P2Y12 Reaction Units Research Articles

Ischemic and Bleeding Events in PENDULUM Patients With High Bleeding Risk and High Platelet Reactivity.

The balance between thrombotic and bleeding risk is of great concern in high bleeding risk (HBR) patients. This study evaluated the relationship between perioperative antiplatelet reactivity and thrombotic and bleeding events in patients at HBR undergoing percutaneous coronary intervention (PCI).Methods and Results: In this post hoc analysis of the PENDULUM (Platelet rEactivity in patieNts with DrUg eLUting stent and balancing risk of bleeding and ischeMic event) registry, patients undergoing PCI were categorized as HBR or non-HBR, and stratified as having high platelet reactivity (HPR; P2Y12reaction unit [PRU] >208) or non-HPR (PRU ≤208). Cumulative incidences of cardiovascular and cerebrovascular events (Journal of the American College of Cardiology expert definitions) and bleeding events (Bleeding Academic Research Consortium criteria) were assessed 12 months after index PCI. The incidence of ischemic and bleeding events was ~3-fold higher in HBR vs. non-HBR patients. Thrombotic/ischemic events were significantly more common in the HPR subgroup in HBR patients (hazard ratio [HR]: 1.59; 95% confidence interval [CI]: 1.11-2.28; P=0.012), but there was no difference in non-HBR patients. After adjustment for covariates, HPR in HBR patients remained an independent factor for thrombotic and ischemic events (HR: 1.69; 95% CI: 1.13-2.54; P=0.011), but not for bleeding events (HR: 1.56; 95% CI: 0.78-3.11; P=0.210). Maintaining adequate PRU levels during PCI is an important factor in improving clinical outcomes, especially for HBR patients.

An alternative reduced dose regimen of ticagrelor for neuroendovascular patients.

There is a growing use of ticagrelor in patients undergoing neuroendovascular procedures, especially those who demonstrate clopidogrel resistance. While multiple dosages are studied in the cardiology literature, the optimal dose for patients with neurological pathology has yet to be established. Here, we describe a single center experience involving 39 patients who underwent neuroendovascular procedures that then received an adjusted lower dose of ticagrelor. A retrospective chart review was performed between 2013 and 2017 for patients on dual anti-platelet therapy (DAPT) for either cervical or intracranial vascular pathologies, as well as stenting of the neurovasculature, including carotid arteries. Patients were placed on ticagrelor if their measured P2Y12 reaction units (PRU) responses to clopidogrel were outside the expected range in our center using the VerifyNow™ P2Y12 test. All patients were maintained on a dose of 45mg twice daily except for one patient who received 22.5mg twice daily. Responsiveness to ticagrelor were measured utilizing the VerifyNow™ P2Y12 test. The mean number of days for follow-up post treatment initiation was 532days. A total of 39 patients were included in the analysis. Of these, 8 patients (21%) received implantation of intracranial stents (5 patients received pipeline embolization devices, 1 patient received stent-assisted coiling, and 2 patients received intracranial stents for atherosclerotic disease). Fourteen patients (35%) received carotid angioplasty and stenting. Seventeen patients (44%) did not receive permanent implantation of a stent. All patients on the lower dose ticagrelor of 45mg twice daily achieved responsiveness (i.e., PRU < 194). Hemorrhagic transformation of ischemic stroke occurred in one patient (2.5%). No other hemorrhagic complications were encountered. No thromboembolic events were recorded aside from one patient (2.5%) with intracranial atherosclerotic disease who had an ischemic event. A lower dose of ticagrelor (45mg twice daily) appears to be safe and effective in this small cohort of patients who are resistant to clopidogrel per P2Y12 testing and who have increased risk of ischemic or hemorrhagic strokes due to neurovascular pathologies and implants. Further randomized studies are required to confirm these findings.

Comparative evaluation of standard maintenance-dose clopidogrel versus low-dose prasugrel in patients with stable coronary artery disease after percutaneous coronary intervention

BackgroundTreatment with low-dose prasugrel might be more beneficial even in chronic stable coronary artery disease (CAD) patients treated with clopidogrel. We compared platelet reactivity between standard maintenance-dose and low-dose prasugrel in stable CAD patients. MethodsThis multicenter study enrolled 164 stable CAD patients receiving dual antiplatelet therapy with aspirin and clopidogrel. Patients were randomly assigned to continue treatment with 75-mg clopidogrel daily (n = 80) or switch to 3.75-mg prasugrel daily (n = 84). Platelet reactivity was evaluated by measuring P2Y12 reaction unit (PRU) before randomization and at 5 and 30 days thereafter using the VerifyNow® assay. Patients were classified into three groups according to CYP2C19-clopidogrel metabolic phenotype: extensive (without a *2 or *3 allele), intermediate (one *2 or *3 alleles), or poor (two *2 or *3 alleles) metabolizers. ResultsThe PRU level was comparable between the two groups at baseline but was significantly lower in the prasugrel group than in the clopidogrel group on days 5 (133.0 vs. 156.8 PRU, P = 0.005) and 30 (124.3 vs. 158.0 PRU, P < 0.001). On day 30, the PRU level was lower in the prasugrel group among patients categorized as poor and intermediate metabolizers but not among extensive metabolizers. ConclusionsLow-dose prasugrel achieves more consistent antiplatelet effects than clopidogrel irrespective of the metabolic phenotype in Japanese patients with stable CAD. Low-dose prasugrel might be also beneficial in the chronic phase without increasing the bleeding risk among stable CAD patients in other countries.

Abstract TP167: Unanticipated Platelet Function Fluctuations Occur During The First 8 Hours After Neurointerventional Procedures In Patients Receiving Dual Anti-platelet Therapy

Antiplatelet agents are administered before and after neuroendovascular surgery to minimize implant-associated thromboembolic events. Dual antiplatelet therapy (DAPT) uses aspirin plus P2Y12 receptor inhibitors: clopidogrel, ticagrelor, or prasugrel. Effects are quantified in P2Y12 reactivity units (PRU) and aspirin reactivity units (ARU) by the point-of-care assay, Accumetrics VerifyNow. We hypothesized that intraoperative events such as anesthesia may affect platelet inhibition, increasing the risk of unanticipated ischemic events in the early postoperative period. This retrospective study was approved by the institutional review board. 50 patients who underwent Verify Now testing preoperatively and within 12 hours postoperatively after placement of cervical or intracranial stents at a single institution (January 1, 2018 - May 25, 2021) were included. PRU values &gt; 194 and ARU values &gt; 550 were considered subtherapeutic. Anesthetic agents, heparin dosage, clopidogrel responsiveness, platelet count, liver function, procedure type and length, NIH stroke scale scores, and demographics were compared to perioperative platelet inhibition values. Our results indicate that P2Y12 inhibition is likely affected by intraoperative events. Approximately 25% of patients exhibited marginal (170-193) or subtherapeutic (&gt; 194) PRU values during the first 8 hours following neuroendovascular procedures. The greatest variation occurred in the ticagrelor group (PRU median change 84) and was more likely to occur with reduced doses of both ticagrelor and clopidogrel. A single prasugrel patient (clopidogrel non-responder) exhibited the greatest absolute change (PRU 156 -&gt; 316). ARU variations were less pronounced suggesting that perioperative aspirin platelet inhibition is more resilient. In conclusion, patients undergoing elective neuroendovascular procedures may be at risk for thromboembolic ischemic complications during the first 8 hours postoperatively due to shifts in P2Y12 mediated platelet inhibition. ARU values were less effected, supporting the use of DAPT as an ongoing clinical standard of care.

Effect of CYP2C19 status on platelet reactivity in Taiwanese acute coronary syndrome patients switching to prasugrel from clopidogrel: Switch Study

Pharmacogenetics is a potential driver of the "East Asian paradox," in which East Asian acute coronary syndrome (ACS) patients receiving dual antiplatelet therapy (DAPT) with clopidogrel following percutaneous coronary intervention (PCI) demonstrate higher levels of platelet reactivity on treatment than Western patients, yet have lower ischemic risk and higher bleeding risk at comparable doses. However, the impact of pharmacogenetics, particularly regarding CYP2C19 genotype, on the pharmacodynamics of P2Y12 inhibitors has not been extensively studied in Taiwanese ACS patients as yet. CYP2C19 genotyping and pharmacogenetic analysis was conducted on 102 subjects from the Switch Study, a multicenter, single-arm, open-label intervention study that examined the effects on platelet activity and clinical outcomes of switching from clopidogrel (75mg daily) to low-dose prasugrel (3.75mg daily) for maintenance DAPT after PCI in 203 Taiwanese ACS patients. Genotyping results revealed that 43.1% were CYP2C19 extensive metabolizers (EM), while 56.9% were reduced metabolizers (RM). After switching to prasugrel, mean P2Y12 reaction units (PRU) values were significantly reduced in both EM and RM populations, while the proportion of high on-treatment platelet reactivity (HPR) patients significantly declined in RM patients. No increase in bleeding risk after switching was observed during follow-up. Multivariate analysis indicated that for RM patients, low estimated glomerular filtration rate (eGFR) and low hemoglobin were associated with greater HPR risk on clopidogrel, but not after switching to prasugrel. Switching to low-dose prasugrel from clopidogrel reduced mean PRU levels and proportion of HPR patients, with more significant reduction in RM patients.

Clopidogrel resistance is common in patients undergoing vascular and coronary interventions.

"Clopidogrel resistance," also defined as heightened platelet reactivity (HPR) while on clopidogrel therapy, may lead to a sub-optimal antiplatelet effect and a potential thrombotic event. There is limited literature addressing the prevalence of HPR in a large cohort of patients receiving either coronary or endovascular interventions. In a large integrated healthcare system, patients with a P2Y12 reaction units (PRU) test were identified. HPR was defined as a PRU ≥ 200 during clopidogrel therapy. Vascular and coronary interventions were identified utilizing CPT codes, HPR prevalence was calculated, and Fischer's exact test was used to determine significance. From an initial cohort of 2,405,957 patients (October 2014 to January 2020), we identified 3301 patients with PRU tests administered. Of these, 1789 tests had a PRU ≥ 200 (HPR overall prevalence, 54%). We then identified 1195 patients who underwent either an endovascular or coronary procedure and had a PRU measurement. This corresponded to 935 coronary and 260 endovascular interventions. In the coronary cohort, the HPR prevalence was 54% (503/935). In the vascular cohort, the HPR prevalence was 53% (137/260); there was no difference between cohorts in HPR prevalence (p = 0.78). "Clopidogrel resistance" or HPR was found to be present in nearly half of patients with cardiovascular disease undergoing intervention. Our data suggest HPR is more common in the cardiovascular patient population than previously appreciated. Evaluating patients for HPR is both inexpensive ($25) and rapid (< 10min). Future randomized studies are warranted to determine whether HPR has a clinically detectable effect on revascularization outcomes.

Relationship between platelet aggregation and stroke risk after percutaneous coronary intervention: a PENDULUM analysis

In patients undergoing percutaneous coronary intervention (PCI) with a stent, high on-treatment platelet reactivity may be associated with an increased risk of stroke. This post hoc analysis of the PENDULUM registry compared the risk of post-PCI stroke according to on-treatment P2Y12 reaction unit (PRU) values. Patients aged ≥ 20 years who underwent PCI were stratified by baseline PRU (at 12 and 48 h post-PCI) as either high (HPR, > 208), optimal (OPR, > 85 to ≤ 208), or low on-treatment platelet reactivity (LPR, ≤ 85). The incidences of non-fatal ischemic and non-ischemic stroke through to 12 months post-PCI were recorded. Almost all enrolled patients (6102/6267 [97.4%]) had a risk factor for ischemic stroke, and most were receiving dual antiplatelet therapy. Of the 5906 patients with PRU data (HPR, n = 2227; OPR, n = 3002; LPR, n = 677), 47 had a non-fatal stroke post-PCI (cumulative incidence: 0.68%, ischemic; 0.18%, non-ischemic stroke). Patients with a non-fatal ischemic stroke event had statistically significantly higher post-PCI PRU values versus those without an event (P = 0.037). The incidence of non-fatal non-ischemic stroke was not related to PRU value. When the patients were stratified by PRU ≤ 153 versus > 153 at 12–48 h post-PCI, a significant difference was observed in the cumulative incidence of non-fatal stroke at 12 months (P = 0.044). We found that patients with ischemic stroke tended to have higher PRU values at 12–48 h after PCI versus those without ischemic stroke.Clinical trial registration: UMIN000020332.

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.

727 Circadian variations of platelet reactivity on Clopidogrel in patients treated with elective percutaneous coronary intervention

Abstract Aims The potential diurnal variations of platelet reactivity in patients on clopidogrel treated with elective percutaneous coronary intervention (PCI) for stable coronary artery disease (CAD) are currently unknown. Methods and results We prospectively enrolled 15 patients with stable CAD treated PCI and on clopidogrel therapy for at least eight days. All patients received their maintenance 75-mg clopidogrel dose at 8 AM. Platelet reactivity was assessed with the Verifynow P2Y12 assay at three different time points (10 AM, 6 PM, and 6 AM). Platelet reactivity is expressed as P2Y12 reaction units (PRU) and PRU thresholds ≥208 and ≥240 were used to define high platelet reactivity (HPR). A significant heterogeneity in diurnal levels of platelet reactivity was found (P = 0.0004), with a peak occurring at the 6 AM assessment. In addition, at the 6 AM evaluation patients showed the highest prevalence of HPR (53.3% of patients with PRU ≥240, 66.7% of patients with PRU ≥208). Conclusions Platelet reactivity in patients with stable CAD treated with PCI and taking clopidogrel in the morning follows a circadian rhythm, thus suggesting that platelet inhibition may not be constant and sufficient throughout the day. Whether an evening or a bis in die administration of clopidogrel may result in a constant and more reliable antiplatelet inhibition, should be investigated in dedicated studies.

Candidate Gene of NOS3, MMP3, AGT, and AGT1R and Pathway Analyses for Platelet Reactivity and Clinical Outcomes of Repeat Revascularization After First PCI in Chinese Patients.

Major disadvantages of the percutaneous coronary intervention (PCI) are the high occurrence of repeat revascularization due to restenosis and disease progression. The current study aimed to identify indicators that can predict the risk of repeat revascularization. A total of 143 patients who underwent PCI and had genetic test results were enrolled. We retrospectively reviewed their medical records after the first PCI. P2Y12 reaction unit (PRU) test results were obtained by VerifyNow; 4 candidate genes (NOS3, MMP3, AGT, and AGT1R) and 380 genes related to platelet activation-related processes and clopidogrel activity were selected for analysis. Repeat revascularization and in-stent restenosis (ISR) were used as clinical outcomes, and PRU and ADP aggregation rates were used as platelet function outcomes in analysis. After the first PCI, the incidence of repeat revascularization at 18, 30, and 42months was 14.1% (20/142), 17.5% (24/137), and 39.7% (31/78), respectively. In the candidate gene analysis, rs7830 (NOS3) was associated with both ADP aggregation rate and 18- and 30-month ISR, and rs 62,275,847 (AGTR1) was associated with both ADP aggregation rate and 30-month ISR. In the pathway, gene-set analysis, the linkage rs471683 and rs7785386 of GNAI1|GNAT3 were associated with PRU and ADP aggregation rate, 18-month and 30-month ISR, and repeat revascularization within 30months. Rs1715389 of GNAI1|GNAT3 was associated with both PRU and ADP aggregation rate, 18-month and 30-month ISR, and repeat revascularization within 30months. Rs7313458 of ITPR2 was associated with PRU and ADP aggregation rate, 18-month and 30-month ISR, and repeat revascularization within 18months. The genetic polymorphisms of rs7830 (NOS3), rs62275874 (AGTR1), linkage rs471683 and rs7785386 (GNAI1|GNAT3), rs1715389 (GNAI1|GNAT3), and rs7313458 (ITPR2) may lead to an increased risk of in-stent restenosis and revascularization after the first PCI in Chinese patients by affecting the efficacy of clopidogrel. The above six SNP may be used as potential genetic biomarkers for high risk of in-stent restenosis and revascularization after the first PCI in Chinese patients.

Carotid Artery Stenting in Patients with Atrial Fibrillation: Direct Oral Anticoagulants, Brief Double Antiplatelets, and Testing Strategy.

Carotid endarterectomy is usually preferred over carotid artery stenting (CAS) for patients with atrial fibrillation (AF). We present our experience with short-course periprocedural triple antithrombotic therapy in 32 patients aged >18 years with nonvalvular AF undergoing CAS. There were no deaths, cardiac events, embolic strokes, hyperperfusion syndrome, intracranial hemorrhage, or stent thrombosis within 30 days. Transient intraprocedural hemodynamic instability in 15/32 (47%) and prolonged instability in 4/32 (13%) was managed conservatively. At a mean 16-month follow-up, there were no new neurological events or deterioration. Mean stenosis was reduced from 78.0% ± 9.7% to 17.3% ± 12.2%. This retrospective study included patients AF who were symptomatic (minor stroke (NIHSS ≤ 5)/TIA) with ICA stenosis >50%, or asymptomatic under DOAC therapy with carotid stenosis >80%, who underwent CAS from 6/2014–10/2020. Patients received double antiplatelets and statins. Antiplatelet therapy effectiveness was monitored. Stenting was performed when P2Y12 reaction units (PRU) were <150. DOACs were discontinued 48 h before angioplasty; one 60 mg dose of subcutaneous enoxaparin was administered in lieu. DOAC was restarted 12–24 h after intervention. Patients were discharged under DOAC and one nonaspirin antiplatelet. 32 patients on DOAC were included (26 male, mean age 71). 19 (59.4%) presented with stroke (ICA stenosis-related in 14); 13 (40.6%) were asymptomatic. Stents were deployed under filter protection following pre-angioplasty; post-angioplasty was performed at least once in 12 patients (37.5%). Our experience suggests that CAS can be safely performed in selected patients with CAS and AF requiring DOAC. The role of CAS in AF patients under DOAC warrants study in rigorous trials.

The Effect of Dapagliflozin on Platelet Function Testing Profiles in Diabetic Patients: The EDGE Pilot Study.

IntroductionThis prospective pharmacodynamic (PD) study assessed the effect of the sodium-glucose co-transporter-2 inhibitor (SGLT2i), dapagliflozin, on platelet reactivity.MethodsPatients with stable coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) (n = 27) who were on maintenance dual antiplatelet therapy (DAPT) of aspirin 81 mg daily, and clopidogrel 75 mg daily were recruited. Platelet function was evaluated with the VerifyNow™ P2Y12 assay (Werfen, Bedford, MA, USA) and assessed prior to initiation of and after 10 days of treatment with dapagliflozin 10 mg once-daily dose regimen. Results were compared with a paired t test.ResultsTreatment with dapagliflozin significantly decreased P2Y12 reaction units (PRU) by 20%, (95% confidence interval (CI) 8.5–32.6%, p value 0.002). The mean difference in PRU was 36.70 (95% CI 16.66–56.75). No patients experienced any serious adverse events (SAEs).ConclusionsSignificantly diminished platelet reactivity was observed on dapagliflozin as compared to without dapagliflozin. This dedicated pharmacodynamic study could be potentially informative and applicable for Trinidadian stable CAD patients with T2DM on DAPT. Further studies are required to confirm these exploratory findings.Clinical Trial RegistrationEDGE ClinicalTrials.gov number NCT04400760.

Hyperacute postprocedural high platelet reactivity: a novel predictor for in-hospital adverse events in acute coronary syndrome with prasugrel loading

Abstract Introduction Postprocedural High platelet reactivity (HPR) seems to associate long term adverse cardiovascular events, mainly intrastent thrombosis. However, the relationship between hyper-acute postprocedural HPR with prasugrel loading and clinical outcomes in acute coronary syndrome (ACS) is still unclear. Moreover, factors contributing HPR in ACS with prasugrel loading are also unknown. Purpose This study aimed to assess the impact of hyper-acute postprocedural HPR with prasugrel loading on clinical outcomes in ACS during hospitalization, as well as to define appropriate cut-off values and identify contributing factors of HPR. Methods We performed a single-centre, retrospective observational study that enrolled 207 patients who underwent emergent PCI for ACS with prasugrel loading. The P2Y12reaction unit (PRU) value was measured immediately after PCI with the VerifyNow System. The primary endpoint was major adverse cardiac events (MACE, defined as the composite of death, myocardial infarction, stroke, heart failure, ventricular arrhythmia needing defibrillation). Results Mean patient age (standard deviation) was 70.5 (±13.0) years, 78.7% were male, and average time from prasugrel intake to PRU calculation was 98.3 (±49.1) min. During a mean hospital stay of 15.9 (±9.3) days, there were 34 in-hospital MACE (16.4%) and 10 deaths (4.8%). Thrombosis events, didn't stand out and mechanical complications, such as cardiac rupture and cardiac tamponade occupies most of cardiovascular death which occurred before 10 days on admission. PRU was significantly higher in MACE group than Non-MACE group (279±65 vs 227±72, p&amp;lt;0.001 respectively). The ROC curve analysis of PRU for discriminating significant in-hospital MACE showed the cut off value of 293 (sensitivity:52.9%, specificity:83.2% [AUC=0.709, p&amp;lt;0.0001]). 47patients (29.4%) were thus categorized as HPR (PRU&amp;gt;293) immediately after emergent PCI. Kaplan-Meyer curve showed MACE events occurred in HPR group than non-HPR group (38.2% vs 10.0%, p&amp;lt;0.001). Multiple cox analysis demonstrated that HPR was independent predictors of MACE in patients with ACS underwent PCI (OR 5.416, 95% CI 2.157–13.598, p&amp;lt;0.0001). Multiple logistic regression model showed female sex, low haemoglobin value, and large mean platelet volume were independent predictors of HPR. Conclusion PRU was significantly higher in MACE group, and appropriate cut-off value of HPR in this study was 293. HPR was independent predictor of MACE during hospitalization, however thrombosis event was not significant. Evidence of clinical impact with postprocedural HPR within 120 minutes after prasugrel loading is scarce. This study shows post-procedural HPR, even without sufficient time after prasugrel intake, can be a useful predictive marker of adverse events during hospitalization. Funding Acknowledgement Type of funding sources: None. PRU between Non-MACE and MACE groupKaplan-Meyer curve

Impact of high platelet reactivity on left ventricular remodeling in patients with acute coronary syndrome

Abstract Background/Introduction Previous studies demonstrated that high platelet reactivity (HPR) predicts future cardiovascular death and coronary events in patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). However, few studies have focused on the impact of HPR on left ventricular remodeling (LVR) and each echocardiographic parameter. Purpose The purpose of this study was to investigate the impact of HPR in ACS patients on LVR and changes in echocardiographic volume indexes and LV ejection fraction. Methods This is a retrospective cohort study of prospectively collected data in a single center that enrolled patients who underwent emergency PCI for ACS including STEMI and NSTEMI with prasugrel loading. The primary outcome of the study was LVR associated with HPR. Secondary endpoints were changes in indexed LVESV, LVEDV, LVEF, E/e' and LAVI between baseline and follow-up. The P2Y12 reaction unit (PRU) value in response to prasugrel was assessed by the VerifyNow P2Y12 assay. Blood samples were collected once per procedure immediately after PCI. LVR index was calculated as the relative change in LVEDV observed at follow-up compared with baseline. LVR was defined as a relative increase in LVEDV ≥20%, measured at follow-up visit compared with the baseline value before discharge. Results A total of 196 ACS patients who underwent emergency PCI between January 2016 and July 2020 were enrolled in the study. The mean age of the study population was 69.9 years, and 76.0% were male. On echocardiography at follow up visit of mean duration of 7.0±4.0 months, LVR was found in 38 patients (19.4%). The optimal cutoff for PRU associated with increased LVR assessed by receiver-operating characteristic curve analysis was 245.5 (AUC: 0.656; 95% CI: 0.564 to 0.749; p=0.003). On the basis of this cutoff, HPR was found in 82 patients (42.1%) and the prevalence of LVR was significantly higher in the HPR group compared to the non-HPR group (30.5% vs. 11.4%; p=0.001). Multiple Cox regression analysis showed that HPR was an independent predictor of LVR (OR 4.22, 95% CI 1.83–9.71, p=0.001). In addition, Δ% EDV and Δ% ESV increased in the HPR group, and decreased in the non-HPR group with significant differences (5.8±32.6% vs. −8.0±26.2% in Δ% EDV; p=0.002, 2.0±37.5% vs. −13.3±33.0% in Δ% ESV; p=0.004, respectively). Δ%EF, Δ%E/e', Δ%LAVI were numerically improved in the non-HPR group compared with the HPR group, but this difference did not reach statistical significance. Conclusion In patients with ACS, HPR defined as PRU ≥246 immediately after emergency PCI was an independent predictor of LVR in the chronic phase. Funding Acknowledgement Type of funding sources: None. Predictors of the presence of LVRChanges (Δ%) of LVEDV and LVESV

Gene polymorphisms of insulin secretion signaling pathway associated with clopidogrel resistance in Han Chinese population.

BackgroundDue to the loss of responsiveness to insulin, diabetes mellitus (DM) patients develop increased platelet reactivity and reduced response to antiplatelet agents. Nevertheless, the relationship between the single‐nucleotide polymorphisms (SNP) of the signal pathway gene of insulin secretion and the effect of clopidogrel is elusive.MethodsBlood samples were collected from patients administered with dual‐antiplatelet therapy (clopidogrel, 75 mg, once daily and aspirin, 100 mg, once daily) after 5 days and completed test within 4 h. The VerifyNow P2Y12 assay was used to measure the platelet functions, and the results were expressed as a P2Y12 reaction unit (PRU). Notably, the selected SNPs were analyzed to demonstrate the functionality of genetic variants.ResultsAnalysis of the study population showed that old age, lower plasma albumin (ALB) level, higher creatinine (CREA) level, higher uric acid (UA) level, lower platelet (PLT) count, and lower plateletcrit (PCT) potentially increased the risk of clopidogrel resistance. In a single‐nucleotide polymorphism rs6056209 of the PCLB1 gene, the AG genotype was a risk factor for clopidogrel resistance (p < 0.05, OR = 1.574). Similarly, the CC and AG genotype in GNAS rs7121 and CCKAR rs1800857 were protective factors (p < 0.05, OR = 0.094; p <0.05, OR = 0.491). TT was a protective factor in rs10814274 of the CREB3 gene (p < 0.05, OR = 0.444). In the RAPGEF4 gene polymorphism rs17746510, TG was the protective genotype, and the TT genotype was a risk factor for clopidogrel resistance. GCG rs5645 was confirmed; there was a relationship between genotypes containing A or G and clopidogrel resistance.ConclusionSingle‐nucleotide polymorphisms of insulin secretion signaling pathway genes trigger clopidogrel resistance.

Antiplatelet Therapy and Periprocedural Risk Factor Analysis for Pipeline Embolization Device Treatment of Unruptured Internal Carotid Artery Aneurysms: A Retrospective, Multicenter Analysis

Aneurysm treatment using the Pipeline Embolization Device has been established but appropriate maintenance of dual antiplatelet therapy (APT) is essential. This multicenter retrospective study assessed whether APT was properly adjusted for clopidogrel resistance and identified risk factors associated with periprocedural complications. Consecutive cases of use of the Pipeline Embolization Device for internal carotid artery aneurysms (>10 mm) between November 2015 and April 2020 were analyzed. Dual APT (aspirin+ clopidogrel) was prescribed before treatment. If preprocedural P2Y12 reaction unit (PRU) values were >240, APT was adjusted. Periprocedural complications were compared between APT nonadjustment and adjustment groups and periprocedural risk factors were also analyzed. A total of 162 procedures were assessed. The mean maximum aneurysm size was 15.35 mm. APT adjustment was required in 47 cases (29.0%), primarily by switching to prasugrel. There were no significant differences in complication incidence between the 2 groups even after propensity score matching. The risk factor independently associated with ischemic complications was a neck size of 8 mm or larger (odds ratio [OR], 5.25; P= 0.018) and restricting analysis to the APT nonadjustment group showed PRU values of 190 or higher (OR, 5.84; P= 0.047) and neck sizes of 8 mm or larger (OR, 7.05; P= 0.029) as significant factors. The risk factor independently associated with hemorrhagic complications was a neck size of 7 mm or larger (OR, 11.57; P= 0.023). APT adjustment for clopidogrel resistance was safe and effective. Neck width was a risk factor for both ischemic and hemorrhagic complications. PRU values of 190 or higher were also associated with ischemic complications.

Severe, Intolerable Fatigue Associated with Hyperresponse to Clopidogrel

Clopidogrel is a commonly used antiplatelet agent for the prevention of thromboembolic complications following neuroendovascular procedures, but anecdotal data have raised concern for the possibility that clopidogrel may induce severe, intolerable fatigue. The purpose of this study is to systematically investigate this phenomenon. We performed a dual-institution, 9-year, retrospective study of patients undergoing clopidogrel therapy for neuroendovascular procedures. Patients were included only if their response to clopidogrel was assessed by platelet function testing using the VerifyNow P2Y12 (VNP) assay. Hyperresponse to clopidogrel was defined as P2Y12 reaction units ≤60. Patients were considered to have had clopidogrel-induced severe fatigue if the onset of symptoms followed the initiation of clopidogrel therapy; symptoms improved following a reduction in the dose of clopidogrel; and symptoms could not be attributed to any other medical explanation. Data were collected on 349 patients. Five patients (1.4%) met criteria for clopidogrel-induced severe fatigue. All 5 patients were female, ages 39-68. VNP assessments obtained while patients were symptomatic revealed hyperresponse to clopidogrel (0-22 P2Y12 reaction units). Symptoms improved in all 5 patients when the dose of clopidogrel was reduced by half. Notably, 30% of patients (n= 103) demonstrated a hyperresponse to clopidogrel on at least 1 VNP assessment, but 98 of these patients did not suffer from severe fatigue. A syndrome of severe fatigue and other constitutional symptoms is a rare but clinically significant side effect of hyperresponse to clopidogrel in patients undergoing neuroendovasular intervention.

Platelet miR-107 Participates in Clopidogrel Resistance after PCI Treatment by Regulating P2Y12

Introduction: High platelet reactivity (HPR) caused by clopidogrel tolerance is an adverse reaction of acute coronary syndrome (ACS) patients who receive clopidogrel antiplatelet therapy after percutaneous coronary intervention (PCI) surgery. Platelet microRNA (miRNA) is related to platelet reactivity. This study explored the mechanism of platelet miRNA in regulating platelet reactivity. Methods: We recruited 50 ACS/PCI patients and divided them into the HPR group (P2Y12 reaction units [PRU] ≥300) and the LPR group (PRU < 170) according to the PRU through the VerifyNow P2Y12 assay. P2Y12-related miRNAs were screened by TargetScan, miRWalk, and Gene Expression Omnibus. The expressions of P2Y12 and miRNAs in the HPR group and the LPR group were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Pearson correlation analysis was used to determine the correlation between P2Y12 and miRNAs. The interactions between P2Y12 and miR-107 were predicted by TargetScan and verified by dual-luciferase reporter assay. The regulation of miR-107 mimic or inhibitor on P2Y12 expression was detected by qRT-PCR and Western blot. Results: There were 22 patients in the LPR group and 28 patients in the HPR group. PY212 was highly expressed in the HPR group compared with the LPR group. We screened the P2Y12-related miRNAs (miR-145-5p, miR-4701-3p, miR-107, and miR-15b-5p), but only miR-107 and miR-15b-5p expressions were downregulated in the HPR group and were negatively correlated with PY212 expression. P2Y12 was the target gene of miR-107. PY212 expression was inhibited by miR-107 overexpression but suppressed by miR-107 silencing. Conclusion: Platelet miR-107 participated in clopidogrel resistance in ACS/PCI patients by regulating P2Y12 expression.

The inhibition rate estimated using VerifyNow can help to predict the thromboembolic risk of coil embolization for unruptured intracranial aneurysms

BackgroundThe role of the inhibition rate of VerifyNow in assessing the thromboembolic risk of coil embolization for unruptured intracranial aneurysms is unclear.ObjectiveTo carry out a retrospective study to determine whether...