Common P-glycoprotein (ABCB1) polymorphisms do not seem to be associated with the risk of rivaroxaban-related bleeding events: Preliminary data.

Introduction: Considering conflicting previous reports, we aimed to evaluate whether the common ABCB1 polymorphisms (rs1128503, rs2032582, rs1045642, rs4148738) affected the risk of bleeding in rivaroxaban-treated patients. Materials and methods: We report preliminary data from a larger nested case-control study. Consecutive adults started on rivaroxaban for any indication requiring > 6 months of treatment were followed-up to one year. Patients who experienced major or non-major clinically relevant bleeding during the initial 6 months were considered cases, whereas subjects free of bleeding over > 6 months were controls. The polymorphisms of interest (rs1128503, rs2032582, rs1045642, rs4148738) were in a strong linkage disequilibrium, hence patients were classified regarding the "load" of variant alleles: 0-2, 3-5 or 6-8. The three subsets were balanced regarding a range of demographic, comorbidity, comedication and genetic characteristics. A logistic model was fitted to probability of bleeding. Results: There were 60 cases and 220 controls. Raw proportions of cases were similar across the subsets with increasing number of ABCB1 variant alleles (0-2, N = 85; 3-6, N = 133; 6-8, N = 62): 22.4%, 21.8%, and 19.4%, respectively. Fully adjusted probabilities of bleeding were also similar across the subsets: 22.9%, 27.5% and 17.7%, respectively. No trend was observed (linear, t = -0.63, df = 273, P = 0.529; quadratic, t = -1.10, df = 273, P = 0.272). Of the 15 identified haplotypes, the completely variant (c.1236T_c.2677T(A)_c.3435T_c.2482-2236A) (40.7%) and completely wild-type (C_G_C_G) (39.5%) haplotypes prevailed, and had a closely similar prevalence of cases: 21.1% vs. 23.1%, respectively. Conclusions: The evaluated common ABCB1 polymorphisms do not seem to affect the risk of early bleeding in patients started on rivaroxaban.

Serum Fibrinogen and Renal Dysfunction as Important Predictors of Left Atrial Thrombosis in Patients with Atrial Fibrillation.

BACKGROUND: As has been shown previously, patients with atrial fibrillation (AF) who have left atrial thrombus (LAT) also have elevated plasma concentrations of fibrinogen. In this study, we tried to determine if this is the consequence of a genetic trait and whether elevated concentrations of fibrinogen could be used to predict LAT in patients with AF. METHODS: We recruited 181 consecutive patients scheduled for pulmonary vein isolation (PVI) or direct current cardioversion. The primary endpoint was the presence of LAT on transesophageal echocardiography (TOE). We recorded routine clinical and biochemical data as well as the polymorphism type of the fibrinogen gene for the ß chain. To control potentially interfering variables, we performed propensity score matching (PSM). Multivariable and univariable logistic regression models (LRM) were computed using the CHA2DS2-Vasc score, the fibrinogen concentration and creatinine clearance as estimated by the Cockcroft-Gault equation. RESULTS: 60 of 181 patients had LAT as detected by TOE. As expected, patients with LAT had significantly higher concentrations of fibrinogen (3.9 vs. 3.6 g/L); p = 0.01 in the unadjusted analysis. After performing PSM, there were no statistically significant differences between the groups, except for creatinine clearance (79.9 vs. 96.8 mL/min); p = 0.01. There were also no differences regarding the -455 G/A ßfibrinogen polymorphism distribution between the two groups. After constructing the LRM, we found no performance enhancement for the CHA2DS2-Vasc score by adding the fibrinogen concentration or creatinine clearance alone, but when all three variables were put together, there was a significant improvement in LAT prediction (AUC 0.64 vs. 0.72), p = 0.026. CONCLUSION: Our study found no evidence of elevated levels of circulating fibrinogen in patients with LAT or a connection between those levels and the A/A and A positive polymorphism. When used together with renal function markers such as creatinine clearance, plasma fibrinogen concentrations can provide additional power to the CHA2DS2-Vasc score for predicting LAT.

Risk Factors for Rivaroxaban-Related Bleeding Events-Possible Role of Pharmacogenetics: Case Series.

Non-vitamin K antagonist oral anticoagulants' interindividual trough concentration variability affects efficacy and safety, especially in bleeding events. Rivaroxaban is metabolised via CYP3A4/5-, CYP2J2-, and CYP-independent mechanisms and is a substrate of two transporter proteins: ABCB1 (MDR1, P-glycoprotein) and ABCG2 (BCRP; breast-cancer-resistance protein). The polymorphisms of these genes may possibly affect the pharmacokinetics of rivaroxaban and, consequently, its safety profile. Rivaroxaban variability may be associated with age, liver and kidney function, concomitant illness and therapy, and pharmacogenetic predisposition. This case series is the first, to our knowledge, that presents multiple risk factors for rivaroxaban-related bleeding (RRB) including age, renal function, concomitant diseases, concomitant treatment, and pharmacogenetic data. It presents patients with RRB, along with their complete clinical and pharmacogenetic data, as well as an evaluation of possible risk factors for RRB. Thirteen patients were carriers of ABCB1, ABCG2, CYP2J2, and/or CYP3A4/5 gene polymorphisms. Possible drug-drug interactions with increased bleeding risk were identified in nine patients. Six patients had eGFR <60 mL/min/1.73 m2. Our data suggest a possible role of multiple factors and their interactions in predicting RRB; however, they also indicate the need for further comprehensive multidisciplinary research to enable safer use of this product based on a personalised approach.

Euglycemic diabetic ketoacidosis: A rare but serious side effect of sodium-glucose co-transporter 2 inhibitors.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are an insulin-independent class of oral antihyperglycemic medication and from recently established therapy in chronic heart failure patients. A rare, but potentially life-threatening complication of SGLT2 inhibitor use is euglycemic diabetic ketoacidosis. We described a case of a middle-aged male patient with type 2 diabetes who developed metabolic ketoacidosis after a few days of empagliflozin administration. SGLT2 inhibitor related ketoacidosis presents with euglycemia or only modestly elevated glucose blood concentrations, which causes delayed detection and treatment of ketoacidosis. There are multiple possible risk factors and mechanism that might contribute to the pathogenesis of ketoacidosis. It is implied that SGLT2 inhibitor use and prescription by non-diabetologists (cardiologists, nephrologists, family physicians, etc.) will continue to grow in the future. It is important to inform the general cardiac public about this rare but serious side effect of SGLT2 inhibitors.

Vascular Ehlers-Danlos syndrome, an often unrecognized clinical entity: a case report of a novel mutation in the COL3A1 gene.

Due to life-threatening complications, vascular Ehlers-Danlos syndrome (vEDS) is the most severe form of EDS. Because the syndrome is associated with a shortened life expectancy and variable clinical presentation, diagnosis confirmed by genetic testing is crucial to determining appropriate treatment. Despite some distinguishing features, this rare disease often goes unrecognized. Apart from surgical or endovascular treatment of serious vascular complications, medical treatment based on celiprolol helps reduce arterial complications. We report on a case of vEDS in a young man who suffered several episodes of severe vascular complications. The diagnosis of vEDS was established based on clinical manifestations and confirmed by genetic testing. A novel heterozygous pathogenic variant in the COL3A1 gene was found. To our knowledge, this is the first case of vEDS caused by this variant.

New Therapeutic Approaches in Treatment of Dyslipidaemia-A Narrative Review.

Dyslipidaemia is a well-known risk factor for the development of cardiovascular disease, a leading cause of morbidity and mortality in developed countries. As a consequence, the medical community has been dealing with this problem for decades, and traditional statin therapy remains the cornerstone therapeutic approach. However, clinical trials have observed remarkable results for a few agents effective in the treatment of elevated serum lipid levels. Ezetimibe showed good but limited results when used in combination with statins. Bempedoic acid has been thoroughly studied in multiple clinical trials, with a reduction in LDL cholesterol by approximately 15%. The first approved monoclonal antibodies for the treatment of dyslipidaemia, PCSK9 inhibitors, are currently used as second-line treatment for patients with unregulated lipid levels on statin or statin combination therapy. A new siRNA molecule, inclisiran, demonstrates great potential, particularly concerning compliance, as it is administered twice yearly and pelacarsen, an antisense oligonucleotide that targets lipoprotein(a) and lowers its levels. Volanesorsen is the first drug that was designed to target chylomicrons and lower triglyceride levels, and olezarsen, the next in-line chylomicron lowering agent, is currently being researched. The newest possibilities for the treatment of dyslipidaemia are ANGPTL3 inhibitors with evinacumab, already approved by the FDA, and EMA for the treatment of familial hypercholesterolemia. This article provides a short summary of new agents currently used or being developed for lipid lowering treatment.

Current concept in the diagnosis, treatment and rehabilitation of patients with congestive heart failure.

Heart failure (HF) is a major public health problem with a prevalence of 1%-2% in developed countries. The underlying pathophysiology of HF is complex and as a clinical syndrome is characterized by various symptoms and signs. HF is classified according to left ventricular ejection fraction (LVEF) and falls into three groups: LVEF ≥ 50% - HF with preserved ejection fraction (HFpEF), LVEF < 40% - HF with reduced ejection fraction (HFrEF), LVEF 40%-49% - HF with mid-range ejection fraction. Diagnosing HF is primarily a clinical approach and it is based on anamnesis, physical examination, echocardiogram, radiological findings of the heart and lungs and laboratory tests, including a specific markers of HF - brain natriuretic peptide or N-terminal pro-B-type natriuretic peptide as well as other diagnostic tests in order to elucidate possible etiologies. Updated diagnostic algorithms for HFpEF have been recommended (H2FPEF, HFA-PEFF). New therapeutic options improve clinical outcomes as well as functional status in patients with HFrEF (e.g., sodium-glucose cotransporter-2 - SGLT2 inhibitors) and such progress in treatment of HFrEF patients resulted in new working definition of the term "HF with recovered left ventricular ejection fraction". In line with rapid development of HF treatment, cardiac rehabilitation becomes an increasingly important part of overall approach to patients with chronic HF for it has been proven that exercise training can relieve symptoms, improve exercise capacity and quality of life as well as reduce disability and hospitalization rates. We gave an overview of latest insights in HF diagnosis and treatment with special emphasize on the important role of cardiac rehabilitation in such patients.