcifications than those using DOA, and whether the regular use of DOAs could limit the onset of calcifications and prevent the neurocognitive disorders met under VKAs.
REFERENCES
[1] J. Ansell, J. Hirsh, E. Hylek, A. Jacobson, M. Crowther, G. Palareti G, American College of Chest Physicians: Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 8th Edition, Chest.
133 (2008) 160S-198S.
[2] C. Annweiler, G. Ferland, P. Barberger-Gateau, A. Brangier, Y. Rolland, O. Beauchet, Vitamin K antagonists and cognitive impairment: Results from a cross-sectional pilot study among geriatric patients, J. Gerontol. A. Biol. Sci. Med. Sci. 70 (2015) 97-101.
[3] G. Ferland, C. Feart, N. Presse, S. Lorrain, F. Bazin, C. Helmer, C. Berr, C. Annweiler, O.
Rouaud, J.F. Dartigues, A. Fourrier-Reglat, P. Barberger-Gateau, Vitamin K antagonists and cognitive function in older adults: The Three-City cohort study, J. Gerontol. A. Biol. Sci. Med.
Sci. 71 (2016) 1356-1362.
[4] A. Brangier, G. Ferland, Y. Rolland, J. Gautier, C. Féart, C. Annweiler, Vitamin K Antagonists and Cognitive Decline in Older Adults: A 24-Month Follow-Up, Nutrients. 10 (2018) 6.
[5] G. Ferland, Vitamin K and the nervous system: an overview of its actions, Adv. Nutr. 3 (2012) 204-212.
[6] S. Tamadon-Nejad, B. Ouliass, G. Ferland. Vitamin K deficiency induced by warfarin is associated with cognitive and behavioral perturbations, and alterations in brain sphingolipids in rats, Front. Aging. Neurosci. 10 (2018) 213.
[7] C. Annweiler, S. Denis, G. Duval, G. Ferland, R. Bartha, O. Beauchet, Use of vitamin K antagonists and brain volumetry in older adults: preliminary results from the gait study, J.
Am. Geriatr. Soc. 63 (2015) 2199-2202.
[8] A. Brangier, S. Celle, F. Roche, O. Beauchet, G. Ferland, C. Annweiler, Use of Vitamin K Antagonists and Brain Morphological Changes in Older Adults: An Exposed/Unexposed Voxel- Based Morphometric Study, Dement. Geriatr. Cogn. Disord. 45 (2018) 18-26.
[9] T.J. Poterucha, S.Z. Goldhaber, Warfarin and Vascular Calcification, Am. J. Med. 129 (2016)
[10] J.L. Cummings, L.F. Gosenfeld, J.P. Houlihan, T. McCaffrey, Neuropsychiatric disturbances associated with idiopathic calcification of the basal ganglia, Biol. Psychiatry. 18 (1983) 591- 601.
[11] Y. Kıroğlu, C. Callı, N. Karabulut, C. Oncel C, Intracranial calcifications on CT, Diagn.
Interv. Radiol. 16 (2010) 263-269.
[12] B. Dubois, A. Slachevsky, I. Litvan, B. Pillon, The FAB: A frontal assessment battery at bedside, Neurology. 55 (2000) 1621-1626.
[13] J.G. Hall, R.M. Pauli, K.M. Wilson, Maternal and fetal sequelae of anticoagulation during pregnancy, Am. J. Med. 68 (1980) 122-140.
[14] L.J. Schurgers, D.V. Barreto, F.C. Barreto, S. Liabeuf, C. Renard, E.J. Magdeleyns, C.
Vermeer, G. Choukroun, Z.A. Massy, The circulating inactive form of matrix gla protein is a surrogate marker for vascular calcification in chronic kidney disease: a preliminary report, Clin. J. Am. Soc. Nephrol. 5 (2010) 568-575.
[15] B. Weijs, Y. Blaauw, R.J. Rennenberg, L.J. Schurgers, C.C. Timmermans, L. Pison, R.
Nieuwlaat, L. Hofstra, A.A. Kroon, J. Wildberger, H.J. Crijns, Patients using vitamin K antagonists show increased levels of coronary calcification: an observational study in low- risk atrial fibrillation patients, Eur. Heart. J. 32 (2011) 2555-2562.
[16] E. Tantisattamo, K.H. Han, W.C. O’Neill, Increased vascular calcification in patients receiving warfarin, Arterioscler. Thromb. Vasc. Biol. 35 (2015) 237-242.
[17] L. Eckersley, J. Stirling, C. Occleshaw, N. Wilson N, Two cases of warfarin-induced tracheobronchial calcification after Fontan surgery, Pediatr. Cardiol. 35 (2014) 954-958.
[18] R.C. Johnson, J.A. Leopold, J. Loscalzo, Vascular calcification: pathobiological mechanisms and clinical implications, Circ. Res. 99 (2006) 1044-1059.
[19] G. Luo, P. Ducy, M.D. McKee, G.J. Pinero, E. Loyer, R.R. Behringer, G. Karsenty, Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein, Nature, 386 (1997) 78-81.
[20] T. Kruger, S. Oelenberg, N. Kaesler, L.J. Schurgers, A.M. van de Sandt, P. Boor, G.
Schlieper, V.M. Brandenburg, B.C. Fekete, V. Veulemans, M. Ketteler, C. Vermeer, W.
Jahnen-Dechent, J. Floege, R. Westenfeld, Warfarin induces cardiovascular damage in mice, Arterioscler. Thromb. Vasc. Biol. 33 (2013) 2618-2624.
[21] G.W. Dalmeijer, Y.T. van der Schouw, E.J. Magdeleyns, C. Vermeer, S.G. Elias, B.K.
Velthuis, P.A. de Jong, J.W. Beulens, Circulating species of matrix gla protein and the risk of vascular calcification in healthy women, Int. J. Cardiol. 168 (2013) e168-e170.
[22] L.J. Schurgers, H.M. Spronk, B.A. Soute, P.M. Schiffers, J.G. DeMey, C. Vermeer, Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats, Blood. 109 (2007) 2823-2831.
Table 1. Summary of the participants' characteristics (n=38)
Total cohort (n=38)
Participants using
P-Value*
VKA (n=19)
DOA (n=19) Demographical measures
Age, years 84 [7] (73-91) 84 [7] (73-91) 84 [7] (73-89) 0.795
Female gender, n (%) 20 (52.6) 10 (52.6) 10 (52.6) 1.000
Clinical measures
FAB score, /18 12 [4] (6-18) 12 [5] (6-18) 12 [4] (6-18) 0.773
Hypertension, n (%) 31 (81.6) 14 (73.7) 17 (89.5) 0.405
Dyslipidaemia, n (%) 19 (50.0) 9 (47.4) 10 (52.6) 0.746
Carotid artery stenosis, n (%) 1 (2.6) 1 (5.3) 0 (0) 1.000
Kidney failure, n (%) 11 (28.9) 5 (26.3) 6 (31.6) 0.721
Anticoagulation
Indication for anticoagulation, n (%)
Atrial fibrillation 36 (94.7) 18 (94.7) 18 (94.7) 1.000
Venous thromboembolism or mechanical valve 2 (5.3) 1 (5.3) 1 (5.3) 1.000
Anticoagulation > 3 months, n (%) 38 (100.0) 19 (100.0) 19 (100.0) 1.000 Burden of intracranial calcifications
Carotid siphons† 3 [1] (1-3) 3 [1] (1-3) 2 [1] (1-3) 0.191
Internal carotids in their horizontal intra-petrous segment 0 [0] (0-1) 0 [1] (0-1) 0 [0] (0-1) 0.418
Intracranial V4 segment of the vertebral arteries 1 [2] (0-3) 1 [2] (0-3) 1 [2] (0-3) 0.977
Basilar artery 0 [0] (0-1) 0 [0] (0-1) 0 [0] (0-1) 1.000
Choroid plexus 1 [0] (1-2) 1 [0] (1-2) 1 [0] (1-2) 0.795
Pallidum 0 [1] (0-1) 0 [0] (0-1) 0 [1] (0-1) 0.418
Falx cerebri 1.5 [1] (0-3) 2 [1] (0-3) 1 [2] (0-2) 0.025
Calcifications in the immediate vicinity of veins or venous plexus 1 [1] (0-3) 1 [1] (0-3) 1 [1] (0-2) 0.563
Others‡ 0 [0] (0-1) 0 [0] (0-1) 0 [0] (0-1) 0.795
Data presented as median [interquartile range] (range) where applicable; CI: confidence interval; DOA: direct oral anticoagulant; FAB: frontal assessment battery;
V4: fourth ventricle; VKA: vitamin K antagonist; *: Comparisons of participants using VKA with those using DOA based on the Chi-square test or Fisher exact test or Mann-Whitney U test, as appropriate; †: intracranial internal carotids; ‡: rare or unusual locations of intracranial calcification. P-values significant (i.e. < 0.05) indicated in bold.
Table 2. Multiple logistic regressions examining the cross-sectional association between the use of vitamin K antagonists (VKA, independent variable) and the global burden of intracranial calcifications (dependent variable), adjusted for potential confounders
b: coefficient of regression corresponding to a change in the global burden of intracranial calcifications; CI: confidence interval; DOA: direct oral anticoagulant; FAB:
frontal assessment battery; b significant (i.e., P-value<0.05) indicated in bold.
Global burden of intracranial calcifications
b [95%CI] P-Value
Use VKA (versus DOA) 1.56 [0.01;3.11] 0.049
Age 0.25 [0.05;0.46] 0.017
Female gender 0.54 [-1.22;2.29] 0.536
FAB score -0.14 [-0.41;0.13] 0.287
Hypertension 1.02 [-1.13;3.17] 0.340
Dyslipidaemia 1.62 [-0.05;3.29] 0.057
Carotid artery stenosis -1.03 [-6.24;4.18] 0.689
Kidney failure -1.55 [-3.59;0.49] 0.130
Indication, atrial fibrillation -1.09 [-4.76;2.59] 0.550
Table 3. Correlation matrix of the use of vitamin K antagonist with the burden of intracranial calcifications by location (n=38)
Characteristic 1. 2. 3. 4. 5. 6. 7. 8. 9.
1. Use of vitamin K antagonist − 0.19 0.20 0.00 0.00 0.08 -0.17 0.41* 0.16
2. Calcification burden in carotid siphons* − 0.21 0.45** 0.05 0.22 -0.19 0.18 0.27 3. Calcification burden in internal carotids in
their horizontal intra-petrous segment
− 0.14 0.28 0.02 0.15 0.03 -0.12
4. Calcification burden in intracranial V4 segment of the vertebral arteries
− 0.32 -0.02 -0.10 -0.10 0.20
5. Calcification burden in basilar artery − -0.13 -0.03 -0.14 -0.27
6. Calcification burden in choroid plexus − -0.08 0.01 0.13
7. Calcification burden in pallidum − 0.06 -0.22
8. Calcification burden in falx cerebri − 0.49**
9. Calcification burden in the immediate vicinity of veins or venous plexus
−
*: P<0.05 (2-tailed); **: P<0.01 (2-tailed)
Figure 1. Representative example of a transverse CT-scan image from one participant using vitamin K antagonist, with the falcian calcifications marked by arrows.
Annexe. Article publié
Contents lists available atScienceDirect
Maturitas
journal homepage:www.elsevier.com/locate/maturitas
Intracranial calci fi cations under vitamin K antagonists or direct oral anticoagulants: Results from the French VIKING study in older adults
Gaëlle Annweilera,b,c, Mathieu Labriffee, Pierre Ménagera,b,c,f, Guylaine Ferlandg, Antoine Brangiera,b,c, Cédric Annweilera,b,c,d,h,*, On behalf of the SAM group
aDepartment of Geriatric Medicine, Angers University Hospital, Angers, France
bAngers University Memory Clinic, Angers, France
cResearch Center on Autonomy and Longevity, Angers, France
dUPRES EA 4638, University of Angers, Angers, France
eDepartment of Radiology, Angers University Hospital, Angers, France
fDepartment of Geriatrics, Le Mans Hospital, Le Mans, France
gMontreal Heart Institute Research Centre & Department of Nutrition, Université de Montréal, Montréal, Quebec, Canada
hRobarts Research Institute, Department of Medical Biophysics, Schulich School of Medicine and Dentistry, the University of Western Ontario, London, ON, Canada
A R T I C L E I N F O Keywords:
Anticoagulation Direct oral anticoagulant Brain
Calcifications Older adults Vitamin K antagonist
A B S T R A C T
Objectives:The use of vitamin K antagonists (VKA) is associated with the onset of vascular and soft-tissue cal- cifications. Whether there are more intracranial calcifications under VKA remains unclear. The objective of this study was to determine whether the regular use of VKA in older adults was associated with an increased burden of intracranial calcifications compared with the use of direct oral anticoagulant (DOA).
Study design:Nineteen patients aged 70 years or more using VKA for more than 3 months and 19 controls (matched for age, gender and indication for anticoagulation) using DOA for more than 3 months were con- secutively included in this study.
Main outcomes measures:The burden of intracranial calcifications was graded by an experienced neuroradiol- ogist from 0 (no burden) to 3 (high burden) according to the quantity, size, intensity and confluence of calci- fications on computed tomography scan of the brain. Age, gender, frontal assessment battery (FAB) score, hy- pertension, dyslipidaemia, carotid artery stenosis, kidney failure and indication for anticoagulation were investigated as potential confounders.
Results: The 19 patients using VKA (median[IQR], 84years[7]; 10females) exhibited a greater burden of falcian calcifications than the 19 controls using DOA (respectively, 2[1] versus 1[2], P = 0.025). Overall, we found that using VKA was directly associated with the global burden of intracranial calcifications (β= 1.54, P = 0.049).
No correlation was found with calcifications in sites other than the falx cerebri.
Conclusions: The use of VKA was associated with a greater burden of intracranial calcifications compared with the use of DOA, specifically in the falx cerebri. Thisfinding may explain part of the neurocognitive morbidity met with VKA.
1. Introduction
Vitamin K antagonists (VKAs) are commonly used for the prophy- laxis and treatment of thromboembolic events, especially in older adults [1]. Unlike direct oral anticoagulants (DOAs), which mechan- isms do not interfere with the cycle of vitamin K, VKAs are inhibitors of the enzymatic conversion of inactive vitamin K epoxide to its reduced active form, thus resulting in a relative state of vitamin K deficiency [1].
Importantly, neurocognitive disorders have been reported among VKA
users compared to those using no blood-thinning drugs [2–4]. The use of VKA was associated with impaired cognitive performance as a whole in previous studies [2,3], specifically with a decline of executive functions in longitudinal studies [4]. These associations were in- dependent of the condition warranting the use of anticoagulation, no- tably the history of atrialfibrillation [2–4]. Thus the most likely ex- planation was based on the decreased bioavailability of the active form of vitamin K under VKA [5,6]. In fact, the use of VKA in animals has been associated with cognitive impairment and a dysregulation of the
https://doi.org/10.1016/j.maturitas.2019.12.003
Received 12 October 2019; Received in revised form 1 November 2019; Accepted 2 December 2019
⁎Corresponding author at: Department of Geriatric Medicine, Angers University Hospital, 49933 Angers cedex 9, France.
E-mail address:Cedric.Annweiler@chu-angers.fr(C. Annweiler).
synthesis of sphingolipids, a constituent of the myelin sheath and neuronal membrane [6], and a reduction of the biological activation of the vitamin K-dependent proteins involved in neuronal physiology and survival [5]. Such changes may account for the onset of pathological morphological brain changes in VKA users [7,8].
Of note, the regular use of VKA has also been associated with the onset of vascular and extra-vascular calcifications, including in the coronary arteries or the tracheobronchial tree [9]. As intracranial cal- cifications could in turn lead to neurocognitive disorders [10], we hy- pothesized that the subcortical executive dysfunction that was observed in older VKA users may have resulted at least in part from a greater burden of intracranial calcifications depending on their quantity, size, confluence and location. The objective of this case-control study was to determine whether the regular use of VKA in older adults was asso- ciated with an increased burden of intracranial calcifications compared to the use of direct oral anticoagulant (DOA), as a comparator not in- terfering with the vitamin K cycle.
2. Methods 2.1. Participants
We conducted the ‘VItamin K Inhibition and NeurocoGnition’
(VIKING) study, a case-control study with a 1:1 ratio (ClinicalTrials.gov ID: NCT03276377). Cases were 19 consecutive patients aged 70 years and older using VKA in the Department of Geriatric Medicine of the University Hospital of Angers, France. Nineteen controls using a DOA matched on age ( ± 5 years), gender and indication for anticoagulation (i.e., atrialfibrillation versus venous thromboembolism or mechanical valve) were selected from other patients in the same Department be- tween 1 January 2015 and 1 June 2017. Diads were screened using the computerized registry of Angers University Hospital, andfinally in- cluded in the analysis after manual review of medical records by one author (PM). Diads were included in the analysis if i) both cases and controls used the anticoagulant for more than 3 months at the time of the inclusion, and ii) both cases and controls underwent a computed tomography of the brain at the time of the inclusion. Main exclusion criteria were severe kidney failure defined as creatinine clearance < 30 mL/min according to Cockcroft-Gault formula, history of any acute medical illness in the preceding 3 months, poor vision, inability to understand or answer the study questionnaires, and refusal to partici- pate in research.
2.2. Anticoagulants
The regular use of VKA (i.e., warfarin, acenocoumarol orfluindione) and DOA (i.e., apixaban, dabigatran, rivaroxaban) was noted from fa- mily physician prescriptions and sought by questioning the patients and relatives. The length of use above 3 months and the reason for treat- ment were checked and collected in a standardized manner from the family physician interview.
2.3. CT scan procedure
Images were acquired on CT scanner at the University Hospital of Angers, France, using a standardized CT protocol. CT is very sensitive for detection and localization of intracranial calcifications [11]. The burden of intracranial calcifications was visually graded by an experi- enced neuroradiologist (ML) from 0 (no burden) to 1 (light burden), 2 (moderate burden) and ultimately 3 (high burden) according to a clinical reading combining the quantity, the size, the intensity and the confluence of calcifications across the brain, without knowledge of any clinical information including participants' age, gender, prior imaging findings or anticoagulants used. The following locations were dis- tinguished: carotid siphons (i.e., intracranial internal carotids), internal carotids in their horizontal intra-petrous segment, intracranial fourth
segment of the vertebral arteries, basilar artery, choroid plexus, pal- lidum (i.e., internal parts of lentiform nucleus), falx cerebri, calcifica- tions in the immediate vicinity of veins or venous plexus, and others (i.e., rare or unusual locations of intracranial calcification). The sum of all site-specific calcification burdens was also calculated to approximate a global burden of intracranial calcifications.
2.4. Covariables
Age, gender, frontal assessment battery (FAB) score, hypertension, dyslipidemia, carotid artery stenosis, kidney failure, and indications for anticoagulation were used as potential confounders in our analysis. The FAB score was used to assess the performance of the executive functions (total score range: 0–18, best), with good to excellent reliability and validity [12]. History of hypertension, dyslipidaemia and carotid artery stenosis was sought from the family physicians correspondence and the patients' files, and by questioning the patients or relatives. The in- dication for anticoagulation (i.e., atrial fibrillation, venous throm- boembolism or mechanical valve) was also sought by questioning the patients, the family physicians and the patients' files. Finally, serum concentration of creatinine was determined using automated standard laboratory methods at the University Hospital of Angers, France. Esti- mated glomerular filtration rate (eGFR) was calculated using the Cockcroft-Gault formula ([(140–ageyears) x weightkg/ creatinineμmol/
L] x1.04 for females, and x1.25 for males). Kidney failure was defined as eGFR≤60 mL/min.
2.5. Statistical analysis
Firstly, the participants’ characteristics were summarized using medians [interquartile range, IQR] or frequencies and percentages, as appropriate. Univariate comparisons between 19 cases using VKA and 19 controls using DOA were performed using the Chi-square test, the Fisher exact test or the Mann-Whitney U test, as appropriate. Secondly, multiple linear regression models were used to examine the association between the use of VKA (independent variable) and the global burden of intracranial calcifications (dependent variable), while adjusting for studied potential confounders. Finally, a Pearson correlation matrix was used to determine which site-specific burdens of intracranial calcifica- tions were specifically linked to the use of VKA in the studied sample. P- values less than 0.05 were considered significant. All statistics were performed using SPSS (version 19.0; SPSS, Inc., Chicago, IL).
2.6. Ethics
The study was conducted in accordance with the ethical standards set forth in the Helsinki Declaration (1983). Ethics approval was ob- tained from the Ethics Board of the University Hospital of Angers, France (2017-19). Informed consent was obtained at enrolment ac- cording to protocols approved by the local institutional review board.
3. Results
Nineteen cases using VKA (median age [IQR], 84 years [7]; 10 fe- males; median all-site calcification burden, 10 [7]) and 19 controls using DOA (84 years [7]; 10 females; median all-site calcification burden, 8 [2]) were recruited. The vast majority (94.7 %) received anticoagulation due to a history of atrialfibrillation, with no difference between cases using VKA and matched controls using DOA. Univariate comparisons between cases and controls showed no differences in the calcification burden across all studied locations, except in the falx cerebri (median, 2 [1] among VKA users versus 1 [2] among DOA users, P = 0.025) (Table 1).
Table 2shows multiple linear regressions between the regular use of anticoagulant and the global burden of intracranial calcifications. Using VKA was associated with a greater burden (fully adjustedβ= 1.56, P G. Annweiler, et al.
= 0.049) compared to DOA used as a reference in the model (β= 0).
The advance in age was also associated with a greater burden of in- tracranial calcifications.
Table 3reports the correlations between the use of VKA and the burden of intracranial calcifications by site. Using VKA correlated po- sitively with the burden of falcian calcifications (r = 0.41 with P = 0.011).Fig. 1shows CT scan transverse image from one representative participant using VKA, with calcifications in the frontal part of the falx cerebri marked by arrows. No correlation was found with the other
locations (Table 3).
4. Discussion
The mainfinding of this case-control study is that, irrespective of all measured potential confounders, the regular use of VKA was associated with a greater burden of intracranial calcifications compared to the use of DOA, specifically in the falx cerebri. In contrast, no correlations were found with the other locations. Thesefindings may provide insight into Table 1
Summary of the participants' characteristics (n = 38).
Total cohort (n = 38) Participants using P-Value*
VKA (n = 19) DOA (n = 19)
Demographical measures
Age, years 84 [7] (73–91) 84 [7] (73–91) 84 [7] (73–89) 0.795
Female gender, n (%) 20 (52.6) 10 (52.6) 10 (52.6) 1.000
Clinical measures
FAB score, /18 12 [4] (6–18) 12 [5] (6–18) 12 [4] (6–18) 0.773
Hypertension, n (%) 31 (81.6) 14 (73.7) 17 (89.5) 0.405
Dyslipidaemia, n (%) 19 (50.0) 9 (47.4) 10 (52.6) 0.746
Carotid artery stenosis, n (%) 1 (2.6) 1 (5.3) 0 (0) 1.000
Kidney failure, n (%) 11 (28.9) 5 (26.3) 6 (31.6) 0.721
Anticoagulation
Indication for anticoagulation, n (%)
Atrialfibrillation 36 (94.7) 18 (94.7) 18 (94.7) 1.000
Venous thromboembolism or mechanical valve 2 (5.3) 1 (5.3) 1 (5.3) 1.000
Anticoagulation > 3 months, n (%) 38 (100.0) 19 (100.0) 19 (100.0) 1.000
Burden of intracranial calcifications
Carotid siphons† 3 [1] (1–3) 3 [1] (1–3) 2 [1] (1–3) 0.191
Internal carotids in their horizontal intra-petrous segment 0 [0] (0–1) 0 [1] (0–1) 0 [0] (0–1) 0.418
Intracranial V4 segment of the vertebral arteries 1 [2] (0–3) 1 [2] (0–3) 1 [2] (0–3) 0.977
Basilar artery 0 [0] (0–1) 0 [0] (0–1) 0 [0] (0–1) 1.000
Choroid plexus 1 [0] (1–2) 1 [0] (1–2) 1 [0] (1–2) 0.795
Pallidum 0 [1] (0–1) 0 [0] (0–1) 0 [1] (0–1) 0.418
Falx cerebri 1.5 [1] (0–3) 2 [1] (0–3) 1 [2] (0–2) 0.025
Calcifications in the immediate vicinity of veins or venous plexus 1 [1] (0–3) 1 [1] (0–3) 1 [1] (0–2) 0.563
Others‡ 0 [0] (0–1) 0 [0] (0–1) 0 [0] (0–1) 0.795
Data presented as median [interquartile range] (range) where applicable; CI: confidence interval; DOA: direct oral anticoagulant; FAB: frontal assessment battery; V4:
fourth ventricle; VKA: vitamin K antagonist; *: Comparisons of participants using VKA with those using DOA based on the Chi-square test or Fisher exact test or Mann- Whitney U test, as appropriate;†: intracranial internal carotids;‡: rare or unusual locations of intracranial calcification. P-values significant (i.e. < 0.05) indicated in bold.
Table 2
Multiple logistic regressions examining the cross-sectional association between the use of vitamin K antagonists (VKA, independent variable) and the global burden of intracranial calcifications (dependent variable), adjusted for potential confounders.
β: coefficient of regression corresponding to a change in the global burden of intracranial calcifications; CI: confidence interval; DOA: direct oral anticoagulant; FAB:
frontal assessment battery;βsignificant (i.e., P-value < 0.05) indicated in bold.
G. Annweiler, et al.
