Residual Platelet Research Articles

Residual platelet reactivity is preferred over platelet inhibition rate in monitoring antiplatelet efficacy: insights using thrombelastography.

Although thrombelastography (TEG) has been widely implemented in the clinical setting of endovascular intervention, consensus on the optimal parameter for defining high ischemic risk patients is lacking due to the limited data about the relationship between various TEG parameters and clinical outcomes. In this article, we report a post hoc analysis of a prospective, single-center cohort study, including 447 patients with acute coronary syndrome (ACS). Arachidonic acid (AA)- or adenosine diphosphate (ADP)-induced platelet-fibrin clot strength (MAAA or MAADP) was indicative of the net residual platelet reactivity after the treatment with aspirin or clopidogrel, respectively. AA% or ADP% was indices of the relative platelet inhibition rate on AA or ADP pathway. We found that each parameter alone was predictive of the risk of 6-month ischemic event, even after adjusting for confounding factors. However, the association between AA% and clinical outcome disappeared when further adjusted for MAAA. Likewise, inclusion of MAADP changed the significant relation between ADP% and clinical outcome. MAADP > 47.0 mm and MAAA > 15.1 mm were identified as the optimal cutoffs by receiver operating characteristic analysis. High MAAA (HR = 3.963; 95% CI: 1.152–13.632; P = 0.029) and high MAADP (HR = 5.185; 95% CI: 2.228–12.062; P < 0.001) were independent predictors when both were included in multivariable Cox regression hazards model. Interestingly, an even higher risk was found for the coexisting high MAAA and high MAADP (HR = 7.870; 95% CI: 3.462–17.899; P < 0.001). We conclude that when performing TEG to predict clinical efficacy, residual platelet reactivity has superiority over platelet inhibition rate as a measure of thrombotic risk in patients treated with aspirin and clopidogrel after ACS.

Clinical and prognostic value of the residual activity of platelets in patients with acute coronary syndrome without st segment elevation

To study clinical prognostic value of residual platelet activity in patients with acute coronary syndrome without ST segment elevation. The study included 120 patients with acute coronary syndrome without ST segment elevation (NSTE ACS) with coronary artery stenting. Testing of residual reactivity of platelets in the subjects was carried out after loading doses of aspirin and P2Y12-inhibitors.Patients were divided into two groups comparable in gender and age: with low residual reactivity of platelets (LRR), n=90 and with high residual reactivity of platelets (HRR), n=30. Between the groups a comparative assessment of clinical-laboratory and instrumental indicators, development of a combined end point (ischemic events) and bleeding during follow-up (16 ± 6 months). The group with HRR was initially heavier: patients with angina pectoris of functional class III, atrial fibrillation, myocardial infarction, was a higher risk on the GRACE (202,6±11 vs. 148,6±7, р=0,03),increased levels of Troponin T (70,0 vs. 45,5%, р=0,02), acute occlusion in the coronary arteries (66,6 vs. 42,4%, р=0,02).The combined endpoint was more often reported in patients with HRR (40 vs. 20,7%, р=0,04). Patients with ADP-aggregation of platelets in the range 0-1 Om had a greater risk of developing hemorrhagic events (17,1 vs. 2,1%, RR 8,05 CI: 1,1-59,9, р=0,01). In patients with NSTE ACSHRR after loading doses of aspirin and P2Y12-inhibitor was associated with the development of repeated atherothrombotic events. Very low LRR was associated with the development of bleeding.

Relationship Between Stent Diameter, Platelet Reactivity, and Thrombotic Events After Percutaneous Coronary Artery Revascularization

Small vessel diameter and residual platelet reactivity are independent predictors of thrombotic events after percutaneous coronary intervention (PCI). We sought to determine whether an interaction exists between residual platelet reactivity and stent diameter regarding the occurrence of stent thrombosis and other adverse events after PCI. We stratified patients in the prospective ADAPT-DES registry who underwent single-lesion PCI according to if they received a small diameter stent (SDS, defined as a stent with a diameter of 2.25 mm). Patients receiving an SDS were compared with patients receiving a stent ≥2.5 mm using Kaplan-Meier rates and multivariable Cox proportional hazards regression. We defined major adverse cardiac events (MACE) as the composite of cardiac death, myocardial infarction, and stent thrombosis (ST). Among 5,608 patients who underwent single-lesion PCI in ADAPT-DES, 222 (4.0%) patients received an SDS. Patients with an SDS were more likely than patients without an SDS to have 3-vessel disease but received, on average, fewer stents and were less likely to present with a thrombotic lesion. Receiving versus not receiving an SDS was associated with increased risk of ST (adjusted hazard ratio 4.35, 95% confidence interval 1.95 to 9.73, p <0.001) as well as MACE (adjusted hazard ratio 1.75, 95% confidence interval 1.11 to 2.75, p = 0.02). There was no statistical interaction between platelet reactivity and SDS regarding ST (p = 0.12) or MACE (p = 0.51). In conclusion, PCI with small drug-eluting stents is associated with a high risk of thrombotic events, including ST. Further studies should explore whether alternative treatment strategies are appropriate in small vessels.

Residual platelet reactivity after pre-treatment with ticagrelor prior to primary percutaneous coronary intervention is associated with suboptimal myocardial reperfusion.

The evidence of a clinical benefit of P2Y12 inhibitor pre-treatment in primary percutaneous coronary intervention (PCI) and the relation between the level of platelet inhibition and myocardial reperfusion with newer potent P2Y12 inhibitors remain unclear. We aimed to assess the relationship between platelet reactivity at the time of primary PCI after pre-treatment with aspirin and ticagrelor and the post-PCI myocardial blush grade (MBG). We prospectively included 61 patients. Platelet reaction units for ticagrelor (PRU) and aspirin reaction units (ARU) were measured using the point-of-care test VerifyNow before PCI. The high on-ticagrelor (PRU >208) and on-aspirin (ARU ⩾ 550) platelet reactivity (HPR and HaPR) were assessed. Patients were divided into two groups according to MBG 3 or <3. MBG 3 was identified in 28 (46%) patients. Mean PRU was lower in such patients as compared with those with MBG <3 (155.82 ± 90.91 vs. 227.42 ± 65.18; p=0.001) while mean ARU was similar between groups. HPR and HaPR were observed in 30 (49.2%) and 11 patients (18%), respectively. HPR but not HaPR was more frequent in the group with impaired MBG (66.7 vs. 28.6%; p=0.003 and 21.2 vs. 14.3%; p=0.48 respectively). Our study shows that higher PRU and the subsequent HPR at the time of primary PCI, after pretreatment with ticagrelor, are the only correlates of post PCI MBG. These findings support the earliest possible loading with ticagrelor prior to primary PCI.

Association Between Hypertension, Platelet Reactivity, and the Risk of Adverse Events After Percutaneous Coronary Intervention (From the ADAPT-DES Study)

Hypertension is associated with vascular and endothelial dysfunction that may result in a greater propensity for reactive platelets to cause thrombosis. We sought to assess whether the risk of major adverse cardiac events (MACE) after percutaneous coronary intervention (PCI) in patients with on-clopidogrel residual high platelet reactivity (HPR) varies in patients with versus without hypertension. Assessment of dual antiplatelet therapy with drug eluting stents (ADAPT-DES) was a prospective, multicenter registry of patients successfully treated with coronary drug-eluting stents (DES). HPR was defined as P2Y12 reaction units (PRU) >208, as assessed by the VerifyNow point-of-care assay. Multivariable Cox proportional hazards regression was used to assess whether the adjusted association between HPR and 2-year risk of MACE (cardiac death, myocardial infarction [MI], or stent thrombosis) was different in patients with versus without hypertension. A total of 6833 of 8582 patients (79.6%) had a history of hypertension. Patients with compared with those without hypertension were older, more likely to have other cardiovascular risk factors, and had higher PRU (190.1 ± 97.3 vs 179.5 ± 94.3; p <0.0001). Patients with hypertension had significantly higher 2-year rates of MACE (7.0% vs 4.4%, p <0.001), all-cause death (4.2% vs 2.5%, p = 0.001), and MI (5.2% vs 3.2%, p <0.001), and had nominally higher rates of stent thrombosis (1.0% vs 0.5%, p = 0.059). A significant interaction was present between hypertension and HPR regarding 2-year MACE risk (adjusted hazard ratio for HPR vs no HPR 1.38, 95% confidence interval 1.14 to 1.68 for patients with hypertension vs 0.81, 95% confidence interval 0.50 to 1.33 for patients without hypertension, p = 0.046). In conclusion, following successful PCI with DES, 2-year MACE rates are increased in patients with both hypertension and residual HPR on clopidogrel. HPR had a greater effect on the risk of adverse events among patients with versus without hypertension.

Association Between Residual Platelet Reactivity on Clopidogrel Treatment and Severity of Coronary Atherosclerosis: Intrinsic Hypercoagulability as a Mediator.

High on-treatment residual platelet reactivity (HRPR) was associated with greater atherosclerosis burden. We examined whether intrinsic hypercoagulability (IHC) could be attributed to that association in patients treated by drug-eluting stents. This retrospective observation enrolled a total of 891 coronary artery disease (CAD) subjects. Platelet and coagulant reactivity was measured by thrombelastography. At least 24h after a 300-mg dose of clopidogrel, adenosine diphosphate (ADP)-induced maximum amplitude of clot strength (MAadp) > 47mm represented HRPR. Thrombin-induced platelet-fibrin clot strength (MAthrombin) and blood fibrinogen surrogated intrinsic coagulability. Using mediation analysis to evaluate the effect of IHC on the relationship between the number of narrowed coronaries and HRPR on clopidogrel. More HRPR on clopidogrel and higher intrinsic coagulability were observed in more severe coronary atherosclerosis, especially in the three-vessel disease. After adjustment for confounding factors, the number of narrowed coronaries (ORadj = 1.343, 95% CI 1.063-1.695, p = 0.013), MAthrombin (ORadj = 1.106, 95% CI 1.058-1.157, p < 0.001), and fibrinogen (ORadj = 1.003, 95% CI 1.001-1.005, p = 0.012) were all independent positive predictors for HRPR. MAthrombin and fibrinogen were meaningful mediators for the significant positive association of the number of narrowed vessels and HRPR on clopidogrel, which were enhanced by around 30% and 43%, respectively, for this effect. This is the first study to demonstrate that the positive correlation between the number of stenotic coronaries and HRPR on clopidogrel may be partly attributed to IHC, which may enhance the risk stratification, guide more precise coagulation in multi-vessel disease after drug-eluting stents, and therefore deserve further study.

Protease‐activated receptor‐mediated platelet aggregation in acute coronary syndrome patients on potent P2Y12 inhibitors

BackgroundDespite the increasing use of potent P2Y12 inhibitors, further atherothrombotic events still impair the prognosis of many acute coronary syndrome (ACS) patients. This may in part be attributable to intact platelet aggregation via the human thrombin receptors protease‐activated receptor (PAR)‐1 and PAR‐4. ObjectiveWe studied PAR mediated platelet aggregation in ACS patients following percutaneous coronary intervention (PCI) with stent implantation in a cross‐sectional study. MethodsPlatelet aggregation to ADP as well as to the PAR‐1 agonist SFLLRN and the PAR‐4 agonist AYPGKF was assessed by multiple electrode aggregometry in 194 ACS patients on dual antiplatelet therapy with aspirin and either prasugrel (n = 114) or ticagrelor (n = 80) 3 days after PCI. ResultsBased on the consensus cutoff value, high on‐treatment residual platelet reactivity to ADP (HRPR ADP) was observed in only 2 prasugrel‐treated patients. Both patients with HRPR ADP had also a normal response to SFLLRN and AYPGKF. Among the 112 prasugrel‐treated patients with adequate P2Y12 inhibition, 50 patients (45%) still had a normal response to SFLLRN, and 70 patients (63%) still had a normal response to AYPGKF. Among the 80 ticagrelor‐treated patients with adequate P2Y12 inhibition, 25 patients (31%) still had a normal response to SFLLRN, and 50 (63%) still had a normal response to AYPGKF. ConclusionNormal platelet aggregation via PAR‐1 and PAR‐4 is preserved in many patients with adequate P2Y12 inhibition by prasugrel and ticagrelor. The present findings may at least in part explain adverse ischemic events despite potent P2Y12 inhibition.

Effect of vitamin D on antiplatelet drug responsiveness in elderly patients with ischemic stroke

Objective To investigate the effect of vitamin D on platelet reactivity after combined treatment with aspirin and clopidogrel in elderly patients with ischemic stroke. Methods A total of 190 elderly patients with ischemic stroke treated with aspirin and clopidogrel in Beijing Bo′ai Hospital from June 2017 to August 2018 were enrolled in this study.Venous blood was collected for platelet aggregation rate, 25-hydroxyvitamin D[25(OH)D] and clinical biochemical indexes during 1~2 weeks.According to 25 (OH) D quartile, the patients were further divided into Q1(≤7.18 μg/L) group (n=50), Q2: (>7.18-≤9.39 μg/L) group (n=50), Q3: (>9.39-≤13.74 μg/L) group (50), Q4: (>13.74 μg/L) (n=40). In order to evaluate the effect of calcitriol on platelet aggregation, platelet rich plasma (PRP) in healthy group (15 cases) and clopidogrel resistance group (15 cases) were treated with calcitriol (10 nmol/L) and saline (37 ℃ pretreatment for 5 minutes), respectively, and to compare the difference of maximum platelet aggregation rate induced by ADP between the two treatments. Results There were significant differences in ADP-induced maximum platelet aggregation rate (MPAR) ((49.36±23.34)%, (48.80±20.90)%, (37.02±18.24)%, (36.02±14.46)%, F=3.426, P=0.018) and clopidogrel resistance (CR)/ clopidogrel sensitive (CS) ratio (30/20, 24/26, 15/35, 10/30, χ2=15.119, P=0.002) among the vitamin D quartiles (increasing). Moreover, the MPAR and CR showed a decreasing trend with the increase of vitamin D concentration.Logistic regression analysis showed that serum 25(OH)D level was an independent inhibited factor for clopidogrel resistance in elderly patients with ischemic stroke (Q4 vs Q1, OR=0.699, 95%CI 0.582~0.838, P<0.001; Q3 vs Q1, OR=0.848, 95%CI 0.755-0.953, P=0.006). In vitro, compared with physiological saline, the aggregation rates of platelet in healthy group and CR group decreased after calcitriol pretreatment, and the difference was statistically significant(healthy group: (69.8±12.7)% vs (58.6±11.5)%, t=12.13, P<0.001; CR group: (65.5±8.3)% vs (56.3±7.6)%, t=11.48, P<0.001). Conclusion Vitamin D reduces the high residual platelet reactivity after antiplatelet therapy.Further study is needed to determine whether vitamin D supplementation may improve the efficacy of clopidogrel. Key words: Ischemic stroke; Antiplatelet therapy; Vitamin D; Drug resistance

Effect of morphine use on oral P2Y12 platelet inhibitors in acute myocardial infarction: Meta-analysis

BackgroundMorphine is the recommended analgesic in acute myocardial infarction (AMI). This recommendation has come under scrutiny because of possible slow uptake of oral antiplatelet agents. ObjectiveWe performed a meta-analysis of all available studies in AMI patients treated with prasugrel or ticagrelor (P2Y12 inhibitors) that reported use of morphine prior to loading the antiplatelet agents to critically assess the safety of co-administration of morphine and the newer P2Y12 inhibitors. MethodsSeveral sources were searched from inception to December 2017 with inclusion of eight studies, largely observational. Mean difference (MD) was calculated for continuous variables, and standardized mean difference (SMD) for platelet function was assessed by the various platelet assays, 2 h after the loading dose of oral P2Y12 inhibitors. ResultsHigher platelet activity was noted among morphine group [SMD = 0.8, 95% confidence interval (CI) = 0.4–1.1, p < 0.01]. Morphine use caused higher odds of “high residual platelet reactivity” at 2 h (odds = 3.3, 95 %CI = 2.2–5.1, p < 0.01). Ticagrelor reached a lower plasma concentration in morphine group (MD = −481.8 ng/ml, 95% CI = −841.2 to −122.4 ng/ml, p < 0.01) with a higher vomiting rate (odds = 5.3, 95% CI = 2.5–11.1, p < 0.01). However, the composite of in-hospital mortality, stroke, and re-infarction was not significantly different between the groups (p = 0.83). ConclusionCo-administration of morphine with P2Y12 inhibitors possibly decreases their efficacy in platelet inhibition. However, this did not translate into higher adverse outcomes because of low event rates, inadequate for analysis. A large randomized study is needed to evaluate the narcotic-P2Y12 interaction.

The effect of smoking on residual platelet reactivity to clopidogrel: a systematic review and meta-analysis

Cigarette smoking is an important cardiovascular risk factor, causing morbidity and mortality. There are many original studies on the impact of smoking, but its influence on platelet ADP-P2Y12 receptor inhibitors lack consistency. Thus, we conducted a systematic review and meta-analysis of already existing data/studies to further explore this issue. PubMed, Web of science, EMBASE, Clinical Trials, and the Cochrane Library were searched from inception to March 2018. Studies investigating the residual platelet reactivity categorized by smoking status and patients treated with platelet ADP-P2Y12 receptor inhibitors qualified the inclusion criteria. The primary outcome was P2Y12 reaction unit (PRU) value measured by VerifyNow P2Y12 assay, compared with different smoking status in ADP-P2Y12 receptor inhibitors treatment groups. Secondary outcome was post-treatment with 5 μmol/L ADP-inhibition of platelet aggregation (ADP-IPA) measured by light transmittance aggregometry (LTA). Of the 4954 citations retrieved, 12 studies involving 16 296 patients with acute coronary syndrome and/or stent deployment using platelet ADP-P2Y12 receptor inhibitors were included for meta-analysis. Pooled analysis revealed that PRU values of current smokers were 25.70 lower than nonsmokers (95% CI −38.81 to −12.60, p = 0.0001), getting better effects of antiplatelet treatment. In the smoking extent subgroup analysis, patients smoking >10 cigarettes/day shown about 46.49 lower of PRU values than patients smoking <10 cigarettes/day (p < 0.00001). Racial subgroup analyses found that smokers had increased platelet inhibition in the Caucasian population. Further, pooled analysis of ADP-IPA values for 1658 patients from five studies showed a significantly lower residual platelet reactivity in current smokers compared to that in nonsmokers (MD = −4.19; 95% CI −6.55 to −1.83; p = 0.0005). This systematic review and meta-analysis suggested that smokers have increased platelet inhibition and lower aggregation in response to clopidogrel than nonsmokers. These residual platelet reactivity observations may help to explain differential clinical outcomes in smokers vs. nonsmokers in large scale clinical trials.

PCSK9 in Haemostasis and Thrombosis: Possible Pleiotropic Effects of PCSK9 Inhibitors in Cardiovascular Prevention.

Since increased cholesterol levels are crucial in determining the development of atheroma, their reduction represents a mainstay in primary and secondary cardiovascular prevention. The most recent spectacular advancement in cholesterol-lowering therapy is represented by proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors. Although their benefit over currently available treatments has been ascribed primarily to their strong low-density lipoprotein (LDL)-cholesterol reducing action, several clues suggest that PCSK9 inhibitors may also influence platelet function and blood coagulation. PCSK9 knockout mice develop less venous and arterial thrombosis and show reduced in vivo platelet activation upon arterial injury. In patients with acute coronary syndromes (ACSs) treated with P2Y12 inhibitors, a direct association between PCSK9 serum levels and residual platelet reactivity was found. A direct correlation between urinary excretion of 11-dehydro-thromboxane-B2, a marker of in vivo platelet activation, and circulating PCSK9 levels was reported in patients with atrial fibrillation. Moreover, recombinant human PCSK9 added in vitro to human platelets potentiated activation induced by weak agonists. Finally, blood clotting factor VIII (FVIII), which is associated with stroke and ACS risk, is cleared from the circulation by members of the LDL receptor (LDLR) family. Given that PCSK9 degrades LDLR, it is conceivable that PCSK9 inhibitors by enhancing the expression of LDLR may slightly decrease circulating FVIII, in this way contributing to the prevention of cardiovascular events. This review aims to discuss the possible and hypothetical interactions between PCSK9 and the haemostatic system and to examine the possible pleiotropic effects of PCSK9 inhibitors in cardiovascular prevention.

Impact of dual antiplatelet therapy with adjusted-dose prasugrel on mid-term vascular response in patients undergoing elective percutaneous coronary intervention with everolimus-eluting stents.

The impact of dual antiplatelet therapy (DAPT) with adjusted-dose (3.75mg/day) prasugrel for Japanese patients has not been fully investigated in terms of local arterial healing following the elective percutaneous coronary intervention (PCI). The ROUTE-01 elective study was a prospective, 12-center and single-arm registry that enrolled 123 patients who underwent elective PCI with everolimus-eluting stents (EESs) under DAPT with a combination of adjusted-dose prasugrel and aspirin. Serial optical coherence tomography (OCT) was performed at the index PCI and 9-month follow-up to assess the relationship between in-stent thorombus (IST) and residual platelet reactivity measuring platelet reactivity unit (PRU). The patients were classified as extensive, intermediate, and poor metabolizers by cytochrome P450 2C19 (CYP2C19) loss-of-function polymorphisms. The prevalence of IST was 9.0% by 9-month OCT, with no difference amongst the three groups (p = 0.886). The incidences of malapposed and uncovered struts were not different among the groups. PRU was not statistically different among the groups. In multivariate logistic regression analysis, the independent predictor for IST on 9-month OCT was irregular protrusion (odds ratio=8.952, p = 0.037) on post-PCI OCT, not CYP2C19 loss-of-function polymorphisms. An adequate anti-thrombotic effect with an acceptable incidence of IST was observed irrespective of CYP2C19 loss-of-function polymorphisms. Our data suggests that adjusted-dose prasugrel and aspirin is a feasible treatment option in Japanese patients treated with EESs in elective PCI.

ASSOCIATION OF PLATELET-DERIVED MICROVESICLES WITH HIGH ON-TREATMENT PLATELET REACTIVITY IN CONVALESCENT ISCHEMIC STROKE PATIENTS TREATED WITH ACETYLSALICYLIC ACID

Elevated concentrations of platelet-derived microvesicles are found in cerebrovascular diseases. The impact of acetylsalicylic acid on these microvesicles remains inconsistent, despite its well-established effect on platelet aggregation. High residual platelet aggregation is defined as high on-treatment platelet reactivity, while “treatment failure” is the occurrence of vascular events despite antiplatelet treatment. The aim of this study was to determine whether the antiaggregatory effect of acetylsalicylic acid correlates with platelet-derived microvesicles in convalescent ischaemic stroke patients and cardiovascular risk factor controls as well as to evaluate the association between high on-treatment platelet reactivity and recurrent vascular events with the studied platelet-derived microvesicle parameters. The study groups consisted of 76 convalescent stroke patients and 74 controls. Total platelet-derived microvesicles, annexino-positive microvesicles number, and platelet-derived microvesicles with surface expression of proinflammatory (CD40L, CD62P, CD31) and procoagulant (PS, GPIIb/IIIa) markers were characterized and quantified using flow cytometry. Cyclooxygenase-1-specific platelet responsiveness, with whole blood impedance platelet aggregation under arachidonic acid stimulation and the serum concentration of thromboxane B2, were evaluated. Neither acetylsalicylic acid intake nor modification of its daily dose caused statistically significant differences in the studied microvesicle parameters. Additionally, no statistically significant differences in the studied microvesicle parameters were revealed between high on-treatment platelet reactivity and non-high on-treatment platelet reactivity subjects in either study subgroup. However, elevated concentrations of PAC-1+/CD61+, CD62P+/CD61+ and CD31+/CD61+ microvesicles were found in stroke patients with treatment failure, defined in this study as a recurrent vascular events in a one-year follow-up period. This study revealed no relationship between circulating microvesicle number and platelet aggregation. The procoagulant and proinflammatory phenotype of circulating platelet-derived microvesicles might contribute to acetylsalicylic acid treatment failure.

High Residual Platelet Reactivity during Aspirin Therapy in Patients with Non-St Segment Elevation Acute Coronary Syndrome: Comparison Between Initial and Late Phases.

BackgroundHigh platelet reactivity (HPR) during therapy with acetylsalicylic acid (ASA) is a poor prognostic factor in acute coronary syndromes (ACS). The prevalence of HPR during ACS is greater than that reported in stable diseases. However, it is unclear whether this prevalence of HPR is a transient phenomenon or a characteristic of this high-risk population.ObjectiveThe main objective is to compare the effects of ASA on platelet function in the initial and late phases of ACS in a single population. Secondary objectives are: correlation between the tests between themselves and the relationship between the tests and the variation of the inflammatory markers (C-reactive protein and interleukin-6).MethodsSeventy patients with non-ST segment elevation (NSTE) ACS in use of 100-200 mg of ASA per day for at least 7 days were prospectively studied. Platelet function was assessed in the first 48 hours and subsequently after 3 months using four methods: VerifyNow™ (VFN), whole blood platelet aggregation (WBPA) with arachidonic acid (AA) and collagen as agonists, and platelet function analyzer (PFA). The level of statistical significance considered was < 0.05.ResultsAccording to the more specific methods (WBPA with AA and VFN), the incidence of HPR was significantly higher in the early phase than in the late phase: WBPA with AA: 31% versus 13%, p = 0.015; VFN: 32% versus 16%, p = 0.049. The other methods tested, which were less specific for ASA, did not show significant differences between phases. The correlation between the methods was weak or moderate (r ranging from 0.3 to 0.5, p < 0.05), and there were no significant associations between HPR and inflammatory markers.ConclusionThe prevalence of HPR during AAS therapy, assessed by specific methods for cyclooxygenase 1 (COX-1), is higher during the acute phase than in the late phase of NSTE ACS.

Independent Predictors of Adverse Cardiovascular Events in Patients With Acute Coronary Syndrome After Percutaneous Coronary Intervention During Hospitalization

to elucidate independent clinical and laboratory predictors of adverse cardiovascular events (ACVE) in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI) with stenting in early inhospital period. We included in this prospective single center study 130 patients with ACS who underwent PCI with stenting. All patients prior to and after PCI received dual antiplatelet therapy with acetylsalicylic acid and clopidogrel. In 12-48 hours after PCI we measured residual platelet reactivity (RPR) using light aggregometry. In 57 patients simultaneously we performed genotyping ofCYP2C19*2 polymorphisms. The following ACVE were used as end-points and were registered during inhospital observation (mean duration 9.7±3.2 days): sudden death, stent thrombosis, arterial thrombosis of other localization, recurrent angina, cardiac rhythm disturbances requiring special therapy. Repetitive ACVE were observed in 32 patients. According to unifactorial regression analysis risk factors of their development were, ADP F-induced RPR (р&lt;0.001), levels of creatinine (р&lt;0.001), hemoglobin (р&lt;0.001), and glucose (р=0.026), age (р=0.01), iron-deficiency anemia (р=0.01), left ventricular ejection fraction (р=0.004), number of stents (р=0.015). According to results of multifactorial regression analysis independent predictors of ACVE were: ADP-induced RPR &gt;76 % (р=0.003), levels of creatinine &gt;189 µmol / L (р=0.003), and hemoglobin &lt;114 g / L (р=0.004). Significant effect of homozygous carriage ofCYP2C19*2 (G681A) (А / А) on development of stent thrombosis was also detected (р=0.028). ADP-induced RPR, levels of creatinine and hemoglobin were found to be independent predictors of inhospital ACVE after myocardial revascularization with stenting in patients with ACS.

Personalisation of antiplatelet therapy and secondary prevention of ischemic stroke.

The purpose of this systematic literature review is to highlight the current approach to the issue of “resistance” to antiplatelet drugs, presentation of a personalized approach to antiplatelet therapy in the treatment and secondary prevention of ischemic stroke, taking into account new foreign and Russian recommendations and research results. To achieve this goal, a systematic search was carried out with subsequent analysis of literary data and online resources. All reviews were indexed in PubMed, Medline, elibrary, CyberLeninka, Google Scholar databases. The article presents the main characteristics of the methods of laboratory evaluation of residual platelet reactivity used in clinical practice. It is shown that one of the rational approaches to improving the effectiveness and safety of antiplatelet therapy is to test the sensitivity ofpatients to the antiplatelet action of drugs (aggregatometry). In turn, pharmacogenetic testing makes it possible to predict the pharmacological response to the drug and is one of the promising prognostic tests that allow to assess the characteristics of individual sensitivity to the appointment of drug therapy. Particular emphasis in this review of the literature is made on a comprehensive approach, including the use ofpharmacogenetic and functional studies, the results and prospects of the results and prospects ofpharmacogenetic testing in the personalization of antiplatelet therapy of ischemic stroke in order to achieve the effectiveness of the greatest effect of antiplatelet drugs and reduce the risk of adverse reactions. This approach is important because it allows you to correct antiplatelet therapy in the treatment and secondary prevention of ischemic stroke in a timely manner, which makes it possible to develop an algorithm to achieve the effectiveness of antiplatelet therapy, choose an individual dose of the drug and the treatment regimen.

A pharmacodynamics comparison of prasugrel and clopidogrel in patients undergoing hemodialysis.

Platelet reactivity in the presence of clopidogrel is deteriorated in patients undergoing hemodialysis (HD). However, the impact of residual platelet reactivity with prasugrel use in Japanese patients on HD remains unclear. This was a prospective, multi-center, single-arm study conducted to compare platelet reactivity of prasugrel 3.75mg per day vs. clopidogrel 75mg per day in patients on chronic HD. We assessed P2Y12 reaction units (PRU) using the VerifyNow® P2Y12 test for all enrolled patients at baseline (clopidogrel treatment) and at 14days (prasugrel treatment) pre- and post-HD. Clinical outcomes data were obtained on day 14. A total of 38 patients on HD were included in this study. The PRU were significantly higher in patients on clopidogrel than in patients on prasugrel in both phases (pre-HD: clopidogrel 226 ± 80 vs. prasugrel 175 ± 82, p < 0.001) (post-HD: clopidogrel 256 ± 67 vs. prasugrel 210 ± 63, p < 0.001). There were no patients with bleeding or adverse events during the two weeks of prasugrel treatment. Prasugrel 3.75mg per day, adjusted for Japanese patients, inhibited platelet aggregation better than clopidogrel, even after hemodialysis, which might contribute to the reduced incidence of major adverse event in patients undergoing HD.

Platelet reactivity in patients with chronic kidney disease undergoing percutaneous coronary intervention

This study aimed to evaluate the platelet reactivity in real-world patients with different chronic kidney disease (CKD) stages after percutaneous coronary intervention (PCI), and to examine whether high residual platelet reactivity (HRPR) is associated with higher incidence of adverse cardiovascular events in a 2-year follow up. A total of 10 724 consecutive patients receiving DAPT with aspirin and clopidogrel after PCI throughout 2013 were enrolled. We applied modified thromboelastography (mTEG) in 6745 patients. Kaplan–Meier analysis and Cox proportional regression analysis were applied to illustrate end points for patients. The prevalence of HRPR for adenosine diphosphate (ADP) was higher in patients with CKD3-5 than patients with CKD1-2 (47.0% vs. 37.3%, p = 0.002), but not for arachidonic acid (AA). No significant difference was observed for MACCE between patients with or without HRPR for ADP (HR 1.004, 95%CI: 0.864–1.167, p = 0.954). Patients with HRPR for ADP was associated with less bleeding events than patients without HRPR for ADP (HR 0.795, 95%CI: 0.643–0.982, p = 0.034). In this large cohort of real-world patients after PCI, the deterioration of renal function was linked to HRPR for ADP. HRPR was not associated with MACCE in patients with CKD in a 2-year follow up. Bleeding risks were significantly lower in PCI patients with versus without HRPR for ADP.

Impact of immature platelet fraction on platelet reactivity during prasugrel maintenance treatment

Residual high on-treatment platelet reactivity (HTPR) despite dual antiplatelet therapy (DAPT) has emerged as a predictor of major ischemic events in patients undergoing percutaneous coronary interventions (PCIs), especially after an acute cardiovascular event. However, its determinants are still poorly defined. Therefore, the aim of the present study was to evaluate the role of the percentage of reticulated platelets on HTPR in patients on DAPT with ASA (100–160 mg) and prasugrel (10 mg).Platelet reactivity and the reticulated platelets fraction (immature platelets fraction [IPF]) were assessed at 30–90 days after an acute coronary syndrome. Aggregation was assessed by multiple-electrode aggregometry. HTPR was defined as ADP test > 417 AU × min.Our population is represented by 180 ACS patients undergoing stent implantation, divided according to median values of IPF (< or ≥ 2.8%). Higher IPF values were associated to lower platelet count (p < 0.001) and a higher rate of active smokers (p = 0.02). No difference was observed in terms of mean platelet reactivity, with different activating stimuli. The prevalence of HTPR on prasugrel did not significantly differ in patients with IPF < or ≥ 2.8% (8%vs. 11.8%, p = 0.46; adjusted OR [95% CI] = 1.89 [0.66–5.4], p = 0.24).Our study showed that in patients treated with prasugrel after PCI for ACS, the immature platelet fraction influences neither platelet reactivity nor the rate of HTPR.

Abstract 16778: Effectiveness of Platelet Inhibition on Reducing High-Intensity Transient Signals to Cerebral Circulation During Tavi

Introduction: Despite the established dual antiplatelet treatment, embolic cerebrovascular events remain a major concern peri-operatively and following Transcatheter Aortic valve Implantation (TAVI). High Residual Platelet Reactivity (RPR) may contribute to platelet aggregation, propagating thrombosis on implanted materials. Therefore, we evaluated whether high RPR may predispose to an increased number of cerebrovascular emboli during the procedure. Methods: Consecutive patients who underwent transfemoral TAVI with Evolut™ R bioprosthesis were prospectively studied. Dual antiplatelet therapy with aspirin and a P2Y12 inhibitor was administered to all patients 24 hours prior to the procedure at loading dose. The number of detected High Intensity Transient Signals (HITS) was assessed using Rimed Digi-Lite™ Transcranial Doppler on both cerebral arteries during the following phases of the procedure; Phase 0: 30 minutes prior to procedure initiation, Phase I: between access site puncture and introduction of the delivery system, Phase II: during the implantation of the bioprosthesis, until the removal of the delivery system. Platelet inhibition was measured prior to the procedure and expressed in PRU, using the VerifyNow® assay and defined as high RPR if PRU≥208. Results: Out of 28 total patients (81±7 years, 18 males (64%)), 12 patients (81±9 years, 8 males (66.7%)) had PRU ≥208 (high RPR group), while 16 patients (81±5 years, 10 males (62.5%)) had PRU&lt;208 (low RPR group). All device implantations were performed without balloon pre-dilation. Among the high RPR group, a statistically significant higher number of HITS was recorded compared to the low RPR group (707±149 vs. 530±152, p: 0.004). This was mainly driven by the number of HITS detected during Phase II, compared to the rest procedure stages (247±84 vs. 165±28, p:0.004). A statistical significant correlation of PRU with the total number of HITS was found (r2: 0.25, p: 0.006). Conclusions: High RPR after dual antiplatelet loading resulted in larger burden of embolic HITS during TAVI. This may has implications for future strategies for cerebral embolic protection.