Eptifibatide provides additional platelet inhibition in Non–ST-Elevation myocardial infarction patients already treated with aspirin and clopidogrel Results of the platelet activity extinction in Non–Q-Wave myocardial infarction with aspirin, clopidogrel, and eptifibatide (PEACE) study

AbstractObjectivesThe present study hypothesis was that eptifibatide offered further antiplatelet efficacy above clopidogrel in non–ST-elevation myocardial infarction (NSTEMI) patients before an expeditive coronary intervention.BackgroundAlthough thienopyridines and glycoprotein (GP) IIb/IIIa antagonists are often co-prescribed in the context of NSTEMI, the antiplatelet interaction of these agents is poorly described and the superiority of GP IIb/IIIa antagonists above thienopyridine treatment alone is not clear.MethodsThirty-two NSTEMI patients treated with aspirin and enoxaparin were studied using flow cytometry to define parameters of platelet activation with a panel of agonists before clopidogrel, after clopidogrel, and during an eptifibatide infusion following the clopidogrel load.ResultsAfter platelet activation with adenosine diphosphate, thrombin receptor-activating peptide, or U46-619, relative reductions in conformationally activated GP IIb/IIIa receptor expression (evaluated with PAC-1) of 48%, 43%, and 33%, respectively (all p < 0.0001), were seen with clopidogrel, but further 80%, 78%, and 72% (all p < 0.0001) reductions were seen with eptifibatide. With the same agonists, fibrinogen binding was significantly reduced after clopidogrel by 70%, 64%, and 81% (all p < 0.0001) and again further reduced with eptifibatide by 90%, 95%, and 69% (all p < 0.0001). The total number of GP IIb/IIIa receptors (measured as P2 expression) and P-selectin expression fell after clopidogrel, after ex vivo stimulation with the same agonists; however, both parameters increased slightly during the eptifibatide infusion.ConclusionsThe activated GP IIb/IIIa expression and fibrinogen binding findings indicate that eptifibatide provides significant potent antiplatelet activity above aspirin and clopidogrel, suggesting additive immediate protection in the treatment of NSTEMI. The P2 and P-selectin findings suggest the possibility of a partial agonist and/or pro-inflammatory effect

A Randomized Comparison of High Clopidogrel Loading Doses in Patients With Non–ST-Segment Elevation Acute Coronary Syndromes The ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) Trial

ObjectivesWe sought to compare the antiplatelet effects of three clopidogrel loading doses (LDs).BackgroundAdministration of a 300-mg clopidogrel LD is beneficial in situations requiring rapid platelet inhibition. Whether higher LDs can provide further benefits remains unknown.MethodsPatients (n = 103) with non–ST-segment elevation acute coronary syndromes were randomized to receive a 300-mg, 600-mg, or 900-mg clopidogrel LD, given on top of other standard therapy (including acetylsalicylic acid). The main outcome measure was inhibition of adenosine diphosphate-induced inhibition of platelet aggregation (IPA); inhibition of platelet activation, inflammatory markers, troponin I release, and major adverse cardiac events also were evaluated; all measures were blindly evaluated.ResultsCompared with the 300-mg LD, greater doses were associated with significantly greater platelet inhibition, with dose-effect relationships observed for onset of action, maximal plateau, 24-h areas under the curves of IPA, and rates of low IPA (<10% at 6 h), using 20 μmol/l major adverse cardiac events. A significant dose-response was also observed for the vasodilator-stimulated phosphoprotein index, a measure of P2Y12receptor inhibition. Similar but nonsignificant trends were observed for troponin release and major adverse cardiac events. Bleeding rates were similar in each group.ConclusionsIn low-to-moderate risk patients with non–ST-elevation acute coronary syndromes, clopidogrel LDs >300 mg provide a faster onset of action, a higher IPA plateau, and greater reductions in platelet activation during the first 24 h. A 900-mg LD may induce a greater antiplatelet effect than 600 mg, when compared with the standard 300-mg regimen. These findings require further clinical confirmation

Vitamine K

Subclasses of vitamin K, their origins, their differential characteristics of absorption and metabolism, their relative effects on gammacarboxylation of various proteins implicated in hemostasis andcoagulation, in bone calcification are not well known even by experts in these fields. These misunderstandings explain errors in recommendations for public and for patients. This review will not expose again the fundamentals on vitamins K as presented in the paper by Marc Guillaumont published in 2000 in this same journal. This 2011 review will try to update our actual knowledge and most of all will insist on their practical implications especially on the management of oral anticoagulant treatments since until recently vitamin K antagonist was the only available type of such a treatment. Several examples illustrate the need for a better understanding of this subject. The fear that diet vitamin K could deregulate the equilibrium of oral vitamin K antagonist treatment leads to recommend a quite total suppression of vitamin K containing components in the diet of anticoagulated patients. This leads to an opposite effect: a high sensitivity to vitamin K and to disequilibrium of the anticoagulant treatment while a comprehensivemoderate and regular diet intake of vitamin K first facilitates the food choice of the patients but also helps to stabilise the treatment of chronically anticoagulated patients. Vitamin K plays a role in bone calcification and in osteoporosis prevention. Until recently the food supplementation with vitamin K in view of preventing osteoporosis in general population was strongly limited due to fear to affect the treatment equilibrium in anticoagulated patients. While an understanding that the effects of moderate supplementation in vitamin K has no or limited effect on anticoagulation and on the long run could at the opposite help to stabilize the daily level of anticoagulation in patients chronically treated with vitamin K

À part le fibrinogène, les facteurs/marqueurs d'hémostase ont-ils aussi une place pour évaluer le risque d'accident cardiovasculaire ischémique ?

Dans leur grande majorité, les événements cardiovasculaires sont une complication thrombotique de lésions d'athérosclérose. En condition de flux sanguin artériel, comme dans les artères coronaires, les facteurs d'hémostase favorisent le risque thrombotique (surtout aux phases initiales), mais les facteurs de coagulation et de fibrinolyse interagissent également. S'il est admis que le fibrinogène est un marqueur/facteur de risque cardiovasculaire, la place, le rôle et l'intérêt des autres paramètres sont toujours controversés. Etant donnée la place des plaquettes (démontrée par l'efficacité préventive des antiplaquettaires dans cette pathologie), on s'attendrait à ce que les marqueurs plaquettaires présentent un intérêt. En fait, en dehors des augmentations du chiffre plaquettaire, il n'y a pas d'autre paramètre plaquettaire évident. Cette absence est due au moins en partie à la difficulté d'étudier les fonctions plaquettaires ex vivo. Plusieurs polymorphismes de glycoprotéines membranaires plaquettaires confèrent un excès modéré de risque, risque qui n'est retrouvé que chez les patients les plus jeunes. Pour la coagulation, il apparaît que la structure du caillot de fibrine est un paramètre important. Ce paramètre implique, outre le fibrinogène, la cinétique de génération de la thrombine, la fonctionnalité du facteur XIII et l'association aux cellules de la coagulation. Les facteurs de coagulation sont à l'évidence impliqués dans la vitesse de génération de la thrombine. L'activité du système fibrinolytique (et en particulier son déficit) est corrélée avec le risque cardiovasculaire. Les marqueurs globaux comme les D-dimères sont potentiellement utiles bien que faiblement corrélés avec la survenue d'événements cliniques. Tous les systèmes d'hémostase, de coagulation et de fibrinolyse sont impliqués dans la réactivité thrombotique (et certains dans l'athérogenèse elle-même). Il s'agit d'un système multifactoriel. Une meilleure prédictibilité des tests d'hémostase peut venir de la mise au point de tests plus représentatifs et de l'évaluation simultanée d'un grand nombre de paramètres (phénotypiques et génotypiques) qui permettraient d'aboutir à des scores de risque

Le fibrinogène a-t-il une place pour évaluer le risque d'accident cardiovasculaire ischémique ?

La plupart des événements cardiovasculaires sont une conséquence thrombotique de l'évolution d'une lésion d'athérosclérose. L'inflammation joue un rôle central tant dans le développement que dans la survenue des complications évolutives des lésions d'athérosclérose (en particulier de rupture de plaques). Les données épidémiologiques montrent de manière concordante que l'augmentation du fibrinogène (par rapport aux valeurs de contrôles appariés) est prédictive du risque d'accident cardiovasculaire aussi bien dans la population générale pour prédire le premier événement cardiovasculaire que chez les patients pour prédire le risque de récidive. La concentration plasmatique du fibrinogène est déterminée à la fois par une prédisposition génétique et par des facteurs acquis et environnementaux. C'est un exemple des interrelations gène-environnement. Il faut prendre conscience que l'augmentation du fibrinogène (responsable de l'augmentation significative du risque) est une augmentation très modérée (comprise dans les valeurs de référence du taux plasmatique). Cela permet de comprendre que ce facteur si prédictif lorsqu'il est considéré d'un point de vue épidémiologique, n'a aucune valeur pour établir le risque cardiovasculaire à un niveau individuel en pratique clinique quotidienne (sauf pour les très fortes augmentations qui ne sont rencontrées que très rarement)

Utilisation et suivi biologique des antivitamines K en pratique médicale courante: Résultats français de l’étude internationale ISAM chez des patients ayant une fibrillation auriculaire

National audienceIntroductionBleeding complications of vitamin K antagonist (VKA) therapy are currently the most frequent iatrogenic event in France.ObjectivesThe aim of the ISAM study, an international longitudinal observational survey was to evaluate the use of VKA treatment and the quality of laboratory monitoring in everyday medical practice.MethodsIn France, a representative sample of general practitioners and cardiologists selected patients with nonvalvular atrial fibrillation who had been treated with VKA for at least 60 days during the past 12 months. Physicians and patients responded to standardized questionnaires collecting retrospective data for the previous year.ResultsOverall, 43 general practitioners and 20 cardiologists recruited 278 patients who completed questionnaires. INR was at least 2 for 264 patients during the study period. During the year preceding inclusion, INR had been within the target range (i.e., between 2.0 and 3.0) 59% of the time and above 3.0 27%. Physicians reported having giving approximately half their patients written recommendations about the VKA dosage regimen, but only 3% supplied a specific VKA information and monitoring booklet. Most patients (65%) reported receiving information on VKA therapy from their general practitioners, although 18% said they had not been informed about their treatment, 44% did not know their target INR, and 66% were unaware that bleeding events were a matter of concern. Finally, 45% of patients reported carrying a card indicating that they were taking VKA.ConclusionOverall, these results show that better education of both physicians and patients could help to improve management, appropriate use and laboratory monitoring of VKA treatment.IntroductionLes hémorragies liées au traitement par antivitamines K (AVK) ont en France la première place des accidents iatrogènes.ObjectifsL’étude internationale, observationnelle, longitudinale et rétrospective ISAM avait pour but d’évaluer l’utilisation des AVK et la qualité de leur suivi biologique en pratique médicale courante.MéthodesDans l’étude française, des médecins généralistes et des cardiologues représentatifs ont sélectionné des patients traités pendant au moins 60 jours au cours des 12 derniers mois par des AVK pour fibrillation auriculaire non valvulaire. Les données rétrospectives sur un an ont été recueillies à l’aide de questionnaires standardisés auprès des médecins et de leurs patients.RésultatsAu total, 43 généralistes et 20 cardiologues ont inclus 278 patients qui ont complété les questionnaires. Deux cent soixante-quatre patients ont eu au moins 2 INR (International Normalized Ratio) pendant la période de l’étude. Dans l’année précédant l’inclusion, les patients ont passé 59% du temps avec un INR dans l’intervalle thérapeutique 2,0–3,0et 27% du temps avec un INR > 3. Les médecins déclaraient donner des recommandations écrites concernant la posologie des AVK à près de la moitié de leurs patients, mais seuls 3% leur remettaient un carnet d’information et de surveillance de traitement par AVK. L’information du traitement était assurée par le médecin généraliste pour 65% des patients. Toutefois, 18 % des patients disaient ne pas être informés sur leur traitement, 44% ne connaissaient pas leur INR cible et 66% ne savaient pas qu’un saignement devait les alerter. Le port d’une carte indiquant le traitement par AVK a été rapporté par 45% des patients.ConclusionII existe une place importante à l’éducation thérapeutique pour améliorer la prise en charge, le bon usage et le suivi biologique du traitement par AVK auprès des médecins et des patients

257 Prevalence of aspirin resistance in stable coronary heart diseased patients and correlation with platelet turn-over

BackgroundAspirin resistance has been widely reported but the underlying mechanisms remain unclear. Previous studies have suggested a relationship between accelerated platelet turn-over and aspirin resistance in patients with coronary artery disease. The purpose of this study was to determine whether aspirin resistance could be linked to accelerated platetet turn-over.MethodsWe performed a prospective monocentric study including 50 consecutive patients with stable coronary artery disease treated by aspirin (75 to 250mg/day) without any other antiaggregant treatment. Aspirin resistance was characterized 24 hours after aspirin intake by light transmission aggregometry using 0.5mg/mL arachidonic acid. Aspirin resistance was defined as >20% residual agregation. Platelet turn-over was estimated at the same time by measurement of mean platelet volume, % of reticulated platelets, serum P-selectin, platelet P-selectin and serum thrombopoietin.ResultsAmong 50 patients (70 ± 11 y.o. mean ± 1,5, 76% male, 52% type 2 diabetes mellitus, 16% active smokers), 18 (36%) were identified as aspirin resistants. Table 1 shows the mean value of markers currently linked to platelet turn-over depending on the presence of aspirin resistance. Serum thrombopoietin was significantly increased in patients with aspirin resistance compared to patients with no aspirin resistance. No statistical difference was demonstrated for mean platelet volume, reticulated platelets, platelet P-selectin and serum P-selectin. Serum thrombopoietin values were not correlated with other platelet turn-over parameters. There was no significant correlation between serum thrombopoietin and inflammatory markers.ConclusionSerum thrombopoietin is associated with aspirin resistance, but no other parameters currently linked to platelet turn-over. Further studies are needed to determine whether serum thrombopoietin can predict aspirin resistance in a larger cohort.Aspirin sensitiveAspirin resistantpPlatelet volume (fl)8.78 ± 0.268.82 ± 0.300.92Reticulated platelet (%)8.4 ± 0.528.6 ± 0.760.82Serup P selectin (ng/ml)42.6 ± 4.2942.9 ± 4.750.97Platelet P selectin (%)11.1 ± 1.09.5 ± 1.50.35Serum thrombopoietin (pg/ml)130.6 ± 11.3319.9 ± 97.80.0

Tinzaparin and enoxaparin given at prophylactic dose for eight days in medical elderly patients with impaired renal function: a comparative pharmacokinetic study.

International audienceLow-molecular-weight heparins (LMWHs) accumulate in patients with impaired renal function. As this accumulation depends on heparin chain length and subsequent reticulo-endothelial/renal elimination, LMWHs might have different pharmacodynamic profiles. The primary objective was to examine if any accumulation effect of two LMWHs, enoxaparin and tinzaparin, occurred after repeated administration of a prophylactic dose over eight days in elderly patients (age >75 years) with creatinine clearance between 20 and 50 ml/min and body weight <65Kg. Patients were openly randomized to two groups (enoxaparin 4,000 IU or tinzaparin 4,500 IU once daily). Anti-Xa was measured on day 1 and day 8. Blood samples were taken at 0, 2, 4, 5, 6, 9, 12, 16 and 24 hours. The primary end point was the accumulation factor calculated as a ratio between the maximal anti-Xa activity on day 1and day 8. Fifty-five patients were included (mean age 87.9 +/- 5.5). The creatinine clearance was 34.7 +/- 11.4 ml/min; the body weight was 52.3 +/- 8.6 kg. The accumulation factor defined was not significant for tinzaparin (1.05, p = 0.29) while it was significantly enhanced for enoxaparin (1.22, p < 0.0001). In this pharmacodynamic study performed in elderly patients with impaired renal function, a statistically significant accumulation effect was observed after eight days of prophylactic treatment with enoxaparin but not with tinzaparin, which are two LMWHs with different chain lengths. Trials based on clinical end points should be conducted to evaluate the clinical relevance of these observations