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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.

Cangrelor is an intravenously administered P2Y12 receptor antagonist, which has been approved for adult patients undergoing percutaneous coronary intervention and, due to its unique pharmacokinetic...

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.

Ticagrelor is a reversible P2Y12 receptor antagonist that is more potent than clopidogrel. When used in combination with aspirin, it reduces cardiovascular events in patients with acute coronary syndrome. However, unbiased review of 5 randomised controlled trials indicates that although statistically significant, the clinical superiority of ticagrelor over clopidogrel is modest. Thus, identification of patients who benefit the most from ticagrelor is a priority. Besides bleeding issues, ticagrelor can frequently cause bouts of dyspnoea, which requires ticagrelor replacement by another P2Y12 receptor antagonist, with a loading dose.

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.

Dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist is currently the standard of care for the prevention of ischemic events in patients with acute coronary syndrome or undergoing percutaneous coronary intervention. Several studies have shown that not all patients benefit from the treatment to the same degree and demonstrated that high on-treatment platelet reactivity may be associated with an increased risk of thrombotic events, while low on-treatment platelet reactivity may be linked to a higher risk of bleeding. Personalized antiplatelet treatment strategies based on platelet function monitoring and genetic testing constitute a promising tool for the prevention of both stent thrombosis and bleeding events, but conclusive evidence that such approaches can improve clinical outcomes is lacking. This review presents the most recent studies on tailored antiplatelet therapy in the management of coronary heart disease, with a focus on the prognosis value of platelet function testing.

The current clinical guidelines for the treatment of patients with acute coronary syndrome (ACS) claim that simultaneous use of two drugs that inhibit platelet activity is mandatory for most patients. This approach known as dual antiplatelet therapy (DAT), in view of the similarity of the mechanisms of the disease development, should be used in both ACS with ST elevation (STE-ACS) and in ACS without ST elevation (non-STE-ACS). In both cases, DAT should combine acetylsalicylic acid (ASA) with a P2Y12 receptor antagonist (ticagrelor, prasugrel or clopidogrel). For Russia, where prasugrel is not registered, the most preferable DAT is the combination of ASA with ticagrelor which has outperformed clopidogrel in terms of efficacy in the PLATO trial. [1]

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.

Background Platelet inhibition is important for patients with coronary artery disease. When dual antiplatelet therapy (DAPT) is required, a P2Y12-antagonist is usually recommended in addition to standard aspirin therapy. The most used P2Y12-antagonists are clopidogrel, prasugrel and ticagrelor. Despite DAPT, some patients experience adverse cardiovascular events, and insufficient platelet inhibition has been suggested as a possible cause. In the present review we have performed a literature search on prevalence, mechanisms and clinical implications of resistance to P2Y12 inhibitors. Methods The PubMed database was searched for relevant papers and 11 meta-analyses were included. P2Y12 resistance is measured by stimulating platelets with ADP ex vivo and the most used assays are vasodilator stimulated phosphoprotein (VASP), Multiplate, VerifyNow (VN) and light transmission aggregometry (LTA). Discussion/conclusion The frequency of high platelet reactivity (HPR) during clopidogrel therapy is predicted to be 30%. Genetic polymorphisms and drug-drug interactions are discussed to explain a significant part of this inter-individual variation. HPR during prasugrel and ticagrelor treatment is estimated to be 3–15% and 0–3%, respectively. This lower frequency is explained by less complicated and more efficient generation of the active metabolite compared to clopidogrel. Meta-analyses do show a positive effect of adjusting standard clopidogrel treatment based on platelet function testing. Despite this, personalized therapy is not recommended because no large-scale RCT have shown any clinical benefit. For patients on prasugrel and ticagrelor, platelet function testing is not recommended due to low occurrence of HPR.

European Guidelines on Myocardial Revascularization recommend clopidogrel loading dose added to acetylsalicylic acid in elective percutaneous coronary interventions (PCIs). However, there is few evidence supporting this recommendation and other P2Y12 inhibitors have not been tested in these patients.To evaluate the effectiveness and safety of different loading doses of clopidogrel and ticagrelor in patients without double antiplatelet therapy and stable coronary artery disease (SCAD) undergoing elective PCI.Retrospective study of 147 consecutive patients with SCAD undergoing elective PCI. Loading P2Y12 inhibitor doses evaluated were: clopidogrel 600 mg, clopidogrel 300 mg, clopidogrel 150 mg, and ticagrelor 180 mg. We analyzed the occurrence of major adverse cardiovascular events and periprocedural myocardial infarction.One hundred twenty-five patients were treated with clopidogrel (16 with clopidogrel 150 mg, 7 with clopidogrel 300 mg, and 93 with clopidogrel 600 mg) and 21 with ticagrelor 180 mg at the catheterization laboratory. The ticagrelor group had a significantly lower postprocedural peak of troponin-I (0.7 ± 3.4 vs. 0.3 ± 0.7 ng/mL; P = 0.02). There were no differences between groups in terms of major bleeding and hemoglobin drop after PCI (0.6 ± 0.8 vs. 4 ± 0.6; P = 0.8). The median of follow-up was 17 months (interquartile range 9-32.7). At the end of follow-up, major adverse cardiovascular event rate was not different between groups.In patients without dual antiplatelet therapy undergoing elective PCI, the use of ticagrelor showed lower postprocedural myocardial injury without more bleeding complications.

The American Urological Association (AUA) guidelines state that continuing anticoagulation and antiplatelet agents in routine ureteroscopy (URS) is safe and without increased risk of complications. However, these recommendations are based on small case series; thus, we sought to analyze bleeding-related complications among patients on antiplatelet therapy (APT).Overall, 4799 URS procedures performed at our institution between June 2009 and February 2016 were identified. Records were then retrospectively reviewed to confirm APT use and to identify periprocedural complications. Antiplatelet agents evaluated included aspirin (low dose and full dose) and P2Y12 receptor antagonists (clopidogrel, prasugugrel, ticagrelor). Patients were excluded if they were taking a concurrent anticoagulant agent or if additional non-URS procedures were performed.Of 4799 URS procedures, 314 (6.5%) were performed on patients taking APT, of which 234 (74.5%) held APT, 63 (20.1%) continued APT, and 17 (5.4%) continued dual APT. The mean age was 70.1 years, and the majority of patients (69.6%) underwent a stone procedure with a stone-free rate of 80.2%. The overall bleeding-related complication rate was 1.9%, whereas the significant bleeding-related event rate was 1.6% and this did not differ among the groups (p = 0.3). The power to detect a 3% difference in bleeding between the groups was 0.95.Continuing APT in patients on chronic therapy does not appear to pose an increased risk of bleeding-related complications. Our findings support the current AUA guidelines as they relate to APT.

During percutaneous coronary intervention, dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist are combined with one of three major strategies for antithrombotic therapy: heparins, bivalirudin, or heparin with an intravenous IIb/IIIa platelet receptor antagonist. Economic constraints in the United States are increasingly driving the choice between these therapies.

Ticagrelor (P2Y12 receptor antagonist) is presently indicated for preventing atherothrombotic events in patients with acute coronary syndrome and patients with a history of myocardial infarction. The PARTHENON clinical development program comprises five randomized, controlled, cardiovascular, indication-seeking outcome studies, aiming to evaluate ticagrelor across the spectrum of patients with atherothrombotic disease. Results of two large-scale trials support a benefit for ticagrelor in patients with acute coronary syndrome (PLATO; ClinicalTrials.gov: NCT00391872) and in patients with a history of myocardial infarction (PEGASUS-TIMI 54; ClinicalTrials.gov: NCT01225562). Ongoing trials will provide information on the efficacy and safety of ticagrelor in patients with acute ischemic stroke or transient ischemic attack (SOCRATES; ClinicalTrials.gov: NCT01994720), peripheral artery disease (EUCLID; ClinicalTrials.gov: NCT01732822) and coronary artery disease in patients with Type 2 diabetes mellitus (THEMIS: ClinicalTrials.gov: NCT01991795).

Adherence to guideline-indicated care for the treatment of non-ST-elevation myocardial infarction (NSTEMI) is associated with improved outcomes. We investigated the extent and consequences of non-adherence to guideline-indicated care across a national health system.A cohort study ( ClinicalTrials.gov identifier: NCT02436187) was conducted using data from the Myocardial Ischaemia National Audit Project ( n = 389,057 NSTEMI, n = 247 hospitals, England and Wales, 2003-2013). Accelerated failure time models were used to quantify the impact of non-adherence on survival according to dates of guideline publication.Over a period of 1,079,044 person-years (median 2.2 years of follow-up), 113,586 (29.2%) NSTEMI patients died. Of those eligible to receive care, 337,881 (86.9%) did not receive one or more guideline-indicated intervention; the most frequently missed were dietary advice ( n = 254,869, 68.1%), smoking cessation advice ( n = 245,357, 87.9%), P2Y12 inhibitors ( n = 192,906, 66.3%) and coronary angiography ( n = 161,853, 43.4%). Missed interventions with the strongest impact on reduced survival were coronary angiography (time ratio: 0.18, 95% confidence interval (CI): 0.17-0.18), cardiac rehabilitation (time ratio: 0.49, 95% CI: 0.48-0.50), smoking cessation advice (time ratio: 0.53, 95% CI: 0.51-0.57) and statins (time ratio: 0.56, 95% CI: 0.55-0.58). If all eligible patients in the study had received optimal care at the time of guideline publication, then 32,765 (28.9%) deaths (95% CI: 30,531-33,509) may have been prevented.The majority of patients hospitalised with NSTEMI missed at least one guideline-indicated intervention for which they were eligible. This was significantly associated with excess mortality. Greater attention to the provision of guideline-indicated care for the management of NSTEMI will reduce premature cardiovascular deaths.

Platelets play a key role in mediating stent thrombosis, which is the major cause of ischemic events immediately after percutaneous coronary intervention (PCI). Antiplatelet therapy is therefore the cornerstone of antithrombotic therapy after PCI. However, the use of antiplatelet agents increases bleeding risk, with more potent antiplatelet agents further increasing bleeding risk. In the past 5 years, potent and fast-acting P2Y12 inhibitors have augmented the antiplatelet armamentarium available to interventional cardiologists. This article reviews the preclinical and clinical data surrounding these new agents, and discusses the significant questions and controversies that still exist regarding the optimal antiplatelet strategy.

Antiplatelet therapy has established clinical benefit on cardiovascular outcome and has reduced the rates of re-infarction/in stent thrombosis following percutaneous coronary intervention in acute coronary syndromes. Major bleeding episodes can occur with antiplatelet therapy and intracranial hemorrhage (ICH) is one of the most feared complications resulting in significant morbidity and mortality. Identification of high risk groups and judicious use of antiplatelet therapy reduces the bleeding risk. Ticagrelor is a newer P2Y12 receptor antagonist with established clinical benefit. However, risks of having an ICH with these newer molecules cannot be ignored. Here, we report a case of spontaneous acute subdural hematoma developing in a patient on antiplatelet therapy with aspirin and ticagrelor. Early recognition, discontinuation of the medication and appropriate management resulted in resolution of hematoma and good clinical outcome. Authors have reviewed the antithrombotic drugs and their tendencies in causing intracranial bleeds from a neurophysicians perspective.

Purpose: Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor antagonist is often used to prevent thrombotic complications after endovascular stent placement. Most of the published experience surrounding DAPT after carotid stenting is with clopidogrel. Ticagrelor may be a promising alternative, especially in patients who may be considered nonresponders to clopidogrel. However, clinical outcomes utilizing DAPT with ticagrelor in a cohort with carotid stenting is lacking. In this case series, we describe our experience with systematic prescribing of ticagrelor after carotid stent placement in 18 patients. Methods: A retrospective review of 18 patients prescribed ticagrelor who underwent carotid stenting between November 2015 and January 2017 was performed. All eligible patients were included in the review. The primary end point of interest was any ischemic stroke or death within 30 days following the procedure. Intracranial hemorrhage was a secondary end point. Results and Conclusions: No patients experienced the primary end point of ischemic stroke or death within 30 days. No intracranial hemorrhages were observed. The use of ticagrelor after carotid stenting may be a reasonable alternative to clopidogrel after carotid stent placement. Randomized trials to support our findings are needed.

Source Citation Hahn JY, Song YB, Oh JH, et al; SMART-CHOICE Investigators. Effect of P2Y12 inhibitor monotherapy vs dual antiplatelet therapy on cardiovascular events in patients undergoing percut...

Ticagrelor is a P2Y12 receptor antagonist used in first-line dual-antiplatelet therapy in coronary artery disease [(1)][1]. Cheyne-Stokes respiration with central sleep apnea was reported in 4 patients after ticagrelor therapy was initiated and disappeared after ticagrelor withdrawal and switch to

BACKGROUND: Maximizing endoscopic ultrasound (EUS) diagnostic yield (DY) and safety is key to providing high quality care, yet the influence of patient and procedure factors on both these outcomes have only been examined using limited sample sizes. AIMS: We aim to examine factors associated with EUS diagnostic yield and adverse event (AE) risk using a large cohort of patients who underwent a EUS procedure at our centre. METHODS: A retrospective chart review of EUS procedures performed between 2009 and 2015 at The Ottawa Hospital was conducted. Data regarding patient demographics and details of the lesion, procedure, medications, and DY were collected. All patient ER visits or hospitalizations within 30 days of the EUS procedure were also collected and reviewed. Relation of the hospital encounter (definitely, possibly, and not) to the EUS procedure was established by consensus using pre-defined criteria. RESULTS: 1647 EUS procedures were examined. The median patient age was 64 (IQR, 53–73) years and 50% were female. Of all EUS cases, 105 (6.4%) presented to the ER or were hospitalized; however, only 58 (3.5%) were related to EUS. DY was 78% for EUS-FNA cases only. Rapid on-site evaluation impacted DY (73% vs. 80%, p = 0.02) but not AE risk (p = 0.53). Multivariate analysis of all cases demonstrated performing a FNA (OR 2.1, 95% CI 1.0–4.4) and having anesthesia-guided sedation (OR 3.9, 95% CI 1.8–8.5) was associated with an increased AE risk. DY was associated being a smoker (OR 0.7, 95% CI 0.5–0.9). Upon separating out EUS-FNA procedures only, we found on multivariate analysis that lesions > 3 cm (OR 2.4, 95% CI 1.1–5.3), using anesthesia-guided sedation (OR 3.9, 95% CI 1.3–12.0), and using a P(2)Y(12) inhibitor (OR 7.9, 95% CI 2.5–25.1) was associated with an increased AE risk. Solid lesions (OR 2.0, 95% CI 1.1–3.6) and lesions > 3 cm (OR 1.9, 95% CI 1.2–3.2) were associated with an increased DY. CONCLUSIONS: Lesions > 3 cm should be subject to fewer FNA passes to decrease AE risk. EUS procedures on patients who expect to receive anesthesia-guided sedation should be reconsidered. Finally, patients receiving P(2)Y(12) inhibitors should not be subject to FNA, unless their medication is stopped. FUNDING AGENCIES: None

Monitoring antiplatelet therapy is critical in patients undergoing cardiac or neurologic stent placement to ensure adequate platelet suppression and prevent thrombosis. Light transmission aggregometry (LTA) using platelet-rich plasma (PRP) is the gold standard to assess platelet responsiveness to aspirin (ASA) and P2Y12 inhibitors (P2Y12-I). Other platforms for antiplatelet therapy monitoring employ whole-blood aggregometry (WBA) via electrical impedance (EA) or ELISA-based detection of urinary metabolites. The goal of this study was to evaluate the concordance of four antiplatelet therapy monitoring platforms. Blood and urine samples from 20 patients receiving antiplatelet therapy prior to neurologic stent placement were prospectively collected. Blood samples were analyzed by LTA using PRP on the Helena AggRAM and by WBA-EA using the Chrono-log Lumi-aggregometer to assess ASA and P2Y12-I response. For the LTA, the maximum amplitude (MA) of the platelet aggregation curve was determined using high-dose (HD) and low-dose (LD) ADP agonist for measuring P2Y12-I response and with arachidonic acid (AA) for ASA response. For the WBA, resistance (ohms) was measured with ADP for P2Y12-I response and with HD and LD collagen for ASA response. Whole-blood samples were also analyzed with the VerifyNow PRUTest to assess platelet response to P2Y12-I. Urine samples were analyzed with AspirinWorks. Concordance of antiplatelet response based on predefined cutoff values (eg, concordant = optimal/optimal, discordant = optimal/suboptimal), as well as correlation between actual units of measure, was determined. When comparing P2Y12-I response determined by LTA and WBA, overall concordance was 55% (correlation was r = 0.75 and 0.65 for HD and LD ADP, respectively). VerifyNow was concordant with LTA in 70% (r = 0.86 and 0.75 for HD and LD ADP, respectively) and with WBA in 45% (r = 0.57) of samples. When comparing ASA response between LTA and WBA, overall concordance was 70% (r = 0.09 and 0.19 for HD and LD collagen, respectively). AspirinWorks was concordant with LTA and WBA in 60% of samples (r = 0.32 for LTA; r = 0.08 LD collagen, r = 0.02 for HD collagen on WBA). In summary, concordance varied between 45% and 70% on the four antiplatelet therapy monitoring platforms. Testing of P2Y12 inhibition showed the best correlation between LTA HD ADP and VerifyNow (r = 0.86). When comparing WBA vs LTA, the strongest correlation was between LD ADP LTA and WBA (r = 0.75). Correlation with ASA inhibition was overall poor between the various assays (r ranging between 0.02 and 0.58). The results from this correlation study support the continued use of LTA with HD and LD ADP and AA; other testing methods can be used as adjuncts when LTA proves difficult to interpret.

Background Ticagrelor, a reversible P2Y12 receptor antagonist, is superior to clopidogrel in decreasing major adverse cardiac events in the setting of acute coronary syndrome. However, a high rate of drug discontinuation secondary to ticagrelor-induced dyspnoea has been observed. Clinical details This is a case of persistent and intolerable ticagrelor-induced dyspnoea in a patient requiring drug discontinuation. A review of the literature on the plausible mechanisms is also provided. Conclusion Dyspnoea is a relatively common side effect of ticagrelor, usually mild and not associated with alteration in pulmonary function. However, in cases of persistent and intolerable dyspnoea, drug discontinuation should be considered. It is imperative that healthcare professionals regularly monitor patients receiving ticagrelor therapy with the aims of maintaining medication adherence and providing appropriate alternatives if dyspnoea becomes intolerable.

P2Y12, a member of the G-protein-coupled receptors, is associated with abnormal platelet aggregation, a condition that contributes to thrombus formation. As receptor antagonists are effective solutions for anti-thrombus, the P2Y12 receptor is a popular drug target. After the recent resolution of the P2Y12 receptor’s crystal structure, pharmacophore modeling and docking were combined to discover potential natural antagonists. Various approaches were used for the validation of the pharmacophore models and the optimization of docking algorithms. Hypo18, which was generated by 24 known antagonists, was determined to be the best hypothesis and is comprised of one ring aromatic, one hydrogen bond acceptor, one exclude volume, and three hydrophobic features. Hypo18 was thus utilized to screen TCMD (version 2009) to identify any potential active compounds, which then resulted in a hit list of 121 compounds with drug-likeness analysis. In addition, docking was used to refine the pharmacophore-based screening results as a cross-linking method. Then, the top 20 compounds with high docking scores were reserved. This paper provides a reliable source for discovering natural P2Y12 receptor antagonists from traditional Chinese herbs.

Selective intensification of platelet inhibition may improve high on treatment platelet reactivity (HPR). We evaluated the efficacy of dual-antiplatelet therapy, including clopidogrel (CPG), compared to new P2Y12-receptor antagonists in patients with HPR undergoing percutaneous coronary intervention, regarding the outcome of composite major adverse cardiac events (MACEs, including death, acute coronary syndrome [ACS], and stent restenosis). The presence of HPR (71 of 181 patients) almost doubled the risk of MACEs. The new antiplatelet agent reduced MACEs (45.8%, 26%, and 16.7% for CPG, prasugrel, and ticagrelor [TGL]; RR 0.36; 0.13-0.98, P = .03, TGL), specifically in patients with ACS. Failure to reduce HPR after the antiplatelet change and diabetes were independent predictors for MACEs. The HPR was early and effectively reduced after changing the antiplatelet therapy, but the intensity of this reduction did not significantly decrease the risk of MACEs. These findings support the benefit of HPR-guided intensification of platelet inhibition. Whether the intensity of this reduction improves the patient’s clinical outcomes deserves further investigation.

BACKGROUND Cangrelor is an intravenous adenosine diphosphate (ADP) P2Y12 receptor antagonist, which has to be administered as a bolus followed by immediate infusion. Nevertheless, in clinical routine deviations from the correct practice, such as delayed infusion onset or interruptions during infusion, may occur. OBJECTIVE The objective of the present study was to investigate the impact of administration delays on cangrelor concentration in a pharmacological simulation setting and to give possible solutions for the clinical practice. METHODS We simulated the effects of different delays in administration of cangrelor in a model based on known pharmacokinetic parameters. Additionally, we calculated the optimal dosage of a second bolus. RESULTS We demonstrate that already a short delay between the bolus and begin of infusion as well as short infusion interruptions considerably affect the serum concentration of cangrelor. Additionally, we estimate the dosage of a possible second bolus which highly depends on the duration of the delay. CONCLUSIONS Our results emphasize that continuous administration of cangrelor is crucial to avoid the critical time frame of increased thrombosis risk. We suggest a strategy for dealing with interruptions by demonstrating that a second bolus allows to reach rapidly an effective but not excessive cangrelor serum concentration.

Scientists and clinicians have been concerned by the lack of a clinically suitable strategy for cardioprotection in patients with acute myocardial infarction despite decades of intensive pre-clinical investigations and a surprising number of clinical trials based on those observations which have uniformly been disappointing. However, it would be a mistake to abandon this search. Rather it would be useful to examine these past efforts and determine reasons for the multiple failures. It appears that earlier clinical trials were often based on results from a single experimental laboratory, thus minimizing the importance of establishing reproducibility in multiple laboratories by multiple scientists and in multiple models. Clinical trials should be discouraged unless robust protection is demonstrated in pre-clinical testing. After approximately 2005 a loading dose of a platelet P2Y12 receptor antagonist became increasingly widespread in patients with acute myocardial infarction prior to revascularization and quickly became standard-of-care. These agents are now thought to be a cause of failure of recent clinical trials since these pleiotropic drugs also happen to be potent postconditioning mimetics. Thus, introduction of an additional cardioprotective strategy such as ischemic postconditioning which uses the same signaling pathway as these P2Y12 antagonists would be redundant and doomed to failure. Additive cardioprotection could be achieved only if the second intervention had a different mechanism of cardioprotection. This concept has been demonstrated in experimental animals. So lack of reproducibility of earlier studies and failure to examine interventions in experimental animals also treated with anti-platelet agents could well explain past failures. These realizations should clear the way for development of interventions which can be translated into successful clinical treatments.

Objective Ticagrelor is a direct-acting, reversibly-binding, oral P2Y12 receptor antagonist. It demonstrates predictable, linear pharmacokinetics. Two studies were undertaken to further elucidate the absolute bioavailability of ticagrelor and its regional absorption in the gastrointestinal (GI) tract. Design and methods In two open-label, randomized, cross-over studies, 12 volunteers received a single dose of ticagrelor: oral 90 mg and 15 mg IV (Study 1); or 100 mg oral suspension vs 100 mg immediate release (IR) tablet (Study 2). After the initial cross-over period in Study 2, patients received 100 mg suspension delivered to specific sites in the GI tract using an Enterion capsule. In both studies, plasma concentrations of ticagrelor and AR-C124910XX were measured following administration of each formulation. Results The mean absolute bioavailability of ticagrelor was 36% (95% confidence interval = 30–42%). Metabolite:parent ratios were higher after oral administration, compared with IV administration (maximum plasma concentration [Cmax] = 0.356 and 0.037; area under the plasma concentration-time curves [AUC] = 0.530 and 0.173, respectively). Following oral administration of the 100 mg IR tablet, the AUC and Cmax of ticagrelor were 78% and 58%, respectively, of those following oral administration of the 100 mg suspension. Exposure to ticagrelor decreased the further down the GI tract it was released: mean Cmax for ticagrelor was 91%, 68%, and 13% that for the oral suspension when released in the proximal small bowel, distal small bowel and ascending colon, respectively; mean AUCs were 89%, 73%, and 32%, respectively. Conclusion The mean absolute bioavailability of ticagrelor was 36% and the proportion of ticagrelor absorbed decreased the further down the GI tract it was released: the mean AUC for ticagrelor was 89% (proximal small bowel), 73% (distal small bowel), and 32% (ascending colon) that of the mean AUC for the orally administered suspension.

1. Genetic polymorphisms in platelet endothelial aggregation receptor 1 (PEAR1) were associated with responsiveness to aspirin and P2Y12 receptor antagonists. This study aimed to investigate whether PEAR1 polymorphism is associated with ticagrelor pharmacodynamics in healthy Chinese subjects. 2. The in vitro inhibition of platelet aggregation (IPA) was evaluated before and after ticagrelor incubated with platelet-rich plasma from 196 healthy Chinese male subjects. Eight polymorphisms at PEAR1 locus were genotyped. Eighteen volunteers (six in each rs12041331 genotype group) were randomly selected. After a single oral 180 mg dose of ticagrelor, plasma levels of ticagrelor and the active metabolite AR-C124910XX were measured and pharmacodynamics parameters including IPA and VASP-platelet reactivity index (PRI) were assessed. 3. No significant difference in ticagrelor pharmacokinetics among rs12041331 genotype was observed. As compared with rs12041331 G allele carriers, AA homozygotes exhibited increased IPA after 15 μM ticagrelor incubation (p 0.01), increased area under the time-effect curve of IPA and lower PRI at 2 h after ticagrelor administration (p 0.05, respectively). Rs4661012 GG homozygotes showed increased IPA after 50 μM ticagrelor incubation as compared to T allele carriers (p 0.01). 4. PEAR1 polymorphism may influence ticagrelor pharmacodynamics in healthy Chinese subjects.