Levels Of Platelet Reactivity Research Articles

Intensity of dual antiplatelet therapy based on thrombotic and bleeding risks after coronary stenting

Abstract Background/Introduction High thrombotic risk (HTR) features are associated with higher ischemic rate, which may be mitigated by potent antiplatelet therapy. However, concomitant high bleeding risk (HBR) may be present, making it unclear whether the intensity of antiplatelet therapy should be prioritized. Purpose This study investigated the prognostic implications of HTR and HBR strata according to intensity of antiplatelet therapy (indicated by platelet reactivity) after coronary stenting. Methods HTR was defined as having at least one of the three risk factors: 1) index presentation with acute coronary syndrome; 2) complex coronary artery disease and stenting; and 3) guideline-directed clinical ischemic risk factors. HBR was determined according to presence of Academic Research Consortium (ARC)-HBR criteria. In addition, high platelet reactivity (HPR) was decided depending on the level of platelet reactivity (> 208 P2Y12 reaction unit measured by VerifyNow assay). Results Among 4,550 patients, HTR features were observed in 3,973 patients (87.3%) and 1,451 (31.9%) met the ARC-HBR criteria. HPR phenotype (n=2563, 56.3%) significantly increased the risk of 4-year ischemic events (adjusted hazard ratio [HRadj]: 1.40; 95% confidence interval [CI]: 1.15-1.70; P=0.001). Among patients who met the ARC-HBR criteria, HPR was not associated with the rate of ischemic events, regardless of HTR features. In cases of non-HBR patients, HPR phenotype increased ischemic events only in patients with HTR feature(s), which risk proportionally increased according to the number of HTR features (HRadj: 0.67, 1.47 and 1.58; 95% CI: 0.22-2.08, 0.94-2.29 and 1.09-2.28 in 0 [9.2%], 1 [31.2%] and ≥2 [27.7%] HTR features). In HBR patients, the risk of major bleeding was not increased by the level of antiplatelet effect. Conclusion HPR phenotype was significantly associated with the risk of ischemic events after coronary stenting, which proportionally increased according to the number of HTR features only if the ARC-HBR criteria were not present. These observations suggested that when concordant, bleeding risk, more than ischemic risk, should inform decision-making on the intensity of antiplatelet therapy.KM curve and HR forest plot for MACCEKM curve and HR forest plot for NACE

Abstract 14703: Platelet Reactivity and Long-Term Outcomes Following Acute Myocardial Infarction

Introduction: A large volume of literature demonstrates a short term (1 year) association between high on treatment platelet reactivity in patients with acute myocardial infarction treated with clopidogrel and adverse cardiovascular outcomes. There is less literature examining whether this association extends beyond the duration of clopidogrel treatment. Hypothesis: That on-treatment platelet reactivity is associated wtih 5-year death and recurrent myocardial infarction in patients with acute myocardial infarction. Methods: We measured platelet reactivity in patients presenting with AMI to Wellington Hospital between 2012 and 2015 who had been treated with clopidogrel prior to angiography using Multiplate P2Y 12 assay (Roche Diagnostics). Platelet reactivity was measured in platelet reactive units (PRU). We examined the relationship between PRU and both death and myocardial infarction at 5 years follow-up. Results: In 921 patients with acute myocardial infarction (mean age 63.2, sd 10.8, 81% NSTEMI 19% STEMI) mean PRU was 39.3 (sd 23.6) PRU, with 74 patients (8%) having a PRU greater than 47, previously described as high on treatment platelet reactivity. 5-year mortality was observed in 10.4% (96 cases) and recurrent myocardial infarction in 12.2% (122 cases). Platelet reactivity was significantly associated with 5-year mortality in Receiver Operator Curve analysis, with AUC 0.58, p=0.009. Mean PRU was 45.8 (sd 27.5) in those who died versus 38.4 (sd 23.2) in those still alive at 5 years (p=0.004, unpaired t-test). Cox regression analysis demonstrated a hazard ratio of 1.01 (95% CI 1.003-1.017, p=0.01) for each increasing unit of PRU. Recurrent MI was not significantly associated with PRU, with an AUC of 0.55, p=0.09). Conclusions: Levels of platelet reactivity were associated with long-term mortality risk in AMI patients. This may suggest platelet reactivity in the acute phase following an AMI is a marker of poor cardiovascular repair, leading to an association with long-term mortality risk

Leptin as predictor of cardiovascular events and high platelet reactivity in patients undergoing percutaneous coronary intervention

Leptin is a hormone involved in the regulation of food intake. Previous studies suggested an interplay between leptin, platelet aggregation, and cardiovascular outcome but this issue was not investigated invivo in patients treated with percutaneous coronary intervention (PCI). We designed a study to evaluate the possible relation between leptin, cardiovascular outcome, and platelet reactivity (PR) in patients undergoing PCI. 155 PCI patients had preprocedural measurements of PR and leptin plasma levels. The latter were assessed by ELISA. Hyperleptinemia was defined as leptin levels ≥14ng/ml. PR was evaluated by the VerifyNowP2Y12 assay and expressed as P2Y12 reaction units (PRU). Patients were divided into three groups based on PR values and defined as low (LPR), normal (NPR), and high (HPR). Patients were followed for up 8 years. The primary endpoint was the incidence of Major Acute Cardiac Events (MACE) at long-term follow-up according to leptin groups. Secondary endpoints were the evaluation of leptin levels according to PR groups and the incidence of periprocedural myocardial infarction (PMI) according to leptin groups. Long-term follow-up was completed in 140 patients. Patients with hyperleptinemia experienced a higher MACE rate than the normoleptinemic group (HR 2.3; CI 95% 1.14-4.6, P=0.02). These results remained unchanged after adjusting for Body Mass Index, hypertension, and gender. Leptin levels were significantly different among groups of PR (P=0.047). Leptin levels were higher in the HPR group (12.61±16.58ng/ml) compared to the LPR group (7.83±8.87ng/ml, P=0.044) and NPR group (7.04±7.03ng/ml, P=0.01). The rate of PMI was higher in hyperleptinemia patients (15.1% vs. 6.5%, P=0.22). This study suggests that high leptin levels are associated with a worse clinical outcome in patients undergoing PCI and with HPR. Further studies are needed to define better the pathophysiological pathways underlying this association.

Implication of diabetic status on platelet reactivity and clinical outcomes after drug-eluting stent implantation: results from the PTRG-DES consortium

BackgroundDiabetes mellitus (DM) is associated with thrombogenicity, clinically manifested with atherothrombotic events after percutaneous cutaneous intervention (PCI). This study aimed to investigate association between DM status and platelet reactivity, and their prognostic implication in PCI-treated patients.MethodsThe Platelet function and genoType-Related long-term Prognosis-Platelet Function Test (PTRG-PFT) cohort was established to determine the linkage of platelet function test (PFT) with long-term prognosis during dual antiplatelet therapy including clopidogrel in patients treated with drug-eluting stent (DES). We assessed platelet reactivity using VerifyNow and ‘high platelet reactivity (HPR)’ was defined as ≥ 252 P2Y12 reaction unit (PRU). Major adverse cardiac and cerebrovascular event (MACCE) was a composite of all-cause death, myocardial infarction, stent thrombosis or stroke.ResultsBetween July 2003 and Aug 2018, DES-treated patients with available PFT were enrolled (n = 11,714). Diabetic patients demonstrated significant higher levels of platelet reactivity (DM vs. non-DM: 225.7 ± 77.5 vs. 213.6 ± 79.1 PRU, P < 0.001) and greater prevalence of HPR compared to non-diabetic patients (38.1% vs. 32.0%, P < 0.001). PRU level and prevalence of HPR were significantly associated with insulin requirement and HbA1c level, as well as diabetic status. DM status and HPR phenotype had a similar prognostic implication, which showed the synergistic clinical impact on MACCE. Association between PRU level and MACCE occurrence seemed higher in diabetic vs. non-diabetic patients. In non-DM patients, HPR phenotype did not significantly increase the risk of MACCE (adjusted hazard ratio [HRadj]: 1.073; 95% confidence interval [CI]: 0.869–1.325; P = 0.511), whereas HPR was an independent determinant for MACCE occurrence among diabetic patients (HRadj: 1.507; 95% CI: 1.193–1.902; P < 0.001).ConclusionThe levels of on-clopidogrel platelet reactivity are determined by diabetic status and the severity of DM. In addition, HPR phenotype significantly increases the risk of MACCE only in diabetic patients.Clinical trial registrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT04734028.

Sex-stratified differences in early antithrombotic treatment response in patients presenting with ST-segment elevation myocardial infarction

The mechanisms underlying the increased risk of bleeding that female patients with ST-segment Elevation Myocardial Infarction (STEMI) exhibit, remains unclear. The present report assessed sex-related differences in response to pre-hospital dual antiplatelet therapy (DAPT) initiation in patients with STEMI. The COMPARE CRUSH trial randomized patients presenting with STEMI to receive a pre-hospital loading dose of crushed or integral prasugrel tablets in the ambulance. In this substudy, we compared platelet reactivity levels and the occurrence of high platelet reactivity (HPR; defined as platelet reactivity ≥208) between sexes at 4 prespecified time points after DAPT initiation, and evaluated post-PCI bleeding between groups. Out of 633 STEMI patients, 147 (23%) were female. Females compared with males presented with significantly higher levels of platelet reactivity and higher HPR rates at baseline (232 [IQR, 209-256] vs 195 [IQR, 171-220], P < .01, and 76% vs 41%, OR 4.58 [95%CI, 2.52-8.32], P < .01, respectively). Moreover, female sex was identified as the sole independent predictor of HPR at baseline (OR 5.67 [95%CI, 2.56-12.53], P < .01). Following DAPT initiation, levels of platelet reactivity and the incidence of HPR were similar between sexes. Post-PCI bleeding occurred more frequently in females compared with males (10% vs 2%, OR 6.02 [95%CI, 2.61-11.87], P < .01). Female sex was an independent predictor of post-PCI bleeding (OR 3.25 [95%CI, 1.09-9.72], P=.04). In this contemporary STEMI cohort, female STEMI patients remain at risk of bleeding complications after primary PCI. However, this is not explained by sex-specific differences in the pharmacodynamic response to pre-hospital DAPT initiation.

Abstract 10481: The Effect of Current Smoking on Platelet Reactivity Measures by Point-of-Care Methods in Patients Treated With and Without Clopidogrel

Introduction: Smoking is associated with worse response to P2Y12 inhibitors. However, the relationship between smoking, platelet reactivity (PR) and traditional risk factors for atherosclerosis is unclear. Hypothesis: To analyze the relationship between smoking, PR and risk factors for atherosclerosis. Methods: A prospective databank of 13 research protocols was retrospectively analyzed. Among 1260 patients included in the analysis, 299 were smokers; 721 had acute coronary syndromes (521 with clopidogrel), and 539 had stable coronary artery disease (4 with clopidogrel). The association between smoking and PR analyzed by Multiplate-ADP (MPADP) and VerifyNow-PRUTest (VNPRU), inflammatory markers (leukocytes and hs-C-reactive protein), creatinine, HbA1c, total cholesterol, HDL-c, LDL-c and triglycerides, was analyzed in univariate and multivariable models. PR results were analyzed as continuous and categorical variables (bellow or above the median). Results: Unadjusted results for the comparison between smokers and non-smokers are depicted in the Table and Figure. In adjusted models, the significant associations between smoking and PR were maintained: 1) MPADP Odds-Ratio (OR)=0.984, p&lt;0.001; 2) VNPRU OR=0.996, P=0.008; 3) MPADPCAT&gt;MD OR=0.450, P&lt;0.001; 4) VNADPCAT&gt;MD OR=0.408, p&lt;0.001; 5) ADPMEDIAN&gt;MD OR=0.394, p&lt;0.001). HDL-c (negative) was the only risk factor for atherosclerosis that correlated independently with smoking in all adjusted models, with leukocytes (positive) and creatinine (negative) showing correlation in 4 of the 5 models. Conclusion: Smoking is independently associated with lower PR and HDL-c levels.

Abstract 9685: Pharmacodynamic and Pharmacokinetic Profiles of Switching Between Cangrelor and Ticagrelor Following Ticagrelor Pre-Treatment: The SWAP-5 Study

Introduction: The lack of drug-drug-interaction (DDI) with the use of ticagrelor in cangrelor-treated patients was demonstrated in studies in which ticagrelor was given at the time of initiation or during cangrelor infusion. However, many patients are pre-treated with ticagrelor and to date there is no data to rule out a DDI when ticagrelor is given prior to starting cangrelor. Methods: SWAP-5 is a randomized, double-blind, placebo-controlled, cross-over, pharmacokinetic (PK) and pharmacodynamic (PD) study conducted in 20 patients with coronary artery disease on aspirin (81mg/qd). Patients were pre-treated with a 180-mg ticagrelor loading dose (LD) and after 1 hour were randomized to placebo or cangrelor (bolus and infusion for 2 hours). Patients crossed over after 1-4 weeks of washout. PK analysis included plasma levels of ticagrelor and its active metabolite, and PD assessments included VerifyNow P2Y 12 reaction units (PRU), light transmittance aggregometry (LTA) with 20 μM ADP as agonist, and vasodilator-stimulated phosphoprotein (VASP), at baseline and 6 time points after ticagrelor LD. Results: Compared to placebo, adding cangrelor to patients pre-treated with ticagrelor resulted in a significant reduction in PRU at 30 min and 1 hour after starting infusion ( Figure ). At 2 hours after stopping the infusion, PRU was low and similar in both groups (16.9 vs. 12.6; mean difference: 4.3; 95% CI: -28.6 to 37.3), meeting the non-inferiority primary endpoint (pre-defined non-inferiority margin 45 PRU). LTA and VASP showed consistent findings. PK tracked PD findings with no difference between groups in plasma levels of ticagrelor and its metabolite (data not shown). Conclusions: SWAP-5 is the first PK/PD study supporting the feasibility of adding cangrelor in patients pre-treated with ticagrelor. This approach resulted in lower levels of platelet reactivity during cangrelor infusion with similar PK/PD profiles after stopping the infusion and no evidence of DDI.

Low platelet reactivity in patients with myocardial infarction treated with aspirin plus ticagrelor

ABSTRACTObjective:Low platelet reactivity levels are associated with higher risk of bleeding in patients receiving dual antiplatelet therapy relative to patients with optimal platelet blockade. This study set out to evaluate the prevalence of low platelet reactivity in patients with acute myocardial infarction treated with ticagrelor and aspirin.Methods:Patients admitted with acute myocardial infarction who were already undergoing dual antiplatelet therapy with aspirin and ticagrelor were enrolled. Blood samples were collected 1 hour before and 2 hours after the maintenance dose of ticagrelor to investigate trough and the peak effects of the drug respectively. Platelet reactivity was measured by three methods: Multiplate®, PFA-100® with Innovance® PFA-P2Y cartridge and PFA-100® with Collagen/ADP cartridge. Platelet reactivity was assessed in the presence of peak levels of ticagrelor and defined according to previously validated cut-offs for each method (<19 AUC, >299 seconds and >116 seconds respectively). The level of significance was set at p<0.05.Results:Fifty patients were enrolled (44% with ST-elevation). Median duration of DAPT was 3 days (interquartile range, 2-5 days). On average, peak and trough platelet reactivity were markedly low and did not differ between different methods. Low platelet reactivity was common, but varied according to analytic method (PFA-100®/Innovance®PFA-P2Y: 86%; Multiplate®: 74%; PFA-100®/Collagen/ADP: 48%; p<0.001).Conclusion:Low platelet reactivity was very common in patients with acute myocardial infarction submitted to dual antiplatelet therapy with ticagrelor and aspirin. Findings of this study justify the investigation of less intensive platelet inhibition strategies aimed at reducing the risk of bleeding in this population, such as lower dose regimens or monotherapy with P2Y12 inhibitors.

Dual Antiplatelet Therapy with 3rd Generation P2Y12 Inhibitors in STEMI Patients: Impact of Body Mass Index on Loading Dose-Response.

This study aims to assess the association between body mass index (BMI) and platelet reactivity in STEMI patients treated with oral 3rd generation P2Y12 inhibitors. Overall, 429 STEMI patients were enrolled in this study. Patients were divided into two groups according to BMI (BMI < 25 vs ≥ 25kg/m2). A propensity score matching (1:1) was performed to balance potential confounders in patient baseline characteristics. Platelet reactivity was assessed by VerifyNow at baseline and after 3rd generation P2Y12 inhibitor (ticagrelor or prasugrel) loading dose (LD). Blood samples were obtained at baseline (T0), 1h (T1), 2h (T2), 4-6h (T3), and 8-12h (T4) after the LD. High on-treatment platelet reactivity (HTPR) was defined as a platelet reactivity unit value ≥ 208 units. After propensity score matching, patients with BMI ≥ 25 had similar values of baseline platelet reactivity, while they had higher level of platelet reactivity at 1 and 2h after the LD and higher rate of HRPT. Furthermore, multivariate analysis demonstrated that BMI ≥ 25 was an independent predictor of HTPR at 2h (OR 2.01, p = .009). Conversely, starting from 4h after the LD, platelet reactivity values and HRPT rates were comparable among the two study groups. A BMI ≥ 25kg/m2 is associated with delayed pharmacodynamic response to oral 3rd generation P2Y12 inhibitor LD, and it is a strong predictor of HTPR in STEMI patients treated by dual antiplatelet therapy with ticagrelor or prasugrel.

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.

Platelet Function and Genotype after DES Implantation in East Asian Patients: Rationale and Characteristics of the PTRG-DES Consortium.

PurposePlatelet function test (PFT) results and genotype hold unique prognostic implications in East Asian patients. The aim of the PTRG-DES (Platelet function and genoType-Related long-term proGnosis in Drug-Eluting Stent-treated Patients with coronary artery disease) consortium is to assess the clinical impact thereof on long-term clinical outcomes in Korean patients with coronary artery disease during dual antiplatelet therapy (DAPT) including clopidogrel.Materials and MethodsSearching publications on the PubMed, we reviewed clopidogrel treatment studies with PFT and/or genotype data for potential inclusion in this study. Lead investigators were invited to share PFT/genotype results, patient characteristics, and clinical outcomes to evaluate relationships among them.ResultsNine registries from 32 academic centers participated in the PTRG-DES consortium, contributing individual patient data from 13160 patients who underwent DES implantation between July 2003 and August 2018. The PTRG-PFT cohort was composed of 11714 patients with available VerifyNow assay results. Platelet reactivity levels reached 218±79 P2Y12 reaction units (PRU), and high on-clopidogrel platelet reactivity based on a consensus-recommended cutoff (PRU >208) was observed in 55.9%. The PTRG-Genotype cohort consisted of 8163 patients with candidate genotypes related with clopidogrel responsiveness. Of those with cytochrome P450 (CYP) 2C19 genotype, frequencies of carrying one and two loss-of-function allele (s) (*2 or *3) were 47.9% (intermediate metabolizers) and 14.2% (poor metabolizers), respectively.ConclusionThe PTRG-DES consortium highlights unique values for on-clopidogrel platelet reactivity and CYP2C19 phenotype that may be important to developing optimal antiplatelet regimens in East Asian patients.Trial RegistrationClinicalTrials.gov Identifier: NCT04734028.

727 Circadian variations of platelet reactivity on Clopidogrel in patients treated with elective percutaneous coronary intervention

Abstract Aims The potential diurnal variations of platelet reactivity in patients on clopidogrel treated with elective percutaneous coronary intervention (PCI) for stable coronary artery disease (CAD) are currently unknown. Methods and results We prospectively enrolled 15 patients with stable CAD treated PCI and on clopidogrel therapy for at least eight days. All patients received their maintenance 75-mg clopidogrel dose at 8 AM. Platelet reactivity was assessed with the Verifynow P2Y12 assay at three different time points (10 AM, 6 PM, and 6 AM). Platelet reactivity is expressed as P2Y12 reaction units (PRU) and PRU thresholds ≥208 and ≥240 were used to define high platelet reactivity (HPR). A significant heterogeneity in diurnal levels of platelet reactivity was found (P = 0.0004), with a peak occurring at the 6 AM assessment. In addition, at the 6 AM evaluation patients showed the highest prevalence of HPR (53.3% of patients with PRU ≥240, 66.7% of patients with PRU ≥208). Conclusions Platelet reactivity in patients with stable CAD treated with PCI and taking clopidogrel in the morning follows a circadian rhythm, thus suggesting that platelet inhibition may not be constant and sufficient throughout the day. Whether an evening or a bis in die administration of clopidogrel may result in a constant and more reliable antiplatelet inhibition, should be investigated in dedicated studies.

Abstract 11338: On-Clopidogrel Platelet Reactivity in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention and Association with Patient Characteristics

Introduction: On-clopidogrel platelet reactivity (PR) is associated with thrombotic and bleeding risk in patients undergoing percutaneous coronary intervention (PCI). Patient-related factors affect the level of PR. Patients with atrial fibrillation (AF) undergoing PCI are treated concomitantly with oral anticoagulants (OAC) potentially interacting with platelet function. This study aimed to investigate the association of PR with demographic and clinical characteristics in these patients. Methods: In this single-centre prospective observational cohort study, patients with AF with an indication for OAC were enrolled during hospitalization after PCI with clopidogrel. TRAP- and ADP- induced PR (TRAP 32 μM, ADP 6.4 μM) were assessed by multiple electrode aggregometry. ADP-induced PR was normalized to TRAP-induced PR (r-ADP-agg). Results: 159 patients were enrolled between May 2020 and May 2021. The median age was 78 years (interquartile range, IQR 72-82), 112 (70%) were male and 39 (25%) presented with ACS. 68 (43%) presented with chronic kidney disease (CKD), defined as GFR&lt;60. 54 (34%) patients received apixaban, 6 (4%) dabigatran, 18 (11%) edoxaban, 74 (47%) rivaroxaban and 4 (3%) marcumar. 128 (81%) patients received clopidogrel loading. Median ADP-induced PR was 12 U (IQR 6-17); median r-ADP-agg was 24% (IQR 14-39). ADP-induced PA is significantly correlated with age (r=-0.22; p=0.035) and platelet count (r=0.22; p=0.006). Compared to the patients without CKD,patients with CKD had a significantly lower ADP-induced PA (median 8 [IQR 10] vs. median 13 [IQR 10]; p&lt;0.001) and r-ADP-agg. (median 20 [IQR 25] vs median 28 [IQR 24]; p=0.003).In a multivariable linear regression, ADP-induced PR was significantly associated with age (r=-0.177, CI:-0.481 to -0.018, p=0.035), immature platelet count (r=0.178, CI: 0.003 to 0.729, p=0.048), and diabetes mellitus (r=0.21, CI: 1.192 to 9.087, p=0.011). CKD was associated with both: lower ADP-PR (r=-0.262, CI:-9.962 to -2.396, p=-0.002) and lower r-ADP-agg (r=-0.253, CI:-9.962 to -2.396, p=0.003). Conclusions: In this patient cohort the association of on-clopidogrel PR as assessed by multiple electrode aggregometry with patient related factors was weak and most pronounced for chronic kidney disease.

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&amp;lt;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&amp;lt;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&amp;lt;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.

Platelet reactivity and clinical outcomes following percutaneous coronary intervention in complex higher-risk patients.

To investigate the levels of platelet reactivity and the impact of high platelet reactivity (HPR) on long-term clinical outcomes of complex higher-risk and indicated patients (CHIP) with stable coronary artery disease (CAD) treated with elective percutaneous coronary intervention (PCI). We enrolled 500 patients undergoing elective PCI for stable CAD and treated with aspirin and clopidogrel. Patients were divided into four groups based on the presence of CHIP features and HPR. Primary endpoint was the occurrence of major adverse clinical events (MACE) at 5 years. The prevalence of HPR was significantly greater in the CHIP population rather than non-CHIP patients (39.9% vs 29.8%, P = 0.021). Patients with both CHIP features and HPR showed the highest estimates of MACE (22.1%, log-rank P = 0.047). At Cox proportional hazard analysis, the combination of CHIP features and HPR was an independent predictor of MACE (hazard ratio 2.57, 95% confidence interval 1.30-5.05, P = 0.006). Among patients with stable CAD undergoing elective PCI and treated with aspirin and clopidogrel, the combination of CHIP features and HPR identifies a cohort of patients with the highest risk of MACE at 5 years, who might benefit from more potent antiplatelet strategies.

Impact of chronic kidney disease on the pharmacodynamic and pharmacokinetic effects of ticagrelor in patients with diabetes mellitus and coronary artery disease.

Patients with diabetes mellitus (DM) and chronic kidney disease (CKD) are at increased risk of atherothrombotic events. Ticagrelor reduces ischaemic events compared to clopidogrel, with the greatest risk reduction in patients with both DM and CKD. How CKD status affects the pharmacodynamic (PD) and pharmacokinetic (PK) profiles of different ticagrelor maintenance dose regimens in patients with DM is unknown. In this randomized, crossover study, patients with DM on treatment with dual antiplatelet therapy (aspirin and clopidogrel) were stratified according to CKD status and randomized to ticagrelor 90 or 60 mg bid. PK/PD assessments were performed at baseline, after 7-10 days of ticagrelor (peak and trough), and after 7-10 days of alternative ticagrelor regimen (peak and trough). PK assessments included plasma concentrations of ticagrelor and its major metabolite. PD assessments included vasodilator-stimulated phosphoprotein (VASP)-platelet reactivity index (PRI), VerifyNow P2Y12, and light transmittance aggregometry (LTA). A total of 92 patients with DM (CKD, n = 44; non-CKD, n = 48) were randomized. Levels of platelet reactivity were lower with the 90 mg compared with the 60 mg ticagrelor dose, which was statistically significant in non-CKD but not in CKD patients for most PD measures. There were no significant differences in the primary endpoint (trough levels of VASP-PRI following ticagrelor 90 mg dosing) between cohorts (31 ± 20 vs. 25 ± 14; P = 0.105). VerifyNow and LTA provided similar findings. PK assessments tracked PD profiles showing increased plasma concentrations of ticagrelor and its major metabolite in CKD compared to non-CKD patients. In patients with DM, although ticagrelor maintenance dose regimens (60 and 90 mg) yield potent P2Y12 inhibition, levels of platelet reactivity tended to be higher and subject to broader variability in non-CKD compared with CKD patients. http://www.clinicaltrials.gov Unique Identifier: NCT02539160.

Low hemoglobin predicts high-platelet reactivity and major cardiovascular ischemic events at long-term follow-up among ACS patients receiving dual antiplatelet therapy with ticagrelor.

Reduced levels of hemoglobin (Hb) represent an established marker of impaired outcomes and increased cardiovascular risk in patients with coronary artery disease, challenging the management of dual antiplatelet therapy (DAPT). However, while anemia has emerged as an independent predictor of suboptimal platelet inhibition in patients receiving clopidogrel, no study has so far evaluated the impact of Hb levels on high-on treatment platelet reactivity (HRPR) with ticagrelor and their prognostic consequences, that were the aim of the present study. Patients on DAPT with ASA + Ticagrelor (90 mg/twice a day) after percutaneous coronary revascularization for ACS were scheduled for platelet function assessment 30-90 days post-discharge. Aggregation tests were performed by multiple electrode aggregometry. Suboptimal platelet inhibition (HRPR-high residual platelet reactivity was defined if above the lower limit of normality (417 AU*min). The primary study endpoint was defined as the occurrence of major cardiovascular events (a composite of cardiovascular death, recurrent acute coronary syndrome [MI], target vessel revascularization) at longest available follow-up. We included 397 patients that were divided according to tertiles values of Hb (< 12.7, 12-7-14.09, ≥14.1g/dl). Patients with lower Hb were older and displayed a more severe cardiovascular risk profile. Mean levels of platelet reactivity were enhanced in patients with lower Hb after stimulation with TRAP peptide (TRAP test, p=.03) and ADP (p=.02). Elevated platelet reactivity (HRPR) on Ticagrelor was more frequent among patients with reduced Hb (16.4% vs. 12% vs. 5.4%, p=.005, adjusted OR [95%CI]=1.71[0.996;3.01], p=.056). At a mean follow-up of 820.9 ± 553.4 days, 21.4% of the patients experienced the primary composite endpoint, with a higher rate of events in patients with lower Hb (27.6% vs. 22.6% vs. 13.5%, p=.006, adjusted HR [95%CI]=1.51[1.12; 2.03], p=.006), mainly driven by a higher rate of recurrent ACS. After correction for baseline differences lower Hb tertiles but not HRPR emerged as independent predictor of MACE (adjusted HR [95%CI]=0.98[0.50; 1.92], p=.95). In the present study, we demonstrated that among patients on DAPT with ASA and ticagrelor after PCI for ACS, lower Hb levels are independently associated with a higher rate of HRPR and an increased rate of major ischemic events, and especially for recurrent ACS, although with no impact on survival. Neutral prognostic effect of HRPR was observed across Hb tertiles.

Abstract 15044: Impact of Chronic Kidney Disease on the Pharmacodynamic and Pharmacokinetic Effects of Ticagrelor in Patients With Diabetes Mellitus and Coronary Artery Disease

Background: Diabetes mellitus (DM) is a key risk factor for the development of chronic kidney disease (CKD) and patients having both risk factors have increased risk of atherothrombotic events, underscoring the importance of antiplatelet therapy. Ticagrelor reduces ischemic events compared with clopidogrel, with the greatest risk reduction in patients with both DM and CKD. However, how CKD status affects the pharmacodynamic (PD) and pharmacokinetic (PK) profiles of different ticagrelor dosing regimens in DM patients is unknown. Methods: This was a prospective, randomized, cross-over study testing the PD/PK profiles of ticagrelor 90mg bid and 60mg bid among DM patients with and without CKD. All patients had coronary artery disease and were on dual antiplatelet therapy with aspirin (81mg qd) and clopidogrel (75mg qd). PD and PK assessments were performed at 3 visits: baseline, after 7-10 days of ticagrelor therapy (pre-crossover; peak and trough), and after 7-10 days of alternative ticagrelor regimen (post-crossover; peak and trough). Results: A total of 92 patients were randomized (CKD-, n=48; CKD+, n=44). Platelet reactivity as assessed by multiple assays (VASP-PRI; VerifyNow P2Y12; LTA) was increased with 60mg compared with 90 mg, which was statistically significant in CKD- but not in CKD+ patients for most PD measures (Figure). Although trough levels of platelet reactivity were numerically lower in CKD+ patients compared with CKD-, there was no significant difference in the pre-defined primary endpoint (trough levels of VASP-PRI following ticagrelor 90 mg dosing) between DM subjects with and without CKD (31±20 vs 25±14; mean difference= 6.4; 95% CI: -1.1 to 14.3; p=0.105; primary endpoint; Figure). PK assessments tracked PD profiles. Conclusions: In patients with DM, platelet inhibition by ticagrelor is similar irrespective of CKD status. However, the PD effects of the 60mg ticagrelor regimen is reduced compared with the 90mg regimen in patients without CKD.

Platelet Reactivity in Hepatitis C Virus-Infected Patients on Dual Antiplatelet Therapy for Acute Coronary Syndrome.

BackgroundCoronary artery disease (CAD) has been recognized as a serious and potentially life‐threatening complication of Hepatitis C Virus (HCV) infection. High on‐treatment platelet reactivity has been associated with high risk of ischemic events in patients with CAD, but data regarding the association with HCV infection are still lacking. This post hoc analysis aims to assess high on‐treatment platelet reactivity, severity of CAD, and long‐term outcomes of patients with acute coronary syndrome (ACS) who were infected with HCV.Methods and ResultsPatients with ACS who were infected with HCV (n=47) were matched to patients with ACS and without HCV (n=137) for age, sex, diabetes mellitus, hypertension, and renal function. HCV‐infected patients with ACS had higher levels of platelet reactivity (ADP10–light transmittance aggregometry, 56±18% versus 44±22% [P=0.002]; arachidonic acid–light transmittance aggregometry, 25±21% versus 16±15% [P=0.011]) and higher rates of high on‐treatment platelet reactivity on clopidogrel and aspirin compared with patients without HCV. Moreover, HCV‐infected patients with ACS had higher rates of multivessel disease (53% versus 30%; P=0.004) and 3‐vessel disease (32% versus 7%; P<0.001) compared with patients without HCV. At long‐term follow‐up, estimated rates of major adverse cardiovascular events (cardiac death, nonfatal myocardial infarction, and ischemia‐driven revascularization) were 57% versus 34% (P=0.005) in HCV‐ and non–HCV‐infected patients with ACS, respectively. In addition, thrombolysis In Myocardial Infarction (TIMI) major bleeding rates were higher in HCV‐infected patients (11% versus 3%; P=0.043) compared with noninfected patients. Multivariable analysis demonstrated that HCV infection was an independent predictor of high on‐treatment platelet reactivity, severity of CAD, and long‐term outcome.ConclusionsIn this hypothesis‐generating study, patients with ACS and HCV infection showed increased on‐treatment platelet reactivity, more severe CAD, and worse prognosis compared with patients without HCV.

Ticagrelor With or Without Aspirin After PCI: The TWILIGHT Platelet Substudy

BackgroundAn evolving strategy in the setting of percutaneous coronary intervention (PCI) involves withdrawal of acetylsalicylic acid (ASA), or aspirin, while maintaining P2Y12 inhibition. However, the pharmacodynamic effects of this approach on blood thrombogenicity and platelet reactivity remain unknown. ObjectivesThis study sought to compare the antithrombotic potency of ticagrelor alone versus ticagrelor plus ASA among high-risk patients undergoing PCI with drug-eluting stents. MethodsThis was a mechanistic substudy within the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) trial, which randomized patients undergoing PCI to ticagrelor plus placebo versus ticagrelor plus ASA following 3 months of dual antiplatelet therapy. Substudy participants were enrolled after randomization, at which time ex vivo assays to quantify thrombus size under dynamic flow conditions and platelet reactivity were performed. Pharmacodynamic assessments were repeated 1 to 6 months thereafter. The primary endpoint was thrombus size at the post-randomization visit with platelet reactivity following stimuli to arachidonic acid, collagen, adenosine diphosphate, and thrombin as secondary endpoints. Results were analyzed using analysis of covariance. ResultsA total of 51 patients were enrolled, among whom 42 underwent perfusion assays at baseline and follow-up with a median time between studies of 1.5 months. The adjusted mean difference in post-randomization thrombus area was similar between groups: −218.2 μm2 (95% confidence interval [CI]: −575.9 to 139.9 μm2; p = 0.22). Markers sensitive to cyclo-oxygenase-1 blockade, including platelet reactivity in response to arachidonic acid (mean difference: 10.9 U; 95% CI: 1.9 to 19.9 U) and collagen (mean difference: 9.8 U; 95% CI: 0.8 to 18.8 U) stimuli were higher among patients receiving placebo, whereas levels of platelet reactivity were similar with adenosine diphosphate and thrombin. ConclusionsAmong high-risk patients receiving drug-eluting stents, the antithrombotic potency of ticagrelor monotherapy is similar to that of ticagrelor plus ASA with respect to ex vivo blood thrombogenicity, whereas markers sensitive to cyclo-oxygenase-1 blockade are increased in the absence of ASA. (Platelet Substudy of the TWILIGHT Trial; NCT04001374).