High On-treatment Platelet Reactivity Group Research Articles

Impact of Platelet Hyperreactivity and Diabetes Mellitus on Ischemic Stroke Recurrence: A Single-Center Cohort Clinical Study.

Ischemic stroke recurrence (ISR) is prevented by inhibiting platelet function. To investigate the impact of high on-treatment platelet reactivity (HTPR) assessed by thromboelastography (TEG) and its risk factors on ISR in individuals who have experienced acute ischemic stroke (AIS) receiving dual anti-platelet therapy (DAPT). At the end of follow-up, a total of 264 patients who met the criteria were enrolled in this cohort study. The primary endpoint event was a recurrence of ischemic stroke within 90 days of onset. The ISR rate was 7.2% (19/264). The recurrence rate in the HTPR group was 15.1% (8/53), which was significantly higher than the 5.2% (11/211) in the non-HTPR group (p = 0.013), and the type 2 diabetes mellitus (T2DM) group (12.5%, 10/80) was also significantly higher compared to the non-T2DM group (4.9%, 9/184) (p = 0.028). T2DM was an isolated risk factor for HTPR (adjusted OR = 3.06, 95% CI 1.57-5.98, P = 0.001). Kaplan-Meier plots showed that the cumulative risk (CR) of ISR was statistically different in the HTPR and T2DM groups compared to the non-HTPR group (log-rank P = 0.009) and the non-T2DM group (log-rank P = 0.026), respectively. The HTPR and T2DM groups had greater hazard ratios (HR) of ISR than the non-HTPR (adjusted HR = 2.78, 95% CI 1.06-7.32, P = 0.038) and non-T2DM (adjusted HR = 2.64, 95% CI 1.01-6.92, P = 0.049) groups. Both HTPR and T2DM are linked to ISR. Platelet Inhibition Rate (PIR) of TEG can early identify patients who are at high risk for having another ischemic stroke in patients undergoing DAPT, and this study may offer more evidence in favor of clinically personalized treatment and secondary prevention tactics.

A study of microRNA-223 in evaluating platelet reactivity in patients with acute ischemic stroke.

To investigate the relationship between plasma microRNA-223 expression and platelet reactivity in patients with acute ischemic stroke (AIS) and to evaluate its predictive value in clopidogrel resistance or high on-treatment platelet reactivity (HTPR). A total of 120 patients with acute ischemic stroke were screened in this study, and 60 patients were included in the acute ischemic stroke group according to the inclusion criteria and platelet reactivity after clopidogrel treatment. control group was 60 non-ischemic stroke patients hospitalized. The levels of phosphorylation of vasodilator-stimulated phosphoprotein (VASP) and adenosine diphosphate-induced platelet aggregation (ADP-PAg) in platelets were detected by flow cytometry. The expression level of plasma microRNA-223 was detected before and after clopidogrel treatment using quantitative real-time polymerase chain reaction (PcR). The AIS group was then divided into the clopidogrel non-HTPR and the clopidogrel HTPR groups based on the relative inhibition rate. We found that: 1) the VASP platelet reactivity index (PRI) was positively correlated with ADP-PAg; 2) before administration, the plasma microRNA-223 expression level and VASP-PRI were higher in the AIS group than in the control group; 3) after administration, the expression level of microRNA-223 was negatively correlated with VASP-PRI; 4) before and after treatment, the plasma microRNA-223 expression level in the clopidogrel HTPR group was lower than in the non-AIS patients; 5) before treatment, there was an interaction between the expression level of microRNA-223 in the plasma and the cYP2c19 loss-of-function (LOF) allele. The study showed that decreased plasma microRNA-223 expression levels in AIS patients indicate an increased risk of clopidogrel HTPR. carrying cYP2c19 LOF alleles may result in the microRNA-223 expression being more distinct. The combined detection of plasma microRNA-223 and cYP2c19 gene polymorphisms may be effective in predicting the occurrence of clopidogrel HTPR in patients with AIS.

Clinical significance of high on-treatment platelet reactivity in patients with prolonged clopidogrel therapy.

Background/AimsProlonged dual antiplatelet therapy (DAPT) with aspirin and clopidogrel beyond 1 year has been shown to reduce ischemic events at the expense of increased bleeding. However, limited data are available on the clinical significance of platelet reactivity (PR) at 1 year.MethodsWe retrospectively identified 331 patients who underwent percutaneous coronary intervention (PCI) and assessed the on-clopidogrel PR using VerifyNow P2Y12 assay at 1 year in a single center. Two hundred eleven patients were on DAPT for > 1 year. The relationship between high on-treatment platelet reactivity (HPR) at 1 year and clinical outcomes beyond 1 year, as well as the longitudinal change in PR was analyzed.ResultsAt 1 year, 135 (64%) patients showed HPR and 76 (36%) did not. There was a significant increase in ischemic endpoint events, including cardiovascular death, non-fatal myocardial infarction, and stroke/transient ischemic attack in patients with compared to without HPR at 1 year (hazard ratio [HR], 2.68; 95% confidence interval [CI], 1.06 to 6.77; p = 0.036). However, the incidence of any Bleeding Academic Research Consortium bleeding was significantly lower in the HPR group (HR, 0.11; 95% CI, 0.02 to 0.65; p = 0.015). In the longitudinal analysis, PR significantly decreased from post-load to 1 year after index PCI in the non-HPR group. Conversely, the HPR group showed high PR from baseline through 1 year.ConclusionsHPR at 1 year may be a useful surrogate for predicting ischemic and bleeding events in patients on prolonged DAPT. Patients with and without HPR at 1 year showed different patterns of longitudinal change in PR.

Association between renal function and platelet reactivity during aspirin therapy in elderly patients with atherosclerotic cardiovascular disease

BackgroundAspirin is the key treatment in the secondary prevention of atherosclerotic cardiovascular disease. High on-treatment platelet reactivity (HTPR) to aspirin has been reported to partially account for the enhanced risk of thrombotic events. In particular, HTPR has been described more frequently among elderly patients. The aim of this study was to identify the clinical and biological factors associated with HTPR in a real-life elderly population.MethodsIn this retrospective study, elderly patients with atherosclerotic cardiovascular disease on regular aspirin treatment were enrolled. Cardiovascular risk factors, routine biological parameters, comorbidities, and concomitant medications were recorded. The upper quartile of the platelet aggregation rate, determined by light transmission aggregometry with arachidonic acid, was defined as the HTPR group.ResultsA total of 304 patients were included (mean age 77 ± 8 years, 76% men). Patients in the HTPR group were older than the patients in the non-HTPR group (mean age: 79 ± 7 vs. 76 ± 8 years, p = 0.008). Patients with moderately decreased estimated glomerular filtration rate (eGFR) had a higher frequency of HTPR than patients with slightly decreased eGFR or normal eGFR (35.8, 22.5, 12.2%, respectively, p < 0.05). In multivariate analysis, an independent risk factor for HTPR was the eGFR (OR: 0.984, 95% CI: 0.980–0.988, p < 0.001).ConclusionsAdvanced age and decreased eGFR are correlated with poor pharmacodynamic response to aspirin.

Should CYP2C19 Genotyping Be Recommended as a Straight Forward Approach to Optimize Clopidogrel Utilization in Patients with Ischemic Stroke Complicated by Type 2 Diabetes Mellitus?

BackgroundThere have been few studies on CYP2C19 genotypes and clopidogrel response associated with ischemic stroke (IS), especially IS complicated by type 2 diabetes mellitus (T2DM). This study aimed to investigate the possible association between CYP2C19 polymorphisms and high on-treatment platelet reactivity (HTPR) in IS patients with T2DM in China.Patients and MethodsA total of 426 consecutive IS patients with T2DM were enrolled in this case-control study and they were divided into HTPR group and non-HTPR group according to the ADP-induced platelet inhibition (PIADP) assessed by thromboelastography (TEG). Genotypes were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Various clinical and demographic data were also recorded. The association between CYP2C19 genetic variants and platelet function was assessed.ResultsCarriers of CYP2C19*2 heterozygous and mutant homozygous genotypes showed significantly lower PIADP than non-carriers (27.2% vs 38.3%, p < 0.001; 27.41% vs 38.3%, p = 0.012, respectively). Compared with the control group, the CYP2C19*2 A allele was more frequent in the HTPR group (34.51% vs 25.82%, p = 0.002). The carriage of CYP2C19*2 mutant allele was significantly associated with increased risk of HTPR (odds ratio (OR) = 1.94, 95% confidence interval (CI) = 1.32–2.85). There was no significant correlation between CYP2C19*3 or *17 genotypes and HTPR risk.ConclusionCYP2C19*2 mutant allele was associated with attenuated platelet response to clopidogrel and increased risk of HTPR in IS patients with T2DM, suggesting that CYP2C19*2 polymorphism might be an important predictor of HTPR in this high-risk population.

Genetic polymorphisms of high platelet reactivity in Chinese patients with coronary heart disease under clopidogrel therapy

The variability in the clinical response to clopidogrel treatment has been attributed to genetic factors, but the specific genes and other risk factors remain unclear. To investigate the incidence of high on-treatment platelet reactivity in coronary heart disease patients following clopidogrel therapy by analyzing the correlation between genetic polymorphisms and high on-treatment platelet reactivity. This study was conducted in the Chinese People's Liberation Army (PLA) general hospital. 578 patients with coronary heart disease undergoing percutaneous transluminal coronary intervention treatment were enrolled. They received dual antiplatelet therapy with aspirin (300mg) plus clopidogrel (300mg) over 24h, or aspirin (100mg/day) and clopidogrel (75mg/day) over 3 days. Patients were divided into two groups according to the adenosine diphosphate inhibition rate. The follow-up lasted at least 12months and adverse endpoint events were recorded. The single nucleotide polymorphisms were detected by MassArray genotyping system. The incidence of HTPR was 15.74% in total, being higher in females than in males (24.29% vs. 13.01%, P < 0.01). Diabetes mellitus, homocysteine and high sensitivity C-reactive protein (hs-CRP) levels were significantly higher in the HTPR group than those in the non-HTPR group (P < 0.05). Polymorphisms of rs1057910 (OR 2.90, P = 0.003), rs2246709 (OR 0.69, P = 0.039), and rs776746 (OR 0.66, P = 0.034) were associated with theincidenceofhigh on-treatment platelet reactivity. Female patients were prone to polymorphisms of rs1057910 (OR 3.24, P = 0.004) and rs776746 (OR 0.57, P = 0.025). Compared to non-high on-treatment platelet reactivity group, no differences in high reactivitygroup were observed with coexisting single nucleotide polymorphisms (14.6% vs. 14.8%, P > 0.05). The adverse endpoint events were significantly higher in the high on-treatment platelet reactivity group than in the non-treatment reactivitygroup. The survival analysis showed that high on-treatment platelet reactivitywas significantly associated with the risk of the endpoint events (P = 0.0219). Gender (female), diabetes mellitus, high levels of homocysteine and hs-CRP were risk factors for high on-treatment platelet reactivity, and high reactivity was a strong predictor for adverse endpoint events in the coronary heart disease patients. The polymorphism of rs1057910 was a risk factor of high on-treatment platelet reactivity while rs2246709 and rs776746 polymorphisms were protective factors, and coexisting single nucleotide polymorphisms didn't increase the incidence of high on-treatment platelet reactivity.

Clopidogrel-associated genetic variants on inhibition of platelet activity and clinical outcome for acute coronary syndrome patients.

Acute coronary syndrome (ACS) has become a vital disease with high mortality worldwide. A combined antiplatelet therapy (aspirin and a P2Y12 antagonist) is commonly used to prevent re-infarction in ACS patients who have undergone percutaneous coronary intervention (PCI). Clopidogrel, a P2Y12 antagonist, plays an important role in the inhibition of platelet aggregation (IPA). However, it is a pro-drug requiring biotransformation by cytochrome P450 (CYP450). The aim of this study is to unravel the effect of clopidogrel-associated genetic variants on inhibition of platelet activity and clinical outcomes in ACS patients. In our study, a total of 196 patients with metabolic gene polymorphism of clopidogrel were enrolled, and their antiplatelet effect as well as their cardiovascular events were collected. Approximately 2mL of venous blood samples were used for genotype detection and another 4mL were collected for platelet reactivity with thrombelastography. The primary clinical end-point was defined as a combination of cardiovascular mortality and revascularization for targeted vascular lesion. Based on the results of IPA, the prevalence of high on-treatment platelet reactivity (HPR) was 17.3% and the majority of patients (82.7%) obtained normal on-treatment platelet reactivity (NPR). The HPR group had significantly higher body mass index (BMI) and lower arachidonic acid (AA) induced IPA (P<0.05). Therapy including Glycoprotein (GP) IIb/IIIa antagonist increased IPA (P<0.05). ADP-induced IPA effect was lower with the presence of CYP2C19*2, *3 and paraoxonase (PON)1 Q192R loss-of-function (LOF) alleles, respectively (P<0.05). Multivariate logistic regression analysis demonstrated that aspirin resistance (AA-induced IPA<50%) had a greater risk of the occurrence of major adverse cardiovascular events (MACE) (OR=3.817; 95% CI: 1.672-8.700; P=0.002). CYP2C19*2 LOF alleles were associated with high risk of MACE in 1-year post PCI operations (OR=2.571; 95% CI: 1.143-5.780; P=0.030). For the ACS patients, the presence of CYP2C19*2 and PON1 Q192R LOF alleles were the major drivers of HPR.

Predictive value of serial platelet function testing on outcome in patients undergoing complex percutaneous coronary intervention

Objective: To observe the predictive value of serial platelet function testing (PFT) on outcome in patients undergoing complex percutaneous coronary intervention (PCI). Methods: Six hundred and two consecutive patients undergoing complex PCI in Anzhen hospital were enrolled during October 2011 to June 2012.Adenosine diphosphate(ADP)-induced platelet aggregation was measured by light transmission aggregometry on the first, sixth and twelfth month after PCI and the mean value was calculated.The cut-off value of high on-treatment platelet reactivity (HTPR) was defined as 40%.The primary endpoint was major adverse cardiovascular and cerebral event (MACCE). Clinical outcomes were analyzed by the Kaplan-Meier method and differences were compared using the log-rank test.Multivariate analyses by Cox proportion hazards regression were applied to identify variables independently associated with the adverse outcomes. Results: Five hundred and eighty-five patients (HTPR, n=285; non-HTPR, n=280) finished the follow-up ((28.47±7.45) months). A total of 33 cases of MACCE were observed during the follow-up, among which 29 cases(8.42%) were in HTPR group and 9 cases (3.21%) in the non-HTPR group.Kaplan-Meier analysis suggested that HTPR was associated with an increased incidence of MACCE (log-rank test, P=0.01). The Cox multivariate analysis indicated that HTPR was an independent risk factor of MACCE (HR=2.69, 95%CI 1.23-5.85, P=0.01) in patients undergoing complex PCI.Incidence of MACCE was similar between HTRP patients receiving standard dual antiplatelet therapy (DAPT) or prolonged DAPT (>12 months). Conclusion: Serial PFT could predict the long-term prognosis of patients underwent complex PCI.

Relationship Between Platelet Reactivity and Culprit Lesion Morphology: An Assessment From the ADAPT-DES Intravascular Ultrasound Substudy

ObjectivesThis study evaluated the relationship between platelet reactivity and plaque morphology using grayscale and radiofrequency intravascular ultrasound (IVUS) virtual histology (VH). BackgroundRecent studies have reported that high on-treatment platelet reactivity (HPR) is associated with higher plaque volume and the presence of multivessel disease; however, the association between HPR and plaque morphology has not been evaluated. MethodsThe ADAPT-DES (Dual AntiPlatelet Therapy With Drug Eluting Stents) intravascular ultrasound substudy was a prospective, multicenter, observational study of 8,582 patients undergoing percutaneous coronary intervention with drug-eluting stents in whom platelet reactivity on clopidogrel was assessed routinely. The current analysis included 909 culprit lesions from 773 patients with pre-intervention grayscale IVUS and IVUS-VH. HPR was defined as platelet reactivity >208 P2Y12 reaction unit in point-of-care P2Y12 testing by the VerifyNow assay, measured during steady-state platelet inhibition in patients receiving an antiplatelet agent. ResultsHPR was associated with 3-vessel coronary artery disease (31.0% vs. 24.4%; p = 0.04). The incidence of fibroatheroma was higher in patients with HPR than those without HPR (77.1% vs. 68.9%; p = 0.01). The HPR group had larger percent plaque and media volume (plaque and media/external elastic membrane volume: 58.1% [95% confidence interval (CI): 57.1% to 59.0%] vs. 56.6% [95% CI: 55.8% to 57.5%]; p = 0.03) and plaque burden at the minimum lumen site (76.7% [95% CI: 75.7% to 77.8%] vs. 75.0% [95% CI: 74.0% to 76.0%]; p = 0.02). Despite a similar prevalence of attenuated plaque, patients with HPR had longer culprit lesion attenuated plaque length (8.0 [95% CI: 7.0 to 9.1] mm vs. 6.5 [95% CI: 5.9 to 7.1] mm; p = 0.01). On multivariate analysis, the presence of angiographic calcium (odds ratio [OR]: 1.85: 95% CI: 1.33 to 2.56; p = 0.0002) and HPR (OR: 1.45; 95% CI: 1.05 to 2.01; p = 0.02) were independent predictors for a culprit lesion fibroatheroma. ConclusionsHPR was associated with increased culprit lesion atherosclerotic burden and adverse plaque morphology among patients undergoing percutaneous coronary intervention. Platelet reactivity might be associated with not only blood clot formation, but also severity of atherosclerosis. (Assessment of Dual AntiPlatelet Therapy With Drug Eluting Stents [ADAPT-DES]; NCT00638794)

The first six-month clinical outcomes and risk factors associated with high on-treatment platelet reactivity of clopidogrel in patients undergoing coronary interventions

Objective:This study attempted to fill the gaps in evidence related to response to clopidogrel treatment in the Turkish population. The study aimed to determine the prevalence, associated risk factors, and clinical outcomes of high on-treatment platelet reactivity (HTPR) of clopidogrel in patients undergoing percutaneous coronary intervention (PCI) in a tertiary cardiovascular hospital in Turkey.Methods:In this prospective studied a total of 1.238 patients undergoing PCI were included in the present study. Blood samples were analyzed using a Multiplate analyzer. All patients were examined in the outpatient clinics at the end of the first and sixth months for recording drug therapy compliance and study endpoints.Results:Among the study population, 324 (30.2%) patients were found to have HTPR (mean age 58.03±11.88 years, 71.7% men). The incidence of HTPR was higher amongst females than amongst males (38.3% vs. 27%, p=0.010). Hypertension and diabetes mellitus were more frequently observed in the HTPR group (57.7% vs. 48.7%, p=0.004; 35% vs. 29.1%, p=0.040, respectively). When the recorded data were analyzed using multinomial regression analysis, hypertension, hemoglobin level, platelet, lymphocyte, and eosinophil count were independently associated with HTPR.Conclusion:On the basis of the results obtained from our study, we conclude that 30.2% of the Turkish population has HTPR. Our results also led us to believe that hypertension is an associated risk factor and decreased hemoglobin level as well as increased platelet counts are laboratory parameters that are strongly associated with the presence of HTPR. However, no differences were observed with regard to cardiovascular mortality and stent thrombosis. (Anatol J Cardiol 2016; 16: 967-73)

Genotype Frequencies of CYP2C19, P2Y12 and GPIIIa Polymorphisms in Coronary Heart Disease Patients of Han Ethnicity, and Their Impact on Clopidogrel Responsiveness.

To investigate the genotype frequencies of cytochrome P450, family2, subfamily C, polypeptide19 (CYP2C19); P2Y12 receptor; and glycoprotein IIIa polymorphisms in patients with coronary heart disease and their impact on clopidogrel responsiveness and major adverse cardiac events (MACEs).A total of 146 coronary heart disease patients of Han ethnicity, on a clopidogrel regimen, were enrolled. Polymerase chain reaction and DNA sequencing were used to detect the genotype and allelic frequencies of CYP2C19 ((*)2,(*)3,(*)17), P2Y12 (C34T, G52T, T744C) and GPIIIa (T1565C) polymorphisms. Clinical and laboratory data were compared between the high on-treatment platelet reactivity (HTPR) versus normal groups.HTPR was identified in 35 (24%) patients. CYP2C19(*)2 (G681A) polymorphism was found to be significantly associated with HTPR (P < 0.05). A allele frequencies were significantly higher in the HTPR group versus the normal group (P < 0.05). On logistic regression analysis, CYP2C19(*)2 (G681A) polymorphism was found to be an independent risk factor associated with HTPR. No link could be established between genetic polymorphisms and recurrence of MACEs, or between HTPR and recurrence of MACEs.The genetic polymorphisms in CYP2C19(*)2 were closely associated with HTPR. The frequency of the A allele of CYP2C19(*)2 was significantly associated with HTPR, with A allele carriers being more likely to develop HTPR.

CYP2C19*2 and Other Allelic Variants Affecting Platelet Response to Clopidogrel Tested by Thrombelastography in Patients with Acute Coronary Syndrome.

Background:To investigate the contributions of CYP2C19 polymorphisms to the various clopidogrel responses tested by thrombelastography (TEG) in Chinese patients with the acute coronary syndrome (ACS).Methods:Patients were screened prospectively with ACS diagnose and were treated with clopidogrel and aspirin dual antiplatelet therapy. CYP2C19 loss of function (LOF) and gain of function (GOF) genotype, adenosine 5′-diphosphate (ADP)-channel platelet inhibition rate (PIR) tested by TEG and the occurrence of 3-month major adverse cardiovascular events and ischemic events were assessed in 116 patients.Results:High on-treatment platelet reactivity (HTPR) prevalence defined by PIR <30% by TEG in ADP-channel was 32.76% (38/116). With respect to the normal wild type, CYP2C19*2, and *3 LOF alleles, and *17 GOF alleles, patients were classified into three metabolism phenotypes: 41.38% were extensive metabolizers (EMs), 56.90% were intermediate metabolizers (IMs), and 1.72% were poor metabolizers (PMs). Of the enrolled patients, 31.47%, 5.17%, and 0.43%, respectively, were carriers of *2, *3, and *17 alleles. The HTPR incidence differed significantly according to CYP2C19 genotypes, accounting for 18.75%, 41.54%, and 100.00% in EMs, IMs, and PMs, respectively. Eighteen (17.24%) ischemic events occurred during the 3-month follow-up, and there was a significant difference in ischemic events between HTPR group and nonhigh on-treatment platelet reactivity group.Conclusions:Genetic CYP2C19 polymorphisms are relative to the inferior, the antiplatelet activity after clopidogrel admission and may increase the incidence of ischemic events in patients with ACS.

Association between platelet reactivity and circulating platelet-derived microvesicles in patients with acute coronary syndrome

High on-treatment platelet reactivity (HPR) to clopidogrel has been shown to increase the risk of cardiovascular events. Platelet-derived microvesicles (PMVs) may be prothrombotic and contribute to the risk of recurrent events observed in patients with HPR. However, PMVs may also serve as biomarkers and be used to assess platelet function. We investigated the association between platelet responses to clopidogrel (measured by whole blood impedance aggregometry) and circulating PMVs in patients with acute coronary syndrome (ACS). Blood samples were obtained at discharge from 200 patients with ACS who had undergone percutaneous coronary intervention (PCI). All patients were loaded with aspirin and clopidogrel before PCI. ADP-induced whole blood impedance aggregometry and measurement of PMVs were performed. Cut-off values for HPR and other reactivity (i.e. normal on-treatment reactivity, NPR and low on-treatment reactivity, LPR) to clopidogrel were set according to data from large prospective studies. We measured PMVs as phosphatidylserine and CD42a positive vesicles, together with CD62P or CD40L, using flow cytometry. ADP-induced platelet aggregation revealed that approximately 20% of patients had HPR. Levels of PMVs were almost two-fold higher in the HPR group compared with patients without HPR (for both CD42a- and CD62P-positive PMVs, p < 0.01). Furthermore, patients with LPR to clopidogrel had significantly fewer PMVs exposing CD62P than patients with HPR or those with NPR to clopidogrel. Patients with HPR during clopidogrel treatment have elevated levels of circulating PMVs, indicating ongoing platelet activation despite clopidogrel treatment. Moreover, in patients with LPR to clopidogrel, circulating PMV numbers are decreased. Taken together, our data suggest that PMVs are potential biomarkers of antiplatelet responses to clopidogrel. If PMVs also have prognostic value after, ACS should be tested in future studies.

ASSA13-15-1 Clinical Characteristics Related with High On-Treatment Platelet Reactivity Receiving Clopidogrel Measured by Thrombelastography in Patients Undergoing Percutaneous Coronary Intervention

Background an Objective Antiplatelet therapy with clopidogrel and aspirin is the current standard of care for patients undergoing PCI. However, recurrent ischemic event occurrence during dual antiplatelet therapy, including stent thrombosis, remains a major concern. We sought to determine whether clinical characteristics will be associated with high on-treatment platelet reactivity receiving clopidogrel measured by thrombelastography. Methods A total of 362 consecutive patients undergoing non-emergent PCI were enrolled in this prospective observational study. A 300mg clopidogrel loading dose was administered on the day before procedure ( > 12h). Blood samples were analysed using a computerised TEG analyser for platelet aggregation. The cut points for high on-treatment platelet reactivity (HPR) were defined as ≥60% ADP-induced aggregation with 2-μmol ADP. All patients below the cut point were defined as exhibiting normal on-treatment platelet reactivity (NPR). Results The prevalence of HPR was 33% measured by TEG. There were more female (41.7% vs 22.3%, P = 0.007), more diabetes mellitus (41.7% vs 24.2%, P = 0.0024) and more smoking patients (12.3% vs 2.6%, P = 0.012) in HPR group than in NPR group, respectively. Meanwhile, elevated plasma triglyceride was common in HPR group than in NPR group (2.5 ± 0.9mmol/L vs 1.9 ± 0.3mmol/L, P = 0.019). Patients with HPR exhibited a higher level of cardiac enzyme including CK-MB (3.1 ± 1.3ng/mL vs 1.8 ± 1.6ng/mL, P = 0.013) and troponin I (0.9 ± 0.3ng/mL vs 0.2 ± 0.4ng/mL, P = 0.01). Conclusions Despite adequate pretreatment with clopidogrel, 33% patients undergoing non-emergent PCI exhibited high on-treatment ADP-induced platelet aggregation measured by thrombelastography. We found that current smoking, high level of HbA1C and TnI, and female gender independently predicted the risk of HPR.

Clinical characteristics associated with high on-treatment platelet reactivity of patients undergoing PCI after a 300 mg loading dose of clopidogrel, measured by thrombelastography

BackgroundDual antiplatelet therapy with clopidogrel and aspirin is the standard of care for patients undergoing percutaneous coronary intervention (PCI).ObjectiveTo determine the clinical characteristics associated with high on-treatment platelet reactivity (HPR)...

Abstract 18022: High On-Treatment Platelet Reactivity Measured by Various Platelet Function Tests: Is the Current VASP-PRI Cutoff Too Low?

Background: High on-treatment platelet reactivity (HPR) to ADP measured by multiple methods has been linked to adverse post-PCI clinical event occurrence. The correlation of HPR cutoffs is still a matter of debate, since the predictive value and HPR group size are different depending on platelet function assays. To determine the comparable cutpoint, we correlated cutpoints for HPR determined by various assays in the same patient cohort. Methods: Platelet measures [5µM ADP-induced light transmission aggregation (LTA5μ MADP); P2Y12 reaction units by VerifyNow (PRU), and platelet reactivity index by VASP assay (PRI)] were evaluated (n=936 pairs, cohort I) in stable CAD patients during P2Y12 receptor inhibitor treatment. These assays also performed in PCI-treated patients receiving standard aspirin and clopidogrel therapy (n=584, cohort II). The HPR cutpoints were defined as LTA 5μ MADP &gt;46%, PRU &gt;235, and PRI &gt;50%. Results: In the stable CAD patients, LTA 5μ MADP showed significant correlations with PRU and PRI (r ≥0.688). In ROC curve analysis using the cutpoint of LTA 5μ MADP (&gt;46%), the matched values of PRU and PRI were &gt;234 (AUC 0.943, p&lt;0.001, sensitivity 87.3% and specificity 87.8%) and &gt;60% (Figure A). Among PCI-treated patients, the prevalence of HPR was highest based on PRI &gt;50% (69%) compared with other criteria (≤55%). The comparable values for LTA 5μ MADP &gt;46% were PRU &gt;235 (AUC 0.850, p&lt;0.001, sensitivity 85.3% and specificity 70.4%) and PRI &gt;59% (Figure B). Conclusion: The published cutoff values for HPR by LTA 5μ MADP and PRU were well correlated, whereas published PRI &gt;50% cutoff value may overestimate the risk of HPR. Updated cutoff of PRI &gt; 60% may better stratify the risk for HPR and can be used in future trials.

Level of Adenosine Diphosphate Receptor P2Y12 Blockade During Percutaneous Coronary Intervention Predicts the Extent of Endothelial Injury, Assessed by Circulating Endothelial Cell Measurement

We aimed to investigate whether clopidogrel-induced inhibition of platelet reactivity could reduce the level of circulating endothelial cells (CEC), reflecting the endothelial injury induced by percutaneous coronary intervention (PCI). Clopidogrel loading dose before percutaneous coronary angioplasty (PCI) reduces platelet activation through a selective and irreversible blockade of the adenosine diphosphate (ADP) receptor P2Y(12). The impact of clopidogrel on endothelial cells has been scarcely studied. A total of 149 patients undergoing PCI for stable angina were enrolled. Levels of CEC were measured at baseline (H0) and 6 (H6) and 24 (H24) h after the procedure using a CD146-based immunomagnetic separation assay. The CEC delta-change (CEC at H6 - CEC at H0) was analyzed according to ADP receptor P2Y(12) blockade, assessed by a vasodilator-stimulated phosphoprotein (VASP) assay after a 600-mg loading dose of clopidogrel. The PCI induced a significant rise in CEC levels 6 h after the procedure. The CEC peak value was significantly higher in patients with high on-treatment platelet reactivity (VASP index ≥50%: 59.6 ± 27.5 cells/ml) as compared with good responders (VASP index <50%: 27 ± 22 cells/ml; p = 0.04). The endothelial injury, assessed by CEC delta-change between H6 and H0, was significantly higher in the high on-treatment platelet reactivity group compared with the good responders group (52.6 ± 25.6 vs. 18.6 ± 23.5, respectively; p < 0.001) and correlated with the VASP index (r = 0.59; p < 0.001). In multivariate analysis, VASP group, the number of diseased vessels, and the number of implanted stents independently predicted the endothelial injury (p < 0.001). Optimal ADP receptor P2Y(12) blockade reduces the endothelial injury during PCI. This protective effect of clopidogrel on endothelial cells could add to the clinical benefit associated with this drug.