PHARMACOGENETICS OF ANTITHROMBOTIC DRUGS: STATUS UPDATE ON THE PROBLEM

Individual Variability ◽

Current Data ◽

P2y12 Inhibitors ◽

Platelet Receptor ◽

Genes Encoding ◽

Clopidogrel Therapy ◽

The Individual ◽

Genetically Determined

The review deals with the main trials devoted to the study of genetic markers of individual variability in drug response to antithrombotic agents. The first part describes the studies of the genes encoding the platelet receptor subunits studied in the association of the possible insufficient effect of acetylsalicylic acid, and transporter proteins and allelic variants with reduced CYP450 functional activity, which are associated with insufficient effect on clopidogrel therapy. The second part considers polymorphisms that determine the individual dose and the risk of bleeding due to excessive hypocoagulation in patients taking warfarin. It also presents current data on the study of genetically determined individual reactions to the new inhibitors: P2Y12 inhibitors (prasugrel and ticagrelor) and direct oral anticoagulants.

Examination of the Effectiveness of Direct Oral Anticoagulants in Comparison to Warfarin in an Obese Population

Journal of Pharmacy Technology ◽

10.1177/87551225211064113 ◽

2021 ◽

pp. 875512252110641

Author(s):

Rachel M. Watson ◽

Carmen B. Smith ◽

Erica F. Crannage ◽

Laura M. Challen

Keyword(s):

Primary Outcome ◽

Oral Anticoagulants ◽

Efficacy And Safety ◽

Class Iii ◽

Vein Thrombosis ◽

Class Iii Obesity ◽

Recurrent Vte ◽

The Individual ◽

Deep Vein

Background: While commonly prescribed today, direct oral anticoagulants (DOACs) have historically been avoided in patients with class III obesity or a weight >120 kg due to limited literature regarding the efficacy and safety in this population. Objective: The overall objective was to examine the effectiveness of DOACs compared to warfarin in a population with obesity. Methods: Patients with a diagnosis of venous thromboembolism (VTE) or atrial fibrillation and a body mass index (BMI) ≥35 kg/m2 from August 1, 2015, to August 1, 2020, were included in this retrospective cohort study. Patients receiving a DOAC were matched in a 1:2 ratio to warfarin. The primary outcome was a composite of stroke or recurrent VTE. Secondary outcomes included the individual components of the primary outcome, hospitalization for bleed, and the primary outcome in patients with a BMI ≥40 kg/m2. Results: A total of 162 patients were included, with 54 and 108 in the DOAC and warfarin groups, respectively. Baseline BMI was similar between groups (45.7 kg/m2 for DOACs vs 43.8 kg/m2 for warfarin), with approximately 70% of patients having a BMI ≥40 kg/m2. The primary outcome occurred in 1 patient (1.9%) in the DOAC group and 2 patients (1.9%) in the warfarin group. The DOAC group had a higher, nonsignificant incidence of bleeding (5.6% vs 0.9%, P = 0.11). There was no difference between groups in incidence of deep vein thrombosis (DVT), pulmonary embolism (PE), or stroke in patients with a BMI ≥40 kg/m2. Conclusion: DOACs may be as efficacious as warfarin in the prevention of stroke or recurrent VTE in patients with a BMI of ≥35 kg/m2. Prospective, randomized trials are warranted to further assess the efficacy and safety of DOACs in this population.

ANTICOAGULANT THERAPY IN CANCER PATIENTS WITH ATRIAL FIBRILLATION. CONSIDERING AGE FACTOR

Успехи геронтологии ◽

10.34922/ae.2020.33.1.013 ◽

2020 ◽

pp. 99-106

Author(s):

В. И. Потиевская ◽

А. А. Ахобеков ◽

М. Ф. Баллюзек

Keyword(s):

Atrial Fibrillation ◽

Cancer Patients ◽

Anticoagulant Therapy ◽

Oral Anticoagulants ◽

Current Data ◽

Related Factors ◽

Age Related ◽

Liver And Kidney ◽

After Cancer

Рассматривается современное состояние вопроса выбора антикоагулянтной терапии при фибрилляции предсердий (ФП) у онкологических больных. Отмечается, что сложность выбора антикоагулянта при злокачественных новообразованиях (ЗНО) определяется такими факторами, как коморбидные сердечно-сосудистые заболевания, нарушения функции печени и почек, метаболические дисфункции, свойственные, прежде всего, пациентам старшей возрастной группы. Приводятся актуальные данные по оценке риска геморрагических и тромбоэмболических осложнений ФП при ЗНО в аспекте возраста. Обсуждаются возможные причины увеличения риска развития ФП во время и после лечения ЗНО, в том числе и в связи с возраст-ассоциированностью этих патологий. Рассмотрены вопросы выбора антикоагулянтов у пациентов, находящихся на активной противоопухолевой терапии, особенно на препаратах из группы прямых оральных антикоагулянтов (ПОАК). Согласно данным обсервационных исследований, именно ПОАК являются перспективным, относительно безопасным и эффективным выбором для онкологических пациентов с ФП, в связи с чем их применение должно активно изучаться в рандомизированных клинических исследованиях с учетом фактора возраста. Подчеркивается, что подбор схемы антикоагулянтной терапии у пациентов с ФП и ЗНО требует междисциплинарного участия кардиологов и онкологов, а часто и гериатров, чтобы индивидуализировать лечение и предложить наиболее эффективную терапию. The current issue of the choice of anticoagulant therapy of atrial ﬁbrillation (AF) in cancer patients is considered. It is noted that the difﬁculty of choosing an anticoagulant in malignancies is largely determined by age-related factors, such as comorbid cardiovascular diseases, liver and kidney dysfunction, metabolic disorders common for in elderly patients. Current data on the risk assessment of hemorrhagic and thromboembolic complications of AF in cancer patients in the aspect of age presented. During and after cancer treatment, the risk of developing AF can increase, also in connection with the age-associated pathology. Possible reasons of it are discussed. The choice of different anticoagulants groups in patients treated with anticancer therapy, including direct oral anticoagulants (DOAC) is considered. According to available data from observational studies, it is the DOAC that is a promising, relatively safe and effective choice for cancer patients with AF, and therefore their use should be actively studied in randomized trials, considering the factor of age. It is particularly noted that solving this problem requires the interdisciplinary involvement of cardiologists, oncologists, and sometimes, geriatrics, to individualize treatment for each case and to offer the most effective therapy.

Effect of Antithrombotic Therapy on Secondary Bleeding After Proctological Surgery

10.21203/rs.3.rs-27989/v1 ◽

2020 ◽

Author(s):

Ryo Maemoto ◽

Shingo Tsujinaka ◽

Yasuyuki Miyakura ◽

Erika Machida ◽

Nao Kakizawa ◽

...

Keyword(s):

Antithrombotic Therapy ◽

Oral Anticoagulants ◽

Individual Risk ◽

Bleeding Rate ◽

Secondary Bleeding ◽

Number Of Patients ◽

Anticoagulant Drugs ◽

The Individual ◽

Median Interval

Abstract Background: The purpose of this study was to identify the incidence and severity of secondary bleeding after proctological surgery for patients with or without antithrombotic therapy.Methods: We retrospectively identified 113 patients who underwent proctological surgery in our hospital from March 2009 to February 2019. In general, antiplatelet drugs were continued and anticoagulant drugs were either substituted or withdrawn prior to the surgery. The severity of secondary bleeding was classified as mild, moderate, severe.Results: Eighteen patients underwent antiplatelet therapy (A group) and 95 patients did not undergo antithrombotic therapy (N group). Secondary bleeding was observed in nine patients (8.0%) and patients in the A group exhibited significantly higher rate of secondary bleeding rate than patients in the N group (39% vs. 2.4%, P < 0.01). The median interval from surgery to the onset of secondary bleeding was 5 (range: 0-11days). The severity of bleeding was the highest in patients administered direct oral anticoagulants (DOAC) and was the lowest in those administered aspirin. There was no mortality or cardiovascular event.Conclusions: Antithrombotic therapy is associated with high risk of secondary bleeding after proctological surgery, particularly in patients who undergo anticoagulant therapy. Delaying of postoperative resumption of anticoagulants may be considered in balancing the individual risk of postoperative thromboembolic complications against the risk of secondary bleeding. Future prospective studies with larger number of patients are needed to determine the appropriate timing of resuming antithrombotic therapy.

Direct Oral Anticoagulants in Chronic Liver Disease

Annals of Pharmacotherapy ◽

10.1177/1060028019841582 ◽

2019 ◽

Vol 53 (10) ◽

pp. 1042-1049 ◽

Cited By ~ 9

Author(s):

Taylor D. Steuber ◽

Meredith L. Howard ◽

Sarah A. Nisly

Keyword(s):

Clinical Trials ◽

Liver Disease ◽

Chronic Liver Disease ◽

English Language ◽

Data Extraction ◽

Oral Anticoagulants ◽

Chronic Liver ◽

Venous Thromboembolic ◽

Objective: To review the use of direct oral anticoagulants (DOACs) in patients with chronic liver disease (CLD). Data Sources: A MEDLINE literature search was performed from 1964 through February 2019 using the following search terms: cirrhosis, chronic liver disease, direct oral anticoagulant, and the individual DOACs. Study Selection and Data Extraction: All English-language human trials and reports that examined DOACs for treatment or prevention of venous thromboembolic (VTE) events in patients with CLD were included. Data Synthesis: A total of 6 clinical trials examining the use of DOACs in patients with CLD were identified. All DOACs have been utilized in patients with CLD, with the exception of betrixaban, for prevention of stroke in atrial fibrillation or treatment of VTE (except for treatment of pulmonary embolism). The studies primarily evaluated patients with mild to moderate liver disease (Child-Turcotte-Pugh class A and B). The DOACs had similar rates of bleeding compared with traditional anticoagulants. Relevance to Patient Care and Clinical Practice: This review evaluates and summarizes the available evidence on DOACs in the setting of CLD. These agents may be more appealing in this population because monitoring or administration may be difficult with traditional anticoagulants (warfarin or low-molecular-weight heparins). Conclusion: Early data suggest that DOACs may be safe in patients with mild to moderate CLD. Should a DOAC be selected as an alternative to traditional anticoagulants, more frequent monitoring should be used because hepatotoxicity may be a concern. Larger clinical trials are needed to address efficacy outcomes as well as differences among individual DOACs in this population.

Type 2 Diabetes, Atrial Fibrillation, and Direct Oral Anticoagulation

Journal of Diabetes Research ◽

10.1155/2019/5158308 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 2

Author(s):

Dana Prídavková ◽

Matej Samoš ◽

Tomáš Bolek ◽

Ingrid Škorňová ◽

Jana Žolková ◽

...

Keyword(s):

Atrial Fibrillation ◽

Type 2 Diabetes ◽

Clinical Course ◽

Oral Anticoagulants ◽

Factor Xa ◽

Current Data ◽

Thrombin Inhibitor

Type 2 diabetes (T2D) is an independent risk factor of stroke and systemic embolism in patients with atrial fibrillation (AF), and T2D patients with AF-associated stroke seem to have worse clinical outcome and higher risk of unfavorable clinical course compared to individuals without this metabolic disorder. Long-term anticoagulation is indicated in majority of T2D patients with AF to prevent adverse AF-associated embolic events. Direct oral anticoagulants (DOACs), direct oral thrombin inhibitor dabigatran, and direct oral factor Xa inhibitors, rivaroxaban, apixaban, and edoxaban, have emerged as a preferred choice for long-term prevention of stroke in AF patients offering potent and predictable anticoagulation and a favorable pharmacology with low risk of interactions. This article reviews the current data regarding the use of DOACs in individuals with T2D and AF.

Management of Cancer-Associated Thrombosis: An Evolving Area

Cancers ◽

10.3390/cancers12102999 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2999

Author(s):

Corinne Frere ◽

Jean M. Connors ◽

Dominique Farge

Keyword(s):

Cancer Patient ◽

Clinical Decision Making ◽

Oral Anticoagulants ◽

Clinical Decision ◽

Patient Centered ◽

Patient Values ◽

The Individual ◽

The Right ◽

Cancer Associated Thrombosis

The management of cancer-associated thrombosis (CAT) is an evolving area. With the use of direct oral anticoagulants as a new option in the management of CAT, clinicians now face several choices for the individual cancer patient with venous thromboembolism. A personalized approach, matching the right drug to the right patient, based on drug properties, efficacy and safety, side effect profile of each drug, and patient values and preference, will probably supplant the one size fits all approach of use of only low-molecular-weight heparin in the near future. We herein present eight translational, clinical research, and review articles on recent advances in the management of CAT published in the Special Issue “Treatment for Cancer-Associated Thrombosis” of Cancers. For now, a multidisciplinary patient-centered approach involving a close cooperation between oncologists and other specialists is warranted to guide clinical decision making and optimize the treatment of VTE in cancer patient.

Anticoagulation Changes Following Major and Clinically Relevant Nonmajor Bleeding Events in Non-valvular Atrial Fibrillation Patients

Journal of Pharmacy Practice ◽

10.1177/08971900211064189 ◽

2021 ◽

pp. 089719002110641

Author(s):

Thane Feldeisen ◽

Constantina Alexandris-Souphis ◽

Brian Haymart ◽

Xiaowen Kong ◽

Eva Kline-Rogers ◽

...

Keyword(s):

Atrial Fibrillation ◽

Drug Class ◽

Oral Anticoagulants ◽

Anticoagulation Therapy ◽

Bleeding Event ◽

Bleeding Events ◽

Anticoagulation Management ◽

Anticoagulation Clinics ◽

Background Bleeding events are common complications of oral anticoagulant drugs, including both warfarin and the direct oral anticoagulants (DOACs). Some patients have their anticoagulant changed or discontinued after experiencing a bleeding event, while others continue the same treatment. Differences in anticoagulation management between warfarin- and DOAC-treated patients following a bleeding event are unknown. Methods Patients with non-valvular atrial fibrillation from six anticoagulation clinics taking warfarin or DOAC therapy who experienced an International Society of Thrombosis and Haemostasis (ISTH)-defined major or clinically relevant non-major (CRNM) bleeding event were identified between 2016 and 2020. The primary outcome was management of the anticoagulant following bleeding (discontinuation, change in drug class, and restarting of same drug class). DOAC- and warfarin-treated patients were propensity matched based on the individual elements of the CHA2DS2-VASc and HAS-BLED scores as well as the severity of the bleeding event. Results Of the 509 patients on warfarin therapy and 246 on DOAC therapy who experienced a major or CRNM bleeding event, the majority of patients continued anticoagulation therapy. The majority of warfarin (231, 62.6%) and DOAC patients (201, 81.7%) restarted their previous anticoagulation. Conclusion Following a bleeding event, most patients restarted anticoagulation therapy, most often with the same type of anticoagulant that they previously had been taking.

Oral Anticoagulants in Atrial Fibrillation Patients With Recent Stroke Who Are Dependent on the Daily Help of Others

Stroke ◽

10.1161/strokeaha.120.033862 ◽

2021 ◽

Author(s):

Louisa Meya ◽

Alexandros A. Polymeris ◽

Sabine Schaedelin ◽

Fabian Schaub ◽

Valerian L. Altersberger ◽

...

Keyword(s):

Atrial Fibrillation ◽

Ischemic Stroke ◽

Proportional Hazards ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Cox Proportional Hazards ◽

Composite Outcome ◽

Unique Identifier ◽

Background and Purpose: Data on the effectiveness and safety of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) in patients with stroke attributable to atrial fibrillation (AF) who were dependent on the daily help of others at hospital discharge are scarce. Methods: Based on prospectively obtained data from the observational Novel-Oral-Anticoagulants-in-Ischemic-Stroke-Patients-longterm registry from Basel, Switzerland, we compared the occurrence of the primary outcome—the composite of recurrent ischemic stroke, major bleeding, and all-cause death—among consecutive patients with AF-stroke treated with either VKAs or DOACs between patients dependent (defined as modified Rankin Scale score, 3–5) and patients independent at discharge. We used simple, adjusted, and weighted Cox proportional hazards regression to account for potential confounders. Results: We analyzed 801 patients (median age 80 years, 46% female), of whom 391 (49%) were dependent at discharge and 680 (85%) received DOACs. Over a total follow-up of 1216 patient-years, DOAC- compared to VKA-treated patients had a lower hazard for the composite outcome (hazard ratio [HR], 0.58 [95% CI, 0.42–0.81]), as did independent compared to dependent patients (HR, 0.54 [95% CI, 0.40–0.71]). There was no evidence that the effect of anticoagulant type (DOAC versus VKA) on the hazard for the composite outcome differed between dependent (HR dependent , 0.68 [95% CI, 0.45–1.01]) and independent patients (HR independent , 0.44 [95% CI, 0.26–0.75]) in the simple model ( P interaction =0.212). Adjusted (HR dependent , 0.74 [95% CI, 0.49–1.11] and HR independent , 0.51 [95% CI, 0.30–0.87]; P interaction =0.284) and weighted models (HR dependent , 0.79 [95% CI, 0.48–1.31] and HR independent , 0.46 [95% CI, 0.26–0.81]; P interaction =0.163) yielded concordant results. Secondary analyses focusing on the individual components of the composite outcome were consistent to the primary analyses. Conclusions: The benefits of DOACs in patients with atrial fibrillation with a recent stroke were maintained among patients who were dependent on the help of others at discharge. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03826927.

How I treat and prevent venous thrombotic complications in patients with lymphoma

Blood ◽

10.1182/blood.2019003689 ◽

2021 ◽

Author(s):

Robert A Schmidt ◽

Agnes YY Lee

Keyword(s):

Trial Design ◽

Randomized Trials ◽

Oral Anticoagulants ◽

Low Molecular Weight ◽

Common Complication ◽

Low Molecular Weight Heparins ◽

Relative Risks ◽

Thrombotic Complications ◽

Venous thromboembolism (VTE) is a common complication occurring in 5-10% of patients with lymphoma. As the complexity of lymphoma management has increased with novel therapies, so too has the treatment of VTE. Therapeutic options for the treatment of cancer-associated VTE have expanded from only warfarin and low-molecular-weight heparins (LMWHs) to include the direct oral anticoagulants (DOACs) apixaban, edoxaban and rivaroxaban. There have been no head-to-head trials comparing different DOACs in this setting and randomized trials comparing a DOAC with LMWH dalteparin differ in trial design and results. Drug-drug interactions, drug-specific side effects and patient selection are important considerations when prescribing anticoagulant therapy. In all patients, the relative risks of thrombosis and bleeding, the availability of the anticoagulant, and the life expectancy of the patient are vital elements in selecting the most appropriate anticoagulant (which can vary over time) for the individual patient. We describe the intricacies and challenges of treating thrombotic complications in patients with lymphoma with an emphasis on evidence and guideline-based care.

Histone H4 acetylation regulates behavioral inter-individual variability in zebrafish

10.1101/100230 ◽

2017 ◽

Cited By ~ 1

Author(s):

Angel-Carlos Román ◽

Julián Vicente-Page ◽

Alfonso Pérez-Escudero ◽

Jose M. Carvajal-González ◽

Pedro M. Fernández-Salguero ◽

...

Keyword(s):

Individual Variability ◽

Histone Deacetylation ◽

Transcriptional Level ◽

Histone H4 ◽

Histone Deacetylase 1 ◽

Histone H4 Acetylation ◽

Genes Encoding ◽

Underlying Mechanisms ◽

The Individual ◽

Genomic Regions

ABSTRACTAnimals can show very different behaviors even in isogenic populations, but the underlying mechanisms to generate this variability remain elusive. We found that laboratory and isogenic zebrafish (Danio rerio) larvae showed consistent individual behaviors when swimming freely in identical wells or in reaction to stimuli. We also found that this behavioral inter-individual variability was reduced when we impaired the histone deacetylation pathway. Individuals with high levels of histone H4 acetylation, and specifically H4K12, behaved similar to the average of the population, but those with low levels deviated from it. More precisely, we found a set of genomic regions whose histone H4 acetylation is reduced with the distance between the individual and the average population behavior. We found evidence that this modulation depends on a complex of Yin-yang 1 (YY1) and histone deacetylase 1 (HDAC1) that binds to and deacetylates these regions. These changes were not only maintained at the transcriptional level but also amplified, as most target regions were located near genes encoding transcription factors. We suggest that stochasticity in the histone deacetylation pathway participates the generation of genetic-independent behavioral inter-individual variability.