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.

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Background Antiplatelet therapy is required in patients with atherosclerotic coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES). Current European and American guidelines recommend 6 months of DAPT in CCS and 12 months after ACS. However, a shorter duration of DAPT may be considered in high bleeding risk (HBR) patients, and a longer duration in those at higher thrombotic risk (HTR). To minimize the risk of thrombotic and bleeding events of an individual patient and therefore improve the overall outcomes of PCI, risk stratification is essential. In particular, bleeding and thrombotic characteristics must be weighed on a case-by-case basis to tailor antiplatelet therapy strategies and decisions over a patient's individual risk profile. We describe an illustrative case of complex PCI in patient with ACS in which defining the appropriate duration of DAPT is a clinical challenge. Clinical case A 68-year-old man with ACS-NSTEMI and anemia was hospitalized in intensive care unit. His medical history was notable for hypertension, dyslipidemia, diabetes mellitus, diabetic retinopathy, chronic kidney disease (CKD) and paroxysmal atrial fibrillation. A transthoracic echocardiogram showed left ventricular ejection fraction of 30% with diffuse hypokinesia, without relevant valvular disease. He was conducted to the cath-lab for a diagnostic coronary angiogram which showed a three-vessel critical CAD. After Heart Team evaluation coronary artery bypass surgery (CABG) was indicated. However, during the hospitalization in intensive care unit there was a worsening of clinical conditions with cognitive impairment due to mesencephalic stroke leading to a new Heart Team assessment that indicated PCI after stabilization of clinical scenario. After two weeks patient was conducted to the cath-lab to undergoing an IVUS guided PCI. PCI of the right coronary artery was performed with implantation of 1 DES (3.0/30 mm) on the middle segment and 1 DES (4.0/15 mm) on the ostial segment. PCI of the left main bifurcation was performed with implantation of 2 DES (4.0/28 mm) with culotte technique. Patients have both HBR and HTR, therefore, after procedure, the new trade off model score introduced by the Academic Research Consoritum (ARC) was applied. Based on his risk factor, the predicted 1-y risk of BARC type 3 to 5 bleeding (51.41%) was greater than the predicted 1-y risk of myocardial infarction or stroke (25.00%). Based on this result we decided to prescribe Triple antithrombotic therapy for 1 week, dual antithrombotic therapy for 12 months and after only oral anticoagulation. Conclusion In the context of patient with several risk factor undergoing complex PCI the stratification of bleeding and thrombotic individual risk is mandatory to define the appropriate duration of DAPT. The new trade-off model score is an important useful tool to identify patients who might benefit from individualized DAPT durations depending on the balance between HBR and HTR characteristics.

Background A number of clinical trials documented clinical benefits of glycoprotein IIb-IIIa inhibitors (GPIs) in the setting of acute coronary syndromes (ACS). The advantage of reducing thrombotic burden at the cost of a higher risk of bleeding has been evaluated in different studies. However, data regarding the use of GPIs as peri-interventional treatment is lacking. Indeed, in current European guidelines GPIs may only be considered in specific ‘bail-out’ situations including high intraprocedural thrombus burden, slow flow, or no-flow with closure of the stented coronary vessel. The REPLACE-2 (Randomised Evaluation in PCI Linking Angiomax to Reduced Clinical Events 2) trial showed that the outcome with bivalirudin and provisional glycoprotein (GP) IIb/IIIa blockade is similar to that of UFH plus planned GP IIb/IIIa inhibition during PCI. Moreover, the use of GPIs as bridge to elective percutaneous coronary intervention (PCI) planned after unsuccessful urgent PCI in patients with NSTE-ACS has never been evaluated. Clinical case A 67-year-old man with multiple risk factors (hypertension, smoking and dyslipidemia) and history of coronary artery disease (CAD) was referred for acute chest pain and 27179 ng/L high-sensitivity-cardiac troponine (HS-cTn) at laboratory testing. The echocardiogram showed inferior and lateral wall hypokinesis with an inspective left ventricular ejection fraction (LVEF) of 40%. Therefore, the patient was conducted in the cath-lab and a coronary angiography was performed showing a thrombotic occlusion of proximal right coronary artery (RCA) due to a large thrombus burden. Then, an urgent PCI was indicated. Different guidewires was unsuccessfully attempted to pass throughout the lesion on the proximal segment of the vessel. Eventually, the patient was monitored in intensive care unit and it was decided to administer a continuous infusion of tirofiban for 48 hours to reduce the thrombus burden. During these two days an improvement of the clinical status, a reduction of HS-cTn and an increase in terms of LVEF were observed. At the end the patient underwent to new invasive coronary angiography that demonstrated significant changes of the thrombus burden translating into plaque modification. A PCI was attempted again. The guidewire reached the distal part of the RCA and 1 DES 3.5/28 mm was implanted with consequent optimal angiographic result. Conclusion In the era of potent and faster acting P2Y12-inhibitors like prasugrel and ticagrelor, the benefit and, more importantly, the safety of GPI, remains discussed. In the current European guidelines on revascularization, GPIs infusion should be considered for bail out with evidence of no-reflow or thrombotic periprocedural complication (Class IIa, level of evidence C). This clinical case shows the potential benefit of administrating GPIs as bridge to PCI in selected patients. Patients with an occluded infarct-related artery and large thrombus burden could benefit from GPIs infusion facilitating PCI.