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Udaya S Tantry,1 Karsten Schror,2 Eliano Pio Navarese,3 Young-Hoon Jeong,4 Jacek Kubica,3 Kevin P Bliden,1 Paul A Gurbel1 1Sinai Center for Thrombosis Research and Drug Development, Sinai Hospital of Baltimore, LifeBridge Health, Baltimore, MD, USA; 2Department of Pharmacology and Clinical Pharmacology, Heinrich-Heine-University, Düsseldorf, Germany; 3Department of Cardiology and Internal Medicine, Nicolaus Copernicus University, Bydgoszcz, Poland; 4Department of Internal Medicine, Gyeongsang National University School of Medicine and Cardiovascular Center, Gyeongsang National University Changwon Hospital, Changwon, South KoreaCorrespondence: Udaya S TantryThrombosis Research Laboratory, Sinai Center for Thrombosis Research and Drug Development, Sinai Hospital of Baltimore, LifeBridge Health, Baltimore, MD, 21215, USATel +1 410-367-2590Fax +1 410-367-2596Email utantry@lifebridgehealth.orgIntroduction: Pharmacologic therapy options for COVID-19 should include antiviral, anti-inflammatory, and anticoagulant agents. With the limited effectiveness, currently available virus-directed therapies may have a substantial impact on global health due to continued reports of mutant variants affecting repeated waves of COVID-19 around the world.Methods: We searched articles pertaining to aspirin, COVID-19, acute lung injury and pharmacology in PubMed and provide a comprehensive appraisal of potential use of aspirin in the management of patients with COVID-19. The scope of this article is to provide an overview of the rationale and currently available clinical evidence that supports aspirin as an effective therapeutic option in COVID-19.Results: Experimental and clinical evidence are available for the potential use of aspirin in patients with COVID-19.Discussion: Aspirin targets the intracellular signaling pathway that is essential for viral replication, and resultant inflammatory responses, hypercoagulability, and platelet activation. With these multiple benefits, aspirin can be a credible adjunctive therapeutic option for the treatment of COVID-19. In addition, inhaled formulation with its rapid effects may enhance direct delivery to the lung, which is the key organ damaged in COVID-19 during the critical initial course of the disease, whereas the 150– 325 mg/day can be used for long-term treatment to prevent thrombotic event occurrences. Being economical and widely available, aspirin can be exploited globally, particularly in underserved communities and remote areas of the world to combat the ongoing COVID-19 pandemic.Keywords: COVID-19, acetyl salicylic acid, platelets, inflammation, lungs, acute respiratory syndrome

Background and Objectives: Ticagrelor, the first reversibly binding oral P2Y(12) receptor antagonist, improves outcomes in patients with acute coronary syndromes (ACS) compared with clopidogrel. In the ONSET-OFFSET study (parallel group trial) and the RESPOND study (crossover trial), the pharmacodynamic effects of ticagrelor were compared with clopidogrel in patients with coronary artery disease (CAD). We now report the pharmacokinetic analyses of ticagrelor, and the exposure-inhibition of platelet aggregation (IPA) relationships from these studies.Patients and Methods: Patients were treated with ticagrelor (180 mg loading dose, 90 mg twice daily maintenance dose) or clopidogrel (600 mg loading dose, 75 mg once daily maintenance dose) in addition to aspirin (acetylsalicylic acid) [75-100 mg once daily]. Ticagrelor administration was for 6 weeks in ONSET-OFFSET. In RESPOND, ticagrelor was given for 14 days before or after 2 weeks of clopidogrel in patients classified as clopidogrel responders or non-responders. Pharmacokinetics and IPA were evaluated following the loading and last maintenance doses. Exposure-IPA relationships were evaluated using a sigmoid maximum effect (E(max)) model.Outcome Measures: The outcome measures were ticagrelor and AR-C124910XX (active metabolite) pharmacokinetics and exposure-IPA relationships in both trials, including the effect of prior clopidogrel exposure, and effects in clopidogrel responders and non-responders in RESPOND.Results: In ONSET-OFFSET, maximum (peak) plasma concentration (C(max)), time to C(max) (t(max)) and area under the plasma concentration-time curve from time 0 to 8 hours (AUC(8)) for ticagrelor were 733 ng/mL, 2.0 hours and 4130 ng · h/mL, respectively; and for AR-C124910XX were 210 ng/mL, 2.1 hours and 1325 ng · h/mL, respectively. E(max) estimates were IPA >97%. Trough plasma ticagrelor (305 ng/mL) and AR-C124910XX (121 ng/mL) concentrations were 5.2 and 7.7 times higher than respective concentration producing 50% of maximum effect (EC(50)) estimates. In RESPOND, ticagrelor mean C(max) and AUC(8) following 2-week dosing were comparable between clopidogrel responders (724 ng/mL and 3983 ng · h/mL, respectively) and non-responders (764 ng/mL and 3986 ng · h/mL, respectively). Pharmacokinetics of ticagrelor were unaffected by prior clopidogrel dosing. E(max) estimates were IPA >96% for both responders and non-responders. Trough plasma concentrations were sufficient to achieve high IPA.Conclusions: Ticagrelor pharmacokinetics in stable CAD patients were comparable to previous findings in stable atherosclerotic and ACS patients, and were not affected by prior clopidogrel exposure or clopidogrel responsiveness. Ticagrelor effectively inhibited platelet aggregation, and trough plasma concentrations of ticagrelor and AR-C124910XX were sufficient to result in high IPA in stable CAD patients. [ABSTRACT FROM AUTHOR]

Background: Poststenting ischemic events occur despite dual-antiplatelet therapy, suggesting that a "one size fits all" antithrombotic strategy has significant limitations. Ex vivo platelet function measurements may facilitate risk stratification and personalized antiplatelet therapy.Methods: We investigated the prognostic utility of the strength of adenosine diphosphate (ADP)-induced (MA(ADP)) and thrombin-induced (MA(THROMBIN)) platelet-fibrin clots measured by thrombelastography and ADP-induced light transmittance aggregation (LTA(ADP)) in 225 serial patients after elective stenting treated with aspirin and clopidogrel. Ischemic and bleeding events were assessed over 3 years.Results: Overall, 59 (26%) first ischemic events occurred. Patients with ischemic events had higher MA(ADP), MA(THROMBIN), and LTA(ADP) (P < .0001 for all comparisons). By receiver operating characteristic curve analysis, MA(ADP) >47 mm had the best predictive value of long-term ischemic events compared with other measurements (P < .0001), with an area under the curve = 0.84 (95% CI 0.78-0.89, P < .0001). The univariate Cox proportional hazards model identified MA(ADP) >47 mm, MA(THROMBIN) >69 mm, and LTA(ADP) >34% as significant independent predictors of first ischemic events at the 3-year time point, with hazard ratios of 10.3 (P < .0001), 3.8 (P < .0001), and 4.8 (P < .0001), respectively. Fifteen bleeding events occurred. Receiver operating characteristic curve and quartile analysis suggests MA(ADP) Conclusion: This study is the first demonstration of the prognostic utility of MA(ADP) in predicting long-term event occurrence after stenting. The quantitative assessment of ADP-stimulated platelet-fibrin clot strength measured by thrombelastography can serve as a future tool in investigations of personalized antiplatelet treatment designed to reduce ischemic events and bleeding. [ABSTRACT FROM AUTHOR]

Objectives: The primary objective of this study was to compare the effect of therapy with bivalirudin alone versus bivalirudin plus eptifibatide on platelet reactivity measured by turbidometric aggregometry and thrombin-induced platelet-fibrin clot strength (TIP-FCS) measured by thrombelastography in percutaneous coronary intervention (PCI) patients. The secondary aim was to study the relation of platelet aggregation and TIP-FCS to the occurrence of periprocedural infarction.Background: Bivalirudin is commonly administered alone to clopidogrel naïve (CN) patients and to patients on maintenance clopidogrel therapy (MT) undergoing elective stenting. The effect of adding eptifibatide to bivalirudin on platelet reactivity (PR) and TIP-FCS, and their relation to periprocedural infarction in these patients are unknown.Methods: Patients (n = 200) stratified to clopidogrel treatment status were randomly treated with bivalirudin (n = 102) or bivalirudin plus eptifibatide (n = 98). One hundred twenty-eight CN patients were loaded with 600 mg clopidogrel immediately after stenting, and 72 MT patients were not loaded. The PR, TIP-FCS, and myonecrosis markers were serially determined.Results: In CN and MT patients, bivalirudin plus eptifibatide was associated with markedly lower PR at all times (5- and 20-microM adenosine diphosphate-induced, and 15- and 25-microM thrombin receptor activator peptide-induced aggregation; p < 0.001 for all) and reduced mean TIP-FCS (p < 0.05). Patients who had a periprocedural infarction had higher mean 18-h PR (p < 0.0001) and TIP-FCS (p = 0.002).Conclusions: For elective stenting, the addition of eptifibatide to bivalirudin lowered PR to multiple agonists and the tensile strength of the TIP-FCS, 2 measurements strongly associated with periprocedural myonecrosis. Future studies of PR and TIP-FCS for elective stenting may facilitate personalized antiplatelet therapy and enhance the selection of patients for glycoprotein IIb/IIIa blockade. (Peri-Procedural Myocardial Infarction, Platelet Reactivity, Thrombin Generation, and Clot Strength: Differential Effects of Eptifibatide + Bivalirudin Versus Bivalirudin [CLEAR PLATELETS-2]; NCT00370045. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Diabetic patients may have a higher prevalence of platelet aspirin resistance than nondiabetic patients. Our goal was to analyze platelet aspirin responsiveness to various aspirin doses in diabetic and nondiabetic patients. RESEARCH DESIGN AND METHODS: We examined the effect of aspirin (81, 162, and 325 mg/day for 4 weeks each) on platelet aspirin responsiveness in 120 stable outpatients (30 diabetic patients and 90 nondiabetic patients) with coronary artery disease (CAD) using light transmittance aggregometry (LTA), VerifyNow, platelet function analyzer (PFA)-100, and levels of urinary 11-dehydro-thromboxane B(2) (11-dh-TxB(2)). RESULTS: In the total group, a low prevalence (0-2%) of aspirin resistance was observed with all aspirin doses as determined by arachidonic acid-induced LTA. Aspirin resistance was higher at the 81-mg dose in diabetic versus nondiabetic patients using collagen-induced LTA (27 vs. 4%, P = 0.001), VerifyNow (13 vs. 3%, P = 0.05), and urinary 11-dh-TxB(2) (37 vs. 17%, P = 0.03). Diabetic patients treated with 81 mg exhibited higher platelet function measured by VerifyNow, collagen- and ADP-induced LTA, and 11-dh-TxB(2) levels (P

Fundamentally, acute coronary syndromes are platelet-centric diseases, resulting from platelet-rich thrombi that develop at the site of vessel wall injury. In addition to aggregation, platelets modulate a plethora of other important pathophysiologic processes, including inflammation and coagulation. Therefore, a primary goal of therapy in the acute setting should be treatment with agents that provide predictable and superior platelet inhibition to prevent further ischemic events that develop from unchecked high platelet reactivity. Translational research studies of patients undergoing percutaneous revascularization have clearly demonstrated that adverse thrombotic outcomes are associated with high platelet reactivity and the latter is now emerging as a potent measurable cardiovascular risk factor. The intensity of antithrombotic therapy is influenced by patient risk. In the highest risk patients with elevated cardiac biomarkers indicative of myonecrosis, current guidelines support the use of early therapy with glycoprotein IIb/IIIa inhibition, aspirin, and clopidogrel. [ABSTRACT FROM AUTHOR]

Introduction: Recent data question the use of aspirin as a bedrock of antiplatelet therapy in patients with arterial diseases. There are controversies regarding the efficacy of aspirin therapy with respect to specific demographic characteristics, dose and formulations, benefit in primary prevention, and duration in secondary prevention. Importantly, to balance the ischemic benefits and the risk of excessive bleeding following a coronary event, recent studies have investigated strategies to discontinue aspirin therapy and continue with P2Y 12 receptor inhibitor monotherapy. However, the precise time when to discontinue aspirin is still unresolved., Areas Covered: Evidence from recent studies evaluating the role of aspirin in primary and secondary prevention studies was collected from a selective literature search. In this review, the authors discuss current recommendations, large-scale studies of aspirin therapy, controversies, and potential future opportunities for aspirin therapy., Expert Opinion: With the new evidence showing lower bleeding risk with aspirin-free strategies in both primary and secondary prevention studies, the role of aspirin is being revaluated with P2Y 12 receptor inhibitor monotherapy. The potential benefits of novel aspirin formulations and alternative delivery methods, such as inhaled aspirin, are undergoing much-needed investigation with the goal of optimizing care for a wide range of patients.

Competing Interests: Declaration of competing interest The authors have no competing interest to declare.

Platelet-fibrin clot formation is a key process in acute arterial thrombosis. The relationship between thrombin-induced platelet-fibrin clot strength (P-FCS) and fibrinogen levels in patients with cardiovascular disease (CVD) and COVID-19 has not been studied. In thhe current study, the contribution of fibrinogen to P-FCS has been explored in healthy subjects (n=157), patients hospitalized with COVID-19 (n=116), and patients with CVD (n=93) using thrombelastography (TEG 6s) with citrate cartridge. We found that thrombin-induced P-FCS, fibrin clot strength (F-CS) and fibrinogen levels (FLEV) were higher among patients with CVD and COVID-19 compared to HS (p<0,05 for all) and highest among patients with COVID-19. P-FCS, an established risk factor for post-PCI ischemic event occurrences, was associated with both F-CS and FLEV (R2=0.67, p<0.001 for both comparisons. These data indicate that fibrinogen levels strongly influence the viscoelastic strength of the platelet-fibrin clot, fibrinogen may be an important driving factor for arterial thrombosis in the presence of potent platelet inhibition and may be as equally important a risk factor as high platelet reactivity. Since P-FCS is significantly associated with fibrinogen levels, the role of fibrinogen as a risk factor for arterial ischemic event occurrences should be further studied to improve antithrombotic therapy personalization., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Whether physiology-guided complete revascularization of nonculprit lesions is superior to culprit lesion-only percutaneous coronary intervention (PCI) in patients with myocardial infarction (MI) and multivessel disease remains debated. Online databases were searched for randomized controlled trials comparing physiology-guided complete revascularization and culprit lesion-only PCI in patients with MI. The outcomes of interest were all-cause death, cardiovascular (CV) death, repeat revascularization, MI, stent thrombosis, and contrast-associated nephropathy/acute kidney injury. Pooled odds ratios, along with 95% confidence intervals (CI) were calculated. A total of 4,849 patients (n = 2,288 physiology-guided complete revascularization, n = 2,561 culprit lesion-only PCI) were included. The mean age was 66 years and 76% were men. At a mean follow-up of 2.5 years, physiology-guided complete revascularization was associated with significant reductions in CV death (odds ratio 0.72, 95% CI 0.54 to 0.97, p = 0.03) and repeat revascularizations (0.50, 95% CI 0.38 to 0.66, p <0.00001) compared with culprit lesion-only PCI. There were no differences between the 2 approaches in all-cause death (0.91, 95% CI 0.69 to 1.19, p = 0.50), MI (0.85, 95% CI 0.59 to 1.21, p = 0.36), stent thrombosis (1.24, 95% CI 0.58 to 2.69, p = 0.58), and contrast-associated nephropathy/acute kidney injury (1.07, 95% CI 0.88 to 1.31, p = 0.50). In conclusion, among patients with MI and multivessel disease, physiology-guided complete revascularization was associated with significant reductions in CV death and revascularizations compared with culprit lesion-only PCI., Competing Interests: Declaration of competing interest J. Dawn Abbott - research (Boston Scientific, Shockwave, Med Alliance), consulting (Medtronic, Recor, Abbott, Penumbra). Aakash Garg - speaker for edwards Lifesciences. All other authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

VerifyNow (VN) test is a less laborious method to assess pharmacodynamics (PD) compared to light transmittance aggregometry (LTA). VN assay has not been used to study the immediate PD effects of acetylsalicylic acid (ASA). Ten healthy volunteers were randomly assigned to a single 162 or 650 mg dose of chewed and swallowed ASA. Pharmacodynamic and pharmacokinetic measurements were performed at baseline and serially up to 60 min after ASA administration. Onset by VN was 20 ± 7 min with 162 mg and 13 ± 7 min with 650 mg ASA ( p  = .07). Onset by 1 mM AA-induced PA was 13 ± 12 min with 162 mg and 7 ± 3 min with 650 mg ASA (p=NS). VN correlated with AA-induced PA ( r  = 0.80, p  < .001) and serum TxB 2 levels ( r = 0.76, p  < .001). 95% inhibition of serum TxB 2 was achieved at 38 ± 22 min and 22 ± 8 min with the 162 and 650 mg ASA, respectively ( p  = .08). The onset and extent of the antiplatelet effect of 650 mg ASA is numerically faster and greater than the 162 mg dose. VN identifies the onset, extent, and dose response to ASA therapy. The ease of using VN should facilitate multicenter PD investigations of ASA.

A heightened risk for thrombosis is a hallmark of COVID-19. Expansive clinical experience and medical literature have characterized small (micro) and large (macro) vessel involvement of the venous and arterial circulatory systems. Most events occur in patients with serious or critical illness in the hyperacute (first 1-2 weeks) or acute phases (2-4 weeks) of SARS-CoV-2 infection. However, thrombosis involving the venous, arterial, and microcirculatory systems has been reported in the subacute (4-8 weeks), convalescent (> 8-12 weeks) and chronic phases (> 12 weeks) among patients with mild-to-moderate illness. The purpose of the current focused review is to highlight the distinguishing clinical features, pathological components, and potential mechanisms of venous, arterial, and microvascular thrombosis in patients with COVID-19. The overarching objective is to better understand the proclivity for thrombosis, laying a solid foundation for screening and surveillance modalities, preventive strategies, and optimal patient management., (© 2024. The Author(s).)

Clopidogrel remains the most widely used P2Y₁₂ receptor inhibitor worldwide and is often used in combination with aspirin for secondary prevention in patients with arterial disease. The drug is associated with a wide response variability with one on three patients exhibiting little or no inhibition of adenosine diphosphate-induced platelet aggregation. It is a prodrug that is mainly metabolized by hepatic cytochrome P450 (CYP) 2C19. Patients who carry a CYP2C19 loss-of-function (LoF) allele have reduced metabolism of clopidogrel that is associated with reduced platelet inhibition compared to non-carriers that is associated with increased risk for thrombotic event occurrences, particularly, stent thrombosis. The United States Food and Drug Administration (US FDA) issued a black box warning in the clopidogrel label highlighting the importance of presence of CYP2C19 LOF allele during the insufficient metabolism of clopidogrel and availability of other potent P2Y₁₂ inhibitor for the treatment in CYP2C19 poor metabolizers. Clinical trials have conclusively demonstrated greater anti-ischemic benefits of prasugrel/ticagrelor in the treatment of patients carrying the CYP2C19 LoF allele. However, uniform use of these more potent P2Y₁₂ inhibitors has been associated with greater bleeding and cost, and lower adherence. The latter information provides a strong rationale for personalizing P2Y₁₂ inhibitor therapy based on the laboratory determination of CYP2C19 genotype. However, cardiologists have been slow to take up pharmacogenetic testing possibly due to lack of provider and patient education, clear cardiology guidelines and, and lack of positive results from adequately sized randomized clinical trials. However, current evidence strongly supports genotyping of patients who are candidates for clopidogrel. Physicians should strongly consider performing genetic tests to identify LoF carriers and treat these patients with more pharmacodynamically predictable P2Y₁₂ inhibitors than clopidogrel.

Background: Debates persist regarding the optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) in coronary artery disease (CAD). Recent trials have introduced a novel approach involving P2Y12 inhibitor monotherapy with ticagrelor or clopidogrel, after a short DAPT. However, the effectiveness and safety of this strategy remains to be established. We aimed to perform a meta-analysis comparing monotherapy with P2Y12 inhibitors versus standard DAPT in patients undergoing PCI at 12 months., Methods: Multiple databases were searched. Six RCTs with a total of 24877 patients were included. The primary endpoint was all-cause mortality at 12 months of follow-up. The secondary endpoints were cardiovascular mortality, myocardial infarction, probable or definite stent thrombosis, stroke events, and major bleeding. The study is registered with PROSPERO (CRD42024499529)., Results: Monotherapy with P2Y12 inhibitor ticagrelor significantly reduced both allcause mortality (HR 0.71, 95 CI [0.55-0.91], P = 0.007) and cardiovascular mortality (HR 0.66, 95% CI [0.49-0.89], P = 0.006) compared to standard DAPT. In contrast, clopidogrel monotherapy did not demonstrate a similar reduction. The decrease in mortality associated with ticagrelor was primarily due to a lower risk of major bleeding (HR 0.56, 95% CI [0.43-0.72], P < 0.001), while the risk of myocardial infarction (MI) remained unchanged (HR 0.90, 95% CI [0.73-1.11], P = 0.32). The risk of stroke was found to be similar across treatments., Conclusions: In comparison to standard DAPT, P2Y12 inhibitor monotherapy with ticagrelor may lead to a reduced mortality. The clinical benefits are driven by a reduction of bleeding risk without ischemic risk trade-off., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Tantry has received honoraria from Wolters Kluwer Pharma. Dr. Farkouh received research grant support from Astra Zeneca and Novartis and served as a consultant to Otitopic. Dr. Gurbel has received consulting fees and/or honoraria from Bayer, Vectura/Otitopic, Janssen, Cleveland Clinic foundation, Wolters Kluwer Pharma, Web MD Medscape, Baron and Budd, Premier Health Care Resource, Baim Institute, and Medforce; institutional research grants from Accriva Diagnostics, AstraZeneca, Bayer, Cronos, Haemonetics, Hikari Dx, Idorisa, Labcorp Drug Development, Novartis, Prolocor, Recor Medical, Vectura Limited, Zoll Medical Corporation; in addition, Dr. Gurbel has two patents, Detection of restenosis risk in patients issued and Assessment of cardiac health and thrombotic risk in a patient. Dr. Gurbel was an expert witness in a lawsuit associated with Plavix. Dr Bonaca has received consulting fees/honoraria from AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Pfizer, and Daiichi Sankyo, outside the submitted work. oung-Hoon Jeong reports honoraria for lectures from AstraZeneca, Sanofi-Aventis, Daiichi Sankyo, Otsuka, Han-mi Pharmaceuticals, Yuhan Pharmaceuticals, and research grants or support from AstraZeneca, Han-mi Pharmaceuticals, Yuhan Pharmaceuticals, and Haemonetics. Dr Navarese received speaker fees from Astra-Zeneca, outside the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Recent studies have shown similar safety and efficacy of short-term dual antiplatelet therapy (DAPT) followed by P2Y12 inhibitor (P2Y12i) monotherapy when compared with standard DAPT. However, the optimal DAPT duration and regimen in acute coronary syndrome (ACS) patients who underwent percutaneous coronary intervention is still unclear. Online databases were searched for randomized controlled trials evaluating P2Y12i monotherapy after short DAPT (≤3 months) versus standard DAPT (≥12 months) in ACS patients. The outcomes of interest were all-cause death, cardiovascular death, myocardial infarction, stent thrombosis, target-vessel revascularization, and major bleeding. Random-effects model was used to calculate pooled odds ratios (OR) and 95% confidence intervals (CI). Six randomized controlled trials with a total of 23,884 patients (n = 11,904 P2Y12i monotherapy, n = 11,980 standard DAPT) were included. Compared with standard DAPT, P2Y12i monotherapy after short DAPT was associated with similar odds of all-cause death (OR 0.86, 95% CI 0.65 to 1.12, p = 0.26) and cardiovascular death (OR 0.75, 95% CI 0.43 to 1.29, p = 0.29) at 1 year. Similarly, there were no significant differences in rates of myocardial infarction (OR 1.09, 0.83 to 1.43, p = 0.53), stent thrombosis (OR 1.09, 95% CI 0.71 to 1.67, p = 0.70) and target-vessel revascularization (OR 0.81, 95% CI 0.65 to 1.01, p = 0.07) between the P2Y12i monotherapy and standard DAPT arms. The P2Y12i monotherapy group had significantly lower major bleeding (OR 0.49, 95% CI 0.38 to 0.64, p < 0.001) when compared with standard DAPT. In conclusion, in patients with ACS who underwent percutaneous coronary intervention, P2Y12i monotherapy after short DAPT significantly reduces bleeding without increasing ischemic risk when compared with standard DAPT therapy., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Aims: Platelet-fibrin clot strength (PFCS) is linked to major adverse cardiovascular event (MACE) risk. However, the association between PFCS and platelet reactivity and their prognostic implication remains uncertain in patients undergoing percutaneous coronary intervention (PCI)., Methods: In PCI-treated patients (n = 2512) from registry data from January 2010 to November 2018 in South Korea, PFCS using thromboelastography and platelet reactivity using VerifyNow were measured. High PFCS (PFCSHigh) was defined as thromboelastography maximal amplitude ≥ 68 mm, and high platelet reactivity (HPR) was defined as >208 P2Y12 reaction units. Patients were stratified into four groups according to maximal amplitude and P2Y12 reaction unit levels: (i) normal platelet reactivity (NPR)-PFCSNormal (31.8%), (ii) HPR-PFCSNormal (29.0%), (iii) NPR-PFCSHigh (18.1%), and (iv) HPR-PFCSHigh (21.1%). Major adverse cardiovascular event (all-cause death, myocardial infarction, or stroke) and major bleeding were followed up to 4 years., Results: High platelet reactivity and PFCSHigh showed an additive effect for clinical outcomes (log-rank test, P < .001). Individuals with NPR-PFCSNormal, NPR-PFCSHigh, HPR-PFCSNormal, and HPR-PFCSHigh demonstrated MACE incidences of 7.5%, 12.6%, 13.4%, and 19.3%, respectively. The HPR-PFCSHigh group showed significantly higher risks of MACE compared with the NPR-PFCSNormal group [adjusted hazard ratio (HRadj) 1.89; 95% confidence interval (CI) 1.23-2.91; P = .004] and the HPR-PFCSNormal group (HRadj 1.60; 95% CI 1.12-2.27; P = .009). Similar results were observed for all-cause death. Compared with HPR-PFCSNormal phenotype, NPR-PFCSNormal phenotype was associated with a higher risk of major bleeding (HRadj 3.12; 95% CI 1.30-7.69; P = .010)., Conclusions: In PCI patients, PFCS and platelet reactivity demonstrated important relationships in predicting clinical prognosis. Their combined assessment may enhance post-PCI risk stratification for personalized antithrombotic therapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Balancing the prevention of thrombosis with bleeding risk when combining anticoagulants and platelet antagonists remains a concern among clinicians, particularly in patients with acute coronary syndrome (ACS) who are treated with potent antiplatelet therapy. This may be because the available antiplatelet and anticoagulants are unable to uncouple physiological hemostasis and pathological thrombosis. Therefore, their use is associated with an unavoidable elevated risk of bleeding., Areas Covered: Evidence available from studies evaluating FXIa inhibitors and milvexian was collected from a selective literature search. In this review, the authors describe the potential role of FXI/XIa in experimental thrombosis, evidence for FXIa inhibition in the treatment of clinical thrombotic events, and highlight the current evidence supporting the role of milvexian, a novel FXIa inhibitor, in patients with ACS., Expert Opinion: The ongoing LIBREXIA-ACS trial is a large-scale study currently investigating milvexian in patients with ACS. This study may support the proof of concept of differentiating physiological hemostasis and pathological thrombosis and achieving maximum antithrombotic efficacy with minimum bleeding risk when used on top of dual antiplatelet therapy with potent P2Y 12 receptor blockers.

Objective: The long-term clinical effect of arterial stiffness in high-risk disease entities remains unclear. The prognostic implications of brachial-ankle pulse wave velocity (baPWV) were assessed using a real-world registry that included patients who underwent percutaneous coronary intervention (PCI)., Methods: Arterial stiffness was measured using baPWV before discharge. The primary outcome was net adverse clinical events (NACE), defined as a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or major bleeding. Secondary outcomes included major adverse cardiac and cerebrovascular events (MACCE: a composite of all-cause death, non-fatal myocardial infarction, or non-fatal stroke), and major bleeding. The outcomes were assessed over a 4-year period., Results: Patients ( n = 3,930) were stratified into high- and low-baPWV groups based on a baPWV cut-off of 1891 cm/s determined through time-dependent receiver operating characteristic curve analysis. baPWV was linearly correlated with 4-year post-PCI clinical events. The high baPWV group had a greater cumulative incidence of NACE, MACCE, and major bleeding. According to multivariable analysis, the high baPWV groups had a significantly greater risk of 4-year NACE (adjusted hazard ratio [HRadj]: 1.44; 95% confidence interval [CI]: 1.12-1.85; p = 0.004), MACCE (HRadj: 1.40; 95% CI: 1.07-1.83; p = 0.015), and major bleeding (HRadj: 1.94; 95% CI: 1.15-3.25; p = 0.012)., Conclusion: In PCI-treated patients, baPWV was significantly associated with long-term clinical outcomes, including ischemic and bleeding events, indicating its value for identifying high-risk phenotypes., Competing Interests: PG has received grants and personal fees from Bayer HealthCare, Otitopic, Amgen, and Janssen, US World-Meds; grants from Instrumentation Laboratory, Hikari Dx, Haemonetics, Medicure, and Idorsia Pharmaceuticals; and personal fees from UpToDate and has patents “Detection of Restenosis Risk in Patients Issued” and “Assessment of Cardiac Health and Thrombotic Risk in a Patient.” Y-HJ has received honoraria for lectures from Daiichi Sankyo, Sanofi-Aventis, Amgen, Han-mi Pharmaceuticals, and Dae-woong Pharmaceuticals; and research grants or support from Yuhan Pharmaceuticals, Han-mi Pharmaceuticals, Sam-jin Pharmaceuticals, Biotronik, and U&I Corporation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kim, Ahn, Shin, Kang, Kim, Bae, Cho, Koh, Park, Hwang, Tantry, Gurbel, Hwang and Jeong.)

Importance: Accurately predicting major bleeding events in non-valvular atrial fibrillation (AF) patients on direct oral anticoagulants (DOACs) is crucial for personalized treatment and improving patient outcomes, especially with emerging alternatives like left atrial appendage closure devices. The left atrial appendage closure devices reduce stroke risk comparably but with significantly fewer non-procedural bleeding events., Objective: To evaluate the performance of machine learning (ML) risk models in predicting clinically significant bleeding events requiring hospitalization and hemorrhagic stroke in non-valvular AF patients on DOACs compared to conventional bleeding risk scores (HAS-BLED, ORBIT, and ATRIA) at the index visit to a cardiologist for AF management., Design: Prognostic modeling with retrospective cohort study design using electronic health record (EHR) data, with clinical follow-up at one-, two-, and five-years., Setting: University of Pittsburgh Medical Center (UPMC) system., Participants: 24,468 non-valvular AF patients aged ≥18 years treated with DOACs, excluding those with prior history of significant bleeding, other indications for DOACs, on warfarin or contraindicated to DOACs., Exposures: DOAC therapy for non-valvular AF., Main Outcomes and Measures: The primary endpoint was clinically significant bleeding requiring hospitalization within one year of index visit. The models incorporated demographic, clinical, and laboratory variables available in the EHR at the index visit., Results: Among 24,468 patients, 553 (2.3%) had bleeding events within one year, 829 (3.5%) within two years, and 1,292 (5.8%) within five years of index visit. We evaluated multivariate logistic regression and ML models including random forest, classification trees, k-nearest neighbor, naive Bayes, and extreme gradient boosting (XGBoost) which modestly outperformed HAS-BLED, ATRIA, and ORBIT scores in predicting clinically significant bleeding at 1-year follow-up. The best performing model (random forest) showed area under the curve (AUC-ROC) 0.76 (0.70-0.81), G-Mean score of 0.67, net reclassification index 0.14 compared to 0.57 (0.50-0.63), G-Mean score of 0.57 for HASBLED score, p-value for difference <0.001. The ML models had improved performance compared to conventional risk across time-points of 2-year and 5-years and within the subgroup of hemorrhagic stroke. SHAP analysis identified novel risk factors including measures from body mass index, cholesterol profile, and insurance type beyond those used in conventional risk scores., Conclusions and Relevance: Our findings demonstrate the superior performance of ML models compared to conventional bleeding risk scores and identify novel risk factors highlighting the potential for personalized bleeding risk assessment in AF patients on DOACs.

Although the cardiovascular (CV) benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with diabetes mellitus (DM) are well known, their effects in patients without DM continue to be explored. We provide a meta-analysis of the available evidence. Online databases were searched for randomized controlled trials (RCTs) comparing SGLT2i to placebo/control in patients without DM. The end points of interest were composite CV death/hospitalization for heart failure (HF) with individual components, all-cause death, major adverse CV events, and serious adverse events. Subgroup analysis was performed according to the type of SGLT2i. Pooled odds ratios (OR) and 95% confidence intervals (CI) were generated through a random-effects model. A total of 6 RCTs with 12,984 patients (6,501 in the SGLT2i group and 6,483 in the placebo group) were included, followed over a mean duration of 17.7 months. Four RCTs had patients with HF, 1 with chronic kidney disease, and 1 with myocardial infarction. The mean age was 64 years, 72% of patients were men and mean hemoglobin A1C was 5.7%. As compared with a placebo, SGLT2i treatment was associated with significant reduction in composite CV death or hospitalization for HF (OR 0.77, 95% CI 0.68 to 0.87, p <0.0001), primarily because of a decrease in hospitalization for HF (OR 0.70, 95% CI 0.60 to 0.81, p <0.00001). No significant differences were found pertaining to CV death (OR 0.86, 95% CI 0.74 to 1.01, p = 0.06), all-cause death (OR 0.89, 95% CI 0.71 to 1.11, p = 0.29) and major adverse CV events (OR 0.95, 95% CI 0.68 to 1.32, p = 0.75). Serious adverse events were lower with use of empagliflozin vs placebo. In conclusion, this study shows significant CV benefits in terms of reduction in CV death or hospitalization for HF in patients without DM treated with SGLT2i as compared with placebo. The underlying heterogeneity of patients in terms of co-morbidities (HF, chronic kidney disease, or myocardial infarction) needs to be considered while interpreting the results., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Genotype based personalized antiplatelet therapy in the setting of percutaneous coronary intervention (PCI) has been studied in clinical trials. Despite the demonstrated risk associated with CYP2C19 loss-of-function (LoF) carriage in clopidogrel-treated PCI patients, real-world implementation of genotyping for PCI has been low. The goal of the current study was to provide CYP2C19 genotype information to the interventionalist prior to the completion of the catheterization to facilitate immediate personalized antiplatelet therapy. Routine personalization of P2Y 12 inhibitor therapy for PCI in a community hospital cardiac catheterization laboratory by POC genotyping with the SpartanRx system was first offered in February 2017. A best practice advisory (BPA) based on the Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 genotype and clopidogrel therapy was placed in the electronic health record prescription medication ordering system. By December 2019, 1,052 patients had CYP2C19 genotype testing, 429 patients underwent PCI with genotype guided antiplatelet therapy, and 250 patients underwent PCI without genotype testing and received antiplatelet therapy at the discretion of the treating physician. BPA compliance was 93. 87% of LoF allele carriers were prescribed ticagrelor or prasugrel whereas 96% of non-LoF allele carriers were prescribed clopidogrel. The genotyping results were available within 1 h and made immediately available for decision making by the interventional cardiologist. POC CYP2C19 genotyping is feasible in a community hospital catheterization laboratory and is associated with high rate of best practice compliance.Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03040622., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Heart failure (HF) patients are at a greater risk for nosocomial infections due to their higher prevalence of comorbidities, readmission rates, and prolonged hospital stays. Clostridioides difficile infection (CDI) remains a common nosocomial infection in hospitalized patients., Aim: To identify patients with a diagnosis of acute HF and stratified based on the presence of CDI, using the National Inpatient Sample (NIS) database from 2016 to 2020., Methods: Adjusted odds ratios (aOR) of in-hospital outcomes were calculated, and a propensity-matched analysis was performed., Findings: Of 536,595 acute HF hospitalizations in this timeframe, 3030 were also diagnosed with CDI (0.56%). Patients with acute HF and CDI had significantly higher in-hospital mortality (adjusted odds ratio: (aOR): 1.91), cardiac arrest (aOR: 1.66), and use of mechanical circulatory support (MCS) (aOR 2.42). In propensity-matched analysis, in-hospital mortality (13.71 vs 8.44%; P=0.005), septic shock (7.54 vs 3.33%; P=0.002), and use of MCS (7.19 vs 3.68%; P=0.009) were significantly higher in HF patients with CDI than without. Coexisting neurological disease (aOR: 3.74) and liver disease (aOR: 2.97) showed the strongest association as independent predictors of mortality. HF patients with CDI had longer hospital stays (14.45 ± 19.40 vs 5.44 ± 7.10 days; P<0.0001) and higher inflation-adjusted total hospital costs ($186,225 ± 376,485 vs $60,740 ± 153,992; P<0.001) compared to those without CDI., Conclusion: The occurrence of concomitant CDI in patients admitted with acute HF exacerbation is associated with worse in-hospital outcomes and deaths as well as longer hospitalizations and greater financial cost., (Copyright © 2023 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

Background: Randomized controlled trials (RCTs) have shown varying results between immediate and staged complete percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS) and multivessel disease (MVD). We conducted a meta-analysis to reconcile the findings., Methods: Online databases were searched for RCTs comparing immediate vs staged complete PCI in patients presenting with ACS. The outcomes of interest were major adverse cardiovascular events (MACE), all cause death, myocardial infarction (MI), cardiovascular death, stent thrombosis, target vessel revascularization (TVR), cerebrovascular events, bleeding and acute kidney injury (AKI)/contrast induced nephropathy (CIN). Risk ratios (RR) with 95 % confidence intervals (CI) were calculated using the random-effects model., Results: Nine RCTs with a total of 3637 patients - 1821 in the immediate PCI group and 1816 in the staged PCI group, were included. The mean age was 64 years, 78 % of patients were men and the mean duration of follow up was 1 year. As compared with staged complete PCI, the immediate PCI group was associated with significant reduction of MI (RR 0.53, 95 % CI 0.36-0.77) and TVR (RR 0.69, 95 % CI 0.53-0.90). The risks of all-cause death, cardiovascular death, MACE, cerebrovascular events, stent thrombosis, bleeding and AKI/CIN were similar in the two groups., Conclusions: In ACS patients selected for complete revascularization strategy, multivessel PCI during the index procedure may be associated with significant reduction in the risk of MI and TVR without harm when compared with a staged PCI strategy., Competing Interests: Declaration of competing interest Rahul Chaudhary receives T32 grant T32HL129964. Rest of the authors declare that there is no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Randomized controlled trials (RCTs) have shown variable cardiovascular (CV) outcomes in overweight or obese patients without diabetes mellitus (DM) who are treated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) vs. placebo. We conducted a meta-analysis of the available studies., Methods: Online databases were searched for RCTs comparing GLP-1 RA to placebo in overweight or obese non-diabetic patients. The clinical endpoints of interest were major adverse CV events (MACE), CV death, all cause death, myocardial infarction (MI), stroke, revascularization, total adverse events and their subtypes. Pooled odds ratios (OR) and 95 % confidence intervals (CI) were calculated using a random-effects model., Results: A total of 10 RCTs with 29,325 patients (n = 16,900 GLP-1 RA, n = 12,425 placebo) were included. The mean age was 48 years and 34 % of patients were men. As compared with placebo, the GLP-1 RA group was associated with significant reduction of MACE (OR 0.79, 95 % CI 0.71-0.89, p < 0.0001), all cause death (OR 0.80, 95 % CI 0.70-0.92, p = 0.002), MI (OR 0.72, 95 % CI 0.61-0.85, p = 0.0001) and revascularization (OR 0.76, 95 % CI 0.67-0.86, p < 0.0001), without any differences in CV death or stroke. Total adverse events, gastrointestinal and gallbladder-related disorders were higher in the GLP-1 RA group, with a similar rate of renal adverse events, malignant neoplasms and acute pancreatitis to placebo., Conclusion: In overweight or obese patients without DM, patients treated with GLP-1 RAs had significantly reduced MACE, all cause death, MI and revascularization when compared with placebo., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Valvular heart diseases (VHDs) significantly impact morbidity and mortality rates worldwide. Early diagnosis improves patient outcomes. Artificial intelligence (AI) applied to electrocardiogram (ECG) interpretation presents a promising approach for early VHD detection. We conducted a meta-analysis on the efficacy of AI models in this context. We reviewed databases including PubMed, MEDLINE, Embase, Scopus, and Cochrane until August 20, 2023, focusing on AI for ECG-based VHD detection. The outcomes included pooled accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value. The pooled proportions were derived using a random-effects model with 95% confidence intervals (CIs). Study heterogeneity was evaluated with the I-squared statistic. Our analysis included 10 studies, involving ECG data from 713,537 patients. The AI algorithms mainly screened for aortic stenosis (n = 6), mitral regurgitation (n = 4), aortic regurgitation (n = 3), mitral stenosis (n = 1), mitral valve prolapse (n = 2), and tricuspid regurgitation (n = 1). A total of 9 studies used convolution neural network models, whereas 1 study combined the strengths of support vector machine logistic regression and multilayer perceptron for ECG interpretation. The collective AI models demonstrated a pooled accuracy of 81% (95% CI 73 to 89, I ²  = 92%), sensitivity was 83% (95% CI 77 to 88, I ²  = 86%), specificity was 72% (95% CI 68 to 75, I ²  = 52%), PPV was 13% (95% CI 7 to 19, I ²  = 90%), and negative predictive value was 99% (95% CI 97 to 99, I ²  = 50%). The subgroup analyses for aortic stenosis and mitral regurgitation detection yielded analogous outcomes. In conclusion, AI-driven ECG offers high accuracy in VHD screening. However, its low PPV indicates the need for a combined approach with clinical judgment, especially in primary care settings., Competing Interests: Declaration of competing interest The authors have no competing interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)