Les anticoagulants oraux directs en 2015 chez le patient âgé: focus chez le sujet fragile

Depuis les études princeps de phase III de non-inf ériorité comparant les anticoagulants oraux directs (AOD) à la warfarine, de nombreuses études ont essayé de répondre à la question de l'efficacité et de la sécurité d'utilisation des AOD chez les patients âgés. Ces études sont des études de sous-groupes complémentaires issues des études princeps ou des études de pharmacovigilance en postmarketing utilisant des données médicoéconomiques à grande échelle. De nombreux biais, par définition, peuvent entraîner une distorsion des résultats dans de telles études, rendant leur interprétation prudente. Aucun essai randomisé contrôlé n'a à ce jour comparé les AOD à la warfarine chez des patients de 80 ans ou plus et a fortiori chez des sujets âgés fragiles. En pratique, chez le patient âgé fragile, il n'y a pas de consensus quant au choix des anticoagulants à prescrire en cas de fibrillation atriale (FA) et de la maladie thromboembolique veineuse (MTEV). Quant au choix de l'AOD à privilégier chez le sujet âgé, faute d'études de comparaison directe disponibles à ce jour, il apparaît difficile de se prononcer. Toutefois, les données disponibles, tant sur le plan pharmacologique que celles issues des études complémentaires, semblent montrer que le dabigatran offre un profil bénéfice/risque moins favorable que les autres AOD. Néanmoins, les résultats prometteurs de l'idarucizumab, antidote du dabigatran, pourraient contribuer à améliorer ce rapport à l'avenir.

L'utilisation des anticoagulants oraux directs chez les patients âgés : les limites de la médecine fondée sur les preuves [The use of the new direct oral anticoagulants among older subjects: The limits of the evidence-based medicine?].

The growing use of direct oral anticoagulants, in particular among older subjects, raises questions about the limits of the evidence-based medicine. The phase III studies that have validated the efficacy and the safety profile of these molecules (dabigatran, rivaroxaban, apixaban, edoxaban) in their both indications, the venous thromboembolic disease and the non-valvular atrial fibrillation raise concerns in four major fields: the financial support of pharmaceutical companies, the links of interest for many authors with the industry, the study design (exclusively non-inferiority studies), and the poor representativeness of the older subjects included. All these points are discussed, using data of sub-groups studies, post-marketing studies and recent meta-analysis. The lack of data for the very old subjects, with frailty or comorbidities, remains the main concern from these phase III studies.

Aetiologies of pulseless electrical activity in out-of-hospital cardiac arrests:A retrospective study and analysis of specific causes

Background: Pulseless electrical activity (PEA) cardiac arrest is defined as a cardiac arrest (CA) presenting with a residual organized electrical activity on the electrocardiogram. In the last decades, the incidence of PEA has regularly increased, compared to other types of CA like ventricular fibrillation or pulseless ventricular tachycardia. PEA is frequently induced by reversible conditions. The "4 (or 5) H" & "4 (or 5) T" are proposed as a mnemonic to asses for Hypoxia, Hypovolemia, Hypo- /Hyperkalaemia, Hypothermia, Thrombosis (cardiac or pulmonary), cardiac Tamponade, Toxins, and Tension pneumothorax. Other pathologies (intracranial haemorrhage, severe sepsis, myocardial contraction dysfunction) have been identified as potential causes for PEA, but their respective probability and frequencies are unclear and they are not yet included into the resuscitation guidelines. The aim of this study was to analyse the aetiologies of PEA out-of-hospital CA, in order to evaluate the relative frequencies of each cause and therefore to improve the management of patients suffering a PEA cardiac arrest. Method: This retrospective study was based on data routinely and prospectively collected for each PEMS intervention. All adult patients treated from January 1st 2002 to December 2012 31st by the PEMS for out-of-hospital cardiac arrest, with PEA as the first recorded rhythm, and admitted to the emergency department (ED) of the Lausanne University Hospital were included. The aetiologies of PEA cardiac arrest were classified into subgroups, based on the classical H&T's classification, supplemented by four other subgroups analysis: trauma, intra-cranial haemorrhage (ICH), non-ischemic cardiomyopathy (NIC) and undetermined cause. Results: 1866 OHCA were treated by the PEMS. PEA was the first recorded rhythm in 240 adult patients (13.8 %). After exclusion of 96 patients, 144 patients with a PEA cardiac arrest admitted to the ED were included in the analysis. The mean age was 63.8 ± 20.0 years, 58.3% were men and the survival rate at 48 hours was 29%. 32 different causes of OHCA PEA were established for 119 patients. For 25 patients (17.4 %), we were unable to attribute a specific cause for the PEA cardiac arrest. Hypoxia (23.6 %), acute coronary syndrome (12.5%) and trauma (12.5 %) were the three most frequent causes. Pulmonary embolism, Hypovolemia, Intoxication and Hyperkaliemia occurs in less than 10% of the cases (7.6 %, 5.6 %, 3.5%, respectively 2.1 %). Non ischemic cardiomyopathy and intra-cranial haemorrhage occur in 8.3 % and 6.9 %, respectively. Conclusions: According to our results, intra-cranial haemorrhage and non-ischemic cardiomyopathy represent noticeable causes of PEA in OHCA, with a prevalence equalling or exceeding the frequency of classical 4 H's and 4 T's aetiologies. These two pathologies are potentially accessible to simple diagnostic procedures (native CT-scan or echocardiography) and should be included into the 4 H's and 4 T's mnemonic.

Association of early repolarization with risk of cardiac mortality in the general population

Early repolarization, which is characterized by an elevation of the J-point on 12-lead electrocardiography, is a common finding that has been considered as benign for decades. However, in the last years, it has been related with vulnerability to idiopathic ventricular fibrillation and with cardiac mortality in the general population. Recently, 4 potential ECG predictors that could differentiate the benign from the malignant form of early repolarization have been suggested. Any previous study about early repolarization has been done in Spain. Aim. To ascertain whether the presence of early repolarization pattern in a resting electrocardiogram is associated with a major risk of cardiac death in a Spanish general population and to determine whether the presence of potential predictors of malignancy in a resting electrocardiogram increases the risk of cardiac mortality in patients with early repolarization pattern. Methods. We will analyse the presence of early repolarization and the occurrence of cardiac mortality in a retrospective cohort study of 4,279 participants aged 25 to 74 years in the province of Girona. This cohort has been followed during a mean of 9.8 years. Early repolarization will be stratified according to the degree of J-point elevation (≥0.1 mV or ≥0.2 mV), the morphology of the J-wave (slurring, notching or any of these two), the ST-segment pattern (ascending or descending) and the localization (inferior leads, lateral leads, or both). Association of early repolarization with cardiac death will be assessed by adjusted Cox-proportional hazards models

Selenomethionine incorporation into amyloid sequences regulates fibrillogenesis and toxicity.

The capacity of a polypeptide chain to engage in an amyloid formation process and cause a conformational disease is contained in its sequence. Some of the sequences undergoing fibrillation contain critical methionine (Met) residues which in vivo can be synthetically substituted by selenomethionine (SeM) and alter their properties.

Construction and validation of a scoring system for the selection of high-quality data in a Spanish population primary care database (SIDIAP)

Background Computerised databases of primary care clinical records are widely used for epidemiological research. In Catalonia, the InformationSystem for the Development of Research in Primary Care (SIDIAP) aims to promote the development of research based on high-quality validated data from primary care electronic medical records. Objective The purpose of this study is to create and validate a scoring system (Registry Quality Score, RQS) that will enable all primary care practices (PCPs) to be selected as providers of researchusable data based on the completeness of their registers. Methods Diseases that were likely to be representative of common diagnoses seen in primary care were selected for RQS calculations. The observed/ expected cases ratio was calculated for each disease. Once we had obtained an estimated value for this ratio for each of the selected conditions we added up the ratios calculated for each condition to obtain a final RQS. Rate comparisons between observed and published prevalences of diseases not included in the RQS calculations (atrial fibrillation, diabetes, obesity, schizophrenia, stroke, urinary incontinenceand Crohn’s disease) were used to set the RQS cutoff which will enable researchers to select PCPs with research-usable data. Results Apart from Crohn’s disease, all prevalences were the same as those published from the RQS fourth quintile (60th percentile) onwards. This RQS cut-off provided a total population of 1 936 443 (39.6% of the total SIDIAP population). Conclusions SIDIAP is highly representative of the population of Catalonia in terms of geographical, age and sex distributions. We report the usefulness of rate comparison as a valid method to establish research-usable data within primary care electronic medical records

Fármacos multifuncionais: monoamina oxidase e α-sinucleína como alvos terapêuticos na doença de Parkinson

Parkinson's disease (PD) is a neurodegenerative disorder associated to selective degeneration of dopaminergic neurons caused by an intricate relationship among dopamine metabolism, oxidative stress and α-synuclein fibrillation. Most therapies for PD have focused on dopamine replacement through the use of both monoamine oxidase inhibitors (MAOIs) and dopamine precursor L-dopa. Interestingly, certain MAOIs have a broad spectrum of action including anti-fibrillogenic properties in α-synuclein aggregation. Herein we revisit the chemical properties of MAOIs and their action on important targets associated with PD, notably α-synuclein fibrillation and dopamine metabolism, discussing the strategies associated with the development of multi-target drugs for neurodegenerative diseases.

CT and PET/CT Hybrid Imaging of Coronary Artery Disease

Coronary artery disease (CAD) is a chronic process that evolves over decades and may culminate in myocardial infarction (MI). While invasive coronary angiography (ICA) is still considered the gold standard of imaging CAD, non-invasive assessment of both the vascular anatomy and myocardial perfusion has become an intriguing alternative. In particular, computed tomography (CT) and positron emission tomography (PET) form an attractive combination for such studies. Increased radiation dose is, however, a concern. Our aim in the current thesis was to test novel CT and PET techniques alone and in hybrid setting in the detection and assessment of CAD in clinical patients. Along with diagnostic accuracy, methods for the reduction of the radiation dose was an important target. The study investigating the coronary arteries of patients with atrial fibrillation (AF) showed that CAD may be an important etiology of AF because a high prevalence of CAD was demonstrated within AF patients. In patients with suspected CAD, we demonstrated that a sequential, prospectively ECG-triggered CT technique was applicable to nearly 9/10 clinical patients and the radiation dose was over 60% lower than with spiral CT. To detect the functional significance of obstructive CAD, a novel software for perfusion quantification, CarimasTM, showed high reproducibility with 15O-labelled water in PET, supporting feasibility and good clinical accuracy. In a larger cohort of 107 patients with moderate 30-70% pre-test probability of CAD, hybrid PET/CT was shown to be a powerful diagnostic method in the assessment of CAD with diagnostic accuracy comparable to that of invasive angiography and fractional flow reserve (FFR) measurements. A hybrid study may be performed with a reasonable radiation dose in a vast majority of the cases, improving the performance of stand-alone PET and CT angiography, particularly when the absolute quantification of the perfusion is employed. These results can be applied into clinical practice and will be useful for daily clinical diagnosis of CAD.

Periprocedural prognostic factors in coronary interventions – retrospective studies

Background: Approximately 11,000 revascularization procedures, either percutaneous coronary interventions (PCI) or coronary artery bypass grafting surgery (CABG), are performed yearly in Finland for coronary artery disease. Periprocedural risk factors for mortality and morbidity as well as long-term outcome have been extensively studied in general populations undergoing revascularization. Treatment choice between PCI and CABG in many high risk groups and risk-stratification, however, needs clarification and there is still room for improvement in periprocedural outcomes. Materials and methods: Cohorts of patients from Finnish hospitals revascularized between 2001 and 2011 were retrospectively analyzed. Patient records were reviewed for baseline variables and postprocedural outcomes (stroke, myocardial infarction, quality of life measured by the EQ-5D –questionnaire, repeat revascularization, bleeding episodes). Data on date and mode of death was acquired from Statistics Finland. Statistical analysis was performed to identify predictors of adverse events and compare procedures. Results: Postoperative administration of blood products (red blood cells, fresh frozen plasma, platelets) after isolated CABG independently and dose-dependently increases the risk of stroke. Patients 80 years or older who underwent CABG had better survival at 5 years compared to those who underwent PCI. After adjusting for baseline differences survival was similar. Patients on oral anticoagulation (OAC) for atrial fibrillation (AF) treated with CABG had better survival and overall outcome at 3 years compared to PCI patients. There was no difference in incidence of stroke or bleeding episodes. Differences in outcome remained significant after adjusting for propensity score. Lower health-related quality of life (HRQOL) scores as measured by the visual analogue scale (VAS) of the EQ-5D questionnaire at 6 months after CABG predicted later major adverse cardiac and cerebrovascular events (MACCE). Deteriorating function and VAS scores between 0 and 6 months on the EQ-5D also independently predicted later MACCE. Conclusions: Administration of blood products can increase the risk of stroke after CABG and liberal use of transfusions should be avoided. In the frail subpopulations of patients on OAC and octogenarians CABG appears to offer superior long-term outcome as compared to PCI. Deteriorating HRQOL scores predict later adverse events after CABG. Keywords: percutaneous coronary intervention, coronary artery bypass grafting, age over 80, transfusion, anticoagulants, coronary artery disease, health-related quality of life, outcome.

Effect of angiotensin-(1-7) on reperfusion arrhythmias in isolated rat hearts

There is increasing evidence that angiotensin-(1-7) (Ang-(1-7)) is an endogenous biologically active component of the renin-angiotensin system (RAS). In the present study, we investigated the effects of Ang-(1-7) on reperfusion arrhythmias in isolated rat hearts. Isolated rat hearts were perfused with two different media, i.e., Krebs-Ringer (2.52 mM CaCl2) and low-Ca2+ Krebs-Ringer (1.12 mM CaCl2). In hearts perfused with Krebs-Ringer, Ang-(1-7) produced a concentration-dependent (27-210 nM) reduction in coronary flow (25% reduction at highest concentration), while only slight and variable changes in contraction force and heart rate were observed. Under the same conditions, angiotensin II (Ang II; 27 and 70 nM) produced a significant reduction in coronary flow (39% and 48%, respectively) associated with a significant increase in force. A decrease in heart rate was also observed. In low-Ca2+ Krebs-Ringer solution, perfusion with Ang-(1-7) or Ang II at 27 nM concentration produced similar changes in coronary flow, contraction force and heart rate. In isolated hearts perfused with normal Krebs-Ringer, Ang-(1-7) produced a significant enhancement of reperfusion arrhythmias revealed by an increase in the incidence and duration of ventricular tachycardia and ventricular fibrillation (more than 30-min duration). The facilitation of reperfusion arrhythmias by Ang-(1-7) was associated with an increase in the magnitude of the decreased force usually observed during the post-ischemic period. The effects of Ang-(1-7) were abolished in isolated rat hearts perfused with low-Ca2+ Krebs-Ringer. The effect of Ang II (27 nM) was similar but less pronounced than that of Ang-(1-7) at the same concentration. These results indicate that the heart is a site of action for Ang-(1-7) and suggest that this heptapeptide may be involved in the mediation of the cardiac effects of the RAS

A simple HPLC-fluorescence method for the measurement of R,S-sotalol in the plasma of patients with life-threatening cardiac arrhythmias

R,S-sotalol, a ß-blocker drug with class III antiarrhythmic properties, is prescribed to patients with ventricular, atrial and supraventricular arrhythmias. A simple and sensitive method based on HPLC-fluorescence is described for the quantification of R,S-sotalol racemate in 500 µl of plasma. R,S-sotalol and its internal standard (atenolol) were eluted after 5.9 and 8.5 min, respectively, from a 4-micron C18 reverse-phase column using a mobile phase consisting of 80 mM KH2PO4, pH 4.6, and acetonitrile (95:5, v/v) at a flow rate of 0.5 ml/min with detection at lex = 235 nm and lem = 310 nm, respectively. This method, validated on the basis of R,S-sotalol measurements in spiked blank plasma, presented 20 ng/ml sensitivity, 20-10,000 ng/ml linearity, and 2.9 and 4.8% intra- and interassay precision, respectively. Plasma sotalol concentrations were determined by applying this method to investigate five high-risk patients with atrial fibrillation admitted to the Emergency Service of the Medical School Hospital, who received sotalol, 160 mg po, as loading dose. Blood samples were collected from a peripheral vein at zero, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0 and 24.0 h after drug administration. A two-compartment open model was applied. Data obtained, expressed as mean, were: CMAX = 1230 ng/ml, TMAX = 1.8 h, AUCT = 10645 ng h-1 ml-1, Kab = 1.23 h-1, a = 0.95 h-1, ß = 0.09 h-1, t(1/2)ß = 7.8 h, ClT/F = 3.94 ml min-1 kg-1, and Vd/F = 2.53 l/kg. A good systemic availability and a fast absorption were obtained. Drug distribution was reduced to the same extent in terms of total body clearance when patients and healthy volunteers were compared, and consequently elimination half-life remained unchanged. Thus, the method described in the present study is useful for therapeutic drug monitoring purposes, pharmacokinetic investigation and pharmacokinetic-pharmacodynamic sotalol studies in patients with tachyarrhythmias.

Effects of short-term administration of estradiol on reperfusion arrhythmias in rats of different ages

Little is known about age-related differences in short-term effects of estradiol on ischemia-reperfusion (I/R) insults. The present study was designed to evaluate the effects of short-term treatment with estradiol on reperfusion arrhythmias in isolated hearts of 6-7-week-old and 12-14-month-old female rats. Wistar rats were sham-operated, ovariectomized and treated with vehicle or ovariectomized and treated with 17β-estradiol (E2; 5 µg·100 g-1·day-1) for 4 days. Hearts were perfused by the Langendorff technique. Reperfusion arrhythmias, i.e., ventricular tachycardia and/or ventricular fibrillation, were induced by 15 min of left coronary artery ligation and 30 min of reperfusion. The duration and incidence of I/R arrhythmias were significantly higher in young rats compared to middle-aged rats (arrhythmia severity index: 9.4 ± 1.0 vs 3.0 ± 0.3 arbitrary units, respectively, P < 0.05). In addition, middle-aged rats showed lower heart rate, systolic tension and coronary flow. Four-day E2 treatment caused an increase in uterine weight. Although E2 administration had no significant effect on the duration of I/R arrhythmias in middle-aged rats, it induced a marked reduction in the rhythm disturbances of young rats accompanied by a decrease in heart rate of isolated hearts. Also, this reduction was associated with an increase in QT interval. No significant changes were observed in the QT interval of middle-aged E2-treated rats. These data demonstrate that short-term estradiol treatment protects against I/R arrhythmias in hearts of young female rats. The anti-arrhythmogenic effect of estradiol might be related to a lengthening of the QT interval.

Induction of chagasic-like arrhythmias in the isolated beating hearts of healthy rats perfused with Trypanosoma cruzi-conditioned medium

Chagas' myocardiopathy, caused by the intracellular protozoan Trypanosoma cruzi, is characterized by microvascular alterations, heart failure and arrhythmias. Ischemia and arrythmogenesis have been attributed to proteins shed by the parasite, although this has not been fully demonstrated. The aim of the present investigation was to study the effect of substances shed by T. cruzi on ischemia/reperfusion-induced arrhythmias. We performed a triple ischemia-reperfusion (I/R) protocol whereby the isolated beating rat hearts were perfused with either Vero-control or Vero T. cruzi-infected conditioned medium during the different stages of ischemia and subsequently reperfused with Tyrode's solution. ECG and heart rate were recorded during the entire experiment. We observed that triple I/R-induced bradycardia was associated with the generation of auricular-ventricular blockade during ischemia and non-sustained nodal and ventricular tachycardia during reperfusion. Interestingly, perfusion with Vero-infected medium produced a delay in the reperfusion-induced recovery of heart rate, increased the frequency of tachycardic events and induced ventricular fibrillation. These results suggest that the presence of parasite-shed substances in conditioned media enhances the arrhythmogenic effects that occur during the I/R protocol.

Involvement of Src tyrosine kinase and protein kinase C in the expression of macrophage migration inhibitory factor induced by H2O2 in HL-1 mouse cardiac muscle cells

Macrophage migration inhibitory factor (MIF), a pleiotropic cytokine, plays an important role in the pathogenesis of atrial fibrillation; however, the upstream regulation of MIF in atrial myocytes remains unclear. In the present study, we investigated whether and how MIF is regulated in response to the renin-angiotensin system and oxidative stress in atrium myocytes (HL-1 cells). MIF protein and mRNA levels in HL-1 cells were assayed using immunofluorescence, real-time PCR, and Western blot. The result indicated that MIF was expressed in the cytoplasm of HL-1 cells. Hydrogen peroxide (H2O2), but not angiotensin II, stimulated MIF expression in HL-1 cells. H2O2-induced MIF protein and gene levels increased in a dose-dependent manner and were completely abolished in the presence of catalase. H2O2-induced MIF production was completely inhibited by tyrosine kinase inhibitors genistein and PP1, as well as by protein kinase C (PKC) inhibitor GF109203X, suggesting that redox-sensitive MIF production is mediated through tyrosine kinase and PKC-dependent mechanisms in HL-1 cells. These results suggest that MIF is upregulated by HL-1 cells in response to redox stress, probably by the activation of Src and PKC.

Kokoeksomisekvenointi varhaislapsuuden selvittämättömissä kuolemantapauksissa

Suomessa esiintyy vuosittain 8-15 selittämätöntä alle yhden vuoden ikäisen lapsen äkkikuolemaa ja noin viidesosa kohdunsisäisten kuolemien syistä jää arvoitukseksi. Arvellaan, että näiden kuolemantapausten taustalla on harvinaisia geneettisiä sairauksia. Tässä työssä tutkittiin Turun Yliopistollisen Keskussairaalan varhaislapsuuden ja loppuraskauden lasten ja sikiöiden kuolemantapauksia vuosilta 2000-2012 niistä potilaista, joista ruumiinavaus lisätutkimuksineen ei ollut paljastanut kuolinsyytä. Tarkempaan tutkimukseen valikoitui neljä potilasta, joista eristettiin DNA:ta kokoeksomisekvenointia varten. Tuloksia verrattiin perimän normaalivaihteluun ja poikkeavat löydökset, joilla voisi olla merkitystä potilaiden kuoleman kannalta, määritettiin. Kolmesta eri potilaasta löydettiin alustavasti merkittäväksi tulkittavat geenivirheet. Potilaalla 1 oli kromosomi 6q24-q25 alueen deleetio, jossa sydämen kehityksen kannalta olennaisen TAB2-geenin toiminta häiriintyy ja potilaille kehittyy vakava synnynäinen sydänvika. Potilaalla 2 oli yhden emäksen mutaatio CPT1A-geenissä, joka aiheuttaa CPT1A-proteiinin puutoksen. CPT1A osallistuu mitokondrioiden kalvoilla pitkäketjuisten rasvahappojen kuljetukseen ja häiriöt sen toiminnassa aiheuttavat merkittäviä energiatasapainon häiriöitä. CPT1A-puutoksen on kuvattu aiheuttavan äkkikuolemia varhaislapsuudesta aikuisuuteen. Potilaalla 3 oli DPP6-geenin yhden emäksen mutaatio. TAB2-geenin häiriö on todennäköisesti ollut merkittävänä tekijänä aiheuttamassa potilaan 1 kliiniset löydökset ja voinut myötävaikuttaa kuolemaan. Myös CPT1A-puutos on mahdollisesti vaikuttanut potilaan 2 kuolemaan. DPP6-geenivirheen ajateltiin aiheuttavan ajoittaista kammiovärinää (paroxysmal ventricular fibrillation type 2), mutta myöhemmin uusissa tutkimuksissa kävi ilmi, että mutaatio ei ole patogeeninen. Vaikka kokoeksomisekvenointimenetelmässä on vielä merkittäviä puutoksia kuolinsyytutkimukseen sovellettaessa ja se soveltuu paremmin tutkimuskäyttöön kuin kliiniseen työhön, se avaa kokonaan uusia mahdollisuuksia aiemmin tuntemattomien lapsen kuolemaan johtavien sairauksien diagnostiikassa.