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 Among dual antiplatelet therapy (DAPT) modulation strategies after acute coronary syndromes (ACS), short duration of DAPT (i.e.; 3 or 6 months) received a class IIa recommendation by European guidelines. However, whether discontinuing aspirin or P2Y12 inhibitor (P2Y12-i) after this period is still a matter of debate. Aims The aim of this study was to compare the overall effects of short DAPT versus standard DAPT in patients presenting with ACS undergoing percutaneous coronary intervention in a two-arm metanalysis, and the relative merits of short DAPT followed by aspirin or P2Y12-i discontinuation in a three-node network meta-analysis using standard DAPT as common comparator. Methods Randomized trials of DAPT modulation strategies in patients with ACS undergoing PCI were identified. All-cause death was the primary outcome. Secondary outcomes included net adverse cardiovascular events (NACE), major adverse cardiovascular events (MACE), and their components. Firstly, we conducted a two-arm random-effect frequentist meta-analysis to compare short DAPT and standard DAPT. Secondly, we conducted a frequentist random-effects network metanalysis to compare the relative merits of the two short DAPT strategies. Treatments were ranked on the basis of p-scores. Results Nineteen studies encompassing 37,789 patients were included. The transitivity assumption was fulfilled. Comparing short DAPT with standard DAPT, no significant differences were noted for the primary outcome, but short DAPT significantly reduced the risk ratio (RR) for any bleeding (RR, 0.68; 95% CI, 0.58 to 0.79), major bleedings (RR, 0.57; 95% CI, 0.41 to 0.78) and minor bleeding (RR, 0.80; 95% CI, 0.64 to 0.98), without increasing the risk for ischemic events. In the three-node network metanalysis, no significant differences were noted in the primary endpoint, all secondary ischemic outcomes and minor bleeding between the three strategies. However, short DAPT followed by aspirin discontinuation significantly reduced the incidence of any bleeding (RR, 0.61; 95% CI, 0.50 to 0.75) and major bleeding (RR, 0.51; 95% CI, 0.37 to 0.70) compared with standard DAPT. The ranking evaluation revealed that short DAPT followed by aspirin discontinuation had the highest probability of being the best treatment for prevention of the primary endpoint, MACE, cardiovascular death, stroke, any bleeding and major bleeding (p-scores 0.78, 0.80, 0.85, 0.73, 0.98, 0.97, respectively), whereas standard DAPT had the highest probability of being the best treatment for prevention of myocardial infarction and stent thrombosis (p-scores 0.84 and 0.79, respectively). Conclusions In patients with ACS undergoing PCI, there was no difference in all-cause death between short DAPT regimens and standard DAPT. However, short DAPT reduced the risk of all types of bleeding, and the major driver for this effect is represented by short DAPT followed by aspirin discontinuation, which significantly reduced the risk for any bleeding and major bleeding. These data suggest that, when a short DAPT course is chosen after an ACS, discontinuing aspirin should be the strategy of choice, rather than discontinuing the P2Y12-i.

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