Anticoagulants In Clinical Practice Research Articles

Tyrosine phosphorylation of recombinant hirudin increases affinity to thrombin and antithrombotic activity.

Thrombin is one of the key enzymes of the blood coagulation system and a promising target for the development of anticoagulants. One of the most specific natural thrombin inhibitors is hirudin, contained in the salivary glands of medicinal leeches. The medicinal use of recombinant hirudin is limited because of the lack of sulfation on Tyr63, resulting in a 10-fold decrease in activity compared to native (sulfated) hirudin. In the present work, a set of hirudin derivatives was tested for affinity to thrombin: phospho-Tyr63, Tyr63(carboxymethyl)Phe, and Tyr63Glu mutants, which mimic Tyr63 sulfation and Gln65Glu mutant and lysine-succinylated hirudin, which enhance the overall negative charge of hirudin, as well as sulfo-hirudin and desulfo-hirudin as references. Using steered molecular dynamics simulations with subsequent umbrella sampling, phospho-hirudin was shown to exhibit the highest affinity to thrombin among all hirudin analogs, including native sulfo-hirudin; succinylated hirudin was also prospective. Phospho-hirudin exhibited the highest antithrombotic activity in in vitro assay in human plasma. Taking into account the modern methods for obtaining phospho-hirudin and succinylated hirudin, they are prospective as anticoagulants in clinical practice.

Features of the use of oral anticoagulants in clinical practice: focus on gastrointestinal complications

The review article presents dates about the physiology and pathophysiology of the hemostasis system, discusses the features of the use of oral anticoagulants in clinical practice. Oral anticoagulants are drugs characterized by predictable pharmacokinetics and pharmacodynamics, a favorable efficacy and safety profile. The article considers the main clinical and pharmacological characteristics of apixaban, rivaroxaban and dabigatran (bioavailability, metabolism, excretion); factors that increase the risk of gastrointestinal bleeding associated with anticoagulant therapy; drug interactions; the possibility of gastroprotection in patients taking oral anticoagulants. In real clinical practice, the reason for not prescribing or unreasonably reducing the dose of oral anticoagulants is the fear of bleeding. In this case, the risks of bleeding, as a rule, are overestimated. Knowledge of bleeding risk factors, prognostic scales and management of risk factors is an approach that can improve the safety of anticoagulant therapy. In clinical practice, the choice of the ideal oral anticoagulants, in addition to taking into account the risk of bleeding, should be based on a comprehensive assessment, including an assessment of the patient's age, risk of stroke and coronary events, renal function, and predicted compliance.

Management of Patients Treated with Direct Oral Anticoagulants in Clinical Practice and Challenging Scenarios.

It is well established that direct oral anticoagulants (DOACs) are the cornerstone of anticoagulant strategy in atrial fibrillation (AF) and venous thromboembolism (VTE) and should be preferred over vitamin K antagonists (VKAs) since they are superior or non-inferior to VKAs in reducing thromboembolic risk and are associated with a lower risk of intracranial hemorrhage (IH). In addition, many factors, such as fewer pharmacokinetic interactions and less need for monitoring, contribute to the favor of this therapeutic strategy. Although DOACs represent a more suitable option, several issues should be considered in clinical practice, including drug-drug interactions (DDIs), switching to other antithrombotic therapies, preprocedural and postprocedural periods, and the use in patients with chronic renal and liver failure and in those with cancer. Furthermore, adherence to DOACs appears to remain suboptimal. This narrative review aims to provide a practical guide for DOAC prescription and address challenging scenarios.

Pharmacogenetic substantiation of personalized prescription of oral anticoagulants in clinical practice

Thromboembolic diseases are of great clinical concern because of their high prevalence and consequences, which are often fatal. Despite significant progress in the prevention and treatment of thrombotic events, patients remain at risk of life-threatening bleeding episodes and other side effects arising from anticoagulant therapy, so the issue of personalizing prescriptions taking into account the genetic characteristics of patients has become urgent. The purpose of the study is to substantiate the need for patient genotype analysis in order to increase the effectiveness and safety of individual pharmacotherapy. The article has a conceptual nature, therefore the following research methods were chosen: systematization and generalization; analysis and specification; abstract and logical. For the search, we used PubMed, PubMedCentral, Google Scholar, dbSNP, Elsevier, Springer from September 2000 to November 2022. The review included studies written in English and Ukrainian. There were analyzed literature data on two main subclasses of oral antithrombotic agents, including oral anticoagulants and antiplatelet agents, namely warfarin, apixaban, rivaroxaban, and clopidogrel. Prognostically significant for evaluating the effectiveness and safety of anticoagulant use, as well as the most studied in this aspect, are CYP2C9 (rs1799853, rs1057910), CYP2C19 (rs4244285, rs4986893, rs12248560), VKORC1 (rs9923231, rs7294, rs9934438), MDR1 (rs4148738, rs2032582, rs1045642), FGB (rs1800787), PAI-1 (rs1799889) genes. The results of CYP2B6, CYP3A4/5 (rs776746), CYP4F2 (rs2108622) genes analysis indicate a certain influence on the anticoagulants metabolism and require further detailed study. Factors such as age, race, sex, smoking, diet, and other medications are known to influence the effectiveness of antithrombotic therapy, but the most influential factor is genetics, which accounts a significant percentage of interindividual variability. Future research should focus on the study of known and novel genetic variants that influence drug metabolism, as well as the molecular mechanisms that contribute to changes in plasma anticoagulant levels. The article provides a brief overview of action mechanisms, pharmacogenetics, and interactions between drugs and the genes responsible for their metabolism. The results indicate the need for studies of gene variants considered in this review before starting anticoagulant therapy, and attention should also be paid to the possibility of inhibitors and inductors influence on components of the metabolic pathway of anticoagulants and gene expression products that participate in their metabolism. The totality of these measures will ensure an increase in the efficiency and safety of individual pharmacotherapy and allow optimizing the choice and dosage of anticoagulants.

Physicians' and pharmacists' views and experiences regarding use of direct oral anticoagulants in clinical practice

Direct oral anticoagulants (DOACs) are increasingly used compared to vitamin K antagonists (VKAs). Guidelines advocate a structured multidisciplinary approach in the management of patients treated with DOACs. The aim of this study was to assess the views and experiences of physicians and pharmacists regarding DOAC use in clinical practice. An online questionnaire was sent to both primary (general practitioners [GPs], community pharmacists) and secondary healthcare professionals (cardiologists, residents in internal medicine and hospital pharmacists) between March and July 2020. The questionnaire covered four topics: (i) current practice, (ii) prescribing behaviour (only for physicians), (iii) self-perceived knowledge about DOACs and (iv) views and opinions about DOACs versus VKAs. In total, 110 physicians and 111 pharmacists completed the survey. Healthcare professionals in secondary care had more experience with DOACs and felt more confident with higher self-perceived knowledge about DOACs compared to their colleagues in primary care. Healthcare professionals' self-perceived knowledge was more or less complementary, for example physicians felt less confident in managing drug-drug interactions (DDIs) where pharmacists reported being more confident in this topic. Physicians reported uncertainties on the potential impact of risk factors - such as older age, lower body weight and DDIs - on appropriate DOAC dosing. Complementarity in physicians' and pharmacists' self-perceived knowledge levels of DOACs may facilitate and necessitate future multidisciplinary collaboration initiatives for the management and follow-up of DOAC patients.

Systematic errors in the choice of dose level of direct oral anticoagulants: urgency of an issue and approaches to its solution

The article presents updated information on the frequency of use of non-recommended low dosing of direct oral anticoagulants (dabigatran, rivaroxaban, apixaban and edoxaban). It gives substantiation of the urgency of the issue of providing the maximum efficiency of the use of anticoagulants in clinical practice, taking into account the high prevalence of atrial fibrillation and the pharmacological characteristics of the most commonly used drugs. The effects of such an unreasonable reduction in anticoagulant doses in elderly and senile patients are discussed. The results of recent observational studies that assessed the relationship between the use of direct oral anticoagulants and the risk of adverse clinical outcomes are presented. The data on the relationship between the use of unreasonably low dosing of anticoagulants in patients with atrial fibrillation, which were recently obtained during the implementation of the GARFIELD-AF registry, are discussed. The data on a rather high variability of concentrations of direct oral anticoagulants are presented. The frequency of using apixaban in an unreasonably reduced dose, as well as the effects of using non-recommended doses of apixaban hold a specific place in the article. The unreasonableness of attempts to further reduce the risk of bleeding due to unreasonable reduction of apixaban dosing is emphasized, taking into account the stable data on the high safety of recommended dosing of apixaban, as well as the possible decrease in the effect if the dose reduction is not recommended. The data on the criteria for dose reduction, which are adopted in different countries, are presented. The proposed terms to designate different doses of direct oral anticoagulants, depending on their study in the course of large, randomized trials are discussed.

Topical Issues in Diagnosis of Coagulopathies and Prevention of Thromboembolic Complications of Atrial Fibrillation in Patients with Liver Cirrhosis

Nowadays the comorbid pathology of liver cirrhosis and atrial fibrillation has been widely discussed and reported in the literature in the light of recent findings from the study of the effectiveness and safety of anticoagulants in this category of patients. The review is devoted to summarizing the existing data on the comorbid course of these diseases from the point of view of the impact of bleeding and thrombosis on the quality of life and mortality of patients and the possibility of using new methods of diagnosis and prevention of these complications.
 The purpose of the review is to focus the attention of physicians and researches on the relevance and prevalence of comorbid course of liver cirrhosis and atrial fibrillation, their complications, and discuss the benefits and possibilities of applying global methods of hemostasis assessment and anticoagulants in clinical practice.
 This article examines the main pathophysiological aspects of «rebalanced hemostasis» theory in liver coagulopathies, its effect on the onset of bleeding and thrombotic events, and considering the clinical benefit of the use of anticoagulants. The disadvantages of traditional coagulation assessment tests compared to the benefits of thromboelastometry (ROTEM) and thromboelastography (TEG), general fulfilling principles and evaluation of their indicators are discussed. Existing research findings on the safety and efficacy of warfarin and direct oral anticoagulants in patients with liver cirrhosis and atrial fibrillation compared with no treatment are highlighted.

P4791Performance of the HAS-BLED, ATRIA, and PRECISE-DAPT Bleeding Risk Scores in Atrial Fibrillation Patients Using Antiplatelet Agents or Oral Anticoagulants

Abstract Background Various bleeding risk scores have been proposed to assess the risk of bleeding in atrial fibrillation (AF) patients undergoing anticoagulation. PRECISE DAPT score has been developed to assess the out-of hospital bleeding risk in patients receiving dual antiplatelet therapy (DAPT). Our objective was to compare the predictive performance between the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio, Elderly, Drugs/Alcohol), ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation), and PRECISE-DAPT (Predicting Bleeding Complication in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet therapy) score in AF patients using antiplatelet agents or anticoagulants Methods We recruited 1,114 consecutive AF patients (51% male; median age, 71 years) receiving antiplatelet agents or oral anticoagulants from January 2014 through December 2018. Major bleeding was defined as according to the Bleeding Academic Research Consortium (BARC) criteria (type 3 or 5: hemodynamic instability, need for transfusion, drop in hemoglobin ≥3 g, and intracranial, intraocular or fatal bleeding). The performance of risk scores were assessed by C-statistic. Results Bleeding events occurred in 135 patients (12.1%) during 30 days, and 72 patients (6.5%) from 30 days till 1-year follow-up. Based on the C-statistic, PRECISE-DAPT score (AUC: 0.72, 95% CI: 0.69–0.75) had a good performance, significantly better than HAS-BLED (AUC: 0.64, 95% CI: 0.61–0.67) (p=0.008) or ATRIA scores (AUC: 0.57, 95% CI: 0.54–0.60) (p<0.001) for 30-days bleeding prediction. Also, PRECISE-DAPT score had a good C-statistic (AUC: 0.72, 95% CI: 0.69–0.75) for 1-year bleeding events compared with HAS-BLED (AUC: 0.64, 95% CI: 0.60–0.67) (p=0.02) or ATRIA (AUC: 0.61, 95% CI: 0.58–0.65) (p=0.01). ROC curve for bleeding Conclusions The PRECISE-DAPT score has been used for assessing bleeding events during DAPT. Also, the PRECISE-DAPT score predicted bleedings better than HAS-BLED or ATRIA scores in AF patients. So, the PRECISE-DAPT score may be considered as bleeding risk score during DAPT or oral anticoagulation in clinical practice.

DABIGATRAN AND IDARUZIZUMAB. NEW OPPORTUNITIES FOR IMPROVING PATIENT SAFETY

The widespread use of new oral anticoagulants in clinical practice requires improving the safety of medication use, i.e. the use of specific reversal agents, if necessary. Idarucizumab, a humanied monoclonal antibody fragment, is the first reversal agent authorized in our country that binds to dabigatran. Its efficacy and safety have been validated in several clinical trials, and its use gains experience in real clinical practice.

Application of prothrombin complex concentrate for reversal of direct oral anticoagulants in clinical practice: indications, patient characteristics and clinical outcomes compared to reversal of vitamin K antagonists

BackgroundProthrombin complex concentrate (PCC) is widely used to reverse the action of direct oral anticoagulants (DOACs) in accordance with current guidelines and because of a lack of specific reversal agents. Indications, clinical characteristics and patient outcomes of patients might differ in comparison to reversal of vitamin K antagonists where reversal with PCC is well established.MethodsOur cohort study explores patient characteristics, indications and clinical outcomes for reversal of all DOAC patients receiving PCC at our university emergency department from 01.06.2012 to 01.07.2017, in comparison with patients on VKA.ResultsOut of 199,982 consultations, we studied 346 patients who were given PCC for reversal of either DOAC (n = 74) or VKA (n = 272). The most common reason for treatment was acute bleeding; in 86.7% of both groups. 37.3% of bleeding was traumatic (p = 0.666). The most frequent bleeding location was intracranial (61.6%, p = 0.881). Gastrointestinal bleeding was more often found in the DOAC group (18.9% vs. 8.8%, p = 0.014). More erythrocyte concentrates (ECs) were given to DOAC patients with blood transfusion (p = 0.014). Tranexamic acid was used more often in DOAC patients than in VKA patients (28.4% vs. 7.4%, p < 0.001). No significant group differences were found for the following patient outcomes: in-hospital mortality, ICU stay, and length of stay at the ICU or in hospital.ConclusionIn DOAC treated patients, PCC was applied more often because of gastrointestinal bleeding and patients received higher numbers of ECs as well as tranexamic acid. No differences were observed with regard to important clinical outcomes.

P4814Prognostic impact of inappropriate doses of direct oral anticoagulants in clinical practice: a subanalysis of the FANTASIIA registry, a prospective, nationwide, real-world, observational study

P4814Prognostic impact of inappropriate doses of direct oral anticoagulants in clinical practice: a subanalysis of the FANTASIIA registry, a prospective, nationwide, real-world, observational study

Effectiveness and safety of anticoagulants for the treatment of venous thromboembolism in patients with cancer.

Anticoagulation is used to treat venous thromboembolism (VTE) in cancer patients, but may be associated with an increased risk of bleeding. VTE recurrence and major bleeding were assessed in cancer patients treated for VTE with the most currently prescribed anticoagulants in clinical practice. Newly diagnosed cancer patients (first VTE 1/1/2013‐05/31/2015) who initiated rivaroxaban, low‐molecular‐weight heparin (LMWH), or warfarin were identified from Humana claims data and observed until end of eligibility or end of data availability. VTE recurrence was a hospitalization with a primary diagnosis of VTE ≥7 days after first VTE. Major bleeding events on treatment were identified using validated criteria. Cohorts were compared using Kaplan–Meier rates at 6 and 12 months and Cox proportional hazards models. Cohorts were adjusted for their differences at baseline. A total of 2428 patients (rivaroxaban: 707; LMWH: 660; warfarin: 1061) met inclusion criteria. Patient characteristics were well balanced after weighting. There was a trend for lower VTE recurrence rates in rivaroxaban users compared to LMWH users at 6 months (13.2% vs. 17.1%; P = .060) and significantly lower at 12 months (16.5% vs. 22.2%; P = .030) [HR: 0.72, 95% CI: (0.52‐0.95); P = .024]. VTE recurrence rates were also lower for rivaroxaban than warfarin users at 6 months (13.2% vs. 17.5%; P = .014) and 12 months (15.7% vs. 19.9%; P = .017) [HR: 0.74, 95% CI: (0.56‐0.96); P = .028]. Major bleeding rates were similar across cohorts. This real‐world analysis suggests cancer patients with VTE treated with rivaroxaban had significantly lower risk of recurrent VTE and similar risk of bleeding compared to those treated with LMWH or warfarin.

New oral anticoagulants in clinical practice – time to replace warfarin?

New oral anticoagulants in clinical practice – time to replace warfarin?

Peri-procedural Anticoagulation in Catheter Ablation for Atrial Fibrillation: A Review.

Catheter ablation for rhythm control in atrial fibrillation has been recognized as an established treatment. Patients with atrial fibrillation suffer from an increased risk of thromboembolic events. Long-term stroke risk and mortality have been shown to be reduced after catheter ablation, still the procedure per se is associated with an additive peri-procedural thromboembolic risk. Maintenance of the thrombotic - bleeding equilibrium in such patients during interventional procedures is compelling. Lack of data from randomized studies along with the recent introduction of novel oral anticoagulants in clinical practice has resulted in a wide variance of antithrombotic treatment approaches. Procedural interruption of anticoagulants, switching of anticoagulation scheme (i.e. from novel oral anticoagulants to vitamin K antagonists), bridging with heparin, timing of re-initiation of therapy and/or utilization of novel oral anticoagulants have all been points of dispute. In the present review we present the available data regarding optimal peri-procedural anticoagulation strategies in patients undergoing catheter ablation for atrial fibrillation.

Evidence update on the use of oral anticoagulants in clinical practice

Evidence update on the use of oral anticoagulants in clinical practice

Use of direct oral anticoagulants in patients with nonvalvular atrial fibrillation according to clinical profile.

The majority of patients with atrial fibrillation should receive oral anticoagulation to reduce the risk of stroke. The limitations of vitamin K antagonists have led to an underuse of anticoagulants in clinical practice which has been associated with a higher risk of stroke, hospitalizations and healthcare costs. Direct oral anticoagulants (DOACs) overcome some of the limitations of vitamin K antagonists and may therefore increase the use of oral anticoagulants in clinical practice. Since no head-to-head trials have been performed, only indirect comparisons can be made among them. In this review, the results of the Phase III randomized controlled trials with DOACs were analyzed, trying to determine whether one or more DOACs could be especially recommended according to different clinical conditions.

Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Clinical Practice: Focus on Rivaroxaban in Stroke Prevention in Patients With Atrial Fibrillation.

Despite direct oral anticoagulants (DOACs) have overcome the most relevant limitations of vitamin K antagonists, many patients with atrial fibrillation are not receiving the appropriate anticoagulant therapy. In addition, when patients are anticoagulated with DOACs, some of them are not taking the dose recommended in the summary of product characteristics. This may be related, at least in part, to the concern about the applicability of findings from randomized clinical trials to real-life patients. In this context, performing studies in daily clinical practice to assess the efficacy and safety of DOACs in real-world setting is mandatory. The aim of this review is to update the current evidence regarding safety of rivaroxaban in clinical practice. The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) showed that rivaroxaban was at least as effective as warfarin for preventing stroke or systemic embolism, with similar rates of major bleeding but with lesser risk of intracranial and fatal bleedings. Data from noninterventional studies and registries have confirmed the good results of ROCKET-AF. Even more, rates of bleeding may be inferior in real-life patients, since they have a lower risk profile than those included in ROCKET-AF.

Adverse events associated with the use of direct-acting oral anticoagulants in clinical practice: beyond bleeding complications.

Non-vitamin K oral anticoagulants, also known as direct oral anticoagulants (DOACs), have entered themarket in 2008 with the expected breakthrough potential of circumventing limitations related to treatmentwith vitamin K antagonists (eg, warfarin) by virtue of their pharmacological properties. Although dataderived from premarketing randomized clinical trials have largely demonstrated the clinical benefit ofDOACs, especially in terms of reduced risk of intracranial bleeding, it is important to monitor the safetyin the postmarketing phase, which better reflects real-world patients with comorbidities and polypharmacotherapy,in order to assess the actual risk-benefit profile. In this critical review, we aimed to evaluatethe evidence on the latest debated safety issues. In the first section, we will discuss: 1) the need forpharmacovigilance (ie, the science and activities relating to the detection, assessment, understanding,and prevention of adverse effects or any other drug-related problems in the real-world setting), and 2) theimportance of properly interpreting postmarketing data to avoid unnecessary alarm. In the second section,emerging and debated safety issues potentially associated with the use of DOACs in the postmarketingsetting will be assessed: 1) the potential coronary risk (which emerged during the preapproval period);2) the occurrence of liver injury (a risk undetected in clinical trials and highlighted by case reports orseries); and 3) the potential for renal damage (a still unclear safety issue). It is anticipated that hepaticand renal issues still require dedicated postauthorization safety studies to ultimately assess causality.

New anticoagulants in clinical practice. Effectiveness and problems

We analyze the effectiveness of new oral anticoagulants and antivitamins K for the treatment of patients with venous problems, atrial fibrillation, and acute coronary syndrome with reference to advantages of this therapy and methods of prevention of complications of these conditions.

Efficacy and safety of novel oral anticoagulants in clinical practice: a report from three centers in Sweden.

IntroductionIn clinical trials new oral anticoagulants (NOAC) have proved to be as effective as warfarin for thromboprophylaxis in atrial fibrillation. The aim of this study was to evaluate the efficacy and safety of these drugs in clinical practise.Methods and resultsAll patients treated with new oral anticoagulants at Skåne University hospital and Halland County Hospital Halmstad between 2009 and September 2013 was identified in the Swedish national quality registry for atrial fibrillation and anticoagulation (AuriculA). Medical records were reviewed to identify thromboembolism and major bleeding and compared to a warfarin cohort with a time in therapeutic range (TTR) of 76%. There were 826 patients, mean age 70.6, follow up 591 years, with atrial fibrillation treated with NOAC. Dabigatran was the initial drug in 79% of the cohort. The incidences of ischemic stroke/ TIA and major bleeding were 1.9 (95% CI; 1.0-3.2) and 2.0 (95% CI; 1.1-3.5) per 100 patient-years respectively. The corresponding incidences for warfarin were 1.5 (95% CI; 1.0-2.2) and 2.5 (95% CI; 1.8-3.3), with no statistical significance between the groups. Two subdural hematomas occurred 0.4 (95% CI; 0.06-1.1) per 100 patient-years. Mean age of patients with complications was 77.9 (±5.9) and 69.3 (±11.3) for those without (p < 0.001). The discontinuation rate was 6.5% and 1.7% was due to dyspepsia for dabigatran, lower than the RE-LY trial.ConclusionThis study, largely based on dabigatran shows that treatment is efficient and safe in everyday clinical practice and not significantly different compared to a warfarin cohort with tight anticoagulation control.Electronic supplementary materialThe online version of this article (doi:10.1186/s12959-014-0029-6) contains supplementary material, which is available to authorized users.