Treatment Platelet Reactivity Research Articles

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

High on-aspirin treatment platelet reactivity and restenosis after percutaneous coronary intervention: results of the Intracoronary Stenting and Antithrombotic Regimen-ASpirin and Platelet Inhibition (ISAR-ASPI) Registry

ObjectiveThe aim of this study was to assess the association between high on-aspirin treatment platelet reactivity (HAPR) and the subsequent risk of restenosis after percutaneous coronary intervention (PCI) with predominantly drug-eluting stents.BackgroundThe association between HAPR and subsequent risk of restenosis after PCI is unclear.MethodsThis study included 4839 patients undergoing PCI (02/2007–12/2011) in the setting of the Intracoronary Stenting and Antithrombotic Regimen-ASpirin and Platelet Inhibition (ISAR-ASPI) registry. Platelet function was assessed with impedance aggregometry using the multi-plate analyzer immediately before PCI and after intravenous administration of aspirin (500 mg). The primary outcome was clinical restenosis, defined as target lesion revascularization at 1 year. Secondary outcomes included binary angiographic restenosis and late lumen loss at 6- to 8-month angiography.ResultsThe upper quintile cut-off of platelet reactivity measurements (191 AU × min) was used to categorize patients into a group with HAPR (platelet reactivity > 191 AU × min; n = 952) and a group without HAPR (platelet reactivity ≤ 191 AU × min; n = 3887). The primary outcome occurred in 94 patients in the HAPR group and 405 patients without HAPR (cumulative incidence, 9.9% and 10.4%; HR = 0.96, 95% CI 0.77–1.19; P = 0.70). Follow-up angiography was performed in 73.2% of patients. There was no difference in binary restenosis (15.2% vs. 14.9%; P = 0.79) or late lumen loss (0.32 ± 0.57 vs. 0.32 ± 0.59 mm; P = 0.93) between patients with HAPR versus those without HAPR.ConclusionsThis study did not find an association between HAPR, measured at the time of PCI, and clinical restenosis at 1 year after PCI.Graphical abstract

Impact of renal failure and high-platelet reactivity on major cardiovascular ischemic events among patients with acute coronary syndrome receiving dual antiplatelet therapy with ticagrelor.

No study has so far evaluated the impact of chronic kidney disease (CKD) on high-on treatment platelet reactivity (HRPR) with ticagrelor and their prognostic consequences, that were therefore the aim of the present study. Patients on dual antiplatelet therapy with ASA+ticagrelor (90mg/twice a day) after percutaneous coronary revascularization for ACS were scheduled for platelet function assessment 30-90 days post-discharge. 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 the longest available follow-up. We included 396 patients, that were divided according to CKD (eGFR <or≥ 60 mL/min). Mean platelet reactivity was comparable irrespective of renal function Prevalence of high platelet reactivity (HRPR) on Ticagrelor was similar among patients with or without CKD (9.7% vs. 11.8%, P=0.84). At a mean follow-up of 939±581.4 days, 21.2% of the patients experienced the primary composite endpoint, with a similar rate of events in patients CKD or normal renal function (22.2% vs. 21.2% HR [95%CI]= 0.92[0.52-1.61], P=0.77), and no difference in survival, ischemic and bleeding endpoints. After correction for baseline differences CKD did not emerge as an independent predictor of either HRPR (adjusted OR [95%CI]=0.47 [0.18;1.25], P=0.13) or MACE (adjusted HR [95%CI]=0.66 [0.34-1.29] P=0.18). In the present study we demonstrated that among ACS patients on DAPT with ASA and ticagrelor after PCI, renal failure is not associated with a higher rate of HRPR or to an increased risk of mortality or major ischemic and bleeding events.

Flow Cytometry Based Platelet Reactivity Testing to Predict the Occurrence of Per-operative Solid Microemboli During Carotid Endarterectomy

Peri-operative antiplatelet therapy (APT) aims to prevent thrombotic events such as stroke. High platelet reactivity ,despite the use use of APT, increases the risk of thrombotic events. Transcranial Doppler imaging (TCD) is used to detect peri-operative microembolic signals (MES) during carotid endarterectomy (CEA). Peri-operative MES are associated with an increased risk of procedural stroke and new silent lesions on diffusion weighted magnetic resonance imaging following surgery. The main components of TCD detected MES are platelet aggregates, and therefore patients displaying multiple MES during surgery could have benefited from more stringent APT. This study investigated whether the use of flow cytometry based platelet reactivity measurements were correlated with the incidence of pre-operative MES and thereby in the future suitable to predict patients at increased risk of peri-operative thrombotic events. Bilateral TCD with MES detection was performed in 197 patients undergoing CEA. Platelet reactivity was assessed with a flow cytometry based platelet reactivity assay measuring platelet response in whole blood. High on treatment platelet reactivity status was assessed for all patients. The secondary outcome was major adverse cardiovascular events (MACE) within one year. In total, 197 patients were included, 49 had peri-operative MES. The platelet response to adenosine diphosphate (ADP) correlated with MES (p= .021), and high on treatment platelet reactivity after adenosine diphosphate stimulation was associated with MACE (OR 2.34, 95% confidence interval 1.126 - 4.890, p= .023). Pre-operative platelet reactivity determined by flow cytometry after ADP stimulation correlated with the occurrence of intra-operative MES and post-operative MACE. Clopidogrel treatment showed the most substantial effect on reducing MES frequency and platelet reactivity measured by flow cytometry.

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.

Clopidogrel underactivity is a common in patients with acute symptomatic severe carotid stenosis

BackgroundClopidogrel is commonly used for secondary stroke prevention in patients with large vessel stenosis. Reduced Clopidogrel high on treatment platelet reactivity (CR) can lead to Clopidogrel underactivity (CU) causing acute thrombosis. However, the prevalence of CU among patients with acute symptomatic carotid disease remains unknown. Therefore, we aimed to find the prevalence and identify the predictors for CU among patients with acutely symptomatic carotid stenosis. Patients and methodsOver the span of 14 months, CR was measured at the time of endovascular procedure in all patients undergoing angiography and stenting because of acute symptomatic carotid stenosis. Only patients treated per institutional protocol with a combination of Clopidogrel and Aspirin were included. CR was measured with VerifyNowP2Y12 reaction units (PRU) and CU was defined as PRU > 208. Patients with CU were compared to those without CU. ResultsThirty-five patients were included (mean age 71.3 ± 10, 76% men) and twelve (34.3%, mean age 71.8 ± 8.4, 58% men) had CU at the time of endovascular intervention. On univariate analysis more severe carotid stenosis was seen in CU patients (92.6 ± 6.5% vs 81.6 ± 13.6%, p = 0.013) and percent stenosis was independently associated with CU on multivariate analysis (p = 0.023). ConclusionsCU is present in 1 of every 3 patients with acutely symptomatic carotid disease. The current results suggest that CR testing should become part of routine care in patients with acutely symptomatic carotid disease.

Impact of Platelet Reactivity in ACS Patients on Clinical Outcomes with Triple Antithrombotic Therapy.

Optimal antithrombotic therapy after percutaneous coronary intervention (PCI) in patients on oral anticoagulants (OAC) remains a clinical conundrum. In fact, combining an OAC with dual antiplatelet therapy (triple antithrombotic therapy, TAT) increases the risk of bleeding. Clopidogrel is the only thienopyridine recommended in TAT patients. Whether its response plays a relevant role in this setting remains uncertain. We aimed to evaluate the level of platelet reactivity inhibition (PRI) achieved by oral TAT in Acute Coronary Syndrome (ACS) patients undergoing PCI and its relationship with outcomes. We performed a multicenter prospective observational study and assessed PRI by vasodilator-stimulated phosphoprotein (VASP) index following a loading dose of clopidogrel. The primary endpoint was the incidence of major adverse cerebral or cardiovascular events (MACCE) at six months based on High on Treatment Platelet Reactivity (HTPR, VASP > 50%). The secondary endpoint was the incidence of bleeding at six months based on Low on Treatment Platelet Reactivity (LTPR, VASP < 16%). 491 patients were followed up for six months: 7.7% experienced MACCE and 17.3% experienced bleeding. There was no significant relationship between HTPR and MACCE, neither between LTPR and bleeding. Vitamin-K antagonist (VKA) treatment was associated with more MACCE and bleeding events, and the majority of events occurred within the first months. VASP index failed to predict outcomes in post-ACS patients with TAT. We confirm that direct acting OAC should be prioritized over VKA in TAT regimen.

Genotyping single-nucleotide polymorphism CYP2C19*2, pharmacodynamic evaluation of high on-clopidogrel treatment platelet reactivity and the cardiologist

Genotyping single-nucleotide polymorphism CYP2C19*2, pharmacodynamic evaluation of high on-clopidogrel treatment platelet reactivity and the cardiologist

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.

Net platelet clot strength of thromboelastography platelet mapping assay for the identification of high on-treatment platelet reactivity in post-PCI patients.

High-on treatment platelet reactivity (HTPR) leads to more prevalence of thrombotic event in patients undergoing percutaneous coronary interventions (PCI). Dual antiplatelet therapy with aspirin in addition to one P2Y12 inhibitor is commonly administrated to reduce HTPR. However, ‘one size fits all’ antiplatelet strategy is widely implemented due to lacking benefits with tailored strategy. One reason for the failure of tailored treatment might be less specificity of the current indicators for HTPR. Therefore, searching for specific indicators for HTPR is critical. Thromboelastograph with platelet mapping (TEGpm) assay has been explored for identifying HTRP. Variables of TEGpm assay, including maximum amplitude (MA) induced by thrombin (MAthrombin), R time, platelet aggregation rate induced by ADP (TEGaradp) and MA induced by ADP (MAadp) have been demonstrated to be able to identify HTPR in post-PCI patients. However, these variables for HTPR might be less specific. Thus, in the present study, a novel variable nMAadp was derived by removing fibrin contribution from MAadp and analyzed for its usefulness in determining HTPR. In addition, MAthrombin, R time, MAadp and TEGaradp were also examined for determining HTPR. In conclusion, nMAadp and TEGaradp were demonstrated to be independent indicators for HTPR; nMAadp had the strongest power to identify HTPR with cutoff value of 26.3 mm; MAthrombin and R time were not significantly different between patients with and without HTPR; combination of TEGaradp and nMAadp further improved the ability to identify HTPR with an AUC of 0.893.

4423 Impact of Gender on High On-Treatment Platelet Reactivity (HPR) and Major Adverse Cardiovascular Events (MACEs) in Caribbean Hispanic patients using Clopidogrel

OBJECTIVES/GOALS: The use of P2Y12 receptor inhibitors like Clopidogrel is crucial in the prevention of thrombotic events in patients with coronary artery disease, peripheral arterial disease, and cerebrovascular disease. Variation in the level of platelet inhibition is present in many patients, and it is associated with the occurrence of major adverse cardiovascular events (MACEs). The term High-on treatment platelet reactivity (HTRP) is used to describe impaired antiplatelet inhibition while on Clopidogrel. Multiple factors have been associated with the presence of HTPR in patients with CAD and PAD, including CYP2C19 loss of function polymorphism, drug-drug interactions, and medical comorbidities. Gender differences are another factor that might influence the levels of platelet inhibition while on Clopidogrel and hence, HTPR. Differences by Gender exist in platelet biology, count, and activation. The evidence for the influence of Gender in HTPR is limited, but a possible association has been described. In this study, we described the association of Gender with HTPR and Major Adverse Cardiovascular Events (MACEs) occurrence. The data is from a sample of Hispano-Caribbean patients on Clopidogrel therapy alone or in combination with Aspirin that were retrospectively evaluated from an ongoing trial in Puerto Rico. The result of this study provided evidence of the influence that Gender has on antiplatelet therapy function and MACEs occurrence. METHODS/STUDY POPULATION: The population in the study consisted of Hispano-Caribbean patients using Clopidogrel alone or in combination with Aspirin for coronary artery disease, peripheral arterial disease, or cerebrovascular disease. The sample was obtained from multiple hospital institutions with cardiovascular services in Puerto Rico during the years 2016-2019. Patients were part of the ongoing trial, “Adopting a precision medicine paradigm in Puerto Rico: leveraging ancestral diversity to identify predictors of Clopidogrel response in Caribbean Hispanics.” The sample size consisted of 150 patients. Participants were recruited during routine medical care, pre-admission evaluation for elective cardiac procedures, or during hospitalization in the participating institutions. Platelet reactivity testing was performed with the system Verify Now® to determine PRU values, and High on-treatment platelet reactivity was defined as PRU ≥208. One year after recruitment, the patients were re-evaluated for the occurrence of MACEs. The association of the variables HTPR, occurrence of MACEs, and Gender were assessed using logistic regression in addition to the role of HTPR and Gender for predicting MACE occurrence. The analysis was done using the statistic software Intellectus ©. RESULTS/ANTICIPATED RESULTS: The sample consisted of 67 females and 83 males with and Mean age of 67.87 years and 61.11 years, respectively. The prevalence of HTPR in the sample was 32.67 % (n = 49) with 36% (n = 24) for females, and 30%(n = 25) for males. The mean PRU values were 179.54 for females and 170.81 for males. The percentage of MACEs one year after recruitment was 29.33 % (n = 44) with 43% on females (n = 19), and 57% on males (n = 25). Logistic regression for Gender predicting HTPR was non-significant with a χ2(2) = 0.55, p = .758, and McFadden R2 = 0.00. Also, logistic regression for the effects of Gender and HTPR on the Odds of MACEs occurrence was not significant based on a model with an alpha of 0.05, χ2(2) = 1.99, p = .370, and McFadden R2 = 0.01. DISCUSSION/SIGNIFICANCE OF IMPACT: The sample consisted of 67 females and 83 males with and Mean age of 67.87 years and 61.11 years, respectively. The prevalence of HTPR in the sample was 32.67 % (n = 49) with 36% (n = 24) for females, and 30%(n = 25) for males. The mean PRU values were 179.54 (±70.42) for females and 170.81(±64.89) for males. The percentage of MACEs one year after recruitment was 29.33 % (n = 44) with 43% on females (n = 19), and 57% on males (n = 25). Logistic regression for Gender predicting HTPR was non-significant with a χ2(2) = 0.55, p = .758, and McFadden R2 = 0.00. Also, logistic regression for the effects of Gender and HTPR on the odds of MACEs occurrence was not significant based on a model with an alpha of 0.05, χ2(2) = 1.99, p = .370, and McFadden R2 = 0.01.

Acetylsalicylic acid resistance in long-term follow-up in subjects after myocardial infarction

Acetylsalicylic acid (ASA) is widely used as an antiplatelet therapeutic drug in secondary prevention. Despite its recognized benefits in treatment of subjects with cardiovascular (CV) diseases, last years brought many reports on ASA resistance or high-on treatment platelet reactivity (HTPR) despite aspirin treatment. The aim of this study is an evaluation of ASA resistance in long-term control basing on the result of arachidonic acidinduced platelet aggregation in reference to the results obtained during first 9 months of observation

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.

Gender Differences in Platelet Reactivity in Diabetic Patients Receiving Dual Antiplatelet Therapy

BackgroundIncreased comorbidities and a perceived high-bleeding risk often prevent the use of dual antiplatelet therapy (DAPT) in female patients. However, more aggressive antiplatelet treatment would certainly offer additional outcome benefits in coronary artery disease, especially among diabetic patients. The aim of the present study was to evaluate the gender differences in high-residual on treatment platelet reactivity (HRPR) among diabetic patients treated with DAPT. MethodsOur population is represented by a consecutive cohort of diabetic patients treated with DAPT (ASA + clopidogrel, ticagrelor or dose-adjusted prasugrel) for an acute coronary syndrome or elective PCI, undergoing platelet reactivity assessment at 30–90 days post-discharge. Aggregation was assessed by multiple-electrode aggregometry and in diabetic patients naïve to antiplatelet therapy, by light transmission aggregometry, surface expression of P-selectin and plasma concentration of Thromboxane B2. ResultsWe included 472 patients, 113 (23.9%) women. Female gender was associated with more advanced age, and increased comorbidities. Mean platelet reactivity did not differ according to gender. The rate of HRPR was similar in women as compared to men (for ASA: adjusted OR[95%CI] = 0.59[0.27–1.33], p = 0.21, for ADP-antagonists: adjusted OR[95%CI] = 1.24[0.25–1.80], p = 0.27), however, the benefits of the new ADP-antagonists on platelet reactivity were lower in women than in men (p interaction = 0.01).No impact of gender on platelet reactivity was confirmed among 50 diabetic patients naïve to antiplatelet therapy. ConclusionsAmong diabetic patients receiving dual antiplatelet therapy gender does not affect platelet reactivity or high-on treatment platelet reactivity. However, the enhanced platelet inhibition provided by the new-ADP antagonists of new-ADP antagonists could be mitigated in women.

Antiaggregation effect of clopidogrel in coronary heart disease patients using omeprazole.

Background Antiplatelet agents used in coronary heart disease (CHD) cause gastrointestinal side effects. Omeprazole can prevent and cure these antiplatelet side effects. Clopidogrel combined with aspirin increases the risk of gastrointestinal tract ulcers and bleeding. This research studied the effect of omeprazole on the antiplatelet effect of clopidogrel. Methods CHD patients using clopidogrel and aspirin receive omeprazole 20 mg in a single dose for 10 days. Platelet antiaggregation point for clopidogrel was measured using VerifyNow P2Y12. The cutoff points used were: low on treatment platelet reactivity (LPR) <85 P2Y12 reaction unit (PRU), normal on treatment platelet reactivity (NPR) 85-208 PRU, and high on treatment platelet reactivity (HPR) >208 PRU. Results Using the paired t-test PRU points pre- and post-omeprazole were 154 ± 85.89 PRU and 169.4 ± 56.15 PRU, respectively. The PRU points were consistent or decreased from the previous PRU points below the HPR cutoff (p: 0.215; >0.05). Before omeprazole use, five patients were categorized as NPR, two patients as LPR, and three patients as HPR. After omeprazole use, two patients, each from HPR and NPR category had a PRU point >208; the rest showed results below the HPR point. Conclusions In this study the PRU points of clopidogrel after omeprazole use showed a PRU <208. The hypothesis that omeprazole may reduce the antiaggregation effect of clopidogrel as shown by the increase in PRU above the cutoff points >208 PRU (HPR) was not proven.

P6406Platelet reactivity in Hepatitis C virus infected patients on dual antiplatelet therapy for acute coronary syndrome

Abstract Background Coronary 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. Purpose We sought to assess platelet reactivity on dual anti-platelet therapy and long-term outcome of acute coronary syndrome (ACS) patients infected with HCV. Methods ACS patients infected with HCV were matched to ACS patients without HCV for age, sex, diabetes, hypertension and renal function. Primary and secondary study endpoints were the proportion of patients with high on treatment platelet reactivity (HTPR) and long-term outcomes, respectively. Results HCV-infected ACS patients had higher levels of platelet reactivity (ADP10-LTA: 56% ± 18% vs. 44% ± 22%; p=0.002; Arachidonic Acid-LTA: 25% ± 21% vs. 16% ± 15%; p=0.011) and higher rate of HTPR on clopidogrel and aspirin compared with non-HCV patients. Multivariable analysis demonstrated HCV-infection to be an independent predictor of HTPR. At follow-up, estimated major adverse clinical events (MACE: cardiac death, non fatal myocardial infarction and any revascularization) were 57% vs. 37%, p=0.006 in HCV-infected ACS and non-HCV, respectively. Also, TIMI major bleeding rates were higher in HCV-infected subjects (11% vs. 3%; p=0.043) as compared with non-infected patients. Platelet function according to HCV status Conclusions ACS patients with HCV infection have increased on treatment platelet reactivity, higher rate of HTPR, MACE and bleedings as compared with non-HCV patients.

Vitamin D levels and platelet reactivity in diabetic patients receiving dual antiplatelet therapy

BackgroundHypovitaminosis D represents an emerging cardiovascular risk factor, and especially among higher-risk subsets of patients, such as in those with diabetes mellitus. The anti-inflammatory and anti-thrombotic properties of vitamin D, in fact, could be even more beneficial among diabetics, where platelet hyperreactivity and suboptimal response to antiplatelet drugs has been associated with poorer outcomes. However, no study has so far evaluated the impact of vitamin D levels on platelet reactivity and high-on treatment platelet reactivity (HRPR) among diabetic patients receiving dial antiplatelet therapy (DAPT). MethodsOur population is represented by a consecutive cohort ofdiabetic patients treated with DAPT (ASA + clopidogrel or ticagrelor or dose-adjusted prasugrel) for an acute coronary syndrome or elective PCI, undergoing platelet reactivity assessment at 30–90 days post-discharge. Aggregation was assessed by multiple-electrode aggregometry. HRPR was defined for values above the lower limit of normality (in non-treated patients). ResultsWe included 440 patients, that were divided according to quartiles values of vitamin D (< 9.4; 9.4–15.59; 15.6–21.64; ≥ 21.65 ng/ml). Among them, 31 were excluded as chronically treated with vitamin D supplementation. Lower vitamin D quartiles were associated with more advanced age (p = 0.01), female gender (p = 0.04), renal failure (p = 0.005), history of previous MI (p = 0.01), CABG and use of diuretics (p = 0.003), severe coronary disease (p = 0.002), but lower ejection fraction (p = 0.001), treatment with statins (p = 0.04) and new ADP-antagonists (p = 0.002). Vitamin D levels related with higher HbA1c (p = 0.001), cholesterol (p = 0.02) and creatinine (p = 0.004) and lower hemoglobin (p = 0.004).The prevalence of HRPR with ASA was low and not related to vitamin D quartiles (3.4% vs 2.7% vs 1.8% vs 2.1%, p = 0.44; adjusted OR[95%CI] = 1.16[0.60–2.26], p = 0.67).The prevalence of HRPR for ADP antagonists was associated to hypovitaminosis D (40.2% vs 29.1% vs 29.4% vs 25.5%, p = 0.03; (adjusted OR[95%CI] = 1.76[1.04–2.98], p = 0.036for I vs II-IV quartile). The impact of vitamin D quartiles, was significant only in patients on new ADP antagonists (n = 225, of whom 81 on prasugrel 5 mg; p = 0.03; adjusted OR[95%CI] = 3.12[1.34–7.49], p = 0.009) but not with clopidogrel (p = 0.85, adjusted OR[95%CI] = 1.05[0.49–2.24], p = 0.89). ConclusionsAmong diabetic patients receiving dual antiplatelet therapy for an acute coronary syndrome or elective percutaneous coronary intervention, severe vitamin D deficiency is associated with a higher ADP-mediated platelet reactivity and rate of HRPR, and especially for new ADP-antagonists over clopidogrel.

Impact of aging on platelet reactivity in diabetic patients receiving dual antiplatelet therapy.

Advanced age and diabetes represent summative conditions in the determination of cardiovascular risk, and especially for the management of dual antiplatelet therapy (DAPT), often requiring balancing between bleeding and thrombotic complications. However, few studies have so far evaluated the impact of age on platelet reactivity and suboptimal platelet inhibition (high-on treatment platelet reactivity-HRPR) on DAPT among diabetic patients, that was, therefore the aim of the present study. In diabetic patients treated with DAPT (ASA + clopidogrel or ticagrelor) platelet reactivity was assessed at 30-90days post-discharge for an acute coronary syndrome or elective PCI. Aggregation was assessed by multiple-electrode aggregometry. HRPR was defined for values above the lower limit of normality (in non-treated patients). Elderly patients were considered ≥ 75years of age. We included 462 patients, among them 149 (32.2%) were ≥ 75years. Elderly patients were more often females (p = 0.006), with lower body size (p = 0.04), acute coronary syndrome at presentation and renal failure (p < 0.001), non-smokers (p = 0.002), in therapy with insulin (p = 0.02) and diuretics (p < 0.001) and lower rate of betablockers (p = 0.02). Age directly related with C reactive protein (p = 0.01), creatinine levels and inversely with hemoglobin (p < 0.001) and triglycerides (p = 0.003). No association was found at linear regression analysis for platelet reactivity and age with different activating stimuli, but for ASPI test (r = 0.12; p = 0.03). No significant difference in HAPR was found in elderly patients (2.4 vs. 3.2%, p = 0.76, OR[95% CI] = 0.45[0.1-2.11], p = 0.31). HRPR for ADP antagonists was similarly not affected by age (30.1% vs. 35.7%, p = 0.28, adjusted OR[95% CI] = 0.78[0.47-1.29], p = 0.33). Comparable results were obtained when considering separately the DAPT strategies with clopidogrel or ticagrelor, or when adjusting our results according to propensity score values. Among diabetic patients receiving dual antiplatelet therapy for an acute coronary syndrome or elective percutaneous coronary intervention, age does not affect platelet reactivity or the rate of high-on treatment platelet reactivity. Similar results were obtained for ASA and clopidogrel or ticagrelor.

Diurnal Variability of On-Treatment Platelet Reactivity in Clopidogrel versus Prasugrel Treated Acute Coronary Syndrome Patients: A Pre-Specified TROPICAL-ACS Sub-Study.

Long-term evidence supports a clustering of cardiovascular events in the early morning and smaller mechanistic studies in aspirin-treated patients have shown increased platelet reactivity at the end of the dosing interval. Comparative pharmacodynamic analyses for different adenosine diphosphate (ADP) receptor inhibitors in percutaneous coronary intervention-treated acute coronary syndrome (ACS) patients are lacking and this pre-specified analysis from the randomized Testing Responsiveness To Platelet Inhibition On Chronic Antiplatelet Treatment For Acute Coronary Syndromes (TROPICAL-ACS) trial aimed for the first time at investigating diurnal variability of on-treatment platelet reactivity in clopidogrel versus prasugrel treated patients. TROPICAL-ACS randomized 2,610 ACS patients to either treatment with prasugrel (control group) or to a platelet function testing-guided de-escalation of anti-platelet treatment with a switch to clopidogrel (guided de-escalation group). This study design enabled a diurnal comparison of on-prasugrel versus on-clopidogrel treatment platelet reactivity under steady-state conditions. For 2,526 patients (97%), both the exact time of blood sampling and the ADP-induced platelet aggregation value (in units, Multiplate analyser) were available. Platelet reactivity in patients on clopidogrel (n = 1,265) was higher and subject to significant diurnal variability (p = 0.019) with a peaking of platelet reactivity in the early morning (5-10 a.m.). In prasugrel-treated patients (n = 1,261), there was no sign for diurnal variability (p = 0.174) or a peaking of platelet reactivity in the morning. The potent ADP receptor inhibitor prasugrel is not subject to diurnal variability while we observed a significant diurnal variability of on-clopidogrel platelet reactivity. The clinical impact of this observation may differ for patients with and without an adequate response to clopidogrel treatment and the issue of diurnal variability of platelet reactivity in ACS patients warrants further investigation.

Prevalence and predictors of high-on treatment platelet reactivity during prasugrel treatment in patients with acute coronary syndrome undergoing stent implantation

BackgroundADP-antagonists such as prasugrel have reduced but yet not overcome the phenomenon of high-on treatment platelet reactivity (HRPR), that has been shown to increase the rate of major cardiovascular events after an acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI). However, the exact prevalence and the principal determinants of suboptimal platelet inhibition in patients treated with dual antiplatelet therapy (DAPT) with prasugrel have not been completely clarified and were therefore the aim of the present study. MethodsWe included patients (<75 years and >60kg) treated with DAPT (aspirin+prasugrel) after PCI, mainly for an ACS. Platelet function test evaluation was performed at 1–3 months from discharge. HRPR was assessed by multiplate impedance aggregometry and defined for results above upper limit of normal after ADP stimulation. ResultsWe included 190 post-ACS patients. HRPR with prasugrel was observed in 19 patients (10%). The prevalence of HRPR was stable in different high-risk subgroups of patients (female gender, hypercholesterolemic, and chronic kidney disease) whereas it was increased in diabetic patients (p=0.045), with a significant interaction between diabetic status and HRPR (p=0.04). However, at multivariate analysis, an impaired metabolic status, with higher levels of glycosylated hemoglobin and low-density lipoprotein (LDL) cholesterol, but not diabetic status, emerged as independent predictors of HRPR with prasugrel [OR (95% CI)=2.1 (1.32–3.33), p=0.002 and OR (95% CI)=1.03 (1.01–1.05), p=0.003, respectively], with a stronger linear relationship between ADP-mediated platelet aggregation and glycosylated hemoglobin levels (r=0.24, p=0.002), than for LDL-cholesterol (r=0.13, p=0.09). ConclusionsIn post-ACS patients treated with PCI and receiving DAPT with prasugrel, HRPR is observed in about 10% of patients. Impaired metabolic status, and especially elevated glycosylated hemoglobin, emerged as independent predictors of the suboptimal effectiveness of prasugrel.