Factor XI inhibition in patients with acute coronary syndrome.

A hypercoagulable condition is typical of patients with acute coronary syndrome and is a determining factor in the genesis of recurrent ischaemic events. Modern pharmacological therapies consisting of antiplatelets and anticoagulants derive their rationale for use on the pathophysiological mechanisms most commonly associated with myocardial infarction (MI); they have contributed to reducing the ischaemic risk of these patients, but left ample room for improvement. In particular, trials that have studied the association of an anticoagulant with antiplatelet drugs have provided promising results in terms of efficacy, but highlighted a significant bleeding risk. Evidence derived from experimental animal and epidemiological studies has shown how factor XI (FXI) deficiency is associated with a reduction in thrombotic events but with modest bleeding. These data added to the role that FXI plays in the coagulation cascade constituted an incipit for the pharmacological attempt to decouple thrombosis from haemostasis by means of the inhibition of this factor. The theoretical assumption that FXI inhibitor drugs may be able to reduce the ischaemic risk without significantly increasing the haemorrhagic risk makes these compounds a potential therapeutic aid for patients in secondary prevention after acute MI. To date, on these patients, we only have data from a Phase 2 trial, PACIFIC-AMI (Study to Gather Information About the Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2 433 334 in Patients Following an Acute Heart Attack). In this study, the primary endpoint-represented by the Bleeding Academic Research Consortium (BARC) composite of Type 2, 3, or 5 bleeding-showed no significant differences between the various doses of asundexian tested (10, 20, and 50 mg quoque die), and between these and placebo (asundexian all doses vs. placebo: hazard ratio, 0.98; 90% confidence interval, 0.71-1.35). The data on efficacy, however, showed neutral results, but it should be noted that the study did not have the adequate statistical power to evaluate this outcome. Valuable information could, therefore, derive in the future from the ongoing Phase 3 trial with milvexian, LIBREXIA-ACS (A Study of Milvexian in Participants After a Recent Acute Coronary Syndrome) and from any future studies that could be started by testing different molecules.

Defining high bleeding risk in patients undergoing transcatheter aortic valve implantation: a VARC-HBR consensus document.

The identification and management of patients at high bleeding risk (HBR) undergoing transcatheter aortic valve implantation (TAVI) are of major importance, but the lack of standardised definitions is challenging for trial design, data interpretation, and clinical decision-making. The Valve Academic Research Consortium for High Bleeding Risk (VARC-HBR) is a collaboration among leading research organisations, regulatory authorities, and physician-scientists from Europe, the USA, and Asia, with a major focus on TAVI-related bleeding. VARC-HBR is an initiative of the CERC (Cardiovascular European Research Center), aiming to develop a consensus definition of TAVI patients at HBR, based on a systematic review of the available evidence, to provide consistency for future clinical trials, clinical decision-making, and regulatory review. This document represents the first pragmatic approach to a consistent definition of HBR evaluating the safety and effectiveness of procedures, devices and drug regimens for patients undergoing TAVI..

Gender equality in medical research: A cardiology-informed examination.

Despite a perceived increase in attention to gender differences in medicine, a comprehensive assessment of gender equality research, particularly in cardiology, remains underexplored. This observational retrospective study, focusing on documents related to "Gender Equality" according to the Sustainable Development Goals, reveals cardiology as a significant area for gender equality research, albeit with a decline in publications post-2018. The analysis highlighted a concentrated effort in the United States and a considerable impact gap between gender-focused and general cardiology research. The global academic community must intensify research into gender disparities, which is essential for achieving professional gender equality and addressing the burden of cardiovascular diseases.

Future of factor XI inhibitors in cardiovascular practice.

Anticoagulation is indicated for treatment and prevention of arterial and venous thrombosis. Targeting different steps of the coagulation process, currently available anticoagulants entail an increased risk of bleeding, which detrimentally impacts on prognosis and hinders the administration of an effective antithrombotic regimen. Factor XI (FXI) inhibition has emerged as a strategy to uncouple prevention of thrombosis from bleeding. Indeed, while FXI is crucial for the amplification phase in pathological thrombosis, it is ancillary in physiological hemostasis. A comprehensive search in several scientific databases has been performed to identify relevant studies in the field. In addition, ongoing trials have been searched for in proper datasets to provide an updated and comprehensive assessment of the current state of investigations on FXI inhibition. Many compounds have been tested to inhibit FXI at different stages (i.e., synthesis, activation, or interactions with target molecules and coagulation factors). These include antisense oligonucleotides, monoclonal antibodies, small molecules, natural peptides and aptamers. In phase 2 studies, FXI inhibitors reduced thrombotic complications without any corresponding increase in bleeding. FXI inhibitors were noninferior and potentially superior to low-molecular-weight heparin in orthopedic surgery and reduced bleeding compared to apixaban in patients with atrial fibrillation. FXI inhibition is also under testing in other conditions, including end-stage renal disease, cancer, or noncardioembolic stroke. FXI inhibition represents a promising and rapidly emerging approach for a number of clinical indications. This article reviews the rationale, evidence, pharmacology, and future applications of FXI inhibition.

Antiplatelet De-Escalation Strategies in Patients Undergoing Percutaneous Coronary Intervention.

Dual antiplatelet therapy-the combination of aspirin and a P2Y12 inhibitor-remains the standard antiplatelet regimen recommended to prevent ischemic complications immediately after percutaneous coronary intervention. Nonetheless, recent advances in stent technologies, percutaneous coronary intervention techniques, adjunctive pharmacotherapy for secondary prevention, and the rising awareness of the prognostic impact of bleeding, which are inevitably associated with dual antiplatelet therapy, led to the investigation of alternative antiplatelet regimens related to fewer bleeding and a preserved ischemic protection. Thrombotic complications occur mostly in the first months after percutaneous coronary intervention, while the risk of bleeding remains stable over time; this observation laid the foundation of the concept of antiplatelet de-escalation, consisting of a more intense antiplatelet regimen early after percutaneous coronary intervention, followed by a less potent antiplatelet therapy thereafter. According to new definitions proposed by the Academic Research Consortium, de-escalation can be achieved by discontinuation of 1 antiplatelet agent, switching from a potent P2Y12 inhibitor to clopidogrel, or by reducing the dose of antiplatelet agents. This review discusses the rationale and the evidence supporting antiplatelet de-escalation, provides practical guidance to use these new regimens, and gives insights into future developments in the field.

Risk Burden of Cancer in Patients Treated With Abbreviated Dual Antiplatelet Therapy After PCI: Analysis of Multicenter Controlled High-Bleeding Risk Trials.

BACKGROUND: Oncological patients with coronary artery disease face an elevated risk of hemorrhagic and ischemic events following percutaneous coronary intervention. Despite medical guidelines recommending minimal dual antiplatelet therapy (DAPT) duration for patients with cancer, dedicated data on abbreviated DAPT in this population is lacking. This study aims to evaluate the occurrence of ischemic and hemorrhagic events in patients with cancer compared with other high-bleeding risk individuals. METHODS: Patient-level data from 4 high-bleeding risk coronary drug-eluting stent studies (ONYX One, LEADERS FREE, LEADERS FREE II, and SENIOR trials) treated with short DAPT were analyzed. The comparison focused on patients with high-bleeding risk with and without cancer, assessing 1-year rates of net adverse clinical events (all-cause death, myocardial infarction, stroke, revascularization, and Bleeding Academic Research Consortium [BARC] types 3 to 5 bleeding) and major adverse clinical events (all-cause death, myocardial infarction, stroke). RESULTS: A total of 5232 patients were included, of whom 574 individuals had cancer, and 4658 were at high-bleeding risk without previous cancer. Despite being younger with fewer risk factors, patients with cancer had higher net adverse clinical event (HR, 1.25; P=0.01) and major adverse clinical event (HR, 1.26; P=0.02), primarily driven by all-cause mortality and major bleeding (BARC 3-5), but not myocardial infarction, stroke, stent thrombosis, or repeat revascularization. Cancer was an independent predictor of net adverse clinical event (P=0.005), major adverse clinical event (P=0.01), and major bleeding (P=0.03). CONCLUSIONS: The present work is the first report on abbreviated DAPT dedicated to patients with cancer. Cancer is a major marker of adverse outcomes and these events had high lethality. Despite short DAPT, patients with cancer experienced higher rates of major bleeding compared with patients without cancer with high-bleeding risk, which occurred mainly after DAPT discontinuation. These findings reinforce the need for a more detailed and individualized stratification of those patients. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03344653, NCT01623180, NCT02843633, NCT0284.

Exploring the impact of cardiologists expertise on publication metrics.

BACKGROUND: In the field of academic cardiology, the assessment of an author's scholarly impact and professional progression heavily relies on publications and citations. This study investigates whether specific cardiology expertise correlates with accelerated professional growth. METHODS: Using data from the 2023 European Society of Cardiology congress, 948 faculty attendees with an h-index of 30 or higher were analyzed. Expertises were categorized into six groups, and their association with publications and citations peaks was explored. RESULTS: Interventional cardiologists exhibited the highest annual publication peak, followed by imaging and electrophysiology experts. However, no significant differences were observed in citation peaks among expertise groups. While imaging experts initially appeared to reach citation peaks faster, this effect diminished after statistical adjustments. Additionally, holding multiple expertise areas prolonged the time to reach publication and citation peaks by approximately six years. CONCLUSION: This study underscores the influence of expertise in interventional cardiology on publication peaks but suggests that citation peaks and career progression velocity remain unaffected by expertise type. Furthermore, it highlights that holding multiple areas of expertise slowers the attainment of career peak for scholarly authors.

Current Management of In-Stent Restenosis.

In-stent restenosis (ISR) remains the primary cause of target lesion failure following percutaneous coronary intervention (PCI), resulting in 10-year incidences of target lesion revascularization at a rate of approximately 20%. The treatment of ISR is challenging due to its inherent propensity for recurrence and varying susceptibility to available strategies, influenced by a complex interplay between clinical and lesion-specific conditions. Given the multiple mechanisms contributing to the development of ISR, proper identification of the underlying substrate, especially by using intravascular imaging, becomes pivotal as it can indicate distinct therapeutic requirements. Among standalone treatments, drug-coated balloon (DCB) angioplasty and drug-eluting stent (DES) implantation have been the most effective. The main advantage of a DCB-based approach is the avoidance of an additional metallic layer, which may otherwise enhance neointimal hyperplasia, provide the substratum for developing neoatherosclerosis, and expose the patient to a persistently higher risk of coronary ischemic events. On the other hand, target vessel scaffolding by DES implantation confers relevant mechanical advantages over DCB angioplasty, generally resulting in larger luminal gain, while drug elution from the stent surface ensures the inhibition of neointimal hyperplasia. Nevertheless, repeat stenting with DES also implies an additional permanent metallic layer that may reiterate and promote the mechanisms leading to ISR. Against this background, the selection of either DCB or DES on a patient- and lesion-specific basis as well as the implementation of adjuvant treatments, including cutting/scoring balloons, intravascular lithotripsy, and rotational atherectomy, hold the potential to improve the effectiveness of ISR treatment over time. In this review, we comprehensively assessed the available evidence from randomized trials to define contemporary interventional treatment of ISR and provide insights for future directions.

Percutaneous interventions for pulmonary embolism.

Pulmonary embolism (PE) ranks as a leading cause of in-hospital mortality and the third most common cause of cardiovascular death. The spectrum of PE manifestations varies widely, making it difficult to determine the best treatment approach for specific patients. Conventional treatment options include anticoagulation, thrombolysis, or surgery, but emerging percutaneous interventional procedures are being investigated for their potential benefits in heterogeneous PE populations. These novel interventional techniques encompass catheter-directed thrombolysis, mechanical thrombectomy, and hybrid approaches combining different mechanisms. Furthermore, inferior vena cava filters are also available as an option for PE prevention. Such interventions may offer faster improvements in right ventricular function, as well as in pulmonary and systemic haemodynamics, in individual patients. Moreover, percutaneous treatment may be a valid alternative to traditional therapies in high bleeding risk patients and could potentially reduce the burden of mortality related to major bleeds, such as that of haemorrhagic strokes. Nevertheless, the safety and efficacy of these techniques compared to conservative therapies have not been conclusively established. This review offers a comprehensive evaluation of the current evidence for percutaneous interventions in PE and provides guidance for selecting appropriate patients and treatments. It serves as a valuable resource for future researchers and clinicians seeking to advance this field. Additionally, we explore future perspectives, proposing "percutaneous primary pulmonary intervention" as a potential paradigm shift in the field.

Antithrombotic strategies for preventing graft failure in coronary artery bypass graft.

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.

Acute and long-term results of percutaneous coronary intervention of bifurcation lesions with the dedicated Bioss Lim C stent: the Italian BIfurcation Observational Spontaneous Study (IBIOSS).

BACKGROUND: Percutaneous coronary intervention (PCI) for bifurcation lesions still represents a clinical challenge. The Bioss Lim C is a dedicated device for bifurcation lesions, features a tapered shape and large cells, and thus appears as a promising adjunct to the current interventional cardiologists' armamentarium. We aimed at conducting a prospective multicenter study focusing on early and long-term results after Bioss Lim C implantation for true coronary bifurcation lesions. METHODS: Patients with true bifurcation lesions in whom Bioss Lim C implantation was attempted were enrolled in four Italian centers. An explicit bifurcation management approach was recommended, leaving however the choice between one- vs. two-stent strategies at operator's discretion. Acute and long-term results were systematically appraised, focusing on an acute composite of complex side branch (SB) rewiring, SB pinching, or SB occlusion (primary efficacy endpoint), as well as major adverse events (MACE, i.e. death, myocardial infarction [MI], or target vessel revascularization [TVR]), individual components of MACE, and stent thrombosis. RESULTS: A total of 207 patients were included, with age of 67.3±10.8 years, and 40 (19.3%) women. The target lesion was located in the left main in 48 (23.2%) patients, whereas proximal reference vessel diameter was 3.69±0.48 mm, and lesion length 20.3±3.4 mm. According to the Medina classification, most patients (60 [30.9%]) had 1-1-1 lesions. Drug-eluting stent implantation in the SB was carried out in 19 (9.3%) subjects, and kissing balloon inflation was used in 67 (32.5%). The primary efficacy endpoint occurred in 27 (13.0%), with side branch (SB) occlusion in two (1.0%), SB pinching in 23 (11.1%), and complex SB rewiring in six (2.9%), and was most frequent in patients with lower body mass index or dyslipidemia. After 24.1±19.5 months, MACE were adjudicated in 23 (11.1%) subjects, with death in 10 (4.8%), MI in six (2.9%), and TVR in seven (3.4%), as well as stent thrombosis in one (0.5%). CONCLUSIONS: This study supports a wider adoption of the Bioss Lim C dedicated bifurcation device, thanks to the favorable acute results as well as long-term clinical outcomes, as well as its versatility for the stenting strategy provisionally or eventually adopted by operators.

Coronary Angiography, Intravascular Ultrasound, and Optical Coherence Tomography for Guiding of Percutaneous Coronary Intervention: A Systematic Review and Network Meta-Analysis.

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.

Periprocedural myocardial infarction and injury.

Periprocedural myocardial infarction (PMI) and injury, pertinent to both cardiac and non-cardiac procedures, have gained increasing recognition in clinical practice. Over time, diverse definitions for diagnosing PMI have been developed and validated among patient populations undergoing coronary revascularization. However, this variety in definitions presents considerable challenges in clinical settings and complicates both the design and interpretation of clinical trials. The necessity to accurately diagnose PMI has spurred significant interest in establishing universally accepted and prognostically meaningful thresholds for cardiac biomarkers elevation and supportive ancillary criteria. In fact, elevations in cardiac biomarkers in line with the 4th Universal Definition of Myocardial Infarction, have been extensively confirmed to be associated with increased mortality and cardiovascular events. In the context of non-coronary cardiac procedures, such as Transcatheter Aortic Valve Implantation, there is a growing acknowledgment of both the high incidence rates and the adverse impact of PMI on patient outcomes. Similarly, emerging research underscores the significance of PMI and injury in non-cardiac surgery, highlighting the urgent need for effective prevention and risk management strategies in this domain.

European Association of Cardio-Thoracic Surgery (EACTS) expert consensus statement on perioperative myocardial infarction after cardiac surgery.

Cardiac surgery may lead to myocardial damage and release of cardiac biomarkers through various mechanisms such as cardiac manipulation, systemic inflammation, myocardial hypoxia, cardioplegic arrest and ischaemia caused by coronary or graft occlusion. Defining perioperative myocardial infarction (PMI) after cardiac surgery presents challenges, and the association between the current PMI definitions and postoperative outcomes remains uncertain. To address these challenges, the European Association of Cardio-Thoracic Surgery (EACTS) facilitated collaboration among a multidisciplinary group to evaluate the existing evidence on the mechanisms, diagnosis and prognostic implications of PMI after cardiac surgery. The review found that the postoperative troponin value thresholds associated with an increased risk of mortality are markedly higher than those proposed by all the current definitions of PMI. Additionally, it was found that large postoperative increases in cardiac biomarkers are prognostically relevant even in absence of additional supportive signs of ischaemia. A new algorithm for PMI detection after cardiac surgery was also proposed, and a consensus was reached within the group that establishing a prognostically relevant definition of PMI is critically needed in the cardiovascular field and that PMI should be included in the primary composite outcome of coronary intervention trials.

Strategy to optimize PeriproCeduraL AnticOagulation in structural transseptal interventions: Design and rationale of the STOP CLOT trial.

BACKGROUND: Both transcatheter edge-to-edge repair (TEER) of mitral regurgitation or left atrial appendage closure (LAAC) require periprocedural anticoagulation with unfractionated heparin (UFH) that is administered either before or immediately after transseptal puncture (TSP). The optimal timing of UFH administration (before or after TSP) is unknown. The Strategy To Optimize PeriproCeduraL AnticOagulation in Structural Transseptal Interventions trial (STOP CLOT Trial) was designed to determine if early anticoagulation is effective in reducing ischemic complications without increasing the risk of periprocedural bleeding. METHODS: The STOP CLOT trial is a multicenter, prospective, double-blind, placebo-controlled, randomized trial. A total of 410 patients scheduled for TEER or LAAC will be randomized 1:1 either early UFH administration (iv. bolus of 100 units/kg UFH or placebo, given after obtaining femoral vein access and at least 5 minutes prior to the start of the TSP) or late UFH administration (iv. bolus of 100 units/kg UFH or placebo given immediately after TSP). Prespecified preliminary statistical analysis will be performed after complete follow-up of the first 196 randomized subjects. To ensure blinding, a study nurse responsible for randomization and UFH/placebo preparation is not involved in the care of the patients enrolled into the study. The primary study endpoint is a composite of (1) major adverse cardiac and cerebrovascular events (death, stroke, TIA, myocardial infarction, or peripheral embolization) within 30 days post-procedure, (2) intraprocedural fresh thrombus formation in the right or left atrium as assessed with periprocedural transesophageal echocardiography, or (3) occurrence of new ischemic lesions (diameter ≥4 mm) on brain magnetic resonance imaging performed 2 to 5 days after the procedure. The safety endpoint is the occurrence of moderate or severe bleeding complications during the index hospitalization. CONCLUSIONS: Protocols of periprocedural anticoagulation administration during structural interventions have never been tested in a randomized clinical trial. The Stop Clot trial may help reach consensus on the optimal timing of initiation of periprocedural anticoagulation. CLINICAL TRIALS REGISTRATION NUMBER: The study protocol is registered at ClinicalTrials.gov, identifier NCT05305612.

Aspirin-free antiplatelet strategies after percutaneous coronary interventions.

Dual antiplatelet therapy (DAPT) with aspirin and a platelet P2Y12 receptor inhibitor is the standard antithrombotic treatment after percutaneous coronary interventions (PCI). Several trials have challenged guideline-recommended DAPT after PCI by testing the relative clinical effect of an aspirin-free antiplatelet approach-consisting of P2Y12 inhibitor monotherapy after a short course (mostly 1-3 months) of DAPT-among patients undergoing PCI without a concomitant indication for oral anticoagulation (OAC). Overall, these studies have shown P2Y12 inhibitor monotherapy after short DAPT to be associated with a significant reduction in the risk of bleeding without an increase in thrombotic or ischaemic events compared with continued DAPT. Moreover, the effects of the P2Y12 inhibitor monotherapy without prior DAPT or following a very short course of DAPT after PCI are being investigated in emerging studies, of which one has recently reported unfavourable efficacy results associated with the aspirin-free approach compared with conventional DAPT. Finally, P2Y12 inhibitor alone has been compared with aspirin alone as chronic therapy after DAPT discontinuation, thus challenging the historical role of aspirin as a standard of care for secondary prevention following PCI. A thorough understanding of study designs, populations, treatments, results, and limitations of trials testing P2Y12 inhibitor monotherapy vs. DAPT or vs. aspirin is required to consider adopting this treatment in clinical practice. This review addresses the use of aspirin-free antiplatelet strategies among patients undergoing PCI without a concomitant indication for OAC, providing an overview of clinical evidence, guideline indications, practical implications, ongoing issues, and future perspectives.

Pharmacological and clinical appraisal of factor XI inhibitor drugs.

The evolution of anticoagulation therapy, from vitamin K antagonists to the advent of direct oral anticoagulants (DOACs) almost two decades ago, marks significant progress. Despite improved safety demonstrated in pivotal trials and post-marketing observations, persistent concerns exist, particularly regarding bleeding risk and the absence of therapeutic indications in specific subgroups or clinical contexts. Factor XI (FXI) has recently emerged as a pivotal contributor to intraluminal thrombus formation and growth, playing a limited role in sealing vessel wall injuries. Inhibiting FXI presents an opportunity to decouple thrombosis from haemostasis, addressing concerns related to bleeding events while safeguarding against thromboembolic events. Notably, FXI inhibition holds promise for patients with end-stage renal disease or cancer, where clear indications for DOACs are currently lacking. Various compounds have undergone design, testing, and progression to phase 2 clinical trials, demonstrating a generally favourable safety and tolerability profile. However, validation through large-scale phase 3 trials with sufficient power to assess both safety and efficacy outcomes is needed. This review comprehensively examines FXI inhibitors, delving into individual classes, exploring their pharmacological properties, evaluating the latest evidence from randomized trials, and offering insights into future perspectives.