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Several studies have demonstrated that, beyond their antithrombotic effects, P2Y12 receptor inhibitors may provide additional off-target effects through different mechanisms. These effects range from the preservation of endothelial barrier function to the modulation of inflammation or stabilization of atherosclerotic plaques, with an impact on different cell types, including endothelial and immune cells. Many P2Y12 inhibitors have been developed, from ticlopidine, the first thienopyridine, to the more potent non-thienopyridine derivatives such as ticagrelor which may promote cardioprotective effects following myocardial infarction (MI) by inhibiting adenosine reuptake through sodium-independent equilibrative nucleoside transporter 1 (ENT1). Adenosine may affect different molecular pathways involved in cardiac fibrosis, such as the Wnt (wingless-type)/beta (β)-catenin signaling. An early pro-fibrotic response of the epicardium and activation of cardiac fibroblasts with the involvement of Wnt1 (wingless-type family member 1)/β-catenin, are critically required for preserving cardiac function after acute ischemic cardiac injury. This review discusses molecular signaling pathways involved in cardiac fibrosis post MI, focusing on the Wnt/β-catenin pathway, and the off-target effect of P2Y12 receptor inhibition. A potential role of ticagrelor was speculated in the early modulation of cardiac fibrosis, thanks to its off-target effect.

Background: Over the past few decades, percutaneous coronary intervention (PCI) has undergone significant advancements as a result of the combination of device-based and drug-based therapies. These iterations have led to the development of polymer-free drug-eluting stents. However, there is a scarcity of data regarding their clinical performance. Furthermore, while various risk scores have been proposed to determine the optimal duration of dual antiplatelet therapy (DAPT), none of them have undergone prospective validation within the context of randomized trials., Design: The PARTHENOPE trial is a phase IV, prospective, randomized, multicenter, investigator-initiated, assessor-blind study being conducted at 14 centers in Italy (NCT04135989). It includes 2,107 all-comers patients with minimal exclusion criteria, randomly assigned in a 2-by-2 design to receive either the Cre8 amphilimus-eluting stent or the SYNERGY everolimus-eluting stent, along with either a personalized or standard duration of DAPT. Personalized DAPT duration is determined by the DAPT score, which accounts for both bleeding and ischemic risks. Patients with a DAPT score <2 (indicating higher bleeding than ischemic risk) receive DAPT for 3 or 6 months for chronic or acute coronary syndrome, respectively, while patients with a DAPT score ≥2 (indicating higher ischemic than bleeding risk) receive DAPT for 24 months. Patients in the standard DAPT group receive DAPT for 12 months. The trial aims to establish the noninferiority between stents with respect to a device-oriented composite end point of cardiovascular death, target-vessel myocardial infarction, or clinically-driven target-lesion revascularization at 12 months after PCI. Additionally, the trial aims to demonstrate the superiority of personalized DAPT compared to a standard approach with respect to a net clinical composite of all-cause death, any myocardial infarction, stroke, urgent target-vessel revascularization, or type 2 to 5 bleeding according to the Bleeding Academic Research Consortium criteria at 24-months after PCI., Summary: The PARTHENOPE trial is the largest randomized trial investigating the efficacy and safety of a polymer-free DES with a reservoir technology for drug-release and the first trial evaluating a personalized duration of DAPT based on the DAPT score. The study results will provide novel insights into the optimizing the use of drug-eluting stents and DAPT in patients undergoing PCI., Competing Interests: Disclosures Dr Piccolo reports personal fees from Abbott Vascular, Biotronik, Terumo, Amgen, Boehringer Ingelheim, and Daiichi-Sankyo, outside the submitted work. Dr Esposito reports personal fees from Abbott Vascular, Amgen, Boehringer Ingelheim, Edwards Lifesciences, Terumo, and Sanofi, outside the submitted work and research grants to the institution from Alvimedica, Boston Scientific, and Medtronic, outside the submitted work., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) in patients at high bleeding risk (HBR) is still debated. The current study, using the totality of existing evidence, evaluated the impact of an abbreviated DAPT regimen in HBR patients., Methods and Results: A systematic review and meta-analysis was performed to search randomized clinical trials comparing abbreviated [i.e. very-short (1 month) or short (3 months)] with standard (≥6 months) DAPT in HBR patients without indication for oral anticoagulation. A total of 11 trials, including 9006 HBR patients, were included. Abbreviated DAPT reduced major or clinically relevant non-major bleeding [risk ratio (RR): 0.76, 95% confidence interval (CI): 0.61-0.94; I2 = 28%], major bleeding (RR: 0.80, 95% CI: 0.64-0.99, I2 = 0%), and cardiovascular mortality (RR: 0.79, 95% CI: 0.65-0.95, I2 = 0%) compared with standard DAPT. No difference in all-cause mortality, major adverse cardiovascular events, myocardial infarction, or stent thrombosis was observed. Results were consistent, irrespective of HBR definition and clinical presentation., Conclusion: In HBR patients undergoing PCI, a 1- or 3-month abbreviated DAPT regimen was associated with lower bleeding and cardiovascular mortality, without increasing ischaemic events, compared with a ≥6-month DAPT regimen., Study Registration: PROSPERO registration number CRD42021284004., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The ischemic injury caused by myocardial infarction activates a complex healing process wherein a powerful inflammatory response and a reparative phase follow and balance each other. An intricate network of mediators finely orchestrate a large variety of cellular subtypes throughout molecular signaling pathways that determine the intensity and duration of each phase. At the end of this process, the necrotic tissue is replaced with a fibrotic scar whose quality strictly depends on the delicate balance resulting from the interaction between multiple actors involved in fibrogenesis. An inflammatory or reparative dysregulation, both in term of excess and deficiency, may cause ventricular dysfunction and life-threatening arrhythmias that heavily affect clinical outcome. This review discusses cellular process and molecular signaling pathways that determine fibrosis and the imaging technique that can characterize the clinical impact of this process in-vivo.

Background: Proton pump inhibitors (PPIs) are frequently prescribed in combination with clopidogrel, but conflicting data exist as to whether PPIs diminish the efficacy of clopidogrel. We assessed the association between PPI use and clinical outcomes for patients treated with percutaneous coronary intervention (PCI) and dual-antiplatelet therapy (DAPT) with clopidogrel plus aspirin., Methods and Results: In the PRODIGY trial, 1,970 patients were randomized to 6- or 24-month DAPT at 30 days from index procedure. Among them, 738 patients (37.5%) received PPI (mainly lansoprazole; 90.1%) at the time of randomization. Proton pump inhibitor users were older, were most likely to be woman, had a lower creatinine clearance, presented more frequently with acute coronary syndrome, and had a higher CRUSADE bleeding score. After adjustment, the primary efficacy end point (composite of all-cause death, myocardial infarction, and cerebrovascular accident) was similar between no PPI and PPI users (9.2% vs 11.5%, adjusted hazard ratio [HR] 1.051, 95% CI 0.788-1.400, P = .736). Bleeding rates did not differ between the 2 groups (Bleeding Academic Research Consortium type 2, 3, or 5: adjusted HR 0.996, 95% CI 0.672-1.474, P = .980). Net clinical adverse events were also similar in no PPI and PPI patients (12.9% vs 14.9%, adjusted HR 0.99, 95% CI 0.772-1.268, P = .93). Results remained consistent at sensitivity analysis when focusing on the 548 patients who remained on PPI for the whole study duration., Conclusions: The current findings suggest that the concomitant use of PPIs, when clinically indicated, in patients receiving clopidogrel is not associated with adverse clinical outcome., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: Recent trials have examined the effect of prolonged dual antiplatelet therapy (DAPT) in a variety of patient populations, with heterogeneous results regarding benefit and safety, specifically with regard to cardiovascular and non-cardiovascular mortality. We performed a meta-analysis of randomized trials comparing more than a year of DAPT with aspirin alone in high-risk patients with a history of prior myocardial infarction (MI)., Methods and Results: A total of 33 435 patients were followed over a mean 31 months among one trial of patients with prior MI (63.3% of total) and five trials with a subgroup of patients that presented with, or had a history of, a prior MI (36.7% of total). Extended DAPT decreased the risk of major adverse cardiovascular events compared with aspirin alone (6.4 vs. 7.5%; risk ratio, RR 0.78, 95% confidence intervals, CI, 0.67-0.90; P = 0.001) and reduced cardiovascular death (2.3 vs. 2.6%; RR 0.85, 95% CI 0.74-0.98; P = 0.03), with no increase in non-cardiovascular death (RR 1.03, 95% CI 0.86-1.23; P = 0.76). The resultant effect on all-cause mortality was an RR of 0.92 (95% CI 0.83-1.03; P = 0.13). Extended DAPT also reduced MI (RR 0.70, 95% CI 0.55-0.88; P = 0.003), stroke (RR 0.81, 95% CI 0.68-0.97; P = 0.02), and stent thrombosis (RR 0.50, 95% CI 0.28-0.89; P = 0.02). There was an increased risk of major bleeding (1.85 vs. 1.09%; RR 1.73, 95% CI 1.19-2.50; P = 0.004) but not fatal bleeding (0.14 vs. 0.17%; RR 0.91, 95% CI 0.53-1.58; P = 0.75)., Conclusion: Compared with aspirin alone, DAPT beyond 1 year among stabilized high-risk patients with prior MI decreases ischaemic events, including significant reductions in the individual endpoints of cardiovascular death, recurrent MI, and stroke. Dual antiplatelet therapy beyond 1 year increases major bleeding, but not fatal bleeding or non-cardiovascular death., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Background: The optimal timing to perform percutaneous coronary interventions (PCIs) in patients undergoing transcatheter aortic valve replacement (TAVR) is not well established. In this meta-analysis, we aimed to compare the outcomes of patients undergoing PCI before versus after TAVR. Methods: A comprehensive literature search was performed including Medline, Embase, and Cochrane electronic databases up to 5 April 2024 for studies that compared PCI before and after TAVR reporting at least one clinical outcome of interest (PROSPERO ID: CRD42023470417). The analyzed outcomes were mortality, stroke, and myocardial infarction (MI) at follow-up. Results: A total of 3 studies involving 1531 patients (pre-TAVR PCI n = 1240; post-TAVR PCI n = 291) were included in this meta-analysis following our inclusion criteria. Mortality was higher in the pre-TAVR PCI group (OR: 2.48; 95% CI: 1.19–5.20; p = 0.02). No differences were found between PCI before and after TAVR for the risk of stroke (OR: 3.58; 95% CI: 0.70–18.15; p = 0.12) and MI (OR: 0.66; 95% CI: 0.30–1.42; p = 0.29). Conclusions: This meta-analysis showed in patients with stable CAD undergoing TAVR that PCI after TAVR is associated with lower mortality compared with PCI before TAVR. [ABSTRACT FROM AUTHOR]

The antithrombotic management of patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) poses numerous challenges. Triple antithrombotic therapy (TAT), which combines dual antiplatelet therapy (DAPT) with oral anticoagulation (OAC), provides anti-ischemic protection but increases the risk of bleeding. Therefore, TAT is generally limited to a short phase (1 week) after PCI, followed by aspirin withdrawal and continuation of 6–12 months of dual antithrombotic therapy (DAT), comprising OAC plus clopidogrel, followed by OAC alone. This pharmacological approach has been shown to mitigate bleeding risk while preserving adequate anti-ischemic efficacy. However, the decision-making process remains complex in elderly patients and those with co-morbidities, significantly influencing ischemic and bleeding risk. In this review, we discuss the available evidence in this area from randomized clinical trials and meta-analyses for post-procedural antithrombotic therapies in patients with non-valvular AF undergoing PCI. [ABSTRACT FROM AUTHOR]

Cardiogenic shock is a dreadful complication of myocardial infarction. Despite widespread use and availability, intra‐aortic balloon pump (IABP) does not reduce mortality nor improves outcomes. Advanced mechanical circulatory support with IMPELLA system can substantially support hemodynamics and improve short‐term prognosis in patients with myocardial infarction and cardiogenic shock. [ABSTRACT FROM AUTHOR]

Background: Complex percutaneous coronary intervention (PCI) is associated with higher ischemic risk, which can be mitigated by long-term dual antiplatelet therapy (DAPT). However, concomitant high bleeding risk (HBR) may be present, making it unclear whether short- or long-term DAPT should be prioritized.Objectives: This study investigated the effects of ischemic (by PCI complexity) and bleeding (by PRECISE-DAPT [PREdicting bleeding Complications in patients undergoing stent Implantation and SubsequEnt Dual AntiPlatelet Therapy] score) risks on clinical outcomes and on the impact of DAPT duration after coronary stenting.Methods: Complex PCI was defined as ≥3 stents implanted and/or ≥3 lesions treated, bifurcation stenting and/or stent length >60 mm, and/or chronic total occlusion revascularization. Ischemic and bleeding outcomes in high (≥25) or non-high (<25) PRECISE-DAPT strata were evaluated based on randomly allocated duration of DAPT.Results: Among 14,963 patients from 8 randomized trials, 3,118 underwent complex PCI and experienced a higher rate of ischemic, but not bleeding, events. Long-term DAPT in non-HBR patients reduced ischemic events in both complex (absolute risk difference: -3.86%; 95% confidence interval: -7.71 to +0.06) and noncomplex PCI strata (absolute risk difference: -1.14%; 95% confidence interval: -2.26 to -0.02), but not among HBR patients, regardless of complex PCI features. The bleeding risk according to the Thrombolysis In Myocardial Infarction scale was increased by long-term DAPT only in HBR patients, regardless of PCI complexity.Conclusions: Patients who underwent complex PCI had a higher risk of ischemic events, but benefitted from long-term DAPT only if HBR features were not present. These data suggested that when concordant, bleeding, more than ischemic risk, should inform decision-making on the duration of DAPT. [ABSTRACT FROM AUTHOR]

Aims Dual antiplatelet therapy reduces non-fatal ischaemic events after acute coronary syndrome (ACS) but increases bleeding to a similar extent. We sought to determine the prognostic impact of myocardial infarction (MI) vs. bleeding during an extended follow-up period to gain insight into the trade-off between efficacy and safety among patients after ACS. Methods and results In 12 944 patients with non-ST-segment elevation ACS from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial, we investigated the relative impact of MI and bleeding occurring>30 days post-ACS and subsequent all-cause mortality. Bleeding was graded according to Bleeding Academic Research Consortium (BARC) criteria. MI was associated with a five-fold increase in mortality. BARC type 2 and 3, but not type 1, bleeding had a significant impact on mortality. MI was associated with a greater risk of mortality compared with BARC 2 [relative risk (RR) 3.5; 95% confidence interval (CI) 2.08-4.77; P<0.001] and BARC 3a bleeding (RR 2.23; 95% CI 1.36-3.64; P=0.001), and a risk similar to BARC 3b bleeding (RR 1.37; 95% CI 0.81-2.30; P=0.242). Risk of death after MI was significantly lower than after BARC 3c bleeding (RR 0.22; 95% CI 0.13-0.36; P<0.001). MI and bleeding had similar time-associations with mortality, which remained significant for several months, still being higher early after the event. Conclusion In patients treated with antiplatelet therapy after ACS, both MI and bleeding significantly impacted mortality with similar time-dependency. Although BARC 2 and 3a bleeding were less prognostic for death than MI, the risk of mortality was equivalent between BARC 3b bleeding and MI, and was higher following BARC 3c bleeding. [ABSTRACT FROM AUTHOR]

Chronic organized thrombus as a result of prior untreated myocardial infarction can determine myocardial ischemia. This entity appears as an angiographically irregular and hazy image; optical coherence tomography is useful to evaluate these ambiguous lesions and guide interventional treatment. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) is a dramatic event often caused by atherosclerotic plaque erosion or rupture and subsequent thrombotic occlusion of a coronary vessel. The low supply of oxygen and nutrients in the infarcted area may result in cardiomyocytes necrosis, replacement of intact myocardium with non-contractile fibrous tissue and left ventricular (LV) function impairment if blood flow is not quickly restored. In this review, we summarized the possible correlation between adenosine system, purinergic system and Wnt/β-catenin pathway and their role in the pathogenesis of cardiac damage following MI. In this context, several pathways are involved and, in particular, the adenosine receptors system shows different interactions between its members and purinergic receptors: their modulation might be effective not only for a normal functional recovery but also for the treatment of heart diseases, thus avoiding fibrosis, reducing infarcted area and limiting scaring. Similarly, it has been shown that Wnt/β catenin pathway is activated following myocardial injury and its unbalanced activation might promote cardiac fibrosis and, consequently, LV systolic function impairment. In this regard, the therapeutic benefits of Wnt inhibitors use were highlighted, thus demonstrating that Wnt/β-catenin pathway might be considered as a therapeutic target to prevent adverse LV remodeling and heart failure following MI. [ABSTRACT FROM AUTHOR]

Background: Longitudinal bleeding risk scores have been validated in patients treated with dual antiplatelet therapy (DAPT) following percutaneous coronary intervention. How these scores apply to the population of patients with acute coronary syndrome (ACS) treated without revascularization remains unknown. The objective was to evaluate and compare the performances of the PRECISE-DAPT, PARIS, and DAPT (bleeding component) bleeding risk scores in the medically managed patients with ACS treated with DAPT.Methods and Results: TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) was a double-blind, placebo-controlled randomized trial conducted from 2008 to 2012 over a median follow-up of 17.0 months in 966 sites (52 countries). High-risk patients with unstable angina or non-ST-segment-elevation myocardial infarction who did not undergo revascularization were randomized to prasugrel or clopidogrel. The PRECISE-DAPT, PARIS, and DAPT (bleeding component) risk scores were applied in the TRILOGY ACS population to evaluate their performance to predict adjudicated non-coronary artery bypass grafting-related GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe/life-threatening/moderate and TIMI (Thrombolysis in Myocardial Infarction) major/minor bleeding with time-dependent c-indices. Among the 9326 participants, median age was 66 years (interquartile range, 59-74 years), and 3650 were females (39.1%). A total of 158 (1.69%) GUSTO severe/life-threatening/moderate and 174 (1.87%) TIMI major/minor non-coronary artery bypass grafting bleeding events occurred. The c-indices (95% CI) of the PRECISE-DAPT, PARIS, and DAPT (bleeding component) scores through 12 months were 0.716 (0.677-0.758), 0.693 (0.658-0.733), and 0.674 (0.637-0.713), respectively, for GUSTO bleeding and 0.624 (0.582-0.666), 0.612 (0.578-0.651), and 0.608 (0.571-0.649), respectively, for TIMI bleeding. There was no significant difference in the c-indices of each score based upon pairwise comparisons.Conclusions: Among medically managed patients with ACS treated with DAPT, the performances of the PRECISE-DAPT, PARIS, and DAPT (bleeding component) scores were reasonable and similar to their performances in the derivation percutaneous coronary intervention populations. Bleeding risk scores may be used to predict longitudinal bleeding risk in patients with ACS treated with DAPT without revascularization and help support shared decision making. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00699998. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: Drug-eluting stents (DES) showed improved efficacy and safety compared with bare-metal stents (BMS), and international guidelines recommend their use as first line treatment. Yet, BMS are still widely used in practice, especially in large coronary vessels. We aimed to compare efficacy and safety of second-generation DES over BMS in large coronary culprit ST-segment elevated myocardial infarction lesions. Methods: We evaluated impact of large coronary stents (maximum size ≥3.50 mm) or smaller stents (<3.50 mm), among 1498 patients with ST-segment elevated myocardial infarction undergoing primary percutaneous coronary intervention, randomly allocated to everolimus-eluting DES or to an equivalent BMS platform in the EXAMINATION trial (Clinical Evaluation of the Xience-V Stent in Acute Myocardial Infarction Trial). Clinical events up to 5 years of follow-up were evaluated. Results: Large coronary stents were used in 683 patients (45.9%). At 5-year follow-up, the crude rate of the primary end point, a composite of all-cause death, any myocardial infarction, or any revascularization, was similar among patients treated with large or smaller coronary stents. The impact of DES versus BMS implantation was consistent irrespective of the stent size both for the primary end point (P int=0.82) and other secondary ischemic end points. Within patients treated with bigger stents, DES implantation was associated to a trend toward a reduction of target lesion (hazard ratio, 0.53; 95% CI, 0.27–1.02; P =0.05) and target vessel revascularization (hazard ratio, 0.60; 95% CI, 0.34–1.03; P =0.066). Conclusions: Our results do not support the preferential use of BMS for patients with large coronary vessels. DES may warrant improved efficacy irrespective of stent size among patients undergoing primary percutaneous coronary intervention. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00828087. [ABSTRACT FROM AUTHOR]