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 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.
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.
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