P2Y12 inhibitors in neuroendovascular surgery: An opportunity for precision medicine

2021 ◽  
pp. 159101992199139
Author(s):  
Axel Rosengart ◽  
Malie K Collins ◽  
Philipp Hendrix ◽  
Ryley Uber ◽  
Melissa Sartori ◽  
...  
Keyword(s):  
Adverse Events ◽  
Precision Medicine ◽  
Point Of Care ◽  
Indirect Evidence ◽  
Cost Benefit ◽  
Interventional Cardiology ◽  
Platelet Inhibition ◽  
Response Monitoring ◽  
P2y12 Inhibitor ◽  
P2y12 Inhibitors

Introduction Dual antiplatelet therapy (DAPT), primarily the combination of aspirin with a P2Y12 inhibitor, in patients undergoing intravascular stent or flow diverter placement remains the primary strategy to reduce device-related thromboembolic complications. However, selection, timing, and dosing of DAPT is critical and can be challenging given the existing significant inter- and intraindividual response variations to P2Y12 inhibitors. Methods Assessment of indexed, peer-reviewed literature from 2000 to 2020 in interventional cardiology and neuroendovascular therapeutics with critical, peer-reviewed appraisal and extraction of evidence and strategies to utilize DAPT in cardio- and neurovascular patients with endoluminal devices. Results Both geno- and phenotyping for DAPT are rapidly and conveniently available as point-of-care testing at a favorable cost-benefit ratio. Furthermore, systematic inclusion of a quantifying clinical risk score combined with an operator-linked, technical risk assessment for potential adverse events allows a more precise and individualized approach to new P2Y12 inhibitor therapy. Conclusions The latest evidence, primarily obtained from cardiovascular intervention trials, supports that combining patient pharmacogenetics with drug response monitoring, as part of an individually tailored, precision medicine approach, is both predictive and cost-effective in achieving and maintaining individual target platelet inhibition levels. Indirect evidence supports that this gain in optimizing drug responses translates to reducing main adverse events and overall treatment costs in patients undergoing DAPT after intracranial stent or flow diverting treatment.

The influence of variation in the P2Y12 receptor gene on in vitro platelet inhibition with the direct P2Y12 antagonist cangrelor

2010 ◽  
Vol 103 (02) ◽  
pp. 379-386 ◽  
Author(s):  
Jochem van Werkum ◽  
Goran Rude ◽  
Frank Leebeek ◽  
Adrian Kruit ◽  
Christian Hackeng ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Rich Plasma ◽  
Receptor Gene ◽  
Platelet Inhibition ◽  
P2y12 Receptor ◽  
P2y12 Inhibitor ◽  
P2y12 Inhibitors ◽  
P2y12 Antagonist ◽  
Single Snps

SummaryNovel P2Y12 inhibitors are in development to overcome the occurrence of atherothrombotic events associated with poor responsiveness to the widely used P2Y12 inhibitor clopidogrel. Cangrelor is an intravenously administered P2Y12 inhibitor that does not need metabolic conversion to an active metabolite for its antiplatelet action, and as a consequence exhibits a more potent and consistent antiplatelet profile as compared to clopidogrel. It was the objective of this study to determine the contribution of variation in the P2Y12 receptor gene to platelet aggregation after in vitro partial P2Y12 receptor blockade with the direct antagonist cangrelor. Optical aggregometry was performed at baseline and after in vitro addition of 0.05 and 0.25 μM cangrelor to the platelet-rich plasma of 254 healthy subjects. Five haplotype-tagging (ht)-SNPs covering the entire P2Y12 receptor gene were genotyped (rs6798347C>t, rs6787801T>c, rs9859552C>a, rs6801273A>g and rs2046934T>c [T744C]) and haplotypes were inferred. The minor c allele of SNP rs6787801 was associated with a 5% lower 20 μM ADP-induced peak platelet aggregation (0.05 μM cangrelor, p<0.05). Aa homozygotes for SNP rs9859552 showed 20% and 17% less inhibition of platelet aggregation with cangrelor when compared to CC homozygotes (0.05 and 0.25 μM cangrelor respectively; p<0.05). Results of the haplotype analyses were consistent with those of the single SNPs. Polymorphisms of the P2Y12 receptor gene contribute significantly to the interindividual variability in platelet inhibition after partial in vitro blockade with the P2Y12 antagonist cangrelor.

255Impact of the type of acute coronary syndrome on the pharmocodynamic response to P2Y12 inhibitors in the acute and maintenance phase of therapy

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
L Lugo Gavidia ◽  
D Vivas ◽  
J M De La Hera ◽  
A Tello-Montoliu ◽  
A L Marcano ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Maintenance Phase ◽  
Platelet Inhibition ◽  
Clinical Indication ◽  
P2y12 Inhibitor ◽  
P2y12 Inhibitors ◽  
Coronary Syndrome ◽  
P2y12 Antagonists ◽  
St Elevation ◽  
The Impact

Abstract Background The presence of an acute coronary syndrome (ACS) is per se a predictor of reduced responsiveness to clopidogrel; in particular, patients with ST-elevation myocardial infarction (STEMI) have impaired clopidogrel-induced platelet inhibition than those with other forms of ACS. However, the impact of the type of ACS on the pharmocodynamic efficacy of more potent P2Y12 antagonists such as prasugrel or ticagrelor has not been fully elucidated to date. Purpose To assess the impact of the type of ACS on platelet inhibition mediated by P2Y12 receptor antagonists in the acute and the maintenance phase of therapy in a contemporary cohort of ACS patients undergoing percutaneous coronary intervention (PCI). Methods Substudy of a prospective, national, multicentre, pharmacodynamic registry conducted in a population of ACS patients undergoing PCI and treated with dual antiplatelet therapy including aspirin and a P2Y12 inhibitor as per clinical indication. Patients were classified according to the ACS diagnosis into groups: a) STEMI, b) non-ST-elevation ACS (NSTEACS), c) unstable angina (UA), and d) other (excluded from the present analysis). Platelet function tests (PFT) were performed at day 1 and day 30 (±5) after PCI and included: 1) VerifyNow P2Y12 assay, expressed as P2Y12 reaction units (PRUs); 2) Vasodilator-stimulated phosphoprotein (VASP) assay; and 3) Multiple electrode aggregometry (MEA). Results A total of 965 patients (372 with STEMI, 395 with NSTEACS and 198 with UA) were included in the present substudy. At day 1, the proportions of patients with each type of ACS according to the P2Y12 inhibitor received were: 1) clopidogrel (n=317): STEMI 35.0%, NSTEACS 34.4% and UA 30.6%; 2) prasugrel (n=192): STEMI 70.3%, NSTEACS 17.7% and UA 12.0%; 3) ticagrelor (n=456): STEMI 27.6%, NSTEACS 55.3% and UA 17.1%. A statistically significant reduced platelet inhibition, measured with the VerifyNow system, was observed in STEMI patients compared with the other forms of ACS in patients receiving clopidogrel (STEMI: 217.3±8.1, NSTEACS: 157.1±7.9 and UA: 164.9±8.6 PRUs; p for STEMI vs. NSTEACS <0.001 and p for STEMI vs. UA <0.001) and ticagrelor (STEMI: 57.7±3.8, NSTEACS: 45.2.1±2.6 and UA: 40.6±4.9 PRUs; p for STEMI vs. NSTEACS 0.008 and p for STEMI vs. UA 0.007), while a numerical trend towards greater platelet reactivity in STEMI compared to UA was observed in subjects receiving prasugrel (Figure). Remarkably, at day 30, no significant differences on platelet inhibition were observed according to the ACS type with any of the P2Y12 inhibitors. Similar results were observed with MEA and VASP assays. PD response according to the ACS type Conclusions Patients presenting with STEMI have impaired platelet inhibition mediated by P2Y12 antagonists compared to other types of ACS during the acute phase of therapy, whereas no difference is observed during the maintenance phase of treatment. Acknowledgement/Funding Funded by Instituto de Salud Carlos III through the project PI13/01012 (co-funded by European Regional Development Fund. ERDF, a way to build Europe)

scholarly journals Do Clopidogrel Nonresponders Have an Increased Risk of Adverse Events during Supra-Aortal Angioplasty and Stenting?

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
Heiko Koerner ◽  
Christian Derveaux ◽  
Maria Alexandrou ◽  
Stefan Graeber ◽  
Christian Roth ◽  
...  
Keyword(s):  
Adverse Events ◽  
Platelet Function ◽  
Primary Endpoint ◽  
Platelet Reactivity ◽  
Point Of Care ◽  
Clinical Status ◽  
Strong Relationship ◽  
Platelet Inhibition ◽  
High Platelet Reactivity ◽  
Increased Risk

Objective. The aim of the present study was to correlate new periprocedural diffusion-weighted imaging (DWI) lesions during stenting of supra-aortal arteries with the level of platelet inhibition using point-of-care analysis.Background. Cardiological studies have shown that patients undergoing coronary PTA have a significantly elevated risk of severe thrombotic complications if patients show insufficient inhibition of platelet function.Methods. From August 2008 to June 2009, 44 patients with an indication of supra-aortal angioplasty and/or stenting were prospectively enrolled. Platelet reactivity was tested using a Multiplate device (Dynabyte). These patients underwent MRI before and after the intervention to determine the prevalence of new DWI lesions. The primary endpoint was the prevalence of DWI lesions; the secondary endpoint was clinical status until discharge from hospital.Results. There was no significant relationship between the primary endpoint and the degree of platelet function. Patients with high platelet reactivity showed the same amount of periprocedural complications as patients with sufficient inhibition of platelets.Conclusions. Clopidogrel did not have a protective effect on periprocedural complications, nor did it decrease the number of silent DWI lesions after the procedure. The predescribed strong relationship between high platelet reactivity and early post-procedural adverse events was not observed in our cohort.

Role of phenotypic and genetic testing in managing clopidogrel therapy

Blood ◽  
2014 ◽  
Vol 124 (5) ◽  
pp. 689-699 ◽  
Author(s):  
Noel C. Chan ◽  
John W. Eikelboom ◽  
Jeffrey S. Ginsberg ◽  
Mandy N. Lauw ◽  
Thomas Vanassche ◽  
...  
Keyword(s):  
Standard Dose ◽  
Standard Of Care ◽  
Platelet Inhibition ◽  
Good Evidence ◽  
P2y12 Inhibitor ◽  
P2y12 Inhibitors ◽  
Coronary Syndrome ◽  
Biomarker Testing ◽  
Clopidogrel Therapy

The P2Y12 inhibitors, clopidogrel, prasugrel, and ticagrelor, are administered in fixed doses without laboratory monitoring. Randomized trials in acute coronary syndrome have shown that prasugrel and ticagrelor are more effective than standard-dose clopidogrel. Nonetheless, standard-dose clopidogrel remains widely used because it causes less bleeding and is less expensive. Patients treated with standard-dose clopidogrel have substantial variability in platelet inhibition, which is partly explained by genetic polymorphisms encoding CYP2C19, the hepatic enzyme involved in biotransformation of clopidogrel to its active metabolite. Some advocate tailoring P2Y12 inhibitor therapy according to the results of routine laboratory testing. Although there is good evidence for analytic, biological, and clinical validity of several phenotypic and genotypic biomarkers, the benefit of a management strategy that incorporates routine biomarker testing over standard of care without such testing remains unproven. Appropriately designed, adequately powered trials are needed but face the challenges of feasibility, cost, and the progressive switch from clopidogrel to prasugrel or ticagrelor.

scholarly journals Point of care airway ultrasound to select tracheal tube and determine insertion depth in cleft repair surgery

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jung Hwan Ahn ◽  
Jae Hyun Park ◽  
Min Soo Kim ◽  
Hyun Cheol Kang ◽  
Il Seok Kim
Keyword(s):  
Adverse Events ◽  
Tracheal Tube ◽  
Point Of Care ◽  
Conventional Group ◽  
Insertion Depth ◽  
Tube Size ◽  
Airway Complications ◽  
Ultrasound Application ◽  
Ultrasound Group ◽  
Airway Ultrasound

AbstractWe aimed to evaluate the efficacy of using airway ultrasonography to select the correct tracheal tube size and insertion depth in pediatric patients who underwent cleft repair surgery as a way to decrease airway complications and adverse events during perioperative periods. Fifty-one patients (age < 28 months) were consecutively divided into conventional (n = 28) and ultrasound (n = 23) groups. Tracheal tube size and insertion depth were determined using the age-based formula and auscultation in the conventional group, whereas using ultrasonographic measurement of subglottic diameter with auscultation and lung ultrasonography in the ultrasound group. We evaluated the initially selected tube size, insertion depth, ventilatory indices, and the incidence of airway complications and adverse events. Tube insertion depth (median [interquartile range]) was significantly greater in the ultrasound group than in the conventional group (13.5 cm [12.5–14.0] vs 13.0 cm [11.8–13.0], P = 0.045). The number of complications and adverse events was significantly higher in the conventional group than in the ultrasound group (32.1% vs 4.3%, P = 0.013). Airway ultrasound application could reduce airway-related complications and adverse events by determining the appropriate tracheal tube size and insertion depth.

Antiplatelet drugs in patients with enhanced platelet turnover: biomarkers versus platelet function testing

2015 ◽  
Vol 114 (09) ◽  
pp. 459-468 ◽  
Author(s):  
Susanne Gruber ◽  
Erik Grove ◽  
Thomas Weiss ◽  
Johann Wojta ◽  
Kurt Huber ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Platelet Reactivity ◽  
Platelet Inhibition ◽  
Antiplatelet Drugs ◽  
P2y12 Inhibitors ◽  
Reticulated Platelets ◽  
Increased Risk ◽  
Key Factor ◽  
Coronary Syndromes ◽  
Function Testing

SummaryPlatelets are key players in atherothrombosis. Antiplatelet therapy comprising aspirin alone or with P2Y12-inhibitors are effective for prevention of atherothrombotic complications. However, there is interindividual variability in the response to antiplatelet drugs, leaving some patients at increased risk of recurrent atherothrombotic events. Several risk factors associated with high on-treatment platelet reactivity (HTPR), including elevated platelet turnover, have been identified. Platelet turnover is adequately estimated from the fraction of reticulated platelets. Reticulated platelets are young platelets, characterised by residual messenger RNA. They are larger, haemostatically more active and there is evidence that platelet turnover is a causal and prognostic factor in atherothrombotic disease. Whether platelet turnover per se represents a key factor in pathogenesis, progression and prognosis of atherothrombotic diseases (with focus on acute coronary syndromes) or whether it merely facilitates insufficient platelet inhibition will be discussed in this state-of-the art review.

scholarly journals Precision Medicine in Interventional Cardiology

2020 ◽  
Vol 15 ◽  
Author(s):  
Thijmen W Hokken ◽  
Joana M Ribeiro ◽  
Peter P De Jaegere ◽  
Nicolas M Van Mieghem
Keyword(s):  
Precision Medicine ◽  
Therapeutic Option ◽  
Computational Modelling ◽  
Interventional Cardiology ◽  
Individual Therapy ◽  
Psychosocial Characteristics ◽  
Personal Variables ◽  
Test Treatments ◽  
The Individual ◽  
Genetic Biomarker

Precision medicine has recently become widely advocated. It revolves around the individual patient, taking into account genetic, biomarker, phenotypic or psychosocial characteristics and uses biological, mechanical and/or personal variables to optimise individual therapy. In silico testing, such as the Virtual Physiological Human project, is being promoted to predict risk and to test treatments and medical devices. It combines artificial intelligence and computational modelling to select the best therapeutic option for the individual patient.

scholarly journals Modeling and Cost Benefit Analysis to Guide Deployment of POC Diagnostics for Non-typhoidal Salmonella Infections with Antimicrobial Resistance

2018 ◽  
Author(s):  
Carrie Manore ◽  
Todd Graham ◽  
Alexa Carr ◽  
Alicia Feryn ◽  
Shailja Jakhar ◽  
...  
Keyword(s):  
Cost Benefit Analysis ◽  
Point Of Care ◽  
Case Fatality ◽  
Cost Benefit ◽  
Antibiotic Use ◽  
Blood Stream ◽  
Antimicrobial Treatment ◽  
Sub Saharan Africa ◽  
Advantages And Disadvantages ◽  
Salmonella Infections

ABSTRACTInvasive non-typhoidal Salmonella (NTS) is among the leading causes of blood stream infections in sub-Saharan Africa and other developing regions, especially among pediatric populations. Invasive NTS can be difficult to treat and have high case-fatality rates, in part due to emergence of strains resistant to broad-spectrum antibiotics. Furthermore, improper treatment contributes to increased antibiotic resistance and death. Point of care (POC) diagnostic tests that rapidly identify invasive NTS infection, and differentiate between resistant and non-resistant strains, may greatly improve patient outcomes and decrease resistance at the community level. Here we present for the first time a model for NTS dynamics in high risk populations that can analyze the potential advantages and disadvantages of four strategies involving POC diagnostic deployment, and the resulting impact on antimicrobial treatment for patients. Our analysis strongly supports the use of POC diagnostics coupled with targeted antibiotic use for patients upon arrival in the clinic for optimal patient and public health outcomes. We show that even the use of imperfect POC diagnostics can significantly reduce total costs and number of deaths, provided that the diagnostic gives results quickly enough that patients are likely to return or stay to receive targeted treatment.

Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement

2003 ◽  
Vol 89 (05) ◽  
pp. 783-787 ◽  
Author(s):  
Iris Müller ◽  
Felicitas Besta ◽  
Christian Schulz ◽  
Steffen Massberg ◽  
Albert Schönig ◽  
...  
Keyword(s):  
Antiplatelet Therapy ◽  
Stent Thrombosis ◽  
Point Of Care ◽  
Coronary Intervention ◽  
Platelet Inhibition ◽  
Point Of Care Testing ◽  
Stent Occlusion ◽  
Percutaneous Coronary ◽  
Baseline Values ◽  
Artery Disease

SummaryDual antiplatelet therapy with aspirin and clopidogrel decreases the rate of stent thrombosis in patients undergoing percutaneous coronary intervention (PCI). However, despite intensified antiplatelet treatment, up to 4.7% of the patients undergoing coronary stenting develop thrombotic stent occlusion, suggesting incomplete platelet inhibition due to clopidogrel resistance. We evaluated the percentage of clopidogrel nonresponders among 105 patients with coronary artery disease (CAD) undergoing elective PCI. All patients were treated regularly with aspirin 100 mg/d and received a loading dose of 600 mg clopidogrel followed by a maintenance dose of 75 mg/d before PCI. Clopidogrel non-responders were defined by an inhibition of ADP (5 and 20 μMol/L) induced platelet aggregation that was less than 10% when compared to baseline values 4 h after clopidogrel intake. Semi-responders were identified by an inhibition of 10 to 29%. Patients with an inhibition over 30% were regarded as responders. We found that 5 (ADP 5 μMol/L) to 11% (ADP 20 μMol/L) of the patients were non-responders and 9 to 26% were semi-responders. Among the group of nonresponders there were two incidents of subacute stent thrombosis after PCI. We conclude that a subgroup of patients undergoing PCI does not adequately respond to clopidogrel, which may correspond to the occurrence of thromboischemic complications. Point-of-care testing may help to identify these patients who may then benefit from an alternative antiplatelet therapy.

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