High Platelet Reactivity Rates Research Articles

Platelet P2Y12 inhibiting therapy in adjunct to vascular dose of rivaroxaban or aspirin: a pharmacodynamic study of dual pathway inhibition vs. dual antiplatelet therapy.

Dual pathway inhibition (DPI) by adding a vascular dose of rivaroxaban to a single antiplatelet agent has emerged as a promising antithrombotic strategy. However, in most studies the antiplatelet agent of choice used in adjunct to a vascular dose of rivaroxaban was aspirin, and data on a P2Y12 inhibitor and how this DPI regimen compares with standard dual antiplatelet therapy (DAPT) are limited. This investigation was a substudy analysis conducted in selected cohorts of patients with stable atherosclerotic disease enrolled from a larger prospective, open-label, parallel-group pharmacodynamic (PD) study. We analysed data from 40 patients treated with either clopidogrel- or ticagrelor-based DAPT first, and clopidogrel- or ticagrelor-based DPI thereafter. PD measures explored key pathways involved in thrombus formation and included markers of (1) P2Y12 reactivity, (2) platelet-mediated global thrombogenicity, (3) cyclooxygenase-1 activity, (4) thrombin receptor-activating peptide (TRAP)-induced platelet aggregation, (5) tissue factor (TF)-induced platelet aggregation, and (6) thrombin generation. Compared with DAPT, on a background of the same P2Y12 inhibitor (clopidogrel or ticagrelor), DPI was associated with reduced thrombin generation, increased markers of cyclooxygenase-1 activity and TRAP-induced platelet aggregation, and no differences in markers of P2Y12 signalling, platelet-mediated global thrombogenicity, and TF-induced platelet aggregation. In an analysis according to P2Y12 inhibitor type, ticagrelor reduced markers of platelet-mediated global thrombogenicity, P2Y12 signalling, and rates of high platelet reactivity compared with clopidogrel. Compared with DAPT with aspirin and a P2Y12 inhibitor, the use of a P2Y12 inhibitor in adjunct to a vascular dose of rivaroxaban as part of a DPI strategy is associated with similar effects on platelet-mediated global thrombogenicity but reduced thrombin generation. A DPI strategy with ticagrelor is associated with enhanced antithrombotic efficacy, the clinical implications of which warrant larger scale investigations. ClinicalTrials.gov identifier: NCT03718429.

Platelet reactivity and bleeding outcomes in female patients presenting with ST-segment elevation myocardial infarction: a COMPARE CRUSH substudy

Abstract Background/Introduction Females presenting with ST-segment elevation myocardial infarction (STEMI) are characterized by an increased risk of bleeding after primary percutaneous coronary intervention (pPCI) compared with males. The reason for increased bleeding rates is multifactorial, including age, comorbidities, vessel anatomy and possible differences in platelet biology. Data about platelet reactivity levels in females versus males presenting with STEMI is scarce. Purpose Investigation of gender-driven variances in platelet reactivity and bleeding outcomes in STEMI patients planned to undergo pPCI. Methods The COMPARE CRUSH trial was a randomized multicenter ambulance trial assessing the effect of prehospital administration of P2Y12 inhibitor loading dose with crushed versus integral prasugrel tablets in STEMI patients. We assessed the occurrence of high platelet reactivity (HPR), predictors of HPR at baseline and bleeding outcomes between females and males. Blood samples were analyzed at four prespecified time points using VerifyNow. Results The COMPARE CRUSH trial included 633 STEMI patients in the period between November 2017 and March 2020. Females more frequently exhibited HPR at baseline than males (76% vs. 41%, odds ratio (OR), 4.58 [95% CI, 2.52 to 8.32], p<0.01). Moreover, female sex was a strong, independent predictor for HPR at baseline (OR, 4.93 [95% CI, 2.30 to 10.57], p<0.01). HPR rates at other time points were not significantly different between females and males. The risk of bleeding within the first 48 hours was significantly increased in females (OR, 6.02 [95% CI, 2.58 to 14.08], p<0.01), but after adjustment for baseline characteristics this increased risk was no longer statistically significant (OR, 2.61 [95% CI, 0.73 to 9.32], p=0.14). Conclusion Female sex is an independent predictor for occurrence of HPR at baseline in STEMI patients. However, females exhibit a stronger platelet inhibition effect by oral P2Y12 inhibitors than males, which may contribute to an increased bleeding risk. A more tailored antiplatelet therapy approach should be considered for female STEMI patients to reduce bleeding risk. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Unrestricted grants from Daiichi-Sankyo and Shanghai MicroPort Medical.

Stent Thrombosis Risk Over Time on the Basis of Clinical Presentation and PlateletReactivity: Analysis From ADAPT-DES.

The aim of this study was to determine the risk period for increased stent thrombosis (ST) after percutaneous coronary intervention (PCI) in patients with acute coronary syndromes (ACS) and whether this increased risk is related to high platelet reactivity (HPR). ST risk after PCI is higher among patients with ACS than those with stable ischemic heart disease. When ST risk is highest in patients with ACS and how that is affected by HPR is unknown. Using the ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) registry, ST rates during 2-year follow-up post-PCI with drug-eluting stents were compared among patients presenting with ACS (myocardial infarction [MI] or unstable angina) or stable ischemic heart disease (non-ACS). Landmark analyses were done at 30days and 1 year post-PCI. Platelet reactivity on aspirin and clopidogrel post-PCI was assessed using VerifyNow assays. Of 8,582 patients, 2,063 presented with MI, 2,370 with unstable angina, and 4,149 with non-ACS. Incidence rates of HPR were 48.0%, 43.3%, and 39.8%, respectively (p<0.001). Within the first 30days post-PCI, patients presenting with MI had increased ST risk compared with patients with non-ACS (hazard ratio [HR]: 4.52; 95% confidence interval [CI]: 2.01 to 10.14; p<0.001). After 30days, relative ST risks were progressively lower and no longer significant between groups (31days to 1 year post-PCI: HR: 1.97; 95%CI: 0.80 to 4.85; >1 year post-PCI: HR: 0.89; 95%CI: 0.27 to 2.92). The elevated ST risk in patients with MI within 30days was largely confined to those with HPR on clopidogrel (HR: 5.77; 95%CI: 2.13 to 15.63; p<0.001). Among patients undergoing PCI, rates of ST during 2-year follow-up were highest in those with MI and lowest in those with non-ACS. Increased ST risk in patients with MI was greatest in the first 30days post-PCI and was observed predominantly among those with increased HPR on clopidogrel. These findings emphasize the importance of adequate P2Y12 inhibition after MI, especially within the first 30days after stent implantation.

Derivation, Validation, and Prognostic Utility of a Prediction Rule for Nonresponse to Clopidogrel: The ABCD-GENE Score

ObjectivesThe aim of this study was to develop a risk score integrating cytochrome P450 2C19 loss-of-function genotypes with clinical risk factors influencing clopidogrel response that would allow the identification with more precision of subjects at risk for high platelet reactivity (HPR) and adverse clinical outcomes. BackgroundClopidogrel is the most broadly used platelet P2Y12 inhibitor. However, a considerable number of patients achieve inadequate platelet inhibition, with persistent HPR, an established marker of increased thrombotic risk, underscoring the need for tools to help identify these subjects. Although carriers of loss-of-function alleles of the cytochrome P450 2C19 enzyme have reduced clopidogrel metabolism leading to increased rates of HPR and thrombotic complications, this explains only a fraction of the pharmacodynamic response to clopidogrel, and a number of clinical factors have also been shown to have contributing roles. MethodsThree prospective and independent studies were used to: 1) develop a risk score integrating genetic and clinical factors to identify patients with HPR while on clopidogrel; 2) investigate the external validity of the risk score; and 3) define clinical outcomes associated with the risk score in a cohort of patients with myocardial infarction treated with clopidogrel. ResultsA risk score ABCD-GENE (Age, Body Mass Index, Chronic Kidney Disease, Diabetes Mellitus, and Genotyping) was developed incorporating 5 independent predictors of HPR: 4 clinical (age >75 years, body mass index >30 kg/m2, chronic kidney disease [glomerular filtration rate <60 ml/min], and diabetes mellitus) and 1 genetic (cytochrome P450 2C19 loss-of-function alleles). The C-statistics for the score as an integer variable were 0.71 (95% confidence interval [CI]: 0.68 to 0.75) and 0.64 (95% CI: 0.60 to 0.67) in the pharmacodynamic derivation and validation cohorts, respectively. A cutoff score ≥10 was associated with the best sensitivity and specificity to identify HPR status. The C-statistics for the score were 0.67 (95% CI: 0.64 to 0.71) for all-cause death and 0.66 (95% CI: 0.63 to 0.69) for the composite of all-cause death, stroke, or myocardial infarction at 1 year. Using multiple models for adjustment, the ABCD-GENE score consistently and independently correlated with all-cause death, as well as with the composite of all-cause death, stroke, or myocardial infarction, both as a continuous variable and by using the cutoff of ≥10. The score did not predict bleeding. ConclusionsThe ABCD-GENE score is a simple tool to identify patients with HPR on clopidogrel and who are at increased risk for adverse ischemic events, including mortality, following an acute myocardial infarction. In patients with a high ABCD-GENE score, long-term oral P2Y12 inhibitors other than clopidogrel should be considered.

High Platelet Reactivity after Transition from Cangrelor to Ticagrelor in Hypothermic Cardiac Arrest Survivors with ST-Segment Elevation Myocardial Infarction.

Transition from cangrelor to oral P2Y12 inhibitors after PCI carries the risk of platelet function recovery and acute stent thrombosis. Whether the recommended transition regimen is appropriate for hypothermic cardiac arrest survivors is unknown. We assessed the rate of high platelet reactivity (HPR) after transition from cangrelor to ticagrelor in hypothermic cardiac arrest survivors. Adult survivors of out-of-hospital cardiac arrest with ST-segment elevation myocardial infarction (STEMI), who were treated for hypothermia (33 °C ± 1) and received intravenous cangrelor during PCI and subsequent oral loading with 180mg ticagrelor were enrolled in this prospective observational cohort study. Platelet function was assessed using whole blood aggregometry. HPR was defined as AUC > 46U. The primary endpoint was the rate of HPR (%) at predefined time points during the first 24 h after cangrelor cessation. Poisson regression was used to estimate the relationship between the overlap time of cangrelor and ticagrelor co-administration and the number of subsequent HPR episodes, expressed as incidence rate ratio (IRR) with 95% confidence interval (95%CI). Between December 2017 and October 2019 16 patients (81% male, 58 years) were enrolled. On average, ticagrelor was administered 39 min (IQR 5–50) before the end of cangrelor infusion. The rate of HPR was highest 90 min after cangrelor cessation and was present in 44% (7/16) of patients. The number of HPR episodes increased significantly with decreasing overlap time of cangrelor and ticagrelor co-administration (IRR 1.03, 95%CI 1.01–1.05; p = 0.005). In this selected cohort of hypothermic cardiac arrest survivors who received cangrelor during PCI, ticagrelor loading within the recommended time frame before cangrelor cessation resulted in a substantial amount of patients with HPR.

Pharmacodynamic study of prasugrel or clopidogrel in non-ST-elevation acute coronary syndrome with CYP2C19 genetic variants undergoing percutaneous coronary intervention (PRAISE-GENE trial)

BackgroundThe CYP2C19*2 or *3 loss-of-function (LOF) allele is associated with high platelet reactivity (HPR) on clopidogrel treatment. East Asians may benefit from a lower dose of prasugrel due to their more potent platelet inhibitory response. The impact of LOF alleles on the pharmacodynamic response to half-dose prasugrel in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI) is unknown. MethodsSeventy patients with the LOF alleles were assigned to half-dose prasugrel (n = 35, 30-mg load followed by 5 mg daily) or clopidogrel (n = 35, 600-mg load followed by 75 mg daily). The primary endpoint was the rate of HPR, defined as VerifyNow-P2Y12 reaction unit (PRU) >235, at 24 h post loading. ResultsPrasugrel achieved a lower PRU compared to clopidogrel after loading (119 [56–175] vs. 245 [189–299]), at 24 h (34 [8–58] vs. 196 [122–244]), and at 30 days (134 [98–189] vs. 203 [144–248]). Prasugrel had a lower rate of HPR after loading (5.7% vs. 57.1%, p <0.001), at 24 h (2.9% vs. 28.6%, p=0.006), and at 30 days (11.4% vs. 34.3%, p=0.004). Prasugrel had a similar rate of optimal platelet reactivity at 30 days (71.4% vs. 60.0%, p=0.450). There was no significant difference in the occurrence of periprocedural myonecrosis within 48 h after PCI with clopidogrel and prasugrel (22.9% vs. 17.1%, p>0.960). ConclusionsHalf-dose prasugrel provided potent platelet inhibition in NSTE-ACS patients that were carriers of the CYP2C19*2 or *3 allele, with a lower rate of HPR. Periprocedural myonecrosis was not significantly different in the 2 groups.

P1934Platelet inhibitory profiles of prasugrel versus ticagrelor in patients with CYP2C19 loss-of-function genotypes undergoing percutaneous coronary intervention: results of a randomized feasibility study

Abstract Background Although clopidogrel is the most widely used P2Y12 inhibitor, loss-of-function (LOF) allelic variants located within the hepatic cytochrome P450 (CYP) 2C19 gene lead to attenuated bioactivation, increased rates of high platelet reactivity (HPR), and worse outcomes in patients undergoing percutaneous coronary intervention (PCI). Drug regulating authorities have suggested using alternative P2Y12 inhibitors (i.e., prasugrel or ticagrelor) in these patients. However, tailoring antiplatelet therapy in clinical practice according to results of genetic testing has been limited due to lack of access to promptly available results. Moreover, there are no head-to-head pharmacodynamic (PD) comparisons of prasugrel vs ticagrelor among patients with CYP2C19 LOF alleles. Purpose The aim of this study was to evaluate the feasibility of using rapid genetic testing in clinical practice and to compare the PD effects of prasugrel vs ticagrelor in patients undergoing PCI with CYP2C19 LOF alleles. Methods This was a prospective, randomized study conducted in patients with stable coronary artery disease and non-ST elevation acute coronary syndrome scheduled for left heart catheterization (LHC) with the intent to undergo PCI. Patients underwent rapid genetic testing using the Spartan RX assay, which defines CYP2C19 genetic status within 1 hour, allowing patients to be genotyped the same day of their LHC. Patients who were carriers of at least one LOF (*2 or *3) allele were randomized to receive either prasugrel [60mg loading dose (LD) - 10mg/day maintenance dose (MD)] or ticagrelor (180mg LD - 90mg b.i.d MD). Blood samples for PD analysis by VerifyNow were collected at 5 time points: baseline (prior to PCI), 30 minutes, 2 hours, 24 hours (or at hospital discharge whichever came first), and 1–4 weeks post-LD. All patients were treated with aspirin. The primary endpoint of our study was the non-inferiority in platelet reactivity, measured as PRU, at 24 hours of prasugrel vs ticagrelor in LOF allele carriers. Results A total of 781 consecutive patients scheduled for LHC were genotyped, of whom 223 (28.5%) were carriers of at least one LOF. Of these, 65 patients underwent PCI and randomized to prasugrel (n=32) vs ticagrelor (n=33). PRU levels at 24 hours were 33 vs 36 (prasugrel vs ticagrelor; mean difference = −3; 95% CI: −28 to 22; p=0.814) meeting the primary endpoint of non-inferiority. Both prasugrel and ticagrelor significantly reduced PRU to a similar extent with no differences between groups at all other time points (Figure). Accordingly, HPR rates were low and similar between groups. PRU by VerifyNow Conclusion Rapid genetic testing using the Spartan assay is feasible providing results in a timely fashion in a real-world clinical practice of patients undergoing PCI. Among patients with CYP2C19 LOF carrier status, prasugrel and ticagrelor are associated with similar levels of platelet inhibition. Acknowledgement/Funding Genetic testing was provided by Spartan RX

P2551A randomized, pharmacodynamic comparison of low dose ticagrelor (60mg bid) to low dose prasugrel (5mg od) in patients with prior myocardial infarction: the ALTIC-2 study

Abstract Background In patients with prior myocardial infarction (MI) and features of high ischemic and low bleeding risk, extending dual antiplatelet therapy beyond 1 year or reinitiating treatment is reasonable. A lower than the standard dose, namely ticagrelor 60mg bid instead of 90mg bid and prasugrel 5mg od instead of 10mg od, may be associated with reduced bleeding risk. In the Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial, ticagrelor 60mg bid reduced the ischemic events, at the cost of increased bleeding events. There is no data on the pharmacodynamic efficacy of ticagrelor 60mg bid over low dose prasugrel (5mg od). Purpose To compare platelet reactivity (PR) between prasugrel 5mg od and ticagrelor 60 mg bid in the chronic phase of stable post-MI patients. Methods The ALTIC-2 was a prospective, single-center, randomized, crossover study involving patients on aspirin 100mg od and PEGASUS-TIMI 54 characteristics: &gt;50 years old with MI 1–3 years earlier and at least one high risk feature (age &gt;65 years, diabetes mellitus, a second MI, multivessel disease, or renal dysfunction). After a 14-day washout period–if on P2Y12 receptor antagonist therapy-, patients were randomized to either ticagrelor 60mg bid or prasugrel 5mg od for 14 days, with a crossover directly to the alternate treatment for another 14 days. PR was assessed by the VerifyNow P2Y12 reaction assay in PRU at baseline, pre and post-crossover, 2 hours post last study-drug dose. Statistical analysis was performed with STATA13.0. Results We recruited 20 eligible patients (80% men, 40% diabetics, 65% smokers, 70% multivessel disease, with a mean age of 64.8±6.3 years) for participation in the study (10 in each treatment sequence). During pre-crossover period, in the group allocated first in prasugrel PR levels (mean ± standard deviation) decreased from 238.4±50 to 128±47 (p&lt;0.0001), while in the group allocated first in ticagrelor levels of PR decreased from 259.6±36 to 30.8±29 (p&lt;0.0001). At the end of the 2 treatments, PR levels decreased to 33±26 in the group allocated first in prasugrel (p=0.0001), while in the group allocated first in ticagrelor levels of PR increased to 136±61 (p=0.0001). Analysis of combined data of PR levels (pre- and post-crossover, primary endpoint) adjusted for baseline values and age showed a difference of PR levels (β: −103, 95% CI: −120 to −85) in favor of ticagrelor. A non-significant period effect was observed and no carry effect was found. The secondary endpoint of high PR (&gt;208 PRU) rate was 0% for ticagrelor and 5.0% for prasugrel. No patient exhibited a major bleeding event at either treatment group. Conclusions In patients with previous MI and at least one other high-risk feature, low dose of ticagrelor results in a significantly lower PR compared to prasugrel 5mg od. Acknowledgement/Funding National and Kapodistrian University of Athens

The ABCB1, CYP2C19, CYP3A5 and CYP4F2 genetic polymorphisms and platelet reactivity in the early phases of acute coronary syndromes.

Abstract Background The aim was to study seven polymorphic markers of genes encoding proteins involved in the absorption, metabolism and pharmacokinetics of clopidogrel among patients with an acute coronary syndrome (ACS), who have undergone percutaneous coronary intervention (PCI). Methods Eighty-one ACS and PCI patients older than 18 years and treated with dual antiplatelet therapy were enrolled in the study. Platelet function testing and ABCB1, CYP2C19, CYP3A5 and CYP4F2 genotyping were performed. The predictive role of categorical variables, such as genotypes (carriers and non-carriers of polymorphism), on platelet reactivity (platelet reactivity units [PRU] platelet inhibition [PI]) was assessed by logistic regression (for categorical outcomes) and linear regression (for continuous outcomes) analysis. A p-value&lt;0.05 was considered significant. The allele frequencies were estimated by gene counting, and Hardy-Weinberg equilibrium was tested using the chi-square test. Results Regarding clopidogrel response, 62 patients (76.5%) were clopidogrel responders and 19 were non-responders (23.5%). Mean PRU value and the percentage of platelet inhibition were 170.0±50.9 PRU and 28.6±19.9%, respectively. The effects of the CYP2C19*2 polymorphisms on PRU (166.0±50.8 vs. 190.7±48.2, p&lt;0.038) and PI (30.6±20.0 vs. 18.1±16.3, p&lt;0.013) were observed, and the rates of high platelet reactivity (HPR) were lower in CYP2C19*1/*1 than those in CYP2C19*1/*2+CYP2C19*2/*2 (16.2% vs. 53.8% p&lt;0.0067). In comparison, no significant difference in PRU value and PI was observed at &lt;5 days between the rest of polymorphisms (p&gt;0.05). Based on the logistic regression analysis, CYP2C19*2 (OR: 4.365, CI: 1.25–17.67, p=0.022) was an independent predictor of HPR at &lt;5 days, as was the stent diameter (OR: 0.219, CI: 0.002–0.229, p=0.049). The remaining polymorphisms had no influence. Conclusions The reactivity of the on-clopidogrel platelet in the early phase of ACS is influenced primarily by the CYP2C19 polymorphisms. We believe that the findings of the present study could supply additional evidence regarding the clinical appropriateness of the CYP2C19 genetic testing for designing suitable antiplatelet therapy in the early phase of ACS.

Ticagrelor with Aspirin on Platelet Reactivity in Minor Stroke or Transient Ischemic Attack: A Randomised, Open-Label, Blinded-Endpoint Trial

Background: Previous studies have shown the therapeutic benefits of using ticagrelor, aspirin, or clopidogrel for stroke. However, limited data are available on the safety and efficacy of ticagrelor plus aspirin compared with clopidogrel plus aspirin for treating patients with acute stroke or transient ischemic attack (TIA). Methods: In this randomized, open-label, controlled, blinded-endpoint trial conducted at 26 centers in China, we compared ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) with clopidogrel (300 mg loading dose, 75 mg daily thereafter) on a background of aspirin (100 mg daily for the first 21 days) for reducing high platelet reactivity (defined as P2Y12 reaction unit>208) in 675 patients with acute minor stroke or TIA during 90 days. Findings: At 90 days, high platelet reactivity occurred in 35 of 280 patients (12.5%) in the ticagrelor/aspirin group and 86 of 290 patients (29.7%) in the clopidogrel/aspirin group (odds ratio [OR], 0.34; 95% confidence intervals [CI], 0.22 to 0.52; P<0.001), and 10.8% versus 35.4% (OR, 0.22, 95% CI, 0.12 to 0.40; P<0.001) of patients carrying CYP2C19 loss-of-function alleles (P=0.04 for interaction). Stroke occurred in 21 of 336 patients (6.3%) in the ticagrelor/aspirin group and 30 of 339 patients (8.8%) in the clopidogrel/aspirin group (hazard ratio, 0.70; 95% CI, 0.40 to 1.22; P=0.20). No difference was observed in the rates of major or minor haemorrhagic events between the ticagrelor and clopidogrel groups (4.8% and 3.5%, respectively; P=0.42). Interpretation: Patients with minor stroke or TIA treated with ticagrelor had a lower rate of high platelet reactivity than those treated with clopidogrel, especially in carriers of the CYP2C19 loss-of-function allele. Funding: Ministry of Science and Technology of the People's Republic of China, Beijing Municipal Science and Technology Commission, Beijing Municipal Commission of Health and Family Planning and AstraZeneca. Declaration of interests: Yilong Wang reports grants from Beijing Municipal Science and Technology Commission and Beijing Municipal Commission of Health and Family Planning. Yongjun Wang reports grants from Ministry of Science and Technology of the People’s Republic of China. Ethical Approval Statement: The PRINCE study protocol and data collection were approved by the ethics committee of Beijing Tiantan Hospital and all of the study centres. An interim analysis was pre-planned in the published protocol. All participants or their representatives provided written consent before being enrolled into the study. The design of the trial was published previously.14 The trial was conducted in accordance with the Declaration of Helsinki.

Effects of statin therapy on platelet reactivity after percutaneous coronary revascularization in patients with acute coronary syndrome.

Statin use is associated with enhanced pharmacodynamic response to clopidogrel in patients with stable coronary artery disease undergoing percutaneous coronary intervention (PCI). However, the impact of statin therapy on clopidogrel response profiles in patients with acute coronary syndrome (ACS) undergoing PCI has not been established and represents the objective of this investigation. On-treatment P2Y12 platelet reactivity was measured using the vasodilator stimulated phosphoprotein (VASP) phosphorylation assay before PCI, at hospital discharge, and at 1month after PCI in ACS patients enrolled in the multicenter, prospective GEne polymorphisms, Platelet Reactivity, and Syntax Score (GEPRESS) study (n = 962). High platelet reactivity (HPR) was defined as platelet reactivity index ≥50%. Statins were prescribed at hospital discharge in 87% (n = 835) of patients. All patients were followed for 1year. The 1-month HPR rate was lower in statin than in non-statin treated patients (39.6 vs 52%, respectively, p = 0.009). This finding was confirmed also among statin-treated patients with high Syntax score (≥15). After adjustment for differences in baseline characteristics, statin use at discharge was independently associated with 1-month HPR rate (odds ratio, 0.58, 95% confidence interval, 0.38-0.89; p = 0.015). In ACS patients undergoing PCI treated with clopidogrel the use of statins at discharge was associated with significantly lower 1-month HPR rates compared with patients not treated with statins.

A head-to-head pharmacodynamic comparison of prasugrel vs. ticagrelor after switching from clopidogrel in patients with coronary artery disease: results of a prospective randomized study.

Pharmacodynamic (PD) studies comparing prasugrel and ticagrelor have reached inconsistent findings. Therefore, a comprehensive investigation comparing the PD effects of prasugrel vs. ticagrelor after switching from clopidogrel therapy, exploring both loading dose (LD) and maintenance dose (MD) regimens represented the aim of this study. Patients (n = 110) with coronary artery disease were randomized to prasugrel (60 mg LD/10 mg MD q.d.) or ticagrelor (180 mg LD/90 mg MD b.i.d) therapy for 1 week. Pharmacodynamic assessments were conducted using three assays (vasodilator-stimulated phosphoprotein, VerifyNow P2Y12, and light transmittance aggregometry, LTA) at baseline, 30 min, 2, 24 h, and 1 week. The impact of initiating ticagrelor MD 12 vs. 24 h after LD administration was also assessed. Switching clopidogrel-treated patients to an LD of prasugrel or ticagrelor was associated with a reduction in platelet reactivity at 30 min and was sustained at all time points up to 1 week with the MD (P < 0.001 for all assays). Platelet reactivity was similar with prasugrel and ticagrelor with all assays at 30 min, 2 h, and 1 week (P > 0.05 for all time points), with the exception of LTA at 30 min (lower with prasugrel; P = 0.003). At 24 h, platelet reactivity was lower among patients initiating ticagrelor MD after 12 vs. 24 h post-LD. Rates of high platelet reactivity (HPR) were markedly reduced and similar between groups. Prasugrel and ticagrelor exert similar levels of P2Y12 inhibition achieving more potent PD effects and reduced HPR rates compared with clopidogrel which are reached promptly following LD and sustained with MD. NCT01852175.

Comparison of half- and standard-dose ticagrelor in Chinese patients with NSTE-ACS

Ticagrelor is a novel direct-acting P2Y12 receptor antagonist used for preventing atherothrombotic events in patients with acute coronary syndromes (ACS). The current recommended dose is 90 mg bid, but a low dose of ticagrelor has not been previously studied in Chinese ACS patients. Therefore, we performed this study to observe the different effects of half- and standard-dose ticagrelor on platelet aggregation in Chinese patients with NSTE-ACS. Sixty-two NSTE-ACS subjects were assigned to half-dose ticagrelor (n = 20), standard-dose ticagrelor (n = 22) and clopidogrel (n = 20) groups. Five days after drug administration, VerifyNow P2Y12 assay was performed to test P2Y12 reaction units (PRU) and inhibition of platelet aggregation (IPA). High-platelet reactivity (HPR) was defined as a PRU > 208. The adverse events, including bleeding events and dyspnoea, were monitored throughout the study. PRU values in the half-dose (44.55 ± 32.88) and standard-dose (39.10 ± 40.02) ticagrelor were dramatically lower than those in the clopidogrel group (189.20 ± 65.22; P < 0.0001). The half-dose (84% ± 10%) and standard-dose (86% ± 13%) ticagrelor both showed greater IPA than clopidogrel (33% ± 20%; P < 0.0001). There were no significant differences in PRU and IPA between the two ticagrelor groups (P = 0.3085 and 0.4028, respectively). HPR rates were significantly lower in the two ticagrelor groups (0% for both) than those in the clopidogrel group (35%). In conclusion, half-dose ticagrelor had a similar inhibitory effect on platelet aggregation as standard-dose ticagrelor in Chinese patients with NSTE-ACS, which was significantly stronger than that of clopidogrel.

0289: Inflammation is the main predictor of high-on aspirin platelet reactivity in stable vascular patients treated with monotherapy

Background High platelet reactivity (HPR) despite antiplatelet treatment is related to ischemic events in patients with coronary artery disease (CAD), but cannot be assessed routinely in all patients. The aim of the study was to identify clinical and biological predictive factors of HPR on aspirin. Methods 333 consecutive patients chronically treated with aspirin for CAD or cerebrovascular disease with potential high risk of ischemic events (complex angioplasty, diabetes, recurrence), in whom platelet reactivity was assessed between 2011 and 2013, were retrospectively analysed. HPR was evaluated just before the next aspirin intake, defined as aggregation ≥20% using light transmission aggregometry with arachidonic acid 0.5 mg/mL (LTA) and closure time Results Median age was 63 years old, 65% were male, with a median BMI of 25.5 kg/m 2 , 28% had diabetes mellitus and 15% moderate to severe chronic renal failure. Median dose of aspirin was 100mg/day (range 75 to 160) and 11% had aspirin twice daily. LTA found HPR in 8.7% patients and PFA in 20.1%. In a multivariate analysis, predictor factors associated with HPR using LTA were fibrinogen (OR: 1.51, p=0.01), CRP (OR: 1.01, p 3.0 mg/mL had a higher rate of HPR (14.6% versus 2.6%, p 3.0 mg/mL) were also associated with a 2.6-fold increased risk of HPR using PFA. Conclusion Inflammation is the main predictor of HPR on aspirin in stable CAD and cerebrovascular patients treated with monotherapy. Further clinical investigations assessing platelet reactivity should focus on patients with inflammatory states.

Abstract 9933: Impact of Antiplatelet Therapy in Patients With Impaired Glucose Tolerance

Background: Patients with diabetes mellitus (DM) have reduced clopidogrel-induced antiplatelet effects and increased rates of high platelet reactivity (HPR) compared with non-DM patients. Although approximately 40% of patients with coronary artery disease (CAD) have a pre-diabetic status characterized by impaired glucose tolerance (IGT). However, the impact of IGT on pharmacodynamic (PD) response to antiplatelet therapy is unknown. Objectives: To investigate the impact of IGT on PD response to antiplatelet therapy in patients with IGT. Methods: A 75g oral glucose tolerance test was performed in 52 stable CAD patients treated with maintenance aspirin and clopidogrel therapy. Blood samples were collected at 3 time-points (baseline, 1 and 2 hours after glucose load). IGT was defined as fasting plasma glucose of 110-126 mg/dl and 2 hour plasma glucose of 140-200 mg/dl. Platelet aggregation was assessed by light transmittance aggregometry using 5 and 20 μmol/L ADP stimuli. HPR rates was defined when both maximal aggregation was ≥ 59% with 20 μmol/L ADP and ≥ 46% with 5 μmol/L ADP. Results: There were 22 subjects (42%) who had IGT. At baseline, patients with IGT showed increased platelet reactivity at 5 μmol/L ADP (45.3±13.7 vs 38.6±13.4; p=0.09) and 20 μmol/L ADP stimuli (57.6±12.6 vs 47.5±14.3; p=0.01), and higher HPR rates (54.5% vs 16.0%; p=0.01) compared with non-IGT patients. Similar results were obtained at 1 hour [5 μmol/L ADP (43.1±13.7 vs 36.4±13.9; p=0.1), 20 μmol/L ADP (55.2±12.2 vs 45.4±14.3: p=0.01), HPR rates (36.4% vs 12.5%; p=0.08)], and 2 hours [5 μmol/L ADP (40.7±14.9 vs 35.8±13.9; p=0.2), 20 μmol/L ADP (52.5±12.4 vs 44.4±13.8: p=0.04), HPR rates (40.9% vs 8.3%; p=0.01)]. Conclusions: Patients with IGT on dual antiplatelet therapy with aspirin and clopidogrel have enhanced platelet reactivity and increased rates of high platelet reactivity compared with non-IGT patients, suggesting platelet dysfunction which is independent of hyperglycemia may exist in pre-diabetic patients.

Standard (180mg) vs high (360mg) loading dose of ticagrelor in patients with STEMI undergoing primary PCI

Purpose: In ST elevation myocardial infarction (STEMI) patients a suboptimal degree of platelet inhibition for the first 2 hours has been described following the standard (180 mg) ticagrelor loading dose (LD). We aimed to compare the pharmacodynamic effect of double (360mg) vs standard LD of ticagrelor in STEMI patients undergoing primary percutaneous coronary intervention (PCI). Methods: We performed a prospective, non-randomized, 2-center study in 42 consecutive, P2Y12 inhibitor naive STEMI patients. Following blood sampling (Hour 0), patients were administered a 360 mg of ticagrelor, immediately before PCI. Platelet reactivity (PR) was assessed at Hour 0, 0.5, 1, 2 and 4 with the VerifyNow assay. PR was assessed at the same time-points in a control group of 32 STEMI patients, who received standard ticagrelor LD. Results: In the high LD group, PR in PRU (least-squares estimates, 95% CIs) tended to increase from Hour 0 (221.5, 200.5-242.4) to Hour 0.5 (257.8, 236.9-278.7), p=0.08. PR at Hour 1 (217.7, 196.8-238.6) did not differ compared to Hour 0 (p>0.99). PR observed at Hour 2 (110.5, 89.6-131.4) and Hour 4 (43.7, 22.8-64.6) was significantly decreased compared to Hour 0 (P<0.001 for both). The high PR rates (threshold 230 PRU) at Hour 0.5, 1, 2 and 4 were 78.6%, 52.4%, 23.8% and 2.4% respectively. In 22 propensity-matched pairs of patients, PR did not differ significantly between standard and high LD group at any time point (Table). View this table: Table 1. Platelet reactivity (VerifyNow PRU) at 0.5, 1, 2 and 4 hours post ticagrelor LD Conclusions: In STEMI patients treated with primary PCI, double the standard LD of ticagrelor results in no significant PR change at Hour 1 compared to baseline. At Hour 2, the double LD of ticagrelor achieves high platelet inhibition in the majority of patients. Double LD of ticagrelor did not appear superior to the standard LD in reducing PR the early hours after intake in STEMI.

Randomized Assessment of Ticagrelor Versus Prasugrel Antiplatelet Effects in Patients With Diabetes

OBJECTIVEIt has been postulated that prasugrel might be the preferred treatment option in diabetes mellitus (DM) patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). We aimed to compare the pharmacodynamic action of ticagrelor versus prasugrel.RESEARCH DESIGN AND METHODSIn a prospective, single-center, single-blind, crossover study, 30 consecutive ACS patients with DM who had been pretreated with clopidogrel were randomized to either 90 mg ticagrelor twice daily or 10 mg prasugrel once daily with a 15-day treatment period. Platelet reactivity (PR) was assessed with the VerifyNow P2Y12 function assay, measured in P2Y12 reaction units (PRU).RESULTSPR was significantly lower after ticagrelor (45.2 PRU [95% CI 27.4–63.1]) compared with prasugrel (80.8 PRU [63.0–98.7]), with a least squares mean difference of –35.6 PRU (−55.2 to −15.9, P = 0.001). High PR rate was 0% for ticagrelor and 3.3% for prasugrel (P = 1.0).CONCLUSIONSIn DM patients with ACS who had been pretreated with clopidogrel and who undergo PCI, ticagrelor achieves a significantly higher platelet inhibition than prasugrel. Both antiplatelet agents effectively treat high PR. The relevance of these findings to the clinical efficacy and safety of ticagrelor and prasugrel in DM patients needs further elucidation.

Randomized Assessment of Ticagrelor Versus Prasugrel Antiplatelet Effects in Patients with ST-Segment–Elevation Myocardial Infarction

Ticagrelor and prasugrel provide stronger platelet inhibition compared with clopidogrel. Direct pharmacodynamic comparison between them has not yet been reported in ST-segment-elevation myocardial infarction patients. In a prospective, single-center, single-blind study, 55 out of 117 (47%) screened consecutive ST-segment-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention were randomized to either ticagrelor 180 mg loading followed by 90 mg bid, or prasugrel 60 mg loading followed by 10 mg od for 5 days. Platelet reactivity (PR) was assessed with the VerifyNow P2Y12 function assay and the Multiplate Analyzer at 0, 1, 2, 6, 24 hours, and 5 days postrandomization. The primary end point, PR with VerifyNow at hour 1, did not differ significantly between patients randomized to ticagrelor versus prasugrel (257.3 P2Y12 reaction unit [PRU], 95% CI 230.8-283.8 versus 231.3 PRU, 95% CI 205.3-257.4; P=0.2). PR did not differ at 2, 6, and 24 hours, although at day 5 it was lower with ticagrelor than prasugrel (25.6 PRU, 95% CI 12.3-38.9 versus 50.3 PRU, 95% CI 36.4-64.1; P=0.01). At hour 2, high on-treatment PR rates (cutoff 208 PRU) were 46.2% and 34.6% for ticagrelor and prasugrel, respectively, decreased significantly thereafter, whereas did not differ significantly between the 2 agents at all the time points of the study. In patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention, both ticagrelor and prasugrel exhibit an initial delay in the onset of their antiplatelet action. Ticagrelor did not appear superior to prasugrel in reducing PR during the first 24 hours of ST-segment-elevation myocardial infarction. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01463163.

Pharmacodynamic effect of prasugrel 5 mg vs clopidogrel 150 mg in elderly patients with high on-clopidogrel platelet reactivity

Elderly patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) frequently exhibit high platelet reactivity (HPR) while on clopidogrel. In the elderly cohort, either prasugrel is not recommended or, if used, halving of the dose has been suggested. We aimed to test the hypothesis that in elderly patients exhibiting HPR after standard treatment with clopidogrel, prasugrel-reduced dose (5 mg) could be more effective than high-dose (150 mg) clopidogrel. Consecutive elderly (≥75 years old) patients with ACS undergoing PCI and loaded with clopidogrel were considered for platelet reactivity (PR) assessment at 24 hours after PCI with the VerifyNow assay (Accumetrics Inc, San Diego, CA), measured in P2Y12 reaction units (PRU). Of 63 screened patients, 30 (47.6%) were found with HPR (defined as PRU ≥230) and 27 of them participated in a prospective, randomized, single-center, single-blind, investigator-initiated, crossover study of platelet inhibition by prasugrel 5 mg/d vs clopidogrel 150 mg/d, with a 15-day treatment period. The primary end point of PR at the end of the 2 study periods was lower in patients receiving low-dose prasugrel than those receiving high-dose clopidogrel (least squares estimates 190.8 [95% CI 161.5-220.1] and 240.8 [95% CI 211.0-270.6], respectively; P = .008). The secondary end point of HPR rate at the end of treatment periods was lower for prasugrel (8/24; 33.3%) compared with clopidogrel (16/24; 66.7%), P = .02. In elderly patients with ACS undergoing PCI and exhibiting HPR after standard clopidogrel treatment, prasugrel 5 mg/d is significantly more efficacious than clopidogrel 150 mg/d in reducing PR and HPR rate.

High on-thienopyridine platelet reactivity in elderly coronary patients: the SENIOR-PLATELET study

The aim of this study was to compare on-thienopyridine platelet reactivity of elderly patients (≥75 years) vs. younger patients (<75 years). Elderly patients represent a growing and challenging segment of the coronary population for whom the effect of dual antiplatelet therapy on platelet inhibition has not been specifically addressed. The SENIOR-PLATELET study included 1331 coronary patients chronically (>14 days) treated with aspirin and a thienopyridine (clopidogrel 75 mg, n= 1027; clopidogrel 150 mg, n= 139; or prasugrel 10 mg, n= 165). Platelet response to clopidogrel and prasugrel was assessed by the VerifyNow assay and light transmission aggregrometry (LTA). Response to treatment, rate of high platelet reactivity (HPR), and inhibition (HPI) were compared in the two age categories. On-treatment platelet reactivity with clopidogrel 75 mg, 150 mg or prasugrel 10 mg was higher in elderly patients (n= 205) than in younger patients (n= 1126) whichever the test used. The difference in P2Y(12) reaction units (PRU) between the two populations was +45 in patients treated with clopidogrel 75 mg (P< 0.0001), +30 in patients treated with clopidogrel 150 mg (P= 0.17), and +20 with prasugrel 10 mg (P= 0.10). Differences in residual platelet aggregation were consistent when measured by LTA. Elderly patients treated with clopidogrel 75 mg were more likely to have HPR than younger patients (38.2 vs. 18.2%, OR: 2.58, 95% CI: 1.76-3.79; P< 0.0001) even after adjustment for potential confounders (adj OR: 1.83, 95% CI: 1.16-2.87; P= 0.009). Elderly patients present an impaired response to clopidogrel with a high rate of HPR. Clopidogrel 150 mg or prasugrel 10 mg blunt, but do not eliminate the difference in response observed between old and young patients.