Prevention and treatment of stroke in patients with chronic kidney disease: an overview of evidence and current guidelines

Chronic kidney disease is strongly associated with an increased risk of stroke, small vessel disease, and vascular dementia. Common vascular factors for stroke, such as hypertension, diabetes, and atrial fibrillation, are more prevalent in patients with chronic kidney disease, accounting for this association. However, factors unique to these patients, such as uremia, oxidative stress, and mineral and bone abnormalities, as well as dialysis-related factors are also believed to contribute to risk. Despite improvements in stroke treatment and survival in the general population, the rate of improvement in patients with chronic kidney disease, especially those who are dialysis dependent, has lagged behind. There is a lack of or conflicting evidence that those with renal disease, particularly when advanced or older, consistently derive benefit from currently available preventive and therapeutic interventions for stroke in the general population. In this review, we explore the complexities and challenges of these interventions in the population with renal disease. Chronic kidney disease is strongly associated with an increased risk of stroke, small vessel disease, and vascular dementia. Common vascular factors for stroke, such as hypertension, diabetes, and atrial fibrillation, are more prevalent in patients with chronic kidney disease, accounting for this association. However, factors unique to these patients, such as uremia, oxidative stress, and mineral and bone abnormalities, as well as dialysis-related factors are also believed to contribute to risk. Despite improvements in stroke treatment and survival in the general population, the rate of improvement in patients with chronic kidney disease, especially those who are dialysis dependent, has lagged behind. There is a lack of or conflicting evidence that those with renal disease, particularly when advanced or older, consistently derive benefit from currently available preventive and therapeutic interventions for stroke in the general population. In this review, we explore the complexities and challenges of these interventions in the population with renal disease. Chronic kidney disease (CKD) is an increasing global health burden with an estimated prevalence of 11% to 13% worldwide.1Hill N.R. Fatoba S.T. Oke J.L. et al.Global prevalence of chronic kidney disease—a systematic review and meta-analysis.PLoS One. 2016; 11e0158765Crossref PubMed Scopus (596) Google Scholar CKD is associated with an 8- to 10-fold increase in cardiovascular mortality, equivalent to that in patients with diabetes or prior myocardial infarction,2Couser W.G. Remuzzi G. Mendis S. et al.The contribution of chronic kidney disease to the global burden of major noncommunicable diseases.Kidney Int. 2011; 80: 1258-1270Abstract Full Text Full Text PDF PubMed Scopus (613) Google Scholar,3Rashidi A. Sehgal A.R. Rahman M. et al.The case for chronic kidney disease, diabetes mellitus, and myocardial infarction being equivalent risk factors for cardiovascular mortality in patients older than 65 years.Am J Cardiol. 2008; 102: 1668-1673Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and even mild reductions in glomerular filtration rate (GFR) are associated with substantial increases in cardiovascular risk.4Fox C.S. Muntner P. Chen A.Y. et al.Use of evidence-based therapies in short-term outcomes of ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction in patients with chronic kidney disease: a report from the National Cardiovascular Data Acute Coronary Treatment and Intervention Outcomes Network registry.Circulation. 2010; 121: 357-365Crossref PubMed Scopus (258) Google Scholar There is a particularly strong association between CKD and cerebrovascular disease. Meta-analyses of cohort studies and trials indicate that reduced GFR increases the risk of stroke by 40%5Lee M. Saver J.L. Chang K.H. et al.Low glomerular filtration rate and risk of stroke: meta-analysis.BMJ. 2010; 341c4249Crossref PubMed Scopus (218) Google Scholar and that proteinuria increases the risk up to 70%6Ninomiya T. Perkovic V. Verdon C. et al.Proteinuria and stroke: a meta-analysis of cohort studies.Am J Kidney Dis. 2009; 53: 417-425Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar even after adjusting for traditional cardiovascular risk factors. These associations may be attributable to a cluster of shared vascular risk factors including hypertension, diabetes mellitus, and atrial fibrillation (AF), but "nontraditional" risk factors such as anemia, hyperuricemia, and mineral bone disorders may also play a role (Figure 1).7Major R.W. Cheng M.R.I. Grant R.A. et al.Cardiovascular disease risk factors in chronic kidney disease: a systematic review and meta-analysis.PLoS One. 2018; 13e0192895Crossref PubMed Scopus (6) Google Scholar CKD is a strong independent predictor of mortality and poor functional outcomes in patients with acute stroke,8Yahalom G. Schwartz R. Schwammenthal Y. et al.Chronic kidney disease and clinical outcome in patients with acute stroke.Stroke. 2009; 40: 1296-1303Crossref PubMed Scopus (158) Google Scholar but there is a lack of clinical trials of prevention and treatment of stroke in the population with renal disease, with most evidence to support use of existing treatments derived from post hoc subgroup analyses.9Maini R. Wong D.B. Addison D. et al.Persistent underrepresentation of kidney disease in randomized, controlled trials of cardiovascular disease in the contemporary era.J Am Soc Nephrol. 2018; 29: 2782-2786Crossref PubMed Scopus (0) Google Scholar,10Covic A. Voroneanu L. Chronic kidney disease and stroke: more observations but no trials.Nephrol Dial Transplant. 2018; 33: 367-370Crossref PubMed Scopus (0) Google Scholar In this review, we explore this evidence for the primary and secondary prevention of stroke and acute treatment. Current recommendations for the primary and secondary prevention of stroke in CKD are outlined in Table 1.11National Collaborating Centre for Chronic Conditions (UK)Chronic Kidney Disease: National Clinical Guideline for Early Identification and Management in Adults in Primary and Secondary Care. Royal College of Physicians, London2008Google Scholar, 12Stevens P.E. Levin A. Evaluation and management of chronic kidney disease: synopsis of the Kidney Disease: Improving Global Outcomes 2012 clinical practice guideline.Ann Intern Med. 2013; 158: 825-830Crossref PubMed Google Scholar, 13Wanner C. Tonelli M. KDIGO Clinical Practice Guideline for Lipid Management in CKD: summary of recommendation statements and clinical approach to the patient.Kidney Int. 2014; 85: 1303-1309Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 14January C.T. Wann L.S. 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Aronow W.S. et al.2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.Circulation. 2018; 138: e484-e594Crossref PubMed Scopus (0) Google Scholar, 17Kernan W.N. Ovbiagele B. Black H.R. et al.Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.Stroke. 2014; 45: 2160-2236Crossref PubMed Scopus (1975) Google Scholar, 18Meschia J.F. Bushnell C. Boden-Albala B. et al.Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association.Stroke. 2014; 45: 3754-3832Crossref PubMed Scopus (603) Google Scholar, 19Ricotta J.J. Aburahma A. Ascher E. et al.Updated Society for Vascular Surgery guidelines for management of extracranial carotid disease.J Vasc Surg. 2011; 54: e1-e31Abstract Full Text Full Text PDF PubMed Scopus (182) Google ScholarTable 1Current available guidelines for the primary or secondary prevention of CV disease in CKDGuidelinesNICE11National Collaborating Centre for Chronic Conditions (UK)Chronic Kidney Disease: National Clinical Guideline for Early Identification and Management in Adults in Primary and Secondary Care. Royal College of Physicians, London2008Google ScholarKDIGO12Stevens P.E. Levin A. Evaluation and management of chronic kidney disease: synopsis of the Kidney Disease: Improving Global Outcomes 2012 clinical practice guideline.Ann Intern Med. 2013; 158: 825-830Crossref PubMed Google Scholar,13Wanner C. Tonelli M. KDIGO Clinical Practice Guideline for Lipid Management in CKD: summary of recommendation statements and clinical approach to the patient.Kidney Int. 2014; 85: 1303-1309Abstract Full Text Full Text PDF PubMed Scopus (180) Google ScholarACC/AHA/ASA14January C.T. Wann L.S. Calkins H. et al.2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons.Circulation. 2019; 140: e125-e151Crossref PubMed Scopus (129) Google Scholar, 15Grundy S.M. Stone N.J. Bailey A.L. et al.2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.J Am Coll Cardiol. 2019; 73: 3168-3209Crossref PubMed Scopus (153) Google Scholar, 16Whelton P.K. Carey R.M. Aronow W.S. et al.2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.Circulation. 2018; 138: e484-e594Crossref PubMed Scopus (0) Google Scholar, 17Kernan W.N. Ovbiagele B. Black H.R. et al.Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.Stroke. 2014; 45: 2160-2236Crossref PubMed Scopus (1975) Google Scholar, 18Meschia J.F. Bushnell C. Boden-Albala B. et al.Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association.Stroke. 2014; 45: 3754-3832Crossref PubMed Scopus (603) Google ScholarSociety for Vascular Surgery19Ricotta J.J. Aburahma A. Ascher E. et al.Updated Society for Vascular Surgery guidelines for management of extracranial carotid disease.J Vasc Surg. 2011; 54: e1-e31Abstract Full Text Full Text PDF PubMed Scopus (182) Google ScholarAntiplatelet therapy•Offer only for secondary prevention, but caution about the increased risk of bleeding•Aspirin is indicated for secondary prevention but not for primary prevention•Aspirin may be considered for primary prevention for GFR 30–45 ml/min and should be given for secondary preventionBP control•Target BP <140/90 mm Hg in general, but <130/80 mm Hg if ACR ≥70 mg/mmol or diabetic•Use preferably RAS antagonist•Individualize targets according to age, CVD, and comorbidities•BP <140/90 mm Hg if not diabetic and UAE <30 mg/24 h•Target BP <130/80 mm Hg•Use RAS antagonistAnticoagulation•Consider apixaban in preference to warfarin if GFR 30–50 ml/min in at-risk nonvavlular AF•Consider reduced-dose NOACs if GFR 15–50 ml/min•Consider warfarin or apixaban in ESKDStatins•Give atorvastatin 20 mm Hg for primary or secondary prevention•Discuss higher doses with the renal specialist if GFR <30 ml/min•Check a lipid profile in all new patients with CKD•If >50 yr and stage 3–5 CKD, treat with statin or statin/ezetimibe•>50-yr-old with stage 1 or 2 CKD, treat with statin•In dialysis-dependent CKD, do not initiate statins but continue if already taking•Initiate a moderate-intensity statin and/or ezetimibe in nondialysis CKD if 40 to 75 yr of age with LDL-C concentration 70–189 mg/dl and at 10-yr ASCVD risk ≥7.5%•In dialysis-dependent CKD, do not initiate statins but continue if already takingCarotid interventions•Consider if symptomatic with moderate to severe stenosis•CEA > CAS•CAS may have a role in selected patientsACC, American College of Cardiology; ACR, albumin/creatinine ratio; AF, atrial fibrillation; AHA, American Heart Association; ASA, American Stroke Association; ASCVD, atherosclerotic cardiovascular disease; BP, blood pressure; CAS, carotid artery stenting; CEA, carotid endarterectomy; CKD, chronic kidney disease; CVD, cardiovascular disease; ESKD, end-stage kidney disease; GFR, glomerular filtration rate; KDIGO, Kidney Disease: Improving Global Outcomes; LDL-C, low-density lipoprotein cholesterol; NICE, National Institute for Health and Care Excellence; NOAC, novel oral anticoagulant; RAS, renin-angiotensin system; UAE, urinary albumin excretion. Open table in a new tab ACC, American College of Cardiology; ACR, albumin/creatinine ratio; AF, atrial fibrillation; AHA, American Heart Association; ASA, American Stroke Association; ASCVD, atherosclerotic cardiovascular disease; BP, blood pressure; CAS, carotid artery stenting; CEA, carotid endarterectomy; CKD, chronic kidney disease; CVD, cardiovascular disease; ESKD, end-stage kidney disease; GFR, glomerular filtration rate; KDIGO, Kidney Disease: Improving Global Outcomes; LDL-C, low-density lipoprotein cholesterol; NICE, National Institute for Health and Care Excellence; NOAC, novel oral anticoagulant; RAS, renin-angiotensin system; UAE, urinary albumin excretion. In high-risk patients with prior vascular disease or some other predisposing condition, antiplatelet therapy has been associated with a 25% relative risk (RR) reduction in nonfatal stroke compared with placebo.20Antithrombotic Trialists' CollaborationCollaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.BMJ. 2002; 324: 71-86Crossref PubMed Google Scholar Despite their proven benefit in the general population, major gaps exist in our understanding of the effects of antiplatelet drugs on thrombosis and bleeding in CKD, particularly in the setting of primary prevention.21Ibrahim H. Rao S.V. Oral antiplatelet drugs in patients with chronic kidney disease (CKD): a review.J Thromb Thrombolysis. 2017; 43: 519-527Crossref PubMed Scopus (1) Google Scholar Clinical practice guidelines are ambiguous about their use in patients with CKD, because those with moderate to severe CKD were systematically excluded from most clinical trials evaluating efficacy and safety.11National Collaborating Centre for Chronic Conditions (UK)Chronic Kidney Disease: National Clinical Guideline for Early Identification and Management in Adults in Primary and Secondary Care. Royal College of Physicians, London2008Google Scholar In a large Cochrane review of 50 randomized controlled trials (RCTs) (27,139 participants) of antiplatelet treatment for the prevention of cardiovascular outcomes in CKD, antiplatelet agents reduced the risk of myocardial infarction (RR, 0.87; 95% confidence interval [CI], 0.76–0.99), but not all-cause mortality (RR, 0.93; 95% CI, 0.8–1.06), cardiovascular mortality (RR, 0.89; 95% CI, 0.70–1.12), or stroke (RR, 1.00; 95% CI, 0.58–1.72).22Palmer S.C. Di Micco L. Razavian M. et al.Antiplatelet agents for chronic kidney disease.Cochrane Database Syst Rev. 2013; : CD008834PubMed Google Scholar Antiplatelet agents increased the risk of major (RR, 1.33; 95% CI, 1.10–1.65) and minor (RR, 1.49; 95% CI, 1.12–1.97) bleeding. Although few studies were available for direct comparison, meta-regression analysis indicated no differences in the relative benefits or harms of treatment by type of antiplatelet agent. They concluded that there is currently insufficient evidence to support the role of antiplatelets in primary prevention, particularly in those with early stages of CKD who do not have clinically evident occlusive cardiovascular disease. However, data on the effects of antiplatelet agents on primary prevention in CKD were available only from a post hoc subgroup analysis of a single study, the Hypertension Optimal Treatment trial.23Jardine M.J. Ninomiya T. Perkovic V. et al.Aspirin is beneficial in hypertensive patients with chronic kidney disease: a post-hoc subgroup analysis of a randomized controlled trial.J Am Coll Cardiol. 2010; 56: 956-965Crossref PubMed Scopus (118) Google Scholar In this trial, the RR of major cardiovascular events were reduced by 9% (95% CI, −9% to 24%), 15% (95% CI, −17% to 39%), and 66% (95% CI, 33%–83%) for patients with a baseline estimated glomerular filtration rate (eGFR) of ≥60, 45 to 59, and <45 ml/min per 1.73 m2, respectively (P = 0.03 for trend), but there was no significant benefit for stroke as an individual end point and a near doubling of the risk of major bleeding (RR, 2.04; 95% CI, 1.05–3.96). In a more recent meta-analysis that focused only on primary prevention studies in CKD, 3 trials—Hypertension Optimal Treatment trial, Heart and Renal Protection trial, and Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes trial—were identified, providing data for 4468 participants.24Major R.W. Oozeerally I. Dawson S. et al.Aspirin and cardiovascular primary prevention in non-endstage chronic kidney disease: a meta-analysis.Atherosclerosis. 2016; 251: 177-182Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Overall, there was no statistically significant reduction in major cardiovascular events including stroke (RR, 0.92; 95% CI, 0.49–1.73; P = 0.79), but there was a high level of heterogeneity between studies (I2 = 71%; P = 0.06) and only 1 trial (Heart and Renal Protection study) was CKD specific. The Aspirin To Target Arterial Events in Chronic Kidney Disease trial (ClinicalTrials.gov identifier: NCT03796156) is an open-label, multicenter primary prevention trial currently underway that is investigating whether the addition of daily aspirin to usual care will reduce the risk of major vascular events in patients with CKD (excluding those at stage 5 or dialysis dependent). The investigators intend on recruiting 25,210 patients and anticipate finishing in 2025. In addition to bleeding concerns, there are reports of high rates of antiplatelet hyporesponsiveness in patients with CKD, which may partially explain poorer outcomes.25Polzin A. Dannenberg L. Sansone R. et al.Antiplatelet effects of aspirin in chronic kidney disease patients.J Thromb Haemost. 2016; 14: 375-380Crossref PubMed Scopus (48) Google Scholar CKD and end-stage kidney disease (ESKD) are independent risk factors for clopidogrel resistance; 50% to 80% of patients with ESKD have high on-treatment residual platelet reactivity (resistance) when treated with clopidogrel.26Tanios B.Y. Itani H.S. Zimmerman D.L. Clopidogrel use in end-stage kidney disease.Semin Dial. 2015; 28: 276-281Crossref PubMed Google Scholar However, it has been suggested that the high burden of comorbidities in patients with CKD may account for this observation rather than CKD itself.27Breet N.J. de Jong C. Bos W.J. et al.The impact of renal function on platelet reactivity and clinical outcome in patients undergoing percutaneous coronary intervention with stenting.Thromb Haemost. 2014; 112: 1174-1181Crossref PubMed Scopus (21) Google Scholar Overall, the current guideline recommendations to generally avoid primary prevention with aspirin in patients with CKD are reasonable in the context of recent randomized trials (ASPirin in Reducing Events in the Elderly study, Aspirin to Reduce Risk of Initial Vascular Events study, and A Study of Cardiovascular Events iN Diabetes)28McNeil J.J. Nelson M.R. Woods R.L. et al.Effect of aspirin on all-cause mortality in the healthy elderly.N Engl J Med. 2018; 379: 1519-1528Crossref PubMed Scopus (152) Google Scholar, 29Gaziano J.M. Brotons C. Coppolecchia R. et al.Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial.Lancet. 2018; 392: 1036-1046Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 30Bowman L. Mafham M. Wallendszus K. et al.Effects of aspirin for primary prevention in persons with diabetes mellitus.N Engl J Med. 2018; 379: 1529-1539Crossref PubMed Scopus (226) Google Scholar that did not find aspirin to be beneficial for stroke prevention in other at-risk groups (elderly, moderate cardiovascular risk, and diabetes, respectively) (Table 1). Anticoagulation has been shown to reduce the risk of stroke by approximately two-thirds in the general population, and it is also associated with reduced stroke severity and lower mortality rates.31Hart R.G. Pearce L.A. Aguilar M.I. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation.Ann Intern Med. 2007; 146: 857-867Crossref PubMed Google Scholar,32Johnsen S.P. Svendsen M.L. Hansen M.L. et al.Preadmission oral anticoagulant treatment and clinical outcome among patients hospitalized with acute stroke and atrial fibrillation: a nationwide study.Stroke. 2014; 45: 168-175Crossref PubMed Scopus (15) Google Scholar However, there is considerable recognition of the underuse of oral anticoagulation for stroke prevention in AF in renal disease, and their use is often complicated by high bleeding rates and uncertain benefit.33Buckley L.F. Rybak E. Aldemerdash A. et al.Direct oral anticoagulants in patients with atrial fibrillation and renal impairment, extremes in weight, or advanced age.Clin Cardiol. 2017; 40: 46-52Crossref PubMed Scopus (6) Google Scholar In particular, there are concerns about warfarin use given the association with vascular calcification due to the inhibition of the enzyme matrix gamma-carboxyglutamate Gla protein that scavenges calcium phosphate in tissues.34Poterucha T.J. Goldhaber S.Z. Warfarin and vascular calcification.Am J Med. 2016; 129 (635.e631–635.e634)Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Outcomes reported with warfarin use in both patients with non–end-stage CKD and dialysis-dependent patients with nonvalvular AF have been conflicting. In a Danish cohort study, warfarin treatment was associated with a significantly decreased risk of stroke or systemic thromboembolism overall (hazard ratio [HR], 0.76; 95% CI, 0.64–0.91; P = 0.003) and in patients requiring renal replacement therapy (HR, 0.44; 95% CI, 0.26–0.74; P = 0.002) but with a nonsignificantly decreased risk in patients with non–end-stage CKD (HR, 0.84; 95% CI, 0.69–1.01).35Olesen J.B. Lip G.Y. Kamper A.L. et al.Stroke and bleeding in atrial fibrillation with chronic kidney disease.N Engl J Med. 2012; 367: 625-635Crossref PubMed Scopus (518) Google Scholar There was an increasing risk of bleeding in all warfarin users with renal disease (HR, 1.33; 95% CI, 1.16–1.53; P < 0.001). This contrasts with the results of Swedish registry data (SWEDEHEART) that showed a lower risk of stroke in both groups without a higher risk of bleeding.36Carrero J.J. Evans M. Szummer K. et al.Warfarin, kidney dysfunction, and outcomes following acute myocardial infarction in patients with atrial fibrillation.JAMA. 2014; 311: 919-928Crossref PubMed Scopus (92) Google Scholar However, the latter cohort was a higher risk group post recent myocardial infarction and included fewer patients on dialysis, limiting the generalizability of their results. A systematic review and meta-analysis of 13 observational studies (>48,500 patients) evaluated the use of warfarin in patients with AF and CKD to assess the risk of ischemic stroke/thromboembolism, major bleeding, and mortality.37Dahal K. Kunwar S. Rijal J. et al.Stroke, major bleeding, and mortality outcomes in warfarin users with atrial fibrillation and chronic kidney disease: a meta-analysis of observational studies.Chest. 2016; 149: 951-959Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar In patients with AF and non–end-stage CKD, warfarin use was associated with a lower risk of ischemic stroke/thromboembolism (HR, 0.70; 95% CI, 0.54–0.89; P = 0.004) and mortality (HR, 0.65; 95% CI, 0.59–0.72; P < 0.00001) but had no effect on major bleeding (HR, 1.15; 95% CI, 0.88–1.49; P = 0.31). Most of the patients included in this analysis had stage 3 or 4 CKD, and this group appears to derive benefit from warfarin with a reasonable safety profile. However, in patients with AF and ESKD, warfarin had no apparent effect on the risk of stroke (HR, 1.12; 95% CI, 0.69–1.82; P = 0.65) and mortality (HR, 0.96; 95% CI, 0.81–1.13; P = 0.60) but increased the risk of major bleeding (HR, 1.30; 95% CI, 1.08–1.56; P = 0.005). A major limitation of this meta-analysis is that it is based solely on observational cohort studies, as there are no RCTs that have addressed this question. However, the majority of studies do not support a protective effect for warfarin in patients with ESKD and AF. Similarly in a 2017 meta-analysis of only patients on dialysis, warfarin was not associated with a significant reduction in ischemic stroke (HR, 0.77; 95% CI, 0.55–1.07), but possibly increased intracranial hemorrhage (HR, 1.93; 95% CI, 0.93–4.00), although without effect on gastrointestinal bleeding (HR, 1.19; 95% CI, 0.8–1.76) or all-cause mortality (HR, 0.89; 95% CI, 0.72–1.11).38Harel Z. Chertow G.M. Shah P.S. et al.Warfarin and the risk of stroke and bleeding in patients with atrial fibrillation receiving dialysis: a systematic review and meta-analysis.Canad J Cardiol. 2017; 33: 737-746Abstract Full Text Full Text PDF PubMed Google Scholar These analyses suggest that warfarin is not associated with a clear benefit but likely increased harm in patients with AF on dialysis. The risk estimates may be confounded though by variable time in the therapeutic range and by the inclusion of low-risk patients not expected to benefit from anticoagulation. However, in the absence of any definitive trial data to support its efficacy or safety, we would not recommend routine use of warfarin in patients with AF on dialysis. It should be reserved for the highest-risk patients in this group, such as those with a history of stroke or a documented cardiac thrombus. The results of the ongoing AVKDIAL trial (Oral Anticoagulation in Hemodialysis Patients; ClinicalTrials.gov identifier: NCT02886962) that will compare vitamin K antagonists with no anticoagulation in dialysis-dependent patients with AF are eagerly awaited. Novel oral anticoagulant agents (NOACs) appear to have at least an equivalent, if not more favorable, safety and efficacy profile when compared with vitamin K antagonists in CKD. Most of the randomized trials of NOACs (Randomized Evaluation of Long-Term Anticoagulation Therapy [RE-LY], Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE], and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation [ROCKET-AF]) have included patients with nonvalvular AF with an eGFR of ≥30 ml/min per 1.73 m2, and therefore, the best evidence for NOAC use is in patients with CKD with an eGFR of 30 to 59 ml/min per 1.73 m2.39Connolly S.J. Ezekowitz M.D. Yusuf S. et al.Dabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009; 361: 1139-1151Crossref PubMed Scopus (7130) Google Scholar, 40Granger C.B. Alexander J.H. McMurray J.J. et al.Apixaban versus warfarin in patients with atrial fibrillation.N Engl J Med. 2011; 365: 981-992Crossref PubMed Scopus (4980) Google Scholar, 41Patel M.R. Mahaffey K.W. Garg J. et al.Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011; 365: 883-891Crossref PubMed Scopus (5459) Google Scholar In a systematic review and meta-analysis of 8 RCTs (9693 participants) that compared NOACs with vitamin K antagonists for stroke prevention in patients with CKD (defined as creatinine clearance of 30–50 ml/min), there was no significant difference in the risk of stroke and systemic thromboembolism (RR, 0.64; 95% CI, 0.39–1.04), recurrent thromboembolism or thromboembolism-related death (RR, 0.97; 95% CI, 0.43–2.15), or bleeding events (RR, 0.89; 95% CI, 0.68–1.16) between NOACs and vitamin K antagonists.42Harel Z. Sholzberg M. Shah P.S. et al.Comparisons between novel oral anticoagulants and vitamin K antagonists in patients with CKD.J Am Soc Nephrol. 2014; 25: 431-442Crossref PubMed Scopus (76) Google Scholar However, although not statistically significant, there was clearly a trend toward better thromboembolic and bleeding outcomes with NOAC use. A recent larger systematic review and meta-analysis of 11 trials (16,787 participants) confirmed superiority of high-dose NOA