Efficacy and safety of direct oral anticoagulants versus vitamin K antagonist for portal vein thrombosis in cirrhosis: A systematic review and meta-analysis.

INTRODUCTION AND AIM: Portal vein thrombosis (PVT) is associated with a higher risk of liver-related complications. Recent guidelines recommend direct-acting anticoagulants (DOAC) in patients with cirrhosis and non-tumoral PVT. However, data on the efficacy and safety of DOAC in these patients remain limited. We aim to investigate the efficacy and safety of DOAC compared to vitamin K antagonists (VKA) to treat non-tumoral PVT in patients with cirrhosis. METHODS: We performed a systematic search of six electronic databases using MeSH term and free text. We selected all studies comparing the use of DOACs with vitamin K antagonist to treat PVT in cirrhosis. The primary outcome was PVT recanalization. Secondary outcomes were and PVT progression, major bleeding, variceal bleeding and death. RESULTS: From 944 citations, we included 552 subjects from a total of 11 studies (10 observational and 1 randomized trial) that fulfilled the inclusion criteria. We found that DOAC were associated with a higher pooled rate of PVT recanalization (RR = 1.67, 95%CI: 1.02, 2.74, I2 = 79%) and lower pooled risk of PVT progression (RR = 0.14, 95%CI: 0.03-0.57, I2 = 0%). The pooled risk of major bleeding (RR = 0.29, 95%CI: 0.08-1.01, I2 = 0%), variceal bleeding (RR = 1.29, 95%CI: 0.64-2.59, I2 = 0%) and death (RR = 0.31, 95%CI: 0.01-9.578, I2 = 80%) was similar between DOAC and VKA. CONCLUSION: For the treatment of PVT in patients with cirrhosis, the bleeding risk was comparable between DOAC and VKA. However, DOAC were associated with a higher pooled rate of PVT recanalization. Dedicated randomized studies are needed to confirm these findings.

Dual therapy with an oral non-vitamin K antagonist and a P2Y12 inhibitor vs triple therapy with aspirin, a P2Y12 inhibitor and a vitamin K antagonist for the treatment of diabetes mellitus patients with co-existing atrial fibrillation following percutaneous coronary intervention: A meta-analysis.

BACKGROUND: In this analysis, we aimed to compare the efficacy and safety of dual therapy (DT) with a non-vitamin K oral anticoagulant (NOAC) and an adenosine diphosphate receptor antagonist (P2Y12 inhibitor) vs triple therapy (TT) with aspirin, a P2Y12 inhibitor and a vitamin K antagonist for the treatment of diabetes mellitus (DM) patients with co-existing atrial fibrillation (AF) following percutaneous coronary intervention (PCI). METHODS: Medical Literature Analysis and Retrieval System Online (MEDLINE), http://www.ClinicalTrials.gov, Excerpta Medical data BASE (EMBASE), Web of Science, Cochrane Central and Google Scholar were the searched databases. Studies that were randomized trials or observational studies comparing DT vs TT for the treatment of DM patients with co-existing AF following PCI were included in this analysis. The adverse cardiovascular outcomes and bleeding events were the endpoints. This meta-analysis was carried out by the RevMan version 5.4 software. Risk ratios (RR) with 95% confidence intervals (CI) were used to represent data and interpret the analysis. RESULTS: A total number of 4970 participants were included whereby 2456 participants were assigned to the DT group and 2514 participants were assigned to the TT group. The enrollment period varied from year 2006 to year 2018. Our current results showed that major adverse cardiac events (RR: 1.00, 95% CI: 0.84-1.20; P = .98), mortality (RR: 1.08, 95% CI: 0.78-1.48; P = .66), myocardial infarction (RR: 1.02, 95% CI: 0.74-1.42; P = .90), stroke (RR: 0.94, 95% CI: 0.53-1.67; P = .84) and stent thrombosis (RR: 1.09, 95% CI: 0.56-2.10; P = .80) were similar with DT versus TT in these patients. However, the risks for total major bleeding (RR: 0.66, 95% CI: 0.54-0.82; P = .0001), total minor bleeding (RR: 0.74, 95% CI: 0.64-0.85; P = .0001), Thrombolysis in Myocardial Infarction (TIMI) defined major bleeding (RR: 0.58, 95% CI: 0.35-0.95; P = .03), TIMI defined minor bleeding (RR: 0.62, 95% CI: 0.42-0.92; P = .02), intra-cranial bleeding (RR: 0.34, 95% CI: 0.13-0.95; P = .04) and major bleeding defined by the International Society on Thrombosis and Hemostasis (RR: 0.68, 95% CI: 0.51-0.90; P = .008) were significantly higher with TT. CONCLUSIONS: DT with a NOAC and a P2Y12 inhibitor was associated with significantly less bleeding events without increasing the adverse cardiovascular outcomes when compared to TT with aspirin, a P2Y12 inhibitor and a Vitamin K antagonist for the treatment of DM patients with co-existing AF following PCI. Hence, DT is comparable in efficacy, but safer compared to TT. This interesting hypothesis will have to be confirmed in future studies.

[Complex management of type 2 heparin-induced thrombocytopenia in patients with major bleeding tendency: two case report]. / Prise en charge de la thrombopénie induite par l'héparine immuno-allergique de type 2 au travers de deux cas cliniques chez des patients à risque hémorragique majeur.

Type 2 heparin-induced thrombocytopenia (HIT 2) is a rare pro-thrombotic disorder occurring in patients treated with heparin. It is defined as a clinical-biological syndrome associating the sudden onset of a thrombocytopenia, characterized by a drop of more than 50% of the initial platelet count, and thrombosis. We report two cases of HIT 2 occurring in patients with major bleeding tendency. The first HIT occurred in a patient whose management, in accordance with current guidelines, made it possible to control the thrombocytopenia and the anticoagulation despite the complexity of adapting and monitoring treatments in the context of recent cerebral hemorrhage. The second refers to an autoimmune HIT, which occurred in a patient whose management required the use of alternative therapies to the standard treatments suggested for HIT 2, to correct the severe refractory thrombocytopenia.

Factors associated to adequate time in therapeutic range with oral vitamin K antagonists in Tunisia.

INTRODUCTION:   The quality of chronic anticoagulation and predictor factors of poor anticoagulant control in patients under acenocoumarol were unknown in North Africa. METHODS: It is an observational study, carried out between November 2015 and November 30, 2016. The international normalized ratio (INR) values were prospectively obtained, and TTR was calculated using the Rosendaal method. RESULTS: Overall, 215 patients were included in this study, with a mean age of 63±0,8 years. The prevalence of poor anticoagulation control was 78.1%; 95% CI [72.2-83.2] (168 patients with TTR less than 65%). The median TTR with the Rosendaal method was 44.4%. After multivariate adjustment, variables significantly associated with adequate anticoagulation level were: history of ischemic stroke (Adjusted OR equal to 4.3, 95% CI: 1.4-12.9), associated prescription of antiplatelet therapy (Adjusted OR equal to 3.5, 95% CI: 1.1-11.2), daily prescribed dose of coumarins less than 6 mg (Adjusted OR equal to 6.4, 95% CI: 1.1- 36) and lower risk of bleeding assessed as HAS-BLED score (Adjusted OR: 0.5, 95% CI: 0.3-0.8). CONCLUSION: The quality of anticoagulation management with VKA among outpatients who received acenocoumarol was suboptimal. Strategies should be undertaken by clinicians and patients to improve the quality of anticoagulation, to address challenges to adverse cardiovascular outcomes in individuals treated with chronic anticoagulation.

Current status of anticoagulation in patients with breast cancer and atrial fibrillation.

OBJECTIVE: Balance between embolic and bleeding risk is challenging among patients with cancer. There is a lack of specific recommendations for the use of antithrombotic therapy in oncologic patients with atrial fibrillation (AF). We compared the embolic and bleeding risk, the preventive management and the incidence of events between patients with and without cancer. We further evaluated the effectiveness and safety of direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) within patients with cancer. METHODS AND RESULTS: The AMBER-AF registry is an observational multicentre study that analysed patients with non-valvular AF treated in Oncology and Cardiology Departments in Spain. 1,237 female patients with AF were enrolled: 637 with breast cancer and 599 without cancer. Mean follow-up was 3.1 years. Both groups were similar in age, embolic risk and bleeding risk. Lack of guidelines-recommended therapies was more frequent among patients with cancer. Compared with patients without cancer, adjusted rates of stroke (hazard ratio [95% confidence interval]) in cancer patients were higher (1.56 [1.04-2.35]), whereas bleeding rates remained similar (1.25 [0.95-1.64]). Within the group of patients with cancer, the use of DOACs vs VKAs did not entail differences in the adjusted rates of stroke (0.91 [0.42-1.99]) or severe bleedings (1.53 [0.93-2.53]). CONCLUSIONS: Antithrombotic management of AF frequently differs in patients with breast cancer. While breast cancer is associated with a higher risk of incident stroke, bleeding events remained similar. Patients with cancer treated with DOACs experienced similar rates of stroke and bleeding as those with VKAs.

Cytostatic hydroxycoumarin OT52 induces ER/Golgi stress and STAT3 inhibition triggering non-canonical cell death and synergy with BH3 mimetics in lung cancer.

Coumarins are natural compounds with antioxidant, anti-inflammatory and anti-cancer potential known to modulate inflammatory pathways. Here, non-toxic biscoumarin OT52 strongly inhibited proliferation of non-small cell lung cancer cells with KRAS mutations, inhibited stem-like characteristics by reducing aldehyde dehydrogenase expression and abrogated spheroid formation capacity. This cytostatic effect was characterized by cell cycle arrest and onset of senescence concomitant with endoplasmic reticulum and Golgi stress, leading to metabolic alterations. Mechanistically, this cellular response was associated with the novel capacity of biscoumarin OT52 to inhibit STAT3 transactivation and expression of its target genes linked to proliferation. These results were validated by computational docking of OT52 to the STAT3 DNA-binding domain. Combination treatments of OT52 with subtoxic concentrations of Bcl-xL and Mcl-1-targeting BH3 protein inhibitors triggered synergistic immunogenic cell death validated in colony formation assays as well as in vivo by zebrafish xenografts.

The Long-Lasting Rodenticide Brodifacoum Induces Neuropathology in Adult Male Rats.

Superwarfarins are very long-lasting rodenticides effective in warfarin-resistant rodents at extremely low doses. The consequences of chronic superwarfarin levels in tissues, due to biological half-lives on the order of 20 days, have not been examined. We now characterized the neurological effects of brodifacoum (BDF), one of the most widely used superwarfarins, in adult male Sprague Dawley rats. Dosing curves established the acute oral lethal dose for BDF as 221 ± 14 µg/kg. Measurement of tissue BDF levels showed accumulation throughout the body, including the central nervous system, with levels diminishing over several days. Immunocytochemical staining showed that both astrocyte and microglial activation was increased 4 days after BDF administration, as were levels of carbonylated proteins, and neuronal damage assessed by fluorojade B staining. Direct toxic effects of BDF on neurons and glia were observed using enriched cultures of cerebellar neurons and cortical astrocytes. Proteomic analysis of cerebellar lysates revealed that BDF altered expression of 667 proteins in adult rats. Gene ontology and pathway analysis identified changes in several functional pathways including cell metabolism, mitochondria function, and RNA handling with ribosomal proteins comprising the largest group. In vitro studies using primary astrocytes showed that BDF suppressed de novo protein synthesis. These findings demonstrate that superwarfarin accumulation increases indices of neuroinflammation and neuropathology in adult rodents, suggesting that methods which minimize BDF toxicity may not address delayed neurological sequelae.

Synthesis and biological evaluation of C-3 aliphatic coumarins as vitamin K antagonists.

Since the discovery of Warfarin in the 1940s, the design of new warfarin-derived anticoagulants for rodent management has been challenging, with mainly structural modifications performed on the C3 position of the coumarin skeleton. In order to better understand the pharmacomodulation of such derivatives, we have synthesized a family of C3 (linear and branched) alkyl-4-hydroxycoumarins, which led to the identification of compounds 5e and 5f as potential short-term active anticoagulants.

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.

Assessment of toxicity and coagulopathy of brodifacoum in Japanese quail and testing in wild owls.

Based on detection of hepatic residues, scavenging and predatory non-target raptors are widely exposed to second generation anticoagulant rodenticides (SGARs). A small proportion, generally <10%, of tested birds are diagnosed as acutely poisoned. Little is known, however, of sub-lethal effects of SGARs, such as interaction of clotting capacity with traumatic injury. Assessment of coagulation function of birds submitted live to wildlife rehabilitators or veterinarians may provide a means of establishing the proportion of animals suffering sub-lethal coagulopathies, as well as identifying individuals requiring treatment. As a first step in exploring the potential of this approach, we dosed Japanese quail (Coturnix japonica) with the SGAR, brodifacoum, at 0, 0.8, 1.4, 1.9, and 2.5 mg/kg and sampled birds at 1, 3, 5 and 7 days post-dosing. Prothrombin time (PT), which measures the extrinsic coagulation pathway, was significantly prolonged in 98% of brodifacoum-exposed quail in a dose- and time-dependent manner. 50-fold prolongation of PT occurred at higher brodifacoum dosages and correlated to hemorrhage found at necropsy. Activated clotting time (ACT), a measure of the intrinsic pathway also increased with dose and time. Hemoglobin (Hb) and hematocrit (Hct) decreased dose- and time-dependently at doses ≥1.4 mg/kg with no significant change at 0.8 mg/kg. Reference intervals for PT (10.0-16.2 s), ACT (30-180 s), Hb (9.6-18.4 g/dl), and Hct (34-55%) were established in Japanese quail. Species-specific reference intervals are required as barn owl PT (17-29 s) and quail PT were different. The proportion of brodifacoum-exposed quail with hemorrhage was not correlated with liver residues, but was correlated with PT, suggesting that this assay is a useful indicator of avian anticoagulant rodenticide exposure. PTs measured in free-living barn owls sampled between April 2009 and August 2010 in the lower Fraser Valley of BC do not suggest significant exposure to SGARs.

Potential antiproliferative effect of isoxazolo- and thiazolo coumarin derivatives on breast cancer mediated bone and lung metastases.

The study highlights the current progress in the development of coumarin scaffolds for drug discovery as novel anticancer agents in metastatic breast cancer. Eight compounds, combining the coumarin core and five membered heterocycles (isoxazoles and thiazoles) in hydrazinyldiene- -chroman-2,4-diones, were characterized in terms of a potential antiproliferative effect on bone (SCP1833) and lung (SCP4175) metastatic breast cancer cell lines using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Cell viability was evaluated after 48 and 72 h of treatment and the 50 % inhibitory concentrations were determined. The results demonstrated dose- and time-dependent activity, with the most potent molecules having a thiazole moiety, without or with additional methyl group(s) attached to the carbon(s) at position(s) 5 and/or 4 in the thiazole ring. These molecules possessed significantly higher potency against both test cell lines compared to 4-hydroxycoumarin.

Probable interaction between an oral vitamin K antagonist and turmeric (Curcuma longa).

We report a probable interaction between a vitamin K antagonist, fluindione, and the herbal medicine turmeric that resulted in the elevation of the international normalized ratio (INR). The case presented here underlines the importance of considering potential exposure to herbal medications when assessing adverse effects.

[Pristinamycin/Vitamin k antagonists drug interaction: a French pharmacovigilance database study]. / Interaction pristinamycine/antivitamine K: analyse de la base française de pharmacovigilance.

OBJECTIVE: To analyse pristinamycin/vitamin K antagonists (VKA) drug interaction by using data recorded in the French pharmacovigilance database (FPVB). METHODS: All cases with an increase effect of a VKA and an association with pristinamycin recorded in the FPVB between 1985 and 2013 were included. Data concerning patients, VKA treatments and side effects were recorded for a descriptive analysis. RESULTS: During this period, 31 reports with a VKA overdose after an association with pristinamycin were included. Fluindione is the most often involved VKA (77% of cases). In 20 cases (65.4%), VKA overdose caused bleeding and 24 cases (77.4%) were serious. CONCLUSION: Although mechanism is unknown, pristinamycine/AVK drug interaction is a reality that needs to be reported in the summary of product characteristics of these drugs and better known by practitioners to act in patients' interest.

[Management of vitamin K antagonists in the elderly]. / Surveillance biologique des antagonistes de la vitamine K chez le patient âgé

Elderly patients of 80 years and above are commonly frail, due to substantial comorbid conditions and numerous medications. Managing elderly patients receiving vitamin K antagonists (VKA) is challenging because those patients are at high risk of both thrombosis and bleeding. Special considerations on the choice of the VKA drug, dosing and monitoring have to be taken into account in the elderly in order to avoid over-anticoagulation and to minimize the haemorrhagic risk which consequences may be dramatic or fatal in this age group. In these patients, INR monitoring is crucial, especially at the start of treatment. The use of dosing algorithms specifically developed for elderly patients allows to decrease over-anticoagulation during the initiation period. INR has to be monitored more frequently in case of acute illness or in case of modification of the associated drugs. Patient information and education are of great importance, even in geriatric patients and has been shown to improve the quality of anticoagulation. Even though the use of direct oral anticoagulants is currently expanding, prescribing VKA in elderly patients in whom the prevalence of severe renal insufficiency remains up to date.