Comparative effects of different antiplatelet strategies in carriers of CYP2C19 loss-of-function alleles: a network meta-analysis.

BACKGROUND: Carriers of cytochrome 2C19 (CYP2C19) loss of function (LoF) alleles treated with clopidogrel have impaired drug metabolism resulting in reduced active metabolite levels, high platelet reactivity (HPR), and an increased risk of thrombotic events. Several alternative antiplatelet therapies have been proposed to overcome HPR in these patients, but their comparative effects remain poorly explored. METHODS: Randomized controlled trials (RCTs) comparing different oral antiplatelet therapies in carriers of CYP2C19 LoF alleles undergoing percutaneous coronary interventions (PCI) were included. A frequentist network meta-analysis was conducted to estimate mean difference (MD) or odds ratios (OR) and 95% confidence intervals (CI). The primary outcome was platelet reactivity assessed by VerifyNow and reported as P2Y12 reaction unit (PRU). The secondary outcome was the rate of HPR. Standard-dose of clopidogrel (75 mg daily) was used as reference treatment. RESULTS: A total of 12 RCTs testing 6 alternative strategies (i.e., clopidogrel 150 mg, prasugrel 3.75 mg, 5 mg, and 10 mg, ticagrelor 90 mg bid, and adjunctive cilostazol 100 mg bid) were included in the network. Compared with standard-dose clopidogrel, the greatest reduction in PRU was observed with prasugrel 10 mg (MD -127.91; 95% CI -141.04; -114.78) and ticagrelor 90 mg bid (MD -124.91; 95% CI -161.78; -88.04), followed by prasugrel 5 mg (MD -76.33; 95% CI -98.01; -54.65) and prasugrel 3.75 mg (MD -73.00; 95% CI -100.28; -45.72). Among other strategies, adjunctive cilostazol (MD-42.64; 95% CI -64.72; -20.57) and high-dose clopidogrel (MD -32.11; 95% CI -51.33; -12.90) were associated with a modest reduction in PRU compared with standard-dose clopidogrel. CONCLUSION: Among carriers of CYP2C19 LoF alleles undergoing PCI, standard-dose prasugrel or ticagrelor are most effective in reducing platelet reactivity, while double-dose clopidogrel and additional cilostazol showed modest effects. Reduced-dose of prasugrel may represent a balanced strategy to overcome HPR without a significant increase in bleeding. The clinical implications of these pharmacodynamic findings warrant further investigation.

Asociación de las características del ensayo con la publicación simultánea y su impacto en citas y menciones: un estudio transversal / Association of trial characteristics with simultaneous publication and its impact on citations and mentions: a cross-sectional study

Introducción y objetivos: Los ensayos clínicos aleatorizados a menudo se presentan en conferencias médicas y se publican al mismo tiempo o después. Los predictores de publicación simultánea y sus consecuencias no están determinados. Nuestro objetivo es caracterizar la práctica de la publicación simultánea, identificar sus predictores y evaluar su impacto. Métodos: En este estudio transversal se incluyeron ensayos clínicos aleatorizados presentados en sesiones de ciencia de última hora de importantes conferencias cardiovasculares desde 2015 hasta 2021. Se analizó la asociación entre las características del ensayo y el momento de la publicación. Se investigó el impacto de la publicación simultánea frente a la no simultánea en el número de citas a 1 año y menciones a 1 mes, así como en el total de citas y menciones en el seguimiento más largo observado. Resultados: De los 478 ensayos incluidos en el análisis, el 48,7% se publicó simultáneamente. Las publicaciones simultáneas tenían mayor probabilidad de presentarse en la sala principal de la conferencia (OR=6,09; IC95%, 1,34-36,92; p=0,029) y se caracterizaban por un tiempo de revisión más corto (OR=0,95; IC95%, 0,91-0,96; p<0,001). Las publicaciones simultáneas se asociaron con un mayor número de citas a 1 año (R2=43,81; IC95%, 23,89-63,73; p<0,001), menciones a 1 mes (R2=132,32; IC95%, 85,42-179,22; p<0,001) y total de citas (R2=222,89; IC95%, 127,98-317,80; p<0,001) en el seguimiento. Conclusiones: Los ensayos clínicos aleatorizados presentados en la sala principal de la conferencia y con un tiempo de revisión más corto tienen mayor probabilidad de publicarse simultáneamente. Las publicaciones simultáneas se asocian con más citas y menciones que las publicaciones no simultáneas. (AU)

Introduction and objectives: Randomized trials are often presented at medical conferences and published simultaneously or later. Predictors of simultaneous publication and its consequences are undetermined. Our aim was to characterize the practice of simultaneous publication, identify its predictors, and evaluate its impact. Methods: In this cross-sectional study, we included randomized trials presented at late-breaking science sessions of major cardiovascular conferences from 2015 to 2021. The association of trial characteristics with the timing of publication was analyzed. The impact of simultaneous vs nonsimultaneous publication was investigated on the number of 1-year citations and 1-month mentions, and the total citations and mentions at the longest observation follow-up. Results: Of 478 trials included in the analysis, 48.7% were published simultaneously. Simultaneous publications were more likely to be presented in the main conference room (OR, 6.09; 95%CI, 1.34-36.92; P=.029) and were characterized by a shorter review time (OR, 0.95; 95%CI, 0.91-0.96; P<.001). Simultaneous publications were associated with higher 1-year citations (R2, 43.81; 95%CI, 23.89-63.73; P<.001), 1-month mentions (R2, 132.32; 95%CI, 85.42-179.22; P<.001) and total citations (R2, 222.89; 95%CI, 127.98-317.80; P<.001). Conclusions: Randomized trials presented in the main conference room and with shorter review time were more likely to be published simultaneously. Simultaneous publications were associated with more citations and mentions than nonsimultaneous publications. (AU)

Percutaneous interventions for pulmonary embolism.

Pulmonary embolism (PE) ranks as a leading cause of in-hospital mortality and the third most common cause of cardiovascular death. The spectrum of PE manifestations varies widely, making it difficult to determine the best treatment approach for specific patients. Conventional treatment options include anticoagulation, thrombolysis, or surgery, but emerging percutaneous interventional procedures are being investigated for their potential benefits in heterogeneous PE populations. These novel interventional techniques encompass catheter-directed thrombolysis, mechanical thrombectomy, and hybrid approaches combining different mechanisms. Furthermore, inferior vena cava filters are also available as an option for PE prevention. Such interventions may offer faster improvements in right ventricular function, as well as in pulmonary and systemic haemodynamics, in individual patients. Moreover, percutaneous treatment may be a valid alternative to traditional therapies in high bleeding risk patients and could potentially reduce the burden of mortality related to major bleeds, such as that of haemorrhagic strokes. Nevertheless, the safety and efficacy of these techniques compared to conservative therapies have not been conclusively established. This review offers a comprehensive evaluation of the current evidence for percutaneous interventions in PE and provides guidance for selecting appropriate patients and treatments. It serves as a valuable resource for future researchers and clinicians seeking to advance this field. Additionally, we explore future perspectives, proposing "percutaneous primary pulmonary intervention" as a potential paradigm shift in the field.

Periprocedural myocardial infarction and injury.

Periprocedural myocardial infarction (PMI) and injury, pertinent to both cardiac and non-cardiac procedures, have gained increasing recognition in clinical practice. Over time, diverse definitions for diagnosing PMI have been developed and validated among patient populations undergoing coronary revascularization. However, this variety in definitions presents considerable challenges in clinical settings and complicates both the design and interpretation of clinical trials. The necessity to accurately diagnose PMI has spurred significant interest in establishing universally accepted and prognostically meaningful thresholds for cardiac biomarkers elevation and supportive ancillary criteria. In fact, elevations in cardiac biomarkers in line with the 4th Universal Definition of Myocardial Infarction, have been extensively confirmed to be associated with increased mortality and cardiovascular events. In the context of non-coronary cardiac procedures, such as Transcatheter Aortic Valve Implantation, there is a growing acknowledgment of both the high incidence rates and the adverse impact of PMI on patient outcomes. Similarly, emerging research underscores the significance of PMI and injury in non-cardiac surgery, highlighting the urgent need for effective prevention and risk management strategies in this domain.

Coronary Angiography, Intravascular Ultrasound, and Optical Coherence Tomography for Guiding of Percutaneous Coronary Intervention: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Results from multiple randomized clinical trials comparing outcomes after intravascular ultrasound (IVUS)- and optical coherence tomography (OCT)-guided percutaneous coronary intervention (PCI) with invasive coronary angiography (ICA)-guided PCI as well as a pivotal trial comparing the 2 intravascular imaging (IVI) techniques have provided mixed results. METHODS: Major electronic databases were searched to identify eligible trials evaluating at least 2 PCI guidance strategies among ICA, IVUS, and OCT. The 2 coprimary outcomes were target lesion revascularization and myocardial infarction. The secondary outcomes included ischemia-driven target lesion revascularization, target vessel myocardial infarction, death, cardiac death, target vessel revascularization, stent thrombosis, and major adverse cardiac events. Frequentist random-effects network meta-analyses were conducted. The results were replicated by Bayesian random-effects models. Pairwise meta-analyses of the direct components, multiple sensitivity analyses, and pairwise meta-analyses IVI versus ICA were supplemented. RESULTS: The results from 24 randomized trials (15 489 patients: IVUS versus ICA, 46.4%, 7189 patients; OCT versus ICA, 32.1%, 4976 patients; OCT versus IVUS, 21.4%, 3324 patients) were included in the network meta-analyses. IVUS was associated with reduced target lesion revascularization compared with ICA (odds ratio [OR], 0.69 [95% CI, 0.54-0.87]), whereas no significant differences were observed between OCT and ICA (OR, 0.83 [95% CI, 0.63-1.09]) and OCT and IVUS (OR, 1.21 [95% CI, 0.88-1.66]). Myocardial infarction did not significantly differ between guidance strategies (IVUS versus ICA: OR, 0.91 [95% CI, 0.70-1.19]; OCT versus ICA: OR, 0.87 [95% CI, 0.68-1.11]; OCT versus IVUS: OR, 0.96 [95% CI, 0.69-1.33]). These results were consistent with the secondary outcomes of ischemia-driven target lesion revascularization, target vessel myocardial infarction, and target vessel revascularization, and sensitivity analyses generally did not reveal inconsistency. OCT was associated with a significant reduction of stent thrombosis compared with ICA (OR, 0.49 [95% CI, 0.26-0.92]) but only in the frequentist analysis. Similarly, the results in terms of survival between IVUS or OCT and ICA were uncertain across analyses. A total of 25 randomized trials (17 128 patients) were included in the pairwise meta-analyses IVI versus ICA where IVI guidance was associated with reduced target lesion revascularization, cardiac death, and stent thrombosis. CONCLUSIONS: IVI-guided PCI was associated with a reduction in ischemia-driven target lesion revascularization compared with ICA-guided PCI, with the difference most evident for IVUS. In contrast, no significant differences in myocardial infarction were observed between guidance strategies.

Pharmacological and clinical appraisal of factor XI inhibitor drugs.

The evolution of anticoagulation therapy, from vitamin K antagonists to the advent of direct oral anticoagulants (DOACs) almost two decades ago, marks significant progress. Despite improved safety demonstrated in pivotal trials and post-marketing observations, persistent concerns exist, particularly regarding bleeding risk and the absence of therapeutic indications in specific subgroups or clinical contexts. Factor XI (FXI) has recently emerged as a pivotal contributor to intraluminal thrombus formation and growth, playing a limited role in sealing vessel wall injuries. Inhibiting FXI presents an opportunity to decouple thrombosis from haemostasis, addressing concerns related to bleeding events while safeguarding against thromboembolic events. Notably, FXI inhibition holds promise for patients with end-stage renal disease or cancer, where clear indications for DOACs are currently lacking. Various compounds have undergone design, testing, and progression to phase 2 clinical trials, demonstrating a generally favourable safety and tolerability profile. However, validation through large-scale phase 3 trials with sufficient power to assess both safety and efficacy outcomes is needed. This review comprehensively examines FXI inhibitors, delving into individual classes, exploring their pharmacological properties, evaluating the latest evidence from randomized trials, and offering insights into future perspectives.

Automated de Novo Design of Olefin Metathesis Catalysts: Computational and Experimental Analysis of a Simple Thermodynamic Design Criterion.

Methods for computational de novo design of inorganic molecules have paved the way for automated design of homogeneous catalysts. Such studies have so far relied on correlation-based prediction models as fitness functions (figures of merit), but the soundness of these approaches has yet to be tested by experimental verification of de novo-designed catalysts. Here, a previously developed criterion for the optimization of dative ligands L in ruthenium-based olefin metathesis catalysts RuCl2(L)(L')(═CHAr), where Ar is an aryl group and L' is a phosphine ligand dissociating to activate the catalyst, was used in de novo design experiments. These experiments predicted catalysts bearing an N-heterocyclic carbene (L = 9) substituted by two N-bound mesityls and two tert-butyl groups at the imidazolidin-2-ylidene backbone to be promising. Whereas the phosphine-stabilized precursor assumed by the prediction model could not be made, a pyridine-stabilized ruthenium alkylidene complex (17) bearing carbene 9 was less active than a known leading pyridine-stabilized Grubbs-type catalyst (18, L = H2IMes). A density functional theory-based analysis showed that the unsubstituted metallacyclobutane (MCB) intermediate generated in the presence of ethylene is the likely resting state of both 17 and 18. Whereas the design criterion via its correlation between the stability of the MCB and the rate-determining barrier indeed seeks to stabilize the MCB, it relies on RuCl2(L)(L')(═CH2) adducts as resting states. The change in resting state explains the discrepancy between the prediction and the actual performance of catalyst 17. To avoid such discrepancies and better address the multifaceted challenges of predicting catalytic performance, future de novo catalyst design studies should explore and test design criteria incorporating information from more than a single relative energy or intermediate.

Association of trial characteristics with simultaneous publication and its impact on citations and mentions: a cross-sectional study.

INTRODUCTION AND OBJECTIVES: Randomized trials are often presented at medical conferences and published simultaneously or later. Predictors of simultaneous publication and its consequences are undetermined. Our aim was to characterize the practice of simultaneous publication, identify its predictors, and evaluate its impact. METHODS: In this cross-sectional study, we included randomized trials presented at late-breaking science sessions of major cardiovascular conferences from 2015 to 2021. The association of trial characteristics with the timing of publication was analyzed. The impact of simultaneous vs nonsimultaneous publication was investigated on the number of 1-year citations and 1-month mentions, and the total citations and mentions at the longest observation follow-up. RESULTS: Of 478 trials included in the analysis, 48.7% were published simultaneously. Simultaneous publications were more likely to be presented in the main conference room (OR, 6.09; 95%CI, 1.34-36.92; P=.029) and were characterized by a shorter review time (OR, 0.95; 95%CI, 0.91-0.96; P<.001). Simultaneous publications were associated with higher 1-year citations (R2, 43.81; 95%CI, 23.89-63.73; P<.001), 1-month mentions (R2, 132.32; 95%CI, 85.42-179.22; P<.001) and total citations (R2, 222.89; 95%CI, 127.98-317.80; P<.001). CONCLUSIONS: Randomized trials presented in the main conference room and with shorter review time were more likely to be published simultaneously. Simultaneous publications were associated with more citations and mentions than nonsimultaneous publications.

Impact of ethnicity on antiplatelet treatment regimens for bleeding reduction in acute coronary syndromes: a systematic review and pre-specified subgroup meta-analysis.

AIMS: Randomized controlled trials (RCTs) testing bleeding reduction strategies using antiplatelet treatment regimens (BRATs) in acute coronary syndromes (ACS) have shown promising results, but the generalizability of these findings may be significantly influenced by the ethnicity of the patients enrolled, given that East Asian (EA) patients show different ischaemic-bleeding risk profile compared to non-EA patients. METHODS AND RESULTS: RCTs comparing a BRAT vs. standard 12-month dual antiplatelet therapy (DAPT) in patients with ACS undergoing percutaneous coronary intervention (PCI) were selected. The primary efficacy endpoint was major adverse cardiovascular events (MACE) as defined in each trial and the primary safety endpoint was minor or major bleeding. Twenty-six RCTs testing seven different BRATs were included. The only strategy associated with a trade-off in MACE was 'upfront unguided de-escalation' in the subgroup of non-EAs (risk ratio 1.16, 95% confidence interval 1.09-1.24). All but aspirin monotherapy-based strategies (i.e. 'short and very short DAPT followed by aspirin') were associated with reduced bleeding compared with standard DAPT in both EA and non-EA patients. There were no significant differences between subgroups, but the lack of RCTs in some of the included strategies and the difference in the certainty of evidence between EA and non-EA patients revealed that the evidence in support of different BRATs in ACS undergoing PCI is influenced by ethnicity. Moreover, absolute risk reduction estimation revealed that some BRATs might be more effective than others in reducing bleeding according to ethnicity. CONCLUSION: The majority of BRATs are associated with reduced bleeding without any trade-off in hard ischaemic endpoints regardless of ethnicity. However, the supporting evidence and relative safety profiles of different BRATs might be significantly affected by ethnicity, which should be taken into account in clinical practice. STUDY REGISTRATION: This study is registered in PROSPERO (CRD42023416710).

PCSK9 inhibitors: current status and emerging frontiers in lipid control.

INTRODUCTION: Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of global mortality, imposing substantial healthcare economic burdens. Among the modifiable risk factors, hypercholesterolemia, especially elevated low-density lipoprotein cholesterol (LDL-C), plays a pivotal role in ASCVD development. Novel therapies such as PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) inhibitors are emerging to address this concern. These inhibitors offer the potential to reduce ASCVD risk by directly targeting LDL-C levels. AREAS COVERED: The article reviews the structural and functional aspects of PCSK9, highlighting its role in LDL receptor regulation. The pharmacological strategies for PCSK9 inhibition, including monoclonal antibodies, binding peptides, gene silencing, and active immunization, are explored. Clinical evidence from various trials underscores the safety and efficacy of PCSK9 inhibitors in reducing LDL-C levels and potentially improving cardiovascular outcomes. Despite these promising results, challenges such as cost-effectiveness and long-term safety considerations are addressed. EXPERT OPINION: Among PCSK9 inhibitors, monoclonal antibodies represent a cornerstone. Many trials have showed their efficacy in reducing LDL-C and the risk for major adverse clinical events, revealing long-lasting effects, with special benefits particularly for statin-intolerant and familial hypercholesterolemia patients. However, long-term impacts, high costs, and patient selection necessitate further research.

Antithrombotic Therapy for Primary and Secondary Prevention of Ischemic Stroke: JACC State-of-the-Art Review.

Stroke is a devastating condition with significant morbidity and mortality worldwide. Antithrombotic therapy plays a crucial role in both primary and secondary prevention of stroke events. Single or dual antiplatelet therapy is generally preferred in cases of large-artery atherosclerosis and small-vessel disease, whereas anticoagulation is recommended in conditions of blood stasis or hypercoagulable states that mostly result in red thrombi. However, the benefit of antithrombotic therapies must be weighed against the increased risk of bleeding, which can pose significant challenges in the pharmacological management of this condition. This review provides a comprehensive summary of the currently available evidence on antithrombotic therapy for ischemic stroke and outlines an updated therapeutic algorithm to support physicians in tailoring the strategy to the individual patient and the underlying mechanism of stroke.

Complete Percutaneous Coronary Revascularization in Acute Coronary Syndromes With Multivessel Coronary Disease: A Systematic Review.

Multivessel disease (MVD) affects approximately 50% of patients with acute coronary syndromes (ACS) and is significantly burdened by poor outcomes and high mortality. It represents a clinical challenge in patient management and decision making and subtends an evolving research area related to the pathophysiology of unstable plaques and local or systemic inflammation. The benefits of complete revascularization are established in hemodynamically stable ACS patients with MVD, and guidelines provide some reference points to inform clinical practice, based on an evidence level that is solid for ST-segment elevation myocardial infarction and less robust for non-ST-segment elevation myocardial infarction and cardiogenic shock. However, several areas of uncertainty remain, such as the optimal timing for complete revascularization or the best guiding strategy for intermediate stenoses. We performed a systematic review of current evidence in the field of percutaneous revascularization in ACS and MVD, also including future perspectives from ongoing trials that will directly compare different timing strategies and investigate the role of invasive and noninvasive guidance techniques. (Complete percutaneous coronary revascularization in patients with acute myocardial infarction and multivessel disease; CRD42022383123).

Diuresis inducida frente a hidratación combinada en pacientes sometidos a procedimientos cardiovasculares percutáneos: metanálisis de ensayos clínicos aleatorizados / Diuresis-matched versus standard hydration in patients undergoing percutaneous cardiovascular procedures: meta-analysis of randomized clinical trials

Introducción y objetivos: La nefropatía inducida por contraste (NIC) es una potencial complicación de los procedimientos que requieren la administración de medio de contraste yodado. El RenalGuard, que suministra una adecuada hidratación combinada con diuresis inducida por furosemida, es una alternativa a las estrategias convencionales de hidratación. Según la literatura disponible, la evidencia sobre el RenalGuard no es concluyente, por lo que hemos realizado un metanálisis utilizando una construcción bayesiana. Métodos Se realizaron búsquedas en Medline, Cochrane Library y Web of Science de ensayos aleatorizados de RenalGuard frente a estrategias estándar de hidratación periprocedimiento. El objetivo primario fue el desarrollo de NIC. Los objetivos secundarios fueron muerte por cualquier causa, shock cardiogénico, edema agudo de pulmón (EAP) e insuficiencia renal que requería terapia de reemplazo renal. Para cada resultado se calculó un riesgo relativo (RR) con el correspondiente intervalo de credibilidad del 95% (ICr95%). Registro número CRD42022378489 en PROSPERO database. Resultados Se incluyeron 6 estudios. El RenalGuard se asoció con una reducción relativa significativa de NIC (mediana de RR=0,54; ICr95%, 0,31-0,86) y EAP (mediana de RR=0,35; 95%ICr, 0,12-0,87). No se observaron diferencias significativas para los otros parámetros secundarios [muerte por cualquier causa (RR=0,49; ICr95%, 0,13-1,08), shock cardiogénico (RR=0,06; ICr95%, 0,00-1,91), terapia de reemplazo renal (RR=0,52; ICr95%, 0,18-1,18)]. El análisis Bayesiano también mostró que el RenalGuard obtuvo una alta probabilidad de posicionarse primero con respecto a todos los objetivos secundarios. Estos resultados fueron consistentes en múltiples análisis de sensibilidad. Conclusiones En los pacientes sometidos a procedimientos cardiovasculares percutáneos, el RenalGuard se asoció con un menor riesgo de NIC y EAP. (AU)

Introduction and objectives: Contrast-associated acute kidney injury (CA-AKI) is a potential complication of procedures requiring administration of iodinated contrast medium. RenalGuard, which provides real-time matching of intravenous hydration with furosemide-induced diuresis, is an alternative to standard periprocedural hydration strategies. The evidence on RenalGuard in patients undergoing percutaneous cardiovascular procedures is sparse. We used a Bayesian framework to perform a meta-analysis of RenalGuard as a CA-AKI preventive strategy. Methods We searched Medline, Cochrane Library and Web of Science for randomized trials of RenalGuard vs standard periprocedural hydration strategies. The primary outcome was CA-AKI. Secondary outcomes were all-cause death, cardiogenic shock, acute pulmonary edema, and renal failure requiring renal replacement therapy. A Bayesian random-effect risk ratio (RR) with corresponding 95% credibility interval (95%CrI) was calculated for each outcome. PROSPERO database number CRD42022378489. Results Six studies were included. RenalGuard was associated with a significant relative reduction in CA-AKI (median RR, 0.54; 95%CrI, 0.31-0.86) and acute pulmonary edema (median RR, 0.35; 95%CrI, 0.12-0.87). No significant differences were observed for the other secondary endpoints [all-cause death (RR, 0.49; 95%CrI, 0.13-1.08), cardiogenic shock (RR, 0.06; 95%CrI, 0.00-1.91), and renal replacement therapy (RR, 0.52; 95%CrI, 0.18-1.18)]. The Bayesian analysis also showed that RenalGuard had a high probability of ranking first for all the secondary outcomes. These results were consistent in multiple sensitivity analyses. Conclusions In patients undergoing percutaneous cardiovascular procedures, RenalGuard was associated with a reduced risk of CA-AKI and acute pulmonary edema compared with standard periprocedural hydration strategies. (AU)

Gender differences in efficacy and safety of antiplatelet strategies for acute coronary syndromes.

INTRODUCTION: Dual antiplatelet therapy (DAPT) represents the cornerstone of secondary prevention in patients presenting with acute coronary syndrome (ACS) and undergoing percutaneous coronary intervention. Despite its undisputed efficacy in reducing thrombotic events, DAPT increases the risk of bleeding, which is associated with higher morbidity and mortality. Novel antiplatelet strategies (i.e. in terms of timing, selection of drugs and their combinations, and modulation strategies) have been tested in randomized trials, suggesting the utility of tailored approaches in selected populations (i.e. patients at high bleeding or ischemic risk). It remains uncertain whether the effect of these strategies is influenced by sex. AREAS COVERED: This narrative review provides an overview of available evidence surrounding sex differences in the efficacy and safety of antiplatelet strategies for ACS and analyzes the potential reasons behind these findings. Relevant content was searched for in PubMed. EXPERT OPINION: Significant differences between women and men exist in terms of clinical presentation, pharmacotherapies, interventional management, and prognosis of ACS. However, these observations do not appear to be attributed to different pharmacodynamic effects of antiplatelet therapies between women and men. Unfortunately, a critical issue depends on women being often underrepresented in clinical trials, leading to a substantial lack of sex-specific evidence.

Mesomeric Acceleration Counters Slow Initiation of Ruthenium-CAAC Catalysts for Olefin Metathesis (CAAC = Cyclic (Alkyl)(Amino) Carbene).

Ruthenium catalysts bearing cyclic (alkyl)(amino)carbene (CAAC) ligands can attain very high productivities in olefin metathesis, owing to their resistance to unimolecular decomposition. Because the propagating methylidene species RuCl2(CAAC)(=CH2) is extremely susceptible to bimolecular decomposition, however, turnover numbers in the metathesis of terminal olefins are highly sensitive to catalyst concentration, and hence loadings. Understanding how, why, and how rapidly the CAAC complexes partition between the precatalyst and the active species is thus critical. Examined in a dual experimental-computational study are the rates and basis of initiation for phosphine-free catalysts containing the leading CAAC ligand C1 Ph , in which a CMePh group α to the carbene carbon helps retard degradation. The Hoveyda-class complex HC1 Ph (RuCl2(L)(=CHAr), where L = C1 Ph , Ar = C6H3-2-O i Pr-5-R; R = H) is compared with its nitro-Grela analogue (nG-C1 Ph ; R = NO2) and the classic Hoveyda catalyst HII (L = H2IMes; R = H). t-Butyl vinyl ether (tBuVE) was employed as substrate, to probe the reactivity of these catalysts toward olefins of realistic bulk. Initiation is ca. 100× slower for HC1 Ph than HII in C6D6, or 44× slower in CDCl3. The rate-limiting step for the CAAC catalyst is cycloaddition; for HII, it is tBuVE binding. Initiation is 10-13× faster for nG-C1 Ph than HC1 Ph in either solvent. DFT analysis reveals that this rate acceleration originates in an overlooked role of the nitro group. Rather than weakening the Ru-ether bond, as widely presumed, the NO2 group accelerates the ensuing, rate-limiting cycloaddition step. Faster reaction is caused by long-range mesomeric effects that modulate key bond orders and Ru-ligand distances, and thereby reduce the trans effect between the carbene and the trans-bound alkene in the transition state for cycloaddition. Mesomeric acceleration may plausibly be introduced via any of the ligands present, and hence offers a powerful, tunable control element for catalyst design.

Eligibility to Intensified Antithrombotic Regimens for Secondary Prevention in Patients Who Underwent Percutaneous Coronary Intervention.

Single antiplatelet therapy (SAPT) and intensified antithrombotic regimens (prolonged dual antiplatelet therapy [DAPT] or dual pathway inhibition [DPI]) are recommended for secondary prevention in patients who underwent percutaneous coronary intervention (PCI) after initial DAPT. We aimed to characterize eligibility to such strategies and to explore to what extent guidelines are applied in clinical practice. Patients who underwent PCI for acute or chronic coronary syndrome who completed initial DAPT were analyzed from a prospective registry. Patients were categorized into SAPT, prolonged DAPT/DPI, or DPI groups as per guideline indication by using a risk stratification algorithm. Predictors of receiving intensified regimens and the divergency of practice from guidelines were investigated. Between October 2019 and September 2021, a total of 819 patients were included. Based on the guidelines, 83.7% of patients qualified for SAPT, 9.6% for any intensified regimen (i.e., prolonged DAPT or DPI), and 6.7% for DPI only. At multivariable analysis, patients were more likely to receive an intensified regimen if they had diabetes, dyslipidemia, peripheral artery disease, multivessel disease, or previous myocardial infarction. Conversely, they were less likely to receive an intensified regimen if they had atrial fibrillation, chronic kidney disease, or previous stroke. Guidelines were not followed in 18.3% of cases. In particular, only 14.3% of candidates to intensified regimens were treated accordingly. In conclusion, although the majority of patients who underwent PCI after the initial period of DAPT were eligible for SAPT, 1 out of 6 had an indication to intensified regimens. However, such intensified regimens were underused among eligible patients.

Pharmacology and Clinical Development of Factor XI Inhibitors.

Therapeutic anticoagulation is indicated for a variety of circumstances and conditions in several fields of medicine to prevent or treat venous and arterial thromboembolism. According to the different mechanisms of action, the available parenteral and oral anticoagulant drugs share the common principle of hampering or blocking key steps of the coagulation cascade, which unavoidably comes at the price of an increased propensity to bleed. Hemorrhagic complications affect patient prognosis both directly and indirectly (ie, by preventing the adoption of an effective antithrombotic strategy). Inhibition of factor XI (FXI) has emerged as a strategy with the potential to uncouple the pharmacological effect and the adverse events of anticoagulant therapy. This observation is based on the differential contribution of FXI to thrombus amplification, in which it plays a major role, and hemostasis, in which it plays an ancillary role in final clot consolidation. Several agents were developed to inhibit FXI at different stages (ie, suppressing biosynthesis, preventing zymogen activation, or impeding the biological action of the active form), including antisense oligonucleotides, monoclonal antibodies, small synthetic molecules, natural peptides, and aptamers. Phase 2 studies of different classes of FXI inhibitors in orthopedic surgery suggested that dose-dependent reductions in thrombotic complications are not paralleled by dose-dependent increases in bleeding compared with low-molecular-weight heparin. Likewise, the FXI inhibitor asundexian was associated with lower rates of bleeding compared with the activated factor X inhibitor apixaban in patients with atrial fibrillation, although no evidence of a therapeutic effect on stroke prevention is available so far. FXI inhibition could also be appealing for patients with other conditions, including end-stage renal disease, noncardioembolic stroke, or acute myocardial infarction, for which other phase 2 studies have been conducted. The balance between thromboprophylaxis and bleeding achieved by FXI inhibitors needs confirmation in large-scale phase 3 clinical trials powered for clinical end points. Several of such trials are ongoing or planned to define the role of FXI inhibitors in clinical practice and to clarify which FXI inhibitor may be most suited for each clinical indication. This article reviews the rationale, pharmacology, results of medium or small phase 2 studies, and future perspectives of drugs inhibiting FXI.