High Platelet Reactivity Patients Research Articles

Gut microbiota induces high platelet response in patients with ST segment elevation myocardial infarction after ticagrelor treatment.

Ticagrelor is a first-line drug for the treatment of acute ST elevation myocardial infarction (STEMI). However, approximately 20% STEMI patients taking ticagrelor exhibited a delayed response and the mechanism was still unclear. To explore the mechanism of the poor response of ticagrelor in post-percutaneous coronary intervention (PCI) patients, we enrolled 65 high platelet reactivity (HPR) patients and 90 controls (normal platelet reactivity [NPR]). Pharmacokinetic assessment result showed that the plasma concentrations of ticagrelor and its metabolism production, AR-C124910XX, were lower in HPR patients than controls. Further single nucloetide polymorphism (SNP) analysis identified that there is no difference in ATP binding cassette subfamily B member 1 (ABCB1) gene expression between the NPR group and the HPR group. Metagenomic and metabolomic analyses of fecal samples showed that HPR patients had higher microbial richness and diversity. Transplantation of the gut microbiota from HPR donors to microbiota-depleted mice obviously decreased plasma concentration of ticagrelor. Our findings highlight that gut microbiota dysbiosis may be an important mechanism for the ticagrelor of HPR in patients with STEMI and support that modify gut microbiota is a potential therapeutic option for STEMI. Our findings highlight that gut microbiota dysbiosis may be an important mechanism for the ticagrelor of HPR in patients with ST elevation myocardial infarction (STEMI) and support that modify gut microbiota is a potential therapeutic option for STEMI. NSFC 82170297 and 82070300 from the National Natural Science Foundation of China.

Not-high before-treatment platelet reactivity in patients with STEMI:prevalence, clinical characteristics, response to therapy and outcomes

Abstract Background Platelet reactivity (PR) has been indicated as a pathophysiological key element for ST-Elevation Myocardial Infarction (STEMI) development. In STEMI patients, PR following pharmacological treatment has been extensively studied with focus on patients with on-treatment high platelet reactivity (HPR). Patients with before-treatment not-high platelet reactivity (NHPR) have been poorly studied so far. Purpose Aim of the study is to investigate the prevalence, clinical characteristics, response to therapy and outcomes of baseline prior to treatment NHPR among patients with STEMI undergoing primary PCI. Methods We analysed the data from 358 STEMI patients with assessment of PR by VerifyNowbefore P2Y12 inhibitor loading dose (LD). All patients received a P2Y12 inhibitor (ticagrelor or prasugrel) LDafter baseline PR assessment. Blood samples were obtained at baseline (T0), and after 1 hour (T1), 2 hours (T2), 4–6 hours (T3) and 8–12 hours (T4) after LD. HPR was defined as Platelet Reactivity Unit values ≥208, while patients with values <208 at baseline were defined as having NHPR. Results Overall, 20% patients had NHPR. Patients with before-treatment NHPR values were more frequently young, of male gender and more frequently smokers (p=0.005), overweight or obese (p=0.009), affected by dyslipidemia (p=0.03) and with a family history of coronary artery disease (p=0.04). Age and male gender resulted both independent predictors of NHPR, even after propensity score adjustment. The percentage of inhibition of PR after ticagrelor or prasugrel LD was similar between HPR and NHPR patients at each time point (figure 1) and residual PR was constantly lower in patients with before-treatment PRU <208 from baseline to 8–12 hours from LD (figure 2). However, patients with HPR showed worse in-hospital clinical outcomes, and the composite adverse outcome endpoint of death, reinfarction, stroke, acute kidney injury or heart failure was significantly higher (10.0% vs 1.4%; p=0.017) as compared with the NHPR group. Conclusions A significant proportion of patients presenting with STEMI has a baseline NHPR; they are predominantly young males with a high-risk cardiovascular profile. NHPR is associated with better in-hospital outcomes as compare with patients with HPR. Further studies are needed to better understand the underlying pathophysiology in order to find out potential personalized treatments in this setting. Funding Acknowledgement Type of funding sources: None.

Not-high before-treatment platelet reactivity in patients with STEMI: prevalence, clinical characteristics, response to therapy and outcomes

Platelet reactivity (PR) has been indicated as a pathophysiological key element for ST-Elevation Myocardial Infarction (STEMI) development. Patients with not-high before-treatment platelet reactivity (NHPR) have been poorly studied so far. The aim of this study is to investigate the prevalence, clinical characteristics, response to therapy and outcomes of baseline prior to treatment NHPR among patients with STEMI undergoing primary PCI. We analyzed the data from 358 STEMI patients with assessment of PR by VerifyNow before P2Y12 inhibitor loading dose (LD). Blood samples were obtained at baseline, and after 1 hour, 2 hours, 4–6 hours and 8–12 hours after LD. High platelet reactivity (HPR) was defined as Platelet Reactivity Unit values ≥208, while patients with values <208 at baseline were defined as having NHPR. Overall, 20% patients had NHPR. Age and male gender both resulted independent predictors of NHPR, even after propensity score adjustment. The percentage of inhibition of PR after ticagrelor or prasugrel LD was similar between HPR and NHPR patients at each time point. However, patients with HPR showed worse in-hospital clinical outcomes, and the composite adverse outcome endpoint of death, reinfarction, stroke, acute kidney injury or heart failure was significantly higher (10.0% vs 1.4%; p = .017) as compared with the NHPR group. In conclusion, a significant proportion of patients presenting with STEMI has a baseline NHPR that is associated with better in-hospital outcomes as compared with patients with HPR. Further studies are needed to better elucidate the potential therapeutic implications of NHPR in terms of secondary prevention.

Platelet microRNA-15b protects against high platelet reactivity in patients undergoing percutaneous coronary intervention through Bcl-2-mediated platelet apoptosis.

BackgroundHigh platelet reactivity (HPR) and low platelet reactivity (LPR) are associated with an increased risk of ischemic/bleeding events in patients undergoing percutaneous coronary intervention (PCI). The role platelet miRNAs carry out in platelet reactivity regulation is largely unknown.MethodsIn this study, we profiled the expression pattern of platelet miRNA in patients undergoing PCI with HPR (n=4) and LPR (n=4) by miRNA microarray screening. The candidate miRNAs were further validated in a larger sample of 17 LPR and 22 HPR patients by quantitative reverse-transcription polymerase chain reaction (RT-qPCR), and miR-15b was found differentially expressed. MiR-15b mimic and inhibitor were transfected into MEG-01 cells, then Bcl-2 protein expression and cell apoptosis were assessed. The relationship between platelet reactivity and platelet apoptosis was further evaluated. ABT-737, a Bcl-2 inhibitor was used to induce platelet apoptosis in PCI patients in vitro, and the influence of enhanced platelet apoptosis on platelet reactivity was explored.ResultsTwo miRNAs were found to be differentially expressed in patients with LPR and HPR using microarray system. Furthermore, the expression of miR-15b, a miRNA known to induce cell apoptosis via targeting of Bcl-2, was confirmed by RT-qPCR (P=0.020) to be 1.4× higher in the platelets of LPR patients than in those of HPR patients. Overexpression of miR-15b was demonstrated to suppress Bcl-2 protein expression and enhance cell apoptosis in a megakaryocyte cell line (MEG-01). The platelets of LPR patients expressed lower levels of Bcl-2 protein than those of HPR patients, and an inverse relationship between platelet reactivity and platelet apoptosis was observed among 44 patients who underwent PCI. Inducing platelet apoptosis in PCI patients in vitro, we observed that their platelet reactivity was decreased in a dose-dependent manner.ConclusionsThrough the promotion of platelet apoptosis, platelet miR-15b negatively regulates platelet reactivity in patients undergoing PCI. Platelet apoptosis may represent a novel antiplatelet target for overcoming HPR in PCI treatment.

Clinical Implications of "Tailored" Antiplatelet Therapy in Patients With Chronic Total Occlusion.

BackgroundClopidogrel nonresponsiveness is a prognostic marker after percutaneous coronary intervention. Prasugrel and ticagrelor provide a better platelet inhibition and represent the first‐line antiplatelet treatment in acute coronary syndrome. We sought to assess the prognostic impact of high platelet reactivity (HPR) and the potential clinical benefit of a “tailored” escalated or changed antiplatelet therapy in patients with chronic total occlusion.Methods and ResultsFrom Florence CTO‐PCI (chronic total occlusion‐percutaneous coronary intervention) registry, platelet function assessed by light transmission aggregometry, was available for 1101 patients. HPR was defined by adenosine diphosphate test ≥70% and optimal platelet reactivity by adenosine diphosphate test <70%. The endpoint of the study was long‐term cardiac survival. Patients were stratified according to light transmission aggregometry results: optimal platelet reactivity (82%) and HPR (18%). Means for the adenosine diphosphate test were 44±16% versus 77±6%, respectively. Three‐year survival was significantly higher in the optimal platelet reactivity group compared with HPR patients (95.3±0.8% versus 86.2±2.8%; P<0.001). With the availability of new P2Y12 inhibitors, a deeper platelet inhibition (46±17%) and similar survival to the optimal platelet reactivity group were achieved in patients with HPR on clopidogrel therapy after escalation. Conversely, HPR on clopidogrel therapy “not switched” was associated with cardiac mortality (hazard ratio 2.37; P=0.003) after multivariable adjustment.ConclusionsHPR on treatment could be a modifiable prognostic marker by new antiaggregants providing a deeper platelet inhibition associated with clinical outcome improvement in complex chronic total occlusion patients. A “tailored” antiplatelet therapy, also driven by the entity of platelet inhibition, could be useful in these high risk setting patients.

Relation of Platelet Indexes to Platelet Reactivity and Periprocedural Myocardial Infarction in Patients Who Underwent Percutaneous Coronary Angioplasty

No comprehensive data are available on the role of platelet indexes (PI) in the periprocedural risk stratification of patients who underwent percutaneous coronary intervention (PCI). The aim of this study was to investigate the relation of PI to platelet reactivity (PR) and periprocedural myocardial infarction (PMI) in patients receiving PCI. A total of 502 PCI patients had preprocedural measurement of PI and PR, the latter assessed by VerifyNow P2Y12 assay. Study end points were incidence of PMI and high platelet reactivity (HPR) according to tertiles of PI and evaluation of PI in HPR patients. Incidence of PMI in the overall population was 6.6%. Rates of PMI were not different in PI tertiles: platelet count (I: 6.0%, II: 7.1%, III: 6.5%; p = 0.74), mean platelet volume (MPV, I: 6.6%, II: 7.3%, III: 5.8%;p = 0.86), platelet distribution width (I: 7.2%, II: 7.2%, III: 5.8%;p = 0.74), and MPV/P ratio (I: 6.6%, II: 6.0%, III: 7.1%; p = 0.91). The occurrence of PMI was significantly different in PR tertiles (I: 3%, II: 5.4%, III: 11.4%; p = 0.006). Platelet count and MPV/P ratio were significantly different in patients with and without HPR (221.8 ± 58.6 × 103/µL vs207 ± 59.4 × 103/µL, p = 0.008; 51.73 ± 15.17 vs 56.7 ± 18.3, p = 0.002).In conclusion, this study showed no relation between PI and PMI in PCI patients but confirms the association of HPR with increased incidence of PMI; thus, PI seem to be not able to identify patients at higher periprocedural risk, but monitoring PR by a bedside assay remains a useful tool for risk stratification.

Prediction of high on-treatment platelet reactivity in clopidogrel-treated patients with acute coronary syndromes

BackgroundAbout 40% of clopidogrel-treated patients display high platelet reactivity (HPR). Alternative treatments of HPR patients, identified by platelet function tests, failed to improve their clinical outcomes in large randomized clinical trials. A more appealing alternative would be to identify HPR patients a priori, based on the presence/absence of demographic, clinical and genetic factors that affect PR. Due to the complexity and multiplicity of these factors, traditional statistical methods (TSMs) fail to identify a priori HPR patients accurately. The objective was to test whether Artificial Neural Networks (ANNs) or other Machine Learning Systems (MLSs), which use algorithms to extract model-like ‘structure’ information from a given set of data, accurately predict platelet reactivity (PR) in clopidogrel-treated patients. MethodsA complete set of fifty-nine demographic, clinical, genetic data was available of 603 patients with acute coronary syndromes enrolled in the prospective GEPRESS study, which showed that HPR after 1month of clopidogrel treatment independently predicted adverse cardiovascular events in patients with Syntax Score >14. Data were analysed by MLSs and TSMs. ANNs identified more variables associated PR at 1month, compared to TSMs. ResultsANNs overall accuracy in predicting PR, although superior to other MLSs was 63% (95% CI 59–66). PR phenotype changed in both directions in 35% of patients across the 3 time points tested (before PCI, at hospital discharge and at 1month). ConclusionsDespite their ability to analyse very complex non-linear phenomena, ANNs or MLS were unable to predict PR accurately, likely because PR is a highly unstable phenotype.

Association of measured platelet reactivity with changes in P2Y12 receptor inhibitor therapy and outcomes after myocardial infarction: Insights into routine clinical practice from the TReatment with ADP receptor iNhibitorS: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome (TRANSLATE-ACS) study

Little is known about the use of platelet function testing to guide choice of P2Y12 receptor inhibitor therapy in routine clinical practice. We studied 671 myocardial infarction (MI) patients treated with percutaneous coronary intervention in the TRANSLATE-ACS Registry who had VerifyNow platelet function testing performed while on clopidogrel treatment during their index hospitalization (April 2010-October 2012). High platelet reactivity (>208 platelet reactivity units [PRU]) was present in 261 (38.9%) patients. Clopidogrel was switched in-hospital to prasugrel in 80 (30.7%) patients with high platelet reactivity and 18 (4.4%) patients with therapeutic platelet reactivity (≤208 PRU). Among high platelet reactivity patients, switch to prasugrel was associated with lower major adverse cardiovascular events (death, MI, stroke, or unplanned revascularization) at 1year (10.0% vs 22.7%, P=.02; adjusted odds ratio [OR] 0.39, 95% CI 0.18-0.85, P=.02) and no significant difference in Bleeding Academic Research Consortium type 2 or higher bleeding (23.8% vs 22.1%, P=.77; adjusted OR 0.91, 95% CI 0.48-1.7, P=.77) compared with patients continued on clopidogrel. No significant differences in major adverse cardiovascular event (22.2% vs 12.8%, P=.25; adjusted OR 1.8, 95% CI 0.47-7.3, P=.38) or bleeding (22.2% vs 19.4%, P=.77; adjusted OR 1.3, 95% CI 0.27-6.8, P=.72) were observed among therapeutic platelet reactivity patients between switching and continuation on clopidogrel. Only one-third of percutaneous coronary intervention-treated MI patients with high on-clopidogrel platelet reactivity were switched to a more potent P2Y12 receptor inhibitor. Intensification of antiplatelet therapy was associated with lower risk of ischemic events at 1year among HPR patients.

A comparative cohort study on personalised antiplatelet therapy in PCI-treated patients with high on-clopidogrel platelet reactivity

In clopidogrel-treated patients undergoing percutaneous coronary intervention (PCI), high platelet reactivity (HPR) is associated with a higher risk for thrombotic events including stent thrombosis (ST). A personalised therapy with selective intensification of treatment may improve HPR patients´ outcome in this setting although recent randomised trials are against this hypothesis. The aim of the ISAR-HPR registry was to assess whether clopidogrel-treated HPR patients benefit from selective intensification of P2Y12 receptor inhibition. For the registry, outcomes were compared between two cohorts. We identified 428 clopidogrel treated HPR patients (AU x min ≥468 on the Multiplate analyser) between 2007-2008 (historical control cohort) without a change of treatment based on platelet function (PF) testing results. Between 2009-2011, we identified 571 HPR patients (guided therapy cohort) and used this information for guidance and selective intensification of P2Y12 receptor directed treatment (reloading with clopidogrel, switch to prasugrel, re-testing) in a setting of routine PF testing. The primary outcome was the composite of death from any cause or ST after 30 days. Major bleeding according to TIMI criteria was also monitored. The incidence of the primary outcome was significantly lower in the guided vs the control cohort (7 [1.2%] vs 16 [3.7%] events; HR 0.32, 95% CI 0.13-0.79; p=0.009). The incidence of major bleeding was numerically but not statistically higher in the guided vs the control cohort (1.9 vs 0.7%; p=0.10). In conclusion, present findings are in support for a PF testing guided antiplatelet therapy with selective intensification of P2Y12 receptor inhibition. The issue of personalised antiplatelet treatment warrants further investigation in randomized and well-controlled clinical trials.

High post-clopidogrel platelet reactivity assessed by a point-of-care assay predicts long-term clinical outcomes in patients with ST-segment elevation myocardial infarction who underwent primary coronary stenting

BackgroundRecent studies have shown that post-clopidogrel high platelet reactivity (HPR), assessed by a point-of-care assay, is associated with a higher risk of adverse events after percutaneous coronary intervention (PCI). We assessed the clinical impact of HPR by the VerifyNow P2Y12 point-of-care assay in 181 patients with ST-segment elevation myocardial infarction (STEMI) who underwent primary PCI with drug-eluting stents (DES) at 3 hospitals. MethodsThe primary endpoint of the study was the 12-month major adverse cardiovascular events (MACE), which comprised cardiovascular death, nonfatal MI and ischemic stroke. All patients received a single loading dose of 600mg clopidogrel and 300mg aspirin followed by a daily maintenance dose of 75mg clopidogrel and 100mg aspirin. ResultsA P2Y12 reaction unit (PRU)≥282 (AUC 0.719, 95% CI 0.588–0.851, p=0.004, sensitivity 68.8%, specificity 73.8%) was the optimal cut-off value in predicting 12-month MACE by receiver operating characteristic curve analysis. Occurrence of MACE was significantly more frequent in patients with HPR (PRU≥282) compared to patients without HPR (20.4% vs. 3.9%, HR 6.24, 95% CI 2.05–18.99, p=0.001). By multivariate analysis, HPR (HR 3.84, 95% CI 1.17–12.58, p=0.026) and elderly patients above 80years of age (HR: 8.13, 95% CI 1.79–37.03, p=0.007) were found to be the significant predictors of 12-month MACE. The MACE-free survival rate was significantly lower in patients with HPR compared to patients without HPR (p<0.001). ConclusionHPR assessed by a point-of-care assay was able to predict 12-month MACE in patients with STEMI who underwent primary PCI with DES.

PLATELET FUNCTION TESTING GUIDED USE OF PRASUGREL IN PATIENTS WITH HIGH ON-CLOPIDOGREL TREATMENT PLATELET REACTIVITY REDUCES THE RISK OF EARLY STENT THROMBOSIS

In clopidogrel treated patients undergoing PCI, high platelet reactivity (HPR) is associated with a higher risk for stent thrombosis (ST). Prasugrel may be advantageous over clopidogrel especially in HPR patients. Here, we report the results of a 5 year-experience of routine platelet function (PF)

Platelet function profiles in the elderly: Results of a pharmacodynamic study in patients on clopidogrel therapy and effects of switching to prasugrel 5 mg in patients with high platelet reactivity

Studies specifically designed to assess clopidogrel response in the elderly as well as treatment alternatives to improve platelet inhibition in this high-risk population are lacking. This study aimed to define pharmacodynamic (PD) profiles, including high platelet reactivity (HPR) rates, among elderly patients on maintenance clopidogrel therapy and to assess the PD effects of prasugrel 5 mg/day in elderly with HPR. This was a prospective observational PD study enrolling consecutive ≥ 75-year-old patients on maintenance clopidogrel therapy (75 mg/day) who were tested for clopidogrel response by the VerifyNow P2Y12 assay and light transmittance aggregometry (LTA). HPR rates were estimated using multiple definitions. HPR patients identified by the VerifyNow P2Y12 assay [P2Y12 reaction unit (PRU) ≥ 230] were switched to prasugrel 5 mg/day, and platelet function testing was performed after 15 days of treatment. PD testing was completed in 100 patients. The HPR prevalence varied between 25% and 32%, depending on the definition used. A PRU ≥ 230 was observed in 25 patients; of these, 20 switched to prasugrel 5 mg/day. This resulted in significant reduction in PRU mean values (279.8 ± 45.1 vs. 171.7 ± 65.2, p=0.0002) with an absolute between-treatment difference of 108.1 (95% confidence intervals 75.2-140.9). Accordingly, switching to prasugrel 5 mg/day overcame HPR in most (80%) patients. Consistently, all LTA measures were significantly lower after prasugrel compared with clopidogrel. In conclusion, a considerable proportion of elderly patients exhibit HPR while on standard clopidogrel therapy. Switching to 5 mg/day prasugrel in elderly patients with HPR is associated with enhanced platelet inhibition and overcomes HPR in the majority of these patients.