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Background The current Canadian Cardiovascular Society antiplatelet therapy guidelines recommend the use of ticagrelor or prasugrel over clopidogrel as first-line platelet P2Y12 receptor antagonists for treatment of moderate- to high-risk acute coronary syndromes. Recently, Effient (prasugrel [Eli Lilly Canada Inc, Toronto, Canada]) was discontinued by its distributor in Canada. Methods Five members of the Canadian Cardiovascular Society antiplatelet therapy 2018 guidelines committee undertook an independent, evidence-based review to outline patients for whom prasugrel should be the optimal P2Y12 agent and discuss alternative strategies to consider without prasugrel. Results Several clinical scenarios where prasugrel should be indicated are identified and discussed. Considerations to be undertaken for alternative therapies are summarized, including a review of national and international guidelines for de-escalation of P2Y12 receptor antagonists. Conclusions The discontinuation of prasugrel poses a challenge for clinicians. Clinicians must consider key factors in determining the best alternate therapy., Introduction Dans ses lignes directrices actuelles sur la thérapie antiplaquettaire, la Société canadienne de cardiologie recommande l’utilisation du ticagrélor ou du prasugrel plutôt que l’utilisation du clopidogrel comme antagonistes des récepteurs plaquettaires P2Y12 de première intention dans le traitement des patients qui présentent un risque modéré à élevé de syndromes coronariens aigus. Depuis peu, le distributeur a cessé la distribution d’Effient (prasugrel) au Canada. Méthodes Cinq membres du comité des lignes directrices 2018 sur la thérapie antiplaquettaire de la Société canadienne de cardiologie ont entrepris une revue indépendante fondée sur les données probantes pour dresser le profil des patients pour lesquels le prasugrel devrait être la meilleure option parmi les antagonistes des récepteurs P2Y12 et se pencher sur les traitements alternatifs en l'absence de prasugrel. Résultats Plusieurs scénarios cliniques où le prasugrel devrait être indiqué sont recensés et abordés. Les réflexions sur les solutions de rechange au traitement, notamment une revue des lignes directrices nationales et internationales en matière de désescalade des antagonistes des récepteurs P2Y12, sont présentées. Conclusions La cessation de la distribution du prasugrel pose problème aux cliniciens. Les cliniciens doivent tenir compte des facteurs clés pour déterminer le meilleur traitement de remplacement.

Over the last decades, antiplatelet agents, mainly aspirin and P2Y12 receptor antagonists, have significantly reduced morbidity and mortality associated with arterial thrombosis. Their pharmacological characteristics, including pharmacokinetic/pharmacodynamics profiles, have been extensively studied, and a significant number of clinical trials assessing their efficacy and safety in various clinical settings have established antithrombotic efficacy. Notwithstanding, antiplatelet agents carry an inherent risk of bleeding. Given that bleeding is associated with adverse cardiovascular outcomes and mortality, there is an unmet clinical need to develop novel antiplatelet therapies that inhibit thrombosis while maintaining hemostasis. In this review, we present the currently available antiplatelet agents, with a particular focus on their targets, pharmacological characteristics, and patterns of use. We will further discuss the novel antiplatelet therapies in the pipeline, with the goal of improved clinical outcomes among patients with atherothrombotic diseases.

Antiplatelet agents, with aspirin and P2Y12 receptor antagonists as major key molecules, are currently the cornerstone of pharmacological treatment of atherothrombotic events including a variety of cardio- and cerebro-vascular as well as peripheral artery diseases. Over the last decades, significant changes have been made to antiplatelet therapeutic and prophylactic strategies. The shift from a population-based approach to patient-centered precision medicine requires greater awareness of individual risks and benefits associated with the different antiplatelet strategies, so that the right patient gets the right therapy at the right time. In this review, we present the currently available antiplatelet agents, outline different management strategies, particularly in case of bleeding or in perioperative setting, and develop the concept of high on-treatment platelet reactivity and the steps toward person-centered precision medicine aiming to optimize patient care.

Background Dual antiplatelet therapy based on aspirin and P2Y12 receptor antagonists such as clopidogrel is currently the primary treatment for coronary artery disease (CAD). However, a percentage of patients exhibit clopidogrel resistance, in which genetic factors play vital roles. This study aimed to investigate the roles of GAS5 (growth arrest‐specific 5) and its rs55829688 polymorphism in clopidogrel response in patients with CAD. Methods and Results A total of 444 patients with CAD receiving dual antiplatelet therapy from 2017 to 2018 were enrolled to evaluate the effect of GAS5 single nucleotide polymorphism rs55829688 on platelet reactivity index. Platelets from 37 patients of these patients were purified with microbeads to detect GAS5 and microRNA‐223‐3p (miR‐223‐3p) expression. Platelet‐rich plasma was isolated from another 17 healthy volunteers and 46 newly diagnosed patients with CAD to detect GAS5 and miR‐223‐3p expression. A dual‐luciferase reporter assay was performed to explore the interaction between miR‐223‐3p and GAS5 or P2Y12 3′‐UTR in (human embryonic kidney 293 cell line that expresses a mutant version of the SV40 large T antigen) HEK 293T and (megakaryoblastic cell line derived in 1983 from the bone marrow of a chronic myeloid leukemia patient with megakaryoblastic crisis) MEG‐01 cells. Loss‐of‐function and gain‐of‐function experiments were performed to reveal the regulation of GAS5 toward P2Y12 via miR‐223‐3p in MEG‐01 cells. We observed that rs55829688 CC homozygotes showed significantly decreased platelet reactivity index than TT homozygotes in CYP2C19 poor metabolizers. Platelet GAS5 expression correlated positively with both platelet reactivity index and P2Y12 mRNA expressions, whereas platelet miR‐223‐3p expression negatively correlated with platelet reactivity index. Meanwhile, a negative correlation between GAS5 and miR‐223‐3p expressions was observed in platelets. MiR‐223‐3p mimic reduced while the miR‐223‐3p inhibitor increased the expression of GAS5 and P2Y12 in MEG‐01 cells. Knockdown of GAS5 by siRNA increased miR‐223‐3p expression and decreased P2Y12 expression, which could be reversed by the miR‐223‐3p inhibitor. Meanwhile, overexpression of GAS5 reduced miR‐223‐3p expression and increased P2Y12 expression, which could be reversed by miR‐223‐3p mimic. Conclusions GAS5 rs55829688 polymorphism might affect clopidogrel response in patients with CAD with the CYP2C19 poor metabolizer genotypes, and GAS5 regulates P2Y12 expression and clopidogrel response by acting as a competitive endogenous RNA for miR‐223‐3p.

Ruptured blister type aneurysms are challenging to treat, and the ideal treatment remains debated. Recently, endovascular procedures, particularly flow diversion, gained popularity in treating blister aneurysms; however, the need for dual antiplatelet therapy remains a significant concern. Cangrelor is a novel intravenous P2Y12 platelet receptor antagonist with reversible binding and rapid onset and offset of action. These characteristics are appealing for use in endovascular procedures and may mitigate some concerns associated with other P2Y12 receptor antagonists. In this manuscript, we present the case of a ruptured blister aneurysm to highlight features of pathogenesis relevant to clinical course and patient management, describe current treatment paradigms, and illustrate the benefits of cangrelor in neurosurgical patients. Previously studied exclusively in the cardiac literature, this is one of the first reports of the use of cangrelor in neuro-endovascular procedures. This is important as cangrelor has the potential for improving the safety of endovascular procedures, especially in patients where treatment is associated with high risks of intraprocedural bleeding or other complications that may require further intervention.

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.

Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Dr. Benz reports a personal research grant from the German Heart Foundation (Deutsche Herzstiftung e.V.). Dr. Johansson reports personal unrestricted research grants from Swedish Heart-Lung Foundation (Hjärt-Lungfonden) and from Stockholm County Council (Region Stockholm). Dr. McIntyre holds a fellowship award from the Canadian Institutes for Health Research (CIHR). Dr. Shoamanesh reports funding support from the Marta and Owen Boris Foundation and the Heart and Stroke Foundation of Canada. Background/Introduction: There is an ongoing controversy surrounding the efficacy and safety of antiplatelet agents in patients with atrial fibrillation (AF). Purpose We aimed to systematically assess the effects of antiplatelets on stroke and other outcomes in patients with AF, both receiving oral anticoagulation or not. Methods We searched MEDLINE, Embase and CENTRAL up until September 2020 to identify randomized trials allocating patients with AF to aspirin or a P2Y12 inhibitor, versus control. Where applicable, we obtained unpublished data from study authors. Random-effects models were applied for meta-analysis. Results Based on 21,518 patients from 18 randomized trials, there was no reduction in stroke with antiplatelet therapy (risk ratio [RR] 0.89, 95% confidence interval [CI] 0.76-1.04). There was a significant qualitative interaction according to whether patients were receiving concomitant oral anticoagulation or not (p Conclusions Antiplatelet therapy did not reduce stroke and increased major bleeding in patients with AF. Antiplatelets did not affect mortality. Subgroup analysis suggests a reduction in stroke with antiplatelets in patients without concomitant oral anticoagulation, and a corresponding signal for harm in those with it. Abstract Figure.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Estonian Research Council Introduction High rates of adherence to myocardial infarction (MI) secondary prevention medications have been reported by several studies in Europe. However, results derived from unselected populations registry based data is scarce. Purpose Aim of our study was to analyse adherence to guideline recommended medications for secondary prevention of MI of unselected patient population in Estonia in 2017-2018 and compare the results with data from 2004-2005. Methods Population studied in 2004-2005 was based on Estonian Health Insurance Fund"s (EHIF) database and in 2017-2018 on Estonian Myocardial Infarction Registry (EMIR). EMIR is an ongoing registry recording data from all patients in Estonia diagnosed with MI (ICD-10 I21 – I22). Patients hospitalised due to MI and survived > 30 days formed the study population. By linking to EHIF"s prescription database medication adherence for angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), statins, beta blockers (BB) and P2Y12 inhibitors clopidogrel and ticagrelor was assessed during one year follow-up period from first hospitalisation during period studied (at least one reimbursed prescription for the drug group during follow-up period). Results 4900 and 5067 index episodes were defined in 2004-2005 and 2017-2018, respectively. Mean age in the study population was 64.7 (+/- 11.5) and 66.5 (+/- 12.1) for men and 72.7 +/- 9.9 and 76.4 +/- 10.9 for women in 2004-2005 and 2017-2018. Rates of medication adherence among patients who survived > 30 days are presented in the Table. Conclusion Adherence to guideline recommended medication for secondary prevention of MI in Estonia has improved considerably over 13 years. Based on our data there is room for advancement, especially among women and the elderly. Rates of medication adherence.2004-20052017-2018p value (comparison between studies)MEN (n = 2365)WOMEN (n = 1660)TOTAL (n = 4025)MEN (n = 2704)WOMEN (n = 1668)TOTAL (n = 4372)BB, No. (%)1907 (80.6)1344 (81.0)3251 (81.0)2265 (84.0)1385 (83.0)3650 (83.5)0.001ACE/ARB, No. (%)1780 (75.3)1317 (79.3)3097 (76.9)1817 (67.2)1070 (64.1)2887 (66.0)< 0.001Statins, No. (%)946 (40.0)826 (50.0)*1772 (44.0)1910 (70.6)1020 (61.2)*2930 (67.0)< 0.001Statin + ACE/ARB + BB, No. (%)999 (42.2)647 (39.0)1646 (40.9)1336 (49.4)686 (41.1)*2022 (46.2)< 0.001None of the above medications, No. (%)130 (5.5)96 (6.0)226 (5.6)214 (7.9)148 (9.0)362 (8.3)< 0.001P2Y12 inhibitorsNANANA2194 (81.1)1147 (69.0)*3341 (76.4)NABB, beta-blockers; ACE/ARB, angiotensin converting enzyme inhibitors/angiotensin II receptor blockers. NA, not available *P < 0.01 for comparison between men and women with Pearson"s χ2 test. Pearson"s χ2 test used for comparison between studies.

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): CytoSorbents Medical Incorporation Background A hemadsorption device containing biocompatible porous polymer beads is easily incorporated into extracorporeal circuits including cardiopulmonary bypass (CPB), extracorporeal membrane oxygenation (ECMO), continuous renal replacement therapy (CRRT), and hemoperfusion. This device has been shown to safely and effectively remove the P2Y12 receptor antagonist ticagrelor and the direct oral anticoagulant (DOAC) rivaroxaban during CPB in patients undergoing emergent cardiac surgery. Importantly, drug removal was associated with significant reductions in surgical bleeding and improved clinical outcomes resulting in CE Mark approval. Apixaban, another DOAC, has gained increasing popularity given its proven efficacy and lower risk of bleeding in clinical use. However, a pressing unmet medical need exists for the mitigation of the bleeding risk encountered in patients on apixaban who require urgent or emergent surgery. Currently approved reversal agents are only indicated in the case of uncontrolled or life-threatening bleeding, but not as preventive measures to mitigate surgical bleeding. Purpose To demonstrate the ability of the extracorporeal hemoadsorption device to remove apixaban from whole blood. Methods The hemoadsorption device was evaluated for removal of apixaban in an in vitro benchtop model using bovine whole blood. The 4L of blood were continuously circulated through a 300 mL porous polymer device over 6 hours at a flow rate of 300 mL/min to evaluate the drug removal kinetics of apixaban. Starting apixaban concentration of 300ng/mL was utilized in the model to reflect standard therapeutic levels. Plasma levels of apixaban over time were measured using liquid chromatography with tandem mass spectrometry (LC-MS-MS). A control setup utilized an identical flow circuit, minus the hemoadsorption device. Results Mean plasma concentration of apixaban was reduced to ∼9.1 ng/mL (equivalent to ∼96.3% removal) over the first 60 min of hemoperfusion with the device. Specifically, mean percent remaining plasma concentration of apixaban following device treatment was 42.2%, 18.6%, 8% and 3.7% after 15, 30, 45 and 60 min of therapy, respectively. Overall, ∼99.7% blood concentration of apixaban was removed over the total 6 h. Drug concentrations remained unchanged in the control circuit, with a statistically significant difference between the control and treatment groups at all time points except 0 h (p Conclusion Apixaban is efficiently removed with hemoadsorption using porous polymer device technology. Drug concentrations were reduced >96% after 60 min. Similarly, efficient benchtop removal utilizing the same technology was observed for ticagrelor and rivaroxaban, and subsequently translated into significant clinical benefit in patients requiring emergent cardiac surgery. The results of the current study hold significant promise for the future clinical applicability of apixaban removal. Abstract Figure. Percent of remaining apixaban over time

Introduction: The combination of aspirin and P2Y12 receptor antagonist is the standard antiplatelet therapy after percutaneous coronary intervention (PCI). Previous trials reported that prasugrel reduced the risk of ischemic events, but increased bleeding events compared to clopidogrel. Hypothesis: The prognostic impact of low-dose prasugrel (3.75 mg/day), which the dose was determined by phase II trial, is different from that of clopidogrel, depending on patient’s bleeding risk. Methods: This study is a subanalysis from the TWINCRE registry that is a multicentral prospective cohort including patients who underwent PCI. We analyzed 1,001 patients who received the combination of aspirin and prasugrel or clopidogrel after PCI. The primary endpoint was a composite of major bleeding event and major adverse cardiovascular and cerebrovascular events (MACCE) including any death, acute coronary syndrome, stent thrombosis, stroke and heart failure hospitalization. Results: There were 490 patients with high bleeding risk (HBR) and 511 patients with low bleeding risk (LBR), based on ARC-HBR criteria. In HBR patients, the Low-dose prasugrel group had significantly lower rates of MACCE (Log-rank, p=0.003) and the composite endpoint than the Clopidogrel group (p=0.001). While, in LBR patients, there was no significant difference in rates of MACCE or the composite endpoint between the groups (p=0.76, p=0.15, respectively), and a higher rate of major bleeding event in the Low-dose prasugrel group (p=0.002). With Cox proportional hazards analysis, low-dose prasugrel has still retained the superiority to clopidogrel regarding with the composite endpoint in HBR patients, even after adjusting with diverse covariates (hazard ratio: 0.33, 95% confidence interval: 0.16-0.65). Conclusion: In the multicenter cohort study in Japan, low-dose prasugrel showed a long-term prognostic superiority to clopidogrel only in HBR patients undergoing contemporary PCI.

Background Combination of a P2Y12 receptor (P2Y12R) antagonist (clopidogrel, prasugrel, ticagrelor) with aspirin is the recommended standard of care for patients with acute coronary syndrome. Selatogrel is a reversible and potent antagonist of P2Y12R. Interestingly, in an experimental thrombosis model in rat, at equivalent antithrombotic effect, blood loss was lower in the presence of selatogrel, compared with clopidogrel or ticagrelor. Purpose To characterise the lower risk of bleeding previously observed with selatogrel Methods Mechanistic studies were performed to profile laser-induced thrombosis in wild-type and P2Y12 deficient mice with real-time intravital microscopy. Ticagrelor and clopidogrel were used as selatogrel comparators. Results Selatogrel, ticagrelor and clopidogrel dose-dependently inhibited laser-induced platelet thrombus formation. At maximal antithrombotic effect, only small mural platelets aggregates, corresponding to the haemostatic seals, were present. The phenotype of these haemostatic seals depended on the P2Y12R antagonist used. In the presence of clopidogrel or ticagrelor, the stability of haemostatic seals was reduced. In contrast, in the presence of selatogrel, the apparent stability was not disturbed. Moreover, equivalent antithrombotic dosing regimens of ticagrelor and clopidogrel interfered with laser-induced calcium mobilisation in the endothelium, restricted subsequent neutrophil adhesion and thus reduced fibrin-mediated stabilisation of the haemostatic seals in wild type mice. The effects of ticagrelor were also observed in P2Y12R-deficient mice, indicating that the effects are P2Y12R independent and off-target. In contrast, an equivalent antithrombotic dosing regimen of selatogrel did not interfere with the process of haemostasis in wild-type or P2Y12R-deficient mice. The degree of interference with the stability of the haemostatic seals correlated with the blood loss profile. The dosing regimens of clopidogrel and ticagrelor, corresponding to the equivalent antithrombotic effects, induced a more pronounced increase in blood loss than that observed with selatogrel. Conclusion Our data offer a novel mechanistic explanation for the differences in bleeding risk of clopidogrel, ticagrelor and selatogrel. Clopidogrel and ticagrelor were found to interfere with haemostasis due to off-target activities. In contrast, selatogrel did not interfere with haemostasis in wild-type and P2Y12-deficient mice, inferring that the process of haemostasis, as defined by formation of haemostatic seals, is independent of P2Y12R. In addition, our data emphasize that the absence of interference with haemostasis is paramount to preserve the advantage of P2Y12R antagonism. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Idorsia Pharmaceuticals Ltd. Allschwil, Switzerland

Background AUGUSTUS randomized patients with atrial fibrillation and ACS and/or PCI to apixaban or VKA and aspirin or placebo for 6 months on background P2Y12 inhibitor. Purpose To characterise the clinical outcomes in patients receiving clopidogrel or ticagrelor. Methods Patients enrolled in AUGUSTUS (n=4614) were grouped by P2Y12 inhibitor at randomization. Baseline characteristics were compared among groups. Rates of ISTH major or CRNM bleeding, definite/probable stent thrombosis (ST), stroke, MI, and death or ischaemic event were quantified and treatment groups were compared according to treatment with clopidogrel or ticagrelor. Results At randomization, patients were treated with clopidogrel (n=4165), ticagrelor (n=280), prasugrel (n=51) or no P2Y12 inhibitor (n=118). Median ages were 71, 69, 66 and 72 years (P Conclusions Apixaban is safer than VKA regardless of P2Y12 inhibitor used. Dropping aspirin reduces bleeding but is associated with numerically higher ST rates regardless of P2Y12 inhibitor used. These data support current recommendations for preferential use of NOAC vs. VKA and individualised choice of P2Y12 inhibitor and timing of aspirin cessation after PCI according to the patient's risks of bleeding and stent thrombosis. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Bristol-Myers Squibb/Pfizer

Background Historically, women (W) with acute coronary syndrome (ACS) have worse outcomes compared with men (M). This fact may occur due to gender-specific differences in the presentation and management of patients (P), which were mainly observed in studies dealing with ST-segment elevation infarction (STEMI). There seems to be a gap of knowledge in gender-specific differences in non- ST elevation myocardial infarction (NSTEMI) and unstable angina (UA). Purpose Assess gender-specific differences in presentation, treatment and outcomes in NSTEMI and UA patients. Methods A retrospective cohort study from consecutive ACS patients enrolled in a multicentre national registry from October 2010 to December 2018 was conducted, identifying 11394 P admitted with NSTEMI or UA. Demographic, clinical and treatment variables were compared between male gender and female gender P. A Cox multivariate regression was performed to evaluate predictor factors of stablished endpoints: mortality at 1-year (1y) and cardiovascular (CV) hospitalization at 1-year. Results A total 11394 P were included, 8145 M (71.5%) and 3249 W (28.5%), mean age of 68±13. W, comparing with M, had higher age (72±12 vs 66±13, p=0.001), higher prevalence of hypertension (85% vs 72%, p=0.001) and diabetes (41% vs 34%, p=0.001) and longer time from symptoms to hospital admission (360 minutes vs 297 minutes, p=0.001). Chest pain was less frequent as first symptom in W (85.6% vs 91.3%, p=0.001). In medical treatment, W had higher chance of not having administration of a loading dose of P2Y12 inhibitor (22.1% vs 18.1, p=0.001) and of being medicated with clopidogrel (85.7% vs 82.1%, p=0.002). At discharge, W were less frequently medicated with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (82.6% vs 84.4, p=0.028). Coronary angiography was less frequently performed in W (77.3% vs 85.7%, p=0.001). Coronary artery disease was less frequently found in the female gender (12.4% vs 4.8%, p=0.001). In-hospital mortality was higher in W (2.9% vs 2.1%), but in the multivariate analysis the female gender was not an independent predictor of in-hospital mortality (OR 1.05 [0.67- 1.65], p=0.823). 1-year mortality was higher in W (9.2% vs 7.3%) and 1-year CV hospitalization was higher in M (16.8% vs 14.4%). After adjusting for covariates in Cox regression analysis, difference was still significant for mortality (HR= 1.274 [1.038 - 1.564], p=0.02) and hospitalization (HR = 0.852 [0.726- 0.998], p=0.047). Conclusion In this NSTEMI and UA cohort, there are important gender-specific differences in comorbidities, diagnosis, management and outcomes. Gender was an independent predictor of 1-year mortality and 1-year CV hospitalization, but not an independent predictor for in-hospital mortality. Funding Acknowledgement Type of funding source: None

Aims To study the pharmacodynamics and pharmacokinetics of selatogrel, a novel P2Y12 receptor antagonist for subcutaneous administration, in patients with chronic coronary syndromes (CCS). Methods and results In this double-blind, randomized study of 345 patients with CCS on background oral antiplatelet therapy, subcutaneous selatogrel (8 mg, n = 114; or 16 mg, n = 115) was compared with placebo (n = 116) (ClinicalTrials.gov: NCT03384966). Platelet aggregation was assessed over 24 h (VerifyNow assay) and 8 h (light transmittance aggregometry; LTA). Pharmacodynamic responders were defined as patients having P2Y12 reaction units (PRU)

Background Ticagrelor reduces ischaemic end points in acute coronary syndromes. However, outcomes of ticagrelor versus clopidogrel in real‐world patients with acute coronary syndromes treated with percutaneous coronary intervention (PCI) remain unclear. We sought to examine whether treatment with ticagrelor is superior to clopidogrel in unselected patients with acute coronary syndromes treated with PCI. Methods and Results We used data from SCAAR (Swedish Coronary Angiography and Angioplasty Registry) for PCI performed in Västra Götaland County, Sweden. The database contains information about all PCI performed at 5 hospitals (∼20% of all data in SCAAR). All procedures between January 2005 and January 2015 for unstable angina/non‒ST‐segment‒elevation myocardial infarction and ST‐segment‒elevation myocardial infarction were included. We used instrumental variable 2‐stage least squares regression to adjust for confounders. The primary combined end point was mortality or stent thrombosis at 30 days, secondary end points were mortality at 30 days and 1‐year, stent thrombosis at 30 days, in‐hospital bleeding, in‐hospital neurologic complications and long‐term mortality. A total of 15 097 patients were included in the study of which 2929 (19.4%) were treated with ticagrelor. Treatment with ticagrelor was not associated with a lower risk for the primary end point (adjusted odds ratio [aOR], 1.20; 95% CI, 0.87–1.61; P =0.250). Estimated risk of death at 30 days (aOR, 1.18; 95% CI, 0.88–1.64; P =0.287) and at 1‐year (aOR, 1.28; 95% CI, 0.86–1.64; P =0.556) was not different between the groups. The risk of in‐hospital bleeding was higher with ticagrelor (aOR, 2.88; 95% CI, 1.53–5.44; P =0.001). Conclusions In this observational study, treatment with ticagrelor was not superior to clopidogrel in patients with acute coronary syndromes treated with PCI.

Background: The optimal anti-coagulation strategy for patients with non-ST-elevation myocardial infarction treated with percutaneous coronary intervention is unclear in contemporary clinical practice of radial access and potent P2Y12-inhibitors. The aim of this study was to investigate whether bivalirudin was superior to heparin monotherapy in patients with non-ST-elevation myocardial infarction without routine glycoprotein IIb/IIIa inhibitor use. Methods: In a large pre-specified subgroup of the multicentre, prospective, randomised, registry-based, open-label clinical VALIDATE-SWEDEHEART trial we randomised patients with non-ST-elevation myocardial infarction undergoing percutaneous coronary intervention, treated with ticagrelor or prasugrel, to bivalirudin or heparin monotherapy with no planned use of glycoprotein IIb/IIIa inhibitors during percutaneous coronary intervention. The primary endpoint was the rate of a composite of all-cause death, myocardial infarction or major bleeding within 180 days. Results: A total of 3001 patients with non-ST-elevation myocardial infarction, were enrolled. The primary endpoint occurred in 12.1% (182 of 1503) and 12.5% (187 of 1498) of patients in the bivalirudin and heparin groups, respectively (hazard ratio of bivalirudin compared to heparin treatment 0.96, 95% confidence interval 0.78–1.18, p=0.69). The results were consistent in all major subgroups. All-cause death occurred in 2.0% versus 1.7% (hazard ratio 1.15, 0.68–1.94, p=0.61), myocardial infarction in 2.3% versus 2.5% (hazard ratio 0.91, 0.58–1.45, p=0.70), major bleeding in 8.9% versus 9.1% (hazard ratio 0.97, 0.77–1.24, p=0.82) and definite stent thrombosis in 0.3% versus 0.2% (hazard ratio 1.33, 0.30–5.93, p=0.82). Conclusion: Bivalirudin as compared to heparin during percutaneous coronary intervention for non-ST-elevation myocardial infarction did not reduce the composite of all-cause death, myocardial infarction or major bleeding in non-ST-elevation myocardial infarction patients receiving current recommended treatments with modern P2Y12-inhibitors and predominantly radial access.

Dual antiplatelet therapy (DAPT) with a P2Y12 receptor antagonist in addition to aspirin is the antiplatelet treatment of choice in patients undergoing percutaneous coronary intervention. Despite DAPT being one of the most widely investigated treatment strategies in the cardiology field, its optimal duration after coronary stenting remains controversial. The balance between the possible benefit of preventing a thrombotic event and the risk of suffering a bleeding complication due to maintenance of therapy is of critical relevance to determine the duration of DAPT in a given patient. Indeed, extended DAPT is associated with a reduction in non-fatal ischemic outcomes, at the cost of increasing the risk of bleeding events. Of note, several factors related to the patient, the procedure, or the device implanted may influence the ischemic and/or bleeding risk profiles of a given patient. Therefore, it is reasonable to recommend that the decision on DAPT duration should be individualized on a case-to-case basis. This review aims to provide a comprehensive overview of the current status of knowledge on duration of DAPT after coronary stenting, focusing on the evidence provided mainly by randomized clinical trials, as well as to discuss the factors that may influence the individual ischemic and bleeding risk profiles for a given patient, and whether the use of risk scores may inform the decision-making process for determining DAPT duration.

Ticagrelor is a P2Y12 receptor antagonist with proven clinical benefit in patients with acute coronary syndrome. Apart from its principal antiplatelet action, pleiotropic effects have been implicated in the clinical profile of ticagrelor, including a potentially beneficial impact on endothelial function. In light of the common presence and prognostic value of endothelial dysfunction in patients with coronary artery disease, several clinical studies have investigated the postulated effect of ticagrelor on endothelial function, yielding conflicting results. Limitations of the relevant studies as well as substantial differences in patient population, study design, and methods may account for these controversial findings. Most of these studies, however, support a beneficial impact of ticagrelor on endothelial function, which seems to be significant in the higher risk patients. In order to elucidate this effect, further research efforts should aim to clarify how quickly does endothelial function respond to ticagrelor, how sustained this response is during the dosing intervals and in the long term, which mechanisms are implicated, and whether this pleiotropic action is clinically significant. Future studies should include larger and diverse populations of patients, assess endothelial function at several time points after treatment initiation, and use multiple methods of endothelial function measurement, while implementing strict methodology. Nevertheless, the extent of the clinical benefit of ticagrelor attributable to actions beyond its potent and consistent antiplatelet effect remains uncertain.

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12-receptor antagonist plays a critical role in secondary prevention after an acute coronary syndrome (ACS). The use of DAPT lowers recurrent ischaemic events, including stent thrombosis, at the expense of bleeding complications when compared with aspirin alone. Based on early studies, a 12-month course of DAPT post-ACS has been recommended in the guidelines for years. A growing body of clinical trial data suggests that in general, patients with a biomarker positive ACS at low risk of bleeding who have tolerated DAPT well should continue beyond 12 months, with periodic reassessment of their bleeding risks. For patients at high risk of bleeding or with significant bleeding events during the initial year of DAPT, a shorter course would be recommended, particularly if second generation drug-eluting stents have been used. Thus, the decision to extend or shorten the duration of DAPT needs to be individualized based on the patient's ischaemic and bleeding risks, including during the initial year of therapy. For most ACS patients, this will mean continuing DAPT beyond a year.

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor antagonist represents the current standard of care to prevent atherothrombotic recurrences in patients with acute coronary syndrome (ACS). However, despite the use of DAPT, the recurrence rate of cardiovascular ischemic events still remains high. This persistent risk may be in part attributed to the sustained activation of the coagulation cascade leading to generation of thrombin, which may continue to play a key role in thrombus formation. The use of vitamin K antagonists (VKAs) as a strategy to reduce atherothrombotic recurrences after an ACS has been previously tested, leading to overall unfavorable outcomes due to the high risk of bleeding complications. The recent introduction of non-VKA oral anticoagulants (NOACs), characterized by a better safety profile and ease of use compared with VKA, has led to a reappraisal of the use of oral anticoagulant therapy for secondary prevention in ACS patients. The present article provides an overview of the rationale and prognostic role of oral anticoagulant therapy in ACS patients as well as recent updated clinical data, in particular with NOACs, in the field and future perspectives on this topic.

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 >208) and on-aspirin (ARU ≥550) platelet reactivity (HPR and HaPR) were assessed. Patients were divided into two groups according to MBG 3 or Results MBG 3 was identified in 28 (46%) patients. Mean PRU was lower in such patients as compared to those with MBG Table 1. Platelet reactivity results Verify Now at admission All Final Blush 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.

Introduction A relevant proportion of patients experiencing ST-segment elevation myocardial infarction (STEMI) has a late presentation after symptoms onset. Temporal trends deriving from a large real-word scenario for this subgroup of patients are lacking. Purpose The aim of the present study was to provide a comprehensive analysis of temporal trends in latecomer STEMI patients, with particular regard to implementation of evidence-based treatments in this population and major in-hospital outcomes. Methods All STEMI patients included in the AMIS Plus Registry from January 1997 to December 2017 were included and patient-related delay was assessed: 27 231 patients were available for the final analysis. STEMI patients were classified as early or latecomers according to patient-related delay (≤ or >12 hours, respectively). Results 22 928 patients were earlycomers (84%) and 4303 patients were classified as latecomers (16%). Across the study period we observed a significant decrease in prevalence of late presentation from 22% to 12.3% (p Figure 1 Conclusion The present study provides a comprehensive picture of temporal trends in late presentation in STEMI over the last 20 years in Switzerland. During the study period in latecomer STEMI population there was a gradual uptake of evidence-based pharmacological treatments and a marked increase in PCI rate. In-hospital mortality was reduced to a third (to an absolute rate of 4.5%) and this reduction seems to be mainly associated with the increasing implementation of PCI.

Introduction The definition of quality criteria in health care is essential to implement structural organization strategies that ensure that patients (P) receive the best care according to the most updated recommendations available at the time they are treated. Quality indicators have recently been defined with regard to the approach and treatment of STEMI in the European Guidelines published in 2017. Objective The authors intend to characterize the level of care provided to P with STEMI inserted into a national multicenter registry since 2011 in order to establish a relationship with international recommendations. Population and methods Descriptive study based on a national multicenter registry. A total of 2051 P admitted to the hospital with the diagnosis of STEMI were included, 1266 P for the year 2011 and 785 P for the year 2016. Results The P of the year 2011 and 2016 presented similar age (64±14 vs 63±13). There was a higher percentage of P admitted by STEMI fast track managed care system in 2016 (36.9% vs 22.2%, p Conclusion The results presented demonstrate a slight improvement in the quality of the care provided to STEMI P. However, there are areas for improvement, in accordance with international recommendations, in particular with regard to reperfusion times.

Ticagrelor, a P2Y12 receptor antagonist, is used in combination with aspirin in patients with coronary artery disease. Recent reports suggest that ticagrelor might induce central sleep apnea (CSA) by increasing chemosensitivity to hypercapnia. We herein describe the case of a patient with positive airway pressure (PAP)-treated obstructive sleep apnea (OSA), in whom PAP-telemonitoring revealed the emergence of CSA and Cheyne-Stokes respiration (CSR) after initiation of ticagrelor for an acute coronary syndrome with preserved left ventricular ejection fraction. Ticagrelor-associated shift from OSA to CSA was confirmed by respiratory polygraphy after PAP withdrawal, and was associated with an increased chemosensitivity to hypercapnia. Ticagrelor discontinuation was associated with the recurrence of pure OSA and the normalization of hypercapnic ventilatory response. A transient recurrence of CSA and CSR was identified by PAP-telemonitoring after accidental reintroduction of the drug. Further studies are required to determine the mechanisms, incidence, and consequences of ticagrelor-associated CSA. CITATION: Paboeuf C, Priou P, Meslier N, Roulaud F, Trzepizur W, Gagnadoux F. Ticagrelor-associated shift from obstructive to central sleep apnea: a case report. J Clin Sleep Med. 2019;15(8):1179–1182.

The platelet aggregation inhibitor ticagrelor, a P2Y12 receptor antagonist, is widely used after angioplasty in patients with acute coronary syndrome. Clinical trial data have shown that it is well tolerated by most patients. We present the case of a 62-year-old woman whose ticagrelor-related asymptomatic and persistent sinus pauses after angioplasty resolved when ticagrelor was replaced with prasugrel.