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Background: Triple antithrombotic therapy (TAT) with aspirin, a P2Y 12 inhibitor, and oral anticoagulation in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) raises concerns about increased bleeding. Regimens incorporating more potent P2Y 12 inhibitors over clopidogrel have not been investigated adequately., Research Design and Methods: A retrospective observational study was performed on 387 patients with AF receiving TAT for 1 month ( n  = 236) or ≤1 week ( n  = 151) after PCI. Major and clinically relevant non-major bleeding and major adverse cardiac and cerebrovascular events (MACCE) were assessed up to 30 days post-procedure., Results: Bleeding was less frequent with ≤1 week versus 1 month of TAT (3.3 vs 9.3%; p  = 0.025) while MACCE were similar (4.6 vs 4.7%; p  = 0.998). No differences in bleeding or MACCE were observed between ticagrelor/prasugrel and clopidogrel regimens. For patients receiving ≤1 week of TAT, no excess of MACCE was seen in the subgroup given no further aspirin post-PCI compared with those given aspirin for up to 1 week (3.6 vs 5.2%)., Conclusions: TAT post-PCI for ≤1 week was associated with less bleeding despite greater use of ticagrelor/prasugrel but similar MACCE versus 1-month TAT. These findings support further studies on safety and efficacy of dual therapy with ticagrelor/prasugrel immediately after PCI.

Inflammation plays a key role in cardiovascular disease by contributing to atherothrombosis. The PLATelet inhibition and patient Outcomes (PLATO) study (NCT00391872) compared ticagrelor to clopidogrel in patients with acute coronary syndromes and demonstrated fewer cardiovascular events with ticagrelor but lower white blood cell counts (WBC) with clopidogrel. In this further analysis of the PLATO biomarker substudy, we assessed associations between WBC and clinical characteristics, biomarker levels, and CYP2C19 polymorphisms.On-treatment mean (SD) WBC in the clopidogrel group was mildly reduced at each stage of follow-up compared with either the ticagrelor group (1 month: 7.27 (2.1) and 7.67 (2.23) x10 9 /L for clopidogrel and ticagrelor, respectively; p < .001) or following cessation of clopidogrel (7.23 (1.97) x10 9 /L, at 6 months vs 7.56 (2.28) x10 9 /L after treatment cessation; P < .001). This occurred independently of baseline biomarkers and CYP2C19 genotype (where known). Adjusting for clinical characteristics and other biomarkers, no significant interaction was detected between clinical risk factors and the observed effect of clopidogrel on WBC.Clopidogrel weakly suppresses WBC, independent of clinical characteristics, baseline inflammatory biomarker levels, and CYP2C19 genotype. Further work is required to determine the mechanism for this effect and whether it contributes to clopidogrel's efficacy as well as therapeutic interaction with anti-inflammatory drugs.

Purpose: Describe CYP2C19 sequencing results in the largest series of clopidogrel-treated cases with stent thrombosis (ST), the closest clinical phenotype to clopidogrel resistance. Evaluate the impact of CYP2C19 genetic variation detected by next-generation sequencing (NGS) with comprehensive annotation and functional studies., Methods: Seventy ST cases on clopidogrel identified from the PLATO trial (n = 58) and Mayo Clinic biorepository (n = 12) were matched 1:1 with controls for age, race, sex, diabetes mellitus, presentation, and stent type. NGS was performed to cover the entire CYP2C19 gene. Assessment of exonic variants involved measuring in vitro protein expression levels. Intronic variants were evaluated for potential splicing motif variations., Results: Poor metabolizers (n = 4) and rare CYP2C19*8, CYP2C19*15, and CYP2C19*11 alleles were identified only in ST cases. CYP2C19*17 heterozygote carriers were observed more frequently in cases (n = 29) than controls (n = 18). Functional studies of CYP2C19 exonic variants (n = 11) revealed 3 cases and only 1 control carrying a deleterious variant as determined by in vitro protein expression studies. Greater intronic variation unique to ST cases (n = 169) compared with controls (n = 84) was observed with predictions revealing 13 allele candidates that may lead to a potential disruption of splicing and a loss-of-function effect of CYP2C19 in ST cases., Conclusion: NGS detected CYP2C19 poor metabolizers and paradoxically greater number of so-called rapid metabolizers in ST cases. Rare deleterious exonic variation occurs in 4%, and potentially disruptive intronic alleles occur in 16% of ST cases. Additional studies are required to evaluate the role of these variants in platelet aggregation and clopidogrel metabolism.

Background: Despite increased atherothrombotic risk in type 2 diabetes mellitus, (T2DM) the best preventative antithrombotic strategy remains undetermined. We defined the effects of three antiplatelet agents on functional readout and biomarker kinetics in platelet activation and coagulation in patients with T2DM., Materials and Methods: 56 patients with T2DM were randomised to antiplatelet monotherapy with aspirin 75 mg once daily (OD), clopidogrel 75 mg OD or prasugrel 10 mg OD during three periods of a crossover study. Platelet aggregation (PA) was determined by light-transmittance aggregometry and P-selectin expression by flow cytometry. Markers of fibrin clot dynamics, inflammation and coagulation were measured. Plasma levels of 14 miRNA were assessed by quantitative polymerase chain reactions., Results: Of the 56 patients, 24 (43%) were receiving aspirin for primary prevention of ischaemic events and 32 (57%) for secondary prevention. Prasugrel was the strongest inhibitor of ADP-induced PA (mean ± SD maximum response to 20μmol/L ADP 77.6 ± 8.4% [aspirin] vs. 57.7 ± 17.6% [clopidogrel] vs. 34.1 ± 14.1% [prasugrel], p < 0.001), P-selectin expression (30 μmol/L ADP; 45.1 ± 21.4% vs. 27.1 ± 19.0% vs. 14.1 ± 14.9%, p < 0.001) and collagen-induced PA (2 μg/mL; 62.1 ± 19.4% vs. 72.3 ± 18.2% vs. 60.2 ± 18.5%, p < 0.001). Fibrin clot dynamics and levels of coagulation and inflammatory proteins were similar. Lower levels of miR-24 (p = 0.004), miR-191 (p = 0.019), miR-197 (p = 0.009) and miR-223 (p = 0.014) were demonstrated during prasugrel-therapy vs. aspirin. Circulating miR-197 was lower in those cardiovascular disease during therapy with aspirin (p = 0.039) or prasugrel (p = 0.0083)., Conclusions: Prasugrel monotherapy in T2DM provided potent platelet inhibition and reduced levels of a number of platelet-associated miRNAs. miR-197 is a potential marker of cardiovascular disease in this population. Clinical outcome studies investigating prasugrel monotherapy are warranted in individuals with T2DM. Trial registration EudraCT, 2009-011907-22. Registered 15 March 2010, https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-011907-22/GB.

Background:  Glycoprotein IIb/IIIa inhibitors (GPIs) in combination with clopidogrel improve clinical outcome in ST-elevation myocardial infarction (STEMI); however, finding a balance that minimizes both thrombotic and bleeding risk remains fundamental. The efficacy and safety of GPI in addition to ticagrelor, a more potent P2Y12-inhibitor, have not been fully investigated., Methods:  1,630 STEMI patients who underwent primary percutaneous coronary intervention (PCI) were analyzed in this subanalysis of the ATLANTIC trial. Patients were divided in three groups: no GPI, GPI administration routinely before primary PCI, and GPI administration in bailout situations. The primary efficacy outcome was a composite of death, myocardial infarction, urgent target revascularization, and definite stent thrombosis at 30 days. The safety outcome was non-coronary artery bypass graft (CABG)-related PLATO major bleeding at 30 days., Results:  Compared with no GPI ( n  = 930), routine GPI ( n  = 525) or bailout GPI ( n  = 175) was not associated with an improved primary efficacy outcome (4.2% no GPI vs. 4.0% routine GPI vs. 6.9% bailout GPI; p  = 0.58). After multivariate analysis, the use of GPI in bailout situations was associated with a higher incidence of non-CABG-related bleeding compared with no GPI (odds ratio [OR] 2.96, 95% confidence interval [CI] 1.32-6.64; p  = 0.03). However, routine GPI use compared with no GPI was not associated with a significant increase in bleeding (OR 1.78, 95% CI 0.88-3.61; p  = 0.92)., Conclusion:  Use of GPIs in addition to ticagrelor in STEMI patients was not associated with an improvement in 30-day ischemic outcome. A significant increase in 30-day non-CABG-related PLATO major bleeding was seen in patients who received GPIs in a bailout situation., Competing Interests: A.W.J.v.‘t H. reports institutional fees and nonfinancial support from AstraZeneca and grants from Medtronic. C.W.H. reports institutional fees and personal fees from AstraZeneca. R.F.S. reports institutional research grants from AstraZeneca and PlaqueTec; consultancy fees from AstraZeneca, Avacta, Bayer, Bristol Myers Squibb/Pfizer, Haemonetics, Idorsia, Novartis, PlaqueTec, and Thromboserin; and honoraria from AstraZeneca and Bayer. J.F.L. reports unrestricted grants from Medtronic, Abbott, Boston Scientific, Biotronik, and Terumo. A.C. reports institutional research grants from Abbott Vascular, Boston Scientific, Cordis, Medtronic, and Orbus Neich, and consulting/lecture fees from Abbott Vascular, AstraZeneca, Biotronik, Ferrer International, Medtronic, and Terumo. U.Z. reports grants and personal fees from AstraZeneca during the conduct of the study, personal fees from Bayer, grants and personal fees from BMS, grants and personal fees from Daiichi Sankyo, personal fees from Boehringer Ingelheim, personal fees from Medicines Company, personal fees from Sanofi, grants and personal fees from Novartis, outside the submitted work. M.J. reports lecture fees from AstraZeneca and Pfizer. K.H. reports lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Sanofi Aventis, and the Medicines Company. J.S. reports the following disclosures during the past two years: Consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, CSL Behring, Gilead Science, and Sanofi-Aventis; Speaker honorariums from AstraZeneca, Amgen, Bayer, Algorythm, and Sanofi-Aventis; and travel supports form Amgen, AstraZeneca, Bayer, and Bristol-Myer Squibb. S.G.G. has received research grant support and/or speaker/consulting honoraria from AstraZeneca, Bayer Bristol Myers Squibb, Daiichi-Sankyo, Eli Lilly, Fenix Group Internation, and Sanofi. L.B. reports lecture fees from AstraZeneca, Bayer, Amgen, Daiichi Sankyo, and Sanofi Aventis., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Heart failure (HF) following acute coronary syndromes (ACS) is associated with worse prognosis; however, the efficacy and safety of ticagrelor in patients with HF and if ticagrelor influences the risk of new-onset HF are unknown., Methods: We examined the efficacy and safety of ticagrelor compared to clopidogrel in patients with ACS in the randomized PLATelet inhibition and patient Outcomes (PLATO) trial subdivided by strata: (1) previous HF and/or clinical signs of HF on admission or (2) no HF on admission. The primary outcome was the combination of cardiovascular death, myocardial infarction, or stroke evaluated by multivariable Cox regression models. The safety outcome was major bleeding. New-onset HF was defined as an HF event after discharge in patients without previous HF., Results: Data were available in 18,556 patients, whom 2,862 (15.4%) patients had HF, including 1,584 (8.5%) patients with previous HF. Patients randomized to ticagrelor had lower risk of the composite end point regardless of HF status: hazard ratio (HR) 0.87 (95% CI: 0.73-1.03) in patients with HF and HR 0.84 (95% CI: 0.75-0.93) in patients with no HF (P = .76). Corresponding HR for major bleeding were HR 1.08 (95% CI: 0.87-1.34) and HR 1.03 (95% CI: 0.94-1.14) (P = .71). There was no difference in new-onset HF at 12 months between patients randomized to ticagrelor (4.1%, n = 278) or clopidogrel (4.0%, n = 276)., Conclusions: In patients with ACS, ticagrelor is more efficacious in protecting against new ischemic events and mortality than clopidogrel irrespective of the presence of HF. There is no difference between ticagrelor or clopidogrel treatment in new-onset HF post-ACS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background There are limited data on how the combination of diabetes mellitus ( DM ) and chronic kidney disease ( CKD ) affects cardiovascular outcomes as well as response to different P2Y 12 receptor antagonists, which represented the aim of the present investigation. Methods and Results In this post hoc analysis of the PLATO (Platelet Inhibition and Patient Outcomes) trial, which randomized acute coronary syndrome patients to ticagrelor versus clopidogrel, patients (n=15 108) with available DM and CKD status were classified into 4 groups: DM +/ CKD + (n=1058), DM +/ CKD - (n=2748), DM -/ CKD + (n=2160), and DM -/ CKD - (n=9142). The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke at 12 months. The primary safety end point was PLATO major bleeding. DM +/ CKD + patients had a higher incidence of the primary end point compared with DM -/ CKD - patients (23.3% versus 7.1%; adjusted hazard ratio 2.22; 95% CI 1.88-2.63; P<0.001). Patients with DM +/ CKD - and DM -/ CKD + had an intermediate risk profile. The same trend was shown for the individual components of the primary end point and for major bleeding. Compared with clopidogrel, ticagrelor reduced the incidence of the primary end point consistently across subgroups ( P-interaction=0.264), but with an increased absolute risk reduction in DM +/ CKD +. The effects on major bleeding were also consistent across subgroups ( P-interaction=0.288). Conclusions In acute coronary syndrome patients, a gradient of risk was observed according to the presence or absence of DM and CKD , with patients having both risk factors at the highest risk. Although the ischemic benefit of ticagrelor over clopidogrel was consistent in all subgroups, the absolute risk reduction was greatest in patients with both DM and CKD . Clinical Trial Registration URL : http://www.clinicatrials.gov . Unique identifier: NCT 00391872.

Aims: To determine whether fibrin clot properties are associated with clinical outcomes following acute coronary syndrome (ACS)., Methods and Results: Plasma samples were collected at hospital discharge from 4354 ACS patients randomized to clopidogrel or ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial. A validated turbidimetric assay was employed to study plasma clot lysis time and maximum turbidity (a measure of clot density). One-year rates of cardiovascular (CV) death, spontaneous myocardial infarction (MI) and PLATO-defined major bleeding events were assessed after sample collection. Hazard ratios (HRs) were estimated using Cox proportional hazards models. After adjusting for CV risk factors, each 50% increase in lysis time was associated with CV death/spontaneous MI [HR 1.17, 95% confidence interval (CI) 1.05-1.31; P < 0.01] and CV death alone (HR 1.36, 95% CI 1.17-1.59; P < 0.001). Similarly, each 50% increase in maximum turbidity was associated with increased risk of CV death (HR 1.24, 95% CI 1.03-1.50; P = 0.024). After adjustment for other prognostic biomarkers (leukocyte count, high-sensitivity C-reactive protein, high-sensitivity troponin T, cystatin C, N-terminal pro B-type natriuretic peptide, and growth differentiation factor-15), the association with CV death remained significant for lysis time (HR 1.2, 95% CI 1.01-1.42; P = 0.042) but not for maximum turbidity. These associations were consistent regardless of randomized antiplatelet treatment (all interaction P > 0.05). Neither lysis time nor maximum turbidity was associated with major bleeding events., Conclusion: Fibrin clots that are resistant to lysis independently predict adverse outcome in ACS patients. Novel therapies targeting fibrin clot properties might be a new avenue for improving prognosis in patients with ACS.

Background: Elevated levels of osteoprotegerin, a secreted tumor necrosis factor-related molecule, might be associated with adverse outcomes in patients with coronary artery disease. We measured plasma osteoprotegerin concentrations on hospital admission, at discharge, and at 1 and 6 months after discharge in a predefined subset (n=5135) of patients with acute coronary syndromes in the PLATO (Platelet Inhibition and Patient Outcomes) trial., Methods and Results: The associations between osteoprotegerin and the composite end point of cardiovascular death, nonprocedural spontaneous myocardial infarction or stroke, and non-coronary artery bypass grafting major bleeding during 1 year of follow-up were assessed by Cox proportional hazards models. Event rates of the composite end point per increasing quartile groups at baseline were 5.2%, 7.5%, 9.2%, and 11.9%. A 50% increase in osteoprotegerin level was associated with a hazard ratio (HR) of 1.31 (95% confidence interval [CI], 1.21-1.42) for the composite end point but was not significant in adjusted analysis (ie, clinical characteristics and levels of C-reactive protein, troponin T, NT-proBNP [N-terminal pro-B-type natriuretic peptide], and growth differentiation factor-15). The corresponding rates of non-coronary artery bypass grafting major bleeding were 2.4%, 2.2%, 3.8%, and 7.2%, with an unadjusted HR of 1.52 (95% CI, 1.36-1.69), and a fully adjusted HR of 1.26 (95% CI, 1.09-1.46). The multivariable association between the osteoprotegerin concentrations and the primary end point after 1 month resulted in an HR of 1.09 (95% CI, 0.89-1.33); for major bleeding after 1 month, the HR was 1.33 (95% CI, 0.91-1.96)., Conclusions: In patients with acute coronary syndrome treated with dual antiplatelet therapy, osteoprotegerin was an independent marker of major bleeding but not of ischemic cardiovascular events. Thus, high osteoprotegerin levels may be useful in increasing awareness of increased bleeding risk in patients with acute coronary syndrome receiving antithrombotic therapy., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Introduction: Patients who undergo percutaneous coronary intervention (PCI) with stenting usually require a period of dual antiplatelet therapy (DAPT) but, when an indication for long-term oral anticoagulation (OAC) such as atrial fibrillation (AF) coexists, triple antithrombotic therapy (TAT) with DAPT and OAC causes concern for excessive bleeding. Achieving the right balance between bleeding and adequate protection from ischemic events remains an issue of debate and subject to ongoing investigation of various antithrombotic regimens and durations. Areas covered: This review describes the landmark clinical trials comparing TAT to a period of dual antithrombotic therapy (DAT) and subsequent meta-analyses. It also describes the international recommendations that have been derived from this evidence and identifies outstanding issues that could be addressed in upcoming or future trials. Expert opinion: The current recommended default strategy of a short period of TAT with clopidogrel followed by the withdrawal of aspirin faces a challenge from the prospect of more consistent P2Y12 inhibition provided by ticagrelor and prasugrel. Ticagrelor monotherapy has already been trialed in patients after PCI without an indication for OAC. DAT with ticagrelor or prasugrel immediately post-procedure could emerge as a comparably safe and more efficacious regimen than one involving clopidogrel in the right setting. [ABSTRACT FROM AUTHOR]

Three oral platelet P2Y12inhibitors, clopidogrel, prasugrel, and ticagrelor, are available for reducing the risk of cardiovascular death and stent thrombosis in patients with acute coronary syndromes (ACS). We sought to compare the efficacy of these antiplatelet drugs in contemporary practice. Data were collected for 10 793 consecutive ACS patients undergoing coronary angiography at Sheffield, UK (2009–2015). Since prasugrel use was mostly restricted to the STEMI subgroup, clopidogrel and ticagrelor were compared for all ACS patients, and all three agents were compared in the STEMI subgroup. Differences in outcomes were evaluated at 12 months by KM curves and log-rank test after adjustment for independent risk factors. Of 10 793 patients with ACS (36% STEMI), 43% (4653) received clopidogrel, 11% (1223) prasugrel and 46% (4917) ticagrelor, with aspirin for all. In the overall group, ticagrelor was associated with lower all-cause mortality compared with clopidogrel (adjusted hazard ratio (adjHR) 0.82, 95% confidence intervals (CI) 0.71–0.96,p= 0.01). In the STEMI subgroup, both prasugrel and ticagrelor were associated with a lower mortality compared with clopidogrel (prasugrel vs. clopidogrel: adjHR 0.65, CI 0.48–0.89,p= 0.007; ticagrelor vs. clopidogrel: adjHR 0.70, CI 0.61–0.99,p= 0.05). Of the 7595 patients who underwent PCI, 78 (1.0%) had definite stent thrombosis by 12 months. Patients treated with ticagrelor had a lower incidence of definite stent thrombosis compared with clopidogrel (0.6% vs. 1.1%; adjHR 0.51, CI 0.29–0.89,p= 0.03). In the STEMI subgroup, there was no significant difference between the three groups (ticagrelor 1.0%, clopidogrel = 1.5%, prasugrel = 1.6%;p= 0.29). In conclusion, ticagrelor was superior to clopidogrel for reduction in both mortality and stent thrombosis in unselected invasively managed ACS patients. In STEMI patients, both ticagrelor and prasugrel were associated with lower mortality compared with clopidogrel, but there was no significant difference in the incidence of stent thrombosis. [ABSTRACT FROM AUTHOR]

The increasing use of antiplatelet therapy, particularly aspirin and oral P2Y12 inhibitors, in the prevention and management of arterial thrombosis, has stimulated extensive pharmacodynamic studies and research into tailored antiplatelet regimens. Many different methodologies have been studied for monitoring antiplatelet drugs and some are now well validated and used in clinical practice. However, clinical studies of tailored antiplatelet therapy have not convincingly demonstrated a benefit of this approach in patients treated with aspirin and clopidogrel, coupled with the fact that more potent antiplatelet therapies have more consistent effects compared with clopidogrel and so may reduce the rationale for monitoring. On the other hand, the optimum timing of urgent surgery after cession of oral antiplatelet therapy may be informed by platelet function testing. This review discusses the differentmethodologies that have been used to monitor the effects of antiplatelet therapy and highlights the current position of platelet function testing in clinical practice. [ABSTRACT FROM AUTHOR]

Cangrelor is a rapid-acting, direct-binding, and reversible P2Y12antagonist which has been studied for use during percutaneous coronary intervention (PCI) in patients with or without pretreatment with an oral P2Y12antagonist. As cangrelor is administered intravenously, it is necessary to switch to an oral P2Y12antagonist following PCI, such as the thienopyridines clopidogrel, and prasugrel or the non-pyridine ticagrelor. Previous studies have suggested a negative pharmacodynamic interaction between cangrelor and thienopyridines. Thisin vitrostudy evaluated the receptor-level interaction between cangrelor and the active metabolite (AM) of clopidogrel or prasugrel by assessing functional P2Y12receptor number using a33P-2MeSADP binding assay. All P2Y12antagonists studied resulted in strong P2Y12receptor blockade (cangrelor: 93.6%; clopidogrel AM: 93.0%; prasugrel AM: 97.9%). Adding a thienopyridine AM in the presence of cangrelor strongly reduces P2Y12receptor blockade by the AM (clopidogrel AM: 7%, prasugrel AM: 3.2%). The thienopyridine AMs had limited ability to compete with cangrelor for binding to P2Y12(% P2Y12receptor blockade after co-incubation with cangrelor 1000 nmol/L: 11.7% for clopidogrel AM 3 µmol/L; 34.1% for prasugrel AM 3 µmol/L). In conclusion,in vitrocangrelor strongly inhibits the binding of clopidogrel and prasugrel AMs to the P2Y12receptor, consistent with the previous observation of a negative pharmacodynamic interaction. Care may need to be taken to not overlap exposure to thienopyridine AMs and cangrelor in order to reduce the risk of thrombotic complications following PCI. [ABSTRACT FROM PUBLISHER]

Objective: The effects of ticagrelor in the subpopulation of patients with ST-elevation myocardial infarction (STEMI) were consistent with those observed in the overall Platelet Inhibition and Patient Outcomes (PLATO) study. However, this subgroup included patients initially or ultimately treated conservatively. The aim of this study is to compare treatment using ticagrelor with treatment using clopidogrel in patients with STEMI undergoing primary percutaneous coronary intervention (PCI).Methods: This post-hoc subgroup analysis compared ticagrelor with clopidogrel in 4949 PLATO patients with STEMI that were treated with primary PCI within 12 h of admission. The primary endpoint was cardiovascular death, myocardial infarction or stroke. The safety endpoint consisted of any major bleeding. Secondary endpoints included stent thrombosis. The analysis was not adequately powered to establish significance of any treatment effects.Results: During a median of 286 days, the primary endpoint occurred in 7.9% of ticagrelor-treated patients versus 8.6% of clopidogrel-treated patients (HR 0.91, 95% CI 0.75 to 1.12, p=0.38). Major bleeding occurred in 6.7% in ticagrelor-treated patients versus 6.8% of clopidogrel-treated patients (HR 0.97, 95% CI 0.77 to 1.22, p=0.79). No interactions were observed for the treatment effect of ticagrelor versus clopidogrel on the primary efficacy (p=0.40) and primary safety endpoints (p=0.15) as compared with the full PLATO population. Treatment with ticagrelor versus clopidogrel reduced the occurrence of definite stent thrombosis (HR 0.58, 95% CI 0.37 to 0.89, p=0.013).Conclusions: In the subset of patients with STEMI treated with primary PCI, ticagrelor compared with clopidogrel was safe, and efficacy outcomes were consistent with the overall PLATO trial.Trial Registration Number: NCT00391872; Results. [ABSTRACT FROM AUTHOR]

Aims Ticagrelor, a direct-acting P2Y12-receptor antagonist, is rapidly absorbed and partly metabolized to the major metabolite AR-C124910XX (ARC). To identify single-nucleotide polymorphisms (SNPs) associated with pharmacokinetics of ticagrelor and clinical outcomes, we performed a genome-wide association study (GWAS) in patients treated with ticagrelor in the PLATO trial. Methods and results A two-stage design was used for the GWAS with discovery (discovery phase: n = 1812) and replication cohorts (replication phase: n = 1941). The steady-state area under the curve (AUCss) values, estimated by the population pharmacokinetic (PK) models, were log transformed and analysed on a genome-wide scale using linear regression. SNPs were analysed against clinical events using Cox-regression in 4990 patients. An SNP (rs113681054) in SLCO1B1was associated with levels of ticagrelor (P = 1.1 × 10-6) and ARC (P = 4.6 × 10-13). This SNP is in linkage disequilibrium with a functional variant (rs4149056) that results in decreased OATP1B1 transporter activity. Ticagrelor levels were also associated with two independent SNPs (rs62471956, P = 7.7 × 10-15 and rs56324128, P = 9.7 × 10-12) in the CYP3A4 region. Further, ARC levels were associated with rs61361928 (P = 3.0 × 10-14) in UGT2B7. At all loci, the effects were small. None of the identified SNPs that affected ticagrelor PK were associated with the primary composite outcome (cardiovascular death myocardial infarction, and stroke), non-CABG-related bleeds or investigator-reported dyspnoea. Conclusion In patients with ACS, ticagrelor pharmacokinetics is influenced by three genetic loci (SLCO1B1, UGT2B7, and CYP3A4). However, the modest genetic effects on ticagrelor plasma levels did not translate into any detectable effect on efficacy or safety during ticagrelor treatment. [ABSTRACT FROM AUTHOR]

Platelet P2Y12 inhibitors have become a central component of the treatment strategy for patients with atherothrombosis due to the importance of platelet P2Y12 receptors in arterial thrombosis. P2Y12 inhibitors effectively reduce the risk of adverse cardiovascular events in patients with acute coronary syndromes (ACS) and patients undergoing percutaneous coronary intervention (PCI). However, despite this, patients with ACS continue to suffer from recurrent atherothrombosis and an increased risk of mortality. In addition, P2Y12 inhibitors increase the risk of bleeding, thereby limiting their clinical benefit. It is therefore clear that further optimizations are needed in the pharmacology and treatment strategies of P2Y12 inhibitors. The objective of these optimizations is to maximize cardiovascular benefit whilst minimizing adverse effects on haemostasis. This review article summarizes the most successful recent strategies in P2Y12 inhibition in order to identify the optimizations and developments that are most likely to be successful in the future. [ABSTRACT FROM AUTHOR]

Objective: To describe specific causes of death and evaluate whether bleeding events and infection contributed to mortality in all ticagrelor-treated and clopidogrel-treated patients with acute coronary syndromes. Methods: In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor significantly reduced rates of vascular and total death compared with clopidogrel. In the 905 patients who died postenrolment in the PLATO trial (n=18 624), reviewers, blinded to study treatment, subclassified direct causes of death and evaluated whether infection or bleeding events contributed to fatal events. Results: Among vascular deaths, there were significantly fewer sudden deaths (63 (0.7%) vs 98 (1.1%), p<0.01) but no significant difference in deaths caused by acute myocardial infarction (179 (1.9%) vs 194 (2.1%), p=0.43) or heart failure (31 (0.3%) vs 42 (0.5%), p=0.20) with ticagrelor compared with clopidogrel. For non-vascular deaths, there was no difference between treatments in deaths directly caused by infection. Although, patients treated with ticagrelor were at lower risk for death where infection was either a direct cause or contributed to death (51 (0.5%) vs 76 (0.8%), HR 0.67 (0.47 to 0.95), p<0.05) but not for bleeding (42 (0.5%) vs 42 (0.5%), HR 0.99 (0.65 to 1.53), p=0.98). Conclusions: In this post hoc analysis, ticagrelor compared with clopidogrel reduced total and cardiovascular mortality, which appeared to be mainly mediated by a reduction in sudden death. Importantly, bleeding causing or contributing to death did not differ between treatments. [ABSTRACT FROM AUTHOR]

In the PLATelet inhibition and patient Outcomes (PLATO) study of patients with acute coronary syndromes, ticagrelor reduced mortality compared to clopidogrel but the mechanisms for this mortality reduction remain uncertain. We analysed adverse events (AEs) consistent with either pulmonary infection or sepsis, and subsequent mortality, in 18,421 PLATO patients treated with ticagrelor or clopidogrel. AEs occurring within 7 days of last dose of study medication were defined as 'on-treatment'. Serial measurements of blood leukocyte counts, C-reactive protein and interleukin-6 were performed. Fewer on-treatment pulmonary AEs occurred in the ticagrelor compared to the clopidogrel group (275 vs. 331 respectively; p = 0.019), with fewer deaths following these AEs (33 vs. 71; p < 0.001), particularly in those who remained on study medication three days after AE onset (10 vs. 43; p < 0.001). There were fewer deaths attributed to sepsis in the ticagrelor group (7 vs. 23; p = 0.003). Leukocyte counts were lower in the clopidogrel group during treatment ( p < 0.0001 at 1, 3 and 6 months) but not at 1 month post-discontinuation. C-reactive protein increased more at discharge in the ticagrelor group (28.0 ± 38.0 vs. 26.1 ± 36.6 mg/l; p < 0.001) and interleukin-6 remained higher during the first month of treatment with ticagrelor. We conclude that the mortality risk following pulmonary AEs and sepsis in acute coronary syndrome patients appears to be lower during ticagrelor compared to clopidogrel therapy. Further work should assess whether ticagrelor and clopidogrel have differential effects on immune signalling. [ABSTRACT FROM AUTHOR]

The superior efficacy of ticagrelor compared with clopidogrel in the management of patients with acute coronary syndrome (ACS), including a significant reduction in cardiovascular death, has led to a search for potential mechanisms for this superiority, such as in this issue of Blood in the work of Aungraheeta et al. They describe a novel property of ticagrelor in its interaction with the P2Y12 receptor as well as confirming adenosine-mediated effects through inhibition of cellular adenosine uptake via equilibrative nucleoside transporter 1 (ENT1). [ABSTRACT FROM AUTHOR]

Dual antiplatelet therapy consisting of clopidogrel in addition to aspirin has previously been the standard of care for patients with acute coronary syndromes (ACS) but international guidelines have been evolving over the last 4 years with the introduction of prasugrel and ticagrelor. In October 2009, prasugrel was approved in the UK by the National Institute of Health and Clinical Excellence (NICE) for use in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI), diabetic patients with non-ST-elevation (NSTE) ACS undergoing PCI and patients with stent thrombosis while other ACS patients were to continue receiving clopidogrel. Ticagrelor was approved in October 2011 by NICE for use in patients with moderate-to-high risk NSTE ACS and STEMI undergoing primary PCI and was recommended in preference to clopidogrel in European guidelines. These recommendations were adopted in our region, constituting a population of 1.8 million. We studied the effect of changing patterns of P2Y12 inhibitor usage on levels of platelet inhibition during maintenance therapy. Patients admitted to Northern General Hospital, Sheffield, with NSTE ACS or STEMI managed with primary PCI were enrolled over two periods of time: May 2010 to November 2011 (T1); and October 2012 to February 2013 (T2). Venous blood samples were obtained at 1 month after the onset of ACS. Light transmittance aggregometry (LTA) was performed and maximum aggregation response to ADP 20 μM was determined. A total of 116 patients were enrolled in T1 of whom 82 were receiving clopidogrel and 34 were receiving prasugrel. Twenty-nine patients were enrolled in T2, all of whom were receiving ticagrelor. Mean LTA results according to treatment with clopidogrel, prasugrel and ticagrelor were 57 ± 18%, 41 ± 20%, and 31 ± 12%, respectively. Prasugrel was associated with significantly lower platelet aggregation responses than clopidogrel ( p < 0.001) and ticagrelor was associated with significantly lower platelet aggregation responses than both prasugrel ( p = 0.015) and clopidogrel ( p < 0.001). We conclude that international guidelines and NICE approval have led to increasing levels of P2Y12 inhibition in ACS patients in this UK centre between May 2010 and February 2013. Ticagrelor was associated with significantly greater P2Y12 inhibition than both clopidogrel and prasugrel during maintenance therapy. [ABSTRACT FROM AUTHOR]

Aims Platelets have a fundamental role in atherothrombosis, but their role in early atherogenesis is unclear. The P2Y12 receptor is responsible for amplifying and sustaining platelet activation and P2Y12 inhibition is crucial in modulating the vessel wall response to injury. We therefore examined the role of platelet vs. vessel wall P2Y12 in early atherogenesis and considered the use of P2Y12 antagonists ticagrelor and clopidogrel in modulating this process. Methods and results ApoE−/− and ApoE−/−P2Y12−/− male mice underwent bone marrow transplantation and were fed a western diet for 4 weeks before assessing atherosclerotic burden. Compared with ApoE−/− controls, platelet P2Y12 deficiency profoundly reduced platelet reactivity but had no effect on atheroma formation, whereas vessel wall P2Y12 deficiency significantly attenuated atheroma in the aortic sinus and brachiocephalic artery (both P < 0.001). ApoE−/− and ApoE−/−P2Y12−/− male mice fed western diet plus either twice-daily doses of ticagrelor (100 mg/kg) or daily clopidogrel (20 mg/kg) for 4 weeks exhibited no significant reduction in atheroma compared with control mice fed mannitol. Attenuated P-selectin expression confirmed platelet P2Y12 inhibition in drug-treated mice. Conclusions Despite its major contribution to platelet reactivity, platelet P2Y12 has no effect on early atheroma formation, whereas vessel wall P2Y12 is important in this process. Ticagrelor and clopidogrel effectively reduced platelet reactivity but were unable to inhibit early atherogenesis, demonstrating that these P2Y12 inhibitors may not be effective in preventing early disease. [ABSTRACT FROM PUBLISHER]

We sought to assess the relationships between platelet reactivity at different time points, CYP2C19*2 and ABCBI status and clinical outcomes in patients with acute coronary syndromes (ACS). Anti-platelet response to clopidogrel was studied prospectively using the VerifyNow (VN) P2Y12 assay at the time of angiography and at 30 days post procedure in 151 patients admitted with ACS who underwent percutaneous coronary intervention (PCI). Troponin T levels were measured at angiography and 16-24 hour following PCI. DNA was extracted and the presence of CYP2C19*2 allele and ABCB 1 polymorphisms were determined. Adverse cardiovascular and cerebral events (ACCE) were assessed at 12 months. High VN P2Y12 response at angiography was associated with a greater peri-procedural rise in troponin T, but not ACCE. However, VN P2Y12 response measured at 30 days was associated with ACCE (19 = 0.017). CYP2C19*2 status was associated with higher VN P2Y12 response at angiography (p < 0.0001) and 30 days (p = 0.006) but not ACCE. Near-patient testing for clopidogrel response was associated with subsequent ACCE when performed 30 days following PCI, but not at angiography. [ABSTRACT FROM AUTHOR]

P2Y12 inhibitors are widely used in patients with acute coronary syndromes and in the secondary prevention of thrombotic events in vascular diseases. Within the past few years, several pharmacological, genetic, and clinical limitations of the second-generation thienopyridine clopidogrel have raised major concerns. High on-treatment platelet reactivity, which is common in clopidogrel-treated patients, and its clinical implications led to the development of the more effective platelet P2Y12 inhibitors prasugrel (a third-generation thienopyridine) and ticagrelor (a cyclopentyl-triazolo-pyrimidine). The pharmacokinetics and pharmacodynamics of prasugrel and ticagrelor indicate that they provide more consistent, more rapid, and more potent platelet inhibition than clopidogrel, which translates into improved ischemic outcomes. Nevertheless, higher efficacy, which is reflected by low on-treatment platelet reactivity, increases the risk of major bleeding events. Therefore, cardiologists might be facing a new challenge in the future: to individualize the level of platelet inhibition in order to decrease thrombotic events without increasing bleeding. The current review focuses on the use of platelet function testing and pharmacogenomic testing in order to identify patients who either do not respond to or are at risk of not responding sufficiently to P2Y12 inhibitors. Moreover, this paper discusses randomized trials, which so far have failed to show that tailored antiplatelet therapy improves clinical outcome, and treatment options for patients with high on-treatment platelet reactivity. [Copyright &y& Elsevier]

Objectives: The PLATO (Platelet Inhibition and Patient Outcomes) angiographic substudy sought to compare the efficacy of ticagrelor versus clopidogrel with respect to angiographic outcomes before and after PCI in the setting of acute coronary syndrome. Background: Greater platelet inhibition has been associated with improved angiographic outcomes before and after percutaneous coronary intervention (PCI). Therefore, it was hypothesized that treatment with ticagrelor, which achieves more rapid, higher, and more consistent platelet inhibition, would be associated with improved angiographic outcomes when compared with those of clopidogrel treatment. Methods: The angiographic cohort consists of 2,616 patients drawn from the 18,624-patient PLATO trial. Clopidogrel naïve or pre-treated patients were randomized to 180 mg of ticagrelor or 300 mg of clopidogrel (75 mg for clopidogrel pre-treated patients). PCI patients were administered, as per treatment group: 1) an additional 90 mg of ticagrelor if >24 h following the initial loading dose; or 2) an optional further 300 mg of clopidogrel or placebo (total 600 mg) prior to PCI. The substudy primary endpoint was the incidence of post-PCI TIMI (Thrombolysis In Myocardial Infarction) myocardial perfusion grade 3 (TMPG 3) among patients who received a study drug prior to PCI. Results: In total, 21.3% of patients were pretreated with clopidogrel prior to randomization. There was a short time interval between randomization and PCI (median: 0.68 [interquartile range (IQR): 0.30 to 2.21] h) among all patients. Post-PCI TMPG 3 was similar between the ticagrelor and clopidogrel groups (47.1% vs. 46.9%; p = 0.96). Likewise, the following pre-PCI outcomes were similar in the ticagrelor and clopidogrel groups, respectively: TMPG 3 (30.5% vs. 31.2%), TIMI flow grade 3 (37.1% vs. 39.3%), corrected TIMI frame count (median: 100 vs. 71 frames), TIMI thrombus grade 0 (24.1% vs. 27.6%), minimum lumen diameter (median: 0.3 [IQR: 0.0 to 0.6] vs. 0.3 [IQR: 0.0 to 0.6] mm) and percentage of diameter stenosis (median: 89 [IQR: 78 to 100] vs. 89 [IQR: 77 to 100]). Conclusions: Neither coronary flow nor myocardial perfusion, evaluated on coronary angiograms performed before or following PCI procedures within a few hours after the start of oral antiplatelet treatment in the setting of acute coronary syndromes, demonstrated a difference with ticagrelor versus clopidogrel. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872) [Copyright &y& Elsevier]

The article presents a research study that investigated the effect and treatment-related complications of ticagrelor versus clopidogrel in elderly patients with acute coronary syndrome. Methods are presented involving the PLATelet inhibition and patient Outcomes (PLATO) trial and the use of Cox proportional hazards models. The results of the comparison of patient characteristics, procedures, and clinical outcomes in elderly and young patients are discussed along with their efficacy and safety.

Background--Patients with acute coronary syndromes and history of stroke or transient ischemic attack (TIA) have an increased rate of recurrent cardiac events and intracranial hemorrhages. Methods and Results--We evaluated treatment effects of ticagrelor versus Clopidogrel in patients with acute coronary syndrome with and without a history of prior stroke or TIA in the PLATelet inhibition and patient Outcomes (PLATO) trial. Of the 18 624 randomized patients, 1152 (6.2%) had a history of stroke or TIA. Such patients had higher rates of myocardial infarction (11.5% versus 6.0%), death (10.5% versus 4.9%), stroke (3.4% versus 1.2%), and intracranial bleeding (0.8% versus 0.2%) than patients without prior stroke or TIA. Among patients with a history of stroke or TIA, the reduction of the primary composite outcome and total mortality at 1 year with ticagrelor versus Clopidogrel was consistent with the overall trial results: 19.0% versus 20.8% (hazard ratio, 0.87; 95% confidence interval, 0.66-1.13; interaction P=0.84) and 7.9% versus 13.0% (hazard ratio, 0.62; 95% confidence interval, 0.42-0.91). The overall PLATO-defined bleeding rates were similar: 14.6% versus 14.9% (hazard ratio, 0.99; 95% confidence interval, 0.71-1.37), and intracranial bleeding occurred infrequently (4 versus 4 cases, respectively). Conclusions--Patients with acute coronary syndrome with a prior history of ischemic stroke or TIA had higher rates of clinical outcomes than patients without prior stroke or TIA. However, the efficacy and bleeding results of ticagrelor in these high-risk patients were consistent with the overall trial population, with a favorable clinical net benefit and associated impact on mortality. [ABSTRACT FROM AUTHOR]

The Platelet Inhibition and Patient Outcomes (PLATO) trial showed that ticagrelor reduced the risk for cardiovascular events in patients with acute coronary syndromes compared to clopidogrel but was associated with increased incidence of dyspnea. This substudy assessed whether ticagrelor affects pulmonary function in patients with acute coronary syndromes: 199 patients enrolled in the PLATO trial and receiving randomized treatment with ticagrelor 90 mg twice daily (n = 101) or clopidogrel 75 mg/day (n = 98) took part in the pulmonary function substudy. Patients with advanced lung disease, congestive heart failure, or coronary artery bypass graft surgery after the index event were excluded. Pulse oximetry (blood oxygen saturation), spirometry (forced expiratory volume in 1 second, forced vital capacity, and forced expiratory flow between 25% and 75% of forced vital capacity before and 20 minutes after inhalation of a β2 agonist), lung volumes (total lung capacity, functional residual capacity, residual volume), and diffusion capacity were performed after patients received study medication for 30 to 40 days. Tests were then repeated <10 days before and approximately 30 days after the discontinuation of study medication. After a mean treatment duration of 31 days, there were no differences between the groups for any of the pulmonary function parameters. At the end of treatment (mean 211 days) and after the discontinuation of study medication (mean 32 days after the last dose), there was also no evidence of a change in pulmonary function in either group. For example, forced expiratory volume in 1 second values before β2 agonist inhalation in the ticagrelor and clopidogrel groups were 2.81 ± 0.73 and 2.70 ± 0.84 L, respectively, at the first visit and did not change significantly at subsequent visits. In conclusion, no effect of ticagrelor on pulmonary function was seen in this cohort of patients with acute coronary syndromes compared to clopidogrel. [ABSTRACT FROM AUTHOR]

Aims To describe the incidence of dyspnoea and its associations with demographic characteristics and clinical outcomes in patients with acute coronary syndromes (ACS) treated with ticagrelor or clopidogrel in the PLATelet inhibition and patient Outcomes (PLATO) study. Methods and results In the PLATO study, 18 624 patients were randomized to receive either clopidogrel [300–600 mg loading dose (LD), 75 mg daily] or ticagrelor (180 mg LD, 90 mg b.i.d.). The occurrence of reported dyspnoea adverse events (AEs) was analysed in the 18 421 patients who received at least one dose of study medication in relation to demographic characteristics, clinical outcomes and other associations of patients with and without dyspnoea. A total of 1339 ticagrelor-treated patients (14.5%) and 798 clopidogrel-treated patients (8.7%) had a dyspnoea AE following randomization, with respectively 39 (0.4%) and 24 (0.3%) classified as severe in intensity. Excluding dyspnoea AEs occurring after the secondary endpoint of myocardial infarction (MI), the yearly rates of the efficacy endpoints in dyspnoea AE patients in the ticagrelor and clopidogrel groups were: for the primary composite of CV death, MI, and stroke, 8.8 and 10.4% (unadjusted P = 0.25; adjusted P = 0.54); for CV death, 3.1 and 4.8% (unadjusted P = 0.024; adjusted P = 0.18); and for total death 3.7 and 6.2% (unadjusted P = 0.004; adjusted P = 0.06), respectively. Conclusions Ticagrelor-related dyspnoea is usually mild or moderate in intensity and does not appear to be associated with differences concerning any efficacy or safety outcomes with ticagrelor compared with clopidogrel therapy in ACS patients. [ABSTRACT FROM PUBLISHER]

The clinical pharmacology of antiplatelet drugs has been reviewed previously by the European Society of Cardiology (ESC) Task force and by the 8th American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines. Moreover, information on the efficacy and safety of antiplatelet drugs in the treatment and prevention of atherothrombosis is provided by collaborative meta-analyses of 287 secondary prevention trials and 6 primary prevention trials. The present document intends to provide practicing physicians with an updated instrument to guide their choice of the most suitable antiplatelet strategy for the individual patient at risk, or with different clinical manifestations, of atherothrombosis. [ABSTRACT FROM PUBLISHER]

Aims Patients with diabetes mellitus (DM) have high platelet reactivity and are at increased risk of ischaemic events and bleeding post-acute coronary syndromes (ACS). In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor reduced the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke, but with similar rates of major bleeding compared with clopidogrel. We aimed to investigate the outcome with ticagrelor vs. clopidogrel in patients with DM or poor glycaemic control. Methods and results We analysed patients with pre-existing DM (n = 4662), including 1036 patients on insulin, those without DM (n = 13 951), and subgroups based on admission levels of haemoglobin A1c (HbA1c; n = 15 150). In patients with DM, the reduction in the primary composite endpoint (HR: 0.88, 95% CI: 0.76–1.03), all-cause mortality (HR: 0.82, 95% CI: 0.66–1.01), and stent thrombosis (HR: 0.65, 95% CI: 0.36–1.17) with no increase in major bleeding (HR: 0.95, 95% CI: 0.81–1.12) with ticagrelor was consistent with the overall cohort and without significant diabetes status-by-treatment interactions. There was no heterogeneity between patients with or without ongoing insulin treatment. Ticagrelor reduced the primary endpoint, all-cause mortality, and stent thrombosis in patients with HbA1c above the median (HR: 0.80, 95% CI: 0.70–0.91; HR: 0.78, 95% CI: 0.65–0.93; and HR: 0.62, 95% CI: 0.39–1.00, respectively) with similar bleeding rates (HR: 0.98, 95% CI: 0.86–1.12). Conclusion Ticagrelor, when compared with clopidogrel, reduced ischaemic events in ACS patients irrespective of diabetic status and glycaemic control, without an increase in major bleeding events. [ABSTRACT FROM PUBLISHER]

The article presents an analysis on the relations between pharcodynamics and CYP2C19 genotype in patients treated with ticagrelor and clopidrogrel cardiovascular drugs. It is stated that in Platelet Inhibition and Patient Outcomes (PLATO) trial, ticagrelor reduced the rate of cardiovascular death and myocardial infarction in patients with acute coronary syndrome (ACS). The Influence of CYP2C19 on platelet function is also discussed.

Atherosclerosis is a diffuse, systemic disorder of the large and medium-sized arterial vessels, affecting the coronary, cerebral and peripheral circulation. Chronic inflammatory processes are the central pathophysiological mechanism largely driven by lipid accumulation, and provide the substrate for occlusive thrombus formation. The clinical sequelae of acute arterial thrombosis, heart attack and stroke, are the most common causes of morbidity and mortality in the industrialized world. Such acute events are characterized by rupture or erosion of the atherosclerotic plaque leading to acute thrombosis. The atherosclerotic process and associated thrombotic complications are collectively termed atherothrombosis. The platelet is a pivotal mediator of various endothelial, immune, thrombotic and inflammatory responses and therefore a key player in the initiation and progression of atherothrombosis. A robust evidence base supports the clear clinical benefits of antiplatelet agents in the primary and secondary therapy of atherothrombotic disorders. Percutaneous coronary and peripheral interventions have an established central role in the management of atherothrombotic disease and demand a greater understanding of platelet biology. In this article, we provide a clinically orientated overview of the pathophysiology of arterial thrombosis and the evidence supporting the use of the various established antiplatelet therapies, and discuss new and future agents. [ABSTRACT FROM PUBLISHER]

Objectives: We prospectively assessed cardiac and pulmonary function in patients with stable coronary artery disease (CAD) treated with ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET (A Multi-Centre Randomised, Double-Blind, Double-Dummy Parallel Group Study of the Onset and Offset of Antiplatelet Effects of AZD6140 Compared With Clopidogrel and Placebo With Aspirin as Background Therapy in Patients With Stable Coronary Artery Disease) study. Background: Ticagrelor reduces cardiovascular events more effectively than clopidogrel in patients with acute coronary syndromes. Dyspnea develops in some patients treated with ticagrelor, and it is not known whether this is associated with changes in cardiac or pulmonary function. Methods: In all, 123 stable aspirin-treated CAD patients randomly received either ticagrelor (180 mg load, then 90 mg twice daily; n = 57), clopidogrel (600 mg load, then 75 mg daily; n = 54), or placebo (n = 12) for 6 weeks in a double-blind, double-dummy design. Electrocardiography, echocardiography, serum N-terminal pro-brain natriuretic peptide, and pulmonary function tests were performed before (baseline) and 6 weeks after drug administration and/or after development of dyspnea. Results: After drug administration, dyspnea was reported by 38.6%, 9.3%, and 8.3% of patients in the ticagrelor, clopidogrel, and placebo groups, respectively (p < 0.001). Most instances were mild and/or lasted <24 h, although 3 patients discontinued ticagrelor because of dyspnea. Eight of 22 and 17 of 22 ticagrelor-treated patients experiencing dyspnea did so within 24 h and 1 week, respectively, after drug administration. In all treatment groups, and in ticagrelor-treated patients with dyspnea, there were no significant changes between baseline and 6 weeks in any of the cardiac or pulmonary function parameters. Conclusions: Dyspnea is commonly associated with ticagrelor therapy, but was not associated in this study with any adverse change in cardiac or pulmonary function. (A Multi-Centre Randomised, Double-Blind, Double-Dummy Parallel Group Study of the Onset and Offset of Antiplatelet Effects of AZD6140 Compared With Clopidogrel and Placebo With Aspirin as Background Therapy in Patients With Stable Coronary Artery Disease [ONSET/OFFSET]; NCT00528411) [Copyright &y& Elsevier]

Platelet P2Y 12 inhibitors have become an essential component of the treatment strategy for patients with acute coronary syndromes and patients undergoing percutaneous coronary intervention. It is now well-established that approximately 30% of patients treated with the P2Y 12 inhibitor clopidogrel display high residual platelet reactivity despite treatment. Patients with high on-treatment platelet reactivity have approximately 2–3-fold greater risk of adverse cardiovascular events and stent thrombosis than those without high platelet reactivity. Conversely, clopidogrel-treated patients with low platelet reactivity display approximately 1.7-fold increased risk of major bleeding. High platelet reactivity is uncommon during treatment with prasugrel and ticagrelor, which achieve a greater reduction in adverse cardiovascular events compared to clopidogrel in ACS patients treated with PCI. This is at the expense of an increase in spontaneous bleeding, however. Minor bleeding events, such as skin haematomas, are more common in prasugrel- and ticagrelor-treated patients that have particularly low platelet reactivity values. These minor bleeding events may occasionally prompt discontinuation of therapy, but their overall prognostic impact is uncertain. However, risk factors for bleeding tend to overlap with risk factors for adverse cardiovascular events. Therefore, patients with these minor bleeding events may also be at higher risk of adverse cardiovascular events, conferring a benefit from low platelet reactivity. Further work is needed to determine the optimal level of platelet reactivity in individuals by taking into account their risk of subsequent adverse cardiovascular events and bleeding. [ABSTRACT FROM AUTHOR]

The aim of these studies was to investigate the extent of platelet P2Y12 receptor inhibition by the thienopyridine active metabolite of prasugrel, R-138727. Blood was taken from healthy volunteers and pre-incubated with R-138727 or cangrelor (AR-C66931MX). Platelet aggregation was assessed in platelet rich plasma (PRP) and whole blood (WB). Vasodilator stimulated phosphoprotein (VASP) phosphorylation, platelet procoagulant activity (annexin V binding and microparticle formation) and calcium mobilisation were measured by flow cytometry. Platelet-leukocyte co-aggregate formation and sCD40L release, both pro-inflammatory responses of platelets, were measured by flow cytometry and ELISA, respectively. P2Y12 receptor antagonism was determined using a radioligand binding assay (33P 2-MeSADP) in resting and stimulated platelets and the effects of clopidogrel administration were also assessed. R-138727 yielded concentration-dependent inhibition of platelet aggregation, VASP phosphorylation inhibition, procoagulant activity and pro-inflammatory responses. In the presence of R-138727 or cangrelor there was increased calcium reuptake following agonist stimulation. R-138727 30 µmol/L and cangrelor 1 µmol/L completely inhibited 33P 2-MeSADP binding, compared to partial inhibition following clopidogrel administration. Platelet activation and granule secretion did not expose an additional pool of P2Y12 receptors. Prasugrel's active metabolite effectively blocks the P2Y12 receptor with the highest concentrations tested yielding complete inhibition of P2Y12-mediated amplification of several important platelet responses. [ABSTRACT FROM AUTHOR]

The efficacy of the platelet P2Y 12 receptor antagonist clopidogrel, which undergoes cytochrome-mediated metabolism to its active form, shows marked inter-individual variability. We investigated whether polymorphic variations in the P2Y 12 gene, which have been linked to platelet aggregation phenotypes, or the cytochrome P450 3A5 gene 6986G&ThickSpace;>&ThickSpace;A polymorphism, which largely determines CYP3A5 expression, influence the response to clopidogrel therapy. Fifty-four patients listed for elective percutaneous coronary intervention were studied using ADP-induced optical aggregometry, whole-blood single platelet counting (WBSPC) aggregometry, and flow-cytometric analysis of platelet P-selectin expression and platelet-monocyte conjugate formation. Platelet reactivity was measured at baseline, 4&ThickSpace;h post clopidogrel 300&ThickSpace;mg, and 10 and 28 days following clopidogrel 75&ThickSpace;mg daily. A further 55 patients were studied using ADP-induced WBSPC at baseline and 4&ThickSpace;h post clopidogrel 600&ThickSpace;mg. Patients were genotyped for P2Y 12 haplotype and the CYP3A5 6986G&ThickSpace;>&ThickSpace;A single nucleotide polymorphism. Neither genotype was found to significantly influence the inhibition of platelet responses by either clopidogrel regimen. In conclusion, common sequence variations within the P2Y 12 and CYP3A5 genes do not contribute any major effect to the inter-patient variability in clopidogrel efficacy. [ABSTRACT FROM AUTHOR]