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Summary Background In patients with acute coronary syndrome (ACS), current international guidelines recommend newer potent and predictable P2Y12 inhibitors as first-line treatment despite a greater bleeding risk compared with clopidogrel. Aim To determine if platelet function testing can predict bleeding in real-life patients with ACS treated with newer P2Y12 inhibitors. Methods In this retrospective study, all consecutive adults admitted to the Lariboisiere University Hospital for ACS, whatever the P2Y12 inhibitor prescribed, who had platelet function testing (vasodilator-stimulated phosphoprotein phosphorylation [VASP] index and aggregation tests) during the initial hospital stay were included. Follow-up was performed to record bleeding events according to the Bleeding Academic Research Consortium (BARC) classification. Results A total of 364 patients were included, treated with ticagrelor (n = 123), prasugrel (n = 105) or clopidogrel (n = 136); 42.3% after an ST-segment elevation myocardial infarction, 27.1% after a non-ST-segment elevation myocardial infarction and 30.6% with unstable angina. Mean age was 64 ± 11 years. Median VASP index was significantly lower with the newer P2Y12 inhibitors (14% under ticagrelor, 14% under prasugrel) than with clopidogrel (42%). Despite these differences in the degree of platelet inhibition, the occurrence of bleeding (BARC 2–5) during follow-up was 7.7% overall, and was similar for all P2Y12 inhibitors (ticagrelor 8.9%; prasugrel 6.6%; clopidogrel 7.4%). For each P2Y12 inhibitor, it was impossible to determine a VASP index threshold under which bleeding was significantly greater during follow-up. Similarly, ADP-induced aggregation was more profoundly inhibited by ticagrelor and prasugrel than by clopidogrel, but this did not allow a threshold to be set for increased haemorrhagic risk. Conclusions Despite the substantial occurrence of bleeding in patients with ACS during follow-up, neither the VASP index nor platelet aggregation test results measured at the acute phase were helpful in predicting bleeding risk. Whether platelet function testing could be helpful later in the course of treatment remains to be evaluated.

International audience; Health effects of dairy fats (DF) are difficult to evaluate, as DF intakes are hard to assess epidemiologically and DF have heterogeneous compositions that influence biological responses. We set out to find biomarkers of DF intake and assess biological response to a summer DF diet (R2), a winter DF diet (R3), and a R3 supplemented with calcium (R4) compared to a plant-fat-based diet (R1) in a randomized clinical trial (n=173) and a 2-year study in mildly metabolically disturbed downsized pigs (n=32). Conventional clinical measures were completed by LC/MS plasma metabolomics/lipidomics. The measured effects were modeled as biological functions to facilitate interpretation.DF intakes in pigs specifically induced a U-shaped metabolic trajectory, reprogramming metabolism to close to its initial status after a one-year turnaround. Twelve lipid species repeatably predicted DF intakes in both pigs and humans (6.6% errors). More broadly, in pigs, quality of DF modulated the time-related biological response (R2: 30 regulated functions, primarily at 6 months; R3: 26 regulated functions, mostly at 6–12 months; R4: 43 regulated functions, mostly at 18 months). Despite this heterogeneity, 9 functions overlapped under all 3 DF diets in both studies, related to a restricted area of amino acids metabolism, cofactors, nucleotides and xenobiotic pathways and the microbiota. In conclusion, over the long-term, DF reprograms metabolism to close to its initial biological status in metabolically-disrupted pigs. Quality of the DF modulates its metabolic influence, although some effects were common to all DF. A resilient signature of DF consumption found in pigs was validated in humans.

Aims: We sought to develop a reproducible animal model for acute myocardial infarction (AMI) in adult atherosclerosis-prone pigs. Methods and results: A coil was placed in the right coronary artery or the left anterior descending artery in 26 downsized spontaneously hypercholesterolaemic pigs and left untreated until thrombotic occlusion. Then, we crossed the thrombotic occlusion with a guidewire, followed by predilatation, thrombus visualisation with optical coherence tomography (OCT) imaging and, finally, deployment of a stent and repeated OCT. After revascularisation, we calculated the index of microcirculatory resistance (IMR). After a feasibility phase (six animals), acute thrombotic occlusion was achieved in all 20 pigs. Eighteen animals were successfully revascularised and survived until sacrifice. Thrombus formation was confirmed by OCT, measurement of thrombin-antithrombin complexes and pathology examination. Myocardial necrosis was confirmed by troponin T elevation, myocardial staining and pathology examination. Distal thrombotic embolisation and microvascular obstruction were supported by increased IMR and pathology examination. Conclusions: A porcine model of thrombotic occlusion AMI in miniaturised adult spontaneously atherosclerosis-prone pigs is feasible by percutaneous intracoronary placement of a coil. The reperfusion by angioplasty completed this model which mirrors human pathological conditions with myocardial infarction, necrosis and distal embolisation.

In patients with acute coronary syndrome (ACS), current international guidelines recommend newer potent and predictable P2YTo determine if platelet function testing can predict bleeding in real-life patients with ACS treated with newer P2YIn this retrospective study, all consecutive adults admitted to the Lariboisière University Hospital for ACS, whatever the P2YA total of 364 patients were included, treated with ticagrelor (n=123), prasugrel (n=105) or clopidogrel (n=136); 42.3% after an ST-segment elevation myocardial infarction, 27.1% after a non-ST-segment elevation myocardial infarction and 30.6% with unstable angina. Mean age was 64±11 years. Median VASP index was significantly lower with the newer P2YDespite the substantial occurrence of bleeding in patients with ACS during follow-up, neither the VASP index nor platelet aggregation test results measured at the acute phase were helpful in predicting bleeding risk. Whether platelet function testing could be helpful later in the course of treatment remains to be evaluated.

Item does not contain fulltext AIMS: The aim of the study was to investigate whether bivalirudin versus unfractionated heparin (UFH) reduces infarct size (IS) for primary percutaneous coronary intervention (PPCI) in large acute myocardial infarction (AMI). METHODS AND RESULTS: This multicentre open-label trial randomised 78 patients undergoing PPCI for large AMI to bivalirudin or UFH. The primary endpoint was IS, assessed by cardiac magnetic resonance (CMR) five days after PPCI. Secondary endpoints included index of microcirculatory resistance (IMR), CMR-assessed microvascular obstruction (MVO) and ejection fraction, and biomarkers for thrombin activity and cell injury. No difference was observed in mean IS at five days (25.0+/-19.7 g for bivalirudin vs. 27.1+/-20.7 g for UFH; p=0.75). Early MVO was numerically lower with bivalirudin (5.3+/-5.8 g vs. 7.7+/-6.3 g; p=0.17), with no significant difference in ejection fraction at 90 days (54.6+/-12.0% vs. 49.1+/-12.1%; p=0.11). In the biomarkers, thrombin-antithrombin complexes were reduced by 4.8 ug/L over the first day for bivalirudin versus an increase of 1.9 ug/L in the heparin arm (p=0.0003). Acute IMR was lower (43.5+/-21.6 vs. 68.7+/-35.8 mmHgxs, respectively; p=0.014). In a planned interim analysis, an approximate 11% reduction in IS was observed with bivalirudin; the trial was discontinued for futility. CONCLUSIONS: This study did not achieve its primary endpoint of significant infarct size reduction in PPCI by prolonged bivalirudin infusion compared to UFH, even though complete thrombin inhibition was achieved in the acute phase, with a lower myocardial microcirculation resistance at the end of the procedure.

The initial STACKENOX (STACK-on to ENOXaparin) study investigated the effect of stacking unfractionated heparin (UFH) onto a chronic treatment with enoxaparin, a common practice in interventional cardiology when a patient treated with enoxaparin receives an additional bolus of UFH at the time of percutaneous coronary intervention. The study brought to light some unexpected consequences on coagulation tests and hemorrhagic risk. This substudy was performed to provide a pharmacological explanation for these observations. Seventy-two healthy individuals previously treated with enoxaparin for 2.5 days received a stack-on of 70 IU/kg intravenous UFH dose 4, 6, or 10 h after the last enoxaparin dose. Anticoagulation activity was monitored by activated partial thromboplastin time, anti-Xa and anti-IIa activities and a thrombin generation test. In parallel, plasma samples of the individuals receiving the chronic enoxaparin treatment obtained at 4, 6, or 10 h after the last enoxaparin dose were spiked in vitro with a dose of UFH reproducing the concentration achieved in vivo after the bolus of UFH alone. In-vivo stack-on of UFH induced an over-anticoagulation identified by changes in anti-Xa and, less markedly, in anti-IIa and activated partial thromboplastin time levels, whereas in-vitro UFH spiking, only produced an additive effect. We hypothesize that the potentiation of UFH on anti-Xa activity observed in vivo may caused by the UFH bolus mobilizing enoxaparin chains stored in the endothelial glycocalyx during chronic pretreatment. This over-anticoagulation and its potential hemorrhagic risk after stack-on of UFH have obvious clinical implications.

Background Despite dual antiplatelet treatment, major ischemic events are common following ST elevation myocardial infarction (STEMI). We aimed to assess high platelet reactivity on aspirin (HPR-aspirin) and its association with P2Y12i (HPR-P2Y12i) during the acute phase of STEMI. Methods We included all consecutive patients admitted for STEMI treated by primary angioplasty in our center for 1 year. All patients received a loading dose followed by a maintenance dose of aspirin (75 mg/day) and prasugrel (ticagrelor or clopidogrel if contraindicated). Platelet reactivity was assessed 4 ± 1 days and 75 ± 15 days after admission using light transmission aggregometry with arachidonic acid (LTA-AA–HPR-aspirin) and VASP (HPR-P2Y12i) to define HPR as well as serum Thromboxane-B2 and LTA-ADP. Major cardiac and cerebrovascular events were recorded for 1 year. Results We included 106 patients – mean age was 61 y.o., 76% were male and 20% had diabetes. STEMI was anterior in 52% and LV ejection fraction at discharge was 51 ± 9%. 50% of patients were treated with prasugrel and 34% with ticagrelor. At day 4 after STEMI, HPR-aspirin was found in 26% patients and HPR-P2Y12i in 7%. HPR- both aspirin and P2Y12i was found in 4%. Diabetes and age were predictors of HPR-aspirin. HPR-aspirin was persistent 75 days later in 36% patients. At 1 year, 7.9% patients had experienced major adverse cardiovascular and cerebrovascular events (MACCE). HPR-aspirin and HPR on both aspirin and P2Y12i were significantly associated with MACCE. Conclusion HPR-aspirin is frequent just after STEMI and associated with MACCE especially when associated with HPR-P2Y12i.

Aim of the study Acute coronary syndrome is one of the main causes of out-of-hospital cardiac arrest (OHCA). OHCA patients are particularly exposed to high platelet reactivity (HPR) under aspirin (ASA) treatment. The aim was to evaluate HPR-ASA in therapeutic hypothermia comatose patients resuscitated from OHCA. Methods and results Twenty-two consecutive patients with OHCA of cardiac origin were prospectively included after therapeutic hypothermia and randomized to receive ASA 100mg per day, either intravenously ( n =13) or orally via a gastric tube ( n =9). ADP inhibitors (prasugrel or, if contra-indicated, clopidogrel) were administered in the event of angioplasty. HPR-ASA was assessed by light transmission aggregometry (LTA) with arachidonic acid (AA) and by the PFA-100 ® system with collagen/epinephrine. Clinical, biological and angiographic characteristics were similar in both groups. Using LTA-AA, maximum aggregation intensity was significantly lower in the intravenous group compared to the oral group (15% vs. 29%, respectively; p =0.04). Overall, 10 patients (45%) had HPR-ASA (38% intravenously vs 56% orally; p =0.7). Similarly, closure time was significantly increased in the IV group (277s vs. 155s, respectively; p =0.04). Conclusion This study suggests that impaired response to both intravenous and oral aspirin is frequent in comatose patients resuscitated from OHCA.

Pendant des annees les seuls anticoagulants oraux a notre disposition ont ete les AVK (anti-vitamines K). Depuis quelques annees sont apparus progressivement les anticoagulants oraux directs (AOD), d’abord le dabigatran (inhibiteur direct de la thrombine) puis le rivaroxaban, l’apixaban et l’edoxaban, inhibiteurs directs de facteur Xa. Ils se caracterisent par une efficacite et un risque hemorragique egaux ou meilleurs que les AVK dans les principales indications ou ils ont ete evalues : prevention et traitement des evenements thromboemboliques veineux et prevention des embolies arterielles peripheriques, en particulier cerebrales, chez les patients porteurs d’une fibrillation auriculaire non valvulaire. Il n’empeche que la non-disposition d’un antidote est presentee et ressentie tant par les prescripteurs que par les patients comme un argument majeur de non-prise/prescription dans la crainte d’une hemorragie majeure a reverser rapidement ou d’un geste chirurgical a pratiquer en urgence. Le dabigatran est le premier AOD a avoir a disposition un antidote immediatement efficace et sans effet secondaire. Cette revue va retracer le developpement de cet anticorps idarucizumab jusqu’aux resultats de l’essai pivot de phase 3. Developpement qui a permis une mise sur le marche acceleree tant aux USA (FDA) qu’en Europe (EMEA).

The optimal duration of anticoagulation after a first episode of unprovoked deep-vein thrombosis is uncertain. We aimed to assess the benefits and risks of an additional 18 months of treatment with warfarin versus placebo, after an initial 6 months of anticoagulation for a first unprovoked proximal deep-vein thrombosis. We conducted a multicenter, randomized, double-blind, controlled trial comparing an additional 18 months of warfarin with placebo in patients with a unprovoked proximal deep-vein thrombosis initially treated for 6 months (treatment period: 18 months; follow up after treatment period: 24 months). The primary outcome was the composite of recurrent venous thromboembolism or major bleeding at 18 months. Secondary outcomes were the composite at 42 months, as well as each component of the composite, and death unrelated to pulmonary embolism or major bleeding, at 18 and 42 months. All outcomes were centrally adjudicated. A total of 104 patients, enrolled between July 2007 and October 2013 were analyzed on an intention-to-treat basis; no patient was lost to follow-up. During the 18-month treatment period, the primary outcome occurred in none of the 50 patients in the warfarin group and in 16 out of 54 patients (cumulative risk, 29.6%) in the placebo group (hazard ratio, 0.03; 95% confidence interval: 0.01 to 0.09; P

Les donnees classiques de l’hemostase et de la thrombose ont montre que les acteurs classiquement impliques sont, d’une part, des facteurs cellulaires avec deux cellules phares : les plaquettes et les cellules endotheliales et, d’autre part, des facteurs plasmatiques : les facteurs d’hemostase, de coagulation et de la fibrinolyse. C’est sur cette vision simplifiee qu’a ete developpe l’arsenal therapeutique dont nous disposons et qui regroupe, d’une part, les anti-plaquettaires et, d’autre part, les anti-coagulants et les procoagulants, et enfin les pro- et anti-fibrinolyiques. Pourtant le benefice clinique de ces antithrombotiques n’est que partiel, mettant en evidence que, soit nos moyens therapeutiques n’ont qu’une activite partielle sur leurs cibles, soit que les cibles identifiees jusqu’alors ne regroupent qu’une partie des intervenants veritablement actifs. Cette revue aura pour but d’expliciter de nouveaux intervenants plus recemment identifies dans l’hemostase et la thrombogenese : de nouvelles cibles contre lesquelles nous n’avons pas d’agent specifique (quoique comme on le verra de vielles molecules peuvent avoir des effets inattendus.

Aspirin is the key treatment in the secondary prevention of atherothrombosis. Interindividual variability of response has been linked to a higher risk for ischemic events. The aim of this study was to identify clinical and biologic factors predicting high on-aspirin platelet reactivity (HPR) in a high-risk, "real-world" population of vascular patients. All platelet testing performed from 2011 to 2013 in consecutive patients receiving long-term treatment with aspirin for coronary or cerebrovascular disease was retrospectively analyzed. Indications for platelet testing were recurrent ischemic events or high-risk angioplasty. HPR was defined as aggregation intensity≥20% using light-transmission aggregometry with arachidonic acid 0.5 mg/ml. Collagen-epinephrine platelet function analysis was also performed (threshold165 seconds). Cardiovascular risk factors, usual biologic parameters, and antiplatelet treatment were recorded. A total of 1,508 patients were included (mean age 63 years, 71% men, 23% with diabetes). Antiplatelet treatment was aspirin alone in 333 patients and dual-antiplatelet therapy in 1,175 patients. HPR was found in 11.1% of patients. In multivariate analysis, independent predictive factors of HPR on light-transmission aggregometry with arachidonic acid were diabetes mellitus (odds ratio [OR] 2.10, 95% confidence interval [CI] 1.39 to 3.16), age (OR 1.25, 95% CI 1.06 to 1.47), fibrinogen level (OR 1.20, 95% CI 1.02 to 1.42), and von Willebrand factor level (OR 1.06, 95% CI 1.03 to 1.09). On light-transmission aggregometry with arachidonic acid and collagen-epinephrine platelet function analysis, fibrinogen remained the main factor associated with HPR (OR 1.33, 95% CI 1.19 to 1.61). Similar results were found in patients treated with aspirin alone or dual-antiplatelet therapy. A fibrinogen level4.0 g/L was associated with a 3.9-fold increased risk for HPR in patients aged75 years. In conclusion, fibrinogen level was the major predictor of HPR on aspirin in this large population of high-risk vascular patients.

Les epistaxis sont la premiere cause de consultation pour un evenement hemorragique dans les services d’urgences.Deux tiers de ces patients adultes presentent une epistaxis idiopathique mais un traitement antithrombotique (anticoagulant et/ou antiplaquettaire) est la premiere etiologie d’induction ou d’aggravation du saignement. Les donnees des USA permettent d’estimer que pendant les annees 2006-8 : 60 000 patients sous traitement AVK ont presente une epistaxis suffisamment grave pour necessiter la consultation d’un service d’urgence. Il est estime qu’un nombre similaire de patient sous aspirine a consulte pour une epistaxis. Donc, dans les annees recentes un tiers des epistaxis pris en charge dans les services d’urgence l’etaient pour un patient sous traitement antithrombotique et d’un point de vue risque, l’aspirine et/ou le clopidogrel comme les AVK augmentent l’incidence des epistaxis d’un facteur 5 a 10 fois. Mais c’est une vision classique des annees passees qui va etre amplifiee/aggravee par la large utilisation des nouveaux anticoagulants et des nouveaux antiplaquettaires recemment commercialises :– parce que les nouveaux antiplaquettaires sont beaucoup plus puissants que ceux classiquement prescrits ;– parce que les nouveaux anticoagulants oraux ne sont plus regulierement monitores comme le sont encore les AVK et qu’ils presentent un risque d’accumulation en cas de mesusage en particulier chez les patients fragiles (degradation de la fonction renale, âge avance, faible poids) ;– parce qu’en France le nombre de patients anticoagules a double dans les toutes dernieres annees, augmentation due a la conjonction de la facilite d’utilisation de ces nouveaux anticoagulants oraux, de la meilleure application des recommandations de prescription associee au vieillissement de la population : avec le vieillissement, les raisons medicales indiquant un traitement anticoagulant, (principalement la fibrillation atriale) augmentent de maniere logarithmique.La prise en charge therapeutique d’une epistaxis chez un patient recevant un traitement anticoagulant doit en premier lieu evaluer les pertes sanguines et leurs consequences circulatoires pour decider de la necessite de les compenser en fonction de leur degre d’intensite et mettre en place la conduite therapeutique la mieux adaptee pour arreter le saignement.Cette attitude therapeutique devra satisfaire a plusieurs principes dont certains sont contradictoires :– identifier la cause de epistaxis : locale (pour mettre en place le moyen le mieux adapte pour stopper le saignement) ou systemique (parmi lesquelles la part du traitement antithrombotique doit etre evaluee) ;– la reponse therapeutique pour moderer ou reverser le traitement antithrombotique doit mettre en balance le risque thrombotique de la pathologie sous-jacente qui a motive la prise du traitement et le risque lie a la spoliation sanguine de l’episode hemorragique actuel pour au mieux stopper l’hemorragie sans faire courir un risque thrombotique majeur au patient ;– quand l’epistaxis est causee ou aggravee par un traitement antithrombotique, il est necessaire d’identifier clairement : la ou les molecules responsables, les traitements associes (comme les AINS ou les IRS), la pathologie ayant indique le traitement antithrombotique et les comorbidites (en pretant une attention speciale a la fonction renale) et si possible de determiner la concentration plasmatique et/ou les consequences hemostatiques pour adapter au mieux la strategie sur l’antithrombotique et l’intervention locale. Ceci permettant de temporiser jusqu’a ce que l’effet du traitement antithrombotique s’attenue ou de decider si une action additionnelle de reversion est necessaire.Comme les nouveaux traitements ont ete recemment introduits sur le marche (certains ne l’etant meme pas encore), a l’heure actuelle, les experiences de prise en charge des evenements hemorragiques et plus specialement des epistaxis sont assez restreintes. Cette revue va essayer d’aider a comprendre les attitudes therapeutiques a conseiller actuellement mais il est a prevoir qu’avec l’acquisition d’experience, il pourra y avoir des ajustements dans le futur.

Background: The patients with a short bowel (SB) frequently require antiplatelet therapy. Resection of the bowel is likely to modify the absorption and first-pass effect of drugs. No data on the absorption and efficacy of the cardiovascular dose of aspirin (75-160 mg) in these patients have been published. Objective: To evaluate the efficacy of a low dose of aspirin in patients with SB caused by mesenteric ischemia. Methods: The efficacy of a low dose of aspirin was assessed in 10 consecutive SB patients, both 1 hour and 24 hours after administration (peak and trough value, respectively). The primary criterion was the inhibition of platelet aggregation, as assessed by light transmission aggregometry, triggered with 0.5 mg/mL arachidonic acid. Biological efficacy of aspirin was also evaluated by serum thromboxane B2 value and by platelet function analyzer-100. Results: At its peak value, aspirin had the expected efficacy, as demonstrated both by light transmission aggregometry and the other methods. However, 24 hours after administration, as many as 30% of patients had lost the pharmacological efficacy of their aspirin. Conclusion: We show for the first time that with at least 30 cm of small intestine, all patients with SB absorb sufficient oral aspirin in a cardiovascular dose to rapidly exert the expected level of antiplatelet activity. But given only once daily, aspirin does not provide stable 24-hour antiplatelet protection in 30% of patients, because of increased platelet turnover, as usually observed in patients with extensive vascular pathology, diabetes, or inflammation.

Les medias s’ingenient a clamer le besoin d’antidotes pour les (nouveaux) anticoagulants oraux directs (ACOD). Pour avoir une juste estimation de ce besoin, il faut prendre en compte :– que pour beaucoup d’autres therapeutiques, il n’existe pas d’antidote et que personne ne s’en emeut, comme par exemple les antiplaquettaires dont en particulier les nouveaux sont aussi hemorragipares ;– que pour le competiteur ancien que sont les AVK (qui eux-memes n’auraient probablement pas l’AMM s’ils presentaient un dossier aujourd’hui), meme si les antidotes sont disponibles (PPSB et vitamine K), les protocoles sont etablis, acceptes et diffuses. Pour autant leur mise en application n’est pas ideale : ils ne sont utilises que dans la moitie des cas ou ils pourraient l’etre, et encore pour 50 % de ces cas ils ne sont pas utilises a la dose preconisee, conduisant de ce fait a des resultats qui, globalement, ne sont pas differents des hemorragies observees sous ACOD pour lesquels les antidotes ne sont pas disponibles ;– les antidotes sont en cours de developpement et devraient etre disponibles mais pas avant deux ans !Ce bruit de fond sur l’absence d’antidotes inquietent les medecins lorsqu’ils prescrivent un ACOD et surtout les patients qui ont l’impression qu’on leur prescrit un traitement dangereux alors qu’ils ne sont pas informes que les AVK sont au moins aussi dangereux. Quand les patients tirent tout le benefice et aucun des inconvenients des AVK, il n’y a pas de raison de s’emouvoir de cette stigmatisation des ACOD mais quand les ACOD pourraient apporter un benefice (ou une securite) pour le patient que les AVK n’apportent pas, il y a peut-etre lieu de s’en emouvoir.Cette mini-revue a pour objectif de faire le point sur ces differentes notions car ici, comme souvent ailleurs, il faut savoir raison garder.

Objective This study sought to determine the rate and potential clinical impact of persistent platelet reactivity (PPR) in unprotected left main (ULMD) stenting. Background PPR under aspirin or thienopyridines is associated with acute events after angioplasty. Methods We prospectively included 125 patients referred for ULMD stenting. For the first 64 patients (ALMA-1), angioplasty was performed under aspirin and clopidogrel without platelet reactivity assessment. For the last 61 patients (ALMA-2), platelet reactivity was assessed before angioplasty: in patients with aspirin-related PPR, aspirin twice daily was given and in those with clopidogrel-related PPR, clopidogrel double dose or prasugrel was used. Results Overall, patients' mean age was 69 ± 13 years, 37% were diabetic, and 37% had non-ST segment elevation myocardial infarction (NSTEMI). Patients' characteristics were similar in both studies with isolated left main in 14% and associated with 1-, 2-, or 3-vessel disease in 23%, 36%, and 27%, respectively. Mean SYNTAX score was 23 ± 9. Procedural characteristics were similar using provisional T stenting in 69%, T stenting in 27%, and other techniques in 4%. In ALMA-2, 28% patients had PPR for aspirin, 29% for clopidogrel, and 8% for both. Aspirin twice daily was given in 28% of patients, clopidogrel double dose in 26%, and prasugrel in 31%. The rate of 1-year major adverse cardiovascular and cerebrovascular events (MACCE) was lower in ALMA-2 versus ALMA-1 (8.2% vs. 20.8%; P = 0.04) as a composite end-point of cardiovascular death or stent thrombosis (0.0% vs. 8.3%; P = 0.02). Conclusion PPR under aspirin and thienopyridines is frequent in ULMD stenting and could be related to subsequent major events.

Notre epoque voit apparaitre de nouveaux types d’anticoagulants, de nature synthetique, agissant directement sur une seule des etapes-cles de la coagulation. Ils sont rapidement actifs par voie orale et ont comme objectif a plus ou moins long terme de remplacer les anticoagulants actuels, les anti-vitamines K (AVK), mais aussi les heparines. L’effet therapeutique reconnu des heparines est une activite anticoagulante (anti-Xa et anti-IIa) agissant de maniere indirecte (cofacteur de l’antithrombine) mais qui n’est portee que par seulement 20 % au mieux des chaines glycaniques composant les preparations commerciales d’heparines, qu’elles soient non fractionnees ou de bas poids moleculaire. Cependant, il faut aussi considerer les effets propres aux chaines glycaniques qui participent aux effets therapeutiques mais aussi potentiellement adverses des preparations d’heparine. Ces effets specifiques des glycanes sont potentiellement differents pour chaque preparation commerciale d’heparines et, en particulier, des heparines de bas poids moleculaire (HBPM) par rapport a l’heparine non fractionnee (HNF) et des HBPM entre elles. Si les effets anticoagulants des heparines pourront potentiellement etre remplaces ceux des nouveaux anticoagulants, les effets glycaniques des heparines eux ne peuvent pas etre remplaces par les molecules synthetiques non glycaniques. Ce remplacement permettra sans doute la limitation de certains risques comme celui de la thrombopenie induite par l’heparine mais les autres effets benefiques intervenant dans l’efficacite globale des heparines et dont l’importance relative reste a mieux evaluer, disparaitront egalement : effets sur les surfaces, effets anti-inflammatoires, effets antineoplasique et antimetastatique, effets anticoagulants annexes (non dependants de l’antithrombine), effet sur la dysfonction endotheliale. Tous ces effets pleiotropiques des heparines qui sont en fait les effets des glycanes feront l’objet de cette courte revue. Ceci a egalement des implications cliniques : a l’ere des generiques et des biosimilaires ou se dessinent des biosimilaires d’heparines (pour le moment seulement a l’etranger), il est important de savoir que leur biosimilarite ne va etre jugee que sur la caracteristique « anticoagulation » cofacteur de l’antithrombine (anti-IIa/anti-Xa) mais que tous les effets glycaniques potentiellement benefiques ou a contrario responsables d’effets adverses ne vont pas etre pris en consideration dans leur evaluation.

Les pathologies thromboemboliques sont une des, si ce n’est la cause majeure de morbidite et de mortalite. Il est etabli et admis que les thromboses arterielles sont differentes des thromboses veineuses mais leur pathogenie implique pour toutes : hemostase primaire, coagulation et fibrinolyse ; c’est la part relative de chacun de ces composants qui varie certes en fonction du type de thrombose et meme a l’interieur de chacune des sous-classes de thromboses. De plus, ces processus de l’hemostase primaire, de la coagulation, de la fibrinolyse sont etroitement lies et cooperent tout aussi etroitement avec d’autres systemes de reponse de l’organisme, en particulier celui de l’inflammation. Les anticoagulants sont utilises pour prevenir la survenue, l’extension, la complication et la recidive des evenements thromboemboliques dans des conditions declenchantes et des formes deja declarees. Jusqu’a maintenant, nous ne disposions comme anticoagulant « traditionnel » en forme injectable que des heparines et en forme orale que des antivitamines K dont on a progressivement appris les limites, les risques et les difficultes d’utilisation. La comprehension des phenomenes impliques dans les mecanismes de thrombogenese est essentielle pour non seulement developper de nouveaux antithrombotiques plus efficaces et avec moins de risques associes, mais surtout de comprendre les specificites de chaque sous-type/sous-classe de thrombose, pour mieux adapter le traitement aux patients qui necessitent une protection antithrombotique : par exemple, les mecanismes de la thrombogenese et la structure des thrombi veineux ne sont pas les memes chez les patients cancereux et non cancereux. Ces dernieres annees ont connu le developpement de nouveaux agents oraux avec des cibles enzymatiques uniques sur les facteurs de coagulation. La meilleure connaissance de la thrombogenese et les resultats des premiers essais avec ces nouvelles molecules nous aident a mieux comprendre la place et l’interet relatif de ces nouvelles cibles therapeutiques.

article i nfo Aim: Atrial fibrillation (AF), the most frequent arrhythmia, is a major independent cardiovascular (CV) risk factor, especially in elderly patients. The interest of Ddimer (DD) measurement for predicting CV risk has been suggested in some subgroups of patients with AF but little is known about the negative prognostic value of DD measurement. The primary aim was to assess whether DD measurement and monitoring could predict the occurrence of subsequent CV events, defined as MI, stroke or transient ischemic attack and arterial embolic events. Methods and results: It was a prospective observational study including patients with AF. Overall 425 patients (mean age 77 years) were included and followed-up every 4 months for a 16-months-mean duration. During this period, 26 patients experienced an endpoint of combined CV events. Patients with DD lower than 334 ng/ml had a very low risk of suffering of CV events (1.7%). Patients who will suffer from a CV event had a higher DD value, just before the occurrence of the CV event, while patients without CV event kept stable levels. Conclusion: We identified a DD threshold defining at any time patients at low risk of CV event. In addition, patients with higher DD levels are at higher risk of CV events, even if they are receiving oral anticoagulants. Otherwise, DD measurement is relevant in elderly patients. DD measurement and monitoring are useful to assess the risk of CV events in usual care. The implications of DD measurement on the choice and the intensity of the antithrombotic treatment remain to be determined.

Les diabetes et en particulier le diabete de type 2 est un tres lourd facteur de risque cardiovasculaire. L’incidence elevee des evenements thrombo-ischemiques cardiovasculaires au cours du diabete de type 2 s’explique par le developpement des lesions spontanees et leur recidive en cas de geste endovasculaire, par leur hyperthrombogenicite qui associe une hyperactivite plaquettaire, une hypercoagulabilite et une hypofibrinolyse. Les plaquettes interviennent doublement d’abord du fait de leur hyperactivite mais aussi de par leur moindre reponse aux traitements antiplaquettaires et en particulier aux deux traitements fondamentaux actuels : l’aspirine et le clopidogrel. C’est dire tout l’interet des nouveaux traitements antiplaquettaires (prasugrel et ticagrelor) dont l’efficacite parait etre relativement moins affectee par le diabete. A cote du risque thrombotique majore des diabetiques, le risque hemorragique global et en particulier celui des traitements antithrombotiques apparait significatif chez les patients diabetiques. Ceci est nettement montre la encore pour les deux antiplaquettaires fondamentaux (l’aspirine et le clopidogrel) et apparait a un degre moindre pour les patients diabetiques avec les nouveaux traitements antiplaquettaires (prasugrel et ticagrelor). On attend donc avec un interet particulier les etudes specifiquement destinees aux patients diabetiques tant en prevention secondaire qu’en prevention primaire pour juger du rapport benefice/risque dans cette population de patients caracterises par le double risque hemorragique et thrombotique.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Increased INR was previously observed in patients treated with warfarin and amoxicillin/clavulanic acid (amoxiclav) combination. To date, no prospective study has yet evaluated the effect of amoxiclav on INR in patients on warfarin therapy and consequently, there are no clear-cut conclusions or clear recommendations for clinicians. WHAT THIS PAPER ADDS • We provided the first systematic prospective evaluation of the interaction between amoxiclav and warfarin and found that amoxiclav did not modify INR in patients treated with stable warfarin therapy in the absence of any infectious or inflammatory syndrome, suggesting that the previously observed INR increase in these patients may not be attributable to a drug–drug interaction. AIMS To investigate whether an interaction exists between amoxicillin/clavulanic acid (amoxiclav) and warfarin in patients treated with stable oral anticoagulant therapy. METHODS In a double-blind, cross-over, placebo-controlled study, 12 patients on stable warfarin therapy, received a 7 day amoxiclav regimen or placebo. RESULTS The mean maximum increase in INR observed was 0.22 ± 0.3 with amoxiclav vs. 0.24 ± 0.6 with placebo (P= 0.94). The day 7–day 1 factor II, R(–) and S(–) warfarin plasma concentrations were similar during the amoxiclav and placebo study periods (P= 0.81, P= 0.45, P= 0.75, respectively). CONCLUSION Amoxiclav did not modify anticoagulation in patients treated with stable warfarin therapy and without infection.

SummaryThe FXIII-A Leu34 genetic variant increases and accelerates fibrin stabilisation; however, its association with premature coronary artery disease (CAD) and thrombotic events remains controversial. FXIII Val34Leu genotype was determined in 242 young individuals (

Platelet activation subsequent to the adhesion of platelets to the vascular wall results in the release of mediators that promote platelet aggregation, which plays a pivotal role in the development of the polyvascular atherosclerotic disease that can be referred to by the acronym 'ATIS' (AtheroThrombosIS). The currently available antiplatelet drugs used to prevent vascular events in patients with cardiovascular disease, including peripheral arterial disease (PAD), include aspirin and thienopyridines such as clopidogrel. These drugs decrease platelet aggregability, each of them by inhibiting a different pathway of platelet activation and recruitment. Aspirin acts by inhibiting thromboxane A2 (TXA2) formation through the inhibition (acetylation) of cyclo-oxygenase. On the other hand, thienopyridines suppress the platelet aggregation adenosine diphosphate (ADP) pathway by inhibiting the platelet P2Y12 subtype of the ADP receptor. The results of the large ATT (Antithrombotic Trialists' Collaboration) meta-analysis of published clinical studies on aspirin, reported in 2002, confirmed the previous meta-analysis and major trials that treatment with aspirin (mixed with other antiplatelet agents in these large meta-analyses) can prevent vascular events in high-risk patients with cardiovascular disease. However, it must be stressed that specifically in PAD patients no significant effect of aspirin was demonstrated in a more recent meta-analysis. This was also the case for primary and secondary prevention in diabetic patients. In keeping with these observations, neither a five-year follow-up study of Japanese diabetic patients in the JPAD (Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes) study, a seven-year follow-up study of UK diabetic patients with PAD in the POPADAD (Prevention of Progression of Arterial Disease and Diabetes) study, nor a very recent Scottish study in the same population of diabetics with PAD revealed a significant beneficial effect for aspirin in preventing ischaemic events. This failure may be a consequence of more rapid recovery of platelet aggregability following each dose of aspirin in these PAD or diabetic populations, with the accelerated platelet turnover resulting in a condition of aspirin resistance. Results of the large scale CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) trial that evaluated clopidogrel in patients with cerebral infarction, myocardial infarction or PAD have found clopidogrel to be significantly more effective than aspirin in preventing ischaemic events in patients with PAD. Furthermore, a subgroup analysis of the study has confirmed the efficacy of clopidogrel in diabetic patients with PAD, showing a significant reduction of events in clopidogrel-treated, compared with aspirin-treated, diabetic patients. These results are also likely to be attributable to the greater frequency of aspirin resistance in aspirin-treated patients in these populations (diabetics and/or PAD). Platelets, through activation and aggregation, have an important role in ATIS. However, although antiplatelet therapy with low-dose aspirin has been reported to prevent vascular events in high-risk patients with cardiovascular disease, recent studies in patients with PAD or diabetes mellitus have failed to support the efficacy of aspirin in preventing vascular events in these patient populations. In contrast, clopidogrel appears to be a useful antiplatelet agent in the prevention of vascular events in patients with PAD or diabetes.

ObjectivesThe purpose of this study was to determine whether the speed of response to clopidogrel loading predicts the final degree of response.BackgroundFast inhibition of platelet aggregation is important in the setting of acute coronary syndromes and percutaneous coronary intervention, but its association with the final degree of inhibition is not well established.MethodsWe performed a post hoc analysis of the ALBION study; early kinetic profiles of adenosine diphosphate 20 μmol/l maximal platelet aggregation (MPA) and ΔMPA (with baseline sample as reference) were studied at 8 time points within the 24 h after clopidogrel loading (300, 600, or 900 mg) in non–ST-segment elevation acute coronary syndrome patients. Low response was defined as ΔMPA

SummaryCompared with the approved dose regimen of clopidogrel (300-mg loading dose [LD], 75-mg maintenance dose [MD]), prasugrel has been demonstrated to reduce ischaemic events in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). In ACS, antiplatelet effects of a prasugrel MD regimen have not been previously compared with either a higher clopidogrel MD or after switching from a higher clopidogrel LD. The objective of this study was to evaluate the antiplatelet effect of a prasugrel 10-mg MD versus a clopidogrel 150-mg MD in patients with ACS who had received a clopidogrel 900-mg LD. Patients with non-ST elevation ACS, treated with aspirin and a clopidogrel 900-mg LD, were randomised within 24 hours post-LD to receive a prasugrel 10-mg or clopidogrel 150-mg MD. After 14 days of the initial MD, subjects switched to the alternative treatment for 14 days. The primary endpoint compared maximum platelet aggregation (MPA, 20 μM adenosine diphosphate [ADP]) between prasugrel and clopidogrel MDs for both periods. Responder analyses between treatments were performed using several platelet-function methods. Of 56 randomised subjects, 37 underwent PCI. MPA was 26.2% for prasugrel 10 mg and 39.1% for clopidogrel 150 mg (p

SummaryWe previously showed that variability of response to clopidogrel is linked to occupancy of the P2Y12 receptor by clopidogrel active-metabolite, and that maximal platelet aggregation intensity (MAI) measured by light transmission aggregometry (LTA) correlates with occupancy. The present study compared a range of ex vivo platelet tests at various levels of P2Y12 occupancy. After screening with clopidogrel 75 mg/day for seven days, subjects were selected to obtain ‘low’, ‘average’ and ‘high’ responders and randomised to clopidogrel (75 mg/day days 1–10; 300 mg day 11), or placebo. Assays were LTA in platelet-rich plasma using 2, 5 and 20 μM ADP, VerifyNow® P2Y12, flow cytometric analysis of platelet activation markers and vasodilator-stimulated phospho-protein (VASP) index, and a thromboelastographic test that is sensitive to clopidogrel. The reference test was P2Y12 receptor occupancy, measured by binding of 33P-2MeS-ADP to platelets. MAI showed the best correlation with P2Y12 occupancy. Similar results were seen with different ADP concentrations and when LTA data were expressed as inhibition of platelet aggregation. A plot of free receptors/cell versus VASP index was biphasic, with poor correlation for low-level P2Y12 occupancy. Sensitivity of the VerifyNow P2Y12 assay decreased at higher clopidogrel responses. Thromboelastography and P-selectin expression had poor correlation with receptor occupancy. In conclusion, LTA data correlate best with P2Y12 occupancy, the gold standard for detecting clopidogrel’s effect at the receptor level. Our results highlight a limitation of the VASP index, which appears unable to distinguish low, average and high responders early after clopidogrel initiation when P2Y12 occupancy is still low.

Resume Les differents types de vitamine K, leurs origines, leurs possibilites relatives d’absorption et de metabolisme, leurs effets relatifs sur la gammacarboxylation de differentes proteines jouant des roles clefs dans l’hemostase et la coagulation et les calcifications sont relativement mal connues meme de milieux dits experts et sont a l’origine d’erreurs de recommandations. Cette revue essaie de faire le point sur l’etat actuel des connaissances et sur ses consequences pratiques, en particulier sur la conduite des traitements anticoagulants oraux qui jusqu’au jour d’aujourd’hui ne repose que sur les antivitamines K. Plusieurs exemples illustrent la necessite d’ameliorer cette connaissance, la sur appreciation de l’effet de l’apport de vitamine K alimentaire sur l’equilibre des traitements par AVK conduit encore a recommander de quasi supprimer toute source de vitamine K alimentaire ce qui a pour effet de rendre les traitements sensibles aux moindres apports et d’augmenter leur instabilite, alors que la comprehension de la necessite d’un apport regulier et modere va faciliter les choix alimentaires des patients traites en chronique et aider a obtenir un equilibre regulier de leurs traitements. La vitamine K alimentaire a un role dans l’ossification et dans la prevention de l’osteoporose, jusqu’a tres recemment la possibilite d’un supplement alimentaire en vitamine K dans des produits alimentaires de grande consommation dans le but d’aider a la lutte contre l’osteoporose dans la population generale a ete totalement bridee par peur de desequilibrer les traitements anticoagulants des patients anticoagules s’ils consommaient ces aliments supplementes en vitamine K, alors que ces effets potentiels seraient tres modestes et pourraient peut-etre meme par leur apport regulier concourir a l’equilibration des traitements par les antivitamines K.

SummarySummary Interindividual variability of response to clopidogrel is currently a subject of much interest. We tested the hypothesis that functional variability in the platelet response to clopidogrel correlates with occupancy of the platelet P2Y12 receptor by clopidogrel active metabolite. Healthy subjects were screened after seven days’ treatment with clopidogrel 75 mg/day to select three clopidogrel-response groups (n=12/group), defined as ‘average’ (40–60% inhibition of platelet aggregation [IPA]), ‘low’ (80% IPA) responders. After a two- to six-week wash-out period, subjects were randomized (double-blind) to clopidogrel 75 mg/day (n=10/group) for 10 days, followed by clopidogrel 300 mg on day 11, or placebo (n=2/group). IPA induced by adenosine diphosphate (ADP), and P2Y12 receptor occupancy were measured repeatedly. The incidence of low responders was 3.7%, and low responses to clopidogrel were maintained during the randomized evaluation phase. Treatment with clopidogrel for 10 days induced a significant increase in P2Y12 receptor occupancy in each group of responders versus placebo; receptor affinity was unchanged. This reduction correlated with IPA response (r=0.54). The additional 300 mg dose of clopidogrel on top of 75 mg chronic treatment increased IPA and P2Y12 receptor occupancy in all groups, but relatively more in low responders. Variability in the response to clopidogrel appears to be linked to differences in P2Y12 receptor occupancy. An additional 300 mg dose of clopidogrel improves both IPA and P2Y12 receptor occupancy mostly in the subset of ‘low’ responders.

Background Although the need for an emergency intervention may merit laboratory measurement of non-vitamin K antagonist oral anticoagulant (NOAC) concentration or anticoagulant activity, NOACs are not supposed to require routine monitoring due to their stable pharmacological profiles compared with warfarin. Aims To examine situations where NOAC measurement may be useful and to provide information about methodologies available to measure NOAC-related anticoagulation activity. Summary of review The routine coagulation tests, including prothrombin time, thrombin time, activated partial thromboplastin time, and international normalized ratio, have variable sensitivities to NOACs. Tests have been developed for use with specific NOACs, e.g. diluted thrombin time or chromogenic factor Xa assays. In emergency situations, such as severe bleeding, stroke, or a requirement for urgent surgery or procedures, there may be a need to assess anticoagulant activity to guide clinical decision making. In cases where neutralization of the anticoagulant effect is warranted, specific reversal agents are likely to become invaluable medical tools. Evidence to date suggests that dosing decisions for NOACs based on clinical features (e.g. age or renal function) can help optimize the benefit–risk balance without assessment of anticoagulant activity in non-emergency routine situations. Conclusions Regular monitoring of NOAC levels does not provide benefits and cannot be recommended at present. In some specific circumstances, e.g. severe bleeding, before urgent surgery, or before thrombolysis, measurement may be beneficial to assess whether a patient is actively anticoagulated. The availability of NOAC-specific reversal agents may change management practices in emergencies.

Background Despite dual antiplatelet treatment with the new P2Y12 platelet receptor antagonists (P2Y12i), major ischemic events are common following ST elevation myocardial infarction (STEMI). Objectives To assess separately resistance to aspirin (HPR-aspirin), resistance to P2Y12i (HPR-P2Y12i) and their association during the acute phase of STEMI in relation to the occurrence of ischemic events. Methods We included all consecutive patients admitted for STEMI in our center between January 2013 and December 2013. All patients received a loading dose followed by a maintenance dose of aspirin (75mg/day) and either clopidogrel, prasugrel or ticagrelor. Platelet reactivity was assessed 4±1 days and 75±15 days after admission using light transmission aggregometry (LTA) with arachidonic acid (AA) and serum Thromboxane-B2 concentration to assess HPR-aspirin and LTA-ADP and VASP index to assess HPR-P2Y12i. Major cardiac and cerebrovascular events (MACCE) were recorded during one year. Results 106 patients (61years old, 76% male, 20% with diabetes) were included. STEMI was anterior in 52% and LV ejection fraction at discharge was 51±9%. At day 4 after STEMI, HPR-aspirin measured by LTA-AA alone was found in 23% patients and was correlated with serum thromboxane inhibition, HPR-P2Y12i (VASP≥50% and LTA-ADP≥65%) was observed only in 7% and combined resistance was present in 4% of the patients. Diabetes and age were predictors of HPR-aspirin. The large use of ticagrelor (34%) and prasugrel (50%) explained the low rate of P2Y12i resistance. HPR-aspirin was persistent 75 days later in 36% patients who were resistance at day 4. At 1 year, 7.9% patients had experienced MACCE. HPR-aspirin alone and HPR for both aspirin and P2Y12i were significantly associated with MACCE. Conclusion Aspirin resistance is frequent just after STEMI and is associated with MACCE especially when associated with P2Y12i resistance.

Background Vitamin K antagonists (VKA) are widely prescribed throughout the world. Patients on VKA therapy require international normalized ratio (INR) monitoring of venous blood to ensure the response remains within the therapeutic window. Point-of-care devices (POC-INR) can safely and easily monitor VKA efficacy but need to be evaluated in practice. The aim of this study was to assess the precision and accuracy of a new POC-INR (Qlab) compared to the laboratory plasma technique and the CoaguChek-XS system. Methods Consecutive patients on VKA referred to our institution were included. The study was designed to analyze 75 patients divided equally in the following subgroups: INR 3. INR was measured with an established laboratory method (INRREF) with an international sensitivity index of 1.0 and by two different POC-INRs: the Qlab (INRQlab) and the CoaguChek-XS systems (INRXS). Results 82 patients treated mainly for atrial fibrillation or venous thromboembolism disease were included. Precision in therapeutic range (INR = 2–3) of both POC-INRs was satisfactory with a coefficient of variation of 4.6% for the Qlab and 4.3% for the CoaguChek-XS. INRRef was 2.70 ± 1.36, INRQlab 2.59 ± 1.25 and INRXS 2.89 ± 1.37. Accuracy was low with the Qlab (R2 = 0.64) and higher with the CoaguChek-XS (R2 = 0.94). The mean relative difference from the INRRef was higher for the Qlab (18.4%) than for the CoaguChek-XS (12.9%). Clinical concordance was lower with the Qlab (78.2%) than with the CoaguChek-XS (90.0%). Conclusion This study suggests that the Qlab has accuracy limitations with clinical consequences. New POC-INR devices require careful evaluation prior to clinical implementation.

International audience; The optimal duration of anticoagulation after a first episode of unprovoked pulmonary embolism is uncertain. To determine the benefits and harms of an additional 18-month treatment with warfarin vs placebo, after an initial 6-month nonrandomized treatment period on a vitamin K antagonist. Randomized, double-blind trial (treatment period, 18 months; median follow-up, 24 months); 371 adult patients who had experienced a first episode of symptomatic unprovoked pulmonary embolism (ie, with no major risk factor for thrombosis) and had been treated initially for 6 uninterrupted months with a vitamin K antagonist were randomized and followed up between July 2007 and September 2014 in 14 French centers. Warfarin or placebo for 18 months. The primary outcome was the composite of recurrent venous thromboembolism or major bleeding at 18 months after randomization. Secondary outcomes were the composite at 42 months (treatment period plus 24-month follow-up), as well as each component of the composite, and death unrelated to pulmonary embolism or major bleeding, at 18 and 42 months. After randomization, 4 patients were lost to follow-up, all after month 18, and 1 withdrew due to an adverse event. During the 18-month treatment period, the primary outcome occurred in 6 of 184 patients (3.3%) in the warfarin group and in 25 of 187 (13.5%) in the placebo group (hazard ratio [HR], 0.22; 95% CI, 0.09-0.55; P = .001). Recurrent venous thromboembolism occurred in 3 patients in the warfarin group and 25 patients in the placebo group (HR, 0.15; 95% CI, 0.05-0.43); major bleeding occurred in 4 patients in the warfarin group and in 1 patient in the placebo group (HR, 3.96; 95% CI, 0.44 to 35.89). During the 42-month entire study period (including the study treatment and follow-up periods), the composite outcome occurred in 33 patients (20.8%) in the warfarin group and in 42 (24.0%) in the placebo group (HR, 0.75; 95% CI, 0.47-1.18). Rates of recurrent venous thromboembolism, major bleeding, and unrelated death did not differ between groups. Among patients with a first episode of unprovoked pulmonary embolism who received 6 months of anticoagulant treatment, an additional 18 months of treatment with warfarin reduced the composite outcome of recurrent venous thrombosis and major bleeding compared with placebo. However, benefit was not maintained after discontinuation of anticoagulation therapy. clinicaltrials.gov Identifier: NCT00740883.

Resume Introduction Les hemorragies liees au traitement par antivitamines K (AVK) ont en France la premiere place des accidents iatrogenes. Objectifs L’etude internationale, observationnelle, longitudinale et retrospective ISAM avait pour but d’evaluer l’utilisation des AVK et la qualite de leur suivi biologique en pratique medicale courante. Methodes Dans l’etude francaise, des medecins generalistes et des cardiologues representatifs ont selectionne des patients traites pendant au moins 60 jours au cours des 12 derniers mois par des AVK pour fibrillation auriculaire non valvulaire. Les donnees retrospectives sur un an ont ete recueillies a l’aide de questionnaires standardises aupres des medecins et de leurs patients. Resultats Au total, 43 generalistes et 20 cardiologues ont inclus 278 patients qui ont complete les questionnaires. Deux cent soixante-quatre patients ont eu au moins 2 INR (International Normalized Ratio) pendant la periode de l’etude. Dans l’annee precedant l’inclusion, les patients ont passe 59% du temps avec un INR dans l’intervalle therapeutique 2,0–3,0et 27% du temps avec un INR > 3. Les medecins declaraient donner des recommandations ecrites concernant la posologie des AVK a pres de la moitie de leurs patients, mais seuls 3% leur remettaient un carnet d’information et de surveillance de traitement par AVK. L’information du traitement etait assuree par le medecin generaliste pour 65% des patients. Toutefois, 18 % des patients disaient ne pas etre informes 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 ete rapporte par 45% des patients. Conclusion II existe une place importante a l’education therapeutique pour ameliorer la prise en charge, le bon usage et le suivi biologique du traitement par AVK aupres des medecins et des patients.

OBJECTIVES We sought to compare the antiplatelet effects of three clopidogrel loading doses (LDs). BACKGROUND Administration of a 300-mg clopidogrel LD is beneficial in situations requiring rapid platelet inhibition. Whether higher LDs can provide further benefits remains unknown. METHODS Patients (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. RESULTS Compared 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 ( 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.

Regular and moderate wine consumption is one of the explanations suggested for the lower incidence of cardiovascular events in France compared with other industrialized countries. We evaluated whether alcohol alone or combined with red wine polyphenols reduced plaque size and/or attenuated thrombotic reactivity at the site of advanced atherosclerotic lesions. Red wine extract, or purified (+)-catechin with alcohol, or alcohol alone, was added for 12 weeks to the drinking water of apoE-deficient (apoE−/−) C57B/ mice and wild-type counterparts. In the apoE−/−mice, all alcohol-containing mixtures were associated with a larger size of aortic atherosclerotic lesions. On the other hand, red wine extract and (+)-catechin significantly inhibited blood thrombotic reactivity (Pex vivothrombus were 64% and 63%, respectively. In the wild-type mice, red wine extract and (+)-catechin tended to reduce thrombogenicity, which was on the whole less marked than in the apoE−/−mice. These findings suggest that a moderate and regular consumption of red wine may protect against clinical cardiovascular events, mainly by attenuating the thrombogenic response rather than by reducing the development of atherosclerotic lesions. This antithrombogenic effect may include normalization of the abnormally high thrombogenic responsiveness in apoE−/−mice as well as a direct antithrombotic effect.

La plupart des evenements cardiovasculaires sont une consequence thrombotique de l'evolution d'une lesion d'atherosclerose. L'inflammation joue un role central tant dans le developpement que dans la survenue des complications evolutives des lesions d'atherosclerose (en particulier de rupture de plaques). Les donnees epidemiologiques montrent de maniere concordante que l'augmentation du fibrinogene (par rapport aux valeurs de controles apparies) est predictive du risque d'accident cardiovasculaire aussi bien dans la population generale pour predire le premier evenement cardiovasculaire que chez les patients pour predire le risque de recidive. La concentration plasmatique du fibrinogene est determinee a la fois par une predisposition genetique et par des facteurs acquis et environnementaux. C'est un exemple des interrelations gene-environnement. Il faut prendre conscience que l'augmentation du fibrinogene (responsable de l'augmentation significative du risque) est une augmentation tres moderee (comprise dans les valeurs de reference du taux plasmatique). Cela permet de comprendre que ce facteur si predictif lorsqu'il est considere d'un point de vue epidemiologique, n'a aucune valeur pour etablir le risque cardiovasculaire a un niveau individuel en pratique clinique quotidienne (sauf pour les tres fortes augmentations qui ne sont rencontrees que tres rarement).

Most cardiovascular events result from a thrombotic complication of atherosclerotic lesions. In arterial vessels such as the coronary bed, an interrelationship of haemostatic, coagulation and fibrinolytic factors is implicated. While it can be demonstrated that fibrinogen is a risk factor/marker, the role of other factors is not well established. Under arterial flow conditions, platelets are predominantly involved in the thrombotic reaction. Yet, apart from a large increase in the platelet count, the involvement of platelet parameters in cardiovascular risk is not clearly evident. The lack of definitive platelet markers is at least partly due to the difficulty of studying platelet function ex vivo. Several polymorphisms of platelet glycoproteins carrying a moderate increase in risk have been reported, but only in younger patients. One potentially important factor for coagulation is the fibrin structure, which is dependent on fibrinogen, the rate of thrombin generation, the activity of factor XIII and the interrelationship of the cells concerned, all of which act on its sensitivity to thrombosis. Coagulation factors largely affect the rate of thrombin generation. The activity of the fibrinolytic system (and principally any deficiency) has a role in the cardiovascular risk. General markers of cardiovascular risk such as D-dimers are potentially useful, but they increase with thrombin generation and are decreased by a deficiency in fibrinolysis. Furthermore, possibly because they are not indicative of the fibrin structure, they are poorly correlated with clinical events. The poor significance of the available haemostatic, coagulation and/or fibrinolytic parameters is probably due to their lack of representativeness, since haemostatic, coagulation and fibrinolytic systems are all involved in the thrombotic response (and some in atherogenesis itself). Atherogenesis is a multifactorial process and numerous moderate risk factors act in association. Better predictability of the haemostatic tests would probably result from both the design of more representative tests and the evaluation of multiple parameters, and would lead to the definition of a risk score. Technological advances will make this possible.

BACKGROUND CD14 pathway is at the crossroads between infection and inflammation. In human pathology, divergent results have been reported on the relationship between a polymorphism in the promoter of receptor CD14 (C260T), expression of soluble CD14 (sCD14) receptor and atherosclerosis. The aim of the study was to investigate in a cross-sectional population-based sample the relationships between C260T polymorphism in CD14 gene, sCD14 blood levels and arterial wall. METHODS Among 1015 subjects, randomly recruited by the Toulouse MONICA center between 1995 and 1997, 899 subjects with complete data for all the measurements, were analyzed. sCD14 was measured using an immuno-enzymatic method. Common carotid intima-media thickness (IMT) and the presence of plaques in the carotid and femoral arteries were assessed by ultrasonography. A genotypic examination for the CD14 C260T polymorphism was performed. RESULTS An increase in sCD14 expression was observed in subjects carrying t allele (P < 0.01). No significant difference in intima-media thickness, number of plaques and pulse wave velocity was noticed according to C260T polymorphism. An interaction (P < 0.05) was observed between C260T polymorphism and current smoking in sCD14 expression: among smokers, no significant change in sCD14 was observed in individuals carrying t allele. CONCLUSION Although (C260T) polymorphism in CD14 gene in this study is associated with expression of sCD14, no significant association was found between this polymorphism and early markers of atherosclerosis. This polymorphism affects plasma levels of sCD14 in relation to current smoking status. Further studies are needed to determine whether this interaction influences the deleterious effect of smoking on vascular events.

BACKGROUND Pulse pressure (PP), C reactive protein (CRP) and soluble intercellular adhesion molecule-1 (sICAM-1) levels have been associated with cardiovascular prognosis. Interestingly, previous reports have shown that PP was associated both with CRP and sICAM-1. The mechanisms underlying these associations remain unknown. On the one hand, it has been shown that PP influences, via endothelial function, the expression of various molecules, which in turn may generate inflammation. On the other hand, inflammation-induced changes in the arterial wall, modifying the PP, may be the confounding factor of these relationships. The aim of the present study was to investigate the role played by the arterial structure and the aortic stiffness on these relationships. METHODS In a cross-sectional population sample of 891 healthy subjects, carotid-femoral pulse wave velocity and blood pressure were measured in the supine position. The common carotid intima-media thickness and the presence of plaques were assessed by ultrasonography. CRP and sICAM-1 levels were measured by an immunonephelemetric method and an immunoenzymatic method, respectively. RESULTS A positive relationship was found between PP and CRP (P < 0.001). This relationship remained after adjustment for classical cardiovascular risk factors, and successively for mean blood pressure, intima-media thickness, presence of plaques and pulse wave velocity (P < 0.05). No significant association was observed between PP and sICAM-1. CONCLUSIONS The results of this study demonstrate that changes in arterial structure and in arterial stiffness are not confounding factors in the relationship between PP and CRP.

Objectives The 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. Background Although 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. Methods Thirty-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. Results After 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 Conclusions The 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.