Anticoagulation in patients with kidney failure on dialysis: factor XI as a therapeutic target
Authors: John Eikelboom, Jürgen Floege, Ravi Thadhani, Jeffrey I. Weitz, Wolfgang C. Winkelmayer
Journal: Kidney International (2021)

Chronic kidney disease is present in almost 10% of the world population and is associated with excess mortality and morbidity. Reduced glomerular filtration rate and the presence and extent of proteinuria, key domains of chronic kidney disease, have both been shown to be strong and independent risk factors for cardiovascular disease. Patients with kidney failure requiring dialysis are at highest risk for cardiovascular events (e.g., stroke or myocardial infarction), and of developing chronic cardiovascular conditions, such as heart failure. Despite the high burden of cardiovascular disease, there is a paucity of evidence supporting therapies to reduce this risk. Although long-term anticoagulant treatment has the potential to prevent thromboembolism in persons with kidney failure on dialysis, this possibility remains understudied. The limited data available on anticoagulation in patients with kidney failure has focused on vitamin K antagonists or direct oral anticoagulants that inhibit thrombin or factor (F) Xa. The risk of bleeding is a major concern with these agents. However, FXI is emerging as a potential safer target for new anticoagulants because FXI plays a greater part in thrombosis than in hemostasis. In this article, we (i) explain the rationale for considering anticoagulation therapy in patients with kidney failure to reduce atherothrombotic events, (ii) highlight the limitations of current anticoagulants in this patient population, (iii) explain the potential benefits of FXI inhibitors, and (iv) summarize ongoing studies investigating FXI inhibition in patients with kidney failure on dialysis. Chronic kidney disease is present in almost 10% of the world population and is associated with excess mortality and morbidity. Reduced glomerular filtration rate and the presence and extent of proteinuria, key domains of chronic kidney disease, have both been shown to be strong and independent risk factors for cardiovascular disease. Patients with kidney failure requiring dialysis are at highest risk for cardiovascular events (e.g., stroke or myocardial infarction), and of developing chronic cardiovascular conditions, such as heart failure. Despite the high burden of cardiovascular disease, there is a paucity of evidence supporting therapies to reduce this risk. Although long-term anticoagulant treatment has the potential to prevent thromboembolism in persons with kidney failure on dialysis, this possibility remains understudied. The limited data available on anticoagulation in patients with kidney failure has focused on vitamin K antagonists or direct oral anticoagulants that inhibit thrombin or factor (F) Xa. The risk of bleeding is a major concern with these agents. However, FXI is emerging as a potential safer target for new anticoagulants because FXI plays a greater part in thrombosis than in hemostasis. In this article, we (i) explain the rationale for considering anticoagulation therapy in patients with kidney failure to reduce atherothrombotic events, (ii) highlight the limitations of current anticoagulants in this patient population, (iii) explain the potential benefits of FXI inhibitors, and (iv) summarize ongoing studies investigating FXI inhibition in patients with kidney failure on dialysis. Chronic kidney disease (CKD), as indicated by a reduced glomerular filtration rate or persistent proteinuria, is a direct cause of global morbidity and mortality.1Matsushita K. Coresh J. Sang Y. et al.Estimated glomerular filtration rate and albuminuria for prediction of cardiovascular outcomes: a collaborative meta-analysis of individual participant data.Lancet Diabetes Endocrinol. 2015; 3: 514-525Abstract Full Text Full Text PDF PubMed Scopus (485) Google Scholar The Global Burden of Disease study estimated the worldwide prevalence of CKD to be 9.1% in 2017.2Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet. 2018; 392: 1736-1788Abstract Full Text Full Text PDF PubMed Scopus (3845) Google Scholar Although the global mortality attributable to noncommunicable diseases, such as cardiovascular disease, cancer, and chronic obstructive pulmonary disease, has declined by 30%, 15%, and 41%, respectively, the age-standardized mortality of CKD has remained unchanged between 1990 and 2017.2Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet. 2018; 392: 1736-1788Abstract Full Text Full Text PDF PubMed Scopus (3845) Google Scholar Therefore, there is a continuing urgent need for improvements in CKD management.2Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet. 2018; 392: 1736-1788Abstract Full Text Full Text PDF PubMed Scopus (3845) Google Scholar,3Konstantinidis I. Nadkarni G.N. Yacoub R. et al.Representation of patients with kidney disease in trials of cardiovascular interventions: an updated systematic review.JAMA Intern Med. 2016; 176: 121-124Crossref PubMed Scopus (90) Google Scholar The burden extends beyond CKD itself, as CKD is also associated with an array of comorbid conditions. In particular, reduced glomerular filtration rate and presence and extent of proteinuria, both key domains of CKD, have been shown to be strong and independent risk factors for cardiovascular disease.1Matsushita K. Coresh J. Sang Y. et al.Estimated glomerular filtration rate and albuminuria for prediction of cardiovascular outcomes: a collaborative meta-analysis of individual participant data.Lancet Diabetes Endocrinol. 2015; 3: 514-525Abstract Full Text Full Text PDF PubMed Scopus (485) Google Scholar Indeed, patients with the most progressive form of CKD, those with end-stage kidney disease, also known as kidney failure4Levey A.S. Eckardt K.U. Dorman N.M. et al.Nomenclature for kidney function and disease: report of a Kidney Disease: Improving Global Outcomes (KDIGO) Consensus Conference.Kidney Int. 2020; 97: 1117-1129Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar requiring dialysis, are at highest risk for cardiovascular events, including myocardial infarction, stroke, and other thromboembolic events, such as deep vein thrombosis and pulmonary embolism. These patients often have evidence of systemic atherosclerosis that can lead to heart failure, abdominal aortic aneurysms, and peripheral artery disease (PAD).1Matsushita K. Coresh J. Sang Y. et al.Estimated glomerular filtration rate and albuminuria for prediction of cardiovascular outcomes: a collaborative meta-analysis of individual participant data.Lancet Diabetes Endocrinol. 2015; 3: 514-525Abstract Full Text Full Text PDF PubMed Scopus (485) Google Scholar However, despite the high burden of cardiovascular disease, there is a paucity of evidence supporting therapies to reduce this risk in patients with kidney failure requiring dialysis. Most cardiovascular outcome trials (randomized or observational) have excluded patients with advanced kidney disease.3Konstantinidis I. Nadkarni G.N. Yacoub R. et al.Representation of patients with kidney disease in trials of cardiovascular interventions: an updated systematic review.JAMA Intern Med. 2016; 176: 121-124Crossref PubMed Scopus (90) Google Scholar Indeed, the few trials that did specifically test cardiovascular interventions in this population were inconclusive. Anticoagulation therapy has the potential to reduce atherothrombotic events and venous thromboembolism (VTE) in patients with kidney failure on dialysis. However, such therapy has been understudied in this patient population because of concerns about the risk of bleeding. Although anticoagulants reduce the risk of thromboembolic events in patients with early-to-moderate-stage CKD,5Diener H.-C. Kleinschnitz C. Non-vitamin K oral anticoagulants in stroke patients: practical issues.J Stroke. 2016; 18: 138-145Crossref PubMed Scopus (12) Google Scholar their use in patients with kidney failure requiring dialysis is complicated by the fact that several oral anticoagulants are cleared by the kidneys. Despite a particularly high unmet need for treatment among patients with kidney failure undergoing dialysis, studies investigating the effectiveness of anticoagulants have therefore typically excluded patients with kidney failure requiring dialysis.6De Vriese A.S. Caluwé R. Bailleul E. et al.Dose-finding study of rivaroxaban in hemodialysis patients.Am J Kidney Dis. 2015; 66: 91-98Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 7Dias C. Moore K.T. Murphy J. et al.Pharmacokinetics, pharmacodynamics, and safety of single-dose rivaroxaban in chronic hemodialysis.Am J Nephrol. 2016; 43: 229-236Crossref PubMed Scopus (109) Google Scholar, 8Stangier J. Rathgen K. Stähle H. et al.Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study.Clin Pharmacokinet. 2010; 49: 259-268Crossref PubMed Scopus (643) Google Scholar, 9Wang X. Tirucherai G. Marbury T.C. et al.Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis.J Clin Pharmacol. 2016; 56: 628-636Crossref PubMed Scopus (200) Google Scholar Moreover, trials of oral anticoagulation in patients with kidney failure on dialysis who have atrial fibrillation have been attempted, but problems with patient recruitment have precluded their planned completion targets. Most of the evidence on long-term anticoagulation in individuals with kidney failure undergoing dialysis has focused on treatment with vitamin K antagonists10Krüger T. Floege J. Vitamin K antagonists: beyond bleeding.Semin Dial. 2014; 27: 37-41Crossref PubMed Scopus (22) Google Scholar or direct oral anticoagulants (DOACs) that inhibit thrombin or factor Xa. However, other targets in the coagulation cascade have recently attracted interest for potential intervention. In particular, factor XI (FXI) plays a key role in thrombosis but appears to be less important for hemostasis; targeting it may, therefore, be particularly attractive in patients undergoing hemodialysis, a population who are particularly prone to bleeding.11Weitz J.I. Fredenburgh J.C. Factors XI and XII as targets for new anticoagulants.Front Med. 2017; 4: 19Crossref PubMed Scopus (61) Google Scholar Phase 2 trials assessing the efficacy and safety of FXI and FXIa inhibitors for the prevention of cardiovascular events in patients with kidney failure undergoing hemodialysis have started enrolling worldwide. This review explains the rationale for such studies by defining the unmet need and describing the burden of disease, with a focus on the contribution of atherothrombotic events to morbidity and mortality. It also highlights the limitations of currently available anticoagulants in patients with kidney failure and the potential advantages of the emerging class of FXI/FXIa inhibitors, and briefly describes ongoing studies investigating FXI inhibition in patients with kidney failure. From 1990 to 2017, the global incidence of kidney failure treated by dialysis increased by 43.1%.12Bikbov B. Purcell C.A. Levey A.S. et al.Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet. 2020; 395: 709-733Abstract Full Text Full Text PDF PubMed Scopus (2017) Google Scholar Globally, 2.62 million people received kidney replacement therapy in 2010; 78% of them underwent dialysis, and 22% lived with a kidney transplant.13Liyanage T. Ninomiya T. Jha V. et al.Worldwide access to treatment for end-stage kidney disease: a systematic review.Lancet. 2015; 385: 1975-1982Abstract Full Text Full Text PDF PubMed Scopus (1180) Google Scholar In the United States alone, the reported prevalence of kidney failure requiring dialysis or kidney transplant in the second quarter of 2020 was 802,759.14US Renal Data SystemUSDRS quarterly update: 2020.https://www.usrds.org/esrd-quarterly-update/Date accessed: October 14, 2021Google Scholar Cardiovascular disease is common in patients with kidney failure. Numerous studies indicate a link between declining kidney function and increased mortality, cardiovascular events, and hospitalizations15Go A.S. Chertow G.M. Fan D. et al.Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (9157) Google Scholar; adjusted mortality in people with kidney failure requiring dialysis was reported as 164 per 1000 patient-years in the United States in 2016.14US Renal Data SystemUSDRS quarterly update: 2020.https://www.usrds.org/esrd-quarterly-update/Date accessed: October 14, 2021Google Scholar Almost half the deaths of people with kidney failure are attributed to cardiovascular disease.14US Renal Data SystemUSDRS quarterly update: 2020.https://www.usrds.org/esrd-quarterly-update/Date accessed: October 14, 2021Google Scholar,16Bansal N. Use of oral anticoagulation for patients with ESRD on hemodialysis with atrial fibrillation: verdict 1.Clin J Am Soc Nephrol. 2016; 11: 2093-2094Crossref PubMed Scopus (6) Google Scholar The risk of cardiovascular events increases with worsening kidney function, with patients starting hemodialysis being particularly likely to experience them.15Go A.S. Chertow G.M. Fan D. et al.Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (9157) Google Scholar,17Eckardt K.-U. Gillespie I.A. Kronenberg F. et al.High cardiovascular event rates occur within the first weeks of starting hemodialysis.Kidney Int. 2015; 88: 1117-1125Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar In addition, compared with the general population, individuals with kidney failure undergoing dialysis in the United States have a 2.1- to 2.3-fold higher risk of pulmonary embolism, depending on the absence or presence of comorbidities.18Tveit D.P. Hypolite I.O. Hshieh P. et al.Chronic dialysis patients have high risk for pulmonary embolism.Am J Kidney Dis. 2002; 39: 1011-1017Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar Moreover, the presence of VTE in patients undergoing dialysis is associated with an increased risk of bleeding and all-cause mortality compared with that seen in patients on dialysis without VTE.19Molnar A.O. Bota S.E. McArthur E. et al.Risk and complications of venous thromboembolism in dialysis patients.Nephrol Dial Transplant. 2018; 33: 874-880PubMed Google Scholar The likelihood of stroke also increases as the glomerular filtration rate declines,20Go A.S. Fang M.C. Udaltsova N. et al.Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study.Circulation. 2009; 119: 1363-1369Crossref PubMed Scopus (345) Google Scholar with risks several fold higher in patients with kidney failure than in the general population.21Seliger S.L. Gillen D.L. Longstreth Jr., W.T. et al.Elevated risk of stroke among patients with end-stage renal disease.Kidney Int. 2003; 64: 603-609Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar,22van Zyl M. Abdullah H.M. Noseworthy P.A. et al.Stroke prophylaxis in patients with atrial fibrillation and end-stage renal disease.J Clin Med. 2020; 9: 123Crossref Scopus (7) Google Scholar In long-term hemodialysis patients, around 44% of overall mortality is due to cardiac disease, with about 22% of these cardiovascular deaths attributed to myocardial infarction.23Herzog C.A. Acute myocardial infarction in patients with end-stage renal disease.Kidney Int Suppl. 1999; 71: S130-S133Abstract Full Text Full Text PDF PubMed Google Scholar Furthermore, there are indications of an early hazard of myocardial infarction related to dialysis initiation. A database review study in the United States reported that 29% of the myocardial infarctions occurred within 1 year and 52% occurred within 2 years of dialysis initiation. In kidney transplant patients, 15% of the myocardial infarctions occurred within the first year after transplantation, and 29% occurred within 2 years.23Herzog C.A. Acute myocardial infarction in patients with end-stage renal disease.Kidney Int Suppl. 1999; 71: S130-S133Abstract Full Text Full Text PDF PubMed Google Scholar Another cardiovascular comorbidity for patients with CKD with significant consequence is PAD. In the general population, the prevalence of PAD increases with age, from 3% to 5% between the ages of 45 and 49 years, to up to 15% to 18% in individuals aged ≥85 years.24Fowkes F.G. Rudan D. Rudan I. et al.Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis.Lancet. 2013; 382: 1329-1340Abstract Full Text Full Text PDF PubMed Scopus (2206) Google Scholar Among patients on hemodialysis, the prevalence of PAD is much higher: a prevalence of 24% in those aged 61 years has previously been reported.25Miskulin D. Bragg-Gresham J. Gillespie B.W. et al.Key comorbid conditions that are predictive of survival among hemodialysis patients.Clin J Am Soc Nephrol. 2009; 4: 1818-1826Crossref PubMed Scopus (62) Google Scholar A retrospective analysis revealed that patients with both CKD and PAD had a mortality of 45%, whereas mortality rates in patients with CKD alone, PAD alone, and neither condition were 28%, 26%, and 18%, respectively.26Liew Y.P. Bartholomew J.R. Demirjian S. et al.Combined effect of chronic kidney disease and peripheral arterial disease on all-cause mortality in a high-risk population.Clin J Am Soc Nephrol. 2008; 3: 1084-1089Crossref PubMed Scopus (77) Google Scholar Patients with kidney failure are greatly affected by PAD and have particularly high rates of amputations. In 2014, the rate of lower extremity amputation in US dialysis patients was 2.66 per 100 person-years, and the 1-year mortality following amputation was 42.6%.27Franz D. Zheng Y. Leeper N.J. et al.Trends in rates of lower extremity amputation among patients with end-stage renal disease who receive dialysis.JAMA Intern Med. 2018; 178: 1025-1032Crossref PubMed Scopus (29) Google Scholar Several reviews explain the pathophysiology of cardiovascular events in kidney failure28Berbari A.E. Links between chronic kidney disease and cardiovascular disease: a bidirectional relationship.in: Berbari A.E. Mancia G. Cardiorenal Syndrome: Mechanisms, Risk and Treatment. Springer Milan, Milan, Italy2010: 3-14Crossref Scopus (1) Google Scholar, 29Provenzano M. Coppolino G. De Nicola L. et al.Unraveling cardiovascular risk in renal patients: a new take on old tale.Front Cell Dev Biol. 2019; 7: 314Crossref PubMed Scopus (51) Google Scholar, 30Cozzolino M. Mangano M. Stucchi A. et al.Cardiovascular disease in dialysis patients.Nephrol Dial Transplant. 2018; 33: iii28-iii34Crossref PubMed Scopus (232) Google Scholar, 31Mavrakanas T.A. Charytan D.M. Cardiovascular complications in chronic dialysis patients.Curr Opin Nephrol Hypertens. 2016; 25: 536-544Crossref PubMed Scopus (27) Google Scholar, 32Aoki J. Ikari Y. Cardiovascular disease in patients with end-stage renal disease on hemodialysis.Ann Vasc Dis. 2017; 10: 327-337Crossref PubMed Google Scholar; as such, a summary is provided here for context. There is evidence of a strong bidirectional relationship between CKD and cardiovascular disease. In the context of the kidney, mechanisms associated with the development of cardiovascular disease include traditional (e.g., age, sex, and family history), nontraditional (e.g., oxidative stress and fibrosis), and CKD (uremia)–related factors, such as disturbances of bone-mineral metabolism, accelerated cardiovascular and valvular calcification, endothelial dysfunction, and uremic cardiomyopathy.28Berbari A.E. Links between chronic kidney disease and cardiovascular disease: a bidirectional relationship.in: Berbari A.E. Mancia G. Cardiorenal Syndrome: Mechanisms, Risk and Treatment. Springer Milan, Milan, Italy2010: 3-14Crossref Scopus (1) Google Scholar In the context of the heart, disturbed hemodynamics and the activation of neurohormonal and inflammatory mediators are associated with the development and progression of CKD.28Berbari A.E. Links between chronic kidney disease and cardiovascular disease: a bidirectional relationship.in: Berbari A.E. Mancia G. Cardiorenal Syndrome: Mechanisms, Risk and Treatment. Springer Milan, Milan, Italy2010: 3-14Crossref Scopus (1) Google Scholar Individuals with CKD, including those with kidney failure, usually have multiple risk factors for cardiovascular disease, many of which result in myocardial and blood vessel remodeling. Modifiable risk factors include hypertension, dyslipidemia, diabetes, albuminuria, estimated glomerular filtration rate, obesity, and smoking; potentially modifiable factors include toxic metabolites, inflammation, oxidative stress, endothelial dysfunction, hyperuricemia, anemia, and malnutrition, whereas nonmodifiable risk factors include age, sex, and family history (Figure 1).33Carracedo J. Alique M. Vida C. et al.Mechanisms of cardiovascular disorders in patients with chronic kidney disease: a process related to accelerated senescence.Front Cell Dev Biol. 2020; 8: 185Crossref PubMed Scopus (49) Google Scholar, 34Jalal D.I. Chonchol M. Targher G. Disorders of hemostasis associated with chronic kidney disease.Semin Thromb Hemost. 2010; 36: 34-40Crossref PubMed Scopus (163) Google Scholar, 35Whaley-Connell A.T. Sowers J.R. Stevens L.A. et al.CKD in the United States: Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) 1999-2004.Am J Kidney Dis. 2008; 51: S13-S20Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar During the later stages of CKD, there is an increased risk of bleeding even in the absence of coagulation-modifying therapies. This reflects a dysfunction of the coagulation system (Figure 2).36Potpara T.S. Ferro C.J. Lip G.Y.H. Use of oral anticoagulants in patients with atrial fibrillation and renal dysfunction.Nat Rev Nephrol. 2018; 14: 337-351Crossref PubMed Scopus (63) Google Scholar Reduced platelet adhesion and aggregation, reflecting alterations in prostaglandin metabolism and thromboxane A2 release, are common findings,37Baaten C. Sternkopf M. Henning T. et al.Platelet function in CKD: a systematic review and meta-analysis.J Am Soc Nephrol. 2021; 32: 1583-1598Crossref Scopus (18) Google Scholar coupled with a reduction in platelet–vessel wall interactions.36Potpara T.S. Ferro C.J. Lip G.Y.H. Use of oral anticoagulants in patients with atrial fibrillation and renal dysfunction.Nat Rev Nephrol. 2018; 14: 337-351Crossref PubMed Scopus (63) Google Scholar CKD-related anemia can exacerbate the impaired platelet–vessel wall interaction due to decreased adenosine diphosphate release and increased production of prostaglandin I2, an inhibitor of platelet aggregation. Therapeutics used in patients with kidney failure may further increase the risk of bleeding: β-lactam antibiotics can interfere with adenosine diphosphate receptors, and aspirin and other nonsteroidal anti-inflammatory drugs are known to affect platelet function via the cyclooxgengase pathway.38Lutz J. Menke J. Sollinger D. et al.Haemostasis in chronic kidney disease.Nephrol Dial Transplant. 2014; 29: 29-40Crossref PubMed Scopus (271) Google ScholarFigure 2Factors contributing to a prohemorrhagic state in patients with kidney failure. ADP, adenosine diphosphate; CKD, chronic kidney disease; GPIb, platelet glycoprotein Ib; GPIIb, platelet glycoprotein IIb; GPIIIa, platelet glycoprotein IIIa; PDGF, platelet-derived growth factor; TGF-β1, transforming growth factor beta 1; vWF, von Willebrand factor.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The high risk of thromboembolic complication in patients undergoing hemodialysis may reflect, at least in part, the impact of extracorporeal devices, such as the dialysis membrane, on their coagulation system as well as other risk factors, such as arrhythmias and temporary interruptions of the extracorporeal circuit occurring during dialysis, in addition to uremic factors, and the presence of inflammation. Indeed, most patients undergoing dialysis are considered to have a hypercoagulable state, as evidenced by high levels of von Willebrand factor, fibrinogen, and D-dimer.39Ambühl P.M. Wüthrich R.P. Korte W. et al.Plasma hypercoagulability in haemodialysis patients: impact of dialysis and anticoagulation.Nephrol Dial Transplant. 1997; 12: 2355-2364Crossref PubMed Scopus (57) Google Scholar Patients with CKD are also at higher risk of intracranial hemorrhage: patients with an estimated glomerular filtration rate <45 ml/min per 1.73 m2 have a 4-fold higher risk of mortality compared with patients with no kidney impairment (estimated glomerular filtration rate >60 ml/min per 1.73 m2).40Molshatzki N. Orion D. Tsabari R. et al.Chronic kidney disease in patients with acute intracerebral hemorrhage: association with large hematoma volume and poor outcome.Cerebrovasc Dis. 2011; 31: 271-277Crossref PubMed Scopus (79) Google Scholar In patients on dialysis, intracranial hemorrhage is associated with the highest mortality risk of all stroke subtypes, and is likely exacerbated by uremic platelet dysfunction and the use of heparin or other anticoagulants during dialysis.41Ghoshal S. Freedman B.I. Mechanisms of stroke in patients with chronic kidney disease.Am J Nephrol. 2019; 50: 229-239Crossref PubMed Scopus (41) Google Scholar The use of long-term anticoagulation therapy in patients with kidney failure is low, likely because of the associated risk of bleeding,42Reinecke H. Brand E. Mesters R. et al.Dilemmas in the management of atrial fibrillation in chronic kidney disease.J Am Soc Nephrol. 2009; 20: 705-711Crossref PubMed Scopus (226) Google Scholar but also due to the uncertainty as to the extent to which the cardiovascular events are atherothrombotic in origin. The approval of newer, target-specific oral anticoagulants for the prevention of cardiovascular events, such as stroke and pulmonary embolism, including the 2 factor Xa inhibitors, rivaroxaban and apixaban, is welcome, yet there are limited data in this population of interest, because individuals with kidney failure undergoing dialysis were excluded from the pivotal trials. Despite this, dose recommendations for the use of these agents in dialysis were subsequently introduced on the basis of scant evidence.43European Medicines AgencyRivaroxaban summary of product characteristics.https://www.ema.europa.eu/en/documents/product-information/xarelto-epar-product-information_en.pdfDate accessed: October 14, 2021Google Scholar, 44European Medicines AgencyApixaban summary of product characteristics.https://www.ema.europa.eu/en/documents/product-information/eliquis-epar-product-information_en.pdfDate accessed: October 14, 2021Google Scholar, 45European Medicines AgencyDabigatran summary of product characteristics.https://www.ema.europa.eu/en/documents/product-information/pradaxa-epar-product-information_en.pdfDate accessed: October 14, 2021Google Scholar These therapies are being used in patients with kidney failure with atrial fibrillation, where there is a known risk of stroke, but are not routinely used in patients with kidney failure without atrial fibrillation. In patients with kidney failure, the rationale for considering anticoagulant therapy over no treatment or the use of acetylsalicylic acid has been reported in patients with atrial fibrillation, because much of the existing, although limited, literature on long-term anticoagulation has focused on this population owing to the elevated stroke risk.46Königsbrügge O. Ay C. Atrial fibrillation in patients with end-stage renal disease on hemodialysis: magnitude of the problem and new approach to oral anticoagulation.Res Pract Thromb Haemost. 2019; 3: 578-588Crossref PubMed Scopus (14) Google Scholar The potential of anticoagulants to prevent major adverse cardiovascular events in patients with kidney failure without atrial fibrillation is even less well supported. However, there are important reasons why anticoagulation should be considered more broadly to prevent adverse cardiovascular outcomes other than ischemic stroke, and several sources of evidence from the general population further support this. The benefits and risks of antithrombotic therapy (both antiplatelet and anticoagulant) must be carefully evaluated in patients at high risk of bleeding.47Chunduri S. Folstad J.E. Vachharajani T.J. Antithrombotic therapy in end-stage renal disease.Hemodial Int. 2017; 21: 453-471Crossref PubMed Scopus (7) Google Scholar Results of observational studies in patients with kidney failure on dialysis suggest that the harms of vitamin K antagonists, such as warfarin, outweigh their potential benefits.16Bansal N. Use of oral anticoagulation for patients with ESRD on hemodialysis with atrial fibrillation: verdict 1.Clin J Am Soc Nephrol. 2016; 11: 2093-2094Crossref PubMed Scopus (6) Google Scholar A systematic review48Pirlog A.-M. Pirlog C.D. Maghiar M.A. DOACs vs vitamin K antagonists: a comparison of phase III clinical trials and a prescriber support tool.Open Access Maced J Med Sci. 2019; 7: 1226-1232Crossref PubMed Scopus (12) Google Scholar of trial