PHARMACOGENETIC BASES OF INDIVIDUAL SENSITIVITY AND PERSONALIZED ADMINISTRATION OF ANTIPLATELET THERAPY IN DIFFERENT ETHNIC GROUPS

Cardiovascular diseases (CVDs) are the leading cause of disability and mortality worldwide. Increased thrombosis is the trigger point for the development of various CVDs and their complications, and therefore, therapy with P2Y12-receptor inhibitors is always pathogenetically justified and vital. However, according to the various data, 10-25% of patients treated with clopidogrel have “resistance” to antiplatelet therapy. The causes for the formation of resistance are still not clear. There is no generally accepted, standard methodology for determining resistance to antiplatelet agents. In addition, there are no methodological approaches to identify the patients with resistance to antiplatelet drugs, and standardized schemes for correcting a low sensitivity to these drugs.The aim of this review was to summarize the available results of foreign and domestic studies devoted to the investigation of the effectiveness and safety problems of antiplatelet drugs administration from the point of view of the genetic predisposition to changes in their metabolism.Materials and methods. For the review, the following information from scientific literature represented in open and accessible sources for the period of 1996-2020, was used: pharmgkb.org, PubMed, Scopus, Web of Science Core Collection, Elibrary. Search queries – “Genetic features+antiplatelet therapy+ethnic groups”, “CYP2C19+clopidogrel+antiplatelet therapy effectiveness”; “Stent retrombosis+CYP2C19 polymorphism+ residual platelet reactivity” and “CYP2C19 polymorphism+ethnic groups+clopidogrel resistance” in both Russian and English equivalents. All these data are placed in electronic databases.Results. Currently, the problem of the resistance formation to antiplatelet drugs is studied insufficiently. The best thought-out issue is the research of the effect of the polymorphic alleles carriage of the CYP2C19 gene on the residual platelet reactivity in the patients administrated with dual antiplatelet treatment, including clopidogrel. In general, the analysis of open literature sources indicates the presence of a statistically significant association between the carrier of slow alleles of the CYP2C19 gene and the residual platelet reactivity, clinically manifested by thrombosis and adverse cardiovascular events. The occurrence frequency of polymorphic carriage of the CYP2C19 gene varies in different ethnic groups, so it cannot be extrapolated to individual subjects, peculiar in the ethnic diversity.Conclusion. To develop preventive and predictive measures aimed at overcoming resistance to antiplatelet agents, as well as working out methodological approaches to personalized prescribtion of this group drugs, a further investigation with the expansion of the search for causes and the study of the other genes participation of the cytochrome P450 system, is required.

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Multifactorial Background for a Low Biological Response to Antiplatelet Agents Used in Stroke Prevention

Medicina ◽

10.3390/medicina57010059 ◽

2021 ◽

Vol 57 (1) ◽

pp. 59

Author(s):

Adam Wiśniewski

Keyword(s):

Ischemic Stroke ◽

Secondary Prevention ◽

Antiplatelet Therapy ◽

Negative Impact ◽

Platelet Reactivity ◽

Antiplatelet Agent ◽

Biological Response ◽

Antiplatelet Agents ◽

Platelet Inhibition ◽

High Risk Group

Effective platelet inhibition is the main goal of the antiplatelet therapy recommended as a standard treatment in the secondary prevention of non-embolic ischemic stroke. Acetylsalicylic acid (aspirin) and clopidogrel are commonly used for this purpose worldwide. A low biological response to antiplatelet agents is a phenomenon that significantly reduces the therapeutic and protective properties of the therapy. The mechanisms leading to high on-treatment platelet reactivity are still unclear and remain multifactorial. The aim of the current review is to establish the background of resistance to antiplatelet agents commonly used in the secondary prevention of ischemic stroke and to explain the possible mechanisms. The most important factors influencing the incidence of a low biological response were demonstrated. The similarities and the differences in resistance to both drugs are emphasized, which may facilitate the selection of the appropriate antiplatelet agent in relation to specific clinical conditions and comorbidities. Despite the lack of indications for the routine assessment of platelet reactivity in stroke subjects, this should be performed in selected patients from the high-risk group. Increasing the detectability of low antiaggregant responders, in light of its negative impact on the prognosis and clinical outcomes, can contribute to a more individualized approach and modification of the antiplatelet therapy to maximize the therapeutic effect in the secondary prevention of stroke.

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Advances in Antiplatelet Therapy for Dentofacial Surgery Patients: Focus on Past and Present Strategies

Materials ◽

10.3390/ma12091524 ◽

2019 ◽

Vol 12 (9) ◽

pp. 1524 ◽

Cited By ~ 16

Author(s):

Gabriele Cervino ◽

Luca Fiorillo ◽

Ines Paola Monte ◽

Rosa De Stefano ◽

Luigi Laino ◽

...

Keyword(s):

Antiplatelet Therapy ◽

Oral Surgery ◽

Case Reports ◽

Case Series ◽

Antiplatelet Agents ◽

Preventive Therapy ◽

Antiplatelet Drugs ◽

Risk Of Bleeding ◽

The Past ◽

Increased Risk

Background: Nowadays, patients involved in antiplatelet therapy required special attention during oral surgery procedures, due to the antiplatelet drugs assumption. The motivations of the assumption may be different and related to the patient’s different systemic condition. For this reason, accordingly to the current international guidelines, different protocols can be followed. The aim of this work is to analyze how the dentist’s approach to these patients has changed from the past to the present, evaluating the risk exposure for the patients. Methods: This review paper considered different published papers in literature through quoted scientific channels, going in search of “ancient” works in such a way as to highlight the differences in the protocols undertaken. The analyzed manuscripts are in the English language, taking into consideration reviews, case reports, and case series in such a way as to extrapolate a sufficient amount of data and for evaluating the past therapeutic approaches compared to those of today. Results: Colleagues in the past preferred to subject patients to substitution therapy with low molecular weight anticoagulants, by suspending antiplatelet agents to treatment patients, often for an arbitrary number of days. The new guidelines clarify everything, without highlighting an increased risk of bleeding during simple oral surgery in patients undergoing antiplatelet therapy. Conclusion: Either patients take these medications for different reasons, because of cardiovascular pathologies, recent cardiovascular events, or even for simple prevention, although the latest research shows that there is no decrease of cardiovascular accidents in patients who carry out preventive therapy. Surely, it will be at the expense of the doctor to assess the patient’s situation and risk according to the guidelines. For simple oral surgery, it is not necessary to stop therapy with antiplatelet agents because the risk of bleeding has not increased, and is localized to a post-extraction alveolus or to an implant preparation, compared to patients who do not carry out this therapy. From an analysis of the results it emerges that the substitutive therapy should no longer be performed and that it is possible to perform oral surgery safely in patients who take antiplatelet drugs, after a thorough medical history. Furthermore, by suspending therapy, we expose our patients to more serious risks, concerning their main pathology, where present.

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Clopidogrel Resistance: Current Issues

Journal of Enam Medical College ◽

10.3329/jemc.v6i1.26381 ◽

2016 ◽

Vol 6 (1) ◽

pp. 38-46

Author(s):

NS Neki

Keyword(s):

Antiplatelet Therapy ◽

Dual Antiplatelet Therapy ◽

Ex Vivo ◽

Platelet Reactivity ◽

Antiplatelet Agents ◽

Clinical Problem ◽

Coronary Intervention ◽

Platelet Activity ◽

Clopidogrel Resistance ◽

Underlying Mechanisms

Antiplatelet agents are mainly used in the prevention and management of atherothrombotic complications. Dual antiplatelet therapy, combining aspirin and clopidogrel, is the standard care for patients having acute coronary syndromes or undergoing percutaneous coronary intervention according to the current ACC/AHA and ESC guidelines. But in spite of administration of dual antiplatelet therapy, some patients develop recurrent cardiovascular ischemic events especially stent thrombosis which is a serious clinical problem. Antiplatelet response to clopidogrel varies widely among patients based on ex vivo platelet function measurements. Clopidogrel is an effective inhibitor of platelet activation and aggregation due to its selective and irreversible blockade of the P2Y12 receptor. Patients who display little attenuation of platelet reactivity with clopidogrel therapy are labeled as low or nonresponders or clopidogrel resistant. The mechanism of clopidogrel resistance remains incompletely defined but there are certain clinical, cellular and genetic factors including polymorphisms responsible for therapeutic failure. Currently there is no standardized or widely accepted definition of clopidogrel resistance. The future may soon be realised in the routine measurement of platelet activity in the same way that blood pressure, cholesterol and blood sugar are followed to help guide the therapy, thus improving the care for millions of people. This review focuses on the methods used to identify patients with clopidogrel resistance, the underlying mechanisms, metabolism, clinical significance and current therapeutic strategies to overcome clopidogrel resistance.J Enam Med Col 2016; 6(1): 38-46

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Antiplatelet drugs: a review of pharmacology and the perioperative management of patients in oral and maxillofacial surgery

Annals of The Royal College of Surgeons of England ◽

10.1308/rcsann.2019.0154 ◽

2020 ◽

Vol 102 (1) ◽

pp. 9-13

Author(s):

H Mahmood ◽

I Siddique ◽

A McKechnie

Keyword(s):

Antiplatelet Therapy ◽

Oral Surgery ◽

Safety Concern ◽

Maxillofacial Surgery ◽

Antiplatelet Agents ◽

Antiplatelet Drugs ◽

Current Evidence ◽

Bleeding Complications ◽

Oral And Maxillofacial Surgery ◽

Number Of Patients

Introduction An increasing number of patients are taking oral antiplatelet agents. As a result, there is an important patient safety concern in relation to the potential risk of bleeding complications following major oral and maxillofacial surgery. Surgeons are increasingly likely to be faced with a dilemma of either continuing antiplatelet therapy and risking serious haemorrhage or withholding therapy and risking fatal thromboembolic complications. While there are national recommendations for patients taking oral antiplatelet drugs undergoing invasive minor oral surgery, there are still no evidence-based guidelines for the management of these patients undergoing major oral and maxillofacial surgery. Methods MEDLINE and EMBASE databases were searched to retrieve all relevant articles published to 31 December 2017. Findings A brief outline of the commonly used antiplatelet agents including their pharmacology and therapeutic indications is discussed, together with the haemorrhagic and thromboembolic risks of continuing or altering the antiplatelet regimen in the perioperative period. Finally, a protocol for the management of oral and maxillofacial patients on antiplatelet agents is presented. Conclusions Most current evidence to guide decision making is based upon non-randomised observational studies, which attempts to provide the safest possible management of patients on antiplatelet therapy. Large randomised clinical trials are lacking.

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Mechanisms of platelet activation: Need for new strategies to protect against platelet-mediated atherothrombosis

Thrombosis and Haemostasis ◽

10.1160/th09-03-0192 ◽

2009 ◽

Vol 102 (08) ◽

pp. 248-257 ◽

Cited By ~ 195

Author(s):

Lisa Jennings

Keyword(s):

Antiplatelet Therapy ◽

Platelet Activation ◽

Platelet Reactivity ◽

Thrombus Formation ◽

Antiplatelet Agents ◽

Bleeding Risk ◽

Adenosine Diphosphate ◽

Adp Receptor ◽

Activation Pathways ◽

New Strategies

SummaryPlatelets are central mediators of haemostasis at sites of vascular injury, but they also mediate pathologic thrombosis. Activated platelets stimulate thrombus formation in response to rupture of an atherosclerotic plaque or endothelial cell erosion, promoting atherothrombotic disease. They also interact with endothelial cells and leukocytes to promote inflammation, which contributes to atherosclerosis. Multiple pathways contribute to platelet activation, and current oral antiplatelet therapy with aspirin and a P2Y12 adenosine diphosphate (ADP) receptor antagonist target the thromboxane A2 and ADP pathways, respectively. Both can diminish activation by other factors, but the extent of their effects depends upon the agonist, agonist strength, and platelet reactivity status. Although these agents have demonstrated significant clinical benefit, residual morbidity and mortality remain high. Neither agent is effective in inhibiting thrombin, the most potent platelet activator. This lack of comprehensive inhibition of platelet function allows continued thrombus formation and exposes patients to risk for recurrent thrombotic events. Moreover, bleeding risk is a substantial limitation of antiplatelet therapy, because these agents target platelet activation pathways critical for both protective haemostasis and pathologic thrombosis. Novel antiplatelet therapies that provide more complete inhibition of platelet activation without increasing bleeding risk could considerably decrease residual risk for ischemic events. Inhibition of the protease-activated receptor (PAR)-1 platelet activation pathway stimulated by thrombin is a novel, emerging approach to achieve more comprehensive inhibition of platelet activation when used in combination with current oral antiplatelet agents. PAR-1 inhibition is not expected to increase bleeding risk, as this pathway does not interfere with haemostasis.

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Antiplatelet Therapy in Secondary Prevention in Patients with Ischaemic Peripheral Arterial Disease

Journal of Integrative Cardiology Open Access ◽

10.31487/j.jicoa.2020.06.05 ◽

2020 ◽

pp. 1-5

Author(s):

Pavel Chrbolka ◽

Zoltán Paluch ◽

Pavel Chrbolka ◽

Gergely Pallag

Keyword(s):

Clinical Trials ◽

Peripheral Arterial Disease ◽

Antiplatelet Therapy ◽

Antiplatelet Agents ◽

Arterial Disease ◽

Effective Therapy ◽

Antiplatelet Drugs ◽

Limb Ischaemia ◽

Acute Limb Ischaemia ◽

Peripheral Arterial

Introduction: Globally, peripheral arterial disease affects almost 200 million individuals at high risk of developing another type of cardiovascular disease with an annual incidence of cardiovascular events and cardiovascular mortality of 4-5% and a risk of acute limb ischaemia and amputation of 5%. All patients with clinical symptomatology of peripheral arterial disease should be treated with statins and antiplatelet drugs. Evidence Acquisition: The authors provide an overview, from the perspective of a clinical pharmacologist, of the pharmacokinetic properties of the antiplatelet agents available, mechanisms of their action, and differences among individual agents in side effects, efficacy and safety as well as a comparison of clinical trials. Evidence Synthesis: In a significant proportion of patients, therapy with clopidogrel is modified, with genetic polymorphism demonstrably preventing effective therapy in a proportion of patients. In cases where an antiplatelet agent other than aspirin is chosen, clopidogrel therapy is rational only if a genetic mutation resulting in ineffective therapy has been ruled out. Effective therapy can be accomplished using the more modern antiplatelet agents with balanced pharmacokinetic and pharmacodynamic properties. Conclusions: Several questions related to treatment of patients with peripheral arterial disease remain to be answered. Expert views on recommended antiplatelet therapy diverge. It would be unethical to ignore the fact that therapy may be ineffective in a proportion of clopidogrel-treated patients. Guidelines for the treatment and prevention of peripheral arterial disease should offer alternative antiplatelet drugs or recommendations to verify a patient´s genetic predisposition. Further clinical trials are warranted to assess the efficacy of individual antiplatelet agents and doses thereof in patients with peripheral arterial disease.

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P25 Polymorphism of CYP2C19 is associated with poor platelet response to clopidogrel and indirectly affect TIMIi-flow among asian patients with STEMI undergoing primary PCI

European Heart Journal ◽

10.1093/ehjci/ehz872.027 ◽

2020 ◽

Vol 41 (Supplement_1) ◽

Author(s):

A Kemalasari ◽

R Sukmawan ◽

S Adiarto

Keyword(s):

Platelet Reactivity ◽

Primary Pci ◽

Platelet Response ◽

Asian Populations ◽

Asian Patients ◽

Timi Flow ◽

Cyp2c19 Polymorphism ◽

Cyp2c19 Gene ◽

Verifynow Assay ◽

P2y12 Reaction Unit

Abstract Background The platelet response to clopidogrel treatment is very important in patients with myocardial infarction undergoing primary PCI. Asian populations have been shown to have higher proportion of CYP2C19 gene polymorphism that may alter biotransformation of clopidogrel, than Caucasians. However, It is unclear whether platelet reactivity measured by P2Y12 reaction unit (PRU) is affected by CYP2C19 polymorphism, and whether it will impair coronary flow among Asian patients with STEMI after primary PCI. Purpose: We sought to define whether polymorphisms on CYP2C19 genes will affect platelet reactivity response to Clopidgrel therapy, and whether subsequently it will affect the TIMI flow in Asian patients with STEMI undergoing primary PCI. Method: We studied 90 patients with STEMI receiving 600 mg loading dose of clopidogrel prior to primary PCI. High-on-treatment platelet reactivity was evaluated using the VerifyNow Assay. Patients with platelet reactivity more than 208 PRU are categorized as non-responders to Clopidogrel. Genotyping of CYP2C19 was performed by real-time polymerase chain reaction (PCR). Post primary PCI TIMI flow was categorized into good (TIMI flow 3), and impaired (TIMI flow <3). Results: Among all 90 patients (median age = 54.5 years old; 93.3% male), there were 36.6 % patients with CYP2C19 polymorhisms, carrying *2 or *3 alleles. Platelet reactivity test revealed 23.4% of all patients were Clopidogrel non-responders. Multivariate analysis showed CYP2C19 polymorphism is associated with Clopidogrel non-reponders (OR 4.7, p = 0.030), along with other factors such as: Diabetes, Renal impairment, and use of proton pump inhibitor drugs. After successful stent implantation during primary PCI, there were 24.4% patients still with TIMI flow < 3. There was no direct correlation between CYP2C19 polymorphism and TIMI flow < 3 after primary PCI. However, we found significant association between Clopidogrel non-reponders and TMI flow < 3 after primary PCI in those STEMI patients (OR 3.3, p = 0.046). Conclusions: In Asian patients with STEMI receiving clopidogrel prior to primary PCI, the CYP2C19 polymorphisms is associated with poor platelet response to Clopidogrel therapy. The Clopidogrel non-responders is associated with impaired TIMI flow after primary PCI.

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Monitoring of antiplatelet therapy

Hämostaseologie ◽

10.5482/ha-1146 ◽

2011 ◽

Vol 31 (01) ◽

pp. 41-51 ◽

Cited By ~ 14

Author(s):

H. Seidel ◽

M. M. Rahman ◽

R. E. Scharf

Keyword(s):

Antiplatelet Therapy ◽

Platelet Function ◽

Platelet Reactivity ◽

Point Of Care ◽

High Sensitivity ◽

Antiplatelet Agents ◽

Daily Practice ◽

Adenosine Diphosphate ◽

Poor Responders ◽

Platelet Aggregometry

SummaryScreening of platelet function can be performed by point-of-care testing followed by platelet aggregometry in response to agonists such as collagen, adenosine diphosphate, epinephrine, and arachidonic acid. Despite in use for decades, this technique is not well standardized. Monitoring of antiplatelet therapy is increasingly applied in patients at high risk for re-thrombosis or bleeding. To assess pharmacological inhibition of platelet function, agonist-induced platelet aggregation, thromboxane B2 (TxB2) and vasodilator-stimulated protein phosphorylation (VASP) are being measured. While serum TxB2 levels of < 2 ng/ml reflect aspirin-induced inhibition of cyclo-oxygenase-1 activity with high sensitivity, VASP exhibits a wide variability upon treatment with clopidogrel or prasugrel. Multiple studies reveal an association between high residual platelet reactivity and adverse cardiovascular events in patients on antiplatelet therapy. However, despite the plethora of platelet function assays currently under investigation, their use in daily practice cannot be recommended. This is due to several reasons: (i) there is no consensus on the method and a respective cut-off value associated with clinical adverse outcome, and (ii) data demonstrating any benefit of tailored antiplatelet therapy and its monitoring (based on assessment of platelet functions) are still limited. Thus, appropriate identification of ‘resistant’ or ‘poor responders’ to antiplatelet agents remains challenging in clinical practice.

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Impact of CYP2C19 polymorphism on residual platelet reactivity in patients with coronary heart disease during antiplatelet therapy

Journal of Cardiology ◽

10.1016/j.jjcc.2010.10.007 ◽

2011 ◽

Vol 57 (2) ◽

pp. 194-201 ◽

Cited By ~ 60

Author(s):

Koichiro Yamamoto ◽

Seiji Hokimoto ◽

Tadasuke Chitose ◽

Kazunori Morita ◽

Takamichi Ono ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Antiplatelet Therapy ◽

Platelet Reactivity ◽

Cyp2c19 Polymorphism

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Prasugrel effectively reduces the platelet reactivity units in patients with genetically metabolic dysfunction of cytochrome P450 2C19 who are treated with long-term dual antiplatelet therapy after undergoing drug-eluting stent implantation

Heart and Vessels ◽

10.1007/s00380-019-01499-7 ◽

2019 ◽

Vol 35 (3) ◽

pp. 312-322 ◽

Cited By ~ 3

Author(s):

Junichiro Shimamatsu ◽

Ken-ichiro Sasaki ◽

Yoshio Katsuki ◽

Tomohiro Kawasaki ◽

Yoshinobu Murasato ◽

...

Keyword(s):

Cytochrome P450 ◽

Antiplatelet Therapy ◽

Stent Implantation ◽

Dual Antiplatelet Therapy ◽

Platelet Reactivity ◽

Late Phase ◽

Coronary Stent ◽

Cyp2c19 Polymorphism ◽

Coronary Stent Implantation

Abstract Dual antiplatelet therapy (DAPT) with aspirin and P2Y12 inhibitor is administered following percutaneous coronary intervention (PCI) with coronary stent implantation. Several studies have reported the effects of switching between P2Y12 inhibitors on platelet reactivity (P2Y12 reaction units: PRU), from acute to late phase after PCI. However, the effect of switching at very late phase is unknown. This study examined the effect on PRU in Japanese coronary heart disease patients with long-term DAPT (aspirin + clopidogrel) when switching from clopidogrel to prasugrel. Ninety-six patients were enrolled in this study. The median DAPT duration at enrollment was 1824.0 days. Twenty-three patients with PRU ≥ 208 at enrollment were randomly assigned into either continuing to receive clopidogrel (Continued Group; n = 11) or switching to prasugrel (Switched Group; n = 12). The primary endpoint was the rate of patients who achieved PRU < 208 at the end of 12 weeks of treatment, which was significantly higher in Switched Group relative to Continued Group (90.0% vs. 36.4%; P = 0.024). The secondary endpoint was the PRU at week 12 in groups subdivided according to cytochrome P450 (CYP) 2C19 genotypes. At week 12, extensive metabolizers (EM Group) had 202.3 ± 60.0 and 174.5 ± 22.3 in Continued Group and Switched Group (P = 0.591), respectively; intermediate and poor metabolizers (non-EM Group) had 229.4 ± 36.9 and 148.4 ± 48.4 in Continued Group and Switched Group (P = 0.002), respectively. The PRU for non-EM Group was significantly reduced in Switched Group. Thus, for patients with long-term DAPT (aspirin + clopidogrel) after PCI with coronary stent implantation, switching from clopidogrel to prasugrel resulted in a stable reduction in PRU, regardless of CYP2C19 polymorphism.

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