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Antiplatelet therapy is key to reducing local thrombotic complications and systemic ischaemic events among patients undergoing percutaneous coronary interventions (PCI), but it is inevitably associated with increased bleeding. The continuous refinement in stent technologies, together with the high incidence of ischaemic recurrences after PCI and the understanding of prognostic implications associated with bleeding, have led to a substantial evolution in antiplatelet treatment regimens over the past decades. Numerous investigations have been conducted to better stratify patients undergoing PCI according to their ischaemic and bleeding risks and to implement antithrombotic regimens accordingly. Evidence from these investigations have resulted in a number of antithrombotic treatment options as recommended by recent guidelines. In this State-of-the-Art review we provide the rationale, summarise the evidence, and discuss current and future directions of antiplatelet treatment regimens after PCI. KEYWORDS • antiplatelet therapy • bleeding • percutaneous coronary intervention • P2Y 12 inhibitors • thrombosis State of the Art by EuroIntervention 2022;17:e1371-e1396 e 1372 EuroIntervention 2022;17:e1371-e1396 e 1373Antiplatelet therapy after PCI and inflammation in case of bleeding, and depletion of 2,3-diphosphoglyceric acid and nitric oxide triggered by blood transfusion which modulates oxygen exchange at the tissue level and favours vasoconstriction and platelet aggregation 36,37 . The risk of bleeding is proportional to the intensity of antithrombotic treatment 38 . This explains why bleeding complications are highest in the early phase post-PCI, given that patients warrant vascular access and are exposed to adjuvant intraprocedural antithrombotic therapy. Whilst both ischaemic and bleeding risks are highest in the periprocedural phase, the risk of bleeding tends to be stable over time while ischaemic risk decreases after 1 to 3 months post-PCI, albeit with variability according to the clinical presentation of the patients and complexity of the PCI 39 . These considerations have stimulated interest for tailoring antiplatelet regimens according to the ischaemic and bleeding risk of the individual patient. Current recommendations on the use of oral antiplatelet therapy after PCIDAPT is the standard of care for patients undergoing PCI 1,[40][41][42][43] . Aspirin (loading dose of 160-325 mg orally or 250-500 mg intravenously, followed by an oral maintenance dose of 75-100 mg once daily [od]) should be administered in all patients. The DAPT regimen,

IMPORTANCE At one end of the coronary artery disease (CAD) spectrum, there are patients with multiple recurrent acute coronary syndromes (rACS), and at the other end there are those with long-standing clinical stability. Predicting the natural history of these patients is challenging because unstable plaques often heal without resulting in ACS. OBJECTIVE To assess in vivo the coronary atherosclerotic phenotype as well as the prevalence and characteristics of healed coronary plaques by optical coherence tomography (OCT) imaging in patients at the extremes of the CAD spectrum. DESIGN, SETTING, AND PARTICIPANTS This is an observational, single-center cohort study with prospective clinical follow-up. From a total of 823 consecutive patients enrolled in OCT Registry of the Fondazione Policlinico A. Gemelli-IRCCS, Rome, Italy, from March 2009 to February 2016, 105 patients were included in the following groups: (1) patients with rACS, defined as history of at least 3 acute myocardial infarctions (AMIs) or at least 4 ACS with at least 1 AMI; (2) patients with long-standing stable angina pectoris (ls-SAP), defined as a minimum 3-year history of stable angina; and (3) patients with a single unheralded AMI followed by a minimum 3-year period of clinical stability (sAMI). Data were analyzed from January to August 2018. EXPOSURES Intracoronary OCT imaging of nonculprit coronary segments. MAIN OUTCOMES AND MEASURES Coronary plaque features and the prevalence of healed coronary plaques in nonculprit segments as assessed by intracoronary OCT imaging. RESULTS Of 105 patients, 85 were men (81.0%); the median (interquartile range) age was 68 (63-75) years. Median (interquartile range) time of clinical stability was 9 (5.0-15.0) years in the ls-SAP group and 8 (4.5-14.5) years in the sAMI group. Patients in the rACS and sAMI groups showed similar prevalence of lipid-rich plaque and thin-cap fibroatheroma, which was significantly higher than in those with ls-SAP (lipid-rich plaque 80.0% [n = 24 of 30] vs 76.3% [n = 29 of 38] vs 37.8% [n = 14 of 37], respectively; P < .001; thin-cap fibroatheroma 40.0% [n = 12 of 30] vs 34.2% [n = 13 of 38] vs 8.1% [n = 3 of 37], respectively; P = .006). Spotty calcifications were more frequently observed in patients with rACS than in those with ls-SAP and sAMI (70.0% [n = 21 of 30] vs 40.5% [n = 15 of 37] vs 44.7% [n = 17 of 38], respectively; P = .04). Healed coronary plaques were rarely observed in patients with rACS, whereas their prevalence was significantly higher in patients with ls-SAP and sAMI (3.3% [n = 1 of 30] vs 29.7% [n = 11 of 37] vs 28.9% [n = 11 of 38], respectively; P = .01). CONCLUSIONS AND RELEVANCE Patients with rACS have a distinct atherosclerotic phenotype compared with those with ls-SAP, including higher prevalence of thin-cap fibroatheroma and lower prevalence of healed coronary plaques, suggesting that atherosclerotic profile and plaque healing may play a role in leading the natural history of patients with CAD.

Aims Guidelines recommend the use of potent P2Y12 inhibitors over clopidogrel for the reduction of ischaemic events in patients with acute coronary syndrome (ACS). However, this comes at the expense of increased bleeding. A guided selection of P2Y12 inhibiting therapy has the potential to overcome this limitation. We aimed at evaluating the comparative safety and efficacy of guided vs. routine selection of potent P2Y12 inhibiting therapy in patients with ACS. Methods and results We performed a network meta-analysis of randomized controlled trials (RCTs) comparing different oral P2Y12 inhibitors currently recommended for the treatment of patients with ACS (clopidogrel, prasugrel, and ticagrelor). RCTs including a guided approach (i.e. platelet function or genetic testing) vs. standard selection of P2Y12 inhibitors among patients with ACS were also included. Incidence rate ratios (IRR) and associated 95% confidence intervals (CIs) were estimated. P-scores were used to estimate hierarchies of efficacy and safety. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the primary safety endpoint was all bleeding. A total of 61 898 patients from 15 RCTs were included. Clopidogrel was used as reference treatment. A guided approach was the only strategy associated with reduced MACE (IRR: 0.80, 95% CI: 0.65–0.98) without any significant trade-off in all bleeding (IRR: 1.22, 95% CI: 0.96–1.55). A guided approach and prasugrel were associated with reduced myocardial infarction. A guided approach, prasugrel, and ticagrelor were associated with reduced stent thrombosis. Ticagrelor was also associated with reduced total and cardiovascular mortality. Prasugrel was associated with increased major bleeding. Prasugrel and ticagrelor were associated with increased minor bleeding. The incidence of stroke did not differ between treatments. Conclusion In patients with an ACS, compared with routine selection of potent P2Y12 inhibiting therapy (prasugrel or ticagrelor), a guided selection of P2Y12 inhibiting therapy is associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided approach for the selection of P2Y12 inhibiting therapy in patients with ACS. Study registration number This study is registered in PROSPERO (CRD42021258603). Key Question A guided selection of P2Y12 inhibiting therapy using platelet function or genetic testing improves outcomes among patients undergoing percutaneous coronary intervention. Nevertheless, the comparative safety and efficacy of a guided versus routine selection of potent P2Y12-inhibiting therapy in acute coronary syndrome has not been explored. Key Finding In a comprehensive network meta-analysis including the totality of available evidence and using clopidogrel as treatment reference, a guided approach was the only strategy associated with reduced major adverse cardiovascular events without any significant trade-off in bleeding. Prasugrel and ticagrelor increased bleeding and only ticagrelor reduced mortality. Take Home Message A guided selection of P2Y12-inhibiting therapy represents the strategy associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided P2Y12 inhibiting therapy in patients with acute coronary syndrome.

Heart failure with preserved ejection fraction (HFpEF) is an increasingly studied entity accounting for 50% of all diagnosed heart failure and that has claimed its own dignity being markedly different from heart failure with reduced EF in terms of etiology and natural history (Graziani et al., 2018). Recently, a growing body of evidence points the finger toward microvascular dysfunction as the major determinant of the pathological cascade that justifies clinical manifestations (Crea et al., 2017). The high burden of comorbidities such as metabolic syndrome, hypertension, atrial fibrillation, chronic kidney disease, obstructive sleep apnea, and similar, could lead to a systemic inflammatory state that impacts the physiology of the endothelium and the perivascular environment, engaging complex molecular pathways that ultimately converge to myocardial fibrosis, stiffening, and dysfunction (Paulus and Tschope, 2013). These changes could even self-perpetrate with a positive feedback where hypoxia and locally released inflammatory cytokines trigger interstitial fibrosis and hypertrophy (Ohanyan et al., 2018). Identifying microvascular dysfunction both as the cause and the maintenance mechanism of this condition has opened the field to explore specific pharmacological targets like nitric oxide (NO) pathway, sarcomeric titin, transforming growth factor beta (TGF-β) pathway, immunomodulators or adenosine receptors, trying to tackle the endothelial impairment that lies in the background of this syndrome (Graziani et al., 2018;Lam et al., 2018). Yet, many questions remain, and the new data collected still lack a translation to improved treatment strategies. To further elaborate on this tangled and exponentially growing topic, we will review the evidence favoring a microvasculature-driven etiology of this condition, its clinical correlations, the proposed diagnostic workup, and the available/hypothesized therapeutic options to address microvascular dysfunction in the failing heart.

Background The clinical impact of different prophylactic anticoagulation regimens among hospitalized patients with COVID-19 remains unclear. We pooled evidence from available randomized controlled trials (RCTs) to provide insights on this topic. Methods and results We searched for RCTs comparing treatment with an escalated-dose (intermediate-dose or therapeutic-dose) versus a standard-dose prophylactic anticoagulation regimen in critically and non-critically-ill COVID-19 patients requiring hospitalization and without a formal indication for anticoagulation. The primary efficacy endpoint was all-cause death, and the primary safety endpoint was major bleeding. Seven RCTs were identified, including 5,154 patients followed on average of 33 days. Compared to standard-dose prophylactic anticoagulation, escalated-dose prophylactic anticoagulation was not associated with a reduction of all-cause death (17.8% vs. 18.6%; Risk Ratio [RR] 0.96, 95% Confidence Interval [CI] 0.78–1.18) but was associated with an increase in major bleeding (2.4% vs. 1.4%; RR 1.73, 95%CI 1.15–2.60). Compared to prophylactic anticoagulation used at a standard-dose, an escalated-dose was associated with lower rates of venous thromboembolism (2.5% vs. 4.7%; RR 0.55, 95%CI 0.41–0.74) without a significant effect on myocardial infarction (RR 0.80, 95%CI 0.47–1.36), stroke (RR 0.94, 95%CI 0.43–2.09), or systemic arterial embolism (RR 1.20, 95%CI 0.29–4.95). There were no significant interactions in the subgroup analysis for critically and non-critically-ill patients. Conclusions Our findings provide comprehensive and high-quality evidence for the use of standard-dose prophylactic anticoagulation over an escalated-dose regimen as routine standard of care for hospitalized patients with COVID-19 who do not have an indication for therapeutic anticoagulation, irrespective of disease severity. Study registration This study is registered in PROSPERO (CRD42021257203).

Diabetes mellitus is an important risk factor for a first cardiovascular event and for worse outcomes after a cardiovascular event has occurred. Cardiovascular disease in diabetes is a progressive process characterized by early endothelial dysfunction, oxidative stress, and vascular inflammation leading to monocyte recruitment and formation of foam cells and fatty streaks, which cause development of atherosclerotic plaques over years 1. Compared with atherosclerotic plaques from individuals without diabetes, those from patients with diabetes are more vulnerable (rupture-prone), and therefore, these plaques are at increased risk of developing superimposed thrombosis because of increased amounts of soft extracellular lipids, inflammation, and prothrombotic milieu; this situation predisposes patients with diabetes to acute cardiovascular events 1. Consequently, in principle, aggressive antithrombotic therapies might be associated with greater clinical benefit in patients with diabetes than in those without the condition. However, the ischaemic protection provided by antithrombotic drugs must be weighed against the drug-related bleeding risk. This Consensus Statement from the Working Group on Thrombosis of the Italian Society of Cardiology provides up-to-date recommendations on primary and secondary prevention of atherothrombotic events in patients with diabetes. We explore the mechanisms of platelet and coagulation activity and analyse the current data on the risk-benefit balance of antiplatelet therapy

The recognition that obstructive disease of the epicardial coronary arteries, causing ischemic heart disease, can be treated with a percutaneous coronary intervention (PCI) has been a major discovery in cardiology in the last 40 years contributing, in particular, to the reduction of mortality associated to acute myocardial infarction (AMI). However, even in the era of drug-eluting stent (DES) implantation, a sizable proportion of patients who undergo PCI may develop late or very late post-implantation complications, that occur in the form of restenosis, neoatherosclerosis and/or in-stent thrombosis. Such complications are clinically relevant since they can cause AMI and negatively impact on the outcome. The underlying pathophysiological mechanisms are complex but related to inhibition of neointimal proliferation by DES that, on the hand, reduces the rate of in-stent restenosis, but, on the other hand, causes dysfunctional vessel healing, persistent inflammation, platelet activation and adverse immunologic responses. Multiple approaches have been developed or are under evaluation to target DES-related complications including pharmacotherapy, procedure-related imaging methods, novel stent designs and drug-delivery methods.The aim of this review is to provide an update on the latest preclinical, translational and clinical pharmacotherapeutic developments in this setting that target novel cellular mechanisms and pathways that might contribute to neoatherosclerosis. Due to the importance of secondary prevention in the reduction of DES-associated complications, this review also provides a short overview of pharmacologic agents that are established or currently being investigated in this regard.