Association between perioperative management of antiplatelet agents and risk of post-endoscopic submucosal dissection bleeding in early gastric cancer: analysis of a nationwide multicenter study.

BACKGROUND AND AIMS: Data are lacking regarding post-endoscopic submucosal dissection (ESD) bleeding in patients with early gastric cancer (EGC) who take antiplatelet agents (APAs), particularly in those taking thienopyridine and cilostazol. We aimed to clarify the association between the status of APA medication and post-ESD bleeding risk. METHODS: This study is a secondary analysis using data from a recently conducted nationwide multicenter study in Japan. We retrospectively reviewed patients treated with APAs or on no antithrombotic therapy recruited from 33 institutions who underwent ESD for EGC between November 2013 and October 2016. The primary outcome of this study was the relationship between the rate of post-ESD bleeding and the status of each APA medication. RESULTS: A total of 9736 patients were included in the analysis. Among 665 aspirin users, the continuation group was significantly associated with post-ESD bleeding (odds ratio [OR], 2.79; 95% confidence interval [CI], 1.77-4.37). Among 227 thienopyridine users, the aspirin or cilostazol replacement group was not significantly associated with post-ESD bleeding (OR, 1.85; 95% CI, .72-4.78). Among 158 cilostazol users, there was no significant association with post-ESD bleeding, irrespective of medication status. The rate of post-ESD bleeding was approximately 10% to 20% irrespective of the status of APA administration among dual-antiplatelet therapy users. No patients experienced thromboembolic events in this study. CONCLUSIONS: Replacement of thienopyridine with aspirin or cilostazol may be acceptable for minimizing both the risk of post-ESD bleeding and thromboembolism in patients with EGC. In patients on cilostazol monotherapy undergoing ESD, continuation of therapy may be acceptable.

The effect of antithrombotic drug use on delayed bleeding with esophageal endoscopic resection.

BACKGROUND AND AIM: Whether antithrombotic drugs increase the risk of post-esophageal endoscopic resection bleeding is unknown. This study examined the effect of antithrombotic drugs, aspirin, thienopyridine, direct oral anticoagulants (DOAC), and warfarin, on post-esophageal endoscopic resection bleeding. METHODS: We enrolled 957 patients (1202 esophageal tumors) treated with endoscopic resection and classified them based on antithrombotic drug use as no use, aspirin, thienopyridine, DOAC, and warfarin. Patients using antiplatelet drugs (i.e. aspirin and thienopyridine) were further sub-classified based on their continued or discontinued use before endoscopic resection. The bleeding rates were compared between these groups to assess the effects of antithrombotic drug use and interruption of antiplatelet therapy on post-esophageal endoscopic resection bleeding. RESULTS: The post-endoscopic resection bleeding rate was 0.3% (95% CI, 0.1-1) in the group without antithrombotic drug use, 4.5% (95% CI, 0.1-23) in the aspirin-continued group, 2.9% (95% CI, 0.1-15) in the aspirin-discontinued group, 0% (95% CI, 0-78) in the replaced thienopyridine with aspirin group, 0% (95% CI, 0-26) in the thienopyridine-discontinued group, 13% (95% CI, 1.6-38) in the DOAC group, and 0% (95% CI, 0-45) in the warfarin group. The post-endoscopic resection bleeding rate in the DOAC group was significantly higher than that in the group without antithrombotic drugs (P = 0.003). The post-endoscopic resection bleeding rates did not differ between the other groups. CONCLUSIONS: Our results suggest that discontinuing aspirin is not necessary for esophageal endoscopic resection while we must be careful regarding DOAC.

Comparative Effectiveness of Machine Learning Approaches for Predicting Gastrointestinal Bleeds in Patients Receiving Antithrombotic Treatment.

Importance: Anticipating the risk of gastrointestinal bleeding (GIB) when initiating antithrombotic treatment (oral antiplatelets or anticoagulants) is limited by existing risk prediction models. Machine learning algorithms may result in superior predictive models to aid in clinical decision-making. Objective: To compare the performance of 3 machine learning approaches with the commonly used HAS-BLED (hypertension, abnormal kidney and liver function, stroke, bleeding, labile international normalized ratio, older age, and drug or alcohol use) risk score in predicting antithrombotic-related GIB. Design, Setting, and Participants: This retrospective cross-sectional study used data from the OptumLabs Data Warehouse, which contains medical and pharmacy claims on privately insured patients and Medicare Advantage enrollees in the US. The study cohort included patients 18 years or older with a history of atrial fibrillation, ischemic heart disease, or venous thromboembolism who were prescribed oral anticoagulant and/or thienopyridine antiplatelet agents between January 1, 2016, and December 31, 2019. Exposures: A cohort of patients prescribed oral anticoagulant and thienopyridine antiplatelet agents was divided into development and validation cohorts based on date of index prescription. The development cohort was used to train 3 machine learning models to predict GIB at 6 and 12 months: regularized Cox proportional hazards regression (RegCox), random survival forests (RSF), and extreme gradient boosting (XGBoost). Main Outcomes and Measures: The performance of the models for predicting GIB in the validation cohort, evaluated using the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive predictive value, and prediction density plots. Relative importance scores were used to identify the variables that were most influential in the top-performing machine learning model. Results: In the entire study cohort of 306 463 patients, 166 177 (54.2%) were male, 193 648 (63.2%) were White, the mean (SD) age was 69.0 (12.6) years, and 12 322 (4.0%) had experienced a GIB. In the validation data set, the HAS-BLED model had an AUC of 0.60 for predicting GIB at 6 months and 0.59 at 12 months. The RegCox model performed the best in the validation set, with an AUC of 0.67 at 6 months and 0.66 at 12 months. XGBoost was similar, with AUCs of 0.67 at 6 months and 0.66 at 12 months, whereas for RSF, AUCs were 0.62 at 6 months and 0.60 at 12 months. The variables with the highest importance scores in the RegCox model were prior GI bleed (importance score, 0.72); atrial fibrillation, ischemic heart disease, and venous thromboembolism combined (importance score, 0.38); and use of gastroprotective agents (importance score, 0.32). Conclusions and Relevance: In this cross-sectional study, the machine learning models examined showed similar performance in identifying patients at high risk for GIB after being prescribed antithrombotic agents. Two models (RegCox and XGBoost) performed modestly better than the HAS-BLED score. A prospective evaluation of the RegCox model compared with HAS-BLED may provide a better understanding of the clinical impact of improved performance.

Association of Rivaroxaban With Thromboembolic Events in Patients With Heart Failure, Coronary Disease, and Sinus Rhythm: A Post Hoc Analysis of the COMMANDER HF Trial.

Importance: Whether anticoagulation benefits patients with heart failure (HF) in sinus rhythm is uncertain. The COMMANDER HF randomized clinical trial evaluated the effects of adding low-dose rivaroxaban to antiplatelet therapy in patients with recent worsening of chronic HF with reduced ejection fraction, coronary artery disease (CAD), and sinus rhythm. Although the primary end point of all-cause mortality, myocardial infarction, or stroke did not differ between rivaroxaban and placebo, there were numerical advantages favoring rivaroxaban for myocardial infarction and stroke. Objective: To examine whether low-dose rivaroxaban was associated with reduced thromboembolic events in patients enrolled in the COMMANDER HF trial. Design, Setting, and Participants: Post hoc analysis of the COMMANDER HF multicenter, randomized, double-blind, placebo-controlled trial in patients with CAD and worsening HF. The trial randomized 5022 patients postdischarge from a hospital or outpatient clinic after treatment for worsening HF between September 2013 and October 2017. Patients were required to be receiving standard care for HF and CAD and were excluded for a medical condition requiring anticoagulation or a bleeding history. Patients were randomized in a 1:1 ratio. Analysis was conducted from June 2018 and January 2019. Intervention: Patients were randomly assigned to receive 2.5 mg of rivaroxaban given orally twice daily or placebo in addition to their standard therapy. Main Outcomes and Measures: For this post hoc analysis, a thromboembolic composite was defined as either (1) myocardial infarction, ischemic stroke, sudden/unwitnessed death, symptomatic pulmonary embolism, or symptomatic deep venous thrombosis or (2) all of the previous components except sudden/unwitnessed deaths because not all of these are caused by thromboembolic events. Results: Of 5022 patients, 3872 (77.1%) were men, and the overall mean (SD) age was 66.4 (10.2) years. Over a median (interquartile range) follow-up of 19.6 (11.7-30.8) months, fewer patients assigned to rivaroxaban compared with placebo had a thromboembolic event including sudden/unwitnessed deaths: 328 (13.1%) vs 390 (15.5%) (hazard ratio, 0.83; 95% CI, 0.72-0.96; P = .01). When sudden/unwitnessed deaths were excluded, the results analyzing thromboembolic events were similar: 153 (6.1%) vs 190 patients (7.6%) with an event (hazard ratio, 0.80; 95% CI, 0.64-0.98; P = .04). Conclusions and Relevance: In this study, thromboembolic events occurred frequently in patients with HF, CAD, and sinus rhythm. Rivaroxaban may reduce the risk of thromboembolic events in this population, but these events are not the major cause of morbidity and mortality in patients with recent worsening of HF for which rivaroxaban had no effect. While consistent with other studies, these results require confirmation in prospective randomized clinical trials. Trial Registration: ClinicalTrials.gov identifier: NCT01877915.

Impact of Reticulated Platelets on the Antiplatelet Effect of the Intravenous P2Y12-Receptor Inhibitor Cangrelor.

BACKGROUND: Reticulated platelets are associated with impaired antiplatelet response to irreversibly acting P2Y12-receptor inhibitors. However, the impact of reticluated platelets (RP) on the reversibly acting injectable P2Y12-receptor inhibitor cangrelor is unknown. Thus, this study sought to investigate the influence of RP on cangrelor and transitioning strategies to oral P2Y12-receptor inhibitors. METHODS: This study randomized 110 patients undergoing elective percutaneous coronary intervention with use of cangrelor to different oral transitioning strategies loading with prasugrel 60 mg or ticagrelor 180 mg at the start of cangrelor (n = 45 each) or loading with clopidogrel 600 mg after discontinuation of cangrelor (n = 20). ADP-induced platelet reactivity was assessed by impedance aggregometry. Reticulated platelets were analysed by an automated whole blood flow cytometry and described as immature platelet count. RESULTS: There was no correlation of reticulated platelets and ADP-induced platelet reactivity in patients under treatment with cangrelor (r = 0.06, p = 0.47). This finding was consistent in all three transitioning strategies. On day 1 following treatment with cangrelor, the correlation of reticulated platelets and platelet reactivity was detectable again in patients receiving thienopyridines but not ticagrelor (all patients r = 0.37, p < 0.001; clopidogrel: r = 0.59, p = 0.01; prasugrel: r = 0.47, p < 0.001; ticagrelor r = 0.22, p = 0.13). CONCLUSION: Platelet inhibition is not influenced by levels of reticulated platelets during infusion of cangrelor independent of oral P2Y12-receptor inhibitor transitioning strategy. These findings underline the potency of cangrelor as immediate and reversibly acting P2Y12-receptor inhibitor.

Cerebrovascular Outcomes With Proton Pump Inhibitors and Thienopyridines: A Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Pharmacokinetic and prior studies on thienopyridine and proton pump inhibitors (PPI) coadministration provide conflicting data for cardiovascular outcomes, whereas there is no established evidence on the association of concomitant use of PPI and thienopyridines with adverse cerebrovascular outcomes. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials and cohort studies from inception to July 2017, reporting following outcomes among patients treated with thienopyridine and PPI versus thienopyridine alone (1) ischemic stroke, (2) combined ischemic or hemorrhagic stroke, (3) composite outcome of stroke, myocardial infarction (MI), and cardiovascular death, (4) MI, (5) all-cause mortality, and (6) major or minor bleeding events. After the unadjusted analyses of risk ratios, we performed additional analyses of studies reporting hazard ratios adjusted for potential confounders. RESULTS: We identified 22 studies (12 randomized controlled trials and 10 cohort studies) comprising 131 714 patients. Concomitant use of PPI with thienopyridines was associated with increased risk of ischemic stroke (risk ratio, 1.74; 95% confidence interval [CI], 1.41-2.16; P<0.001), composite stroke/MI/cardiovascular death (risk ratio, 1.14; 95% CI, 1.01-1.29; P=0.04), and MI (risk ratio, 1.19; 95% CI, 1.00-1.40; P=0.05). Likewise, in adjusted analyses concomitant use of PPI with thienopyridines was again associated with increased risk of stroke (hazard ratios adjusted, 1.30; 95% CI, 1.04-1.61; P=0.02), composite stroke/MI/cardiovascular death (hazard ratios adjusted, 1.23; 95% CI, 1.03-1.47; P=0.02), but not with MI (hazard ratios adjusted, 1.19; 95% CI, 0.93-1.52; P=0.16). CONCLUSIONS: Co-prescription of PPI and thienopyridines increases the risk of incident ischemic strokes and composite stroke/MI/cardiovascular death. Our findings corroborate the current guidelines for PPI deprescription and pharmacovigilance, especially in patients treated with thienopyridines.

Differences in outcomes in patients with stable coronary artery disease managed by cardiologists versus noncardiologists. Results from the international prospective CLARIFY registry.

INTRODUCTION    Clinical outcomes of patients with stable coronary artery disease (CAD) may differ between those primarily managed by cardiologists versus noncardiologists. OBJECTIVES    Our main objective was to analyze the clinical outcomes of outpatients with stable CAD in relation to the specialty of the managing physicians. PATIENTS AND METHODS    We studied 32 468 outpatients with stable CAD included in the CLARIFY registry, with up to 4 years of follow­up data. Cardiologists provided medical care in 84.1% and noncardiologists in 15.9% of the patients. Primary outcome was the composite of cardiovascular death, nonfatal myocardial infarction (MI), or stroke. RESULTS    Important differences in management as well as demographic and clinical characteristics were observed between the groups at baseline. Patients treated by cardiologists were younger and more of them had dyslipidemia, hypertension, and diabetes. The use of ß­blockers and thienopyridines, as well as history of percutaneous coronary intervention were more frequent in this group. More patients treated by noncardiologists had a history of MI as well as concomitant peripheral artery disease and asthma or chronic obstructive pulmonary disease. They also had lower left ventricular ejection fraction and more often received lipid­lowering drugs. After adjustment for baseline differences, patients treated by cardiologists had a lower risk of the primary outcome (adjusted hazard ratio, 0.80; 95% confidence interval, 0.68­0.94; P = 0.0067) and of most secondary outcomes, but greater risk of bleeding. CONCLUSIONS Outpatients with stable CAD managed by cardiologists had a lower rate of cardiovascular outcomes than those managed by noncardiologists. We did not find clear evidence that cardiologists provided superior guideline­based treatment, so the differences in outcome were most likely due to unquantifiable differences in patient characteristics.

Dual antiplatelet therapy is associated with prolonged survival after lower extremity revascularization.

BACKGROUND: Dual antiplatelet therapy (DAPT) after coronary stenting prolongs survival by preventing both in-stent thrombosis and other cardiovascular atherothrombotic events. Patients with peripheral artery disease (PAD) typically have a heavy burden of unrevascularized coronary artery disease and also stand to benefit from increased atherothrombotic protection with DAPT. The potential benefit of DAPT compared with aspirin alone in patients with PAD is not well described. METHODS: We identified all patients undergoing an initial elective lower extremity revascularization (bypass or endovascular) from 2003 to 2016 in the Vascular Quality Initiative registry discharged on aspirin or aspirin plus a thienopyridine antiplatelet agent (DAPT). We first estimated models predicting the likelihood of receiving DAPT and then used inverse probability weighting to account for baseline differences in the likelihood of receiving DAPT and compared late survival. For sensitivity analysis, we also performed Cox proportion hazard modeling on the unweighted cohorts and generated adjusted survival curves. RESULTS: We identified 57,041 patients undergoing lower extremity revascularization (28% bypass). Of 15,985 bypasses (69% for critical limb ischemia [CLI]), 38% were discharged on DAPT. Of 41,056 endovascular interventions (39% for CLI), 69% were discharged on DAPT. Analyses using inverse probability weighting demonstrated a small survival benefit to DAPT at 1 year for bypass (93% vs 92% [P = .001]) and endovascular interventions (93% vs 92% [P = .005]) that was sustained through 5 years of follow-up (bypass, 80% vs 78% [P = .004]; endovascular, 76% vs 73% [P = .002]). When stratified by severity of PAD, DAPT had a survival benefit for patients with CLI undergoing bypass (5 years, 70% vs 66% [P = .04]) and endovascular intervention (5 years, 71% vs 67% [P = .01]) but not for patients with claudication (bypass, 89% vs 88% [P = .36]; endovascular, 87% vs 85% [P = .46]). The protective effect of DAPT was similar when using Cox proportional hazard models after bypass (hazard ratio, 0.81 [95% confidence interval, 0.72-0.90]) and endovascular intervention (hazard ratio, 0.89 [95% confidence interval, 0.83-0.95]). CONCLUSIONS: DAPT at time of discharge was associated with prolonged survival for patients with CLI undergoing lower extremity revascularization but not for those with claudication. Further research is needed to quantify the risks associated with DAPT and to identify subgroups at increased risk of thrombotic and bleeding complications to guide medical management of patients with PAD.

Impact of an integrated treatment algorithm based on platelet function testing and clinical risk assessment: results of the TRIAGE Patients Undergoing Percutaneous Coronary Interventions To Improve Clinical Outcomes Through Optimal Platelet Inhibition study.

Assessment of platelet reactivity alone for thienopyridine selection with percutaneous coronary intervention (PCI) has not been associated with improved outcomes. In TRIAGE, a prospective multicenter observational pilot study we sought to evaluate the benefit of an integrated algorithm combining clinical risk and platelet function testing to select type of thienopyridine in patients undergoing PCI. Patients on chronic clopidogrel therapy underwent platelet function testing prior to PCI using the VerifyNow assay to determine high on treatment platelet reactivity (HTPR, ≥230 P2Y12 reactivity units or PRU). Based on both PRU and clinical (ischemic and bleeding) risks, patients were switched to prasugrel or continued on clopidogrel per the study algorithm. The primary endpoints were (i) 1-year major adverse cardiovascular events (MACE) composite of death, non-fatal myocardial infarction, or definite or probable stent thrombosis; and (ii) major bleeding, Bleeding Academic Research Consortium type 2, 3 or 5. Out of 318 clopidogrel treated patients with a mean age of 65.9 ± 9.8 years, HTPR was noted in 33.3 %. Ninety (28.0 %) patients overall were switched to prasugrel and 228 (72.0 %) continued clopidogrel. The prasugrel group had fewer smokers and more patients with heart failure. At 1-year MACE occurred in 4.4 % of majority HTPR patients on prasugrel versus 3.5 % of primarily non-HTPR patients on clopidogrel (p = 0.7). Major bleeding (5.6 vs 7.9 %, p = 0.47) was numerically higher with clopidogrel compared with prasugrel. Use of the study clinical risk algorithm for choice and intensity of thienopyridine prescription following PCI resulted in similar ischemic outcomes in HTPR patients receiving prasugrel and primarily non-HTPR patients on clopidogrel without an untoward increase in bleeding with prasugrel. However, the study was prematurely terminated and these findings are therefore hypothesis generating.

Manejo de la antiagregación y anticoagulación periendoscópica: introducción a antiagregantes y anticoagulantes orales más novedosos / Management of antiplatelet and anticoagulant therapy for endoscopic procedures: Introduction to novel oral anticoagulants

El desarrollo de novedosos fármacos antitrombóticos en los últimos años y su amplia prescripción en la población con patología cardiovascular y circulatoria ha ampliado el espectro de medicamentos que deben tenerse en cuenta a la hora de realizar un procedimiento endoscópico. La balanza entre el riesgo trombótico que presentan los pacientes debido a su patología subyacente y riesgo hemorrágico que conllevan algunas técnicas endoscópicas debe conocerse a fondo por parte de los gastroenterólogos. Los nuevos anticoagulantes orales suponen un reto adicional. Estos agentes, dirigidos específicamente frente a los factores IIa o Xa, no tienen métodos de monitorización del grado de anticoagulación ni antídoto que revierta su efecto, al igual que ocurre con los antiagregantes. Comprender aspectos claves de estos fármacos aportará los conocimientos necesarios para determinar el momento ideal de realización de la técnica y el tiempo de suspensión de los agentes antitrombóticos, con el fin de ofrecer la máxima seguridad para los pacientes y optimizar los resultados (AU)

The development of novel antithrombotic therapy in the past few years and its prescription in patients with cardiovascular and circulatory disease has widened the spectrum of drugs that need to be considered when performing an endoscopic procedure. The balance between the thrombotic risk patients carry due to their medical history and the bleeding risk involved in endoscopic procedures should be thoroughly analyzed by Gastroenterologists. New oral anticoagulants (NOACs) impose an additional task. These agents, that specifically target factor IIa or Xa, do not dispose of an anticoagulation monitoring method nor have an antidote to revert their effect, just as with antiplatelet agents. Understanding the fundamental aspects of these drugs provides the necessary knowledge to determine the ideal period the antithrombotic therapy should be interrupted in order to perform the endoscopic procedure, offering maximum safety for patients and optimal results (AU)

Effects of P2Y12 receptor antagonists beyond platelet inhibition--comparison of ticagrelor with thienopyridines.

The effect and clinical benefit of P2Y12 receptor antagonists may not be limited to platelet inhibition and the prevention of arterial thrombus formation. Potential additional effects include reduction of the pro-inflammatory role of activated platelets and effects related to P2Y12 receptor inhibition on other cells apart from platelets. P2Y12 receptor antagonists, thienopyridines and ticagrelor, differ in their mode of action being prodrugs instead of direct acting and irreversibly instead of reversibly binding to P2Y12 . These key differences may provide different potential when it comes to additional effects. In addition to P2Y12 receptor blockade, ticagrelor is unique in having the only well-documented additional target of inhibition, the equilibrative nucleoside transporter 1. The current review will address the effects of P2Y12 receptor antagonists beyond platelets and the protection against arterial thrombosis. The discussion will include the potential for thienopyridines and ticagrelor to mediate anti-inflammatory effects, to conserve vascular function, to affect atherosclerosis, to provide cardioprotection and to induce dyspnea.

Management of acute coronary syndromes in a developing country; time for a paradigm shift? an observational study.

BACKGROUND: There are limited contemporary data on the presentation, management and outcomes of acute coronary syndromes (ACS) in Sri Lanka. We aimed to identify the critical issues that limit optimal management of ACS in Sri Lanka. METHODS: We performed a prospectively observational study of 256 consecutive patients who presented with ACS between November 2011 and May 2012 at a tertiary care general medical unit in Sri Lanka. RESULTS: We evaluated data on presentation, management, in-hospital mortality, and major adverse cardiovascular events (MACE) of participants. Smoking, alcohol abuse, and obesity were more common in patients with ST elevation myocardial infarction (STEMI) (P < 0.05). Discharge diagnoses were STEMI in 32.8 % (84/256) and unstable angina (UA)/non-ST elevation myocardial infarction [NSTEMI] in 67.1 % (172/256) of participants. The median time (IQR) from onset of pain to presentation was 60 (319) minutes for STEMI and 120 (420) for UA/NSTEMI (P = 0.058). A median delay of 240 min was noted in patients who had presented initially to smaller hospitals. Cardiac markers were assessed in only 35 % of participants. In-hospital anti-platelet use was high (>92 %). Only 70.2 % of STEMI patients received fibrinolytic therapy. Fewer than 20 % of patients were received fibrinolytic therapy within 30 min of arrival. Major adverse cardiac events (MACE) were recorded in 11.9 % of subjects with STEMI and 11.6 % of those with UA/NSTEMI (P = 0.5). According to logistic regression analysis, body mass index (P = 0.045) and duration of diabetes (P = 0.03) were significant predictors of in-hospital MACE. On discharge, aspirin, thienopyridine, and statins were prescribed to more than 90 % of patients. Only one patient underwent coronary angiography during the index admission. CONCLUSIONS: Delays in presentation and in initiation of thrombolytic therapy and coronary interventions are key hurdles that need attention to optimize ACS care in Sri Lanka.

Historical perspective and contemporary management of acute coronary syndromes: from MONA to THROMBINS2.

Acute coronary syndrome (ACS) remains a major burden on morbidity and mortality in the United States. Medical professionals and students often use the mnemonic 'MONA' (morphine, oxygen, nitroglycerin and aspirin) to recall treatments for ACS; however, this list of therapies is outdated. We provide a historical perspective on 'MONA,' attempt to uncover its origin in the medical literature, and demonstrate the myriad changes that have occurred over the last 50 years of ACS management. We have developed a novel mnemonic, 'THROMBINS2' (thienopyridines, heparin/enoxaparin, renin-angiotensin system blockers, oxygen, morphine, beta blocker, intervention, nitroglycerin, statin/salicylate) to help bedside clinicians recall all the elements of contemporary ACS management. We demonstrate the mortality benefit for each component of contemporary ACS management, correlating the continued improvement with historical data on mortality after myocardial infarction. We encourage providers to utilize this mnemonic to explore options and guide treatments in ACS patients.

Selective inhibitors of Plasmodium falciparum glycogen synthase-3 (PfGSK-3): New antimalarial agents?

Plasmodium falciparum glycogen synthase kinase-3 (PfGSK-3) is one of the eukaryotic protein kinases that were identified as essential for the parasite causing malaria tropica. Although the physiological functions of PfGSK-3 are still unknown, it had been suggested as a putative target for novel antimalarial drugs. The high structural similarity of PfGSK-3 and its human orthologue HsGSK-3 makes the development of selective PfGSK-3 inhibitors a challenging task. Actually, established GSK-3 inhibitors are either unselective or are more potent for inhibition of the mammalian GSK-3. A high throughput screening campaign identified thieno[2,3-b]pyridines as a new class of PfGSK-3 inhibitors. Systematic variation of the substitution pattern at the parent scaffold led to compounds which selectively inhibited the plasmodial enzyme. These compounds also exhibited activity against erythrocyte stages of the parasites. A hypothetical explanation for the selectivity of the new antimalarial compounds was enunciated based on the results of docking a selective inhibitor into a PfGSK-3 homology model and by comparison of the results with an X-ray structure of HsGSK-3 co-crystallized with a similar but unselective compound. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.

Genetic determined low response to thienopyridines is associated with higher systemic inflammation in smokers.

AIM: To investigate whether the interactions of CYP2C19*2 and CYP2C19*17 with smoking are associated with the levels of P2Y12 receptor inhibition and CRP, in on-thienopyridine post-stenting patients. METHODS & RESULTS: At 1-month follow-up, the interactions of smoking and CYP2C19 polymorphisms on the vasodilator-stimulated phosphoprotein - platelet reactivity index (VASP PRI), and CRP were explored in three metabolizing groups (1128 patients) as follow: poor metabolizers (*2 carriers/*17 noncarriers); intermediate metabolizers (*2 carriers/*17 carriers or *2 noncarriers/*17 noncarriers); and ultrarapidmetabolizers (*2 allele noncarriers/*17 carriers). The interactions of metabolizing status and smoking was significant for CRP (p = 0.001) but not for VASP PRI (p = 0.734). CONCLUSION: Interaction between CYP2C19 polymorphisms and smoking modifies on-treatment CRP level of post-stenting, on-thienopyridine patients. This effect seems to be independent to the level of P2Y12 receptor inhibition.

Antiplatelet therapy discontinuation and the risk of serious cardiovascular events after coronary stenting: observations from the CREDO-Kyoto Registry Cohort-2.

Relation of antiplatelet therapy (APT) discontinuation with the risk of serious cardiovascular events has not been fully addressed yet. This study is aimed to evaluate the risk of ischemic event after APT discontinuation based on long-term APT status of large cohort. In the CREDO-Kyoto Registry Cohort-2 enrolling 15939 consecutive patients undergoing first coronary revascularization, 10470 patients underwent percutaneous coronary intervention either with bare-metal stents (BMS) only (N=5392) or sirolimus-eluting stents (SES) only (N=5078). Proportions of patients taking dual-APT were 67.3% versus 33.4% at 1-year, and 48.7% versus 24.3% at 5-year in the SES and BMS strata, respectively. We evaluated daily APT status (dual-, single- and no-APT) and linked the adverse events to the APT status just 1-day before the events. No-APT as compared with dual- or single-APT was associated with significantly higher risk for stent thrombosis (ST) beyond 1-month after SES implantation (cumulative incidence rates beyond 1-month: 1.23 versus 0.15/0.29, P<0.001/P<0.001), while higher risk of no-APT for ST was evident only until 6-month after BMS implantation (incidence rates between 1- and 6-month: 8.43 versus 0.71/1.20, P<0.001/P<0.001, and cumulative incidence rates beyond 6-month: 0.31 versus 0.11/0.08, P=0.16/P=0.08). No-APT as compared with dual- or single-APT was also associated with significantly higher risk for spontaneous myocardial infarction (MI) and stroke regardless of the types of stents implanted. Single-APT as compared with dual-APT was not associated with higher risk for serious adverse events, except for the marginally higher risk for ST in the SES stratum. In conclusion, discontinuation of both aspirin and thienopyridines was associated with increased risk for serious cardiovascular events including ST, spontaneous MI and stroke beyond 1-month after coronary stenting.

Thienopyridine derivatives as risk factors for bleeding following high risk endoscopic treatments: Safe Treatment on Antiplatelets (STRAP) study.

BACKGROUND AND STUDY AIMS: The optimal method of perioperative management of antiplatelet agents during endoscopic procedures that carry a high risk of bleeding is still controversial. The aim of this study was to evaluate the safety of continuing aspirin treatment during these procedures in an Asian population. PATIENTS AND METHODS: A multicenter, prospective, observational cohort study was conducted at six high volume endoscopy centers in Japan. The study included patients at high risk of thromboembolism who were regularly taking antiplatelet agents (e. g. thienopyridine derivatives and aspirin). Enrolled patients continued their aspirin therapy, and underwent endoscopic procedures that had a high risk of bleeding for treatment of lesions in the upper and lower gastrointestinal tracts. The primary end point was the rate of major bleeding complications after endoscopic procedures. RESULTS: The study was terminated in accordance with predetermined safety criteria because 7 of 28 consecutive patients experienced major bleeding complications (25.0 %; 95 % confidence interval 10.7 % - 44.9 %). All major bleeding complications occurred following endoscopic submucosal dissection (ESD; 6 stomach, 1 colon). Univariate analysis showed that postoperative administration of thienopyridine derivatives was the only significant factor associated with postoperative bleeding (P = 0.01). Subanalysis of gastric ESD (23 lesions in 19 patients) confirmed that the administration of thienopyridine derivatives (P = 0.01) and that of multiple agents (P = 0.02) were the significant factors. All bleeding complications (postoperative day 11.2 ±â€Š3.5) occurred after resuming thienopyridine derivative therapy postoperatively (postoperative day 2.3 ±â€Š2.4). CONCLUSION: In Asian patients taking thienopyridine derivatives with aspirin, cautious postoperative care is necessary for those undergoing endoscopic procedures that are associated with a high risk of bleeding, especially gastric ESD. Continuation of aspirin alone during these endoscopic procedures may be acceptable. STUDY REGISTRATION: UMIN000009176.

Antiplatelet and anticoagulant drugs management before gastrointestinal endoscopy: do clinicians adhere to current guidelines?

BACKGROUND: Managing antiplatelet and anticoagulant drugs before endoscopy may be challenging. AIMS: To assess whether the pre-endoscopic management of antiplatelet/anticoagulant drugs is adherent to current guidelines and the influence of patients' characteristics, referring physician's specialty, type of endoscopic procedure and therapeutic regimen on adherence. METHODS: Two hundred and twenty patients taking aspirin, thienopyridines or warfarin and scheduled for upper endoscopy (± biopsies), variceal band ligation, colonoscopy (± biopsies or polypectomy), were prospectively analyzed. RESULTS: In 109 patients (49.5%) the management of antiplatelet/anticoagulant drugs was thoroughly compliant with guidelines. Neither demographic characteristics, nor in/outpatient status, nor type of endoscopic procedure, nor physician's specialty influenced the adherence but the therapeutic regimen had a significant impact (p < 0.0001) as compliance was less likely in patients on warfarin. Unwarranted drugs withholding was more frequent before colonoscopy than upper endoscopy (p = 0.0001). Warfarin was stopped longer than recommended more frequently than aspirin (p = 0.009). The International Normalized Ratio was properly checked before endoscopy in 47.7% of patients. Among the 55 patients who withheld warfarin, the decision about bridging to low molecular weight heparin was appropriate in 21 (38.2%). CONCLUSIONS: Compliance with guidelines is low especially in the management of warfarin, both among gastroenterologists and other physicians.

Aspirin, clopidogrel, and the surgeon.

The rising use of antiplatelet therapy for primary prevention and secondary prevention of cardiovascular and cerebrovascular events poses a dilemma for physicians in the perioperative period. The proven benefits of aspirin in preventing further thrombotic events in patients with prior ACS or stroke make it difficult to withdraw this therapy. The risk of hypercoagulability associated with surgery is also independent of antiplatelet withdrawal, but adds to the rebound effect of platelet responsiveness. Therefore, aspirin should be continued whenever feasible. Similarly, the use of thienopyridines such as clopidogrel, especially for the prevention of stent thrombosis, should be maintained for at least the recommended time frame, if not longer. It is recognized that maintaining antiplatelet therapy is also not without risk, as bleeding complications have been well documented. Unfortunately, current perioperative guidelines do not often provide a simple solution for management. Therefore, the risk of bleeding has to be weighed against the risk of thrombosis, and decisions should be made with all providers caring for the patient on an individual basis.

Antiagregación: resistencia a fármacos tradicionales y papel de los nuevos antiplaquetarios / Antiplatelet therapy: Resistance to traditional antiaggregation drugs and role of new antiplatelet agents

La agregación plaquetaria desempeña un papel fundamental en la aparición de episodios cardiovasculares mayores (ECM) relacionados con la aterotrombosis, cobrando un mayor protagonismo tras la aparición de la angioplastia con stent. El doble tratamiento antiagregante con aspirina y clopidogrel en pacientes que se han sometido a una intervención coronaria percutánea ha demostrado ampliamente sus efectos beneficiosos en la reducción de ECM en comparación con aspirina sola. Estos beneficios también se han demostrado en el tratamiento a corto y largo plazo en el tratamiento conservador de pacientes con enfermedad arterial coronaria. Sin embargo, a pesar de la doble antiagregación, un importante número de pacientes tuvieron un nuevo ECM relacionado con una inhibición plaquetaria incompleta. Muchos estudios sugieren una importante variabilidad interindividual en la respuesta a fármacos antiagregantes en probable relación con el uso de distintas técnicas de medición de la agregabilidad. Por otro lado, existen artículos en la literatura médica que relacionan la menor respuesta a antiagregantes con un mayor riesgo de recurrencia de ECM. Es cada vez más evidente que la resistencia al tratamiento antiplaquetario convencional es un tema clínicamente relevante que necesita ser tomado en cuenta para llevar a cabo un tratamiento individualizado. En este sentido, los nuevos fármacos antiagregantes, como prasugrel y ticagrelor, parecen una alternativa razonable a los fármacos tradicionales cuando la respuesta a estos está reducida, cobrando un papel cada vez más relevante en distintos documentos de consenso (AU)

Platelet aggregation plays a key role in the development of major cardiovascular events (MACE) related to atherothrombosis. Since the appearance of coronary stenting, the importance of measuring and modulating platelet activity has considerably increased in the scientific literature during the last decade. Double antiplatelet therapy with aspirin and clopidogrel administrated to stent carriers has widely demonstrated its efficacy in the prevention of MACE compared with aspirin alone. These benefits are also present when a conservatory approach is chosen for acute coronary syndrome management. However, there are an important number of patients who develop MACE despite optimal dual antiplatelet therapy, most likely related to an incomplete platelet activity inhibition. Many studies suggest an important inter-individual variability in the response to the drugs, maybe related, at least in part, to the use of different assessment techniques of platelet aggregation. Other authors suggest an incomplete platelet inhibition as a possible explanation for the presence of MACE in patients under optimal antiplatelet therapy. Resistance to usual drugs has become a clinically relevant issue that requires an individual approach where new antiplatelet agents, such as prasugrel or ticagrelor, could play an important role as stated in current consensus documents (AU)