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Inflammation leads to atherosclerosis and acute coronary syndromes (ACS). We performed a prospective, observational study to assess association between the concentrations of inflammatory markers (high sensitivity C-reactive protein, hsCRP; high sensitivity interleukin6, hsIL-6; soluble CD40 ligand, sCD40 L) and platelet reactivity in 338 patients with ACS treated with ticagrelor and prasugrel. We also assessed whether hsCRP, hsIL-6, and sCD40 L are associated with standard inflammatory markers (white blood cell [WBC] and fibrinogen), and whether they differ according to patient diabetic status and pre-treatment with statins. Concentrations of hsCRP and concentrations of hsIL-6 and sCD40 L were assessed using turbidimetric assay and enzyme-linked immunosorbent assay, respectively. Platelet reactivity was measured using multiple electrode aggregometry. There was only a weak inverse correlation between hsIL-6 and platelet reactivity (r≤-0.125). In contrast, concentration of hsIL6 and hsCRP positively correlated with WBC and fibrinogen (r ≥ 0.199). Insulin-dependent diabetes mellitus (IDDM) was associated with higher concentration of hsIL-6 ( p = .014), whereas pre-treatment with statins - with lower concentration of hsIL-6 ( p = .035). In conclusion, inflammatory state does not affect the antiplatelet efficacy of potent P2Y12 inhibitors in the acute phase of ACS, confirming the safety and efficacy of potent P2Y12 inhibitors in patients with a high inflammatory burden.

Aims: To evaluate long-term safety and efficacy of ticagrelor monotherapy in patients undergoing percutaneous coronary interventions (PCIs) in relation to chronic obstructive pulmonary disease (COPD) at baseline and the occurrence of dyspnoea reported as adverse event (AE) that may lead to treatment non-adherence., Methods and Results: This is a non-prespecified, post hoc analysis of the randomized GLOBAL LEADERS trial (n = 15 991), comparing the experimental strategy of 23-month ticagrelor monotherapy following 1-month dual antiplatelet therapy (DAPT) after PCI with the reference strategy of 12-month DAPT followed by 12-month aspirin monotherapy. Impact of COPD and dyspnoea AE (as a time-dependent covariate) on clinical outcomes was evaluated up to 2 years. The primary endpoint was a 2-year all-cause mortality or non-fatal, centrally adjudicated, new Q-wave myocardial infarction. The presence of COPD (n = 832) was the strongest clinical predictor of 2-year all-cause mortality after PCI [hazard ratio (HR) 2.84; 95% confidence interval (CI) 2.21-3.66; P adjusted = 0.001] in this cohort (n = 15 991). No differential treatment effects on 2-year clinical outcomes were found in patients with and without COPD (primary endpoint: HR 0.88; 95% CI 0.58-1.35; P = 0.562; P int = 0.952). Overall, at 2 years dyspnoea was reported as an AE in 2101 patients, more frequently among COPD patients, irrespective of treatment allocation (27.2% in experimental arm vs. 14.5% in reference arm, P = 0.001). Its occurrence was not associated with a higher rate of the primary endpoint (P adjusted = 0.640) in the experimental vs. the reference arm., Conclusion: In this exploratory analysis, COPD negatively impacted long-term prognosis after PCI. Despite higher incidence of dyspnoea in the experimental arm, in particular among COPD patients, the safety of the experimental treatment strategy appeared not to be affected., Clinical Trial Registration Unique Identifier: NCT01813435., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Activated platelets contribute to thrombosis and inflammation by the release of extracellular vesicles (EVs) exposing P-selectin, phosphatidylserine (PS) and fibrinogen. P2Y12 receptor antagonists are routinely administered to inhibit platelet activation in patients after acute myocardial infarction (AMI), being a combined antithrombotic and anti-inflammatory therapy. The more potent P2Y12 antagonist ticagrelor improves cardiovascular outcome in patients after AMI compared to the less potent clopidogrel, suggesting that greater inhibition of platelet aggregation is associated with better prognosis. The effect of ticagrelor and clopidogrel on the release of EVs from platelets and other P2Y12-exposing cells is unknown. This study compares the effects of ticagrelor and clopidogrel on (1) the concentrations of EVs from activated platelets (primary end point), (2) the concentrations of EVs exposing fibrinogen, exposing PS, from leukocytes and from endothelial cells (secondary end points) and (3) the procoagulant activity of plasma EVs (tertiary end points) in 60 consecutive AMI patients. After the percutaneous coronary intervention, patients will be randomized to antiplatelet therapy with ticagrelor (study group) or clopidogrel (control group). Blood will be collected from patients at randomization, 48 hours after randomization and 6 months following the index hospitalization. In addition, 30 age- and gender-matched healthy volunteers will be enrolled in the study to investigate the physiological concentrations and procoagulant activity of EVs using recently standardized protocols and EV-dedicated flow cytometry. Concentrations of EVs will be determined by flow cytometry. Procoagulant activity of EVs will be determined by fibrin generation test. The compliance and response to antiplatelet therapy will be assessed by impedance aggregometry. We expect that plasma from patients treated with ticagrelor (1) contains lower concentrations of EVs from activated platelets, exposing fibrinogen, exposing PS, from leukocytes and from endothelial cells and (2) has lower procoagulant activity, when compared to patients treated with clopidogrel. Antiplatelet therapy effect on EVs may identify a new mechanism of action of ticagrelor, as well as create a basis for future studies to investigate whether lower EV concentrations are associated with improved clinical outcomes in patients treated with P2Y12 antagonists.

To investigate the safety and efficacy of an early platelet function testing (PFT)-guided de-escalation of dual antiplatelet treatment (DAPT) in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) with bioresorbable vascular scaffolds (BVS). Early DAPT de-escalation is a new non-inferior alternative to 12-months DAPT in patients with biomarker positive ACS treated with stent implantation. In this post-hoc analysis of the TROPICAL-ACS trial, which randomized 2610 ACS patients to a PFT-guided DAPT de-escalation (switch from prasugrel to clopidogrel) or to control group (uniform prasugrel), we compared clinical outcomes of patients (n = 151) who received a BVS during the index PCI. The frequency of the primary endpoint (cardiovascular death, myocardial infarction, stroke or BARC ≥ 2 bleeding) was 8.8% (n = 6) in the de-escalation group vs. 12.0% (n = 10) in the control group (HR 0.72, 95% CI 0.26-1.98, p = 0.52) at 12 months. One early definite stent thrombosis (ST) occurred in the control group (day 19) and 1 possible ST (sudden cardiovascular death) in the de-escalation group (day 86), both despite prasugrel treatment and in a background of high on-treatment platelet reactivity assessed at day 14 after randomization (ADP-induced platelet aggregation values of 108 U and 59 U, respectively). A PFT-guided DAPT de-escalation strategy could potentially be a safe and effective strategy in ACS patients with BVS implantation but the level of platelet inhibition may be of particular importance. This hypothesis-generating post-hoc analysis requires verification in larger studies with upcoming BVS platforms.

Platelet P2Y 12 receptors play a key role in platelet activation and thrombus formation. Accordingly, P2Y 12 receptor antagonists are the cornerstone of secondary prevention of atherothrombotic events in patients undergoing percutaneous coronary intervention (PCI). The availability of different oral P2Y 12 antagonists (clopidogrel, prasugrel, ticagrelor) along with the introduction of the first intravenous P2Y 12 antagonist cangrelor offer an opportunity to individualize antiplatelet therapy according to the changing clinical setting. The recent International Expert Consensus provided the first recommendations on switching between the P2Y 12 antagonists. While the consensus greatly helps to guide switching between P2Y 12 antagonists, a number of controversial clinical scenarios remain where the evidence regarding the optimal switch strategy is scarce. In such clinical scenarios, understanding of the (i) pharmacological properties of P2Y 12 antagonists, (ii) recent evidence from pharmacodynamics studies, clinical trials and registries, and (iii) factors affecting the efficacy and safety of the P2Y 12 antagonists, all summarized below, are crucial to choose the optimal switch strategy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Activated platelets release platelet extracellular vesicles (PEVs). Adenosine diphosphate (ADP) receptors P2Y1 and P2Y12 both play a role in platelet activation, The present hypothesis herein is that the inhibition of these receptors may affect the release of PEVs., Methods: Platelet-rich plasma from 10 healthy subjects was incubated with saline, P2Y1 antagonist MRS2179 (100 μM), P2Y12 antagonist ticagrelor (1 μM), and a combination of both antagonists. Platelets were activated by ADP (10 μM) under stirring conditions at 37°C. Platelet reactivity was assessed by impedance aggregometry. Concentrations of PEVs- (positive for CD61 but negative for P-selectin and phosphatidylserine) and PEVs+ (positive for all) were determined by a state-of-the-art flow cytometer. Procoagulant activity of PEVs was measured by a fibrin generation test., Results: ADP-induced aggregation (57 ± 13 area under curve {AUC] units) was inhibited 73% by the P2Y1 antagonist, 86% by the P2Y12 antagonist, and 95% when combined (p < 0.001 for all). The release of PEVs- (2.9 E ± 0.8 × 10⁸/mL) was inhibited 48% in the presence of both antagonists (p = 0.015), whereas antagonists alone were ineffective. The release of PEVs+ (2.4 ± 1.6 × 10⁷/mL) was unaffected by the P2Y1 antagonist, but was 62% inhibited by the P2Y12 antagonist (p = 0.035), and 72% by both antagonists (p = 0.022). PEVs promoted coagulation in presence of tissue factor., Conclusions: Inhibition of P2Y1 and P2Y12 receptors reduces platelet aggregation and affects the release of distinct subpopulations of PEVs. Ticagrelor decreases the release of procoagulant PEVs from activated platelets, which may contribute to the observed clinical benefits in patients treated with ticagrelor.

Introduction: Bleeding is an independent risk factor of mortality in patients with acute coronary syndromes (ACS). BleeMACS project focuses on long-term bleeding events after hospital discharge, thus we evaluated gender-related differences in post-discharge bleeding among patients with ACS., Materials and Methods: We investigated 13,727 ACS patients treated with percutaneous coronary intervention and discharged on dual antiplatelet therapy (either with clopidogrel or prasugrel/ticagrelor). Endpoint was defined as intracranial bleeding or any other bleeding leading to hospitalization and/or red blood transfusion., Results: Post-discharge bleeding was reported more frequently in females as compared with males (3.7% vs. 2.7%, log-rank P = 0.001). Females (n = 3165, 23%) were older compared to men (69.0 vs. 61.5 years, P < 0.001) and with more comorbidities. Hence, in multivariate analysis female sex was not identified as an independent risk factor of bleeding (HR 1.012, CI 0.805 to 1.274, P = 0.816). Administration of newer antiplatelet agents compared to clopidogrel was associated with over twofold greater bleeding rate in females (7.3% vs. 3.5%, log-rank P = 0.004), but not in males (2.6% vs. 2.7%, log-rank P = 0.887). Differences among females remained significant after propensity score matching (7.2% vs 2.4%, log-rank P = 0.020) and multivariate analysis confirmed that newer antiplatelet agents are independent risk factor for bleeding only in women (HR 2.775, CI 1.613 to 4.774, P < 0.001)., Conclusions: Bleeding events occurred more frequently in women, but female sex itself was not independent risk factor. Administration of newer antiplatelet agents was identified as independent risk factor of bleeding after hospital discharge in female gender, but not in male patients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: A poor ability of recommended risk scores for predicting in-hospital bleeding has been reported in elderly patients with acute coronary syndromes (ACS). No study assessed the prediction of post-discharge bleeding in the elderly. The new BleeMACS score (Bleeding complications in a Multicenter registry of patients discharged with diagnosis of Acute Coronary Syndrome), was designed to predict post-discharge bleeding in ACS patients. We aimed to assess the predictive ability of the BleeMACS score in elderly patients., Methods: We assessed the incidence and characteristics of severe bleeding after discharge in ACS patients aged ≥ 75 years. Bleeding was defined as any intracranial bleeding or bleeding leading to hospitalization and/or red blood transfusion, occurring within the first year after discharge. We assessed the predictive ability of the BleeMACS score according to age by Fine-Gray proportional hazards regression analysis, calculating receiver-operating characteristic (ROC) curves and the area under the ROC curves (AUC)., Results: The BleeMACS registry included 15,401 patients of whom 3,376/15,401 (21.9%) were aged ≥ 75 years. Elderly patients were more commonly treated with clopidogrel and less often treated with ticagrelor or prasugrel. Of 3,376 elderly patients, 190 (5.6%) experienced post-discharge bleeding. The incidence of bleeding was moderately higher in elderly patients (hazard ratio [HR], 2.31, 95% confidence interval [CI], 1.92-2.77). The predictive ability of the BleeMACS score was moderately lower in elderly patients (AUC, 0.652 vs. 0.691, p  = 0.001)., Conclusion: Elderly patients with ACS had a significantly higher incidence of post-discharge bleeding. Despite a lower predictive ability in older patients, the BleeMACS score exhibited an acceptable performance in these patients., Competing Interests: None., (Schattauer GmbH Stuttgart.)

A group of Polish experts in cardiology and emergency medicine, encouraged by the European Society of Cardiology (ESC) guidelines, have recently published common recommendations for medical emergency teams regarding the pre-hospital management of patients with acute coronary syndrome. Due to the recent publication of the 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation and 2017 focused update on dual antiplatelet therapy in coronary artery disease the current panel of experts decided to update the previous standpoint. Moreover, new data coming from studies presented after the previous document was issued were also taken into consideration.

Circulating cell-derived microvesicles (MV) represent a subject of increasing interest in recent years as potential effectors in thrombosis, inflammation and vascular injury. Although several studies demonstrated an association between MV plasma concentrations and clinical manifestations of atherosclerosis as well as a clear effect of cardiovascular pharmacotherapy on MV formation pattern, the application of this promising biomarkers in clinical cardiology has been hindered so far due to heterogeneity of the hitherto studies employing non-standardized methodologies. Recently great progresses have been done and international initiatives were started to unify the pre-analytical and analytical procedures, improve the comparison of measurements between the laboratories and increase detector sensitivity of flow cytometry - a golden standard for MV assessment. Likewise, the concept of a "therapeutic window" of P2Y12 inhibitor therapy was introduced, as the prognostic significance of bleeding consequences is equally important with that of ischemic events, particularly with the expanding use of more potent P2Y12 inhibitors. In this review we summarize currently available studies on circulating MV in terms of cardiovascular diagnosis, risk stratification and influence of antiplatelet agents on the MV release to postulate possible future role of MV as supplementary biomarker in monitoring of individual response to antiplatelet therapy. Methodological pitfalls faced in the previous studies and obstacles that need to be addressed before further trials and translation of MV-based assays into clinical practice were defined., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Bleeding events after an acute coronary syndrome have a negative impact on prognosis. Available risk scores are limited by suboptimal accuracy, prediction of only in-hospital events and absence of patients treated with new antiplatelet agents in the current era of widespread use of percutaneous coronary intervention., Design: The BleeMACS (Bleeding complications in a Multicenter registry of patients discharged after an Acute Coronary Syndrome) project is a multicenter investigator-initiated international retrospective registry that enrolled more than 15 000 patients discharged with a definitive diagnosis of acute coronary syndrome and treated with percutaneous revascularization. The primary end point is the incidence of major bleeding events requiring hospitalization and/or red cell transfusion concentrates within 1 year. An integer risk score for bleeding within the first year after hospital discharge will be developed from a multivariate competing-risks regression., Conclusion: The BleeMACS registry collaborative will allow development and validation of a risk score for prediction of major bleeding during follow-up for patients receiving contemporary therapies for acute coronary syndrome.

The objective of this study was to investigate whether rare missense genetic variants in several genes related to platelet functions and acetylsalicylic acid (ASA) response are associated with the platelet reactivity in patients with diabetes type 2 (T2D) on ASA therapy. Fifty eight exons and corresponding introns of eight selected genes, including PTGS1, PTGS2, TXBAS1, PTGIS, ADRA2A, ADRA2B, TXBA2R, and P2RY1 were re-sequenced in 230 DNA samples from T2D patients by using a pooled PCR amplification and next-generation sequencing by Illumina HiSeq2000. The observed non-synonymous variants were confirmed by individual genotyping of 384 DNA samples comprising of the individuals from the original discovery pools and additional verification cohort of 154 ASA-treated T2DM patients. The association between investigated phenotypes (ASA induced changes in platelets reactivity by PFA-100, VerifyNow and serum thromboxane B2 level [sTxB2]), and accumulation of rare missense variants (genetic burden) in investigated genes was tested using statistical collapsing tests. We identified a total of 35 exonic variants, including 3 common missense variants, 15 rare missense variants, and 17 synonymous variants in 8 investigated genes. The rare missense variants exhibited statistically significant difference in the accumulation pattern between a group of patients with increased and normal platelet reactivity based on PFA-100 assay. Our study suggests that genetic burden of the rare functional variants in eight genes may contribute to differences in the platelet reactivity measured with the PFA-100 assay in the T2DM patients treated with ASA.

Background and Aim: High platelet reactivity (HPR) and presence of CYP2C19 loss-of-function alleles are associated with higher risk for periprocedural myocardial infarction in clopidogrel-treated patients undergoing percutaneous coronary intervention (PCI). It is unknown whether personalised treatment based on platelet function testing or genotyping can prevent such complications., Methods: The ONSIDE-TEST is a multicentre, prospective, open-label, randomised controlled clinical trial aiming to assess if optimisation of antiplatelet therapy based on either phenotyping or genotyping is superior to conventional care. Patients will be randomised into phenotyping, genotyping, or control arms. In the phenotyping group, patients will be tested with the VerifyNow P2Y12 assay before PCI, and patients with a platelet reactivity unit greater than 208 will be switched over to prasugrel, while others will continue on clopidogrel therapy. In the genotyping group, carriers of the *2 loss-of-function allele will receive prasugrel for PCI, while wild-type subjects will be treated with clopidogrel. Patients in the control arm will be treated with standard-dose clopidogrel. The primary endpoint of the study is the prevalence of periprocedural myocardial injury within 24 h after PCI in the controls as compared to the phenotyping and genotyping group. Secondary endpoints include cardiac death, myocardial infarction, definite or probable stent thrombosis, or urgent repeat revascularisation within 30 days of PCI. Primary safety outcome is Bleeding Academic Research Consortium (BARC) type 3 and 5 bleeding during 30 days of PCI., Summary: The ONSIDE TEST trial is expected to verify the clinical utility of an individualised antiplatelet strategy in preventing periprocedural myocardial injury by either phenotyping or genotyping., Trial Registration: ClinicalTrials.gov: NCT01930773.

Introduction: Transcatheter aortic valve implantation (TAVI) is associated with bleeding that increases mortality. Dual antiplatelet therapy (DAPT) is recommended in TAVI, however little is known about pre-procedural DAPT use and its impact on hemostasis. We sought to determine the frequency, predictors and bleeding events in patients receiving DAPT before TAVI., Methods: Three-hundred-and-three (n=303, 78.6±7.6years, 49% female, EuroScore 23.1±16.9) consecutive patients undergoing TAVI were prospectively analyzed and followed for in-hospital events. According to pre-procedural antiplatelet status study population was divided into 2 groups: patients receiving aspirin and clopidogrel (DAPT) and those on aspirin only or no antiplatelet therapy (noDAPT)., Results: Pre-procedural DAPT was used in 139 cases (46%). Previous PCI (OR 4.8, [2.8-8.3], p<0.0001), implantation of self-expandable prosthesis (OR 2.2, [1.2-4], p=0.007) femoral access (OR 2.2, [1.1-4.5], p=0.029) and platelet count (OR 1.006, [1.002-1.01], p=0.002) were identified as independent predictors of pre-procedural DAPT. No difference was observed in the rates of any bleeding (23% in DAPT vs. 24.4% in noDAPT, p=0.930) or major/life-threatening bleeding (12.2% in DAPT vs. 14.7% in noDAPT, p=0.715). Propensity-score matching analysis did not alter the results. GFR <30ml/min was the strongest predictor of bleeding (OR 4.3, [1.9-9.9], p=0.0005). There was a trend towards lower frequency of MI and stroke/TIA in DAPT as compared with noDAPT (3.6% vs. 9.8%, p=0.082)., Conclusions: Pre-procedural DAPT is frequent and does not increase short-term bleeding complications or need for transfusion following TAVI. Possible impact of DAPT use before TAVI on ischemic complications needs to be investigated in larger populations., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background and Objectives: While evidence in support of aspirin use in secondary prevention is well documented, the role of aspirin in primary prevention remains unclear. We conducted a systematic literature review to evaluate aspirin use in cardiovascular disease (CVD) and cancer primary prevention, and consider whether aspirin's role is set to become more clearly defined based on past and prospective studies., Data Sources: Utilizing PubMed, the reviewers identified appropriate Medical Subject Headings (MeSH) terms to establish CVD-based studies, cancer-based studies, and studies on adherence., Study Eligibility Criteria: Date restrictions of May 31, 2008 to May 31, 2013 were applied to capture the most robust meta-analyses and randomized controlled trials. Websites of relevant EU and US scientific societies were used to identify the key guidelines for aspirin use in primary prevention of CVD, and ClinicalTrials.gov was used to establish future or ongoing trials., Results: Evidence in support of aspirin prophylaxis is conflicting, though some meta-analyses have underlined potential benefit in reducing cardiovascular events. Despite this apparent benefit, bleeding risk with aspirin is consistently higher versus control, and remains a concern. A reduction of cancer incidence and mortality after a least 3 and 5 years treatment, respectively, is also apparent with aspirin., Conclusion: Available data on aspirin in primary prevention suggest a modest benefit for patients at high risk of CVD, and a promising benefit for those at risk of cancer. Future studies should help to elucidate whether the benefit of aspirin outweighs risk in appropriate patient groups.

The objective of this study was to use genome-wide association approach and pooled DNA strategy to search for new genomic loci associated with inter-individual differences in platelet reactivity in the diabetic patients during acetylsalicylic acid (ASA) treatment. Study cohort consisted of 297 diabetic patients who had been taking ASA (75 mg daily) for at least 3 months. We tested association of single nucleotide polymorphisms (SNPs) genotyped using high density microarray platform with several platelet reactivity assays, followed by individual genotyping of most significant SNPs identified in the microarray genomic scan. The highest statistical significance (p value of 0.0001-0.008 in individual genotyping) was observed for SNP located within the regulatory G-protein signaling (RGS) 7 gene (rs2502448) using recessive genetic model. The diabetic patients on ASA treatment and homozygotes for its minor allele were characterized by increased odds ratio of at 3.45 (confidence interval: 1.82-6.53) for high on ASA platelet reactivity (i.e. impaired ASA response) when compared with homozygotes for wild-type allele. The genome-wide approach might provide an opportunity to identify novel candidate genes and pathways related to platelet activation in diabetic patients.

Bleeding negatively affects prognosis and adherence to antiplatelet therapy after acute coronary syndromes (ACSs). The potential association of on-aspirin platelet reactivity and bleeding is not established. We sought to determine whether low on-aspirin platelet reactivity (LAPR) is associated with bleeding events and antiplatelet therapy compliance in patients with ACSs receiving coronary stenting. On-aspirin platelet reactivity was measured by the VerifyNow™ Aspirin assay (Accumetrics Inc., San Diego, CA, USA) in 531 patients with ACS. Cut-offs for LAPR were calculated by receiver-operating characteristic curve (ROC) analysis. Bleeding was reported according to Bleeding Academic Research Consortium (BARC) definition. The endpoints were minor bleeding (BARC types 1 or 2), major bleeding (BARC types 3 or 5) and antiplatelet therapy cessation during 6-months follow-up. By ROC analysis the VerifyNow™ Aspirin assay was able to distinguish between patients with and without minor bleeding (area under the curve [AUC] 0.66, 95 % confidence interval [CI] 0.62-0.70, P < 0.0001) whereas major bleeding could not be predicted by the assay (AUC 0.54, 95 % CI 0.49-0.58, P = 0.473). By logistic regression, LAPR was associated with increased risk of minor bleeding (odds ratio [OR] 4.32, 95 % CI 2.78-6.71, P < 0.0001) but not major bleeding (OR 2.05, 95 % CI 0.83-5.06, P = 0.117). Antiplatelet therapy discontinuation was more frequent in patients with LAPR as compared to those with no LAPR (21.6 vs. 9.1 %, P = 0.0008). In conclusion, early point-of-care on-aspirin platelet reactivity testing in ACS may identify patients with increased risk of minor bleeding events and subsequent discontinuation of antiplatelet therapy. The possible impact of LAPR on major bleeding needs to be determined in larger trials.

Background: The aim of the study was to compare the effects of 2 strategies of antiplatelet treatment (i.e., 150 mg ASA vs. 75 mg clpoidogrel) on plasma level of inflammatory markers in type 2 diabetes mellitus (T2DM) patients with high platelet reactivity (HPR)., Methods: Study cohort consisted of 304 T2DM patients on chronic ASA therapy (75 mg per day) participating in the Aspirin Versus/Or Clopidogrel in Aspirin-resistant Diabetics inflammation Outcomes (AVOCADO) study. Patients with HPR defined as Platelet Function Analyzer (PFA)-100 collagene/epinephrine closure time (CEPI-CT) < 193 s (n = 80) were randomized to 150 mg of ASA or 75 mg of clopidogrel in 2:3 ratio, respectively. Concentrations of the selected inflammatory markers, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, solubleCD40 ligand (sCD40L), and high sensitivity C-reactive protein (hsCRP), were measured and compared in both treatment groups before and after 8 weeks of treatment in both groups., Results: Out of 234 patients included into final analysis, the total of 34.2% (n = 80) patients displayed HPR, of which 14.1% (n = 33) were randomized into 150 mg of ASA group and 20.1% (n = 47) into 75 mg of clopidogrel group. Treatment with clopidogrel was a positive predictor (stepwise multiple regression analysis) of reduction of sCD40L concentration (odds ratio [OR] 4.15; p = 0.013), while treatment with 150 mg ASA was a positive predictor of reduction of IL-6 concentration (OR 4.38; p = 0.033). There was no statistically significant differences between clopidogrel and ASA 150 mg treatment in respect to predictive value for decreased hsCRP concentrations or increased TNF-α concentrations., Conclusions: Increasing the dose of ASA from 75 mg to 150 mg daily or switching ASA 75 mg to clopidogrel 75 mg daily may reduce concentrations of some inflammatory markers (in particular hsCRP, IL-6 and CD40L) in T2DM patients with HPR treated previously with 75 mg of ASA.

Background: The objective of this study was to investigate the association between plasma concentrations of salicylic acid (SA) and other minor acetylsalicylic acid (ASA) metabolites and high on ASA platelet reactivity assessed with different methods in type 2 diabetic patients (T2DM)., Methods: Study cohort consisted of 293 T2DM patients on chronic ASA therapy. Platelet function inhibition was analyzed using measurements of serum thromboxane B2 (S-TxB2), VerifyNow Aspirin and Platelet Function Analyzer (PFA)-100 assays. The concentration of ASA metabolites in plasma was measured with a high-performance liquid chromatography (HPLC)., Results: In logistic regression analysis both ASA dose/kg of body weight and plasma SA concentration were found to be predictive of S-TxB2 concentrations above 0.72 ng/mL cut-off point (OR 16.9, 95% CI 2.29-125.8, p = 0.006 and OR 5.34, 95% CI 2.67-10.68, p < 0.001, respectively). When using the VerifyNow Aspirin Assay, the concentrations of SA were significantly lower (p = 0.007) in the group with high on ASA platelet reactivity when compared with the group with normal on ASA platelet reactivity. In logistic regression analysis plasma SA concentration was found to be predictive of VerifyNow Aspirin Reaction Units (ARU) ≥ 550 (OR 3.86, 95% CI 1.86-8.00, p < 0.001)., Conclusions: Our study suggests that disturbances of pharmacokinetic mechanisms might contribute to lower plasma SA levels, and subsequently incomplete inhibition of thromboxane A2 synthesis as measured with S-TxB2 concentrations and increased platelet reactivity measured with VerifyNow in T2DM patients.

Background and Aim: Retrospective evaluation of stroke risk in all patients with atrial fibrillation (AF) admitted to cardiology, internal medicine, and neurology wards in a single Polish district hospital in 2006 and 2010 using two risk stratification schemes, CHADS₂ vs. CHA₂DS₂VASc risk scores and identification of independent predictors of guideline-compliant oral anticoagulant (OAC) treatment., Methods: We analysed case records of 613 patients with AF (including 300 patients in 2006 and 313 patients in 2010) treated in a district hospital - the John Paul II Western Hospital (Szpital Zachodni) in Grodzisk Mazowiecki, to evaluate their stroke risk and therapy prescribed at discharge., Results: The mean patient age in the overall study population (49% of men) was 74.3 years (74.8, 77.5, and 71.9 years, respectively, in patients with paroxysmal, permanent and persistent AF). Patients > 75 years old comprised 58.6% of the study group, and those < 65 years old comprised 16.6% of the study group. The most common concomitant diseases were hypertension (65.9%), chronic heart failure (61.7%), coronary artery disease (43.1%), at least moderate mitral and/or tricuspid regurgitation (36.4%), and peripheral arterial disease (36%). Indications for OAC treatment were present in 85% (using the CHADS₂ score) or 95% (using the CHA₂DS₂VASc score) patients but this therapy was prescribed at discharge in only 39% of the study group (240 patients). Compared to patients who were not prescribed OAC, those prescribed OAC treatment were younger, more often male, with permanent AF, valvular heart disease, and hypertension. In patients without OAC treatment at discharge, the following conditions were found more frequently than in patients prescribed OAC treatment: paroxysmal AF(49.8% vs. 33.3% in OAC patients), established coronary artery disease (46.1% vs. 38.3%), previous myocardial infarction (27%vs. 18.7%), prior coronary revascularisation (11.2% vs. 6.6%), alcohol abuse (4.2% vs. 0.8%), renal failure (31.6% vs. 21.6%), and stroke or transient ischaemic attack (TIA; 19.3% vs. 12%). In multivariate logistic regression analysis, we identified 5 independent predictive factors associated with prescribing OAC at discharge, including persistent AF vs. paroxysmal AF (odd sratio [OR] = 5.27), permanent AF vs. paroxysmal AF (OR = 1.86), hypertension (OR = 1.50), previous stroke and/or TIA (OR = 0.59), and age > 75 years vs. < 65 years (OR = 0.53)., Conclusions: Despite a high stroke risk as determined by both scores, only 39% of patients received OAC. In the studied population, independent predictors for prescribing OAC at discharge included arterial hypertension (in accordance with the guidelines) and younger patient age, no history of stroke/TIA, and AF other than paroxysmal. The practice of OAC and/or antiplatelet therapy use in AF patients discharged from a Polish district hospital was not compliant with the current ESC guidelines either in 2006 or in 2010.

Background: Diabetes mellitus type 2 (DM2) is associated with high platelet reactivity both in patients who do not receive antiplatelet drugs and in those treated with acetylsalicylic acid (ASA). The pathomechanism of this phenomenon has not been fully understood., Aim: 1. To evaluate variability of platelet reactivity in patients with DM2 treated with oral antidiabetic drugs and receiving chronic ASA therapy. 2. To identify independent predictors of high platelet reactivity during ASA therapy in patients with DM2., Methods: We studied 171 patients with DM2 treated with oral antidiabetic drugs and receiving long-term treatment with 75 mg of ASA daily, selected among the participants of the prospective AVOCADO study. Platelet function was simultaneously evaluated using 4 methods: 1. measurement of serum thromboxane B2 (TXB2) concentration; 2. measurement of urinary 11-dehydrothromboxane B2 (11-dhTXB2) concentration; 3. VerifyNow® automated analyser; 4. PFA-100® automated analyser.High platelet reactivity was defined as at least 3 of the following criteria: 1. serum TXB2 concentration in the upper quartile;2. urinary 11-dhTXB2 concentration in the upper quartile; 3. value ≥ 550 aspirin reaction units (ARU) by VerifyNow®;4. collagen-epinephrine closure time (CEPI-CT) below median of readings other than 300 s by PFA-100®. In all patients, DM2 control was evaluated, insulin resistance was measured using HOMA-IR, and routine laboratory tests were performed, including full blood count, renal function parameters, and inflammation markers., Results: Mean patient age was 67.8 years, and median duration of DM2 was 5 years. We found poor agreement between different tests of platelet function. ARU ≥ 550 (VerifyNow®) was found in 14.0% of patients, and CEPI-CT below median of readings other than 300 s (PFA-100®) was found in 32.8% of patients. Our criteria of high platelet reactivity were met by 9.9% of patients. In multivariate logistic regression analysis, independent predictors of high platelet reactivity despite ASA therapy included chronic heart failure, current smoking, and higher leukocyte count., Conclusions: 1. Patients with DM2 are characterised by large variability of platelet reactivity, with little agreement between various methods. 2. Smoking, chronic heart failure, and subclinical inflammation may be associated with high platelet reactivity in patients with DM2 treated with ASA.

Background: Type 2 diabetes (T2DM) patients are at increased risk of cardiovascular events despite long-term acetylsalicylic acid (ASA) therapy. This study was performed to establish the prevalence of high platelet reactivity (HPR) on ASA in T2DM and to identify its predictors., Methods: The study included 185 T2DM on chronic ASA therapy and to assess platelet reactivity during long-term ASA therapy, we applied the point-of-care method VerifyNow(®) aspirin test (Accumetrics, San Diego, CA, USA)., Results: Compared with the low platelet reactivity (LPR) group, patients with HPR had higher triglyceride levels (145 vs. 118 mg/dL, p = 0.041), were less frequently treated with statins (57.1% vs. 75.3%; p = 0.038) and tumor necrosis factor-alpha (TNF-α) concentrations were higher (2.15 vs. 1.74 pg/mL; p = 0.052). In a multivariate analysis only statin therapy (OR 0.375; 95% CI 0.15-0.91; P = 0.030) and lower concentrations of TNF-α (for each 1.0 pg/ml: or 1.3; 95% ci 1.00-1.72; p = 0.046) were predictive of LPR., Conclusions: Our study provides indirect evidence that the beneficial effect of statins on platelet activity may be related to their non-lipid-mediated, pleiotropic mechanisms of action. This might have been partly related to decreased platelet reactivity in patients receiving statin therapy. In our study in patients with T2DM, platelet reactivity on ASA therapy measured with VerifyNow(®) was associated with TNF-α concentrations and statin therapy. These results may imply a role for subclinical systemic inflammation and a beneficial effect of statins in the development of HPR in T2DM.

Background: Aspirin (ASA) is an effective antiplatelet drug that reduces the risk of myocardial infarction, stroke, or death by approximately 25% in patients who are at increased risk of cardiovascular events. However, many patients with cardiovascular disease do not respond to ASA treatment and are deemed ASA resistant. The term "ASA resistance" has been used to describe not only the lack of expected pharmacologic effects of ASA on platelets but also poor clinical outcomes, such as recurrent vascular events, in patients treated with ASA., Aim: In this prospective observation of patients with stable coronary artery disease (CAD) who received ASA for secondary prevention, we investigated factors responsible for ASA resistance by determining ASA response using the PFA-100 analyser and evaluating relation of ASA resistance to various studied parameters., Methods: Platelet function tests with the PFA-100 point-of-care system were performed in 92 patients with CAD (mean age 68 +/- 8 years, 36 females) who had been taking 75-150 mg of ASA daily for secondary prevention for at least 3 months. Each patient had an angiographically documented CAD with stable angina. ASA resistance was defined as a normal collagen/epinephrine closure time (CEPI-CT) on the PFA-100 (< or = 150 s). Patients with CT > or = 250 s were defined as ASA responders and patients with CT between 150 and 250 s as semi-responders., Results: Using a collagen/epinephrine-coated cartridge on the PFA-100, the prevalence of platelet inhibition failure was 29%, while 30% of patients were semi-responders. In our study population, adequate response to ASA was found in 40% of patients. In multivariate logistic regression analysis, parameters independently related to platelet inhibition failure included compliance to ASA therapy [odds ratio (OR) 0.8, 95% confidence interval (CI) 0.20-0.35, p = 0.001], total cholesterol/HDL cholesterol level ratio > 2.99 (OR 0.19, 95% CI 0.05-0.81, p = 0.02), and heart rate > 69 bpm (OR 4.44, 95% CI 1.37-14.38, p = 0.01)., Conclusions: In patients with stable CAD, about one third of the subjects were ASA resistant by PFA-100. Our study shows that non-compliance could be one of the most important risk factors responsible for high residual platelet activity in patients with stable CAD taking ASA. Thus, non-compliant patients should be carefully educated about the mechanism of action of this drug to understand the necessity and long-term benefits of treatment with ASA.

Oral antiplatelet drugs are a cornerstone of modern pharmacotherapy in cardiovascular atherothrombotic diseases. The efficacy of acetylsalicylic acid (ASA, aspirin) and clopidogrel in decreasing the risk of adverse events in coronary heart disease patients has been well established in the past 20 years. Despite chronic oral antiplatelet therapy, a number of atherothombotic events continue to occur. In recent years, a number of reports in the literature have shown possible relationships between residual platelet activity, as measured with a variety of laboratory tests, and clinical outcome, raising the possibility that 'resistance' to oral antiplatelet drugs may underlie many such clinical adverse events. The present position paper, conveyed within a group of clinical cardiologists with expertise in thrombosis appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society, has been further elaborated and endorsed by the Working Group on Thrombosis of the European Society of Cardiology. It aims at summarizing the main findings in this complex area, issuing opinions in cases of high controversy, and fostering future research in this area to obtain reliable laboratory and clinical data for the resolution of the many problems still open.

Objective: Antiplatelet therapy is a class I indication in perioperative care after coronary artery bypass grafting to prevent graft occlusion. We sought to determine whether continuation of aspirin until surgery day suppresses platelet activity in the early period after off-pump coronary artery bypass grafting (OPCAB)., Material and Methods: Forty-two patients at mean age of 62.5 (+/-7.9) years were included. Average risk rate (EuroScore logistic) was 2.2 (+/-1.7) %. In all patients collagen/epinephrine stimulated platelet plug formation (closure time, CT) (CEPI-CT, s) using a platelet function analyzer (PFA-100), troponin I (TnI), creatine kinase-MB (CK-MB), ST segment elevation were evaluated a day before surgery, 4h after chest closure, 24 and 120 h after surgery., Results: Preoperative mean CEPI-CT was 224.8 (+/-79.7)s. In 13 (30%) patients aspirin resistance (CEPI-CT<163 s.) was observed. In 4, 24 and 120 h time points CEPI-CT was significantly reduced: 164.4 (+/-79), 168.5 (+/-83.3) and 167.5 (+/-80.4), respectively (p<0,001). TnI and CK-MB (ng/ml) levels raised in respective time points: 4 h (0.26 range 4; 1.9 range 6), 24 h (0.2 range 6; 2.6 range 8), 120 h (0.04 range 2; 0.6 range 5). ST segment elevation (mV) changed in time: 4h (0.7 range 3.5), 48 h (0.7 range 2.8) and 120 h after surgery (0.2 range 1.5). There were no significant correlations between CEPI-CT and TnI, CK-MB, ST segment elevation found., Conclusion: Aspirin therapy continued until surgery day does not protect against acute platelet activation in patients after OPCAB.

Background: Coexisting polymorphisms of the genes affecting clopiogrel resistance may influence platelet activation., Methods and Results: In 105 patients with acute coronary syndrome (ACS) treated with percutaneous coronary intervention, platelet function was measured and registered as closure time in the test with collagen and adenosine diphosphate (CADP-CT). Patients were followed for 12 months for death or recurrent myocardial infarction (MI). Genotyping revealed 7 carriers of both the C allele of P2Y12 and A allele of CYP2C19 (group 1), 14 carriers of the T allele of P2Y12 and A allele of CYP2C19 (group 2), 17 carriers of the C allele of P2Y12 and G allele of CYP2C19 (group 3) and 67 carriers of the T allele of P2Y12 and G allele of CYP2C19 (controls). The median CADP-CT value was significantly lower in group 1 than in group 2 or 3 (p<0.01) or controls (p<0.002), but did not differ between group 2 or 3 and controls. There were 2 cardiovascular deaths and 4 MI during follow-up, and the median CADP-CT value was lower in these patients (p=0.09)., Conclusions: Coexisting, rather then single, polymorphisms of different genes may be related to persistent platelet activation while on clopidogrel, which raises concern about harm in patients with ACS.

Background: The study was designed to determine whether impaired antiplatelet response to clopidogrel but not to aspirin may be responsible for loss of pleiotropic effects of the drug., Methods: Study included 34 consecutive patients with STEMI undergoing primary percutaneous coronary intervention (PCI) with stent implantation treated with aspirin (loading dose 300 mg followed by 75 mg/day) and clopidogrel (loading dose 600 mg followed by 75 mg/day). On the basis of Platelet Function Analyzer (PFA)-100 test which measured closure times (CT) in test with collagen/epinephrine (CEPI-CT) or collagen/adenosine diphosphate (CADP-CT) patients were stratified after 7 days from admission as full aspirin or clopidogrel responders (CEPI-CT or CADP-CT = 300 sec., respectively) and non-full aspirin or clopidogrel responders (CEPI-CT or CADP-CT < 300 sec., respectively). High sensitivity C-reactive protein (hs-CRP) was measured at baseline and after 7 days of treatment., Results: All patients received comparable statin treatment. Median and interquartile ranges (IQR) of hs-CRP increased significantly from 2.5 mg/L (0.4-44.8) at baseline to 8.05 mg/L (1.4-33.9) at day 7 (P = .002) in non-full clopidogrel responders subgroup and only slightly in the full clopidogrel responders subgroup (2.45 mg/L, IQR 0.4-48.3 vs. 4.2 mg/L, IQR 1.9-17.5) (P = .3) remaining within reference intervals. On the contrary median and IQR of hs-CRP increased significantly in both non-full aspirin responders (2.4 mg/L, IQR 1.3-3.3 vs. 5.8 mg/L, IQR 3.2-14.8, P = .01) and full aspirin responders (2.9 mg/L, IQR 2.0-3.7 vs. 5.6 mg/L, IQR 4.3-12.9, P = .04)., Conclusions: Impaired antiplatelet response to clopidogrel but not to aspirin may contribute to smaller anti-inflammatory response in patients with ST-elevation myocardial infarction.

Introduction: Persistent platelet function while on antiplatelet therapy affects outcomes in patients with acute coronary syndromes (ACS)., Aim: To evaluate whether platelet reactivity measured by collagen-epinephrine (CEPI) or collagen-ADP (CADP) closure times (CT) with Platelet Function Analyzer 100 (PFA-100) is related to very early, in-hospital cardiovascular events in patients with ACS., Methods: The study included 91 patients with ACS undergoing percutaneous coronary intervention (PCI) with stent implantation who were treated with aspirin and clopidogrel. Patients were stratified in accordance with both CEPI-CT (<190 s or >190 s), reflecting aspirin resistance, and our own cut-off point for CADP-CT measured at a mean of 6 days after admission. In-hospital events included re-infarction, cardiac arrest, recurrent angina, severe arrythmias, pulmonary oedema and cardiogenic shock., Results: Patients were divided into 4 study groups: group 1 with CADP-CT <104 s (n=10, 11.0%), group 2 with CEPI-CT <190 s (n=10, 11.0%), group 3 with CADP-CT <104 s and CEPI-CT <190 s (n=9, 9.9%) and a control group with both CT values above the cut-off limits (n=62, 68.1%). The baseline clinical characteristics and received treatment of each subgroup were similar. A test for a trend between controls, group 1 or 2 and group 3 disclosed statistical significance (p <0.001). When analysed separately, only patients from group 3 had a higher incidence of negative outcomes compared to controls (p <0.005; relative risk RR - 9.0; 95% CI 2.4-33.9)., Conclusions: Enhanced platelet function after PCI when measured under high shear rates by both PFA-100 cartridges is independently associated with the most unfavourable in-hospital clinical outcome.