High On-treatment Platelet Reactivity In Patients Research Articles

Gut microbiota as predictors of the occurrence of high on-treatment platelet reactivity in acute ischemic stroke patients.

In this study, we aimed to investigate the association between gut microbiota and high on-treatment platelet reactivity (HTPR) in patients with acute ischemic stroke (AIS). We enrolled a total of 48 AIS patients, including 19 HTPR patients and 29 non-high on-treatment platelet reactivity (NHTPR) patients, along with 10 healthy controls. Clinical and laboratory data, as well as stool samples, were collected from all participants. The composition and function of gut microbiota were assessed using 16S rRNA sequencing. Differences in the gut microbiota between the two groups were analyzed, and a diagnostic model based on the gut microbiota was established using random forest model. HTPR patients exhibited a decreased microbial richness compared to NHTPR patients. Additionally, the relative abundance of unidentified_Clostridia and Ralstonia was lower in HTPR patients. Significant differences in biological functions, such as toxoplasmosis, were observed between the two groups. The combination of Ralstonia, unidentified-Clostridia, Mailhella, Anaerofustis, and Aggregatibacter showed excellent predictive ability for HTPR occurrence (AUC=0.896). When comparing AIS patients with healthy controls, alterations in the microbiota structure were observed in AIS patients, with imbalances in short-chain fatty acid-producing bacteria and pathogenic bacteria. Significant differences in biological functions, such as oxidative phosphorylation, were noted between the two groups. The combination of Alloprevotella, Terrisporobacter, Streptococcus, Proteus, and unidentified_Bacteria exhibited strong predictive power for AIS occurrence (AUC=0.994). This study is the first to uncover the microbial characteristics of HTPR in AIS patients and demonstrate the predictive potential of specific bacterial combinations for HTPR occurrence.

High on-treatment platelet reactivity in peripheral arterial disease: A systematic review.

To highlight current evidence pertaining to the measurement methods and prevalence of high on-treatment platelet reactivity (HTPR) in patients with PAD, as well as to evaluate the relationship between HTPR and recurrent adverse cardiovascular and limb events in PAD patients. A systematic review of English-language literature on HTPR in patients with PAD. An electronic literature search of PubMed and Medline was performed in May 2021. A total of 29 studies with a total number of 11,201 patients with PAD were identified. HTPR during clopidogrel treatment ranges from 9.8 to 77%, and during aspirin treatment ranges from 4.1 to 50% of PAD patients. HTPR was associated with adverse clinical outcomes. The need for limb revascularisation was higher in patients with HTPR during clopidogrel use. Similarly, HTPR during aspirin use in the PAD population was predictive of adverse cardiovascular events (HR 3.73; 95% CI, 1.43-9.81; p = .007). A wide range of techniques were applied to measure platelet resistance, without consensus on cut-off values. Furthermore, differing patient populations, a variety of antiplatelet regimens, and differing clinical endpoints highlight the high degree of heterogeneity in the studies included in this review. No consensus on technique or cut-off values for HTPR testing has been reached. Patients with HTPR are potentially at a greater risk of adverse limb-related and cardiovascular events than patients sensitive to antiplatelet therapy illustrating the need for clinical implementation of HTPR testing. Future research must aim for consistent methodology. Adaptation of antiplatelet therapy based on HTPR results requires further exploration.

Guided Anti-P2Y12 Therapy in Patients Undergoing PCI: Three Systematic Reviews with Meta-analyses of Randomized Controlled Trials with Homogeneous Design.

The value of guided therapy (GT) with anti-P2Y12 drugs in percutaneous coronary intervention (PCI) is unclear. Meta-analyses lumped together randomized controlled trials (RCTs) with heterogeneous designs, comparing either genotype-GT or platelet function test (PFT)-GT with unguided therapy. Some meta-analysis also included RCTs that did not explore GT, but included the effects of switching patients with high on-treatment platelet reactivity (HTPR) to alternative therapies (HTPR-Therapy). We performed three distinct systematic reviews/meta-analyses, each exploring only RCTs with homogeneous design. MEDLINE, Embase, and Central databases were searched for RCTs testing genotype-GT, PFT-GT, or HTPR-Therapy in PCI-treated patients, through October 1, 2022. Two reviewers extracted the data. Risk ratios (RRs) (95% confidence intervals) were calculated. Primary outcomes were major bleedings (MBs) and major adverse cardiovascular events (MACE). In seven genotype-GT RCTs, RRs were: MB, 1.06 (0.73-1.54; p = 0.76); MACE, 0.65 (0.47-0.91; p = 0.01), but significant risk reduction was observed in RCTs performed in China (0.30, 0.16-0.54; p < 0.0001) and not elsewhere (0.75, 0.48-1.18; p = 0.21). In six PFT-GT RCTs, RRs were: MB, 0.91 (0.64-1.28, p = 0.58); MACE, 0.82 (0.56-1.19; p = 0.30): 0.62 (0.42-0.93; p = 0.02) in China, 1.08 (0.82-1.41; p = 0.53) elsewhere. In eight HTPR-Therapy RCTs, RRs were: MB, 0.71 (0.41-1.23; p = 0.22); MACE, 0.57 (0.44-0.75; p < 0.0001): 0.56 (0.43-0.74, p < 0.0001) in China, 0.58 (0.27-1.23, p = 0.16) elsewhere. No GT strategy affected MB. Overall, genotype-GT but not PFT-GT reduced MACE. However, genotype-GT and PFT-GT reduced MACE in China, but not elsewhere. PFT-GT performed poorly compared to HTPR-Therapy, likely due to inaccurate identification of HTPR patients by PFT.

Antiplatelet therapy adjustment improved the radiomic characteristics of acute silent cerebral infarction after stent-assisted coiling in patients with high on-treatment platelet reactivity: A prospective study.

We aimed to investigate the effects of high on-treatment platelet reactivity (HPR) and antiplatelet therapy adjustment on high-risk radiomic features in patients with antiplatelet therapy adjustment on acute silent cerebral infarction (ASCI) who had unruptured intracranial aneurysms (UIA) after stent placement. This single-institution study prospectively included 230 UIA patients who had ACSI after stent placement in our hospital between January 2015 and July 2020. All patients underwent magnetic resonance imaging with diffusion-weighted imaging (MRI-DWI) after stent placement and 1,485 radiomic features were extracted from each patient. The least absolute shrinkage and selection operator regression methods were used for selection of high-risk radiomic features associated with clinical symptoms. In addition, 199 patients with ASCI were classified into three groups: controls without HPR (n = 113), HPR patients with standard antiplatelet therapy (n = 63) and HPR patients with antiplatelet therapy adjustment (n = 23). We compared high-risk radiomic features between three groups. Of the patients who had acute infarction after MRI-DWI, 31 (13.5%) exhibited clinical symptoms. Eight risk radiomic features associated with clinical symptoms were selected, and the radiomics signature exhibited good performance. In ASCI patients, compared with controls, the radiomic characteristics of ischemic lesion in HPR patients were consistent with the following high-risk radiomic features associated with clinical symptoms: higher gray-level values, greater variance in intensity values, and greater homogeneity. However, the adjustment of antiplatelet therapy in HPR patients modified the high-risk radiomic features, which showed lower gray-level values, less variance in intensity values, and more heterogeneous texture. The radiomic shape feature of elongation showed no notable difference between three groups. Adjustment of antiplatelet therapy might reduce the high-risk radiomic features of UIA patients with HPR after stent placement.

CD80 DNA methylation and single-nucleotide polymorphism associated with clopidogrel response: a whole-genome DNA methylation analysis in acute coronary syndrome

BackgroundDual antiplatelet therapy with clopidogrel and aspirin is the primary treatment for patients who undergo percutaneous coronary intervention. However, the interindividual difference in clopidogrel response is remarkable, and high on-treatment platelet reactivity (HTPR) can increase the risk of thrombotic events after percutaneous coronary intervention. ObjectiveWe studied novel accessible factors that possibly affect clopidogrel response in DNA methylation. MethodsMethylation 850K bead chips were used to detect DNA methylation levels. The platelet reactivity index (PRI) was determined in 330 subjects with acute coronary syndrome (ACS) after administration of clopidogrel 300 mg loading dose or at least 5 days of 75 mg daily maintenance dose. ResultsOverall, 32 discovery samples showed extreme clopidogrel response: 16 with HTPR (PRI > 75%) and 16 with non-HTPR (PRI < 26%). Overall, 61 differential methylation loci (DMLs) were observed between the 2 groups. Most were in the open sea and intergenic regions in the genome. In the validation stage, HTPR showed a lower level of CD80_cg06300880 methylation. Carriers of rs34394661 AA genotype, a CpG-single-nucleotide polymorphism at the CD80_cg06300880 locus, showed an increased odds for HTPR (overall odds ratio of patients with ACS = 7.31, 95% CI: 1.69-31.59, P = .008; non-ST elevation myocardial infarction-ACS: odds ratio = 12.69, 95% CI: 1.68-96.08, P = .01) and decreased CD80_cg06300880 methylation (P < .0001). Multivariate regression analysis showed that both CYP2C19 poor metabolizers and CD80_rs34394661 AA (P = .009) genotype were associated with higher odds for HTPR in the overall samples. In contrast, CD80_cg06300880 methylation (P = .002) caused lower odds for HTPR in patients with non-ST elevation myocardial infarction-ACS. ConclusionCD80_cg06300880 and CpG-single-nucleotide polymorphism rs34394661 could be independent predictors of HTPR with clopidogrel therapy.

High On-Treatment Platelet Reactivity in Patients Undergoing Complex Percutaneous Coronary Interventions.

Patient response to P2Y12 inhibitor therapy is heterogeneous, and those with high on-treatment platelet reactivity (HTPR) are at an increased risk of thrombotic complications. The aim of our study was to determine whether selecting a high-risk patient group of individuals after complex percutaneous coronary intervention (PCI) would show the clinical benefit of HTPR testing for preventing thrombotic complications. Blood samples of patients after complex PCI were acquired 1 day and 1 month after the intervention. The samples were tested using vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) and platelet function assay (PFA). The occurrence of clinically significant stent thrombosis with repeated revascularization of the target vessel was observed over a 1-year period. One day after PCI, 37% of patients had HTPR as established by VASP-P. One month after PCI, the percentage of patients with HTPR decreased to 30.9%. According to PFA, 1 day after PCI, 33.3% of patients had HTPR. This percentage declined to 19.8% after 1 month. All measurements identified a significantly higher proportion of HTPR in patients on clopidogrel compared to ticagrelor and prasugrel. Two cases of early stent thrombosis and 1 case of late stent thrombosis were identified. Further study of adenosine diphosphate receptor blocker on-treatment response in patients undergoing complex PCI is necessary.

Admission hyperglycemia as an independent predictor of clopidogrel high on-treatment platelet reactivity in ischemic stroke patients

Background: Admission hyperglycemia is a predictor of poor prognosis after ischemic stroke (IS). Previous studies have found that admission hyperglycemia was related to clopidogrel high on-treatment platelet reactivity (HTPR) in diabetic patients with myocardial infarction. However, reports on associations between admission hyperglycemia and clopidogrel HTPR remain scarce in IS patients. In this study, we assessed the correlation between admission hyperglycemia and clopidogrel HTPR in patients with IS. Methods: In this retrospective study, we included IS patients who were treated with clopidogrel for at least 5 days. Thromboelastography (TEG) was used to evaluate the platelet function. Clopidogrel HTPR was defined if adenosine diphosphate (ADP)-induced platelet fibrin clot strength (MAADP)&gt; 47 mm. Otherwise, it would be defined as clopidogrel normal on-treatment platelet reactivity (NTPR). Two groups were divided according to admission glucose of 7.8 mmol/L, consistent with previous studies on admission hyperglycemia. The independent risk factors of clopidogrel HTPR were assessed by multivariate logistic regression analysis. Results: A total of 147 patients were evaluated, and 42(28.57%) of patients were identified as clopidogrel HTPR. In the hyperglycemia group (admission glucose level ≥7.8mmol/L), 40.38% patients were defined as clopidogrel HTPR, which was significantly higher than in the normoglycemia group (22.11%, admission glucose level&lt;7.8mmol/L) (P=0.019). According to multivariate analysis, hyperglycemia was independently associated with clopidogrel HTPR (OR=8.36, 1.47-47.55, P=0.017). Admission glucose level was linearly correlated with MAADP (r=0.29, P=0.005). Furthermore, with the increase of admission glucose level tertiles, the incidence of clopidogrel HTPR increased gradually (P for trend=0.008). Conclusions: Admission hyperglycemia is an independent predictor of clopidogrel HTPR and the glucose level is linearly correlated with MAADP in IS patients. Besides, with the increase of glucose level tertiles, the incidence of clopidogrel HTPR increases gradually.

High on-treatment platelet reactivity is associated with poor outcomes after ischemic stroke: A meta-analysis.

High on-treatment platelet reactivity (HTPR) determined by platelet function assays is present in certain patients with ischemic stroke or transient ischemic attack (TIA). However, it is unclear whether HTPR is associated with poor clinical outcomes. Our study aimed to investigate the relationship of HTPR with recurrent vascular events in ischemic stroke or TIA. Pubmed (MEDLINE), EMBASE, and Cochrane Library were searched for eligible studies from inception to January 1, 2022. Stata 17.0 software was used to calculate the risk ratio (RR). Subgroup and sensitivity analyses were conducted to assess the source of heterogeneity. A random-effects model was used when heterogeneity was present. Primary endpoint of the meta-analysis was the risk ratio of recurrent vascular events in HTPR Patients. While stroke and TIA, all-cause death, early neurological deterioration, early new ischemic lesions, and stroke severity measured by National Institute of Health Stroke Scale (NIHSS) scores at admission were also pooled. Thirty articles (7995 patients) were eligible including 28 cohort studies and 2 prospective case-control studies. The prevalence of HTPR varied from 5.9% to 60%. HTPR was associated with an increased risk of recurrent vascular events (RR=2.94, 95% CI 2.04-4.23), stroke recurrence (RR=2.05; 95% CI 1.43-2.95), and all-cause mortality (RR=2.43; 95% CI 1.83-3.22). Subgroup analysis showed that HTPR determined by optical aggregometry, Verify-Now system and 11dh TXB2 is related to a higher risk of recurrent vascular events (RR=3.53, 95% CI 1.51-9.40; RR=2.16, 95% CI 1.02-4.56; RR=3.76, 95% CI 1.51-9.40, respectively). Moreover, patients with HTPR had an increased incidence of early neurological deterioration (RR=2.75; 95% CI 1.76-4.30) and higher NIHSS scores at admission (Mean difference 0.19, 95% CI 0.01-0.36). This meta-analysis demonstrates HTPR is associated with higher risk of recurrent vascular events, early neurological deterioration and increased severity in patients with ischemic stroke and TIA. HTPR measured by platelet function assays may guide the use of antiplatelet agents in ischemic stroke and TIA.

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

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

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.

Impact of high on-treatment platelet reactivity after angioplasty in patients with critical limb ischemia

ObjectivesDual antiplatelet therapy (DAPT) with aspirin and clopidogrel is standard of care in patients with peripheral artery disease (PAD) after percutaneous transluminal angioplasty (PTA). However, high on treatment platelet reactivity (HTPR) to DAPT is frequent and associated with major adverse limb events (MALE) in PAD patients. Nevertheless, association of MALE and HTPR in patients with critical limb ischemia (CLI) is not known. Moreover, comorbidities might confound response to antiplatelet medication further. Hence, in this trial we analyzed pharmacodynamic responses to DAPT and clinical events in CLI patients post PTA. MethodsIn this prospective single center pilot analysis, we included 71 CLI patients. Patients received DAPT after PTA. Antiplatelet effect were measured by light transmission aggregometry (LTA) and vasodilator-stimulated protein phosphorylation assay (VASP). MALE, major adverse cardiac and cerebrovascular events (MACCE) and BARC bleeding within 12 months follow-up were assessed. ResultsMean age of patients was 73.37 ± 7.36 years and 47 (66.2%) were male. Overall HTPR appeared in 46 patients (64.8%). MALE and MACCE showed no differences between patients with and patients without HTPR. However, bleeding was higher in patients with sufficient pharmacodynamic response to DAPT (Bleeding - HTPR: 13.4% vs. no HTPR: 36.0%; log-rank HR: 0.32; 95% CI 0.1079 to 0.9396 p = 0.0217). This finding remained robust in multivariate analysis. ConclusionHTPR to DAPT is frequent in CLI patients. However, bleeding was higher in patients with sufficient response to DAPT. Ischemic events did not differ. Hence, CLI patients might benefit from an alternative antithrombotic approach.

Intensified P2Y12 inhibition for high-on treatment platelet reactivity

High on treatment platelet reactivity (HPR) during treatment with clopidogrel has been consistently found to be strong risk factor for recurrent ischemic events after percutaneous coronary intervention (PCI). Insufficient P2Y12 receptor inhibition contributes to HPR measured by the VerifyNow (VN) assay. Prasugrel and ticagrelor are more potent P2Y12 inhibitors than clopidogrel and commonly substituted for clopidogrel when HPR is documented, however benefit of VN guided intensified antiplatelet therapy is uncertain. We identified patients who had undergone platelet reactivity testing after PCI with VN after pretreatment with clopidogrel (n = 252) in a single center observational analysis. Patients who had HPR defined as PRU > 208 were switched to alternate P2Y12 inhibitors. Primary clinical endpoint was 1-year post PCI combined cardiovascular death, myocardial infarction (MI), and stent thrombosis. One hundred and eight (43%) subjects had HPR and were switched to prasugrel (n = 60) and ticagrelor (n = 48). Risk of recurrent 1-year primary endpoint remained higher for HPR patients switched to either ticagrelor or prasugrel as compared to subjects who had low on treatment platelet reactivity (n = 144) (LPR) on clopidogrel [Hazard Ratio: 3.5 (95% CI 1.1-11.1); p = 0.036)]. Propensity score matched analysis demonstrated higher event rates in patients with HPR on alternate P2Y12 inhibitor as compared to patients with LPR (log-rank: p = 0.044). The increased risk of recurrent events associated with HPR measured by VN is not completely attenuated by switching to more potent P2Y12 inhibitors. Non-P2Y12 mediated pathways likely contribute to increased incidence of thrombotic events after PCI in subjects with HPR.

Impact of Continuous P2Y12 Inhibition Tailoring in Acute Coronary Syndrome and Genetically Impaired Clopidogrel Absorption.

Clopidogrel is still widely used in acute coronary syndrome despite the development of more potent P2Y12 inhibitors. Previously, we conducted a trial that evaluated serial clopidogrel dose adjustment based on platelet function testing in acute coronary syndrome patients with initial high on-treatment platelet reactivity (HTPR). In this substudy, we performed post hoc analysis of the effect of ABCB1 genetic variants C3435T and G2677T/A on platelet inhibition and outcomes. There were no differences in the proportion of HTPR patients among C3435T carriers and noncarriers in both interventional and control group. G2677T carriers expressed significantly higher proportion of HTPR pattern throughout 12-month follow-up in the control group with no difference in the interventional group. There was no difference in ischemic outcomes between C3435T and G2677T carriers and noncarriers in both groups of patients. The results indicate that ABCB1 genotyping is not useful to guide clopidogrel therapy tailoring to improve high-risk patient management.

Reasons for the Failure of Platelet Function Testing to Adjust Antiplatelet Therapy: Pharmacodynamic Insights From the ARCTIC Study.

In the ARCTIC trial (Assessment by a Double Randomization of a Conventional Antiplatelet Strategy Versus a Monitoring-Guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption Versus Continuation One Year After Stenting), treatment adjustment following platelet function testing failed to improve clinical outcomes. However, high-on-treatment platelet reactivity (HPR) is considered as a predictor of poor ischemic outcome. This prespecified substudy evaluated clinical outcomes according to the residual platelet reactivity status after antiplatelet therapy adjustment. We analyzed the 1213 patients assigned to the monitoring arm of the ARCTIC trial in whom platelet reactivity was evaluated by the VerifyNow P2Y12 test before percutaneous coronary intervention and during the maintenance phase (at 14 days). HPR was defined as platelet reaction unit≥235U. The primary ischemic end point, a composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization and the safety end point of major bleeding were assessed according to the platelet reactivity status. Before percutaneous coronary intervention, 35.7% of patients displayed HPR (n=419). During the acute phase, between percutaneous coronary intervention and the 14-day platelet function testing, ischemic (adjusted hazard ratio, 0.94 [95% CI, 0.74-1.18]; P=0.58) and safety outcomes (hazard ratio, 1.28 [95% CI, 0.22-7.59]; P=0.78) were similar in HPR and non-HPR patients. During the maintenance phase, the proportion of HPR patients (n=186, 17.4%) decreased by 56%. At 1-year, there was no difference for the ischemic end point (5.9% versus 6.0%; adjusted hazard ratio, 0.79 [95% CI, 0.40-1.58]; P=0.51) and a nonsignificant higher rate of major bleedings (2.7% versus 1.0%, hazard ratio, 2.83 [95% CI, 0.96-8.41]; P=0.06) in HPR versus non-HPR patients. The proportion of HPR was halved after platelet function testing and treatment adjustment but without significant ischemic benefit at 1 year. HPR seems more as a modifiable risk marker than a risk factor of ischemic outcome. URL: https://www.clinicaltrials.gov. Unique identifier: NCT00827411.

Measuring high on-treatment platelet reactivity in clinical practice; should we use a panel of platelet function tests?

: High on-treatment platelet reactivity (HPR) on P2Y12-inhibitors in patients treated with dual antiplatelet therapy is strongly associated with adverse ischaemic events. Studies have shown conflicting results with regard to the correlation and agreement between the different tests. Several assays are available to establish HPR. A composite advice based on more than one test might be a better way to identify HPR patients. To compare HPR rates and agreement between individual platelet function tests and a panel of three tests In our large percutaneous coronary intervention centre, all patients who suffered a stent thrombosis were invited back to a dedicated clinic. Platelet function testing was performed in all patients and matched control patients. HPR rates were compared between individual tests and with a composite comprised of three tests. A total of 242 patients were included, of whom in 193 patients all tests were available. HPR rates ranged from 14.6% [VerifyNow cut-off >235 platelet reactivity units (PRU)] to 49.7% (Vasodilator-Stimulated Phosphoprotein Assay). HPR according to the composite advice (≥2 out of 3 tests indicating HPR) was present in 29.8% of patients. The best correlation with the composite advice was observed with light transmittance aggregometry (kappa = 0.78) and VerifyNow (lower cut-off >208 PRU; kappa = 0.68). VerifyNow with cut-off more than 235 PRU identified the smallest proportion of patients with HPR, whereas Vasodilator-Stimulated Phosphoprotein Assay seemed to 'over-identify' HPR. In this real life patient cohort, a large variability was observed between four different platelet function tests. The use of a composite advice based on three tests is a promising alternative.

Platelet function monitoring for the prediction of clinical outcomes: A pooled analysis of the randomized ARCTIC and ANTARCTIC trials

Platelet function testing offers the possibility to individualize antiplatelet therapy in coronary artery disease patients but failed to improve clinical outcomes in randomized trials. However, high-on-treatment platelet reactivity (HPR) remains a risk factor for recurrent ischemic events and low-on-treatment platelet reactivity (LPR) is a risk factor for bleedings. We collected data of patients assigned to the monitoring arm of the randomized ARCTIC and ANTARCTIC trials that evaluated the platelet reactivity by the VerifyNow P2Y12 test two weeks after coronary stenting. HPR was defined by PRU ≥ 208, LPR by PRU ≤ 85 and optimal platelet reactivity (OPR) by 85. Among the 1418 patients included, HPR was present in 269 patients (18.9%), OPR was reached in 681 patients (48.0%) and LPR in 468 patients (33.0%). The primary composite endpoint occurred in 9.7%, 11.5% and 14.3% respectively. There was no significant difference in the net clinical benefit between HPR and OPR patients (adjusted HR: 0.91(0.48–1.72); P = 0.77) and between LPR and OPR patients (adjusted HR: 1.13 (0.67–1.90); P = 0.64). There were no difference in the individual clinical endpoints between the three groups. ROC curve analysis demonstrated that PRU when used for treatment adjustment has a limited ability to discriminate net clinical benefit, ischemic or bleeding complications (curve–c index = 0.55, 0.51 or 0.59, respectively). Two weeks after stenting, an optimal platelet reactivity was obtained in less than half of the population. The net clinical benefit of these patients was not different from that of patients with HPR and LPR who had treatment adjustment.

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.

Point of Care Tests VerifyNow P2Y12 and INNOVANCE PFA P2Y Compared to Light Transmittance Aggregometry After Fibrinolysis.

Detection of high on-treatment platelet reactivity (HPR) by point-of-care tests has not been validated after successful fibrinolysis for ST-elevation myocardial infarction. We assessed the validity of the point-of-care VerifyNow P2Y12 (VN) and INNOVANCE PFA P2Y (PFA) tests on HPR compared to light transmittance aggregometry (LTA) in these patients. The HPR was identified in 10 (34.5%) patients, 15 (51.7%) patients, and 14 (50%) patients using LTA, VN, and PFA, respectively. Discrepancies were observed between the tests despite significant correlations between platelet reactivity measures by LTA and VN (r = 0.74; P < .0001) and LTA and PFA (r = .75; P < .0001). Compared to LTA, VN and PFA were associated with a 92% and 53% and 92% and 64% positive predictive value (PPV) and negative predictive value (NPV), respectively, in detecting HPR. When combined, VN and PFA results yielded 90% and 100% PPV and NPV values if discrepancies between the 2 tests were considered as non-HPR. The VN or PFA identify patients without HPR correctly but overestimate the proportion of HPR patients. The association of the 2 tests, in case of HPR, improves the accuracy of the detection of HPR.

Proteinuria Predicts Resistance to Antiplatelet Therapy in Ischemic Stroke.

The occurrence of a stroke while on antiplatelet agents presents a therapeutic dilemma. One of the main causes for recurrent strokes is antiplatelet resistance more commonly known as high on treatment platelet reactivity (HTPR). Prior studies have established that proteinuria is associated with HTPR following myocardial infarction. Here, we investigated whether dipstick proteinuria correlates with HTPR in patients presenting with stroke. We performed a retrospective cohort analysis of 102 patients admitted for a recurrent ischemic stroke that had either a VerifyNow aspirin or VerifyNow clopidogrel laboratory test performed to assess platelet reactivity. Dipstick proteinuria was defined as >30mg/dl (2+ or more). HTPR was defined as an aspirin resistance unit >550 for aspirin and a P2Y12 reactivity unit >208 for clopidogrel. Patients with proteinuria on dipstick were significantly more likely to have HTPR to either aspirin (p value 0.017) or clopidogrel (p value 0.017). After controlling for age, smoking, diabetes, hypertension, CAD and GFR, proteinuria was an independent predictor of HTPR for patient taking aspirin (p=0.025). Platelet resistance is an entity that undermines the activity of antiplatelet agents in reducing stroke risk. Here, we demonstrate an association with increased platelet reactivity and proteinuria. This highlights a potential new therapeutic target in reducing future stroke risk.

Clopidogrel High On-Treatment Platelet Reactivity in Patients with Carotid Artery Stenosis Undergoing Endarterectomy. A Pilot Study.

A considerable number of patients do not achieve an adequate response to clopidogrel. Our study aimed to evaluate genetic and non-genetic factors as possible risks for clopidogrel high on-treatment platelet reactivity (HTPR) in patients (n=112) with carotid artery stenosis undergoing endarterectomy (CEA). Using multiple-electrode impedance aggregometry (MEA) the antiplatelet effectiveness of clopidogrel was measured after 24 h, 7 and 30 days of clopidogrel treatment, which was introduced after elective CEA at a dose of 75 mg daily, for at least 30 days. HTPR was observed among 25% patients after clopidogrel therapy for 30 days. Further analysis showed that 53.3% of patients carrying the CYP2C19*2 gene variant had clopidogrel-HTPR, while in the wild type group there were 14.6% (p<0.001). Multivariate logistic regression analysis identified the CYP2C19*2 variant allele (OR 4.384; 95% CI 1.296-14.833, p=0.017) and high total cholesterol level (OR 2.090; 95% CI 1.263-3.459, p=0.004) as the only independent risk factors for clopidogrel-HTPR. The CYP2C19*2 gene variant and high total cholesterol level were major factors for clopidogrel- HTPR in patients with carotid artery stenosis undergoing CEA.