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. 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. 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. This study is registered in PROSPERO (CRD42021258603). 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. 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. 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. Forest plots and ranking of treatments for primary outcomes. Guided selection of P2Y₁₂ inhibiting was the only strategy associated with reduced major adverse cardiovascular events without any increase of bleeding (forest plots). Ranking of treatments according to P-scores showed guided therapy to be the strategy with the best balance between safety and efficacy. P-scores range between 0 and 1: the higher the P-score value, the higher the likelihood that a therapy is more effective or safe. Guided approach showed the best P-score for MACE (0.931) and the second-best P-score for all bleeding (0.569). Clopidogrel showed the best P-score for all bleeding (0.983) but the poorest P-score for MACE (0.199). Prasugrel showed the second-best P-score for MACE (0.673) but a poor P-score for all bleeding (0.233). Ticagrelor showed a poor P-score for both MACE and all bleeding (0.198 and 0.214, respectively). CI, confidence interval; IRR, incidence rate ratio; MACE, major adverse cardiovascular events.

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.

Pathology and imaging studies have demonstrated that plaque rupture and erosion are the most common substrates of acute coronary syndrome (ACS) and sudden cardiac death.^1-5 Efforts to identify high-risk patients have focused on advanced imaging methods to detect single vulnerable atherosclerotic plaques such as thin-cap fibroatheroma (TCFA).⁶ However, the risk of acute myocardial infarction (AMI) or sudden cardiac death related to these lesions is rather low, as observed in the Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study and other imaging studies.^7,8 These findings are in keeping with numerous pathologic observations demonstrating that many (if not most) plaques destabilize without resulting in a clinical syndrome.^9,10 This final event, in fact, conceivably depends on a delicate balance between prothrombotic and thrombosis-resisting factors.^6,11 At 1 extreme, thrombus formation associated with plaque rupture or erosion is contained, and plaque healing occurs. At the other extreme, several prothrombotic factors (eg, plaque rupture/erosion, systemic prothrombotic milieu, and inflammatory state) coincide in a perfect storm culminating in ACS.^6,11 Based on these observations, healed plaque ruptures or erosions may be considered as a signature of an aborted ACS within the coronary tree. Optical coherence tomography (OCT) has been validated for the detection of healed coronary plaques against histology.¹² Yet the prevalence and characteristics of healed coronary plaques in vivo remain unknown. For this purpose, we conducted an observational cohort study in patients at the extremes of the clinical spectrum of coronary artery disease assessed by OCT imaging and coronary angiography: at one extreme, patients with a history of multiple acute coronary events, and at the other extreme, those with long-standing stable coronary artery disease who have never been clinically unstable. To include the full spectrum, we enrolled a third group of patients with single unheralded AMI followed by long-term stability. These 3 groups of patients were followed up for the occurrence of adverse events.

Diabetes mellitus is an important risk factor for a first cardiovascular event and for worse outcomes after a cardiovascular event has occurred. This situation might be caused, at least in part, by the prothrombotic status observed in patients with diabetes. Therefore, contemporary antithrombotic strategies, including more potent agents or drug combinations, might provide greater clinical benefit in patients with diabetes than in those without diabetes. In this Consensus Statement, our Working Group explores the mechanisms of platelet and coagulation activity, the current debate on antiplatelet therapy in primary cardiovascular disease prevention, and the benefit of various antithrombotic approaches in secondary prevention of cardiovascular disease in patients with diabetes. While acknowledging that current data are often derived from underpowered, observational studies or subgroup analyses of larger trials, we propose antithrombotic strategies for patients with diabetes in various cardiovascular settings (primary prevention, stable coronary artery disease, acute coronary syndromes, ischaemic stroke and transient ischaemic attack, peripheral artery disease, atrial fibrillation, and venous thromboembolism). Finally, we summarize the improvements in cardiovascular outcomes observed with the latest glucose-lowering drugs, and on the basis of the available evidence, we expand and integrate current guideline recommendations on antithrombotic strategies in patients with diabetes for both primary and secondary prevention of cardiovascular disease.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated significant cardiovascular (CV) benefits particularly in patients with diabetes mellitus (DM), but the safety and efficacy of different GLP-1 RAs across diverse populations remain insufficiently defined. Previous meta-analyses of GLP-1 RAs have been limited by restricted populations, omission of recent trials, or incomplete safety synthesis; this study integrates the latest evidence across 21 RCTs and diverse populations using advanced meta-analytic methods. Randomized controlled trials comparing GLP-1 RAs vs controls or placebo were included. Analyses were conducted in pre-specified subgroups based on the GLP-1 RA used. Pre-specified subgroups according to DM, kidney function, obesity or heart failure (HF) were also performed. Main outcomes comprised mortality (all-cause and CV), trial-defined major adverse cardiovascular events (MACE) and serious adverse events (SAEs). GRADE and trial sequential analyses were performed to evaluate certainty and conclusiveness of findings, respectively. A total of 21 trials encompassing 99,592 patients were included. Eight different GLP-1 RAs were used (lixisenatide, liraglutide, exenatide, semaglutide, efpeglenatide, dulaglutide, albiglutide, and tirzepatide), each administered at therapeutic doses and compared vs placebo or controls. Mean follow-up duration was 2.4 years. We found conclusive, high certainty, evidence that GLP-1 RAs reduced all-cause death (IRR 0.88, 95% CI 0.84-0.92, NNT=121), CV death (IRR 0.87, 95% CI 0.81-0.92, NNT=170) and MACE (IRR 0.87, 95% CI 0.83-0.91, NNT=66), compared with controls. GLP-1 RAs reduced SAE (-9%), myocardial infarction (-15%), acute kidney failure (-9%), HF (-15%), and infections (-10%), but increased gastrointestinal (GI; +63%) and gallbladder (+26%) disorders. There were no differences in stroke, pancreatitis or neoplasm between groups. Results were mostly consistent across subgroups. Analysis by GLP-1 RA type revealed potential differences in efficacy and safety profiles. GLP-1 RAs reduce mortality and MACE in high-risk populations, highlighting benefits beyond glycemic control. These come at increased GI and gallbladder risks. Variation in efficacy and tolerability supports tailoring GLP-1 RA therapy to individual patient characteristics and treatment goals.