Factor XIa Inhibition: Is It a Novel Alternative Antithrombotic Strategy for High-Risk ACS Patients?

Abstract

HomeCirculationVol. 146, No. 16Factor XIa Inhibition: Is It a Novel Alternative Antithrombotic Strategy for High-Risk ACS Patients? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBFactor XIa Inhibition: Is It a Novel Alternative Antithrombotic Strategy for High-Risk ACS Patients? Ying X. Gue, Diana A. Gorog and Gregory Y.H. Lip Ying X. GueYing X. Gue Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom (Y.X.G., G.Y.H.L.). Search for more papers by this author , Diana A. GorogDiana A. Gorog https://orcid.org/0000-0002-9286-1451 School of Life and Medical Sciences, Postgraduate Medical School, University of Hertfordshire, United Kingdom (D.A.G.). Faculty of Medicine, National Heart and Lung Institute, Imperial College, London, United Kingdom (D.A.G.). Search for more papers by this author and Gregory Y.H. LipGregory Y.H. Lip Correspondence to: Gregory Y.H. Lip, MD, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool, L7 8TX, United Kingdom. Email E-mail Address: [email protected] https://orcid.org/0000-0002-7566-1626 Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom (Y.X.G., G.Y.H.L.). Department of Clinical Medicine, Aalborg University, Denmark (G.Y.H.L.). Search for more papers by this author Originally published27 Aug 2022https://doi.org/10.1161/CIRCULATIONAHA.122.061987Circulation. 2022;146:1207–1209This article is a commentary on the followingA Multicenter, Phase 2, Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Dose-Finding Trial of the Oral Factor XIa Inhibitor Asundexian to Prevent Adverse Cardiovascular Outcomes After Acute Myocardial InfarctionOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: August 28, 2022: Ahead of Print Despite revascularization and optimal secondary prevention, including dual antiplatelet therapy (DAPT), patients with acute coronary syndrome (ACS) remain at risk of recurrent ischemic events, with up to 7% risk of recurrent myocardial infarction at 3 years.1 To address this residual risk, previous studies have investigated the benefit of increasing the intensity of antithrombotic medication, through the addition of an oral anticoagulant (factor Xa inhibitor or vitamin K antagonist) to antiplatelet therapy.2,3 Although studies have generally shown that this approach results in significantly fewer ischemic events, it came at a significant cost of excess major hemorrhage. Even adding a low dose of rivaroxaban (2.5 or 5 mg twice daily) to DAPT in the ATLAS ACS 2–TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 51) study was associated with a significantly increased risk of major bleeding including intracranial hemorrhage.2 Thus, there remains an important unmet need for an antithrombotic agent that reduces ischemic risk without increasing bleeding, especially where dual pathway inhibition (especially with increasingly potent antiplatelet agents) is increasingly considered to reduce arterial thromboembolism.4Article, see p 1196Asundexian is a novel, orally bioavailable inhibitor of factor XIa (FXIa).5 Asundexian is a novel, orally bioavailable inhibitor of factor XIa (FXIa). Factor XI (FXI) deficiency in humans and experimentally-induced animals is associated with reduced risk of ischemic stroke and venous thromboembolism, but unlike factor VIII deficiency, spontaneous bleeding is rare in FXI deficiency, and in response to trauma or surgery, bleeding is much milder. It is interesting to note that a recent retrospective cohort study reported that when matched to a general population, patients with any FXI deficiency are at higher risk of severe bleeding (adjusted hazard ratio, 2.56 [95% CI, 1.13–5.81]) and clinically relevant nonsevere bleeding (adjusted hazard ratio, 1.45 [95% CI, 1.08–1.97]).6 Most cases were postprocedural, hence highlighting the low likelihood of spontaneous bleeding; however, when stratified by severity of deficiency, partial FXI deficiency was associated with an increase in severe bleeding, whereas severe FXI deficiency was not. This finding further highlights that the observed differences may be because of potential overlaps between hematologic conditions rather than because of dose-related FXI deficiency responses.6FXIa inhibition therefore appears to be a potentially attractive avenue in which additional antithrombotic effects can be achieved without compromising hemostasis.7,8 In the recently published phase 2 trial in patients with atrial fibrillation, asundexian was associated with significantly lower rates of major bleeding compared with apixaban, with nearly complete FXIa inhibition.9 Other FXIa inhibitors such as IONIS-416858 and AB023 are in development, or tested in various clinical settings.10In this issue of Circulation, the investigators of the PACIFIC-AMI (Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2433334 in Patients Following an Acute Heart Attack) trial report on the pharmacodynamics, safety, and efficacy of adding asundexian to DAPT in patients with recent myocardial infarction.11 In this phase 2, randomized double-blind trial, patients with ACS considered to be at high ischemic risk (defined as meeting at least 1 of the following criteria: ≥65 years of age; previous myocardial infarction, peripheral arterial disease, or coronary artery bypass grafting; diabetes) but without increased risk of bleeding, were randomized within 5 days of the index ACS event to asundexian 10, 20, or 50 mg, or a placebo once daily for up to 12 months. The majority of patients received prasugrel or ticagrelor as the P2Y12 inhibitor in addition to aspirin, and nearly all patients underwent revascularization with percutaneous coronary intervention.Although asundexian achieved dose-dependent inhibition of FXIa with >90% inhibition with the 50-mg dose, there was no difference in the main safety outcomes of Bleeding Academic Research Consortium types 2, 3, or 5 when comparing all pooled asundexian doses with placebo. Regarding the efficacy outcome of the composite of cardiovascular death, myocardial infarction, stroke, or stent thrombosis, although there were numerically fewer events observed with increased asundexian dose, none of the asundexian groups had event rates lower than the placebo group.The phase 2 study is important, showing the apparent safety of asundexian in addition to DAPT in ACS, although the lack of signal for reducing ischemic events is disappointing. However, the fewer number of ischemic events seen with the 50-mg dose of asundexian is encouraging and suggests the need to properly evaluate the potential ischemic benefits of this dose. Such an evaluation would be best demonstrated in a population at high ischemic risk and the population in PACIFIC-AMI (average age, 68 years)—with only half of patients experiencing ST-segment elevation—may not have been truly representative of the most high risk patients. Given the reassuring safety profile, a large phase 3 trial in the future should focus on patients with high ischemic risk, without excluding those considered to be at increased risk of bleeding. As the authors allude to in their Discussion, there may perhaps be a role in augmenting clinical outcomes in patients with both high bleeding risk and high ischemic risk.The study also raises a number of new questions. What is the optimal level of FXIa inhibition required to achieve desired outcomes? Is it all or nothing, or can this be tailored to a patient’s risk profile? Should the optimal treatment duration be a short course to alleviate the initial highest risk period or—given its relatively safe profile, even in addition to DAPT—a prolonged period of treatment beyond the first year of ACS? Could FXIa inhibition be used as a substitute for a conventional DAPT post-ACS instead using single antiplatelet with FXIa inhibitor? If so, should that be aspirin or a P2Y12 inhibitor? Would there be differences among ethnicities in sensitivity to this new class of drugs, particularly to the risk of bleeding?12We congratulate the investigators in presenting this much-welcomed novel therapeutic agent as an addition to the antithrombotic armamentarium in ACS, which appears not to increase bleeding complications, a common shortfall with modern era antithrombotic therapy.13 Although more data on safety and efficacy are required, we can exercise cautious optimism in the application of FXIa inhibition in ACS and other therapeutic areas, potentially offering patients tailored antithrombotic therapy commensurate with their risk profile. Indeed, FXIa inhibitors are being investigated as thromboprophylaxis for stroke prevention in atrial fibrillation and secondary prevention of stroke.As with all new drug therapies, more information leads to more questions. We look forward to future phase 3 studies using FXIa inhibition in ACS patients to assess whether this therapeutic option can reduce thrombotic events in those at high ischemic risk, while avoiding excess bleeding.Article InformationSources of FundingNone.Disclosures None.FootnotesCirculation is available at www.ahajournals.org/journal/circThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 1208.Correspondence to: Gregory Y.H. Lip, MD, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool, L7 8TX, United Kingdom. Email gregory.[email protected]ac.uk