VerifyNow Assay Research Articles

Perioperative platelet reactivityover time inpatients undergoing vascular surgery: An observational pilot study.

Despite Antiplatelet therapy (APT), cardiovascular patients undergoing revascularisation remain at high risk for thrombotic events. Individual response to APT varies substantially, resulting in insufficient protection from thrombotic events due to high on-treatment platelet reactivity (HTPR) in ≤40% of patients. Individual variation in platelet response impairs APT guidance on a single patient level. Unfortunately, little is known about individual platelet response to APT over time, timing for accurate residual platelet reactivity measurement, or the optimal test to monitor residual platelet reactivity. To investigate residual platelet reactivity variability over time in individual patients undergoing carotid endarterectomy (CEA) treated with clopidogrel. Platelet reactivity was determined in patients undergoing CEA in a prospective, single-centre, observational study using the VerifyNow (change in turbidity from ADP-induced binding to fibrinogen-coated beads), the VASP assay (quantification of phosphorylation of vasodilator-stimulated phosphoprotein), and a flow-cytometry-based assay (PACT) at four perioperative time points. Genotyping identified slow (CYP2C19*2 and CYP2C19*3) and fast (CYP2C19*17) metabolisers. Between December 2017 and November 2019, 50 patients undergoing CEA were included. Platelet reactivity measured with the VerifyNow (p = < .001) and VASP (p = .029) changed over time, while the PACT did not. The VerifyNow identified patients changing HTRP status after surgery. The VASP identified patients changing HTPR status after eight weeks (p = .018). CYP2C19 genotyping identified 13 slow metabolisers. In patients undergoing CEA, perioperative platelet reactivity measurements fluctuate over time with little agreement between platelet reactivity assays. Consequently, HTPR status of individual patients measured with the VerifyNow and VASP assay changed over time. Therefore, generally used perioperative platelet reactivity measurements seem unreliable for adjusting perioperative APT strategy.

Intensity of dual antiplatelet therapy based on thrombotic and bleeding risks after coronary stenting

Abstract Background/Introduction High thrombotic risk (HTR) features are associated with higher ischemic rate, which may be mitigated by potent antiplatelet therapy. However, concomitant high bleeding risk (HBR) may be present, making it unclear whether the intensity of antiplatelet therapy should be prioritized. Purpose This study investigated the prognostic implications of HTR and HBR strata according to intensity of antiplatelet therapy (indicated by platelet reactivity) after coronary stenting. Methods HTR was defined as having at least one of the three risk factors: 1) index presentation with acute coronary syndrome; 2) complex coronary artery disease and stenting; and 3) guideline-directed clinical ischemic risk factors. HBR was determined according to presence of Academic Research Consortium (ARC)-HBR criteria. In addition, high platelet reactivity (HPR) was decided depending on the level of platelet reactivity (&amp;gt; 208 P2Y12 reaction unit measured by VerifyNow assay). Results Among 4,550 patients, HTR features were observed in 3,973 patients (87.3%) and 1,451 (31.9%) met the ARC-HBR criteria. HPR phenotype (n=2563, 56.3%) significantly increased the risk of 4-year ischemic events (adjusted hazard ratio [HRadj]: 1.40; 95% confidence interval [CI]: 1.15-1.70; P=0.001). Among patients who met the ARC-HBR criteria, HPR was not associated with the rate of ischemic events, regardless of HTR features. In cases of non-HBR patients, HPR phenotype increased ischemic events only in patients with HTR feature(s), which risk proportionally increased according to the number of HTR features (HRadj: 0.67, 1.47 and 1.58; 95% CI: 0.22-2.08, 0.94-2.29 and 1.09-2.28 in 0 [9.2%], 1 [31.2%] and ≥2 [27.7%] HTR features). In HBR patients, the risk of major bleeding was not increased by the level of antiplatelet effect. Conclusion HPR phenotype was significantly associated with the risk of ischemic events after coronary stenting, which proportionally increased according to the number of HTR features only if the ARC-HBR criteria were not present. These observations suggested that when concordant, bleeding risk, more than ischemic risk, should inform decision-making on the intensity of antiplatelet therapy.KM curve and HR forest plot for MACCEKM curve and HR forest plot for NACE

Impact of transfusion on platelet aggregation and biomarkers in myocardial infarction patients with anemia: an ancillary study of the randomized REALITY trial

Abstract Importance Higher rates of thrombotic events have been reported in patients with myocardial infarction (MI) requiring blood transfusion. The impact of transfusion strategies on biomarkers of thrombosis and inflammation is still unknown. Objective Compare the impact of a liberal vs a restrictive transfusion strategy in anemic MI patients on P2Y12 mediated platelet reactivity and biomarkers of thrombosis and inflammation. Design and Setting: Prespecified ancillary study of the multicentric randomized REALITY trial, performed in 6 French centers between February 2018 and September 2019 (Figure). Patients randomized to a liberal (hemoglobin ≤10g/dL) or a restrictive (hemoglobin ≤8g/dL) transfusion strategy had platelet reactivity measured at baseline and after randomization. Participants: One hundred anemic acute MI patients from the REALITY trial (666 randomized patients). Measurements: Measurements of platelet reactivity included a centralized blinded VASP-PRI assay and PRU measured locally using encrypted VerifyNow assay. Biomarkers of thrombosis (P-selectin, PAI-1, vWF) and inflammation (TNF-α) were also measured. The primary endpoint was the change in the VASP-PRI (difference from baseline and post randomization) between the two randomized groups. Results Among 100 patients included (n=50 in each group), the most frequent P2Y12 inhibitors used was clopidogrel (48%) while 16% of the patients did not receive any P2Y12 inhibitors. Transfused patients received on average 2.4±1.6 units of packed red blood cells. We found no differences between groups in change in P2Y12-mediated platelet aggregation before and after randomization, measured either by the VASP PRI (difference 4.3%; 95% CI (-5.4% to 14.1%)) or by the PRU (difference 23.5; 95% CI (-20.8 to 67.8)). Similar results were found in transfused patients (n=71) regardless of the randomized group, VASP PRI (difference 1.6%; 95% CI (-6.7% to 10.0%)) or PRU (difference -17.6; 95% CI (-41.0 to 5.7)). We did not find an impact of transfusion strategy or transfusion itself in the levels of P-selectin, PAI-1, vWF and TNF-α. Conclusion and Relevance A liberal or a restrictive transfusion strategy does not impact platelet reactivity and biomarkers in MI patients with anemia, supporting the lack of clinically relevant difference in thrombotic risk between both strategies.

Evaluation of Cangrelor Use After Percutaneous Coronary Intervention in Patients With Mechanical Circulatory Support

To describe cangrelor use in patients on concurrent mechanical circulatory support who underwent postpercutaneous coronary intervention. A single-center, retrospective, cohort study. At a quaternary teaching hospital. Included patients were ≥18 years old, admitted to the intensive care unit, underwent percutaneous coronary intervention with stent placement, initiated on mechanical circulatory support, and received cangrelor in the postpercutaneous coronary intervention period. Retrospectively analyzed cangrelor use in patients on mechanical circulatory support. The primary outcome was the incidence of thrombosis and bleeding events during cangrelor administration. Additional outcomes included initial cangrelor dose, number of cangrelor dose adjustments per patient, survival from mechanical circulatory support, and mortality within 30 days. Overall, 19 patients were included in this study. In total, 14 patients (74%) experienced a bleeding event; however, 93% were classified as a minor bleed. There was 1 major bleeding event. There were no thrombotic events observed during cangrelor administration. The median initial cangrelor dose was 0.5 µg/kg/min. There were 10 patients who underwent dose adjustment, with the majority being dose reductions based on antiplatelet monitoring (VerifyNow assay). Survival from mechanical circulatory support occurred in 17 patients (89%), and 30-day mortality occurred in 8 patients (42%). For patients receiving cangrelor as a bridge to oral P2Y12 inhibitor therapy on mechanical circulatory support, the authors observed a low rate of major bleeding and no episodes of thrombosis. Lower starting doses appear feasible with no observed increased risk of thrombotic complications. Future studies are needed to confirm these observations.

P2Y12 Inhibitor Monotherapy Combined With Colchicine Following PCI in ACS Patients: The MACT Pilot Study

BackgroundAfter a brief period of dual antiplatelet therapy, P2Y12 inhibitor monotherapy in the absence of aspirin effectively reduces bleeding without increasing recurrent ischemia in patients undergoing percutaneous coronary intervention (PCI). In addition, early anti-inflammatory therapies may have clinical benefits in acute coronary syndrome (ACS) patients. ObjectivesThe aim of this study was to investigate the feasibility of ticagrelor or prasugrel P2Y12 inhibitor monotherapy combined with colchicine immediately after PCI in patients with ACS. MethodsThis was a proof-of-concept pilot trial. ACS patients treated with drug-eluting stents were included. On the day after PCI, low-dose colchicine (0.6 mg daily) was administered in addition to ticagrelor or prasugrel maintenance therapy, whereas aspirin therapy was discontinued. The primary outcome was any stent thrombosis at 3 months. The key secondary outcomes were platelet reactivity measured by the VerifyNow assay (Accriva) before discharge and a reduction in high-sensitivity C-reactive protein (hs-CRP) over 1 month. ResultsWe enrolled 200 patients, 190 (95.0%) of whom completed the 3-month follow-up. The primary outcome occurred in 2 patients (1.0%): 1 definite and 1 probable stent thrombosis. The level of platelet reactivity overall was 27 ± 42 P2Y12 reaction units, and only 1 patient had high platelet reactivity (>208 P2Y12 reaction units). The hs-CRP levels decreased from 6.1 mg/L (IQR: 2.6-15.9 mg/L) at 24 hours after PCI to 0.6 mg/L (IQR: 0.4-1.2 mg/L) at 1 month (P < 0.001), and the prevalence of high-inflammation criteria (hs-CRP ≥2 mg/L) decreased from 81.8% to 11.8% (P < 0.001). ConclusionsIn ACS patients undergoing PCI, it is feasible to discontinue aspirin therapy and administer low-dose colchicine on the day after PCI in addition to ticagrelor or prasugrel P2Y12 inhibitors. This approach is associated with favorable platelet function and inflammatory profiles. (Mono Antiplatelet and Colchicine Therapy [MACT]; NCT04949516)

Randomized, Double-Blind, Active Comparator Pharmacodynamic Study of Platelet Inhibition with Crushed and Integral Formulations of Clopidogrel and Ticagrelor in Acute Coronary Syndrome.

Crushed formulations of specific antiplatelet agents produce earlier and stronger platelet inhibition. We studied the platelet inhibitory effect of crushed clopidogrel in patients with acute coronary syndrome (ACS) and its relative efficacy compared with integral clopidogrel, crushed and integral ticagrelor. We aimed to compare the platelet inhibitory effect of crushed and integral formulations of clopidogrel and ticagrelor in patients with acute coronary syndrome (ACS). Overall, 142 patients with suspected ACS were randomly assigned to receive crushed or integral formulations of clopidogrel or ticagrelor. Platelet inhibition at baseline and 1 and 8h was assessed using the VerifyNow assay. High on-treatment platelet reactivity (HTPR) ≥ 235 P2Y12reaction units (PRUs) 1h after the medication loading dose was also determined. The PRU and percentage inhibition median (interquartile range) at 1h for the different formulations were as follows: crushed clopidogrel: 196.50 (155.50, 246.50), 9.36 (- 1.79, 25.10); integral clopidogrel: 189.50 (159.00, 214.00), 2.32 (- 2.67, 19.89); crushed ticagrelor: 59.00 (10.00, 96.00), 75.53 (49.12, 95.18); and integral ticagrelor: 126.50 (50.00, 168.00), 40.56 (25.59, 78.69). There was no significant difference in PRU or percentage platelet inhibition between the crushed and integral formulations of clopidogrel (p=0.990, p=0.479); both formulations of ticagrelor were superior to the clopidogrel formulations (p<0.05). On paired comparison, crushed ticagrelor showed robust early inhibition of platelets compared with the integral formulation (p=0.03). Crushed clopidogrel exhibited the maximal HTPR of 34.3%, but was < 3% for both formulations of ticagrelor. The platelet inhibitory effect of crushed clopidogrel is not superior to integral preparation in patients with ACS. Crushed ticagrelor produced maximal platelet inhibition acutely. HTPR rates in ACS are similar and very low with both formulations of ticagrelor, and maximal with crushed clopidogrel. Clinical Trials Registry of India identifier number CTRI/2020/06/025647.

CARC13: Evaluation of Response to Aspirin Platelet Therapy and Hemocompatibility-Related Adverse Events with the HeartMate 3 Left Ventricular Assist Device

Background: Left ventricular assist device (LVAD) patients usually are prescribed a combination of anticoagulation and aspirin (ASA) therapy. HeartMate 3 (HM3) demonstrates reduced hemocompatibility-related adverse events (HRAEs) including stroke, thrombosis and bleeding. However, it’s not known whether ASA responders vs. non-responders are non-inferior in the incidence of HRAEs, and whether there are temporal changes in ASA sensitivity during HM3 support. Methods: This prospective, observational, single-center cohort study included 21 HM3 LVAD patients (Age: 59.0±11.1 years, female: 4.8%, BMI: 29.6±6.1kg/m2) implanted between 2019 and 2021, with serial ASA platelet sensitivity assays (VerifyNow Assay). ASA platelet therapy resistance was defined by ASA reactivity units (ARU) > 550. Primary endpoint was the incidence of HRAEs (ASA responders vs. non-responders) 6 months before initial assessment and until the next outpatient follow-up visit (3 months ± 30 days). Secondary endpoint was the temporal change in ASA resistance. Results: Eight (38.1%) patients were ASA resistant at the first ARU assessment (426 days after HM3 implantation) and 21.1% (p=0.38) during follow-up, without ARU changes over time (512±64 vs. 491±53, p=0.22). ASA responders and non-responders received a comparable ASA daily dose per-protocol (108±28mg vs. 100±28mg, p=0.43), without significant differences in baseline demographics (age: 62±9 vs. 55±14 years, p=0.17; female: 0% vs. 12.5%, p=0.38; BMI: 29±7 vs. 32±3, p=0.55; ischemic heart failure: 46.2% vs. 25.0%, p=0.45) or risk factors (Atrial fibrillation: 30.8% vs. 25.0%, diabetes: 30.8% vs. 37.5% and stroke history: 15.4% vs. 12.5%, p>0.99). The incidence of HRAEs was comparable between ASA responders and non-responders 6 months before the first measurement (15.4% vs. 0.0%, p=0.26) and between the two ARU measurements (0.0% vs. 12.5%, p=0.22). Conclusion: Although the ASA resistance varies considerably between LVAD outpatients, without significant changes over time, the HM3 demonstrated excellent hemocompatibility. Further large-scale multicenter studies are needed to confirm the findings of this study that ASA plays only a minor role in antithrombotic treatment with HM3 and can be safely removed.

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.

Association of Antiretroviral Therapy with Platelet Function and Systemic Inflammatory Response in People Living with HIV: A Cross-Sectional Study.

People living with HIV (PLWHIV) present an increased risk of adverse cardiovascular events. We aimed to assess whether antiretroviral therapy (ART) pharmacologically enhances platelet reactivity and platelet activation intensity, and explore the potential association with underlying inflammatory status. This was a cross-sectional cohort study carried out among PLWHIV on diverse ART regimens. Platelet reactivity and activation intensity were assessed using the bedside point-of-care VerifyNow assay, in P2Y12 reaction units (PRU), measurements of monocyte-platelet complexes, and P-selectin and GPIIb/IIIa expression increase, following activation with ADP, respectively. Levels of major inflammatory markers and whole blood parameters were also evaluated. In total, 71 PLWHIV, 59 on ART and 22 healthy controls, were included in this study. PRU values were significantly elevated in PLWHIV compared to controls [Mean; 257.85 vs. 196.67, p < 0.0001], but no significant differences were noted between ART-naïve or ART-experienced PLWHIV, or between TAF/TDF and ABC based regimens, similar to systemic inflammatory response. However, within-group analysis showed that PRUs were significantly higher in ABC/PI vs ABC/INSTI or TAF/TDF + PI patients, in line with levels of IL-2. PRU values did not correlate strongly with CD4 counts, viral load, or cytokine values. P-selectin and GPIIb/IIIa expression increased following ADP activation and were significantly more prominent in PLWHIV (p < 0.005). Platelet reactivity and platelet activation intensity were shown to be increased in PLWHIV, but they did not appear to be related to ART initiation, similar to the underlying systemic inflammatory response.

Abstract 26: Low Hematocrit Falsely Elevates P2Y12 Values Leading To More Aggressive Therapy In Carotid Artery Stent Patients

Introduction: Plavix resistance is an independent risk factor for thromboembolic complications following carotid artery stent (CAS) placements. The VerifyNow P2Y12 assay is the best studied in gauging for Plavix responsiveness. Its performance is affected when hematocrit (HCT) value is &lt;33%, and the prevalence of anemia in acute stroke patients is 30%. Hence, we studied the effect of low HCT on P2Y12 response units (PRU) in patients with symptomatic carotid artery stenosis who received CAS. Methods: We included symptomatic carotid artery patients who suffered ischemic strokes and received CAS during the same hospitalization with PRU measured via VerifyNow assay. Therapeutic PRU is defined as ≤180. Primary outcomes were the comparisons of PRU and the proportion of non-responders between low (&lt;33) and high (≥33) HCT groups. Secondary outcomes evaluated for switch in therapy in non-responders and the rate of major hemorrhages. Results: 78 of 127 symptomatic carotid artery patients met inclusion criteria. Mean age was 70.5 with 38.5% females. 23 of 78 had HCT &lt; 33. Baseline characteristics between low and high HCT groups were similar except for hemoglobin (9.4 vs. 12.7, p&lt;0.01), HCT (28.2 vs. 37.5, p&lt;0.01), diabetes (69.6 vs. 29.1%, p&lt;0.01), pre-CAS antithrombotic load (Plavix 300mg load, 43.5 vs. 81.8%; Plavix 600mg load, 39.1 vs. 12.7%, p&lt;0.01). Despite more aggressive pre-loading in low group, mean PRU was substantially higher (220.1 vs. 148.3, P&lt;0.01) leading to higher proportion of non-responders (69.6 vs. 38.1%, p&lt;0.01). 34 of 37 non-responders had changes from aspirin and Plavix 75mg to more aggressive therapeutic regimen. Rate of major hemorrhages was higher in non-responder low HCT group vs. the rest without significance (18.8 vs. 3.2%, p=0.15). Conclusion: In symptomatic carotid patients receiving CAS, low HCT is associated with increased PRU, resulting in some to be falsely categorized as non-responders receiving more aggressive therapy unnecessarily.

Inadequate response to antiplatelet therapy in patients with peripheral artery disease: a prospective cohort study

BackgroundPatients with peripheral artery disease (PAD) are treated with preventive strategies to improve the cardiovascular risk. The incidence of cardiovascular events and mortality however remains high in PAD populations. We therefore aimed to better characterize PAD patients suffering from cardiovascular events and mortality in order to tailor preventive treatment.MethodsBetween 2018 and 2020, 246 PAD outpatients (17 newly diagnosed, 229 with known PAD) were prospectively enrolled in this observational cohort study. Patient data and blood samples were collected after inclusion, and the primary composite endpoint (myocardial infarction, elective coronary revascularization, ischemic stroke, acute limb ischemia, mortality) was evaluated after one year. Secondary outcomes included platelet reactivity, measured using the VerifyNow assay, and medication adherence, assessed using the Morisky Medication Adherence Scale-8 (MMAS-8). Logistic regression models were used to identify associations between characteristics and the occurrence of events.ResultsThe cohort comprised 207 patients with claudication and 39 with chronic limb threatening ischemia. Twenty-six (10.6%) patients suffered from an event during follow-up. Prior myocardial infarction (OR 3.3 [1.4–7.7]), prior ischemic stroke (OR 4.5 [1.8–10.9]), higher levels of creatinine (OR 5.2 [2.2–12.6]), lower levels of high-density lipoprotein (OR 4.2 [1.5–10.6]) and lower haemoglobin levels (OR 3.1 [1.3–7.1]) were associated with events. Patients with events had more often high on-treatment platelet reactivity (HTPR) on aspirin (OR 5.9 [1.4–25.1]) or clopidogrel (OR 4.3 [1–19.3]). High adherence to medication was associated with the occurrence of events (OR 4.1 [1–18]).ConclusionsPatients suffering from cardiovascular events and mortality were characterized by prior cardiovascular events as compared to patients who did not experience any events. Antiplatelet therapy was not optimally protective despite high medication adherence, and HTPR was independently associated with the occurrence of events. More research is needed on alternative treatment strategies such as dual antiplatelet therapy or combinations with anticoagulant drugs.Trial registrationThe Medical Ethics Committee (METC) of the MUMC+ approved the study (NL63235.068.17) and the study was registered in the Netherlands Trial Register (NTR7250).

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.

Derivation of a Novel Scoring System Predicting High Platelet Reactivity on Prasugrel in Patients with Coronary Artery Disease.

High platelet reactivity (HPR) has been associated with an increased risk of thrombotic events in patients undergoing percutaneous coronary intervention. HPR has been well examined in patients treated with clopidogrel; however, HPR on prasugrel is poorly investigated. Four prospective studies were pooled, in which platelet reactivity on prasugrel was measured using VerifyNow assay; genotyping of CYP2C19 was also performed. Factors associated with HPR on prasugrel were identified using multivariable analysis to develop a risk prediction model. In total, 180 patients were examined in this study, of whom 51 (28%) had HPR on prasugrel. The multivariable analysis indicated that hypertension, diabetes, hemodialysis, and the number of CYP2C19 loss-of-function (LOF) alleles are significant factors for HPR on prasugrel. These four factors were then incorporated to develop the HHD-GENE score. The receiver operating characteristic curve analysis showed that the HHD-GENE score predicted HPR on prasugrel (area under the curve (AUC) 0.74, best cutoff value 5, p＜0.001). With the best cutoff value, patients with the HHD-GENE score ≥ 5 had a significantly increased risk of HPR on prasugrel than their counterpart (50% vs. 18%, p＜0.001). The HHD-GENE score consisting of hypertension, diabetes, hemodialysis, and CYP2C19 LOF alleles may be useful in identifying patients on prasugrel who are at high risk for HPR. External validation is needed to define the clinical utility of this novel scoring system.

Clopidogrel Resistance Among Ischemic Stroke Patients and Its Risk Factors in Indonesia.

Clopidogrel is a common antiplatelet used as secondary prevention of ischemic stroke, known to have better efficacy than aspirin, with a equivalent safety profile. However, clopidogrel resistance is not uncommon but has not been widely studied in Asia. This study will further assess clopidogrel resistance and its risk factors. A cross-sectional study was conducted at Rumah Sakit Universitas, Indonesia, and Rumah Sakit Cipto Mangunkusumo, Indonesia in 2020-2021. All patients had had at least one episode of ischemic stroke. Clopidogrel resistance was assessed using a VerifyNow assay. 57 subjects were enrolled in this study. We found 15.8% of subjects were clopidogrel resistant. Gender was significantly associated with clopidogrel resistance, with males having 80% lower clopidogrel resistance (OR 0.2 (95% CI 0.022 - 0.638); P=0.006). Meanwhile, smoking was not associated with clopidogrel responsiveness (P=0.051). We found no association between haemoglobin, blood glucose, HbA1c, cholesterol, liver enzymes, serum urea concentration or creatinine levels and clopidogrel resistance. Clopidogrel remains an effective treatment to prevent recurrent ischemic stroke in Indonesia. Further studies are needed to assess gene polymorphism and clopidogrel resistance, which may explain the findings of this study.

Differences in Optimal Platelet Reactivity after Potent P2Y12 Inhibitor Treatment in Acute Coronary Syndrome Patients Undergoing Percutaneous Coronary Intervention.

Background: East Asian patients receiving treatment with the potent P2Y12 inhibitors prasugrel or ticagrelor experience more potent platelet inhibition than with clopidogrel. Methods: This study investigated differences in OPR rates with reduced doses of prasugrel (n = 38) or ticagrelor (n = 40) for maintenance therapy in 118 Korean ACS patients who had undergone PCI, in comparison to conventional-dose clopidogrel (n = 40). We assessed drug responses at one- and three-months post-PCI with VerifyNow and multiple electrode aggregometry assays. Results: At the one-month period, patients receiving standard-dose prasugrel or ticagrelor had lower platelet reactivity as determined by the three assays than those receiving the conventional dose of clopidogrel (VN: p = 0.000; MEA: p = 0.000; LTA: p = 0.000). At the 3-month point, platelet reactivity was lower in those receiving reduced-dose prasugrel or ticagrelor than the clopidogrel-treated patients (VN: p = 0.000; MEA: p = 0.012; LTA: p = 0.002). Prasugrel resulted in significantly lower platelet inhibition than ticagrelor as determined by VN and LTA (VN: p = 0.000; LTA: p = 0.003). At three months, there was a significant overall difference in OPR among the three groups when measured by VN (p < 0.001), but not when measured by MEA (p = 0.596). OPR in the reduced-dose prasugrel group was not significantly different to the clopidogrel group at three months (VN: p = 0.180; MEA: p = 0.711). OPR in the reduced-dose ticagrelor group was similar to clopidogrel as determined by MEA at three months, but was different when assessed by VN (VN: p = 0.000; MEA: p = 0.540). Compared to standard-dose, the reduced-dose prasugrel OPR rate was significantly increased (VN: p = 0.008; MEA: p = 0.020). Conclusions: OPR values for reduced-dose prasugrel and conventional-dose clopidogrel at three months were similar but higher than for reduced-dose ticagrelor as determined by VN, but no differences were noted by MEA. The MEA assay might have less sensitivity and consistency than the VN assay. Further studies are needed to explore this discrepancy.

Platelet Function and Genotype after DES Implantation in East Asian Patients: Rationale and Characteristics of the PTRG-DES Consortium.

PurposePlatelet function test (PFT) results and genotype hold unique prognostic implications in East Asian patients. The aim of the PTRG-DES (Platelet function and genoType-Related long-term proGnosis in Drug-Eluting Stent-treated Patients with coronary artery disease) consortium is to assess the clinical impact thereof on long-term clinical outcomes in Korean patients with coronary artery disease during dual antiplatelet therapy (DAPT) including clopidogrel.Materials and MethodsSearching publications on the PubMed, we reviewed clopidogrel treatment studies with PFT and/or genotype data for potential inclusion in this study. Lead investigators were invited to share PFT/genotype results, patient characteristics, and clinical outcomes to evaluate relationships among them.ResultsNine registries from 32 academic centers participated in the PTRG-DES consortium, contributing individual patient data from 13160 patients who underwent DES implantation between July 2003 and August 2018. The PTRG-PFT cohort was composed of 11714 patients with available VerifyNow assay results. Platelet reactivity levels reached 218±79 P2Y12 reaction units (PRU), and high on-clopidogrel platelet reactivity based on a consensus-recommended cutoff (PRU >208) was observed in 55.9%. The PTRG-Genotype cohort consisted of 8163 patients with candidate genotypes related with clopidogrel responsiveness. Of those with cytochrome P450 (CYP) 2C19 genotype, frequencies of carrying one and two loss-of-function allele (s) (*2 or *3) were 47.9% (intermediate metabolizers) and 14.2% (poor metabolizers), respectively.ConclusionThe PTRG-DES consortium highlights unique values for on-clopidogrel platelet reactivity and CYP2C19 phenotype that may be important to developing optimal antiplatelet regimens in East Asian patients.Trial RegistrationClinicalTrials.gov Identifier: NCT04734028.

Relationship between Transient Cortical Blindness and Contrast Medium Leakage That Occurs after Endovascular Treatment of Posterior Circulation Aneurysms.

The mechanism of transient cortical blindness after endovascular treatment-a rare phenomenon-has not been elucidated; however, it is assumed to be related to contrast medium leakage (CML). We investigated the relationship between postoperative CML and cortical blindness in patients who underwent endovascular treatment for vascular lesions of posterior circulation. This retrospective cohort study included 28 patients who underwent endovascular treatment for posterior circulation aneurysms at our hospital between January 2014 and December 2018. Cerebral CT was performed immediately after endovascular treatment and 24 h later. CT images were retrospectively evaluated with special interest in the presence and distribution of leakage of the contrast medium (CM). Patients were classified into the following three groups based on CT findings: Group A, no CML (11 patients); Group B, unilateral CML (5 patients); and Group C, bilateral CML (9 patients). The posterior circulation aneurysms were located in the basilar artery in 13 (52.0%) cases, in the posterior cerebral artery in 1 (4.0%) case, and in the vertebral artery in 11 (44.0%) cases. There was no difference regarding the adjunctive technique used for endovascular treatment between the groups. Patients in Group C used a significantly larger amount of CM than those in the other two groups. A longer operation time was associated with a larger amount of CM used during treatment. VerifyNow assay revealed that the P2Y12 reaction unit was significantly lower in Groups B and C. Cortical blindness was transiently observed in 2 of 9 patients (22.2%) in Group C, both of which showed CML surrounding the bilateral parieto-occipital sulcus. Both patients with cortical blindness showed bilateral CML, both of which showed CML surrounding the bilateral parieto-occipital sulcus. The CM-induced blood-brain barrier disruption may be the cause of cortical blindness.

MicroRNAs as Novel Biomarkers for P2Y12 - Inhibitors Resistance Prediction.

AimThe aim of this study is to assess 6 micro-RNAs: miR-126, miR-223, miR-150, miR-29, miR-34, miR-142 as potential biomarkers for P2Y12- inhibitors resistance prediction.MethodsEighty patients with an acute coronary syndrome undergoing percutaneous coronary intervention treated in a multidisciplinary hospital in Moscow with DAPT (either with ticagrelor, n=45, or clopidogrel, n=35) were enrolled. The carriership of 6 clinically relevant polymorphisms for ticagrelor and 17 for clopidogrel was detected. Expression levels of six prospective miRNAs were measured. The activity of CYP3A4 isoenzyme was measured as the ratio of the concentrations of cortisol and 6β-hydroxycortisol.ResultsThe polymorphisms of the P2Y12-inhibitors ADME genes that demonstrated statistically significant connection with miRNA expression levels are as follows: P2Y12R (A>G, rs3732759) and miR-29 (p=0.017), miR-34 (p=0.003); CYP2C19*17 (C-806T, rs1224856) and miR-142 (p=0.012); PON1 (Q192R, rs662) and miR-29 (p=0.004), ABCG2 (G>T, rs2231142) and miR-34 (p=0.007). MiRNAs expression levels showed connection with the results of the platelet reactivity assessment by utilizing VerifyNow assay (“Instrumentation laboratory”, MA, US). MiR-126 (β coefficient=−0.076, SE=0.032, p=0.021), miR-223 (β coefficient=−0.089, SE=0.041, p=0.032), miR-29 (β coefficient=−0.042, SE=0.018, p=0.026), miR-142 (β coefficient=−0.072, SE=0.026, p=0.008) have the potential to be used as biomarkers and may substitute platelet reactivity testing.ConclusionThis study has revealed new biomarkers for P2Y12-inhibitors resistance testing: miR-29, miR-34, miR-126, miR-142, miR-223.

Lignocaine versus opioids in coronary intervention: assessing antiplatelet activity and ticagrelor levels (LOCAL) study

Abstract Background Opioid analgesia impairs the bioavailability and antiplatelet effect of oral P2Y12 inhibitors prompting investigation of mitigation strategies including identifying alternative analgesic agents. Purpose To assess the impact of intravenous fentanyl and lignocaine on the bioavailability and antiplatelet effect of ticagrelor in patients with unstable angina and non-ST elevation myocardial infarction, as well as their procedural analgesic efficacy and safety. Methods The LOCAL trial was a prospective, single centre, double-blind, randomized, controlled trial where intravenous lignocaine was the experimental analgesic agent assessed in this trial compared to intravenous fentanyl as procedural analgesia during coronary angiography and percutaneous coronary intervention. Patients with an indication for dual antiplatelet therapy and no contraindication were given 180mg of ticagrelor orally as integral tablets with 250 mL of tap water at the end of the case. Blood was sampled at time 0, 0.5, 1, 2 and 4 hours post administration of ticagrelor for pharmacokinetic and comprehensive pharmacodynamic analysis. Results Seventy patients undergoing coronary angiography with an indication for ticagrelor loading were included in the pharmacokinetic and pharmacodynamic analysis. Plasma ticagrelor levels at 2 h post loading dose were significantly lower in the fentanyl compared to lignocaine treatment arm (476 vs. 792 ng/mL, p=0.02, see figure 1). The area under the plasma-time curves for ticagrelor (987 vs. 2189 ng.h/mL, p=0.001) and its active metabolite (173 vs. 394 ng.h/mL, p&amp;lt;0.001) were both significantly lower in the fentanyl arm. Platelet reactivity assessed by the VerifyNow assay was higher at all time points after baseline in the fentanyl compared to lignocaine arm. The VASP flow cytometry assay demonstrated higher platelet reactivity at 2 hours in the fentanyl group (40% vs. 22% platelet reactivity index, p=0.001). The Multiplate Analyzer demonstrated higher platelet reactivity in the fentanyl arm at 60 minutes (43 vs. 26 area under the curve units, p=0.001) as did expression of activated platelet GpIIb/IIIa receptor (2829 vs. 1426 geometric mean fluorescence intensity (GMFI), p=0.006) and P-selectin (439 vs. 211 GMFI, p=0.001). High on-treatment platelet reactivity (HPR) was significantly higher in the fentanyl arm at 60 min using the MPA (41% vs. 9%, p=0.002) and 120 min using the VFN (30% vs. 3%, p=0.003) and VASP (37% vs. 6%, p=0.002) assays (see figure 2). Both drugs were well tolerated with a high level of patient satisfaction (fentanyl 94% vs. lignocaine 97%, p=0.56). Conclusion(s) Unlike fentanyl, lignocaine does not impair the bioavailability or delay the antiplatelet effect of ticagrelor. Both drugs were well tolerated and effective with a high level of patient satisfaction for procedural analgesia. Systemic pain medication during PCI should be reconsidered and if performed, lignocaine is a beneficial alternative to fentanyl. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): TBA Figure 1. Ticagrelor and AM pharmacokineticsFigure 2. Ticagrelor pharmacodynamics

Effects of lignocaine vs. opioids on antiplatelet activity of ticagrelor: the LOCAL trial.

We assessed the impact of intravenous fentanyl and lignocaine on the pharmacokinetics and pharmacodynamics of ticagrelor in patients with unstable angina and non-ST-elevation myocardial infarction and their procedural analgesic efficacy and safety. Seventy patients undergoing coronary angiography with ticagrelor loading were included in the pharmacokinetic and pharmacodynamic analyses of this randomized trial. Plasma ticagrelor levels 2 h post-loading dose were significantly lower in the fentanyl arm than in the lignocaine treatment arm (598 vs. 1008 ng/mL, P = 0.014). The area under the plasma-time curves for ticagrelor (1228 vs. 2753 ng h/mL, P < 0.001) and its active metabolite (201 vs. 447 ng h/mL, P = 0.001) were both significantly lower in the fentanyl arm. Expression of activated platelet glycoprotein IIb/IIIa receptor (2829 vs. 1426 mean fluorescence intensity, P = 0.006) and P-selectin (439 vs. 211 mean fluorescence intensity, P = 0.001) was significantly higher at 60 min in the fentanyl arm. A higher proportion of patients had high on-treatment platelet reactivity in the fentanyl arm at 60 min using the Multiplate Analyzer (41% vs. 9%, P = 0.002) and 120 min using the VerifyNow (30% vs. 3%, P = 0.003) and VASP (37% vs. 6%, P = 0.002) assays. Both drugs were well tolerated with a high level of patient satisfaction. Unlike fentanyl, lignocaine does not impair the bioavailability or delay the antiplatelet effect of ticagrelor. Both drugs were well tolerated and effective with a high level of patient satisfaction for procedural analgesia. Routine procedural analgesia during percutaneous coronary intervention should be reconsidered and if performed, lignocaine is a beneficial alternative to fentanyl.