Précis
Factor XI inhibitors show promise as a safer alternative to direct oral anticoagulants for preventing and treating thrombosis, offering similar efficacy with reduced bleeding risk.
Abstract
Anticoagulation therapy has been evolving since the early 1900s with substantial advancements that have helped shape the treatment of indications such as atrial fibrillation and venous thromboembolism. Direct oral anticoagulants (DOACs) have been deemed the gold standard of treatment for these indications. However, the increased risk of bleeding that comes with DOAC use has proven to be a significant limitation. Currently, factor XI inhibitors are undergoing clinical trials for use in the prevention and treatment of thrombosis. These agents have promising clinical profiles, offering similar efficacy as the current gold standard while presenting with fewer bleeding incidents. Findings from phase 2 clinical trials comparing factor XI inhibitors with DOACs, dual antiplatelet therapy, or placebo showed that the inhibitors had no significant increase in bleeding and exhibited similar efficacy to currently accepted therapy. Phase 3 clinical trials are comparing therapies such as factor XI inhibitors abelacimab (MAA868; Anthos Therapeutics), asundexian (BAY-2433334; Bayer), and milvexian (BMS-986177/JNJ-70033093; Bristol Myers Squibb and Johnson & Johnson) with low-molecular-weight heparins, DOACs, antiplatelet therapies, or placebo; many of these trials have upcoming completion dates. As ongoing clinical trials provide insight into these agents, we will learn about their efficacy and safety profiles. Although there are essential barriers to cross before their clinical use, they have the potential to advance the progress of anticoagulation. This review discusses current anticoagulation therapy, the mechanism of action of factor XI inhibitors, and individual factor XI inhibitors that are active in clinical trials.
Introduction
Direct oral anticoagulants (DOACs) are the current mainstay of treatment and prevention of thrombosis. DOACs and vitamin K antagonists (VKAs), such as warfarin, are utilized for many indications, including atrial fibrillation, venous thromboembolism (VTE), and mechanical heart valves. DOACs eliminated the need for routine international normalized ratio (INR) monitoring and decreased dietary restrictions that accompany VKAs; however, there are limitations with these current treatment options.
New anticoagulants targeting factors in the intrinsic or contact coagulation pathway are under development. Factor XI (FXI) inhibitors are particularly promising new agents being investigated in clinical trials for atrial fibrillation, ischemic stroke, VTE, and more. By inhibiting factors in the intrinsic pathway, these agents can potentially prevent and treat thromboembolic complications while lowering the bleeding risk in patients who utilize them. This article addresses the unmet needs in anticoagulation therapy, how FXI inhibitors could overcome the challenges faced, and FXI clinical trials to date.
History of Anticoagulation
In 1916, unfractionated heparin (UFH) was the first anticoagulant drug discovered, and it was approved for clinical use in the 1930s (Figure 11-4). UFH inhibits thrombin (factor IIa) and factors VIIa, IXa, Xa, and XIa. This inhibits coagulation by preventing fibrin formation.
In 1939, dicoumarol was extracted from moldy clover following investigation of a mysterious disease in which cattle and sheep were dying from internal bleeding.1 In the 1940s to 1950s, warfarin was further derived from dicoumarol because it had more favorable pharmacokinetics; it was approved by the FDA in 1954. Warfarin also provided the advantage of an orally administered anticoagulation option. This was in contrast to its predecessor, which required intravenous or subcutaneous administration.
Following the development of dicoumarol and warfarin, understanding of thromboembolic diseases grew, leading to the discovery of key players in the coagulation cascade and the derivation of low-molecular-weight heparins (LMWHs) from UFH in the 1970s. Although LMWHs are also injectable, they provide the benefit of being administered as a fixed dose, which reduces the need for regular concentration monitoring and provides the option for outpatient treatment.2 LMWHs include enoxaparin (Lovenox; Sanofi-Aventis), dalteparin (Fragmin; Pfizer), and tinzaparin (Innohep; LEO Pharma). These agents inhibit thrombin and FXa; however, FXa is predominant. Enoxaparin was approved by the FDA in 1993, dalteparin in 1994, and tinzaparin in 2000.3
UFH and LMWHs can reduce VTE complications in hip or knee arthroplasty and during prolonged immobilization from surgical procedures.4 They are also used in acute coronary syndromes to treat and prevent thrombosis complications. Fondaparinux (Arixtra; GSK), which inhibits only FXa, was approved by the FDA in 2001.3 Fondaparinux is a synthetic form of injectable direct thrombin inhibitors, including bivalirudin (Angiomax; Meitheal Pharmaceuticals) and argatroban (Novastan; Mitsubishi Tanabe Pharma Corporation), which were approved in the 2000s.2 Fondaparinux was also approved for the prevention and treatment of VTE and is conveniently dosed once daily due to its longer half-life.4
Injectable direct thrombin inhibitors bivalirudin and argatroban also were approved by the FDA in the early 2000s.3 Bivalirudin is used as an alternative to UFH in patients undergoing percutaneous coronary interventions, and argatroban is used as an alternative to heparin for patients with heparin-induced thrombocytopenia.4
Newer DOACs include the oral direct thrombin inhibitor dabigatran (Pradaxa; Boehringer Ingelheim), as well as oral direct FXa inhibitors rivaroxaban (Xarelto; Johnson & Johnson and Bayer), apixaban (Eliquis; Bristol Myers Squibb), and edoxaban (Savaysa; Daiichi Sankyo Company). Dabigatran and rivaroxaban were approved by the FDA in the early 2010s.3 They were followed by apixaban, which was approved by the FDA in 2012, and edoxaban, which was approved in 2015. In 2018, the FDA approved the monoclonal antibody idarucizumab (Praxbind; Boehringer Ingelheim), which is used as a reversal agent for dabigatran.3
DOACs quickly grew in popularity and replaced other anticoagulation therapies because of their ease of oral administration and ability to bypass the heparin bridging period for most indications. DOACs’ quick onset of action means that heparin bridging is not routinely needed. Originally, patients would have to be treated with heparin for 5 to 7 days upon admission, then slowly transition to a VKA. This increased bleeding risk because the 2 anticoagulants were administered simultaneously. DOACs also do not require frequent monitoring and do not have any dietary restrictions.2
Fortunately, newer anticoagulants, such as DOACs and direct thrombin inhibitors, also have minimal food and drug interactions. Although these medications still have some drug interactions, they are considerably fewer than those associated with warfarin.5 Dark leafy greens and oils are the primary sources of vitamin K, and many processed food items also contain substantial amounts. Warfarin interferes with cyclic interconversion of vitamin K and its 2,3-epoxide (vitamin K1 epoxide), so when vitamin K is added to the diet, the anticoagulant effect of warfarin may fluctuate.6 Generally, if patients have a constant amount of vitamin K in their diet, their health care provider will be able to keep their INR stable. With most of the newer anticoagulants eliminating the need for this consistency, patients can eat a wider variety of foods. This has led to overall better health for patients and more dietary freedom. Notably, although rivaroxaban must be taken with food, there are no dietary restrictions. Since the discovery of DOACs in 2010, a new class of anticoagulants has yet to hit the market.
Limitations With Current Anticoagulation Therapy
Anticoagulation therapy aims to control thrombosis while maintaining hemostasis. Current available therapies have shown efficacy in the prevention and treatment of thrombosis; however, the increased risk of bleeding has called attention to the need for safer options. In clinical trials, DOACs were shown to be at least as effective as heparin and warfarin for the prevention of stroke in patients with atrial fibrillation and the prevention and treatment of VTE. DOACs were also associated with lower rates of intracranial bleeding.7-11
Between 2017 and 2019, anticoagulants were the most common cause of drug-related emergency department (ED) visits in the US.12 Out of the current available anticoagulant therapies, DOACs have a more favorable risk-benefit profile. The rates of anticoagulation-related ED visits were lower with DOACs when compared with VKAs such as warfarin.13 Despite DOACs’ more favorable overall risk-benefit profile, they were found to cause more gastrointestinal bleeding than warfarin.14
DOACs have also led to unfavorable results in certain indications that require patients to take warfarin, such as mechanical heart valves and triple-positive antiphospholipid syndrome.15,16 In addition, DOACs have not been adequately tested in patients with severely impaired renal function, impaired liver function, or extremes of body weight.17,18
Anticoagulation is an important developing field of medical research. With the limitations of current anticoagulant therapies, there remains a need for new therapies to provide additional options for patients.
Mechanism of Action of Factor XI Inhibitors
The proposal of FXI as a target for anticoagulation stems from hemophilia C, a rare genetic FXI deficiency disorder. The prevalence is 1 in every 1 million people worldwide but is reported more frequently in people of Ashkenazi, Arabic, and Iraqi Jewish descent.19 Hemophilia C is associated with reduced risk of thrombosis and increased bleeding tendencies. To understand how FXI can be used as a clinical target of interest, we must first assess its role in the coagulation cascade.
The coagulation cascade can be segmented into 2 initial pathways, extrinsic and intrinsic, which later converge into the common pathway (Figure 220,21). The extrinsic pathway is activated by trauma or injury to the vessel, which exposes tissue factor (TF) to the blood. The newly exposed TF becomes bound to calcium and factor VIIa to form the TF:VIIa complex. This complex is able to activate FX, turning it into FXa, and enters the common pathway to form a stable clot. The TF:VIIa complex also converts FIX to FIXa, which has a cofactor of FVIIIa.21 This extrinsic or TF pathway serves to bring the body back to hemostasis after experiencing trauma by forming a clot at the site of bleeding.20,21
The intrinsic pathway is activated by triggers within the body, such as atherosclerotic plaques, various polyanions, neutrophil extracellular traps, and implanted medical devices.20,21 In the presence of these triggers, FXII self-activates and starts a signaling cascade that activates FXI, then FIX, and subsequently FX, which brings us back to the common pathway and production of thrombin and clot formation. FXI/XIa serves as a positive feedback mechanism to thrombin, therefore exponentially increasing the production of thrombin and causing a rapid expansion of the thrombus.20 This pathway is the cause of pathological thrombus formation and is the mechanism behind thromboembolic diseases.
Current anticoagulation therapies primarily target FX, the first step in the common pathway. This leads to FX inhibitors exerting their anticoagulation effects in both settings of hemostasis and thrombus formation, leading to an increased bleeding risk following injury or trauma.
The promise of FXI/XII inhibitors is the potential to uncouple the intrinsic and extrinsic pathways and stop pathological thrombus formation while avoiding hemostasis.21 The inhibition of the intrinsic or contact pathway would allow the prevention of thrombus formation within the body while still allowing the blood to clot when a person is injured.
Factor XI vs Factor XII
As anticoagulation research continues, FXI and FXII have been identified as promising drug targets. These intrinsic pathway factors have been shown in animal studies to be important in thrombosis and nonessential in hemostasis.22 Although FXII deficiency is not associated with abnormal bleeding, extrinsic pathway FVII and FVIII deficiency results in severe bleeding and the need for prophylactic therapies.22 Patients with FXI deficiency have reported bleeding episodes, and one study’s results showed that FXI-deficient patients have a greater risk for clinically relevant bleeding.23 Although this risk is mild, it is still of concern.
FXII as a target would seem more favorable as a potential agent with no risk of bleeding, but there are other characteristics to consider. Concerns of FXII as a drug target include the contribution of FXII to thrombosis initiated by TF, potential for feedback activation of FXII by thrombin to bypass FXIIa inhibition, and weak epidemiology data linking FXII to thrombosis.24
Although epidemiologic studies have shown links between FXI levels and thrombosis, links were not found between FXII and thrombosis.25 In these studies, those with congenital FXI deficiency were observed to have lower incidences of ischemic strokes, VTE, and myocardial infarction (MI).25 However, FXII did not show similar findings. Other studies have found that patients with higher FXI levels are more prone to ischemic stroke and VTE.26 These studies present the link of coagulation factor levels with the risk of thrombosis to be stronger for FXI than for FXII.27 Characteristics of FXI and FXII as targets for anticoagulation are summarized in Table 1.22-27
FXI’s central role in coagulation and inflammation gives FXI inhibitors the potential to be efficacious against antiphospholipid syndrome or thrombosis secondary to blood contact with medical devices.24 This unique position allows inhibition of FXI to be efficacious in indications not well treated with FXa inhibitors and instead requiring treatment with warfarin.
The Factor XI Inhibitors
Mechanisms to inhibit FXI include antisense oligonucleotides (ASOs), monoclonal antibodies (mAbs), and small-molecule drugs. Each approach varies in pharmacokinetic and pharmacodynamic properties (Table 228).
Most FXI inhibitors exhibit minimal renal elimination and are hepatically metabolized. These pharmacokinetics suggest potential drug-drug interactions and the accumulation of the drug in patients with kidney and liver impairments.24
Small Molecules
The small molecule FXI inhibitors include asundexian (BAY-2433334; Bayer) and milvexian (BMS-986177/JNJ-70033093; Bristol Myers Squibb and Johnson & Johnson). These agents reversibly bind to FXIa and block its activity, inhibiting progression through the intrinsic or contact pathway in the coagulation cascade.
Asundexian has a limited degree of renal elimination, whereas milvexian is primarily metabolized through the hepatic cytochrome P450 system, with a limited amount undergoing renal elimination.29 Although most milvexian is eliminated through the liver, trial results revealed no significant difference in pharmacokinetics between patients with mild or moderate hepatic impairment and healthy individuals.30 Phase 3 clinical trials are ongoing for both of these agents.
Asundexian and Milvexian Clinical Trials
Phase 2 clinical trials have studied FXI inhibitors in efficacy and safety compared with DOACs and placebo. PACIFIC-AF (NCT04218266) was a randomized, double-blind study that compared asundexian at 20 or 50 mg once daily with apixaban 5 mg twice daily (2.5 mg twice daily if the criteria for dose reduction were met) for stroke prevention in patients with atrial fibrillation31; 753 patients were included in the study. Efficacy outcomes included ischemic stroke, systemic embolism, MI, or cardiovascular (CV) death. Safety outcomes included major or clinically relevant nonmajor bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH). Results indicated that patients taking asundexian 20 or 50 mg once daily had lower bleeding rates when compared with those taking apixaban with similar efficacy rates.31
PACIFIC-STROKE (NCT04304508) was a randomized, double-blind, placebo-controlled study investigating asundexian at 10, 20, or 50 mg once daily compared with placebo in patients with acute noncardioembolic ischemic stroke in addition to antiplatelet therapy.32 The primary efficacy outcome was the dose-response effect on the composite of incident MRI-detected covert brain infarcts and recurrent symptomatic ischemic stroke at or before 26 weeks. The primary safety outcome was major or clinically relevant nonmajor bleeding, as defined by the ISTH. This trial did not show a reduction in the composite of covert brain infarction or ischemic stroke and did not show an increase in the composite of bleeding when compared with placebo.32
PACIFIC-AMI (NCT04304534) was a randomized, double-blind, placebo-controlled study investigating asundexian at 10, 20, or 50 mg once daily compared with placebo in patients within 5 days of their MI.33 Study participants also received dual antiplatelet therapy with aspirin and a P2Y12 inhibitor. The primary efficacy outcome was a composite of CV death, MI, stroke, or stent thrombosis. The investigators found that asundexian, in addition to dual antiplatelet therapy, resulted in dose-dependent, near-complete inhibition of FXIa activity without a significant increase in bleeding.33
AXIOMATIC-SSP (NCT03766581) was a randomized, double-blind, placebo-controlled, dose-finding trial that compared milvexian at 25 mg once daily or 25, 50, 100, or 200 mg twice daily vs placebo.34 The dose response of milvexian was studied for recurrent schemic cerebral events and major bleeding events in patients with recent ischemic stroke or transient ischemic attack. This therapy was added to dual antiplatelet therapy. Study findings did not indicate a reduction of symptomatic ischemic stroke or covert brain infarction or a significant increase in bleeding risk.34
OCEANIC-AF (NCT05643573) was a phase 3 clinical study designed to evaluate the efficacy and safety of asundexian compared with apixaban in patients with atrial fibrillation at risk for stroke. This randomized, multicenter, double-blind, double-dummy trial is assessing the potential of asundexian as an alternative anticoagulation therapy. Participants received asundexian once daily and apixaban matching placebo twice daily, with an active comparator of participants who received apixaban 2.5 or 5 mg twice daily with asundexian matching placebo once daily. Primary end points included the time to first occurrence of composite of stroke or systemic embolism, time to first occurrence of major bleeding, time to first occurrence of composite of stroke, systemic embolism, and major bleeding. This study aimed to provide insights into the potential role of asundexian in the management of stroke risk in patients with atrial fibrillation. This trial was terminated early due to the inferior efficacy of asundexian compared with apixaban. This decision was made by an independent monitoring committee.35
OCEANIC-STROKE (NCT05686070) is a phase 3, randomized, placebo-controlled study designed to evaluate the efficacy and safety of asundexian compared with placebo in patients who have recently experienced an ischemic stroke or transient ischemic attack. Given the high recurrence risk in this population, identifying a safe and efficacious therapy is of paramount importance. This multicenter trial is comparing the rates of stroke recurrence and major bleeding events between the asundexian and placebo arms. Participants will receive either once-daily asundexian or a matching placebo for a duration ranging from 3 to 31 months. The study protocol includes regular follow-up assessments conducted every 3 months, either in person or via telephone, to monitor patient outcomes and safety. Participants in OCEANIC-STROKE trial must be 18 years or older with a recent history of noncardioembolic stroke. This comprehensive investigation aims to provide crucial insights into the potential role of asundexian in secondary stroke prevention, addressing a significant unmet need in cerebrovascular disease management. The study is projected to conclude by October 2025.36
LIBREXIA-AF (NCT05757869) is a phase 3, double-blind, double-dummy, parallel-group study designed to assess the efficacy and safety of milvexian vs apixaban in patients with atrial fibrillation to prevent cardioembolic stroke or VTE. Participants receive milvexian at 100 mg twice daily and placebo that matches apixaban; participants receiving the active comparator receive apixaban at 2.5 or 5 mg twice daily. The primary end point is the time to first occurrence of stroke and non–central nervous system systemic embolism. This study’s estimated completion date is May 2027.37
LIBREXIA-STROKE (NCT05702034) is a phase 3, randomized, double-blind, placebo-controlled study designed to assess the efficacy of milvexian compared with placebo to reduce the risk of recurrent ischemic stroke. Patients receive milvexian at 25 mg twice daily or placebo. Antiplatelet therapy, following international and local guidelines, is required for all participants. This study includes patients who have experienced an ischemic stroke, characterized by a neurological deficit due to acute brain infarction, with a National Institutes of Health Stroke Scale score of 7 or less. The use of an anticoagulant in secondary stroke prevention would be a novel indication. Antiplatelet agents are the mainstay of treatment following an initial stroke; however, this study will provide insight on whether milvexian has the potential to be an effective option as well. This study is projected to be completed by December 2026.38
The LIBREXIA-ACS trial (NCT05754957) will assess whether milvexian, in addition to antiplatelet therapy standard care, is superior to placebo in reducing the risk of major adverse CV events, including CV death, MI, and ischemic stroke. This phase 3, randomized, double-blind, placebo-controlled, event-driven trial is investigating the safety and efficacy of milvexian following a recent acute coronary syndrome. Patients are randomly assigned to receive milvexian at 25 mg twice daily or placebo. The primary outcome will be time to the first occurrence of a major adverse CV event, defined as ischemic stroke, MI, or CV death. This trial is estimated to be completed by October 2026.39
mAbs
Abelacimab (MAA868; Anthos Therapeutics), osocimab (BAY 1213790; Bayer and Aronora), and xisomab 3G3 (AB023; Aronora) are mAbs that bind to FXI or FXIa. These agents are not metabolized by cytochrome P450, eliminating the potential for drug-drug interactions through this mechanism. These mAbs are predominantly eliminated by phagocytic cells and the reticuloendothelial system.29
Osocimab and Xisomab Clinical Trials
A small double-blind phase 2 trial (NCT03612856) evaluated 2 doses of xisomab compared with placebo in patients with end-stage renal disease undergoing hemodialysis. The study demonstrated xisomab’s safety, as it reduced the frequency of occlusive events necessitating hemodialysis circuit exchange without compromising hemostasis.40 There are currently no dose reductions needed for renal or hepatic impairments.
Phase 3 clinical trials for osocimab and xisomab have not started, and confirmation from larger trials is needed before these agents are to be considered for approval and clinical use. Phase 3 clinical trials are ongoing for abelacimab.
Abelacimab Clinical Trials
LILAC-TIMI 76 (NCT05712200) is an ongoing phase 3 clinical study evaluating the efficacy and safety of abelacimab at 150 mg monthly compared with placebo in patients diagnosed with atrial fibrillation or atrial flutter. The study focuses on individuals who are traditionally considered at high risk for anticoagulation therapy because of elevated bleeding risk factors. Participants are required to have at least 1 significant bleeding risk factor, such as daily use of antiplatelet medication, history of bleeding in a critical anatomical area, renal disease, frailty, or a history of recurrent falls. The primary objective is to assess whether abelacimab can provide a safe alternative for anticoagulation in patients who are typically deemed too high risk for standard anticoagulation therapy. This study aims to address an important clinical need for patients who require thromboprophylaxis but have contraindications to current anticoagulation options. The study’s estimated completion date is March 2025.41
Patients with malignancies are at an increased risk of thrombotic events and often need antithrombotic therapy for VTE prophylaxis. The phase 3 clinical ASTER trial (NCT05171049) is designed to evaluate the efficacy and safety of abelacimab compared with apixaban in the treatment of cancer-associated VTE. This randomized, open-label, blinded end point evaluation compares monthly administrations of abelacimab 150 mg with apixaban 10 mg followed by 5 mg twice daily over a 6-month treatment period. The study is assessing the relative merits of these 2 anticoagulation strategies in patients with cancer-associated VTE. Primary end points include the incidence of bleeding events, rates of treatment discontinuation, and VTE recurrence. Investigators seek to provide valuable insights into optimal anticoagulation management for oncology patients at risk of thrombotic complications. This study is estimated to be completed in September 2025.42
MAGNOLIA (NCT05171075) is a phase 3 multicenter, blinded end point study designed to evaluate the efficacy and safety of abelacimab 150 mg monthly compared with dalteparin in patients with VTE and concomitant gastrointestinal or genitourinary malignancies. Dalteparin will be administered daily at 200 IU/kg/d for the first month and then 150 IU/kg/d thereafter. During the 6-month treatment period, monthly administration of abelacimab is compared with daily injections of dalteparin. Primary end points encompass VTE recurrence rates, incidence of bleeding events, and treatment discontinuation rates. This investigation aims to provide valuable insights into the management of cancer-associated thrombosis, potentially offering an alternative to the current standard of care with a more convenient dosing regimen. This trial is projected to be completed in September 2025.43
ASOs
Fesomersen (Ionis) is currently the only ASO in clinical development for thrombosis indications. This agent reduces the hepatic synthesis of FXI and has a limited degree of renal elimination.28 In a phase 2 study (NCT02553889), fesomersen was investigated in patients with end-stage renal disease undergoing hemodialysis. The results indicated that fesomersen was well-tolerated and did not increase the incidence of major bleeding events compared with placebo.44 Furthermore, the pharmacokinetics of fesomersen remained similar regardless of whether it was administered before or after hemodialysis.44 Phase 3 studies are needed to confirm whether this agent can safely and effectively progress in clinical development.
Limitations and Future Directions
About the Authors
Michelle Krey is a transitions of care and ambulatory care pharmacy intern at UCHealth and a class of 2025 PharmD candidate at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences in Denver.
Sophia Villa is a pharmacy intern at Safeway, a student ambassador at the University of Colorado Anschutz Medical Campus, and a class of 2025 PharmD candidate at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences in Denver.
Jonathan Arnon, PharmD, is a staff pharmacist at Walgreens in Washington, DC.
The FXI inhibitors undergoing clinical trials have potential roles in anticoagulation therapy. Although clinical trials continue, there are various potential indications for which FXI inhibitors could be indicated. Clinical indications in which DOACs are the mainstay of treatment and prevention, such as atrial fibrillation and VTE, are routes to explore with FXI inhibitors. Contraindications and patient populations in which DOACs are not currently used are also potential areas to dive into with these new agents. Testing in clinical contexts, such as acute coronary syndrome or ischemic stroke, where there is no foreseeable use of anticoagulants at this time, could be other indications to study. Data from early clinical trials of FXII inhibitors will provide insight regarding the potential path forward.
The use of these agents in real practice will require confirmation from larger clinical trials. The results of ongoing phase 3 clinical trials will either further confirm or exclude places in therapy for FXI inhibitors. If approved for clinical use, postmarketing trials will hold a lot of value regarding the safety profile of these agents as they enter practice for long-term use.
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The authors have nothing to disclose.
