Importance of using a pharmacogenetic approach to predict individual pharmacokinetics and safety profile of apixaban

In recent years, there has been a trend towards increased prescribing of direct-acting oral anticoagulants (DOACs) due to favourable pharmacokinetics and pharmacodynamics without the need for regular coagulation monitoring. However, recent studies have documented individual variability in plasma DOAC levels. DOAC pharmacogenetics is a relatively new area of research. There is a need to understand the role of pharmacogenetics in the adaptation of anticoagulant therapy according to a patient’s genetic characteristics. This scientific review of current data on the impact of different gene polymorphisms on apixaban pharmacokinetics broadens the understanding of the clinical relevance of genotyping for treatment efficacy and safety.

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Research trials in the older stroke patient

Stroke in the Older Person ◽

10.1093/med/9780198747499.003.0029 ◽

2020 ◽

pp. 437-450

Author(s):

Kailash Krishnan ◽

Nikola Sprigg

Keyword(s):

Clinical Trials ◽

Older People ◽

Stroke Patient ◽

Oral Anticoagulants ◽

Intravenous Thrombolysis ◽

Lipid Lowering ◽

Good Communication ◽

Decompressive Hemicraniectomy ◽

The Impact

‘Research trials in the older stroke patient’ examines the challenges of research in older people, the phenomenon of ageism, the impact of frailty, trials of acute treatments like intravenous thrombolysis and endovascular therapy, acute lowering of blood pressure, and decompressive hemicraniectomy. Trials looking at secondary prevention, including cardioembolism, role of the newer oral anticoagulants (DOACs), carotid endarterectomy, lipid lowering, antihypertensive therapy, are examined. The broader issue of difficulties in recruiting older people to stroke trials and the potential solutions are discussed. Until recently most participants in clinical trials of stroke have been relatively young with little or no comorbidity. With a group growing more than any other, it becomes a priority to understand the challenges in recruiting and retaining older patients into clinical trials. Barriers to recruitment relate to both researchers and participants; solutions include good communication, logistical support, and innovative study design and sampling. Further research will hopefully narrow the gap to those seen in real-world clinical practice.

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Impact of weight on the efficacy and safety of direct-acting oral anticoagulants in patients with non-valvular atrial fibrillation: a meta-analysis

EP Europace ◽

10.1093/europace/euz361 ◽

2020 ◽

Vol 22 (3) ◽

pp. 361-367 ◽

Cited By ~ 3

Author(s):

Aaqib H Malik ◽

Srikanth Yandrapalli ◽

Suchith Shetty ◽

Wilbert S Aronow ◽

Diwakar Jain ◽

...

Keyword(s):

Atrial Fibrillation ◽

Major Bleeding ◽

Oral Anticoagulants ◽

Outcome Data ◽

Phase Iii ◽

Safety And Efficacy ◽

Low Bmi ◽

Direct Acting ◽

The Impact ◽

Direct Acting Oral Anticoagulants

Abstract Aims This study sought to determine the impact of weight and body mass index (BMI) on the safety and efficacy of direct-acting oral anticoagulants (DOACs) compared with warfarin in patients with non-valvular atrial fibrillation. Methods and results A systematic literature search was employed in PubMed, Embase, and Cochrane clinical trials with no language or date restrictions. Randomized trials or their substudies were assessed for relevant outcome data for efficacy that included stroke or systemic embolization (SSE), and safety including major bleeding and all-cause mortality. Binary outcome data and odds ratios from the relevant articles were used to calculate the pooled relative risk. For SSE, the data from the four Phase III trials showed that DOACs are better or similarly effective with low BMI 0.73 (0.56–0.97), normal BMI 0.72 (0.58–0.91), overweight 0.87 (0.76–0.99), and obese 0.87 (0.76–1.00). The risk of major bleeding was also better or similar with DOACs in all BMI subgroups with low BMI 0.62 (0.37–1.05), normal BMI 0.72 (0.58–0.90), overweight 0.83 (0.71–0.96), and obese 0.91 (0.81–1.03). There was no impact on mortality in all the subgroups. In a meta-regression analysis, the effect size advantage of DOACs compared with warfarin in terms of safety and efficacy gradually attenuated with increasing weight. Conclusion Our findings suggest that a weight-based dosage adjustment may be necessary to achieve optimal benefits of DOACs for thromboembolic prevention in these patients with non-valvular atrial fibrillation. Further dedicated trials are needed to confirm these findings. PROSPERO 2019 CRD42019140693. Available from: https://www.crd.york.ac.uk/prospero/display_record.php? ID=CRD42019140693.

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Oral Anticoagulant Therapy—When Art Meets Science

Journal of Clinical Medicine ◽

10.3390/jcm8101747 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1747 ◽

Cited By ~ 2

Author(s):

Patricia Lorena Cîmpan ◽

Romeo Ioan Chira ◽

Mihaela Mocan ◽

Florin Petru Anton ◽

Anca Daniela Farcaş

Keyword(s):

Oral Anticoagulant Therapy ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Prosthetic Heart Valve ◽

Genetic Alterations ◽

Individual Variability ◽

Vein Thrombosis ◽

Direct Acting ◽

Deep Vein ◽

Higher Sensitivity

Anticoagulant treatment is extremely important and frequently encountered in the therapy of various cardiovascular diseases. Vitamin K antagonists (VKA) are in use for the prevention and treatment of arterial and venous thromboembolism, despite the introduction of new direct-acting oral anticoagulants (NOAC). The VKA still have the clear recommendation in patients with a mechanical prosthetic heart valve replacement or moderate to severe mitral stenosis of the rheumatic origin, in deep vein thrombosis associated with congenital thrombophilia, and in cases where NOAC are prohibited by social condition (financial reason) or by comorbidities (extreme weight, severe renal or liver disease). VKA dosing required to reach the targeted therapeutic range varies largely between patients (inter-individual variability). This inter-individual variability depends on multiple environmental factors such as age, mass, diet, etc. but it is also influenced by genetic determinism. About 30 genes implicated in the metabolism coumarins derivatives were identified, the most important being CYP2C9 and VKORC, each with several polymorphisms. Herein, we review the data regarding genetic alterations in general and specific populations, highlight the diagnosis options in particular cases presenting with genetic alteration causing higher sensitivity and/or resistance to VKA therapy and underline the utility of NOAC in solving such rare and difficult problems.

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Risk of Hepatocellular Carcinoma after HCV Clearance by Direct-Acting Antivirals Treatment Predictive Factors and Role of Epigenetics

Cancers ◽

10.3390/cancers12061351 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1351 ◽

Cited By ~ 1

Author(s):

Luca Rinaldi ◽

Riccardo Nevola ◽

Gianluigi Franci ◽

Alessandro Perrella ◽

Giusy Corvino ◽

...

Keyword(s):

Risk Factors ◽

Hepatocellular Carcinoma ◽

Immune Surveillance ◽

Liver Stiffness ◽

Virologic Response ◽

Direct Acting Antivirals ◽

Direct Role ◽

Direct Acting ◽

The Impact

Direct-acting antivirals (DAAs) induce a rapid virologic response (SVR) in up to 99% of chronic hepatitis C patients. The role of SVR by DAAs on the incidence or recurrence of hepatocellular carcinoma (HCC) is still a matter of debate, although it is known that SVR does not eliminate the risk of HCC. In this review, we made an updated analysis of the literature data on the impact of SVR by DAAs on the risk of HCC as well as an assessment of risk factors and the role of epigenetics. Data showed that SVR has no impact on the occurrence of HCC in the short–medium term but reduces the risk of HCC in the medium–long term. A direct role of DAAs in the development of HCC has not been demonstrated, while the hypothesis of a reduction in immune surveillance in response to the rapid clearance of HCV and changes in the cytokine pattern influencing early carcinogenesis remains to be further elucidated. HCV induces epigenetic alterations such as modifications of the histone tail and DNA methylation, which are risk factors for HCC, and such changes are maintained after HCV clearance. Future epigenetic studies could lead to identify useful biomarkers and therapeutic targets. Cirrhosis has been identified as a risk factor for HCC, particularly if associated with high liver stiffness and α-fetoprotein values, diabetes and the male sex. Currently, considering the high number and health cost to follow subjects’ post-HCV clearance by DAAs, it is mandatory to identify those at high risk of HCC to optimize management.

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Recent advances in the analysis of nanoparticle-protein coronas

Nanomedicine ◽

10.2217/nnm-2019-0381 ◽

2020 ◽

Vol 15 (10) ◽

pp. 1037-1061

Author(s):

Muhammad Ovais ◽

Susheel Kumar Nethi ◽

Saleem Ullah ◽

Irshad Ahmad ◽

Sudip Mukherjee ◽

...

Keyword(s):

Protein Corona ◽

Recent Decade ◽

The Body ◽

Pharmacokinetics And Pharmacodynamics ◽

Physiological Factors ◽

Characterization Methods ◽

Biological Fate ◽

Circulation Distribution ◽

The Impact

In spite of radical advances in nanobiotechnology, the clinical translation of nanoparticle (NP)-based agents is still a major challenge due to various physiological factors that influence their interactions with biological systems. Recent decade witnessed meticulous investigation on protein corona (PC) that is the first surrounds NPs once administered into the body. Formation of PC around NP surface exhibits resilient effects on their circulation, distribution, therapeutic activity, toxicity and other factors. Although enormous literature is available on the role of PC in altering pharmacokinetics and pharmacodynamics of NPs, understanding on its analytical characterization methods still remains shallow. Therefore, the current review summarizes the impact of PC on biological fate of NPs and stressing on analytical methods employed for studying the NP-PC.

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The Role of Thrombophilia in Pregnancy

Thrombosis ◽

10.1155/2013/516420 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 26

Author(s):

Elisabeth M. Battinelli ◽

Ariela Marshall ◽

Jean M. Connors

Keyword(s):

Pregnancy Outcome ◽

Oral Anticoagulants ◽

New Oral Anticoagulants ◽

Thrombotic Disease ◽

Therapeutic Anticoagulation ◽

Physical Changes ◽

The Impact ◽

Physiologic Changes Of Pregnancy ◽

In Pregnancy

Thrombotic disease is a major cause of peripartum morbidity and mortality worldwide. Development of thrombosis in pregnancy is multifactorial due to the physiologic changes of pregnancy—which induce a relative hypercoagulable state—as well as physical changes leading to increased stasis and also the effects of both the inherited and the acquired thrombophilias. In this review, we discuss the impact of each of these factors on the development of thrombosis as well as the evidence for the impact of pregnancy-associated thrombosis on pregnancy outcome. We then discuss the use of both prophylactic and therapeutic anticoagulation during pregnancy and the puerperium. We review the indications and dosing recommendations for administration of anticoagulation in a context of discussing the evidence including the lack of evidence and formal guidelines in this area. We briefly address the role of the new oral anticoagulants in pregnancy and conclude that significant further research in women with thrombophilias and pregnancy-associated thrombosis may help clarify the management of this condition in the future.

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PHARMACOGENETICS OF ANTITHROMBOTIC DRUGS: STATUS UPDATE ON THE PROBLEM

Atherothrombosis Journal ◽

10.21518/2307-1109-2018-2-115-129 ◽

2018 ◽

pp. 115-129

Author(s):

Ekaterina S. Kropacheva

Keyword(s):

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

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.

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The possible role of Saponin in Type-II Diabetes- A review

Current Diabetes Reviews ◽

10.2174/1573399816666200516173829 ◽

2020 ◽

Vol 16 ◽

Cited By ~ 1

Author(s):

Neeraj Choudhary ◽

Gopal Lal Khatik ◽

Ashish Suttee

Keyword(s):

Secondary Metabolites ◽

Type Ii Diabetes ◽

Structural Diversity ◽

Complete Information ◽

Current Data ◽

Type Ii ◽

Glucose Levels ◽

Therapeutic Benefits ◽

The Impact

Background: The possible role of secondary metabolites in the management of diabetes is a great concern and constant discussion. This characteristic seems relevant and should be the subject of thorough discussion with respect to saponin. Objective: Current data mainly focus on the impact of saponin in the treatment of type-II diabetes. The majority of studies emphasis on other secondary metabolites such as alkaloids and flavonoids but very few papers are there representing the possible role of saponin as these papers express the narrow perspective of saponin phytoconstituents but lacking in providing the complete information on various saponin plants. The aim of the study was to summarize all available data concerning the saponin containing plant in the management of type-II diabetes. Methods: All relevant papers on saponin were selected. This review summarizes the saponins isolation method, mechanism of action, clinical significance, medicinal plants and phytoconstituents responsible for producing a therapeutic effect in the management of diabetes. Results: The saponin is of high potential with structural diversity and inhibits diabetic complications along with reducing the hyperglycemia through different mechanisms thereby providing scope for improving the existing therapy and developing the novel medicinal agents for curing diabetes. Conclusion: Saponins having potential therapeutic benefits and are theorized as an alternative medication in decreasing serum blood glucose levels in the patient suffering from diabetes.

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Prescribing and Safety of Direct-Acting Oral Anticoagulants Compared to Warfarin in Patients with Atrial Fibrillation on Chronic Hemodialysis

Pharmacy ◽

10.3390/pharmacy8010037 ◽

2020 ◽

Vol 8 (1) ◽

pp. 37 ◽

Cited By ~ 1

Author(s):

Estella Davis ◽

Dallin Darais ◽

Kevin Fuji ◽

Paige Nekola ◽

Khalid Bashir

Keyword(s):

Atrial Fibrillation ◽

Oral Anticoagulants ◽

Chronic Hemodialysis ◽

Average Dose ◽

Chi Square ◽

Direct Acting ◽

Risk For Bleeding ◽

The Impact ◽

Area Health ◽

Direct Acting Oral Anticoagulants

ESRD patients receiving hemodialysis (HD) were excluded from landmark trials evaluating direct-acting oral anticoagulants (DOACs) in atrial fibrillation (AF). The objective was to evaluate prescribing and bleeding with DOACs compared to warfarin in AF patients with chronic HD. A retrospective, observational study of patients receiving warfarin or DOAC from April 2010-April 2016 from area health system hospitals and Dialysis Clinics, Inc. records. Data was analyzed using descriptive statistics, ANOVA, and chi-square. Ninety-one patients were included with warfarin as the initial OAC in most patients (n = 76) at average dose of 29 mg/week. Fifteen patients were initially prescribed apixaban (n = 12) or dabigatran (n = 3). Most switches in OAC therapy were to apixaban. When the initial OAC was a DOAC, it was not dosed appropriately in five with one bleed, two dosed appropriately had bleeds. When initial warfarin was switched to a DOAC, it was not dosed appropriately in seven with five bleeds. More bleeds occurred with warfarin alone (n = 18) vs. those on warfarin switched to DOAC (n = 5) vs. DOAC alone (n = 3), p = 0.022. All but four patients that bled had HAS-BLED scores three or higher. Warfarin was most often prescribed and associated with a higher incidence of bleeding compared to DOACs in this population of patients at high risk for bleeding. Larger studies should be conducted to analyze the impact of DOAC dose appropriateness on safety and clinical outcomes.

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Associative relationship between atopy, HLA complex genes and other genes

Rossiiskii Allergologicheskii ZHurnal ◽

10.36691/rja1206 ◽

2019 ◽

Vol 16 (3) ◽

pp. 5-25

Author(s):

N G Astafyeva ◽

B A Shamgunova ◽

D Yu Kobzev ◽

I Ae Michailova

Keyword(s):

Molecular Mechanisms ◽

Complex Structure ◽

Clinical Manifestations ◽

Current Data ◽

Genetic Determinants ◽

Genetic Characteristics ◽

Hla Genes ◽

Histocompatibility Complex ◽

History Of

This review presents current data on the associative relationships of genes of the major histocompatibility complex (HLA) and other genes with atopy. Despite the long history of studying the role of HLA class genes in atopy and the introduction of modern technologies and methods, many unresolved issues remain, including the difficulties caused by the heterogeneity of the human population, the complex structure and disequilibrium of linkage between different HLA genes. Although phenotypic heterogeneity is considered as the main limitation in understanding the genetic determinants of atopy, only a few studies have examined the relationships of its typical clinical manifestations induced by aeroallergens with certain HLA genes. The identified molecular mechanisms and genetic characteristics open up the possibility of using new therapeutic targets and modifying existing drugs.

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