Introduction. - As an anti-aggregant that has demonstrated its superiority in the management of acute coronary syndrome, Ticagrelor is an inhibitor of adenosine recapture by red blood cells. Regadenoson, an adenosine agonist, is a preferred cardiac pharmacological stress in patients with a history of spastic bronchopathy. A synergistic effect of both drugs is therefore theoretically expected if they are combined during myocardial scintigraphy. In 2015, European Association of Nuclear Medicine did not rule on the use of Regadenoson in patients previously treated with Ticagrelor. The objective of this work is to study the frequency of adverse events in these patients during Regadenoson stress. Materials and methods. - We retrospectively included patients who underwent a myocardial scintigraphy with pharmacological stress by Regadenoson between February 2016 and February 2019. We compared the frequency of expected side effects of Regadenoson in patients treated with Ticagrelor and not treated with Ticagrelor. The data were analysed using a logistic regression model including patient characteristics and side effects. Results. - Seventeen treated patients were included for 49 untreated patients. There was no significant difference in the frequency of each adverse event between treated and untreated patients. However, a higher number of side effects have been reported in treated patients than in untreated patients. No major adverse event was reported. Conclusion. - In order to rule about the use of Regadenoson in patients treated with Ticagrelor, a larger study is needed to support the hypothesis of more noted minor side effects and which of them should be more encountered. (C) 2019 Elsevier Masson SAS. All rights reserved.

Le ticagrélor (Brilique®) est un anti-agrégant plaquettaire de la classe des CPTP (cyclo-pentyl-triazolo-pyrimidines). Fréquemment associé à l’aspirine, cet antagoniste des récepteurs P2Y12, dont le ligand habituel est l’ADP, augmente la concentration plasmatique en adénosine. Dès lors, chez les patients explorés par scintigraphie myocardique de perfusion après un stress pharmacologique par dipyridamole ou directement par adénosine, une plus grande sévérité des effets secondaires du stress serait légitimement observable. Le régadénoson (Rapiscan®), agoniste sélectif des récepteurs A2A de l’adénosine, constitue un stress pharmacologique réalisable notamment chez les patients modérément asthmatiques. Nous proposons une étude prospective préliminaire afin d’étudier la fréquence et la gravité des effets indésirables chez les patients traités par ticagrélor lors d’un stress pharmacologique par régadénoson. Sept patients coronaropathes traités par ticagrélor ont été inclus entre février et juillet 2016. Pour chacun de ces patients, le patient suivant exploré par régadénoson et non traité par ticagrélor a nourri un groupe témoin ; 5 patients témoins sur 7 présentent ainsi une coronaropathie documentée. Pour les 14 patients, les constantes (Tension Artérielle, Fréquence Cardiaque, Fréquence Respiratoire, saturation capillaire en O2) ont été mesurées avant et après l’administration du régadénoson. La surveillance clinique et électrique a été consignée. Aucune différence statistiquement significative n’a été décelée entre les deux groupes concernant les paramètres cliniques (variation de la TA systolique, augmentation de la FC, variation de la FR et augmentation de la saturation en O2), l’apparition d’effets secondaires habituels (vertiges, céphalées, nausées, vomissements, angor, palpitations, dyspnée, flush), et l’électrocardiogramme. Aucun évènement indésirable grave n’a été déploré. À propos d’un effectif réduit de patients traités par ticagrélor et stressés par régadénoson lors d’une scintigraphie myocardique de perfusion, on ne montre pas de modification du profil d’effets secondaires observé. Un effectif de patients plus important est nécessaire pour étayer ces conclusions, dans la mesure où une potentialisation pharmacologique du régadénoson par le ticagrélor est envisageable au plan théorique.

Le syndrome de Takotsubo se caractérise habituellement par une présentation mimant cliniquement et électriquement un syndrome coronaire aigu, avec ballonisation de l’apex du ventricule gauche à l’échocardiographie ; la coronarographie exclut alors une coronaropathie sténosante significative. Nous rapportons le cas d’un diagnostic atypique puisque fortuit. Une patiente de 60 ans se présente en consultation cardiologique dans le cadre du suivi d’une hypercholestérolémie sévère, sans autre facteur de risque cardiovasculaire organique. L’ECG montre une abrasion des ondes R en antérieur et des ondes T biphasiques en latéral. L’échocardiographie met en évidence une akinésie apicale isolée, avec conservation de la fraction d’éjection ventriculaire gauche (FEVG) globale. La scintigraphie myocardique de perfusion (99 mTc-tétrofosmine) n’allègue pas d’ischémie myocardique sous stress (effort sous maximal significatif et Dipyridamole à 0,70 mg/kg), huit jours après la consultation initiale, il existe toutefois une altération de l’épaississement en antéro-apical. La scintigraphie à la 123I-mIBG et la TEP/TDM au 18F-FDG sont typiques d’une cardiopathie adrénergique apicale en montrant, respectivement, un déficit adrénergique et une lacune métabolique glucosée. La coronarographie élimine une sténose coronaire significative et le recouvrement de la cinétique apicale ventriculaire gauche est constaté échographiquement lors de la consultation à trois mois. Le polymorphisme du syndrome de Takotsubo est connu (formes apicale, médio-ventriculaire, inversée, focale). Concernant le facteur déclenchant, l’hyperadrénergie semble le dénominateur commun de l’altération transitoire de la FEVG et, à ce titre, on retrouve souvent un stress émotionnel ou une circonstance organique (hémorragie sous arachnoïdienne, phéochromocytome) expliquant cette hyperadrénergie. Toutefois, pour cette patiente, c’est l’interrogatoire attentif qui a décelé un stress professionnel semblant à l’origine de ce Takotsubo cliniquement muet. La résolution du conflit professionnel a d’ailleurs coïncidé avec le recouvrement de la cinétique apicale ventriculaire gauche. Devant des troubles de la cinétique segmentaire ventriculaire gauche de découverte fortuite, après avoir éliminé une origine ischémique, il semble légitime d’évoquer une cause adrénergique. Dans ce cadre, la médecine nucléaire apporte une imagerie caractéristique, utile au diagnostic.

The new direct oral anticoagulants (DOA) such as dabigatran, rivaroxaban or apixaban are an evolution in the management of patients requiring curative anticoagulation. However, behind the simplicity of prescribing and monitoring, several questions remain about their daily use. The aim of this prospective study was to measure the feelings of general practitioners (GP), angiologists (AP) and cardiologists (CP), potential prescribers of this new anticoagulant family.Between December 2012 and May 2013, a questionnaire including five open questions and 11 questions using a positioning on an analogic visual scale (AVS 0 to 10) was subjected to GP, AP and CP in Alsace.Responses from 224 physicians (150 GP, 35 AP and 39 CP) were collected. Thus, 83% of GP, 83% of AP and 100% of CP were prescribers of DOA. However, among these prescribing doctors, the feeling was not the same and the trend of prescription was lower in GP (2.0 [1.1-3.2] AVS units) than in AP (3.1 [2.0-5.6]) and in CP (5.0 [1.2-8.7]) (P<0.0001 in multivariate analysis). The female doctors tended to prescribe DOA in younger patients than male doctors (respectively 66.1 [52.5-76.7] vs. 75.0 [65.7-81.0] years; P=0.004). The DOA were more considered as progress by AP and CP (respectively 7.8 [5.3-9.0] and 7.9 [7.0-8.7] AVSu) than by GP (6.1 [4.8-8.2] AVSu; P=0.02 in multivariate analysis). The answer about the eventual replacement of vitamin K antagonists by the DOA was very mixed whatever the practitioner group (5.1 [3.0-7.8] AVSu; P=0.139). The ease to use and the lack of biological monitoring were the main arguments leading to the prescription but the attitude of practitioners was very balanced by the lack of experience on the bleeding risk and the lack of available antidote.If the DOA are considered as an improvement for the physicians, the enthusiasm remains cautious whatever the type of practiced medicine. The results of clinical trials and the clinical experience should better appreciate the ongoing change in the field of anticoagulation.

BACKGROUND:The new direct oral anticoagulants (DOA) such as dabigatran, rivaroxaban or apixaban are an evolution in the management of patients requiring curative anticoagulation. However, behind the simplicity of prescribing and monitoring, several questions remain about their daily use. The aim of this prospective study was to measure the feelings of general practitioners (GP), angiologists (AP) and cardiologists (CP), potential prescribers of this new anticoagulant family.METHOD:Between December 2012 and May 2013, a questionnaire including five open questions and 11 questions using a positioning on an analogic visual scale (AVS 0 to 10) was subjected to GP, AP and CP in Alsace.RESULTS:Responses from 224 physicians (150 GP, 35 AP and 39 CP) were collected. Thus, 83% of GP, 83% of AP and 100% of CP were prescribers of DOA. However, among these prescribing doctors, the feeling was not the same and the trend of prescription was lower in GP (2.0 [1.1-3.2] AVS units) than in AP (3.1 [2.0-5.6]) and in CP (5.0 [1.2-8.7]) (P<0.0001 in multivariate analysis). The female doctors tended to prescribe DOA in younger patients than male doctors (respectively 66.1 [52.5-76.7] vs. 75.0 [65.7-81.0] years; P=0.004). The DOA were more considered as progress by AP and CP (respectively 7.8 [5.3-9.0] and 7.9 [7.0-8.7] AVSu) than by GP (6.1 [4.8-8.2] AVSu; P=0.02 in multivariate analysis). The answer about the eventual replacement of vitamin K antagonists by the DOA was very mixed whatever the practitioner group (5.1 [3.0-7.8] AVSu; P=0.139). The ease to use and the lack of biological monitoring were the main arguments leading to the prescription but the attitude of practitioners was very balanced by the lack of experience on the bleeding risk and the lack of available antidote.CONCLUSIONS:If the DOA are considered as an improvement for the physicians, the enthusiasm remains cautious whatever the type of practiced medicine. The results of clinical trials and the clinical experience should better appreciate the ongoing change in the field of anticoagulation.

Cancer patients are a high-risk population for venous thromboembolism (VTE); the natural history of gonadal vein thrombosis (GVT) occurring in cancer patients is not well described in the medical literature.Utilizing a software program the computerized tomographic scan reports of patients at a single cancer center from January 1, 2004 to June 30, 2011 were searched for the term GVT. Patients included in this analysis had a diagnosis of cancer, an isolated GVT (i.e. no evidence of thrombosis at another site), no symptoms referable to the GVT, and at least six months of follow-up information. All subsequent recurrent VTE events were confirmed by imaging studies.196 cancer patients with GVT were identified. The majority of patients in this analysis had metastatic disease (118, 61.2%) as well as active cancer (167, 85.2%). Twenty patients (10.8%) developed recurrent VTE (median follow-up 14.5 months); median time to recurrent VTEs was 5.5 months (range 0–19 months). When considering only patients with without a recent history of gynecologic surgery, VTE recurrence rates were 14.3%. Active cancer was the only risk factor significantly associated with recurrent VTE (P = 0.047).Based upon the patient’s risk factors for VTE, treatment of an incidentally detected GVT in cancer patients with anticoagulation, as per guidelines for other VTE sites, may be indicated in certain high risk subgroups, especially those patients with active cancer who have not had prior pelvic surgery.

The CYP2C19*2 genetic variant is known to contribute to low responsiveness to clopidogrel treatment, leading to a higher rate of cardiovascular events. Systematic identification of the 2C19*2 carriers to predict the individual patient's response to clopidogrel is a matter of debate. Data of the VASP-02 study comparing patients’ responsiveness to 75 and 150 mg/day maintenance dose of clopidogrel (Aleil et al., J Am Coll Cardiol Intv 2008) were reanalyzed by determining the 2C19*2 carrier status of the patients. Platelet reactivity index (PRI) was determined using the VASP method. A PRI>69% defines low responsiveness to clopidogrel. In the 37 non responder patients, 42.4% were 2C19*2 carriers versus 22.0% in the responder patients (p=0.022). After multivariate analysis, 2C19*2 polymorphism and high body weight were two independent predictors of high PRI (odds ratio [95% confidence interval] 3.39 [1.06-10.84] p=0.039 and 3.14 [1.19-8.30] p=0.021) respectively. Increasing the maintenance dose of clopidogrel from 75 to 150 mg/day in non responder patients resulted in a significant decrease of PRI from 76.4±4.6 to 62.8±10.4% (p<0.01) in 2C19*2 carriers and from 76.1±5.3 to 60.8±13.4% (p<0.01) in non carriers. The mean decrease of PRI after doubling the dose was not significantly different between carriers and non carriers of the genetic variant (−13.6±9.3 and −15.3±11.8% p=0.39, respectively). CYP2C19*2 is an important determinant of the responsiveness to clopidogrel while other independent factors such as body weight also are involved. Hyporesponsiveness in 2C19*2 carriers can be easily overcome by doubling the maintenance dose of clopidogrel. Thus, combined functional pharmacodynamic monitoring and genetic determination of CYP profile should help improve patient's responsiveness to clopidogrel.

Le syndrome d'apnée du sommeil (SAS) est un facteur de risque cardio vasculaire. Il est fréquemment associé au diabète de type 2. La glycoprotéine V soluble (GPVs), marqueur de thrombose libérée par les plaquettes en présence de thrombine, est augmentée chez le diabétique soulevant la question de l'implication du SAS dans l'activation plaquettaire. Le but de notre travail était d'étudier les taux plasmatiques de GPVs chez des patients obèses en fonction de la sévérité du SAS et de rechercher une association avec les paramètres respiratoires et lipidiques. Cette étude prospective concerne 32 patients obèses non diabétiques hospitalisés pour suspicion de SAS de mai 2005 à décembre 2007. Chaque patient bénéficiait d'un enregistrement polysomnographique nocturne avec dosage de GPVs (méthode ELISA) le lendemain de l'examen. Le diagnostic de SAS était retenu si l'index d'apnée-hypopnée était ≥ 10/H. Parmi les 32 patients (sexe ratio 1/1, age = 56 ± 14 ans, IMC = 34 ± 8 kg/m2, HTA : 44 %) 17 patients avaient un SAS. Le taux de GPVs était respectivement de 25,8 ± 8,7 versus 24,6 ± 5,9 μg/L chez les patients avec et sans SAS (valeur chez le sujet sain : 25 ± 3 μg/L). Il n'y avait pas de corrélation entre le taux de GPVs et l'index d'apnée hypopnée (p = 0.986). Il existait une corrélation positive entre la GPVs et la saturation moyenne en O2 (p = 0,017). La GPVs était retrouvée plus basse pour des valeurs élevées de HDL-cholestérol (p = 0,051). La GPVs n'est pas augmentée chez le patient obèse ayant un SAS. La corrélation négative entre la GPVs et le HDL-cholestérol pourrait s'expliquer par un effet inhibiteur du HDL-cholestérol sur l'activation plaquettaire et la génération de thrombine à la surface des cellules.

The biological response to clopidogrel displays wide interindividual variability [1] and hyporesponsiveness is associated with a poorer clinical outcome after an acute coronary syndrome or percutaneous coronary intervention [2]. The mechanisms of this interindividual variability of clopidogrel responsiveness have not yet been completely elucidated but are thought to involve poor compliance [3], intrinsic high platelet reactivity [1], variable intestinal absorption [4], possible drug–drug interactions [5-7] or variable metabolization of the prodrug in the liver [8-10]. Concerning the latter, work by Hulot et al. [10] has demonstrated the influence of CYP2C19 loss-of-function (LoF) polymorphisms on the biological responsiveness in healthy volunteers. More recently, a paper by Trenk et al., [11] in the Journal of American College of Cardiology, two papers by Simon et al. and Mega et al. published in the New England Journal of Medicine and one paper in The Lancet by Collet et al. confirmed and extended previous reports that the polymorphism of CYP450 2C19 subtypes is an important determinant of responsiveness to clopidogrel and subsequent cardiovascular events [12-14]. These observations point to the interest of genotyping patients for whom clopidogrel therapy is indicated. We would like to contribute our own data to the debate on the appropriateness of determining the patient's genomic profile. Our vasodilator-stimulated phosphoprotein (VASP)-02 study comparing the responses of 153 patients to 75 and 150 mg day−1 maintenance doses of clopidogrel [15] was re-analyzed after determining the 2C19*2 polymorphisms in these patients. The 2C19*2 profiles were matched to the response to clopidogrel as measured using the VASP assay. Patients with a platelet reactivity index (PRI) of > 69% were classed as poor responders. Among 37 poor responders (32/95 receiving 75 and 5/58 receiving 150 mg day−1 clopidogrel), 42% were CYP2C19*2LoF carriers (60% of poor responders to 150 mg day−1) vs. 22% among responder patients (P = 0.022), confirming a significant determination of the response to clopidogrel. Interestingly, CYP2C19*2LoF carriers displayed the same PRI (62.1 ± 19.1%) as G/G genotypes receiving a proton pump inhibitor (63.9 ± 17.1%, P = 0.94). As such inhibitors are known to be 2C19 substrates, this confirms the presence of a drug–drug interaction effect. However, the existence of poor responders not carrying the LoF mutation and responders carrying the mutation indicates that other factors also influence the responsiveness. Thus, in poor responders with the 2C19*2 wild type (G/G), the body weight was significantly higher than in responders carrying the 2C19*2LoF variant (90.2 ± 13.0 vs. 79.9 ± 13.6 kg respectively, P = 0.021). A multivariate analysis showed 2C19*2LoF and high body weight to be two independent predictors of a high PRI [odds ratio (95% confidence interval): 3.39 (1.06–10.84) (P = 0.039) and 3.14 (1.19–8.30) (P = 0.021) respectively] (Table 1). In poor responders, increasing the dose of clopidogrel from 75 to 150 mg day−1 resulted in a significant decrease in PRI, from 76.4 ± 4.6 to 62.8 ± 10.4% (P < 0.01) in CYP2C19*2LoF carriers and from 76.1 ± 5.3 to 60.8 ± 13.4% (P < 0.01) in non-carriers (Table 2). This effect was not significantly different between carriers and non-carriers (−13.6 ± 9.3 and −15.3 ± 11.8% respectively, P = 0.39), indicating that a weak response was easily overcome. In summary, our data indeed indicate that CYP2C19*2 is an important determinant of the response to clopidogrel but suggest that other factors such as body weight are also important to consider. An effect of high body weight limiting the biological efficacy of clopidogrel has already been described [16]. On the other hand, the sub-group analyses in the TRITON study pointed to a higher bleeding risk with prasugrel in low body weight patients [17]. Thus, if an effect of body weight on the biological and clinical efficacy of clopidogrel clearly seems to exist, its mechanisms are not yet known and remain to be investigated. In parallel, drug–drug interactions such as those observed with proton pump inhibitors also occur [6]. Therefore, to establish a patient's responsiveness to clopidogrel, determination of the CYP profile alone may neglect other important determinants and lead to inappropriate treatment. Combination of the genetic data with pharmacodynamic monitoring remains necessary. This work was sponsored and supported by Association de Recherche et de Développement en Médecine et Santé Publique (ARMESA), Etablissement Français du Sang (EFS)-Alsace with a research grant from Sanofi-Aventis and Bristol-Myers Squibb. The authors state that they have no conflict of interest.

We investigated whether maintenance therapy with clopidogrel 150 mg/day produces higher platelet inhibition than the standard 75 mg/day dose, and whether the higher maintenance dose increases plate...

Plasma levels of soluble platelet glycoprotein V are linked to fasting blood glucose in patients with type 2 diabetes -