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

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

Atherosclerotic cardiovascular disease is a major health concern worldwide and requires effective preventive measures. Lp(a) (lipoprotein [a]) has recently garnered attention as an independent risk factor for astherosclerotic cardiovascular disease, with proinflammatory and prothrombotic mechanisms contributing to its atherogenicity. On an equimolar basis, Lp(a) is ~5 to 6 times more atherogenic than particles that have been widely associated with adverse cardiovascular outcomes, such as LDL (low-density lipoprotein). Lp(a) can enter the vessel wall, leading to the accumulation of oxidized phospholipids in the arterial intima, which are crucial for initiating plaque inflammation and triggering vascular disease progression. In addition, Lp(a) may cause atherothrombosis through interactions between apoA (apolipoprotein A) and the platelet PAR-1 (protease-activated receptor 1) receptor, as well as competitive inhibition of plasminogen. Because Lp(a) is mostly determined on genetic bases, a 1-time assessment in a lifetime can suffice to identify patients with elevated levels. Mendelian randomization studies and post hoc analyses of randomized trials of LDL cholesterol–lowering drugs showed a causal link between Lp(a) concentrations and cardiovascular outcomes, with therapeutic reduction of Lp(a) expected to contribute to estimated cardiovascular risk mitigation. Many Lp(a)-lowering drugs, including monoclonal antibodies, small interfering ribonucleic acids, antisense oligonucleotides, small molecules, and gene editing compounds, are at different stages of clinical investigation and show promise for clinical use. In particular, increased Lp(a) testing and treatment are expected to have a substantial impact at the population level, enabling the identification of high-risk individuals and the subsequent prevention of a large number of cardiovascular events. Ongoing phase 3 trials will further elucidate the cardiovascular benefits of Lp(a) reduction over the long term, offering potential avenues for targeted interventions and improved cardiovascular outcomes.

Despite advances in secondary prevention, adverse cardiovascular events still occur after acute myocardial infarction (AMI). Contributing to residual cardiovascular risk, acute and persistent inflammation is a stronger predictor of recurrent events and mortality than low-density lipoprotein cholesterol. The inflammatory response following AMI is a finely regulated, multiphase process, beginning with a proinflammatory phase followed by a reparative phase. Disruptions in its regulation lead to persistent low-grade inflammation and worse clinical outcomes. Modulating inflammation has emerged as a promising secondary prevention strategy, with several drugs being tested with conflicting results regarding their efficacy and safety. Recently, novel approaches have reignited the interest in anti-inflammatory strategies after AMI. However, key knowledge gaps remain regarding potential class effects, drug choice, patient selection, and the optimal administration timing. This review provides an updated and comprehensive overview of inflammatory mechanisms after AMI and critically appraises the evolving clinical evidence surrounding anti-inflammatory therapies for secondary cardiovascular prevention.

Efforts to enhance risk stratification in patients with coronary artery disease have driven the pursuit of early detection of rupture-prone plaques—before destabilization and the onset of life-threatening thrombosis—giving rise to the concept of the vulnerable plaque (VP). Invasive diagnostic modalities closely mirror histology and provide instrumental information on VP hallmarks and their prognostic significance. However, limited positive predictive value and invasive nature restrict their use for systematic screening. Noninvasive techniques offer broader application potential, but their specificity and resolution remain inferior to those of invasive techniques. A deeper understanding of the complex interplay between traditional ischemic risk factors, anatomic settings, rheological effects and systemic influences contributing to plaque evolution and rupture has refined our approach to identifying and managing VPs. Systemic therapies have been shown to counteract plaque progression and stabilize VPs by thickening the fibrous cap, decreasing atheroma and necrotic core volumes, and reducing inflammation. In parallel, the hypothesis of sealing and passivating VPs by intravascular imaging-guided preventive stenting is gaining support after the promising results of clinical trials and substantial advances in contemporary device performance and biocompatibility. Upcoming evidence will be instrumental in defining the net benefit of novel diagnostic tools and therapeutic strategies for VPs.

Coronary artery bypass graft (CABG) procedures face challenges related to graft failure, driven by factors such as acute thrombosis, neointimal hyperplasia, and atherosclerotic plaque formation. Despite extensive efforts over four decades, the optimal antithrombotic strategy to prevent graft occlusion while minimizing bleeding risks remains uncertain, relying heavily on expert opinions rather than definitive guidelines. To address this uncertainty, we conducted a review of randomized clinical trials and meta-analyses of antithrombotic therapy for patients with CABG. These studies examined various antithrombotic regimens in CABG such as single antiplatelet therapy (aspirin or P2Y₁₂ inhibitors), dual antiplatelet therapy, and anticoagulation therapy. We evaluated outcomes including the patency of grafts, major adverse cardiovascular events, and bleeding complications and also explored future perspectives to enhance long-term outcomes for CABG patients. Early studies established aspirin as a key component of antithrombotic pharmacotherapy after CABG. Subsequent randomized controlled trials focused on adding a P2Y₁₂ inhibitor (such as clopidogrel, ticagrelor, or prasugrel) to aspirin, yielding mixed results. This article aims to inform clinical decision-making and guide the selection of antithrombotic strategies after CABG.