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Review

New pharmacotherapeutic options for oral anticoagulant treatment in atrial fibrillation patients aged 65 and older: factor XIa inhibitors and beyond

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Pages 1335-1347 | Received 15 Mar 2023, Accepted 25 May 2023, Published online: 29 May 2023

References

  • Tsao CW, Aday AW, Almarzooq ZI, et al. Heart disease and stroke statistics—2022 update: a report from the American heart association. Circulation. 2022;145(8):e153–e639. DOI:10.1161/CIR.0000000000001052
  • Kamel H, Bartz TM, Elkind MSV, et al. Atrial cardiopathy and the risk of ischemic stroke in the CHS (Cardiovascular Health Study). Stroke. 2018;49(4):980–986. DOI:10.1161/STROKEAHA.117.020059
  • Kamel H, Hunter M, Moon YP, et al. Electrocardiographic left atrial abnormality and risk of stroke: northern manhattan study. Stroke. 2015;46(11):3208–3212. DOI:10.1161/STROKEAHA.115.009989
  • Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the framingham study. Stroke. 1991;22(8):983–988.
  • Feinberg WM, Blackshear JL, Laupacis A, et al. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med. 1995;155(5):469–473. DOI:10.1001/archinte.1995.00430050045005
  • Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994;154(13):1449–1457. DOI:10.1001/archinte.1994.00420130036007
  • Hart RG, Benavente O, McBride R, et al. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med. 1999;131(7):492–501. DOI:10.7326/0003-4819-131-7-199910050-00003
  • Gomes T, Mamdani MM, Holbrook AM, et al. Rates of hemorrhage during warfarin therapy for atrial fibrillation. CMAJ. 2013;185(2):E121–127. DOI:10.1503/cmaj.121218
  • Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955–962. DOI:10.1016/S0140-6736(13)62343-0
  • Rutherford OW, Jonasson C, Ghanima W, et al. Effectiveness and safety of oral anticoagulants in elderly patients with atrial fibrillation. Heart. 2022;108(5):345–352. DOI:10.1136/heartjnl-2020-318753
  • Zoppellaro G, Zanella L, Denas G, et al. Different safety profiles of oral anticoagulants in very elderly non-valvular atrial fibrillation patients. A retrospective propensity score matched cohort study. Int J Cardiol. 2018;265:103–107.
  • Alamneh EA, Chalmers L, Bereznicki LR. Suboptimal use of oral anticoagulants in atrial fibrillation: has the introduction of direct oral anticoagulants improved prescribing practices? Am J Cardiovasc Drugs. 2016;16(3):183–200.
  • Steinberg BA, Shrader P, Thomas L, et al. Off-label dosing of non-vitamin K antagonist oral anticoagulants and adverse outcomes: the ORBIT-AF II registry. J Am Coll Cardiol. 2016;68:2597–2604.
  • Ruiz Ortiz M, Muniz J, Rana Miguez P, et al. Inappropriate doses of direct oral anticoagulants in real-world clinical practice: prevalence and associated factors. A subanalysis of the FANTASIIA Registry. Europace. 2018;20(10):1577–1583. DOI:10.1093/europace/eux316
  • Caso V, de Groot JR, Sanmartin Fernandez M, et al. Outcomes and drivers of inappropriate dosing of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation: a systematic review and meta-analysis. Heart. 2023;109(3):178–185. DOI:10.1136/heartjnl-2022-321114
  • Denas G, Pengo V. Emerging anticoagulants. Expert Opin Emerg Drugs. 2011;16(1):31–44.
  • Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369(13):1206–1214. DOI:10.1056/NEJMoa1300615
  • Pengo V, Denas G, Zoppellaro G, et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018;132(13):1365–1371. DOI:10.1182/blood-2018-04-848333
  • Connolly SJ, Karthikeyan G, Ntsekhe M, et al. Rivaroxaban in rheumatic heart disease–associated atrial fibrillation. N Engl J Med. 2022;387(11):978–988. DOI:10.1056/NEJMoa2209051
  • Petersen P, Godtfredsen J. Atrial fibrillation–a review of course and prognosis. Acta Med Scand. 1984;216(1):5–9.
  • Petersen P, Boysen G, Godtfredsen J, et al. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK Study Lancet. 1989;1:175–179.
  • Hindricks G, Potpara T, Dagres N, et al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): the task force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J. 2021;42(5):373–498. DOI:10.1093/eurheartj/ehaa612
  • Lip GY, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest. 2010;137(2):263–272. DOI:10.1378/chest.09-1584
  • Singer DE, Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med. 2009;151(5):297–305. DOI:10.7326/0003-4819-151-5-200909010-00003
  • Pengo V, Legnani C, Noventa F, et al. Oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and risk of bleeding. A multicenter inception cohort study. Thromb Haemost. 2001;85(03):418–422. DOI:10.1055/s-0037-1615599
  • van Asch CJ, Luitse MJ, Rinkel GJ, et al. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol. 2010;9(2):167–176. DOI:10.1016/S1474-4422(09)70340-0
  • Held C, Hylek EM, Alexander JH, et al. Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial. Eur Heart J. 2015;36(20):1264–1272. DOI:10.1093/eurheartj/ehu463
  • Desai J, Granger CB, Weitz JI, et al. Novel oral anticoagulants in gastroenterology practice. Gastrointest Endosc. 2013;78(2):227–239.
  • Srivastava P, Gailani D. The rebirth of the contact pathway: a new therapeutic target. Curr Opin Hematol. 2020;27(5):311–319. DOI:10.1097/MOH.0000000000000603
  • Weitz JI, Chan NC. Advances in antithrombotic therapy. Arterioscler Thromb Vasc Biol. 2019;39(1):7–12.
  • Matafonov A, Leung PY, Gailani AE, et al. Factor XII inhibition reduces thrombus formation in a primate thrombosis model. Blood. 2014;123(11):1739–1746. DOI:10.1182/blood-2013-04-499111
  • Bird JE, Smith PL, Wang X, et al. Effects of plasma kallikrein deficiency on haemostasis and thrombosis in mice: murine ortholog of the Fletcher trait. Thromb Haemost. 2012;107(06):1141–1150. DOI:10.1160/TH11-10-0682
  • Merkulov S, Zhang WM, Komar AA, et al. Deletion of murine kininogen gene 1 (mKng1) causes loss of plasma kininogen and delays thrombosis. Blood. 2008;111(3):1274–1281. DOI:10.1182/blood-2007-06-092338
  • Tillman B, Gailani D. Inhibition of factors XI and XII for prevention of thrombosis induced by artificial surfaces. Semin Thromb Hemost. 2018;44(1):60–69.
  • Emsley J, McEwan PA, Gailani D. Structure and function of factor XI. Blood. 2010;115(13):2569–2577. DOI:10.1182/blood-2009-09-199182
  • Al-Horani RA, Desai UR. Factor XIa inhibitors: a review of the patent literature. Expert Opin Ther Pat. 2016;26(3):323–345.
  • Bertaggia Calderara D, Zermatten MG, Aliotta A, et al. How to capture the bleeding phenotype in FXI-Deficient patients. Hamostaseologie. 2020;40(04):491–499.
  • Cao Y, Wang Y, Zhou Z, et al. Liver-heart cross-talk mediated by coagulation factor XI protects against heart failure. Science. 2022;377(6613):1399–1406. DOI:10.1126/science.abn0910
  • Asakai R, Chung DW, Davie EW, et al. Factor XI deficiency in Ashkenazi Jews in Israel. N Engl J Med. 1991;325(3):153–158.
  • Salomon O, Steinberg DM, Koren-Morag N, et al. Reduced incidence of ischemic stroke in patients with severe factor XI deficiency. Blood. 2008;111(8):4113–4117. DOI:10.1182/blood-2007-10-120139
  • Preis M, Hirsch J, Kotler A, et al. Factor XI deficiency is associated with lower risk for cardiovascular and venous thromboembolism events. Blood. 2017;129(9):1210–1215. DOI:10.1182/blood-2016-09-742262
  • Endler G, Marsik C, Jilma B, et al. Evidence of a U-shaped association between factor XII activity and overall survival. J Thromb Haemost. 2007;5(6):1143–1148. DOI:10.1111/j.1538-7836.2007.02530.x
  • Gomez-Outes A, Suarez-Gea ML, Perez-Cabeza AI, et al. Pharmacotherapy for stroke prevention in nonvalvular atrial fibrillation: current strategies and future directions. Expert Opin Pharmacother. 2022;23(17):1941–1955. DOI:10.1080/14656566.2022.2149323
  • Girolami A, Ferrari S, Cosi E, et al. Thrombotic events in severe FXII deficiency in comparison with unaffected family members during a long observation period. J Thromb Thrombolysis. 2019;47(3):481–485. DOI:10.1007/s11239-019-01819-8
  • Peyvandi F, Palla R, Menegatti M, et al. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European network of rare bleeding disorders. J Thromb Haemost. 2012;10(4):615–621. DOI:10.1111/j.1538-7836.2012.04653.x
  • Bolton-Maggs PH, Patterson DA, Wensley RT, et al. Definition of the bleeding tendency in factor XI-deficient kindreds–a clinical and laboratory study. Thromb Haemost. 1995;73(02):194–202.
  • Santoro C, Di Mauro R, Baldacci E, et al. Bleeding phenotype and correlation with factor XI (FXI) activity in congenital FXI deficiency: results of a retrospective study from a single centre. Haemophilia. 2015;21(4):496–501. DOI:10.1111/hae.12628
  • Duga S, Salomon O. Congenital factor XI deficiency: an update. Semin Thromb Hemost. 2013;39(06):621–631.
  • Bentley R, Hardy LJ, Scott LJ, et al. Drugs in phase I and II clinical development for the prevention of stroke in patients with atrial fibrillation. Expert Opin Investig Drugs. 2021;30(10):1057–1069. DOI:10.1080/13543784.2021.1897786
  • Revenko AS, Gao D, Crosby JR, et al. Selective depletion of plasma prekallikrein or coagulation factor XII inhibits thrombosis in mice without increased risk of bleeding. Blood. 2011;118(19):5302–5311. DOI:10.1182/blood-2011-05-355248
  • Weitz JI, Fredenburgh JC. Factors XI and XII as targets for new anticoagulants. Front Med. 2017;4:19.
  • Salomon O, Steinberg DM, Seligshon U. Variable bleeding manifestations characterize different types of surgery in patients with severe factor XI deficiency enabling parsimonious use of replacement therapy. Haemophilia. 2006;12(5):490–493.
  • Eikelboom J, Floege J, Thadhani R, et al. Anticoagulation in patients with kidney failure on dialysis: factor XI as a therapeutic target. Kidney Int. 2021;100(6):1199–1207. DOI:10.1016/j.kint.2021.08.028
  • Pandey A, Verma R, Eikelboom J, et al. Factor XI inhibitors: what should clinicians know. Curr Opin Cardiol. 2023;38:88–93.
  • De Caterina R, Prisco D, Eikelboom JW. Factor XI inhibitors: cardiovascular perspectives. Eur Heart J. 2023;44(4):280–292. DOI:10.1093/eurheartj/ehac464
  • Buller HR, Bethune C, Bhanot S, et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med. 2015;372(3):232–240. DOI:10.1056/NEJMoa1405760
  • Weitz JI, Bauersachs R, Becker B, et al. Effect of osocimab in preventing venous thromboembolism among patients undergoing knee arthroplasty: the FOXTROT randomized clinical trial. JAMA. 2020;323:130–139.
  • Weitz JI, Strony J, Ageno W, et al. Milvexian for the prevention of venous thromboembolism. N Engl J Med. 2021;385(23):2161–2172. DOI:10.1056/NEJMoa2113194
  • Shoamanesh A, Mundl H, Smith EE, et al. Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke): an international, randomised, double-blind, placebo-controlled, phase 2b trial. Lancet. 2022;400(10357):997–1007. DOI:10.1016/S0140-6736(22)01588-4
  • Sharma M, Molina CA, Toyoda K, et al. Rationale and design of the AXIOMATIC-SSP phase II trial: antithrombotic treatment with factor XIa inhibition to optimize management of acute thromboembolic events for secondary stroke prevention. J Stroke Cerebrovasc Dis. 2022;31(10):106742. DOI:10.1016/j.jstrokecerebrovasdis.2022.106742
  • Rao SV, Kirsch B, Bhatt DL, et al. A 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 infarction. Circulation. 2022;146(16):1196–1206. DOI:10.1161/CIRCULATIONAHA.122.061612
  • Ocak G, Rookmaaker MB, Algra A, et al. Chronic kidney disease and bleeding risk in patients at high cardiovascular risk: a cohort study. J Thromb Haemost. 2018;16(1):65–73. DOI:10.1111/jth.13904
  • Timp JF, Braekkan SK, Versteeg HH, et al. Epidemiology of cancer-associated venous thrombosis. Blood. 2013;122(10):1712–1723.
  • Weitz JI, Eikelboom JW. What is the future of factor XI inhibitors? Circulation. 2022;146(25):1899–1902.
  • Lorentz CU, Tucker EI, Verbout NG, et al. The contact activation inhibitor AB023 in heparin-free hemodialysis: results of a randomized phase 2 clinical trial. Blood. 2021;138(22):2173–2184. DOI:10.1182/blood.2021011725
  • Walsh M, Bethune C, Smyth A, et al. Phase 2 study of the factor XI antisense inhibitor IONIS-FXI(Rx) in patients with ESRD. Kidney Int Rep. 2022;7(2):200–209. DOI:10.1016/j.ekir.2021.11.011
  • Yi BA, Freedholm D, Widener N, et al. Pharmacokinetics and pharmacodynamics of abelacimab (MAA868), a novel dual inhibitor of factor XI and factor XIa. J Thromb Haemost. 2022;20(2):307–315. DOI:10.1111/jth.15577
  • Piccini JP, Caso V, Connolly SJ, et al. Safety of the oral factor XIa inhibitor asundexian compared with apixaban in patients with atrial fibrillation (PACIFIC-AF): a multicentre, randomised, double-blind, double-dummy, dose-finding phase 2 study. Lancet. 2022;399(10333):1383–1390. DOI:10.1016/S0140-6736(22)00456-1
  • Russo Krauss I, Pica A, Merlino A, et al. Duplex–quadruplex motifs in a peculiar structural organization cooperatively contribute to thrombin binding of a DNA aptamer. Acta Crystallogr D Biol Crystallogr. 2013;69(12):2403–2411. DOI:10.1107/S0907444913022269
  • Liu M, Zaman K, Fortenberry YM. Overview of the therapeutic potential of aptamers targeting coagulation factors. Int J Mol Sci. 2021;22(8):22. DOI:10.3390/ijms22083897
  • Chen X, Ma Y, Xie Y, et al. Aptamer-based applications for cardiovascular disease. Front Bioeng Biotechnol. 2022;10:1002285.
  • Chabata CV, Frederiksen JW, Sullenger BA, et al. Emerging applications of aptamers for anticoagulation and hemostasis. Curr Opin Hematol. 2018;25(5):382–388.
  • Woodruff RS, Sullenger BA. Modulation of the coagulation cascade using aptamers. Arterioscler Thromb Vasc Biol. 2015;35(10):2083–2091.
  • Esposito V, Scuotto M, Capuozzo A, et al. A straightforward modification in the thrombin binding aptamer improving the stability, affinity to thrombin and nuclease resistance. Org Biomol Chem. 2014;12(44):8840–8843. DOI:10.1039/C4OB01475H
  • Riccardi C, Meyer A, Vasseur JJ, et al. Fine-tuning the properties of the thrombin binding aptamer through cyclization: effect of the 5’-3’ connecting linker on the aptamer stability and anticoagulant activity. Bioorg Chem. 2020;94:103379.
  • Povsic TJ, Lawrence MG, Lincoff AM, et al. Pre-existing anti-PEG antibodies are associated with severe immediate allergic reactions to pegnivacogin, a PEGylated aptamer. J Allergy Clin Immunol. 2016;138(6):1712–1715. DOI:10.1016/j.jaci.2016.04.058
  • Povsic TJ, Vavalle JP, Aberle LH, et al. A Phase 2, randomized, partially blinded, active-controlled study assessing the efficacy and safety of variable anticoagulation reversal using the REG1 system in patients with acute coronary syndromes: results of the RADAR trial. Eur Heart J. 2013;34(31):2481–2489. DOI:10.1093/eurheartj/ehs232
  • Lincoff AM, Mehran R, Povsic TJ, et al. Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): a randomised clinical trial. Lancet. 2016;387(10016):349–356. DOI:10.1016/S0140-6736(15)00515-2
  • Aljohani MM, Chinnappan R, Eissa S, et al. In Vitro selection of specific DNA aptamers against the anti-coagulant dabigatran etexilate. Sci Rep. 2018;8(1):13290. DOI:10.1038/s41598-018-31327-3
  • Ebrahimi R, Barzegari A, Teimuri-Mofrad R, et al. Selection of specific aptamer against rivaroxaban and utilization for label-free electrochemical aptasensing using gold nanoparticles: first announcement and application for clinical sample analysis. Biosensors (Basel). 2022;12(10):12. DOI:10.3390/bios12100773
  • Li T, Liu J, Wu W. Factor XI, a potential target for anticoagulation therapy for venous thromboembolism. Front Cardiovasc Med. 2022;9:975767.
  • Perera V, Wang Z, Lubin S, et al. Effects of itraconazole and diltiazem on the pharmacokinetics and pharmacodynamics of milvexian, a factor XIa inhibitor. Cardiol Ther. 2022;11(3):407–419. DOI:10.1007/s40119-022-00266-6
  • Cohen O, Ageno W. Coming soon to a pharmacy near you? FXI and FXII inhibitors to prevent or treat thromboembolism. Hematology Am Soc Hematol Educ Program 2022. 2022;2022(1):495–505.

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