Abstract 1122‐000043: Vorapaxar as An Alternative for Ticagrelor Resistance in Neuroendovascular Intervention

Introduction : Perioperative dual‐antiplatelet therapy (DAPT) for flow diversion (FD) limits thromboembolic complications. Practice of DAPT varies across the neuroendovascular field but typically includes aspirin and an ADP receptor antagonist such as clopidogrel, prasugrel, or ticagrelor. Unfortunately, resistance to DAPT medications remains a concern for neuroendovascular intervention, and there is a current lack of standard alternatives for such resistance. The main goal of this abstract is to discuss ticagrelor resistance and to inform possible therapeutic options. Methods : We report a case of vorapaxar treated FD for an intracranial aneurysm in a patient with ticagrelor resistance. FD was deployed for a left internal carotid artery (ICA) blister aneurysm and bilateral ICA dissecting pseudoaneurysms (Figure 1). We also provide a narrative review on previous reports of ticagrelor resistance and associated treatment responses. We used the keywords: “ticagrelor,” “resistance,” “hypo‐response,” “stent thrombosis,” and “aneurysm.” These were implemented in various combinations with Boolean operators in three databases: PubMed, Ovid MEDLINE, and Ovid EMBASE. Results : During a complicated clinical course, the patient had three thromboembolic complications while on DAPT with ticagrelor or prasugrel leading to transition of antiplatelet therapy to vorapaxar. Thromboelastography with platelet mapping (TEG‐PM) routinely demonstrated inadequate platelet inhibition, which was confirmed with platelet function analyzer‐100. Initial TEG‐PM results were 0.0% ADP receptor inhibition and MA‐ADP of 62.2 mm. Repeat angiograms also indicated thromboembolic formation after each of the three events (Figure 1). After introduction of vorapaxar, the patient had adequate platelet inhibition with TEG‐PM results of 49.1% ADP receptor inhibition and MA‐ADP of 48.3 mm. At 84 days follow‐up, the patient was fully recovered with complete occlusion of the aneurysms. In a narrative review of the literature, there were ten previously reported cases of ticagrelor resistance or hypo‐response: three cases in the neuroendovascular literature and seven cases in the cardiovascular literature. Among all of the cases, there was a variability in protocol for treating patients with suggested ticagrelor resistance. All three neuroendovascular cases either employed another ADP receptor antagonist in hopes that the resistance would not generalize or eliminated DAPT altogether and settled for aspirin alone. In some of the cardiovascular cases, ticagrelor was even continued after patients exhibited laboratory evidence of resistance or hypo‐response. Conclusions : Given the paucity of cases describing ticagrelor resistance or hypo‐response in the neuroendovascular and cardiovascular literature, management of DAPT should remain a multifactorial decision depending on the clinical situation. Moreover, we need to consider therapeutic alternatives for cases of resistance such as thrombin receptor antagonists, specifically PAR1 receptor antagonists like vorapaxar. High quality randomized controlled trials are needed to elucidate the safety and efficacy of vorapaxar in neuroendovascular procedures.

ADP-receptor antagonists in patients with acute myocardial infarction complicated by cardiogenic shock: a pooled IABP-SHOCK II and CULPRIT-SHOCK trial sub-analysis

Purpose The purpose of this pooled analysis is to compare the clinical outcome of patients with acute myocardial infarction complicated by cardiogenic shock treated with either clopidogrel or the newer, more potent ADP-receptor antagonists prasugrel or ticagrelor. Patients from the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) and Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) trial were included. Methods and results For the current analysis, the primary endpoint was 1-year mortality and the secondary safety endpoint was moderate or severe bleedings until hospital discharge with respect to three different ADP-receptor antagonists. Eight hundred fifty-six patients were eligible for analysis. Of these, five hundred seven patients (59.2%) received clopidogrel, one hundred seventy-eight patients (20.8%) prasugrel and one hundred seventy-one patients (20.0%) ticagrelor as acute antiplatelet therapy. The adjusted rate of mortality after 1-year did not differ between prasugrel and clopidogrel (hazard ratio [HR]: 0.81, 95% confidence interval [CI] 0.60–1.09, padj=0.17) or between ticagrelor and clopidogrel treated patients (HR: 0.86, 95% CI 0.65–1.15, padj=0.31). In-hospital bleeding events were significantly less frequent in patients treated with ticagrelor vs. clopidogrel (HR: 0.37, 95% CI 0.20–0.69, padj=0.002) and not different in patients treated with prasugrel vs. clopidogrel (HR: 0.73, 95% CI 0.43–1.24, padj=0.24), see Table 1. Conclusion This pooled sub-analysis is the largest analysis on safety and efficacy of three oral ADP-receptor antagonists and shows that an acute therapy with either clopidogrel, prasugrel or ticagrelor is no predictor of 1-year mortality. Treatment with ticagrelor seems to be associated with less in-hospital moderate and severe bleeding events in comparison to clopidogrel. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): German Heart FoundationEuropean Union 7th Framework Program

The P2Y12 Receptor Antagonist Ticagrelor Ameliorates Pulmonary Hypertension

Background: Pulmonary arterial hypertension (PAH) is a disease that the pulmonary artery is abnormally elevated. P2Y12 is an adenosine diphosphate (ADP) receptor and it act as the target of thienopyridine antiplatelet drugs by controlling vascular remodeling. Inhibition of P2Y12 receptor in the process of PAH was explored in this study.Methods: The PAH model was established in Sprague-Dawley rats by single subcutaneous injection of 60 mg/kg monocrotaline (MCT). The ticagrelor solution (a selective P2Y12R inhibitor) was intraperitoneally injected into rats at a dose of 14 mg/kg from the time of MCT injection to day 28.Results: In the lung tissues of PAH rats, the marked P2Y12R was detected. Treatment with ticagrelor greatly decreased P2Y12R level and efficiently abolished the upregulation of α-SMA as demonstrated by Western blot and RT-PCR. The wall thickness and occlusion score of the pulmonary arterioles showed that blockade of P2Y12R could relieve lung remodeling caused by PAH. The haemodynamic changes at 4 weeks determined that P2Y12R inhibition affected RV pressure and right heart hypertrophy.Conclusions: P2Y12R might be involved in the pathogenesis of PAH. Blockade of P2Y12R has potential in treating PAH.

A genetic polymorphism in P2RY1 impacts response to clopidogrel in cats with hypertrophic cardiomyopathy

Clopidogrel is converted to its active metabolite by cytochrome P450 isoenzymes and irreversibly inhibits platelet activation by antagonizing the adenosine-diphosphate (ADP) receptor. It is frequently used in cats with hypertrophic cardiomyopathy (HCM) to prevent thromboembolic complications. However, significant interpatient variability of the response to clopidogrel therapy has been suspected. In this study, we assessed the impact of single nucleotide polymorphisms (SNPs) within ADP receptor (P2RY1, P2RY12) and cytochrome P450 isoenzyme (CYP2C41) genes on platelet inhibition by clopidogrel administration in cats with HCM. Forty-nine cats completed the study, and blood samples were obtained before and after clopidogrel therapy to assess the degree of platelet inhibition based on flow cytometry and whole blood platelet aggregometry. Plasma concentrations of clopidogrel metabolites were measured after the last dose of clopidogrel. Whole blood platelet aggregometry revealed a significant reduction of platelet inhibition by clopidogrel in cats with the P2RY1:A236G and the P2RY12:V34I variants. The association with the P2RY1:A236G variant and clopidogrel resistance remained significant after adjustment for multiple comparisons. This study demonstrated that a genetic polymorphism in the P2RY1 gene altered response to clopidogrel therapy and suggests that clinicians may consider alternative or additional thromboprophylactic therapy in cats with the P2RY1:A236G variant.

Clopidogrel vs. prasugrel vs. ticagrelor in patients with acute myocardial infarction complicated by cardiogenic shock: a pooled IABP-SHOCK II and CULPRIT-SHOCK trial sub-analysis

Aims The aim of this pooled sub-analysis of the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) and Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) trial was to compare the clinical outcome of patients with acute myocardial infarction complicated by cardiogenic shock treated either with clopidogrel or the newer, more potent ADP-receptor antagonists prasugrel or ticagrelor. Methods and results For the current analysis the primary endpoint was 1-year mortality and the secondary safety endpoint was moderate or severe bleedings until hospital discharge with respect to three different ADP-receptor antagonists. 856 patients were eligible for analysis. Of these, 507 patients (59.2%) received clopidogrel, 178 patients (20.8%) prasugrel and 171 patients (20.0%) ticagrelor as acute antiplatelet therapy. The adjusted rate of mortality after 1-year did not differ significantly between prasugrel and clopidogrel (hazard ratio [HR]: 0.81, 95% confidence interval [CI] 0.60–1.09, padj = 0.17) or between ticagrelor and clopidogrel treated patients (HR: 0.86, 95% CI 0.65–1.15, padj = 0.31). In-hospital bleeding events were significantly less frequent in patients treated with ticagrelor vs. clopidogrel (HR: 0.37, 95% CI 0.20 -0.69, padj = 0.002) and not significantly different in patients treated with prasugrel vs. clopidogrel (HR: 0.73, 95% CI 0.43 -1.24, padj = 0.24). Conclusion This pooled sub-analysis is the largest analysis on safety and efficacy of three oral ADP-receptor antagonists and shows that acute therapy with either clopidogrel, prasugrel or ticagrelor is no independent predictor of 1-year mortality. Treatment with ticagrelor seems independently associated with less in-hospital moderate and severe bleeding events compared to clopidogrel. This finding might be due to selection bias and should be interpreted with caution. Graphic abstract

Genetic Polymorphisms Impact Response to Clopidogrel in Feline Hypertrophic Cardiomyopathy

Clopidogrel is converted to its active metabolite by cytochrome P450 isoenzymes and irreversibly inhibits platelet activation by antagonizing the adenosine-diphosphate (ADP) receptor. It is frequently used in cats with hypertrophic cardiomyopathy (HCM) to prevent thromboembolic complications. However, significant interpatient variability of the response to clopidogrel therapy has been suspected. In this study, we assessed the impact of single nucleotide polymorphisms (SNPs) within ADP receptor (P2RY1, P2RY12) and cytochrome P450 isoenzyme (CYP2C41) genes on platelet inhibition by clopidogrel administration in cats with HCM. Forty-nine cats completed the study, and blood samples were obtained before and after clopidogrel therapy to assess the degree of platelet inhibition based on flow cytometry and whole blood platelet aggregometry. Plasma concentrations of clopidogrel metabolites were measured after the last dose of clopidogrel. Whole blood platelet aggregometry revealed a significant reduction of platelet inhibition by clopidogrel in cats with the P2RY1:A236G and the P2RY12:V34I variants. The association with the P2RY1:A236G variant and clopidogrel resistance remained significant after adjustment for multiple comparisons. This study demonstrated that a genetic polymorphism in the P2RY1 gene altered response to clopidogrel therapy and suggests that clinicians may consider alternative or additional thromboprophylactic therapy in cats with the P2RY:A236G variant.

Clopidogrel responder status is uninfluenced by CYP2C19*2 in Danish patients with stroke

Background Antiplatelet therapy is a cornerstone of secondary stroke prevention, but the responsiveness to antiplatelet medication varies among patients. Clopidogrel is a pro-drug that requires hepatic transformation to reach its active metabolite. Single nucleotide polymorphisms (SNPs) in key enzymes or the target adenosine diphosphate (ADP) receptor on the platelet surface are believed to be involved in clopidogrel-mediated platelet inhibition and decreased antiplatelet effect with high-on-treatment platelet reactivity (HTPR). Objective This study investigated whether specific SNPs in key hepatic enzymes (CYP2C19*2, *3, *17, CYP3A4*1G, and NR1I2) or the ADP receptor (PR2Y12) are associated with HTPR to clopidogrel. Patients & methods This observational study included patients with ischemic stroke (IS) and transient ischemic attacks (TIAs) receiving clopidogrel at a dose of 75 mg/day. Patients were genotyped for eight different SNPs in the genes encoding CYP2C19, CYP3A4, NR1I2, and the P2Y12 receptor. Results Of the 103 patients that were included, 30.7% carried the CYP2C19*2 allele and had higher platelet reaction unit (PRU) values than non-carriers, but no patients showed HTPR. Carriers of the *17 allele had higher platelet inhibition but showed no difference in PRU values compared with non-carriers. The remaining SNPs were neither associated with PRU nor with platelet inhibition. Conclusions Patients with IS and TIAs treated with 75 mg clopidogrel/day do not have HTPR. A genetic analysis of CYP2C19*2, *3, *17, CYP3A4*1G, and NR1I2 revealed no associations with clopidogrel HTPR. CYP2C19*2 carriers and patients with HTPR in the acute phase after ischemic stroke or transient ischemic attacks exhibit higher PRU values, but not long-term treatment HTPR.

P2Y12-dependent regulation of emergency hematopoiesis after myocardial infarction

Introduction Inflammation is essential for wound healing after myocardial infarction (MI). Leukocytes, especially neutrophils and monocytes, orchestrate removal of necrosis and regulation of tissue remodeling. Beside local recruitment from the blood, leukocyte supply via increased hematopoiesis is of major relevance for post-ischemic myocardial inflammation. Little is known about the pathways that carry the signals for increased demand for leukocytes from the site of injury to upstream hematopoietic stem cells (LSK) in the bone marrow (BM). In this study, we investigate the role of the P2Y12-ADP-receptor mediated regulation for emergency hematopoiesis after MI. Methods For standardized MI, a model of permanent coronary ligation was used in C57/Bl6 and P2Y12−/− mice. Changes in plasmatic ADP levels after MI were screened using ELISA, whereas the expression of the P2Y12-ADP-receptor in cell populations isolated from the BM was investigated by qPCR. CFU assays added further functional insight on hematopoietic proliferation in vitro. The effect of P2Y12 on the hematopoietic system after MI was investigated by inhibiting the P2Y12-receptor via prasugrel and compared to inhibition of the thromboxane pathway via acetylsalicylic acid (ASA). Proliferation of LSK in BM and leukocyte composition in blood, BM and infarct tissue after MI were assessed via FACS. Leukocyte composition in the infarcted myocardium was validated by immunohistochemistry. Finally, left ventricular function (LV-EF) and remodeling were investigated by echocardiography. Results 24 h after MI, we found a peak of plasmatic ADP levels. LSK as upstream hematopoietic progenitors in the BM express a P2Y12-receptor, which was validated on transcriptional and protein level. Whereas ADP stimulation of LSK led to significantly larger colony growth in vitro on the one hand, percentage of cycling LSK were significantly reduced 48 h after MI in P2Y12−/− mice compared to WT mice, assessed by Ki67/DAPI cell cycle analysis. Prasugrel treatment showed similar effects, translating into reduced numbers of downstream hematopoietic progenitors GMP and MDP 72 h after MI. Treatment with ASA however had no significant effect neither on cycling LSK nor progenitor populations. Consequently, decreased medullary hematopoiesis under P2Y12-inhibition led to reduced infiltration of inflammatory cells in the infarct tissue 7 days after MI, finally resulting in significantly improved outcome in terms of LV-EF 3 weeks after MI. Conclusion In this study, we demonstrate that P2Y12-mediated signaling is involved in emergency hematopoiesis after MI and advocates post-MI inflammation. In turn, inhibition of P2Y12-mediated signaling contributes to improved wound healing and prevention of adverse cardiac remodeling after MI, which adds a yet unknown mechanism to the success story of modern P2Y12-receptor blockers. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft

Stronger inhibitory effects of ticagrelor plus aspirin compared with clopidogrel plus aspirin on arachidonic acid induced platelet aggregation in patients with acute coronary syndrome with PCI

Antagonists of the adenosine diphosphate (ADP) receptor, P2Y12 may inhibit platelet aggregation resulting from stimulation with arachidonic acid (AA). The potent P2Y12 blocker, ticagrelor has greater anti-platelet effects than clopidogrel. We explored the effects of ticagrelor versus clopidogrel on mean maximum aggregation ratios (MAR%) in response to AA stimulation in patients receiving conventional aspirin dosages. A total of 613 acute coronary syndrome (ACS) patients were followed from October 2017 to October 2018. At the 1- and 6-month follow-up visit, mean AA-MAR% was lower in the ticagrelor group when compared with the clopidogrel group (28.9% vs. 31.7%, 28.4% vs. 31.0%, P<0.001 and P=0.001, respectively). BARC1-2 bleeding occurred with greater frequency with ticagrelor rather than clopidogrel treated patients (29.3% vs. 9.5%, P<0.001; 23.5% vs. 9.3%, P<0.001). Excessive platelet inhibition and decreased AA-MAR% were considered the main reasons for the severe subcutaneous/dermal bleeding in ticagrelor treated patients. Continuous...