Hepatic and Vascular Vitamin K Status in Patients with High Cardiovascular Risk.

Vitamin K dependent proteins (VKDP), such as hepatic coagulation factors and vascular matrix Gla protein (MGP), play key roles in maintaining physiological functions. Vitamin K deficiency results in inactive VKDP and is strongly linked to vascular calcification (VC), one of the major risk factors for cardiovascular morbidity and mortality. In this study we investigated how two vitamin K surrogate markers, dephosphorylated-undercarboxylated MGP (dp-ucMGP) and protein induced by vitamin K absence II (PIVKA-II), reflect vitamin K status in patients on hemodialysis or with calcific uremic arteriolopathy (CUA) and patients with atrial fibrillation or aortic valve stenosis. Through inter- and intra-cohort comparisons, we assessed the influence of vitamin K antagonist (VKA) use, vitamin K supplementation and disease etiology on vitamin K status, as well as the correlation between both markers. Overall, VKA therapy was associated with 8.5-fold higher PIVKA-II (0.25 to 2.03 AU/mL) and 3-fold higher dp-ucMGP (843 to 2642 pM) levels. In the absence of VKA use, non-renal patients with established VC have dp-ucMGP levels similar to controls (460 vs. 380 pM), while in HD and CUA patients, levels were strongly elevated (977 pM). Vitamin K supplementation significantly reduced dp-ucMGP levels within 12 months (440 to 221 pM). Overall, PIVKA-II and dp-ucMGP showed only weak correlation (r2 ≤ 0.26) and distinct distribution pattern in renal and non-renal patients. In conclusion, VKA use exacerbated vitamin K deficiency across all etiologies, while vitamin K supplementation resulted in a vascular VKDP status better than that of the general population. Weak correlation of vitamin K biomarkers calls for thoughtful selection lead by the research question. Vitamin K status in non-renal deficient patients was not anomalous and may question the role of vitamin K deficiency in the pathogenesis of VC in these patients.

Is antivitamin K reversal required in patients with cirrhosis undergoing liver transplantation?

BACKGROUND: Antivitamin K agent (AVK) reversal in patients with cirrhosis awaiting liver transplantation (LT) is not defined in guidelines. We investigated the effect of reversion with prothrombin complex concentrate (PCC) on intraoperative transfusion, bleeding, and safety in LT patients on AVK. STUDY DESIGN AND METHODS: In 511 patients undergoing LT, we identified 25 patients treated with AVK (AVK group) and 13 patients with incidental portal vein thrombosis (PVT) without AVK (incidental PVT group). Fifty patients who underwent LT without PVT or AVK matched by age, model for end stage of liver disease (MELD), body mass index (BMI), and cirrhosis etiology were selected as the control group. RESULTS: There were no significant differences between the three groups in intraoperative blood loss, transfusion, and postoperative bleeding. In the AVK group, there were no differences between patients who received PCC and those who did not in intraoperative blood loss, red blood cells, fibrinogen, and platelet transfusion, or postoperative bleeding. PCC use had no effect on RBC transfusion in patients who had international normalized ratio or clotting time above versus below median values of the two parameters at baseline (2.3 and 103 s, respectively). No thrombotic events were detected in patients who received PCC. DISCUSSION: These data suggest that systematic administration of PCC to revert AVK prior to LT should be reconsidered.

Edoxaban versus Vitamin K Antagonist for Atrial Fibrillation after TAVR.

BACKGROUND: The role of direct oral anticoagulants as compared with vitamin K antagonists for atrial fibrillation after successful transcatheter aortic-valve replacement (TAVR) has not been well studied. METHODS: We conducted a multicenter, prospective, randomized, open-label, adjudicator-masked trial comparing edoxaban with vitamin K antagonists in patients with prevalent or incident atrial fibrillation as the indication for oral anticoagulation after successful TAVR. The primary efficacy outcome was a composite of adverse events consisting of death from any cause, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, or major bleeding. The primary safety outcome was major bleeding. On the basis of a hierarchical testing plan, the primary efficacy and safety outcomes were tested sequentially for noninferiority, with noninferiority of edoxaban established if the upper boundary of the 95% confidence interval for the hazard ratio did not exceed 1.38. Superiority testing of edoxaban for efficacy would follow if noninferiority and superiority were established for major bleeding. RESULTS: A total of 1426 patients were enrolled (713 in each group). The mean age of the patients was 82.1 years, and 47.5% of the patients were women. Almost all the patients had atrial fibrillation before TAVR. The rate of the composite primary efficacy outcome was 17.3 per 100 person-years in the edoxaban group and 16.5 per 100 person-years in the vitamin K antagonist group (hazard ratio, 1.05; 95% confidence interval [CI], 0.85 to 1.31; P = 0.01 for noninferiority). Rates of major bleeding were 9.7 per 100 person-years and 7.0 per 100 person-years, respectively (hazard ratio, 1.40; 95% CI, 1.03 to 1.91; P = 0.93 for noninferiority); the difference between groups was mainly due to more gastrointestinal bleeding with edoxaban. Rates of death from any cause or stroke were 10.0 per 100 person-years in the edoxaban group and 11.7 per 100 person-years in the vitamin K antagonist group (hazard ratio, 0.85; 95% CI, 0.66 to 1.11). CONCLUSIONS: In patients with mainly prevalent atrial fibrillation who underwent successful TAVR, edoxaban was noninferior to vitamin K antagonists as determined by a hazard ratio margin of 38% for a composite primary outcome of adverse clinical events. The incidence of major bleeding was higher with edoxaban than with vitamin K antagonists. (Funded by Daiichi Sankyo; ENVISAGE-TAVI AF ClinicalTrials.gov number, NCT02943785.).

[GFHT proposals for management of discordance between the International normalized ratio measured in the laboratory and by self-testing]. / Propositions du GFHT pour la gestion des discordances entre l'International normalized ratio mesuré au laboratoire et en automesure.

The lack of quality control for patient point-of-care (POC) INR devices is an issue that has led the French health authorities to make recommendations: a laboratory INR (lab INR) has to be performed at the same time as the POC INR every 6 months. However, the differences observed between the two INRs, POC and lab INRs, are not necessarily due to a failure of the POC INR device. We present here a review of the different causes of discrepancies between INR results, which are the basis of the proposals of the Groupe français d'études sur l'hémostase et la thrombose (GFHT) on the management of lab and POC INR discrepancies. Pre-analytical conditions may account for discrepancies (sampling, transport and storage conditions), as well as analytical factors (mainly the nature of the thromboplastin used) and the clinical context (inflammatory or autoimmune diseases, polycythaemia...). The interpretation of INR discrepancies is not always easy and these proposals aim at standardizing the procedure to be followed in order to make the most appropriate decision for the patient.

[INR and vitamin K antagonists management by the primary care physicians in Normandy]. / Gestion de l'INR et des antivitamines K par les médecins généralistes de Normandie.

The main objective of our study was to carry out a statement of the knowledge and the management of the VKA by the General Practitioners (GPs) of Normandy and to evaluate their experience of the use of DOA with a questionnaire; 471 of the 1951 GPs requested responded. When the INR was stable in a patient affected with atrial fibrillation, the GPs participating dosed it again 4 weeks later, modified the dosage when the INR was below 1.9 or upper 3.2. The risk of stroke was overestimated to 6.2% per year with fluindione and to 31.5% without curative anticoagulation. The mean TTR was overstated to 84%. When the INR was at 4.4, the risk of serious cerebral bleeding was overestimated at 12.4%. 80.26% of the GPs skipped the next dose and 11.25% controlled the INR the day after. So, few GPs used the HAS protocol. After the INR decreased to 3.6, the GPs diminished the dose of 14.62%. 70% of the GPs, responded using only their experience for AVK management. Fluindione was the most to use VKA by 52.7% of them although 24.42% thought it was the most effective. The majority of GPs thought the DOA were a least as effective than the VKA, without being responsible of more bleeding (77.92%) and improved the quality of life of the patients (88.54%). Although the DOA's prescriptions increase, the improvement of the VKA management have to stay a concern for the GPs.

Epidemiology of thromboembolic and hemorrhagic events in patients with atrial fibrillation under anti-vitamin K.

BACKGROUND: Atrial fibrillation is the most common heart rhythm disorder in the general population. It is associated with increased cardiovascular morbidity and mortality. Given this risk, anticoagulant therapy is vital. AIM: To estimate the incidence of thromboembolic and hemorrhagic events in patients with Atrial fibrillation and treated by oral anticoagulant in a cardiology department. METHODS: We carried out an observational longitudinal study over a period of three years (January 2013 - December 2015) in the external consultation of cardiology of Farhat Hached hospital of Sousse. Pre-established individual records were used as a source and tool for data collection. RESULTS: Overall, 200 patients were eligible. Forty-nine percent had valvular atrial fibrillation. After an average follow-up of 2.6 years, 15 thromboembolic events were noted affecting 13 patients (6.5%), with an incidence of 2.8%. We found a significant association between TTR <50% and the occurrence of stroke and transient ischemic events. Half of the patients had minor bleeding and 9.5% had major bleeding, with an incidence of 3.6%. No significant correlation between these accidents and the TTR was found. In addition, 9.5% of patients were hospitalized for international normalized ratio equilibration. They were mainly patients with valvular atrial fibrillation (72%) (p = 0.002). CONCLUSION: Anticoagulant therapy with anti-vitamin-K remains the most adequate treatment. Thus, a well-conducted treatment ensures a reduction in thromboembolic risk and minimizes the occurrence of hemorrhages inherent to this therapy. Therefore, an assessment of the quality of anticoagulation is essential.

Diagnosing and treating antiphospholipid syndrome: a consensus paper.

INTRODUCTION: The antiphospholipid syndrome (APS) is defined by the occurrence of venous and/or arterial thrombosis and/or pregnancy-related morbidity, combined with the presence of antiphospholipid antibodies (aPL) and/or a lupus anticoagulant (LAC). Large, controlled, intervention trials in APS are limited. This paper aims to provide clinicians with an expert consensus on the management of APS. METHODS: Relevant papers were identified by literature search. Statements on diagnostics and treatment were extracted. During two consensus meetings, statements were discussed, followed by a Delphi procedure. Subsequently, a final paper was written. RESULTS: Diagnosis of APS includes the combination of thrombotic events and presence of aPL. Risk stratification on an individual base remains challenging. 'Triple positive' patients have highest risk of recurrent thrombosis. aPL titres > 99th percentile should be considered positive. No gold standard exists for aPL testing; guidance on assay characteristics as formulated by the International Society on Thrombosis and Haemostasis should be followed. Treatment with vitamin K-antagonists (VKA) with INR 2.0-3.0 is first-line treatment for a first or recurrent APS-related venous thrombotic event. Patients with first arterial thrombosis should be treated with clopidogrel or VKA with target INR 2.0-3.0. Treatment with direct oral anticoagulants is not recommended. Patients with catastrophic APS, recurrent thrombotic events or recurrent pregnancy morbidity should be referred to an expert centre. CONCLUSION: This consensus paper fills the gap between evidence-based medicine and daily clinical practice for the care of APS patients.

Synthesis, characterization and unravelling the molecular interaction of new bioactive 4-hydroxycoumarin derivative with biopolymer: Insights from spectroscopic and theoretical aspect.

In the progress of small molecule as drug candidates, 4-hydroxycoumarin based compounds bearing a crucial place as potent antibiotic agents with appreciable safety in drug invention. Being synthetically and easily obtainable, 4-hydroxycoumarin related compounds with planar structure have been promoted predominantly as DNA targeting agent. Nevertheless, here we elucidate the synthesis, characterization and theoretical study of bio-active small molecule 4-hydroxy-3,4'-bichromenyl-2,2'-dione (4HBD). Then we have illuminated the binding interactions of 4HBD with calf thymus DNA (ctDNA), which is particularly designed for biological application. Extensive investigations of the binding of 4HBD with ctDNA are provided by utilizing multi-spectroscopic and molecular docking approaches, including UV-vis absorbance, steady-state, time-resolved fluorescence spectroscopy and circular dichroism study. The calculated binding and quenching constant value from quantitative data analysis of absorption and emission spectroscopy shows that 4HBD binds to the ctDNA groove. Further confirmation of the same is found by comparative displacement and iodide quenching studies. Negative enthalpy, negative free energy and positive entropy change imply a hydrophobic force monitors the association of 4HBD with the biomacromolecule. Interestingly the small molecule (4HBD) shows potential anti-bacterial activity against the model pathogenic gram-negative (Escherichia coli and Pseudomonas aeruginosa) and gram-positive (Bacillus subtilis and Staphylococcus aureus) bacteria. The noncytotoxic nature of the 4HBD is demonstrated in vitro with the help of MTT assay by normal kidney epithelial (NKE), breast cancer cells (MCF-7) and human prostate cancer cell (PC3) lines. Hemolytic assay exhibits insignificant hemolysis of human erythrocyte cells at the minimum inhibitory concentration (MIC) of these tested bacteria. In this regard the present invention of 4-hydroxycoumarin based antimicrobial and noncytotoxic 4HBD molecule holds future promise in the development of new antibiotics.

Evaluation of patients' knowledge on their vitamin K antagonist treatment.

INTRODUCTION: Vitamin K antagonists (VKA) are currently the most prescribed oral anticoagulant treatment in Tunisia. Despite the standardization of biological monitoring and the better definition of therapeutic objectives, their side effects are a frequent reason for hospitalization. AIM: To evaluate patients' knowledge about their VKA treatment. METHODS: We realized a cross-sectional descriptive study in the Cardiology Department of HabibThameur Hospital from September to October 2016. A questionnaire consisting of 14 items was used in a semi-directed interview in order to assess patients' knowledge on their VKA treatment. RESULTS: Our study included one hundred patients. Mean age was 61 ± 12 years and sex ratio of 1.8. Forty-eight per cent were illiterate. The median duration of AVK intake was 5 years. Atrial fibrillation (AF) was the most frequent indication (57%). Eighty percent of patients had more than five correct answers on the eight items of knowledge: VKA's name (96%), tablet description (93%), dose (99%), time (94%), VKA's effect (70%), INR (56%), treatment's risk (49%) and the target INR (20%). Twenty-two percent had more than four correct answers on the 6 items of know-how: what to do in case of haemorrhage (70%), what to do in case of oblivion (45%), interactions precautions to be observed with food (13%), activities advised against (49%) and medical procedures advised against (27%). In multivariate analysis, only prior VKA information was significantly associated with a better knowledge of VKA (p = 0.027). CONCLUSION: Our patients' knowledge on their VKA treatment was insufficient to ensure the safety and efficacy of treatment. The creation of a therapeutic education program on is therefore necessary to reduce the iatrogenic risk of this treatment.

[Educational and information needs of patients under vitamin K antagonist therapy]. / Quels besoins d'information et d'éducation des patients traités par les anti-vitamines K ?

BACKGROUND: Adverse events related to vitamin K antagonists (VKA) represent a major public health problem. Informative tools and educative program contributes to the reduction of iatrogenic risk. The purpose of our study is to assess representations and information needs of patients under VKA therapy in order to develop a suitable therapeutic education program. METHODS: Individual semi-structured interviews were conducted among both long term VKA therapy patient and patients initiating VKA. The thematic analysis allowed us to explore patient's speech qualitatively and semi-quantitatively. RESULTS: The main needs in information concerned the modalities of treatment (27.6%), side effects (24.1%), precautions and management of VKA treatment (24.1%). Origin of the disease (P=0.022) and drug mechanism of action (0.012) were specially asked about by patients initiating their treatment. CONCLUSION: Patients under VKA therapy reported needs for information on both their pathology and their anticoagulant therapy. The therapeutic education approach will enable us to adapt the educational tools and messages to the needs of patients under VKA therapy.

[Vitamine K antagonists overdose: Physician adherence to the French guidelines]. / Surdosages en antivitamines K : audit de la prise en charge hospitalière.

INTRODUCTION: Vitamin K antagonists (VKA) are drugs with a major risk of side effect. Guidelines have been published in 2008 by the Haute Autorité de santé (HAS) concerning the management of an excessively elevated INR ratio. Our research aimed to assess physicians' adherence to those guidelines. METHODS: We realized a retrospective, multicentric study. One hundred and ten cases of excessively elevated INR ratio were identified and analyzed. RESULTS: Overall physicians adherence was 58%. However, patients with the most elevated INR, i.e., INR>6, were treated according to guidelines in only 33% of the cases. The use of vitamin K was the major source of mistakes. The rate of mortality was 20%. CONCLUSION: Adherence to HAS guidelines seems finally limited. It is necessary to put in place procedures to secure the behavior of physicians.

The international normalized ratio (INR): What reagent, what instrument? The assessment of the agreement between INR values according to different reagent/instrument combinations.

WHAT IS KNOWN AND OBJECTIVE: The international normalized ratio (INR) is widely used to monitor patients on vitamin K antagonists. This study aimed to assess the agreement of INR values obtained with different thromboplastin/instrument combinations. MATERIAL AND METHODS: International normalized ratio was determined on plasmas from 330 patients undergoing antivitamin K treatment (with acenocoumarol), using two calibration methods and four reagent/instrument combinations: Both Neoplastine CI and Neoplastine CI Plus on STA-R instrument from Diagnostica STAGO, Asnières, France; and both Thromborel S and Innovin on SYSMEX 2100i instrument from Siemens Health Care Diagnostics, Marbung, Germany. The agreement analysis was done using the Bland-Altman plot and the Cohen Kappa coefficient. RESULTS: The mean of the differences between the INR values and the limits of agreement were -0.07 [-0.51 to 0.38] for the Neoplastine CI plus and Neoplastine CI reagents, -0.08 [-1.18 to 1.03] for the Thromborel S and Innovin reagents when the INR was calculated, -0.1 [-1.15 to 0.95] for the Thromborel S and Innovin reagents when the INR was directly calibrated and -0.1 [-0.7 to 0.5] for the Neoplastine CI plus and Thromborel S. Cohen's kappa coefficients were 0.94, 0.76, 0.85 and 0.82, respectively. NEW FINDINGS AND CONCLUSION: The agreement between the four reagent/instrument combinations was high enough to classify patients as inefficaciously or efficaciously anticoagulated. The data interpretation should always be related to the clinical purpose.

Incidence and impact of atrial arrhythmias on thrombotic events in MPNs.

Atrial arrhythmias (AA) induce a high rate of thromboses and require vitamin K antagonists (VKA) or direct anticoagulants (DOAC) prescriptions. Essential thrombocythemia (ET) and polycythemia vera (PV) are also pro-thrombotic diseases. The prevention of thromboses is based on the association of cytoreductive drug and low-dose aspirin (LDA). We studied the incidence and complications of AA among patients with ET or PV. We identified 96/713 patients (13.5%) carrying AA. These patients were older (median 72.1 vs. 61.3 years old, p < 0.0001). In a case-control analysis, we observed that patients with AA had a higher frequency of cardiovascular risk factors (77/96, 80% vs. 61/96, 61%; p = 0.01). A higher incidence of thromboses before and after myeloproliferative neoplasm (MPN) diagnosis was seen in this group: 26/96, 27.1% vs. 14/96, 14.6% (p = 0.03) and 34/96, 35% vs. 18/96, 18.8% (p = 0.009). Most of the events were arterial (82 vs. 61%, p = 0.09). This translates into a shorter thrombosis-free survival (11.0 vs. 21.6 years, p = 0.01). Continuation of LDA in this situation exposed patients to more thrombotic events (p = 0.04) but VKA did not seem to be good anticoagulant drugs either. The association of AA and MPN is more frequent than expected. AA clearly increased the thrombotic risk of these patients. Anticoagulant drugs should be carefully managed between cardiologists and hematologists. Association of LDA and VKA or the role of DOAC in such population should be rapidly discussed to reduce the thrombotic rate.

Effect of ramadan fasting on acenocoumarol-induced antocoagulant effect.

Eating patterns, food intake and type of alimentation vary greatly during the month of ramadan. Furthermore, fasting, which practiced during the month of ramadan, can have an impact on drug's metabolism. These two factors, fasting and eating habits changes during the month of ramadan, may impact acenocoumarol anticoagulant effect, translated by variations of INR values. The aim of our study was to see ramadan fasting effects on INR variations in patients treated by acenocoumarol. A prospective monocentric study was conducted during the ramadan month on fasting outpatients that were treated by acenocoumarol. Baseline INR values (e.i. most recent available value before the month of ramadan) were compared to INR values obtained during the month of ramadan. All patients were monitored for signs of secondary haemorrhagic complications linked to treatment by anti-vitamin K (AVK). Thirty patients were included in the study with a sex ratio 1. Patients mean age was 65 years. Around two thirds of the patients were treated by AVK for atrial fibrillation. The majority of patients (94%) have been treated by AVK for more than a year. Mean INR was significantly higher during the month of ramadan than baseline (3.51 vs 2.52; p< 0.0001). There were also more overdoses during the month of ramadan than baseline (9 vs. 0; p=0.014). The increased INR values highlights the need of a close monitoring of INR values during the month of ramadan, particularly in patients with a high haemorrhagic risk.

[Stroke prevention in patients with atrial fibrillation]. / Prévention de l'AVC chez les patients avec une fibrillation auriculaire.

Oral anticoagulation with vitamin K antagonists (VKA) was the cornerstone of stroke prevention in atrial fibrillation (AF). This review article presents the state of the art, with regard to the treatment options developed over the past few years, the new oral anticoagulants (NOAC). A search in PubMed for relevant published studies has been performed. Dabigatran and apixaban were superior to warfarin to reduce stroke risk or systemic embolism ; dabigatran, rivaroxaban and edoxaban were non-inferior. All NOAC are globally non-inferior to warfarin for stroke prevention in non-valvular AF and they have a superior safety profile, with a reduced intracranial bleeding risk. They are now the first choice for treatment.

Les antagonistes de la vitamine K (AVK) ont été pendant longtemps la référence comme prévention de l'accident vasculaire cérébral (AVC) chez les patients souffrant de fibrillation auriculaire (FA). Cet article de revue propose une mise à jour des options thérapeutiques développées ces dernières années, à savoir les nouveaux anticoagulants oraux (NACO). Une recherche des études pertinentes a été effectuée dans PubMed. Il apparaît ainsi que le dabigatran et l'apixaban sont supérieurs à la warfarine pour réduire les AVC et les embolies systémiques ; le dabigatran, le rivaroxaban et l'édoxaban sont non inférieurs. Tous les NACO sont donc globalement non inférieurs à la warfarine pour prévenir les AVC dans la FA non valvulaire et ils ont un profil de sécurité supérieur, avec un moindre risque d'hémorragie intracrânienne. Ils représentent maintenant le traitement de premier choix.

Emerging Tools for Stroke Prevention in Atrial Fibrillation.

Ischaemic strokes resulting from atrial fibrillation (AF) constitute a devastating condition for patients and their carers with huge burden on health care systems. Prophylactic treatment against systemic embolization and ischaemic strokes is the cornerstone for the management of AF. Effective stroke prevention requires the use of the vitamin K antagonists or non-vitamin K oral anticoagulants (NOACs). This article summarises the latest developments in the field of stroke prevention in AF and aims to assist physicians with the choice of oral anticoagulant for patients with non-valvular AF with different risk factor profile.

[Non valvular atrial fibrillation: the place of the new anticoagulants]. / La fibrillation atriale non valvulaire : place des nouveaux anticoagulants.

Atrial fibrillation (AF) increases the risk of mortality and stroke. The prevention of these complications is based on oral anticoagulants that are more efficient than salycilates. As compared with antivitamins K agents, new oral anticoagulants are promising for patients presenting non valvular atrial fibrillation because of lower cerebral hemorragic risk (with respect of assessment of renal function and therapeutic compliance). Available studies and recommendations are presented.