High Residual Platelet Reactivity Research Articles

Application of Raman spectroscopy using an original optical sensor to assess the laboratory efficacy of antiplatelet drugs

The main method for monitoring the laboratory effectiveness of antiplatelet drugs in modern clinical practice is aggregometry, but this method is not without limitations. In this connection, there is an objective need to develop alternative methods. One of the promising areas is the method of Raman spectroscopy (RS).Objective: development of a method to detect high residual platelet reactivity (RPR) in patients with CVD receiving acetylsalicylic acid (ASA) or clopidogrel by giant Raman spectroscopy (GRS) using an original optical biosensor.Material sand Methods. Platelet-rich plasma of patients with cardiovascular diseases (CVD) was investigated by Raman spectroscopy using an original optical biosensor. Platelet aggregation activity was investigated using a Siemens PFA-200 aggregometer with three types of cartridges – Collagen/EPI, Collagen/ADP, and P2Y. Fisher’s linear discriminant analysis was performed using Statistica 13.0 package.Results. Raman spectra analysis using different values of frequency shifts (970 cm-1 or 1590 cm-1), allows to evaluate laboratory ineffectiveness separately for ASA and clopidogrel. Thus, the number of patients with high residual platelet reactivity (RPR) was 41.7 % ± 6.3 % with ASA and 36.7 % ± 6.2 % with clopidogrel therapy; similar values using aggregometry were 43.5 % ± 10.3 % and 30.4 % ± 9.6 %.Conclusion. Application of the method of Raman spectroscopy using the original optical biosensor allows to distinguish patients with high RPR in the population of patients with CVD receiving antiaggregant therapy.

Reduction of thrombus burden by cangrelor in ticagrelor-loaded st-elevation myocardial infarction patients with high residual platelet reactivity: the imaging sub-study of the ERMIT randomized trial

Abstract Background Residual high platelet reactivity (HPR) at the time of primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) is associated with higher residual thrombus burden and the subsequent suboptimal reperfusion. Purpose We sought to determine the impact of intravenous Cangrelor on the residual post-PCI thrombus burden in patients with HPR admitted for primary PCI in a prespecified intracoronary optical coherence tomography (OCT) sub-study of the ERMIT randomized trial. Methods In the ERMIT trial patients pre-treated with ticagrelor and aspirin with residual HPR (baseline platelet reactivity unit >208) were randomly assigned in a 1:1 ratio to receive cangrelor on top of standard therapy or standard therapy alone prior to PCI. The primary endpoint of the sub-study was the relative thrombus volume quantified on OCT. Other OCT quantified parameters were predefined as secondary endpoints. Results After screening of 128 patients, a total of 60 patients with HPR were enrolled and randomized. The OCT sub-study included 53 patients, 29 in the cangrelor and 24 in the control group. As reported in the table, baseline characteristics were similar between the groups. The post-PCI PRU was dramatically lower in the cangrelor as compared to the standard group (p<0.001). The primary endpoint was 4.5% [3.4;7.2] versus 6.9% [5.2;8.5], (p=0.03) in the cangrelor and control groups respectively. All other imaging parameters confirmed the significantly lower thrombus burden in patients receiving cangrelor (Table). Conclusion The imaging sub-study of the randomized ERMIT trial shows that cangrelor use is associated with a more effective platelet inhibition and lower post-PCI residual thrombus burden in ticagrelor-loaded STEMI patients with residual HPR. The clinical implications of such finding warrant larger size trials.Table

Cangrelor use in ticagrelor-loaded ST-elevation myocardial infarction patients with high residual platelet reactivity: a randomized controlled trial

Abstract Background Despite the use of potent P2Y12 inhibitor, many patients still present with high platelet reactivity (HPR) at the time of primary percutaneous coronary intervention (PCI). HPR is associated with impaired myocardial reperfusion and the subsequent poor outcome. Purpose We sought to determine the impact of Cangrelor -a rapid and potent intravenous P2Y12 inhibitor- on myocardial reperfusion in patients with HPR admitted for primary PCI in a randomized trial. Methods Patients pre-treated with ticagrelor and aspirin with residual HPR (baseline platelet reactivity unit (PRU) > 208) were randomly assigned in a 1:1 ratio to receive cangrelor (experimental group) or not (control group) just before PCI. The primary endpoint was optimal myocardial reperfusion defined as a final myocardial blush grade (MBG) 3 assessed by an independent core laboratory. Results After screening of 128 patients, a total of 60 patients were with HPR were enrolled and randomized. The ticagrelor loading dose to PRU measurement times were 83 ± 32 and 90 ± 47 minutes in the experimental and control groups, respectively. Baseline PRU were 245 ± 30 and 252 ± 35 in the experimental and standard group, respectively. A final MBG 3 was observed in 21/30 (55%) and 17/30 (45%) the experimental and standard groups (p=0.29). A final TIMI flow grade 3 was observed in 30/30 (100%) and 27/30 (90%) the experimental and standard groups (p=0.24). Peak troponin levels after PCI were 51381 ± 50047 and 51078 ± 63960 ng/L (p=0.98) in the experimental and standard group, respectively. At the end of the PCI, control PRU were 36 ± 57 and 198 ± 107 (p<0.0001) in the experimental and standard group, respectively. One patient of the experimental group presented an in-hospital major bleeding (BARC 3). Conclusion In ticagrelor-loaded STEMI patients with residual HPR at the time of PCI, cangrelor use was associated with a more effective platelet inhibition but failed to significantly improve the rates of optimal final myocardial blush grades.

Frequency of CYP2C19, P2RY12, ITGB3, ITGA2, and eNOS3 gene polymorphism in patients with myocardial infarction

The aim of the study was to assess the distribution of polymorphic variants G681A (*2) of the CYP2C19 gene, H1/H2 of the P2RY12 gene, T1565C of the ITGB3 gene, C807T of the ITGA2 gene, and T786C of the eNOS3 gene in the population of the Grodno region, and to study their associations with myocardial infarction (MI). The study of the population consists of 493 people, including 400 patients with MI aged 31 to 74 years and 93 people of the control group aged 32 to 60 years. Research data (clinical and genotyping performed by polymerase chain reaction) were analyzed using STATISTICA 10.0 software. The prevalence of carriage of genotypes associated with high residual platelet reactivity and variability in response to dual antiplatelet therapy among patients with MI was 25.2 % for the G681A polymorphic locus of the CYP2C19 gene (GA + AA), and for the H1/H2 polymorphic locus of the P2RY12 gene (H1/H2 + H2/H2) – 40.0 %, for the C807T polymorphic locus of the ITGA2 gene (CT + TT) – 65.8, for the T1565C polymorphic locus of the ITGB3 gene (TC + CC) – 25.5, for the polymorphic locus T786C of the eNOS gene (TC + CC) – 69.2 %. Among the individuals of the control group, the frequency of occurrence of these genotypes was 18.3, 46.2, 60.2, 37.6, 48.4 %, respectively. In patients with MI, compared to the control group, the TT genotype of the eNOS gene was less common (χ2 = 13.6, p = 0.0002), the CC genotype of the eNOS gene (χ2 = 5.4, p = 0.02) and the allele 786C of the eNOS gene (χ2 = 15.1, p = 0.0001) were more often detected. The carriage of the 786C allele of the eNOS gene increased the risk of MI in the studied population (OR = 2.0, 95 % CI: 1.41‒2.82, p = 0.0001). Gender differences were not found in the distribution of genotypes and alleles within the studied groups. There were no differences in carriage by the number of combinations of minor alleles between the control group and patients with MI. The most common combinations of minor alleles in both groups were comparable.

Adjunctive Cilostazol in Patients With High Residual Platelet Reactivity After Drug-Eluting Stent Implantation: A Randomized, Open-Label, Single-Center, Prospective Study (ADJUST-HPR).

Cilostazol as an adjunct to dual antiplatelet therapy (DAPT) postcoronary stenting may further reduce vascular occlusion risks. The aim of this study was to assess the impact of cilostazol on high residual platelet reactivity (HRPR) in patients undergoing drug-eluting coronary stent implantation. In a randomized, open-label, single-center, prospective study, the degree of platelet inhibition by cilostazol 100 mg twice daily was assessed on top of conventional DAPT compared with standard clopidogrel and low-dose aspirin combination in poststent patients with HRPR. HRPR was defined as P2Y12 units (PRU) > 240 as measured by the VerifyNow P2Y12 assay. In addition, the platelet activity was assessed by light transmittance aggregometry (LTA) and Multiplate electrode analyzer (MEA). The total of 148 patients were screened, and HRPR was observed in 64 (43.2%). Those were randomized for DAPT versus triple therapy (TAPT). After 30 days, TAPT group exhibited significantly lower rate of HRPR when assessed by all 3 devices (VerifyNow: 40.0 vs. 66.7% P = 0.04, LTA: 6.7 vs. 30.0% P = 0.02, MEA: 10.0 vs. 30.0% P = 0.05 L all vs. DAPT). Also, higher absolute mean difference in TAPT versus DAPT group after 30 days (VerifyNow: 71.3 ± 38.2 vs. 24.6 ± 40.2 P < 0.001, LTA: 23.9 ± 15.1 vs. 9.4 ± 11.8 P < 0.001, MEA: 9.3 ± 12.9 vs. 2.4 ± 17.3 P = 0.08) was observed. Cilostazol in addition to standard DAPT reduces the incidence of HRPR and diminishes further platelet activity in poststent patients. Whether this favorable laboratory finding will affect clinical outcomes requires an adequately powered randomized trial.

Individualized antiplatelet therapy for non-cardiogenic ischemic stroke

ObjectiveThis research aims to investigate the impact of individualized antiplatelet therapy guided by thromboelastography with platelet mapping (TEG-PM) on the clinical outcomes of patients with non-cardiogenic ischemic stroke. MethodsAmong a total of 1264 patients, 684 individuals diagnosed with non-cardiogenic ischemic stroke underwent TEG-PM testing. Based on the adjustment of antiplatelet medication, these patients were divided into individual and control groups. Within the individual group, in accordance with the TEG-PM test results, a Maximum amplitude (MA) value greater than 47mm was defined as high residual platelet reactivity (HRPR), while an MA value less than 31mm was defined as low residual platelet reactivity (LRPR). Patients with arachidonic acid (AA) less than 50% and adenosine diphosphate (ADP) less than 30% were classified as aspirin-resistant or clopidogrel-resistant. Treatment strategies for antiplatelet medication were subsequently adjusted accordingly, encompassing increment, decrement, or replacement of drugs. Meanwhile, the control group maintained their original medication regimen without alterations. ResultsThe individual group included 487 patients, while the control group had 197. In the individual group, approximately 175 patients (35.9%) were treated with increased medication dosages, 89 patients (18.3%) with reduced dosages, and 223 patients (45.8%) switched medications. The results showed that the incidence rate of ischemic events in the individual group was lower than that of the control group (5.54% vs. 12.6%, P = 0.001), but no significant difference was observed in bleeding events. Cox regression analysis revealed age (hazard ratio, 1.043; 95% CI, 1.01-1.078; P = 0.011) and coronary heart disease (hazard ratio, 1.902; 95% CI, 1.147-3.153; P = 0.013) as significant risk factors for adverse events. ConclusionIndividualized antiplatelet therapy based on TEG-PM results can reduce the risk of ischemic events in patients with non-cardiogenic ischemic stroke without increasing the risk of bleeding events or mortality. Advanced age and coronary heart disease were identified as risk factors affecting the outcomes of individualized antiplatelet therapy.

Cangrelor in contemporary patients with ST-segment elevation myocardial infarction pretreated with Ticagrelor: Pharmacodynamic data from the POMPEII study

BackgroundThere are limited data to assess pharmacodynamic (PD) profiles of patients with STEMI undergoing primary percutaneous coronary intervention (PCI) and receiving cangrelor after pretreatment with ticagrelor. MethodsThe PharmacOdynaMic effects of cangrelor in PatiEnts wIth acute or chronIc coronary syndrome undergoing percutaneous coronary intervention (POMPEII) registry (NCT04790032) is a prospective study conducted at Federico II University of Naples enrolling all patients undergoing PCI receiving cangrelor at operator’s discretion. PD assessments were performed with 3 assays: (1) the gold standard light transmittance aggregometry (LTA) (20- and 5-μM adenosine diphosphate [ADP] stimuli); (2) VerifyNow P2Y12-test; (3) Multiplate electrode aggregometry (MEA), ADP-test. ResultsWe analyzed 13 STEMI patients pretreated with ticagrelor within 1 h at the time they underwent primary PCI receiving cangrelor. All patients showed low maximal platelet aggregation at 30-minute during cangrelor infusion, as well as at 3 h and 4–6 h (corresponding to 1 h and 2–4 h after stopping cangrelor infusion) with no cases of high residual platelet reactivity. These results were consistent with all assays. ConclusionsPD data show that in contemporary real-world STEMI patients pretreated within 1 h with ticagrelor undergoing primary PCI, adding cangrelor resulted in fast and potent platelet inhibition, thus suggesting that cangrelor may bridge the gap until ticagrelor reaches its effect.

Clopidogrel-Related High Residual Platelet Reactivity Associated with Estimated Glomerular Filtration Rate in Patients with Acute Ischemic Stroke

Introduction: There are few studies on the relationship between the occurrence of clopidogrel-related high residual platelet reactivity (HRPR) and estimated glomerular filtration rate (eGFR) at admission in patients with ischemic stroke. The aim of this study was to investigate the possible relationship between the two. Methods: Patients who were hospitalized and diagnosed with acute ischemic stroke were recruited from July 1, 2017, to June 30, 2018, at Shanghai TCM-Integrated Hospital. Renal function was measured within 24 h of enrollment and eGFR was calculated. Patients were tested for platelet reactivity using the VerifyNow system after 7 days of antiplatelet therapy with clopidogrel 75 mg/d alone, and patients with P2Y12 reaction unit values ≥230 were diagnosed with HRPR. The association between HRPR and eGFR was analyzed. Results: A total of 274 patients were enrolled in the study, of whom 91 (33.21%) had HRPR. Multivariate logistic regression analysis suggested that an increased risk of HRPR was independently associated with female sex and reduced eGFR (female sex: OR = 2.24, 95% CI: 1.26–3.99, p = 0.006; mild chronic kidney disease [CKD]: OR = 2.95, 95% CI: 1.47–5.93, p = 0.002; moderate CKD: OR = 3.07, 95% CI: 1.08–8.75, p = 0.04). Conclusion: Decreased eGFR is an independent risk factor for the occurrence of HRPR in patients with ischemic stroke.

ДЕТЕРМИНАНТЫ ВЫСОКОЙ И НИЗКОЙ ОСТАТОЧНОЙ РЕАКТИВНОСТИ ТРОМБОЦИТОВ ПРИ ПРИЕМЕ КЛОПИДОГРЕЛА В 1-2 СУТКИ ИНФАРКТА МИОКАРДА

The aim of the study was to determine the clinical and laboratory factors that determine high and low platelet reactivity in patients taking clopidogrel on day 1-2 of myocardial infarction (MI). Material and Methods. A total of 405 patients (322 men and 83 women) with MI aged 31 to 74 years were examined. Group 1 included patients with low residual platelet reactivity (LRPR) – 89 people, group 2 consisted of patients with optimal platelet reactivity (OPR) – 223 people, group 3 was composed of patients with high residual platelet reactivity (HRPR) – 93 people. Platelet aggregation was assessed on a Multiplate impedance aggregometer (Germany) with several aggregation inducers. A blood test and a study of morphometric parameters of platelets were performed by the cytoflow method on an automated hematology analyzer Sysmex XS-500i (Japan). The study of the level of soluble CD40 ligand (sСD40L) and sP-selectin was performed in 140 patients, von Willebrand factor (VWF) and endothelin-1 were assessed in 150 people on the enzyme immunoassay analyzer Sunrise (TECAN, Austria) using Fine Biotech kits (China). All studies were performed upon admission to the hospital on day 1-2 of MI (at least 12 hours after the administration of a loading dose of clopidogrel). Results. A one-way linear regression analysis identified the following factors that independently affect the value of the ADP-test: age (β=-0.21, 95% CI: -0.42 – -0.0095; p=0.04); total cholesterol (β=1.4, 95% CI: 0.26–2.56; p=0.04); white blood cell count (β= 0.57, 95% CI: 0.003–1.14; p=0.049); hemoglobin (β=-0.16, 95% CI: -0.27 – -0.044; p=0.0067); platelet count (β=1.4, 95% CI: 0.26 – 2.56; p=0.04); PCT (β=76.8, 95% CI: 41.5 – 112.1; p=0.000024); TRAP-test (β=0.4, 95% CI: 0.33–0.46; p&lt;0.000001); CD40L (β=0.044, 95% CI: 0.013–0.074; p=0.005); sP-selectin (β=2.3, 95% CI: 0.63 – 3.97; p=0.007); VWF (β=0.06, 95% CI: 0.016 – 0.11; p=0.0085). To determine the probability of HRPR developing a binary logistic regression model was constructed based on the observational data of a sample of 398 patients, which included the following indicators: age, white blood cell count, mean platelet volume (MPV) and platelet distribution width (PDW) values, results of TRAP-test and the level of creatinine. At the probability cut-off p=0.4746, the sensitivity of the constructed model was 74.2%, specificity - 74.1%, classification accuracy – 74.1%, the area under the ROC-curve – 0.795 (CI: 0.745 – 0.844). To determine the probability of developing LRPR, a binary logistic regression model was constructed based on the observational data of 143 patients, which included the following indicators: the number of leukocytes, MPV and TRAP-test values, fibrinogen and VWF levels. With a probability cut-off p=0.5589, the sensitivity of this model was 84.6%, specificity – 77.8%, classification accuracy – 79.0%, the area under the ROC-curve – 0.826 (CI: 0.747 – 0.905). Conclusion. On days 1-2 of MI, 22% of patients with an excessive response to clopidogrel and 23% with an insufficient response to clopidogrel were identified. The determinants of HRPR are age, white blood cell count, MPV, PDW, TRAP-test and creatinine levels. The determinants of LRPR are white blood cell count, MPV values, spontaneous platelet aggregation, detected by the TRAP-test, the level of fibrinogen and VWF.

Association of polymorphic variants of &lt;i&gt;CYP2C19&lt;/i&gt;, &lt;i&gt;P2RY12&lt;/i&gt;, &lt;i&gt;ITGB3&lt;/i&gt;, &lt;i&gt;ITGA2&lt;/i&gt; and &lt;i&gt;eNOS3&lt;/i&gt; genes with high residual platelet reactivity while taking clopidogrel and acetylsalicylic acid at different terms of myocardial infarction

Aim. Study of the association of polymorphic variants of CYP2C19 (G681A), P2RY12 (H1/H2), ITGB3 (T1565C), ITGA2 (C807T), eNOS3 (T786C) genes with high residual platelet reactivity (HRPR) to clopidogrel and acetylsalicylic acid (ASA) at different terms of myocardial infarction (MI).Material and methods. The study included 400 patients with MI aged 31-74 years, 317 (79,3%) men and 83 (20,7%) women. Platelet aggregation performed on days 1-2, 12-14 and 28-30 of MI, and genotyping by the polymerase chain reaction were analyzed using the STATISTICA 10.0 program.Results. Differences were found in ADP-test 1-3 depending on the CYP2C19 (G681A) polymorphism, ADP-test 1 depending on the P2RY12 (H1/H2) polymorphism, ADP-test 2 depending on the ITGB3 (T1565C) polymorphism, ASPI-test 1 depending on the eNOS (T786C) polymorphism. The risk of HRPR to clopidogrel is higher in 681A CYP2C19 allele carriers compared to the G681 carriers throughout the entire observation period: initially odds ratio (OR) of 1,8 (1,14-2,88), p=0,012, on days 12-14 of MI, OR of 1,7 (1,08-2,68), p=0,023 and on days 28-30 of MI, OR of 2,3 (1,42-3,81), p=0,0008. The risk of HRPR to clopidogrel is higher in AA CYP2C19 genotype carriers compared to GG genotype carriers, on days 1-2 of MI (OR 6,5 (1,16-36,4), p=0,033), on days 28-30 of MI (OR 7,8 (1,26-48,0), p=0,027). The risk of HRPR to clopidogrel on days 1-2 of MI is higher in H2 P2RY12 locus carriers compared to H1 locus carriers (OR 1,5 (1,02-2,22), p=0,039). The risk of HRPR to ASA on days 1-2 of MI is higher in the 786C eNOS3 allele carriers compared to T786 allele carriers (OR 1,4 (1,02-1,96), p=0,036). Carriers of haplotypes of minor alleles of CYP2C19 + ITGA2 + P2RY12 + eNOS genes (OR 3,9 (1,13-13,65), p=0,032) and CYP2C19 + ITGA2 + eNOS genes (OR 5,1 (1,7214,96), p=0,0032) have higher risk of HRPR to dual antiplatelet therapy (DAPT) on days 28-30 of MI compared to the rest of patients.Conclusion. The association of HRPR to clopidogrel with the CYP2C19 (G681A) polymorphism was found during the entire observation period, with the P2RY12 (H1/H2) polymorphism on days 1-2 of MI, with the ITGB3 (T1565C) polymorphism on days 10-12 of MI. The association of HRPR to ASA with eNOS (T786C) polymorphism was found on days 1-2 of MI. Minor allele haplotypes of the CYP2C19 + ITGA2 + P2RY12 + eNOS genes and CYP2C19 + ITGA2 + eNOS genes were associated with a higher risk of developing HRPR to DAPT on days 28-30 of MI.

The association between higher FFAs and high residual platelet reactivity among CAD patients receiving clopidogrel therapy.

Metabolic abnormalities are associated with the occurrence, severity, and poor prognosis of coronary artery disease (CAD), some of which affect the antiplatelet efficacy of clopidogrel. Free fatty acids (FFAs) is a biomarker for metabolic abnormalities, and elevated FFAs is observed among CAD patients. Whether FFAs enhances residual platelet reactivity induced by adenosine diphosphate (ADP) while using clopidogrel was unknown. The purpose of our study is exploring the issue. Current study included 1,277 CAD patients using clopidogrel and used logistic regression to detect whether the higher level of FFAs is associated with high residual platelet reactivity (HRPR). We additionally performed subgroup and sensitivity analyses to evaluate the stability of the results. We defined HRPR as ADP-induced platelet inhibition rate (ADPi) < 50% plus ADP-induced maximum amplitude (MAADP) > 47 mm. 486 patients (38.1%) showed HRPR. The proportion of HRPR among patients with higher FFAs (>0.445 mmol/L) is greater than among patients with lower FFAs (46.4% vs. 32.6%, P < 0.001). Multivariate logistic regression demonstrated that higher FFAs (>0.445 mmol/L) is independently associated with HRPR (adjusted OR = 1.745, 95% CI, 1.352-2.254). After subgroup and sensitivity analyses, the results remained robust. The higher level of FFAs enhances residual platelet reactivity induced by ADP and is independently associated with clopidogrel HRPR.

P210 PLATELET REACTIVITY IN ELDERLY PATIENTS WITH ACUTE CORONARY SYNDROME AND ATRIAL FIBRILLATION

Abstract Background Previous studies showed that incidence of antiplatelet therapy resistance is higher in elderly patients. There is a paucity of data about the response to antiplatelet therapy in patients with atrial fibrillation (AF). The purpose of this study is to analyze platelet reactivity during dual antiplatelet therapy (DAPT) in elderly patients (≥ 75 years) with acute coronary syndrome (ACS), stratifying them by the presence or absence of AF. Methods From the PRATO–ACS registry we selected 160 patients (81±5 years; 45% female) treated with DAPT (Aspirin 100 mg daily and Clopidogrel 75 mg daily). At discharge they were tested with the VerifyNow assay to measure platelet reactivity in aspirin (aspirin–reaction unit – ARU) and in clopidogrel (P2Y12–reaction unit – PRU). Low response to aspirin was defined as ARU ≥550; low response to clopidogrel was defined as PRU ≥ 208; high response was defined as PRU values ≤ 85. Results The ARU and PRU values for patients divided according to the presence of AF are shown in the Figure 1. Conclusions In this series of elderly ACS patients, AF was associated with higher residual platelet reactivity under both clopidogrel and aspirin. AF patients were significantly more clopidogrel low responders than non–AF, while non–AF patients were significantly more high responders. No difference was found for aspirin low responders between AF and no AF patients.

Platelet and Monocyte Activation After Transcatheter Aortic Valve Replacement (POTENT-TAVR): A Mechanistic Randomized Trial of Ticagrelor Versus Clopidogrel

BackgroundInflammation and thrombosis are often linked mechanistically and are associated with adverse events after transcatheter aortic valve replacement (TAVR). High residual platelet reactivity (HRPR) is especially common when clopidogrel is used in this setting, but its relevance to immune activation is unknown. We sought to determine whether residual activity at the purinergic receptor P2Y12 (P2Y12) promotes prothrombotic immune activation in the setting of TAVR. MethodsThis was a randomized trial of 60 patients (enrolled July 2015 through December 2018) assigned to clopidogrel (300mg load, 75mg daily) or ticagrelor (180mg load, 90 mg twice daily) before and for 30 days following TAVR. Co-primary endpoints were P2Y12-dependent platelet activity (Platelet Reactivity Units; VerifyNow) and the proportion of inflammatory (cluster of differentiation [CD] 14+/CD16+) monocytes 1 day after TAVR. ResultsCompared to clopidogrel, those randomized to ticagrelor had greater platelet inhibition (median Platelet Reactivity Unit [interquartile range]: (234 [170.0-282.3] vs. 128.5 [86.5-156.5], p < 0.001), but similar inflammatory monocyte proportions (22.2% [18.0%-30.2%] vs. 25.1% [22.1%-31.0%], p = 0.201) 1 day after TAVR. Circulating monocyte-platelet aggregates, soluble CD14 levels, interleukin 6 and 8 levels, and D-dimers were also similar across treatment groups. HRPR was observed in 63% of the clopidogrel arm and was associated with higher inflammatory monocyte proportions. Major bleeding events, pacemaker placement, and mortality did not differ by treatment assignment. ConclusionsResidual P2Y12 activity after TAVR is common in those treated with clopidogrel but ticagrelor does not significantly alter biomarkers of prothrombotic immune activation. HRPR appears to be an indicator (not a cause) of innate immune activation in this setting.

The Role of Dual Antiplatelet in Stent-Assisted Coiling in Wide-Neck Aneurysm

Highlight: Dual antiplatelet is the gold standard for endovascular treatment of wide-neck aneurysms. The role of dual antiplatelet is to prevent stent thrombosis after treatment. The thrombosis rate reported during stent-assisted coiling is quite high. ABSTRACT Stent-assisted coiling (SAC) in wide-neck aneurysm treatment is associated with antiplatelet use. Dual antiplatelet therapy (DAPT) has been the gold standard for protecting against thrombosis events and is widely accepted for endovascular embolization treatment with a stent-assisted or flow diverter. Some patients experience vascular events due to the reduced efficacy of antiplatelet agents despite taking DAPT. The reported thrombosis rates during stent-assisted coiling embolization range from 2% to 20%. Thromboembolic complications, such as in-stent thrombosis, can manifest in 4.6% of cases. The correlation between platelet reactivity during treatment and bleeding events remains unclear. However, the association between High Residual Platelet Reactivity (HRPR) or hyporesponsiveness and ischemic events is well established. Based on various laboratory definitions, hyperresponsiveness in patients with clopidogrel occurs in about 14–30% of patients due to major and minor bleeding. Therefore, the optimization of antiplatelet therapy has developed significantly in the neurointerventional community.

The impact of high on-treatment platelet reactivity and fibrinogen levels on ischemic events in patients with ST elevation myocardial infarction: a prospective observational study.

After treatment, high residual platelet reactivity (HRPR) is considered as an essential risk factor for recurrent ischemic events. To evaluate the impact of fibrinogen on HRPR after implantation of emergency drug-eluting stents (DES) in patients treated with aspirin and clopidogrel or ticagrelor due to ST-elevation myocardial infarction (STEMI) and to explore the predictive values of HRPR and fibrinogen for adverse ischemic events at 12months. This single-center prospective observational study analyzed patients with STEMI who underwent primary percutaneous coronary intervention (PCI) with second-generation DES implantation from January 2017 to December 2018. Platelet reactivity was measured by thromboelastography (TEG) at 60-72h after primary PCI. HRPR was defined as the adenosine diphosphate-induced maximum amplitude (MAADP) > 47mm. A total of 919 patients were analyzed, of which 512 (55.8%) received aspirin and clopidogrel and 406 (44.2%) received aspirin and ticagrelor. Elevated fibrinogen levels were associated with an increased prevalence of HRPR (P < 0.001). High fibrinogen (quartile IV, ≥ 410mg/dL) was an independent risk factor for HRPR after multivariate regression (odds ratio 6.556, 95% confidence interval [CI]: 3.200-13.431, P < 0.001). When analyzed by Kaplan-Meier survival curves, the combination of high fibrinogen and HRPR was strongly predictive for ischemic major adverse cardiac events at 12months compared to the group without HRPR and with low fibrinogen (hazard ratio 9.681, 95% CI: 4.467-20.98, log-rank P < 0.001). Similar results were confirmed in subgroups according to different dual antiplatelet therapies. A combination of high fibrinogen and HRPR may identify recurrent adverse ischemic events over 12months. Ticagrelor exhibited more potent platelet inhibition and a better prognosis than clopidogrel.

Impact of the Xinsorb Scaffold-Related Parameters on Platelet Reactivity in Patients with Single De Novo Coronary Artery Lesions Undergoing Clopidogrel Treatment.

This study aimed to assess the relationship between stent parameters and platelet function, as well as the platelet reactivity profiles over time in patients treated with the Xinsorb scaffold. Adenosine diphosphate-induced maximal amplitude was measured as clopidogrel on-treatment platelet reactivity using thrombelastography. High residual platelet reactivity was defined as MAADP > 47 mm. Platelet function testing was induced at baseline, discharge, and 6- and 12-month visits. A total of 40 individuals undergoing Xinsorb scaffold implantation and platelet function testing were included. No adverse events were recorded during follow-up. No correlation was observed among thrombelastography indices, stent diameters, and stent coverage surface area. Significant correlation was found between MAADP and lengths of stents (Spearman rank correlation = 0.324, P =.031). Multiple logistic regression analyses demonstrated that high levels of high-density lipoprotein cholesterol was an independent protective factor for high residual platelet reactivity (odds ratio = 0.049, 95% confidence interval = 0.011-0.296, P =.016). No significant risk factors were identified; MAADP presented to be 20.6 [13.1-36.2] mm, 26.8 [18.2-35.0] mm, and 30.0 [19.6-33.4] mm 48 hours, 6 months, and 12 months after procedure, respectively; 12-month MAADP was significantly higher than the 48-hour MAADP (P =.026). There was no obvious trend for platelet response status over time. Among patients on a clopidogrel-based dual antiplatelet treatment regimen following Xinsorb scaffold implantation, stent parameters had no significant effects on platelet reactivity. The high residual platelet reactivity phenotype is relatively stable over time. High residual platelet reactivity is more likely to occur in patients with lower high-density lipoprotein cholesterol levels.

351 MULTIPLE PHARMACODYNAMIC ASSESSMENTS OF CANGRELOR EFFECTS IN ELECTIVE COMPLEX PCI: DATA FROM PHARMACODYNAMIC EFFECTS OF CANGRELOR IN PATIENTS WITH ACUTE OR CHRONIC CORONARY SYNDROME UNDERGOING PERCUTANEOUS CORONARY INTERVENTION REGISTRY

Abstract Aims Complex percutaneous coronary intervention (PCI) patients have greater risk of peri-procedural complications, with potential to be associated with poor short-term and late prognosis. Cangrelor is an intravenous P2Y12 receptor inhibitor characterized by rapid onset and offset effect of platelet inhibition which reduced the risk of thrombotic complications. Cangrelor use is currently approved in patients naïve from oral P2Y12 inhibitors with chronic (CCS) or acute coronary syndrome (ACS) undergoing PCI with a IIb recommendation by European guidelines. Yet, the process of switching from cangrelor to oral P2Y12 inhibitor remains uncertain. Methods and Results POMPEII study (NCT04790032) is a prospective registry conducted at Federico II University of Naples enrolling all patients undergoing PCI and receiving cangrelor administration. Pharmacodynamic (PD) assessments were performed at baseline, at 30 minutes, 3 hours and 4-6 hours after cangrelor initiation with 3 assays: 1) the gold standard light transmittance aggregometry (LTA) (20- and 5-µM adenosine diphosphate [ADP] stimuli); 2) VerifyNow P2Y12-test; 3) Multiplate electrode aggregometry (MEA), ADP-test. We enrolled 41 patients undergoing elective complex PCI. All patients were P2Y12 inhibitor naïve and received aspirin, unfractionated heparin, and cangrelor (30-µg/kg bolus followed by 4-µg/kg/min infusion for 2 hours) prior to the start of PCI per standard of care. All patients showed low P2Y12 reactivity at 30 minutes during cangrelor infusion with a mean inhibition of platelet aggregation (IPA, %) of 55.7±18.0% at LTA 20-µM ADP test (34% with IPA ≤50%, 19.5% with IPA≥70%, 4.9% with IPA ≥80% and none IPA ≥90%). High residual platelet reactivity (HRPR) was observed in 1 case (2.4%) as shown by LTA (both 20- and 5-µM ADP stimuli) but not confirmed by VerifyNow and MEA. HRPR was observed in 55% at at 3h and 22.5% at 4-6h at LTA 20-µM and consistently with other assays. All patients with HRPR after cangrelor stop had received clopidogrel as switching drug, while no HRPR was observed in the 4 patients switching to ticagrelor. Conclusions Cangrelor showed to be effective and safe in patients undergoing complex PCI at high thrombotic risk. The switch from cangrelor to clopidogrel could expose patients to a variable period of on-treatment HRPR with inadequate platelet inhibition probably due to the fast offset of cangrelor effect and delay of oral drug effect, while the use of ticagrelor soon after cangrelor start might be ideal to cover the gap. This might be of relevance in such a delicate clinical setting.

747 HIGH PLATELET REACTIVITY AFTER DAPT IN PATIENTS WITH ACUTE CORONARY SYNDROME AND ATRIAL FIBRILLATION

Abstract Background The incidence of atrial fibrillation (AF) in patients who undergo percutaneous coronary intervention (PCI) is not negligible, especially in the elderly. Both oral anticoagulation (OAC) and dual anti-platelet therapy (DAPT) are recommended by main guidelines, therefore is essential to balance the prevention of ischemic events with the risk of bleeding. Evidences from literature suggest that incidence of anti-platelet therapy resistance is higher in elderly patients. There is a paucity of data about the response to antiplatelet therapy in patients with AF. The purpose of this study is to analyze platelet reactivity during DAPT (aspirin + clopidogrel) in elderly patients hospitalized for acute coronary syndrome (ACS), stratifying them by the presence or absence of AF. Methods We analyzed data of patients admitted to our center for ACS. All patients were ≥ 75 years old and treated with DAPT (Aspirin 100 mg daily and Clopidogrel 75 mg daily). At discharge they were tested with a point-of-care antiplatelet-function test (VerifyNow assay) to assess the platelet response to aspirin in aspirin-reaction units (ARU) and to clopidogrel in P2Y12-reaction units (PRU). Low response to aspirin was defined as ARU ≥550; low response to clopidogrel was defined as PRU ≥208; high response was defined as PRU values ≤ 85. Results Among the 216 patients included in the registry we selected 154 of these [median age 81 (IQR 77-87) years; 45% female] who were submitted to the platelet function tested before discharge. Patients were divided into two groups: AF (43 pts); non-AF (111 pts). The table shows the platelet reactivity values by two groups. Conclusions In this series of elderly patients with ACS, AF was associated with higher residual platelet reactivity with both clopidogrel and aspirin. AF patients were significantly less responsive to clopidogrel than non-AF, while among non-AF patients there were significantly more high responders. No difference was found for aspirin low responders between AF and non-AF group. This evidence could assume clinical significance in the choice of antiplatelet drugs to be combined with chronic anticoagulant therapy for AF.

Elevated serum C1q is an independent predictor of high residual platelet reactivity in CAD patients receiving clopidogrel therapy.

BackgroundInflammation increases the risk of thrombosis in coronary artery disease (CAD) patients and affects the antiplatelet efficacy of clopidogrel. C1q interacts with platelets to activate platelets and induce thrombosis by participating in and regulating the inflammatory response. Whether C1q affects adenosine diphosphate (ADP)-induced platelet reactivity during clopidogrel therapy was unclear and our study aimed to explore the issue.MethodWe enrolled 1,334 CAD patients receiving clopidogrel therapy and evaluated the association between C1q level and high residual platelet reactivity (HRPR) using logistic regression and restricted cubic spline (RCS). HRPR was defined as ADP-induced maximum amplitude (MAADP) > 47 mm plus ADP-induced platelet aggregation (ADPi) < 50%.ResultsA total of 516 patients (38.7%) performed HRPR. The frequency of HRPR increases with the increase in C1q level (26.3%, 38.4%, 43.2%, and 46.7% for the 1st to 4th quartile of C1q). The result of multivariate logistic regression demonstrated elevated C1q as an independent predictor for HRPR (2nd quartile: OR = 1.722, 95% CI 1.215–2.440; 3rd quartile: OR = 2.015, 95% CI 1.413–2.874; 4th quartile: OR = 2.362, 95% CI 1.631–3.421, compared to the 1st quartile). RCS depicted the nonlinear relationship between C1q and HRPR risk (p for non-linear < 0.05).ConclusionThe current research is the first to explore the association of C1q and ADP-induced platelet reactivity and to demonstrate elevated C1q as an independent risk factor for HRPR in CAD patients during clopidogrel therapy.

Platelet aggregation under the conditions of vortex flow in vitro in patients with chronic heart failure

Aim. To compare the effect of increased concentrations of aggregation inducers (five-fold addition) under standard conditions and under the conditions of vortex flow in vitro on platelet aggregation in patients with chronic heart failure (CHF).Materials and methods. The study included 28 patients. The activity of platelet aggregation in platelet-rich plasma (PRP) was evaluated according to light transmission curves (%) and the average size of aggregates (relative units (rel. units)). The aggregation inducer was added once at 10 seconds of the study (standard procedure) and five times at 10 seconds, 1, 2, 3, and 4 minutes of the study with a constant stirring rate of 800 rpm. The same parameters were evaluated under the conditions of vortex flow, which was created by changing the stirring rate of the PRP from 800 rpm to 0 rpm and again to 800 rpm by pressing the centrifugation button on the analyzer.Results. In the course of the study, the size of the aggregates increased in patients with CHF only under the conditions of vortex flow. When a collagen aggregation inducer was added both at the concentration of 2 mmol / l and 10 mmol / l, platelet aggregation parameters increased under the conditions of vortex flow. During the study of epinephrine-induced platelet aggregation in patients with CHF, an increase in the aggregation parameters was revealed, both at five-fold addition of the inducer and under the conditions of vortex flow compared with the standard method.Conclusion. The proposed methodological approaches to creating the conditions for vortex flow in vitro and to five-fold addition of epinephrine showed an increase in the size of the aggregates and the degree of platelet aggregation. Collagen-induced aggregation under the conditions of vortex flow revealed 7 (25%) patients with high residual platelet reactivity (HRPR), and epinephrine-induced aggregation detected 15 (54%) patients with HRPR.