Level Of Platelet Inhibition Research Articles

The impact of sex on platelet responses to aspirin in patients with peripheral artery disease.

Women with peripheral artery disease (PAD) have poorer limb salvage outcomes in spite of having lower risk factors for vascular disease than their male counterparts. Mono antiplatelet therapy with aspirin is the cornerstone of medical treatment for PAD to reduce the risk of arterial thrombosis, but platelets in women may have a variable response to this standard of care compared to men. Viscoelastic assays, such as thromboelastography with platelet mapping (TEG-PM), have been utilized to identify prothrombotic states and may provide insight into a patient's real-time coagulation profile and their response to specific antiplatelet medications. The aim of this prospective, observational study was to delineate the sex differences in platelet function using TEG-PM in patients with PAD on aspirin post-revascularization for PAD. All patients with PAD undergoing revascularization on aspirin monotherapy were prospectively enrolled between December 2020 and September 2023. The cohort was divided by sex, demographics, medications, procedure type, and outcomes were documented. Serial perioperative TEG-PM assays (1, 3, and 6 months) were performed up to 6 months postoperatively and platelet function was evaluated in both groups. Statistical analysis between women and men was performed to identify sex-specific differences in platelet function. Over the study period, a total of 303 patients were enrolled. Of this cohort, 149 patients met the study criteria and 266 samples were analyzed; 52 (34.89%) were women and 97 (65.11%) were men. In the platelet mapping assay, women showed significantly greater MAActF and MAAA, than men (16.66 vs. 14.94, p < .03 and 37.26 vs. 32.38, p < .01, respectively) indicating stronger thrombotic propensity. Additionally, platelet inhibition was significantly lower in women compared to men (52.95% vs. 61.65%, p < .05). In clinical outcomes reported as thrombotic events, women showed significantly higher occlusion in the area of intervention than men (4 vs. 1, p < .05). There is a growing awareness of the variations in the natural course, underlying mechanisms, and resulting outcomes of cardiovascular conditions, including PAD, in relation to sex. In this study, women did not achieve the same levels of platelet inhibition and displayed a procoagulant tendency in comparison to men when administered aspirin. Overall, aspirin monotherapy may be potentially sufficient for men, but women may require increased doses and/or additional antiplatelet medications to achieve an equivalent therapeutic effect.

Comparison of the effects of the GPIIb-IIIa antagonist Zalunfiban and the P2Y12 antagonist Selatogrel on Platelet Aggregation

Understanding the pharmacodynamic effects of platelet inhibitors is standard for developing more effective antithrombotic therapies. An example is the antithrombotic treatment of acute coronary syndrome (ACS), in particular ST-elevated myocardial infarction (STEMI) patients who are in need for rapid acting strong antithrombotic therapy despite the use of aspirin and oral P2Y12-inhibitors. In this study, we evaluated two injectable platelet inhibitors under clinical development (the P2Y12 antagonist selatogrel and the GPIIb-IIIa antagonist zalunfiban) that may be amenable to pre-hospital treatment of STEMI patients. Platelet reactivity was assessed at inhibitor concentrations that represent clinically relevant levels of platelet inhibition (IC20-50%, 1/2Cmax, and Cmax). Light transmission aggregometry (LTA), was used to evaluate the initial rate of aggregation (primary slope, PS) and maximal aggregation (MA). Both adenosine diphosphate (ADP) and thrombin receptor agonist peptide (TRAP) were used as agonists. Zalunfiban demonstrated similar inhibition of platelet aggregation when blood was collected in PPACK or TSC, whereas selatogrel demonstrated greater inhibition in PPACK. In this study, using PPACK anticoagulant, selatogrel and zalunfiban affected PS in response to ADP equivalently at all drug concentrations tested. In contrast, zalunfiban had significantly greater potency at its Cmax concentration compared to selatogrel using TRAP as agonist. Upon evaluation of MA responses at lower doses, selatogrel had greater inhibition of MA in response to ADP than zalunfiban; however, at concentrations that represent Cmax, the drugs were equivalent. Zalunfiban also had greater inhibition of MA in response to TRAP at the Cmax dose. These data suggest that zalunfiban may provide greater protection in reducing thrombus formation than selatogrel, especially since thrombin is an early, key primary agonist in the pathophysiology of thrombotic events.

Platelet reactivity index after treatment of clopidogrel versus ticagrelor based on CYP2C19 genotypes among patients undergoing percutaneous coronary intervention: results of a randomized study

Abstract Funding Acknowledgements Type of funding sources: None. Background Although clopidogrel is the basic drug for antiplatelet therapy in patients with coronary artery disease (CAD). However, loss of function (LOF) allelic variants located within the CYP2C19 gene may reduce the production of clopidogrel active metabolites and weaken the antiplatelet effect, increasing platelet rates reactivity and associated with increased rates of adverse events after percutaneous coronary intervention (PCI). Thus, drug regulatory authorities have warned of clopidogrel's reduced efficacy and suggested using alternative treatments (such as ticagrelor). However, in clinical practice, the strategy of genotype-guided selection for antiplatelet therapy has been limited by the lack of access to immediately available results. Purpose We sought to evaluate the effect of point-of-care genetic testing for CYP2C19 genotypes on the antiplatelet choice of therapy (i.e., clopidogrel vs ticagrelor), using platelet reactivity index (PRI) as a proxy of clinical outcome Method This study was a prospective, randomized, parallel design, an open-label investigation conducted among Malaysian patients with stable coronary artery disease (SCAD) undergoing PCI. Patients underwent rapid point-of-care genetic testing using the nested allele-specific multiplex PCR assay, which defines CYP2C19 genetic status within 3 hours, allowing patients to be genotyped on the same day before PCI. Patients who were carriers of at least one +LOF or -LOF (*2 or *3) allele was randomized to receive either clopidogrel [600mg loading dose (LD) - 75mg/day maintenance dose (MD)] or ticagrelor (180mg LD - 90mg MD). The induced platelet reactivity index (PRI) was assessed by Vasodilator-Associated Stimulated Phosphoprotein (VASP) Assay to whole blood at one standardized time point after 4 hours of LD. All patients were treated with aspirin. The primary endpoint of the study was the non-inferiority in platelet reactivity, measured as PRI, at 4 hours of clopidogrel vs ticagrelor in +LOF or -LOF allele carriers Result In 1638 SCAD patients, 94 underwent PCI and were genotyped and randomized to receive either clopidogrel (n=44) or ticagrelor (n=50). A total of 42 (44.68%) were carriers of at least one +LOF. PRI levels at 4 hours for clopidogrel vs ticagrelor 44 and 40, respectively (mean difference = 23.08; 95% CI: 17 to 30; p=&amp;lt;0.001); this will meet the primary endpoint of superiority in a non-inferiority. Ticagrelor significantly reduced PRI more than clopidogrel. The cross-tabulation of the response classification showed that ticagrelor is superior to clopidogrel based on the -LOF and +LOF (P= 0.005 and &amp;lt;0.001, respectively) Conclusion A rapid point-of-care genetic test using a nested allele-specific multiplex PCR assay can be used to personalize antiplatelet therapy and provides timely results for patients undergoing PCI. In addition, the results showed that ticagrelor was superior to clopidogrel in the level of platelet inhibition in both groups (+LOF or -LOF)

Comparison of Ischemic and Bleeding Events Between Short-Duration Versus Long-Duration Tirofiban Regimens in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention.

Tirofiban has been used historically as a bridge to platelet inhibition with clopidogrel in ST-segment myocardial infarction (STEMI) during percutaneous coronary intervention (PCI) to prevent stent thrombosis. However, ticagrelor and prasugrel reach similar levels of platelet inhibition at 30 minutes to that of clopidogrel at 6 hours, challenging the need for long-duration tirofiban. This 1-year, retrospective cohort study compared ischemic and bleeding outcomes of short-duration versus long-duration tirofiban regimens in patients with STEMI who received ticagrelor or prasugrel at the time of PCI. The primary outcome was major adverse cardiovascular events (MACEs) including cardiovascular mortality, recurrent myocardial infarction, urgent target vessel revascularization, or stroke. Secondary outcomes included individual MACE, all-cause mortality, bleeding events defined by the International Society on Thrombosis and Hemostasis, thirty-day readmissions for MACE and bleeding, and tirofiban pharmacy cost. A total of 283 charts were reviewed and 177 included (short duration n = 57; long duration n = 120). MACE rates were similar between short-duration and long-duration groups (0 [0%] vs. 5 [4.2%]; P = 0.18), including 4 cardiovascular deaths and 1 recurrent myocardial infarction. Bleeding event rates were also similar in short-duration versus long-duration groups including major bleeds (2 [3.5%] vs. 2 [1.7%]; P = 0.60) and clinically relevant nonmajor bleeds (3 [5.3%] vs. 9 [7.5%]; P = 0.75). Cost analysis indicated lower pharmacy cost with the short-duration group. In this cohort of patients with STEMI receiving a fast-acting P2Y12 inhibitor, the length of tirofiban infusion did not affect ischemic or bleeding outcomes, yet short-duration regimens were lower cost.

Excessive platelet inhibition following Pipeline embolization of intracranial aneurysms

BackgroundHigh levels of platelet inhibition have been associated with hemorrhagic complications following Pipeline embolization of intracranial aneurysms. We therefore titrate clopidogrel dosing to maintain a moderate level of platelet inhibition...

Objective Coagulation Profiling Provides Novel Insight into Potential Risk Factors for Peripheral Artery Disease in Women

The prevalence and burden of peripheral artery disease (PAD) is equal, if not higher, in women as compared with men, and it is known that clinical outcomes in women after revascularization procedures are worse. However, women are notably under-represented in existing PAD studies, contributing to a significant gap in clinical knowledge regarding the risk factors and nature history of female-specific disease. Traditional comorbidities associated with cardiovascular disease and PAD are more prevalent in men than women, suggesting that alternative etiologies may be contributing to atherosclerosis in female patients. Thromboelastography with platelet mapping (TEG-PM) measures the viscoelastic properties of a blood clot as a dynamic process and may provide an integral key to the next stage of patient-centered hypercoaguability assessment. This prospective observational study aimed to characterize the clinical and TEG-PM profiles of female and male patients prior to lower extremity revascularization procedures. All patients undergoing named vessel revascularization during December 2020 to December 2021 at a large tertiary institution were prospectively included. TEG-PM assays were performed on patients prior to surgery. These data, along with clinical metrics, were compared between men and women. Univariate analysis was performed using the Student t test for continuous variables and the Fisher exact test for binary variables. One hundred twenty-one patients were enrolled, of which 40 (39.6%) were female. Female patients had significantly lower rates of hypertension (62.5% vs 88.9%; P < .01) and diabetes (25.0% vs 54.3%; P < .01) as compared with men. There were no significant differences in age at time of enrollment, body mass index, smoking status, or hyperlipidemia between groups (Table I). TEG-PM data demonstrated significantly higher levels of platelet aggregation in female patients compared with male patients (62.8 ± 36.6 vs 43.6 ± 34.9; P = .03) and significantly lower levels of platelet inhibition in female patients (37.2 ± 36.6 vs 56.4 ± 34.9; P = .03) (Fig 1). There was no significant difference in the use of monoantiplatet therapy (62.5% vs 61.7%; P = 1.00), dual antiplatelet therapy (22.5% vs 38.2%; P = 1.00), or anticoagulation (30.0% vs 46.9%; P = .08) between groups (Table I). In this preoperative cohort, we found traditional PAD risk factors, such as hypertension and diabetes, to be significantly higher in men compared with women. Viscoelastic data, however, showed significantly greater platelet reactivity in women compared with men. This important insight demonstrates that the prevailing paradigm of risk stratification and disease modification may not fit the female population with PAD, and provides an important basis for further research into gender-specific coagulation profiles.TableClinical and thromboelastography with platelet mapping metrics between female and male patients with peripheral arterial diseaseFemaleMean (SD) or No.(%)MaleMean (SD) or No.(%)PTotal patients4081Clinical factors Age, y69.1 (±11.7)67.4 (±10.2).50 BMI, kg/m226.8 (±8.9)27.5 (±4.9).65 Ever smoker19 (46.3)36 (44.4).85 HTN25 (62.5)72 (88.9)<.01 HLD27 (67.5)44 (54.3).18 DM10 (25.0)44 (54.3)<.01TEG values R time6.5 (±2.6)6.5 (±3.0).94 K time2.0 (±1.5)1.8 (±1.2).50 α-angle66.9 (±10.0)69.3 (±12.2).33 MA57.6 (±8.1)60.8 (±8.5).46Platelet mapping values % Platelet aggregation62.8 (±36.6)43.6 (±34.9).03 % Platelet inhibition37.2 (±36.6)56.4 (±34.9).03Anthrombotic therapy MAPT25 (62.5)50 (61.7)1.00 DAPT9 (22.5)31 (38.2)1.00 Full-dose AC12 (30.0)38 (46.9).08AC, Anticoagulation; BMI, body mass index; DAPT, dual antiplatelet therapy; DM, diabetes mellitus; HLD, hyperlipidemia; HTN, hypertension; MAPT, mono antiplatelet therapy; SD, standard deviation; TEG, thromboelastography.Boldface P indicates statistical significance. Open table in a new tab

Abstract 13782: Platelet Aggregation and Adenosine Levels Among Patients With Stable Chronic Coronary Artery Disease Taking Ticagrelor or Prasugrel

Introduction: Both, ticagrelor and prasugrel are important anti-ADP drugs, being superior to clopidogrel in patients with acute coronary syndromes (ACS). Whether those drugs have different effects among patients in the long run (&gt; 1 year) after ACS, however, is not completely understood. We therefore sought to directly compare the pharmacodynamic action of ticagrelor vs prasugrel in patients with chronic coronary artery disease (CCAD). Methods: This was a prospective, double blinded, randomized trial that compared platelet inhibition and adenosine levels with ticagrelor (180mg loading dose, followed by 90 mg BID) versus prasugrel (60mg loading dose, followed by 10 mg QD). Patient was eligible if suffered a documented episode of ACS at least 1 year before randomization, had age between 18 and 75 years, and was using aspirin 100 mg chronically. Platelet aggregation between groups was compared with the Multiplate ADP® assay, performed at baseline and after 15 days on study medication. Adenosine plasma levels were measured with high performance liquid chromatography at the same time points. Results: We randomized 87 patients (mean age 61,3 years, 83,9% with prior coronary angioplasty), being 40 allocated to ticagrelor and 47 to prasugrel. The study main results are described at Figure 1 (platelet aggregation) and Figure 2 (plasma adenosine levels). Conclusion: In stable patients after ACS, despite significant higher levels of adenosine plasma levels in the ticagrelor group, in comparison with the prasugrel group, similar levels of platelet inhibition were observed in both groups, suggesting that the role of adenosine in platelet aggregation is not an important one.

Pharmacokinetics, Pharmacodynamics and Safety of Ticagrelor in Children with Sickle Cell Disease: Results of a Two-Part Phase 2 Study

▪ INTRODUCTIONActivated platelets promote the adhesion of sickle cells to endothelial cells and the formation of platelet-leukocyte aggregates, contributing to vaso-occlusion (VOC). It has been suggested that inhibition of platelet reactivity may reduce the rate of VOCs in sickle cell disease (SCD). A study with ticlopidine reported a reduced rate of VOCs versus placebo. A recent, placebo-controlled, pediatric study with prasugrel showed a non-significant reduction in VOCs events, which was likely due to the low level of platelet inhibition. Ticagrelor is a reversible P2Y12 receptor antagonist shown to inhibit ADP-induced platelet aggregation and is approved for use in adults with coronary artery disease (CAD). A phase 2 study was conducted to characterize the pharmacokinetic (PK), pharmacodynamic (PD) and safety profiles of ticagrelor in children aged 2-17 years with SCD (HbSS or HbS/β0; NCT02214121). METHODSThis study was conducted in 2 parts: Part A was an open-label, randomized, dose-ranging study in which patients received two single doses of ticagrelor 1 week apart, followed by twice daily (bid) ticagrelor for 1 week. Initially, single doses of 0.125-0.563 mg/kg were given, followed by repeated dosing with 0.125 mg/kg bid. Individual platelet response was used to inform further dosing. After an interim analysis including the first 14 patients in Part A, single doses were increased to a maximum of 2.25 mg/kg and repeated dosing up to 0.75 mg/kg bid. Part B (optional) immediately followed the repeated dosing in Part A: patients were randomized 2:1 to continue ticagrelor with the same dose used during Part A or matching placebo as a double-blind treatment for 4 weeks. Safety was assessed during both parts, pain and analgesic use were recorded daily in an eDiary, and painful crises were reported at each visit. Exposure to ticagrelor and the active metabolite (AR-C124910XX), as well as the subsequent platelet inhibition, were determined after single and repeated doses in Parts A and B. RESULTSA total of 45 children with SCD, mean age 11.2 years (range: 3-17) received study drug in Part A and 23 (15 ticagrelor, 8 placebo) children, mean age 10.0 years (range: 3-17) in Part B. Most patients were of African descent (35/45 in Part A and 22/23 in Part B). Ticagrelor exposure increased approximately dose-linearly, with maximum plasma concentration values ranging from 15.2 to 566.6 ng/mL (with 0.125 mg/kg to 2.25 mg/kg) for ticagrelor and 3.1-156.0 ng/mL for AR-C124910XX. The parent:metabolite ratio in children with SCD was similar to that previously observed in adults. Mean P2Y12 reaction units (PRU) after single doses of ticagrelor decreased from pre-dose to 2 hours post-dose (change from baseline: -23.4 to -207.8 PRU for 0.125 mg/kg to 2.25 mg/kg), and returned towards baseline up to the last timepoint (6 or 8 hours' post-dose). In Part B, no difference was seen between the placebo and ticagrelor groups in pain ratings and analgesic use, although the study was not statistically powered to detect differences in these outcomes. Ticagrelor was well tolerated, with no bleeding during treatment and no patient discontinued treatment due to an adverse event. CONCLUSIONSThe PK/PD profile of ticagrelor in children with SCD was suitably characterized and the exposure-response relationship appeared similar to that previously observed in adults with CAD. Ticagrelor was well tolerated and no safety concerns were raised. The potential to impact SCD-related pain crises needs further evaluation, as the number of patients, low doses for some patients and short study duration limit the efficacy conclusions from this study. DisclosuresHsu:AstraZeneca: Other: steering committee for HESTIA trial; Emmi: Other: consultant for Emmi. Sarnaik:AstraZeneca: Other: Advisory Board. Amilon:AstraZeneca: Employment. Rensfeldt:AstraZeneca: Employment. Berggren:AstraZeneca: Employment.

Dual Testing to Achieve Low On-treatment Platelet Reactivity for Aneurysm Embolization.

Although point-of-care tests are used extensively to test platelet function before endovascular aneurysm treatment, their use and validity are still debated. We compared the results of two point-of-care tests (VerifyNow® and Multiplate®) for assessing patients treated with stents and flow diverters and determined their relation to periprocedural complications. All patients undergoing treatment of intracranial aneurysms were tested using both methods and were retrospectively evaluated. Patients with acute subarachnoid hemorrhage and those who had to be maintained on anticoagulants for unrelated diseases were excluded. An acceptable level of platelet inhibition was required on both tests to commence with treatment, otherwise antiplatelet medication was adjusted to reach this level. Mean PRU(platelet reactivity units) and ADP AUC(adenosine diphosphate area under the aggregation curve) were 68 ± 66 and 23 ± 15, respectively, in 295patients. Both tests showed agood correlation (r = 0.45). Both tests were able to predict hemorrhagic events but not ischemic events. When patients with very low reactivity (PRU < 60) were compared to the rest of the group, there were more hemorrhagic events in the first group but the overall rate of complications were similar (p = 0.27). In this largest study comparing two widely used commercial platelet function tests, the correlation between the tests were less than ideal; however, the very low platelet reactivity attained by the help of dual platelet testing did not result in an increased overall complication rate.

Investigation of the interaction between proton pump inhibitors and clopidogrel using VerifyNow P2Y12 assay.

Background: Randomized trials and observation studies have revealed conflicting results regarding the interaction between clopidogrel and proton pump inhibitors (PPIs). The aim of our study was to provide laboratory evidence regarding whether PPIs blunt the antiplatelet reactivity of clopidogrel.Methods: We included records of Asian patients who received clopidogrel treatment for cardiovascular or cerebrovascular events and the VerifyNow P2Y12 assay for platelet reactivity monitoring. The responsiveness of antiplatelet effect to clopidogrel was analyzed according to 3 criteria:(1)percentage of platelet inhibition (PI) > 20%,(2)absolute P2Y12 reaction unit (PRU) < 235, and(3)PRU < 262.Results: Patients treated without PPIs did not differ significantly from those concomitantly treated with PPIs in terms of levels of PI (25.7% ± 24.3% vs 23.0 ± 25.3%, P = .4315), PRU (187.3 ± 74.0 vs 197.4 ± 77.3, P = .3373), or responsiveness to antiplatelet (adjusted absolute risk, 3.5%; 95% confidence interval, − 10.7 to 17.7%; P = .6297). Patients treated with lansoprazole, esomeprazole, pantoprazole, and rabeprazole exhibited no significant differences in PRU or PI levels compared with those treated without PPIs. By contrast, patients treated with dexlansoprazole exhibited a significantly decreased level of PI (25.7% ± 24.3% vs 14.0% ± 21.6%, P = .0297) and responsiveness to clopidogrel under the criterion PI > 20% (adjusted absolute risk: 10.5%; 95% confidence interval: 2.6% to 43.6%; P = .0274).Conclusion: No robust interaction between clopidogrel and PPIs was found, but caution should be exercised in the concomitant use of dexlansoprazole and clopidogrel in Asians.

Abstract 13384: Cangrelor Pk / Pd Analysesin Neonates After Palliation of Congenital Heart Disease (chd)

Background: Thrombotic events contribute significantly to early mortality in neonates with CHD requiring a systemic-to-pulmonary artery shunt. However, thromboprophylaxis remains suboptimal with few pharmacological agents studied and shown to be of benefit. The P2Y 12 inhibitor cangrelor is effective in preventing early coronary artery stent thrombosis in adults. Cangrelor dosing and safety have yet to be established in neonates. Hypotheses: (1) Cangrelor administered by infusion will yield drug levels capable of inhibiting maximal platelet aggregation by &gt; 90% without causing an increase in bleeding. (2) A novel microfluidic technology can yield robust results related to inhibition of thrombus formation using significantly less blood than for LTA. Methods: This IRB approved, prospective, open-label, single-arm study was conducted between January 2017 and August 2019. Cangrelor, 0.5 μg/kg/min (n=7) or 0.25 μg/kg/min (n=8), was administered intravenously 6-10h after placement of a systemic-to-pulmonary artery shunt (n=8), right ventricle-to-pulmonary artery shunt (n=6), or ductal stent (n=1) for 1h. Plasma levels and PD properties of cangrelor were determined, the latter by light transmission aggregometry (LTA) and microfluidic assay (MFA). Informed consent was obtained (NCT02765633). Results: 15 participants that received cangrelor had single ventricle physiology (12 of 15) and underwent a Norwood procedure (11 of 15). Cangrelor 0.5 μg/kg/min dosing met all PD endpoints, yielding a higher level of platelet inhibition (mean ± SD) than the 0.25 μg/kg/min dose as assessed by LTA (89 ± 11.4% vs 73.3 ± 16.9%, respectively). Results from MF studies were comparable but required 3-fold less blood for testing. PK analysis revealed rapid drug clearance with 86.7% of participants having undetectable levels by 10 minutes post-infusion and 70% with full recovery in platelet function at 1 hour. SAEs and AEs that occurred were not related drug administration, including bleeding. Conclusion: Favorable PK and PD properties of cangrelor 0.5 μg/kg/min dosing and an acceptable safety profile warrant further evaluation in neonates following palliative cardiac procedures.

Evening aspirin intake results in higher levels of platelet inhibition and a reduction in reticulated platelets - a window of opportunity for patients with cardiovascular disease?

Cardiovascular events occur most frequently in the early morning. Similarly, the release of reticulated platelets (RP) by megakaryocytes has a peak in the late night and early morning. Which aspirin regimen most effectively inhibits platelets during these critical hours is unknown. Hence, the primary objective of this trial was to assess platelet function and RP levels at 8.00 AM, in stable cardiovascular (CVD) patients, during three different aspirin regimens. In this open-label randomized cross-over study subjects were allocated to three sequential aspirin regimens: once-daily (OD) 80 mg morning; OD-evening, and twice-daily (BID) 40 mg. Platelet function was measured at 8.00 AM & 8.00 PM by serum Thromboxane B2 (sTxB2) levels, the Platelet Function Analyzer (PFA)-200® Closure Time (CT), Aspirin Reaction Units (ARU, VerifyNow®), and RP levels. In total, 22 patients were included. At 8.00 AM, sTxB2 levels were the lowest after OD-evening in comparison with OD-morning (p = <0.01), but not in comparison with BID. Furthermore, RP levels were similar at 8.00 AM, but statistically significantly reduced at 8.00 PM after OD-evening (p = .01) and BID (p = .02) in comparison with OD-morning. OD-evening aspirin intake results in higher levels of platelet inhibition during early morning hours and results in a reduction of RP levels in the evening. These findings may, if confirmed by larger studies, be relevant to large groups of patients taking aspirin to reduce cardiovascular risk.

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.

Prasugrel Versus Ticagrelor in Patients With CYP2C19 Loss-of-Function Genotypes: Results of a Randomized Pharmacodynamic Study in a Feasibility Investigation of Rapid Genetic Testing

The feasibility of rapid genetic testing in patients undergoing percutaneous coronary intervention (PCI) and the comparison of the pharmacodynamic effects of prasugrel versus ticagrelor among carriers of cytochrome P450 2C19 loss-of-function alleles treated with PCI has been poorly explored. Rapid genetic testing using the Spartan assay was shown to be feasible and provides results in a timely fashion in a real-world setting of patients undergoing coronary angiography (n=781). Among patients (n=223, 28.5%), carriers of at least 1loss-of-function allele treated with PCI (n=65), prasugrel, and ticagrelor achieve similar levels of plateletinhibition. (A Pharmacodynamic Study Comparing Prasugrel Versus Ticagrelor in Patients Undergoing PCI With CYP2C19 Loss-of-function [NCT02065479]).

Trials and Tribulations of Viscoelastic-Based Determination of Fibrinogen Concentration.

Acquired fibrinogen deficiency is a major determinant of severe bleeding in different clinical conditions, including cardiac surgery, trauma, postpartum hemorrhage, liver surgery, and transplantation. The existing guidelines recommend to supplement fibrinogen in patients with severe bleeding when the fibrinogen concentration is <1.5 g/L. Viscoelastic tests (VETs) provide a fast determination of the fibrinogen contribution to clot firmness and allow prompt treatment of acquired fibrinogen deficiency. However, different VET devices are presently available on the market, based on different technologies and different activators and platelet inhibitors. The available tests are the functional fibrinogen (FF, thromboelastography), the fibrinogen contribution to clot firmness (fibrinogen determination [FIBTEM], thromboelastometry), and the fibrinogen contribution to clot strength (FCS, sonorheometry). All these tests have a moderate to very good correlation with the Clauss fibrinogen assays; however, when comparing VET-based fibrinogen contribution to clot firmness with Clauss fibrinogen concentration, strong differences occur within the same test under different conditions and between different tests. The most widely studied test is the thromboelastometric FIBTEM; the best predictor of a Clauss fibrinogen <1.5 g/L is placed at a maximum clot firmness around 8 mm of amplitude. Fewer data are available for thromboelastographic FF, but the correspondent value is in the range of 12 mm. Overall, due to an incomplete inhibition of platelet contribution, FF overestimates the fibrinogen contribution with respect to FIBTEM. Data on sonorheometry FCS are limited and conflicting. When addressing the correlation between different tests, it is good in general, but no fixed conversion factors can be proposed, due to a considerable dispersion of the experimental points. In conclusion, VET-based fibrinogen tests are certainly powerful tools that are presently suggested by the existing guidelines; however, when using them for clinical decision-making, users should consider the possible sources of bias, which include the different level of platelet inhibition, the role of platelet count and function, the possible different degrees of blood activation with tissue factor, the important role of factor XIII in stabilizing the fibrin clot, and others.

P325 Inadequate inhibition of platelet function after exercise in patients with ischemic mitral regurgitation qualified for cardiosurgery treatment

Abstract Purpose Human platelets play a major role in the pathophysiology of cardiovascular diseases. The aim of our study was to determine the relationship between exercise and level of platelet inhibition in patients (pts) after myocardial infarction (MI) with at least moderate ischemic mitral regurgitation (IMR) qualified for cardiosurgical treatment - coronary artery bypass grafting alone (CABG) or CABG with mitral reconstruction (CABGmr). Methods We collected venous blood samples from 70 pts (M 41, 66 ± 9 years) with at least moderate IMR, 3-24 weeks after MI. Platelet reactivity was estimated with the use of rapid, point-of-care platelet analyzer as the time for flowing whole blood to occlude a collagen-epinephrine ring, with shorter closure times (CEPI-CT), indicating greater activity. CEPI-CT was evaluated before (CEPI-CT rest) and 20 min after ExE (CEPI-CT ExE). Inadequate inhibition of the TXA2-dependent activation pathway was defined as CEPI-CT &amp;lt; 193 seconds. All the patients received 75-100 mg of aspirin daily (without clopidogrel treatment). Effective regurgitation orifice (ERO) was used for quantitative IMR assessment (moderate ≥10-20, severe ≥ 20 mm²). In all pts symptom-limited echocardiography (echo) semi-supine exercise test (ExE) was performed with Schiller system. All the pts were referred for CABG (multivessel coronary disease, ejection fraction (EF) 42,6 ± 10,1%, wall motion score index (WMSI) 1.65 ± 0.36). Results We observed inadequate platelet in 26 (37%) pts at rest (CEPI-CT &amp;lt; 193 sec., despite regular aspirin therapy) and in 48 (68%) pts in 20 min. after exercise. We observed a significant decrease in CEPI–CT in all analyzed group (rest vs exe: 202 sec. vs 124 sec., respectively; p &amp;lt; 0,0001) and also in pts with moderate IMR as well as with severe IMR. We didn’t observe a significant change in platelet count and mean platelet volume (MPV) between rest and exercise. Conclusions: 1. Inadequate antiplatelet effect of aspirin at rest was observed in 37% pts after MI with IMR. 2. Symptoms limited exercise test has revealed inadequate platelet inhibition (TXA2 –dependent activation pathway) in 68% of patients after MI with IMR. 3. Aspirin may have a limited antithrombotic effect after physical exercise in patients after MI with significant IMR.

P329Residual platelet reactivity after pre-treatment with ticagrelor prior to primary percutaneous coronary intervention is associated with suboptimal myocardial reperfusion

Abstract Background The evidence of a clinical benefit of P2Y12 inhibitor pre-treatment in primary percutaneous coronary intervention (PCI) and the relation between the level of platelet inhibition and myocardial reperfusion with newer potent P2Y12 inhibitors remain unclear. Objectives We aimed to assess the relationship between platelet reactivity at the time of primary PCI after pre-treatment with aspirin and ticagrelor and the post-PCI myocardial blush grade (MBG). Methods We prospectively included 61 patients. Platelet reaction units for ticagrelor (PRU) and aspirin reaction units (ARU) were measured using the point-of-care test VerifyNow before PCI. The high on-ticagrelor (PRU &gt;208) and on-aspirin (ARU ≥550) platelet reactivity (HPR and HaPR) were assessed. Patients were divided into two groups according to MBG 3 or &lt;3. Results MBG 3 was identified in 28 (46%) patients. Mean PRU was lower in such patients as compared to those with MBG &lt;3 (155.82±90.91 vs 227.42±65.18; p=0.001) while mean ARU was similar between groups. HPR and HaPR were observed in 30 (49.2%) and 11 patients (18%), respectively. HPR but not HaPR was more frequent in the group with impaired MBG (66.7 vs 28.6%; p=0.003 and 21.2 vs 14.3%; p=0.48 respectively). Table 1. Platelet reactivity results Verify Now at admission All Final Blush &lt;3 Final Blush 3 p n=61 (100%) n=33 (54%) n=28 (46%) PRU P2Y12 194.56±85.32 227.42±65.18 155.82±90.91 0.001 Base 193.54±49.01 194.79±45.68 192.07±53.48 0.83 Inhibition of platelet aggregation (%) 15.61±29.85 5.7±17.55 27.29±36.79 0.007 ARU 463.97±76.45 472.58±72.5 453.82±81 0.34 PRU &gt;208 30 (49.1%) 22 (66.7%) 8 (28.6%) 0.003 ARU ≥550 11 (18%) 7 (21.2%) 4 (14.3%) 0.48 Verify Now at day 1 n=57 n=30 n=27 p PRU P2Y12 40.86±41.43 47.27±45.87 33.74±35.35 0.21 Base 196.98±36.19 193.67±30.67 200.81±41.97 0.47 Inhibition of platelet aggregation (%) 79.8±17.96 76.37±20.54 83.77±13.78 0.11 ARU = Aspirin reaction units; PRU = P2Y12 reaction units. Conclusion In conclusion, our study shows that higher PRU and the subsequent HPR at the time of primary PCI, after pretreatment with ticagrelor, are the only correlates of post PCI MBG. These findings support the earliest possible loading with ticagrelor prior to primary PCI. Acknowledgement/Funding The study was supported by grants from Terumo. The funder has no role in any step of the study.

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

Residual platelet reactivity after pre-treatment with ticagrelor prior to primary percutaneous coronary intervention is associated with suboptimal myocardial reperfusion.

The evidence of a clinical benefit of P2Y12 inhibitor pre-treatment in primary percutaneous coronary intervention (PCI) and the relation between the level of platelet inhibition and myocardial reperfusion with newer potent P2Y12 inhibitors remain unclear. We aimed to assess the relationship between platelet reactivity at the time of primary PCI after pre-treatment with aspirin and ticagrelor and the post-PCI myocardial blush grade (MBG). We prospectively included 61 patients. Platelet reaction units for ticagrelor (PRU) and aspirin reaction units (ARU) were measured using the point-of-care test VerifyNow before PCI. The high on-ticagrelor (PRU >208) and on-aspirin (ARU ⩾ 550) platelet reactivity (HPR and HaPR) were assessed. Patients were divided into two groups according to MBG 3 or <3. MBG 3 was identified in 28 (46%) patients. Mean PRU was lower in such patients as compared with those with MBG <3 (155.82 ± 90.91 vs. 227.42 ± 65.18; p=0.001) while mean ARU was similar between groups. HPR and HaPR were observed in 30 (49.2%) and 11 patients (18%), respectively. HPR but not HaPR was more frequent in the group with impaired MBG (66.7 vs. 28.6%; p=0.003 and 21.2 vs. 14.3%; p=0.48 respectively). Our study shows that higher PRU and the subsequent HPR at the time of primary PCI, after pretreatment with ticagrelor, are the only correlates of post PCI MBG. These findings support the earliest possible loading with ticagrelor prior to primary PCI.

Arandomised, investigator-initiated, clinical trial of the effects of fentanyl on P2Y12-receptor inhibition in patients with ST-elevation myocardial infarction who are pre-treated with crushed ticagrelor: rationale and design of the Opioids aNd crushed Ticagrelor In Myocardial infarction Evaluation (ON-TIME3) trial.

BackgroundFast and accurate platelet inhibition is an important therapeutic goal in the acute treatment of patients with ST-elevation myocardial infarction (STEMI). Platelet inhibitory effects induced by oral P2Y12-receptor antagonists are delayed in STEMI patients undergoing primary percutaneous coronary intervention (PCI) due to haemodynamic changes and delayed gastro-intestinal absorption. Concomitant use of opioids, although recommended in the American College of Cardiology/American Heart Association and European Society of Cardiology STEMI guidelines, further delays gastro-intestinal absorption. To date, trials investigating alternative analgesics in STEMI patients have been scarce. This trial aims to assess the feasibility of a novel drug strategy for treatment of STEMI patients with crushed ticagrelor in combination with paracetamol (acetaminophen) instead of opioids.HypothesisSTEMI patients who are pre-treated with crushed ticagrelor and paracetamol have a higher level of platelet inhibition after primary PCI than patients pre-treated with crushed ticagrelor and fentanyl.Study designThe Opioids aNd crushed Ticagrelor In Myocardial infarction Evaluation (ON-TIME 3) trial is a randomised controlled trial designed to examine whether administration of paracetamol instead of fentanyl can optimise platelet inhibition in STEMI patients who are pre-treated with crushed ticagrelor in the ambulance. One hundred and ninety patients with STEMI will be randomised (1:1 fashion) to intravenous (IV) fentanyl or IV paracetamol. The primary endpoint is the level of platelet reactivity units measured immediately after primary PCI.SummaryThe ON-TIME 3 trial (NCT03400267) aims to achieve optimal platelet inhibition and pain relief in STEMI patients receiving crushed ticagrelor in the ambulance by investigating IV fentanyl and IV paracetamol as analgesics.