Is “one size fits all” anti-aggregation really effective? Variability in the response to P2Y12 receptor inhibitors in obese patients

Abstract Background Different “ex vivo” studies have shown both a greater platelet activation and higher rates of resistance to clopidogrel in obese patients. Although there is less evidence, less prasugrel activity has also been observed in these patients. Our aim was to study the variability of the response to clopidogrel, ticagrelor and prasugrel in obese patients, defined as a body mass index ≥30. Methods Prospective, multicenter, observational, pharmacodynamic study, conducted in a Spanish population of patients with an acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI) and double anti-aggregation with acetylsalicylic acid and a P2Y12 receptor inhibitor. Platelet function tests were performed the morning after the ICP and 30 days after it, including: 1) VerifyNow P2Y12 assay; 2) multiple electrode aggreometry (Multiplate); and 3) VASP analysis. Results Of the total patients included (988), 300 were obese (30.3%). The obese group was younger (62.8±12 years vs 64.9±12), had a higher incidence of arterial hypertension (76.3% vs. 56.7%), diabetes mellitus (35% vs. 27.5%); and lower incidence of chronic kidney disease (7.7% vs. 17%). There were no differences in the acute phase (day 1 after PCI) in the pharmacodynamic response to any of the P2Y12 inhibitors used. After 30 days, greater platelet aggregation (decreased response) was documented in obese patients treated with prasugrel according to VASP tests (PRI in non-obese 23.9±13% vs. 30.4±14.7% in obese, p 0.035) and MEA (area under the aggregation units curve in non-obese 251.7±104.1 vs 320±166.7 in obese, p 0.007) and a numerical trend with VerifyNow. A trend in the same direction was also observed in patients treated with clopidogrel that did not reach statistical significance with all the platelet function tests used. No differences were observed in the ticagrelor group. Conclusion Obese patients with an ACS treated with PCI have a worse response to thienopyridines than non-obese patients in the maintenance phase of antiaggregant treatment, while the response to ticagrelor is not affected by obesity. Completing the clinical follow-up proposed by the registry is necessary to know if these differences have an implication in cardiovascular events. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Fondo de Investigaciones Sanitarias (FIS)

Download Full-text

Platelet Function Test Use for Patients with Coronary Artery Disease in the Early 2020s

Journal of Clinical Medicine ◽

10.3390/jcm9010194 ◽

2020 ◽

Vol 9 (1) ◽

pp. 194 ◽

Cited By ~ 2

Author(s):

Pierre Fontana ◽

Marco Roffi ◽

Jean-Luc Reny

Keyword(s):

Platelet Function ◽

Large Scale ◽

Bleeding Risk ◽

Added Value ◽

Antiplatelet Drugs ◽

Platelet Function Tests ◽

Platelet Function Test ◽

P2y12 Inhibitors ◽

Coronary Syndrome ◽

Function Tests

In the field of antithrombotics, precision medicine is of particular interest, as it may lower the incidence of potentially life-threatening side effects. Indeed, antiplatelet drugs such as P2Y12 inhibitors are one of the most common causes of emergency admissions for drug-related adverse events. The last ten years have seen a continuous debate on whether platelet function tests (PFTs) should be used to tailor antiplatelet drugs to cardiovascular patients. Large-scale randomized studies investigating the escalation of antiplatelet therapies according to the results of PFTs were mostly negative. Potent P2Y12 inhibitors are recommended as a first-line treatment in acute coronary syndrome patients, bringing the bleeding risk at the forefront. De-escalation from prasugrel or ticagrelor to clopidogrel is now considered, with or without the use of a PFT. This review covers recent advances in escalation and de-escalation strategies based on PFTs in various clinical settings. It also describes the main features of the most popular platelet function tests as well as the potential added value of genetic testing. Finally, we detail practical suggestions on how PFTs could be used in clinical practice.

Download Full-text

Pharmacodynamic comparison of optimal platelet reactivity by multiple platelet function tests in Korean acute coronary syndrome patients with half-dose ticagrelor or prasugrel treatment

European Heart Journal ◽

10.1093/ehjci/ehaa946.1733 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

M.H Kim ◽

C.D Jin ◽

K Song ◽

G.M Lee ◽

H.Y Moon ◽

...

Keyword(s):

Acute Coronary Syndrome ◽

Platelet Function ◽

Platelet Reactivity ◽

Standard Dose ◽

Light Transmittance ◽

Funding Source ◽

Platelet Function Tests ◽

Coronary Syndrome ◽

Function Tests ◽

Half Dose

Abstract Background East Asians treated with potent P2Y12 inhibitors, prasugrel or ticagrelor exhibit more potent platelet inhibition than clopidogrel. Whether half-dose de-escalation strategy would improve optimal platelet reactivity at maintenance in East Asian patients with acute coronary syndrome (ACS) remains uncertain. Method In de-escalation strategy single center study, eligible Korean ACS patients (n=96) were assigned to receive standard-dose ticagrelor (n=33), prasugrel (n=28), followed by half-dose reduction at 1 month for maintenance, and clopidogrel (n=35) as control. Platelet reactivity was measured by VerifyNow, light transmittance aggregometry (LTA) and multiple electrode aggregometry (MEA). The investigators aim to compare optimal platelet reactivity status (OPR, defined as 85–208 P2Y12 reaction unit [PRU] for VerifyNow (VN), 16%–47% for LTA and 19–46 U for MEA) among 3 different platelet function tests at 3 months post PCI. Results At 3 months, ticagrelor achieved significantly lower PRU (17 [6–51] vs. 95 [61–151] vs. 172 [111–204]) than prasugrel and clopidogrel, resulting OPR rate 10% vs. 57.7% vs. 60.0%, respectively. Similar results were observed at LTA method (2% [0–12] in ticagrelor vs. 18% [13–22] in prasugrel vs. 18% [11–30] in clopidogrel), with OPR rate 11.8% vs. 69.2% vs. 50.0%, respectively. However, platelet reactivity was similar by MEA method (16 [13–20] in ticagrelor vs. 17 [13–22] in prasugrel vs. 19 [14–28] in clopidogrel), with OPR rate 33.3% vs. 40.0% vs. 42.0%, respectively (all p>0.005). Among the three tests, resulting higher correlation between VN and LTA (r=0.745), MEA and LTA vs. MEA and VN showed lower correlations (r=0.412 and r=0.303). (Fig.) Conclusion In Korean ACS patients with half-dose de-escalation strategy after 1 month, OPR rate in ticagrelor is still rare during 3-month treatment by VN and LTA methods, however, prasugrel appears comparable to clopidogrel. VN/LTA might overestimate platelet function than MEA or MEA underestimate OPR rate than VN/LTA. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): National Research Foundation of Korea

Download Full-text

Impact of smoking habit on platelet reactivity in a cohort of patients admitted due to an acute coronary syndrome

European Heart Journal ◽

10.1093/ehjci/ehaa946.1548 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

J.C Gomez Polo ◽

D Vivas Balcones ◽

A.L Marcano Fernandez ◽

J Playan Escribano ◽

L.M Lugo Gavidia ◽

...

Keyword(s):

Acute Coronary Syndrome ◽

Platelet Function ◽

Platelet Reactivity ◽

Smoking Habit ◽

Tertiary Care ◽

Funding Source ◽

P2y12 Inhibitors ◽

Lower Response ◽

Coronary Syndrome ◽

The Impact

Abstract Background Several pharmacodynamic studies have shown the impact of smoking habit on platelet reactivity; with a reduction on platelet aggregation. Wether this inhibition in platelet reactivity is due to tobacco effects in platelet signaling pathways or due to a pharmacodynamic interaction with antiplatelet therapies is not well stablished. Purpose Our aim was to study the influence of smoking habit in platelet reactivity and in the response to P2Y12 inhibitors. Methods Patients admitted in four tertiary care hospitals due to an acute coronary syndrome that undergone percutaneous coronary intervention (PCI) were consecutively and prospectively recruited. All the patients received dual antiplatelet therapy with aspirin and a P2Y12 inhibitor following current European Guidelines. Platelet function was assessed at day 1 and day 30 post-PCI by VerifyNow P2Y12, VASP (Vasodilator-stimulated phosphoprotein) y MEA (Multiple electrode aggregometry). Results A total of 1000 patients were enrolled, of whom 12 had to be excluded due to inaccurate processing of blood samples. 372 patients (37,6%) had smoking habit. Non-smoking patients showed higher prevalence of high blood pressure [423 (68.7%) vs 196 (52.7%)] and diabetes mellitus [213 (34.6%) vs 81 (21.8%)]. Smoking patients were younger [57.3 (9,6) years old vs 68.4 (11.1)], with higher incidence of acute coronary syndrome with ST segment elevation [184 patients (49,5%) vs 241 (39.1%), p<0,001]. There were no differences in platelet function at day 1. When analysing platelet function 30 days post-PCI, a lower inhibition of platelet reactivity in non-smoking patients as compared with smoking patients was observed in those treated with clopidogrel, with higher prevalence of clopidogrel-resistance in non-smoking patients (VerifyNow, 51,2% prevalence of high platelet reactivity in non-smoking patients vs 34,9% 30 days after PCI, p=0,023). On the other hand, smoking patients that received ticagrelor did not show any differences. Patients with smoking habit treated with prasugrel showed a lower response of borderline statistical significance. Conclusion Smoking habit was associated with a lower response to prasugrel of borderline significance, and with higher response to clopidogrel, according with previous studies suggesting a pharmacodynamics interaction between tobacco use and P2Y12 inhibitors. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Fondo de Investigaciones Sanitarias (FIS)

Download Full-text

Variable responsiveness to clopidogrel and aspirin among patients with acute coronary syndrome as assessed by platelet function tests

Thrombosis Research ◽

10.1016/j.thromres.2007.10.018 ◽

2008 ◽

Vol 122 (3) ◽

pp. 336-345 ◽

Cited By ~ 37

Author(s):

Boris Shenkman ◽

Shlomi Matetzky ◽

Paul Fefer ◽

Hanoch Hod ◽

Yulia Einav ◽

...

Keyword(s):

Acute Coronary Syndrome ◽

Platelet Function ◽

Platelet Function Tests ◽

Coronary Syndrome ◽

Function Tests

Download Full-text

Comparison between hirudin and citrate in monitoring the inhibitory effects of P2Y12 receptor antagonists with different platelet function tests

Journal of Thrombosis and Haemostasis ◽

10.1111/j.1538-7836.2009.03585.x ◽

2009 ◽

Vol 7 (11) ◽

pp. 1929-1932 ◽

Cited By ~ 16

Author(s):

C. A. C. M. PITTENS ◽

H. J. BOUMAN ◽

J. W. VAN WERKUM ◽

J. M. TEN BERG ◽

C. M. HACKENG

Keyword(s):

Platelet Function ◽

P2y12 Receptor ◽

Inhibitory Effects ◽

Platelet Function Tests ◽

Receptor Antagonists ◽

Function Tests

Download Full-text

Platelet function tests for the monitoring of P2Y12 inhibitors

Expert Opinion on Medical Diagnostics ◽

10.1517/17530051003725139 ◽

2010 ◽

Vol 4 (3) ◽

pp. 251-265 ◽

Cited By ~ 1

Author(s):

Nicoline J Breet ◽

Jochem W van Werkum ◽

Heleen J Bouman ◽

Jurriën M ten Berg ◽

Christian M Hackeng

Keyword(s):

Platelet Function ◽

Platelet Function Tests ◽

P2y12 Inhibitors ◽

Function Tests

Download Full-text

THE EFFECT OF ARTERIAL DE-ENDOTHELIALIZATION ON IN VIVO AND EX VIVO PLATELET FUNCTION TESTS IN THE BABOON

10.1055/s-0038-1643950 ◽

1987 ◽

Author(s):

H F Kotze ◽

P N Badenhorst ◽

A du ◽

P Heyns ◽

...

Keyword(s):

Carotid Artery ◽

Platelet Function ◽

Cell Injury ◽

Ex Vivo ◽

Balloon Catheter ◽

Left Carotid Artery ◽

Platelet Function Tests ◽

Platelet Factor ◽

Function Tests

The effect of endothelial cell injury on platelet function was evaluated in eight baboons with a normal vasculature. Endothelium was removed with a balloon catheter. On each baboon, the left carotid artery was de-endothelialized on day 0 and the right carotid artery and abdominal aorta on day 7. Mean platelet density (MPD; gm/ml), circulating platelet aggregate ratio (CPA), the number of electron-dense bodies per platelet (DBP) , and the plasma concentration (ng/ml) of platelet factor 4 x(PF4) and beta thromboglobulin (bTG) were determined on day -7 (baseline). These ex vivo measurements were repeated on days 1, 9 and 16. The mean lifespan (MPLS) and sites of sequestration of In-111-labelled platelets were determined from day 7 onwards. The results of the ex vivo platelet function tests were:De-endothelialization of only the left carotid artery did not affect ex vivo platelet function. More extensive denudation decreased MPD, and increased CPA, PF4 and bTG. CPA were still abnormal 7 days after the insult. MPLS, 120±21 hours, was shorter (p<0.05) than normal, 145±15 hours. The sequestration pattern of senescent platelets was normal. We conclude that a decrease in the MPD, an increase in CPA, bTG and PF4, and a shortened MPLS are the most sensitive tests for in vivo platelet activation.

Download Full-text

The Activity Of PhthalazinoL In Basic Platelet Function Tests

10.1055/s-0038-1653263 ◽

1981 ◽

Author(s):

R N Saunders ◽

S L Smith ◽

N S Nicholson

Keyword(s):

Platelet Function ◽

Ex Vivo ◽

Platelet Function Tests ◽

Antithrombotic Agent ◽

Serotonin Content ◽

Positive Effects ◽

Arterial Blood ◽

Function Tests ◽

Induced Aggregation

Phthalazinol (EG-626, SC-32840) was evaluated in several basic platelet function tests in comparison with known antiplatelet agents. The IC50șs for collagen-, ADP-, and thrombin-induced aggregation of human platelets in vitro were 28, 51 and 88 µM, respectively. Phthalazinol (100 µM) did not alter the cAMP levels of rat platelets in vitro in either the presence or absence of PGE1. When administered orally to retired breeder rats, Phthalazinol prevented the formation of platelet aggregates as determined by the Wu and Hoak technique with ED50’s of 5.5 and 18.7 mpk, i.g. at 3 and 24 hours, respectively, post injection. Phthalazinol did not alter the platelet serotonin content in rats even when administered at 100 mg/kg orally for three days. In an ex vivo disaggregation assay, arterial blood from anesthetized cats was perfused over rabbit tendon strips and recirculated to the cat. The resulting platelet build-up (200-400 mg) was significantly (p < .001) reversed (67% loss) by the i.v. infusion of Phthalazinol at 15 mg/kg. Phthalazinol has demonstrated positive effects in several platelet evaluation models and is a potentially unique antithrombotic agent.

Download Full-text

Comparison of three common whole blood platelet function tests for in vitro P2Y12 induced platelet inhibition

Journal of Thrombosis and Thrombolysis ◽

10.1007/s11239-019-01971-1 ◽

2019 ◽

Vol 50 (1) ◽

pp. 135-143 ◽

Cited By ~ 4

Author(s):

Joao D. Dias ◽

Torben Pottgiesser ◽

Jan Hartmann ◽

Daniel Duerschmied ◽

Christoph Bode ◽

...

Keyword(s):

Platelet Function ◽

Whole Blood ◽

Linear Models ◽

Point Of Care ◽

Platelet Function Tests ◽

Blood Samples ◽

P2y12 Inhibitors ◽

Function Tests ◽

Increased Risk

Abstract In the context of interventional cardiology, platelet function testing may identify patients treated with P2Y12-inhibitors at an increased risk of mortality, thrombosis and bleeding. Several whole blood point-of-care platelet function analyzers are available; however, inter-device differences have not been examined systematically. To compare three platelet function tests under standardized in vitro conditions. Healthy volunteer (n = 10) blood samples were spiked with increasing concentrations of ticagrelor (0–7500 ng/mL) and/or ASA (0–3280 ng/mL), measured on three platelet function analyzers (TEG®6s, Multiplate®, and VerifyNow®) and respective Effective Concentration (EC) levels EC10, EC50 and EC90 were calculated. Repeatability was assessed in a separate group of pooled blood samples (n = 10) spiked with ticagrelor at EC10, EC50 and EC90. ASA had no impact on ADP-activated channels for all three devices. TEG®6s was able to distinguish (p ≤ 0.05) between all ticagrelor EC zones; VerifyNow® and Multiplate® were able to distinguish between three and two zones, respectively. Multiplate® showed the largest window between EC10 and EC90 (19–9153 ng/mL), followed by TEG®6s (144–2589 ng/mL), and VerifyNow® (191–1100 ng/mL). Drug effect models distribution of disagreements were identified for TEG®6s (5.0%), VerifyNow® (8.3%), and Multiplate® (13.3%). TEG®6s showed the smallest average coefficient of variation between EC conditions (5.1%), followed by Multiplate® (14.1%), and VerifyNow® (17.7%). Linear models could be generated between TEG®6s and Multiplate®, but not VerifyNow®. Significant differences were found between whole blood point-of-care platelet function analyzers and the clinical impact of these differences needs to be further investigated.

Download Full-text

Abstract 20657: Plasma MicroRNAs Correlate With Platelet Reactivity in Patients With Acute Coronary Syndrome: Association With Platelet Function

Circulation ◽

10.1161/circ.130.suppl_2.20657 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Manuel Mayr ◽

Dorothee Kaudewitz ◽

Philipp Skroblin ◽

Peter Willeit ◽

Anna Zampetaki ◽

...

Keyword(s):

Acute Coronary Syndrome ◽

Platelet Function ◽

Platelet Reactivity ◽

Platelet Inhibition ◽

Platelet Function Tests ◽

Coronary Syndrome ◽

Function Tests ◽

Custom Made ◽

Detailed Assessment ◽

Plasma Mirnas

Introduction: Platelets contribute plasma microRNAs (miRNAs). Levels of platelet-related miRNAs change in plasma in response to platelet inhibition. Hypothesis: It is currently unclear how plasma miRNAs correlate to platelet function in patients with acute coronary syndrome (ACS). Methods: We measured plasma miRNAs in 125 patients with a history of ACS (STEMI, NSTEMI or unstable angina) who have undergone detailed assessment of platelet function 30 days after the acute event. Results: Using custom-made quantitative real-time polymerase chain reaction plates, 92 miRNAs were assessed in patients on different anti-platelet therapies (clopidogrel, prasugrel, aspirin). Key platelet-related miRNAs were correlated with platelet function tests, including optical aggregometry using the agonists ADP and arachidonic acid, VerifyNow P2Y12 assay and vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay. Significant associations were obtained for miR-126 with the VerifyNow (rp=0.347, n=39, P=0.033) and VASP assay (rp=0.224, n=125, P=0.013). Other abundant platelet miRNAs also showed strong correlations with the VASP assay: miR-223 (rp =0.231, P=0.003), miR-191 (rp =0.243, P=0.007), miR-24 (rp =0.246, P=0.006), miR-197 (rp=0.293, P=0.008), miR-30b (rp=0.230, P=0.010) and miR-20b (rp=0.231 , P=0.010). Conclusions: Levels of platelet-related plasma miRNAs correlate with platelet function tests in ACS patients. Our findings reinforce the concept that platelets are an important contributor to the plasma miRNA pool.

Download Full-text