Chronic Kidney Disease and Stroke Nada El Husseini, Omran Kaskar, and Larry B. Goldstein Chronic kidney disease (CKD) is associated with an increased risk of both ischemic and hemorrhagic stroke. In addition to shared risk factors, this higher cerebrovascular risk is mediated by several CKD-associated mechanisms including platelet dysfunction, coagulation disorders, endothelial dysfunction, inflammation, and increased risk of atrial fibrillation. CKD can also modify the effect of treatments used in acute stroke and in secondary stroke prevention. We review the epidemiology and pathophysiology that link CKD and stroke and the impact of CKD on stroke outcomes. Interdisciplinary collaboration between nephrologists, pharmacists, hematologists, nutrition therapists, primary care physicians, and neurologists in providing care to these subjects may potentially improve outcomes. Q 2014 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Chronic kidney disease, Stroke, Thrombolysis, Alteplase, Stroke prevention

Introduction CKD affects at least 20 million people in the United States, and the prevalence of CKD is particularly common among adults older than 70 years. Diabetes and hypertension further increase this risk, with nearly 1 of 3 adults with diabetes and 1 of 5 adults with hypertension having CKD.1 This huge group of patients is burdened with a particularly high risk for both ischemic and hemorrhagic stroke. Reduced estimated glomerular filtration rate (eGFR) and elevated amounts of albuminuria are associated with an increased risk for incident stroke.2 In the Reasons for Geographic and Racial Differences in Stroke study, among participants 45 years or older of age and with an eGFR less than 45 mL/ min/1.73 m2 who were free of a history of stroke or transient ischemic attack at baseline, the incidence of stroke symptoms over a median of 2.1 years was 20.7%.2 In addition to the effect of common risk factors, stroke risk is increased through several CKD-associated mechanisms, such as hyperhomocysteinemia, inflammation, oxidative stress, anemia, endothelial dysfunction, arterial stiffness, and predisposition to atrial fibrillation. The management of stroke in the setting of CKD may be limited by a greater risk of treatment-related side effects because of impaired kidney drug clearance and increased bleeding tendencies. This quandary requires close collaboration among different clinical disciplines that manage the CKD population.

The Epidemiological Association Between Kidney Impairment and Stroke Risk factors for stroke identified in the general population, including older age, hypertension, diabetes, obesity, and cigarette smoking, are also the risk factors for the genesis From Department of Neurology, Duke University Medical Center, Durham, NC; and Department of Neurology, Wake Forest University Baptist Medical Center, Winston-Salem, NC. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Nada El Husseini, MD, MHSc, Wake Forest University Baptist Medical Center, Medical Center Boulevard, WinstonSalem, NC 27157. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2014.09.001

500

of CKD.3 For this reason, an association between stroke risk and CKD is not surprising. The risk of stroke, however, increases incrementally with stages of CKD in a doselike effect, a relationship that is independent of other vascular comorbidities. Proteinuria, which is an early marker of kidney disease, is associated with an increased risk of stroke. After adjusting for other vascular risk factors and independent of reduced eGFR, proteinuria confers a 71% increase in the risk of stroke (risk ratio [RR] 1.71; 95% confidence interval [CI] 1.39-2.10, P ¼ .008).4 If the GFR is diminished, the risk can be even greater. A metaanalysis incorporating data from 33 studies and 280,000 patients found that stroke risk increased by more than 43% (RR 1.43, 95% CI 1.30-1.57; P , .001) in patients with a GFR less than 60 mL/min compared with patients with normal eGFR, independent of other clinical factors.5 The risk of stroke was also higher in those with a GFR less than 40 mL/min compared with those with a GFR of 40 to 60 mL/min, suggesting a dose-like effect. One prospective study found that the combination of CKD and anemia was associated with a substantial increase in stroke risk (hazard ratio [HR] 5.43, 95% CI 2.04-14.41), independent of other known risk factors.6 Because of subclinical cerebrovascular disease, CKD is also associated with increased risk of cerebral microhemorrhages and cognitive impairment.7,8 The situation is even more grave for patients with advanced CKD. The US Renal Data Systems reported that, in 2011, 3.1% of all deaths of dialysis patients were because of stroke, but cerebrovascular events may have also accounted for a portion of the 26.9% of deaths attributed to sudden cardiac death.9

Kidney Replacement Therapy and Stroke Risk These prior studies confirm that with more advanced stages of CKD the risk of stroke increases; however, the risk of stroke seems disproportionally increased among individuals with ESRD undergoing dialysis.10 For example, patients with ESRD receiving hemodialysis have about a 2 to 10 times greater incidence of stroke compared with the general population (RR 6.1, 95% CI 5.1-7.1 for Caucasian men; RR 4.4, 95% CI 3.3-5.5 for African American men; RR 9.7, 95% CI 8.2-11.2 for Caucasian women; RR 6.2, 95% CI 4.8-7.6 for African American women). Rates of stroke vary between 10 and 33 per 1000 patient-years depending on study population and design. Those with ESRD also have a higher

Advances in Chronic Kidney Disease, Vol 21, No 6 (November), 2014: pp 500-508

Chronic Kidney Disease and Stroke

501

prevalence of hemorrhagic strokes compared with the mined causes. Advanced CKD (eGFR , 30 mL/min) is general population (HR 6.83, 95% CI 5.89-7.92).11,12 also associated with a higher risk of hemorrhagic transforThe heightened risk of stroke in advanced CKD, particumation of an initially ischemic stroke.12 In 1 study, after larly those on dialysis, likely results from the interplay of adjusting for other risk factors, the risk of hemorrhagic the vascular comorbidities associated with kidney impairtransformation was nearly 3-fold higher (odds ratio ment and pathology resulting from uremia, such as [OR] 2.90; 95% CI 1.26-6.68, P ¼ .012) in subjects with accelerated vascular calcification and the malnutritioneGFR less than 30 mL/min.15 Thus, the incidence of primary hemorrhagic stroke increases as GFR declines.16 inflammation-atherosclerosis syndrome. In subjects unIn addition, CKD is associated with an increase in the dergoing hemodialysis, stroke rates peak at 10 to 35 per severity of hemorrhagic stroke. In 1 study comparing 1000 patient-years with hemorrhagic stroke accounting those with moderate-to-severe CKD (GFR , 45 mL/min) for 20% to 30% of all events. Older age, hypertension, diawith those with normal kidney function, hematoma volbetes, and established cerebrovascular disease are addiume was 2.3 times greater (P ¼ .04) in those with CKD tional risk factors for stroke. Dialysis initiation and was associated with more than 6-fold higher odds constitutes the highest risk period.12 Advanced kidney disease is also associated with worse survival and functional of lobar location (95% CI 1.59-24.02).17 This evidence sug12 gests that hemorrhagic strokes are more prevalent in paoutcome. The additional risk of stroke conferred by ESRD persists tients with severe CKD. even among individuals who already have significant stroke risk because of conditions, such as atrial fibrillaCKD and Stroke Outcomes tion.10 This independent increased risk could be because Irrespective of stroke subtype, patients with CKD who had of the impact of metabolic disturbances associated with a stroke have greater neurologic deficits, worse functional reduced eGFR. In the setting outcomes, and higher morof ESRD, however, the tality rates compared with CLINICAL SUMMARY additional exposure to dialthose patients without ysis and dialysis-specific CKD.18 In-hospital mortal Independent of other vascular co-morbidities, the risk of medications may also be ity after stroke is increased stroke increases incrementally with worsening stages of contributing to cerebrovascuamong those with CKD CKD. lar risk. In a study of 21,000 with the risk higher in those US dialysis patients aged with more severe kidney  CKD increases the risk of stroke-related neurological 67 years or older, stroke rates deficits, worse functional outcomes and mortality. impairment. Similarly, pabegan to rise about 3 months tients receiving hemodialy Kidney impairment affects platelet and endothelial function, before the start of dialysis sis have a 3-fold higher risk coagulation factors, arterial wall thickness, systemic and peaked during the first of death after acute stroke inflammation, homocysteine levels, and risk of atrial 30 days of dialysis. Transient compared with nonhemofibrillation. fluid shifts leading to hemodialysis patients, an effect  Advanced CKD may modify the degree of therapeutic effect dynamic instability are one that is independent of and side effects profile of medications commonly prescribed potential mechanism underother risk factors.19,20 After for stroke such as IV-tPA, anticoagulants, antiplatelet agents, 13 lying this risk. In a study stroke, a GFR of 15 to and statins. of a nationwide retrospective 44 mL/min was associated cohort in Taiwan, and after with 1-year mortality of adjusting for all potential 2.8% (95% CI 1.3-6.0).20 confounders and competing risk of death, patients Pathophysiology receiving peritoneal dialysis had a lower risk of hemorThe multiple pathophysiological effects of kidney rhagic stroke (HR 0.75; 95% CI 0.58-0.96) compared with dysfunction contribute to stroke risk in patients with those receiving hemodialysis, although the risk of ischemic CKD (Fig 1). These include direct effects of kidney impairstroke was similar.11 ment on platelet and endothelial function, coagulation factors, arterial wall thickness, systemic inflammation, Stroke Subtype and CKD homocysteine levels, and risk of atrial fibrillation. Ischemic and hemorrhagic strokes occur through distinct pathophysiological mechanisms, and it is plausible that Platelet Dysfunction CKD might promote specific subtypes of stroke. HemorPatients with CKD can manifest either bleeding diatheses or rhagic strokes can be intraparenchymal or subarachnoid. thrombotic tendencies. The risk of intracranial hemorrhage Ischemic strokes can occur as a result of local large-vessel (ICH) is in part related to platelet dysfunction. In vitro occlusion, small-vessel occlusion, and embolism from a studies with platelets from patients with kidney failure proximal source, such as an abnormal heart valve or show diminished platelet degranulation, reductions in another cardiac source. One cohort study found that stored platelet adenosine diphosphate and serotonin, and 76% of strokes in patients receiving dialysis were decreased platelet synthesis of thromboxane.21 There is ischemic.14 The largest proportion was because of cardiogenic embolism (28%), followed by small-vessel occlusion also decreased activation of glycoprotein IIb-IIIa receptors (20%) and large-artery atherothrombosis (11%), with 18% on the platelet membrane leading to reduced binding of having multiple possible causes and 23% having undeterplatelets to Von Willebrand factor and fibrinogen.18 Uremia

502

El Husseini et al

by itself also contributes to the higher risk of stroke in patients with CKD.25

Accelerated Atherosclerosis CKD is associated with accelerated atherosclerosis, likely because of a combination of inflammation, uremia, hyperhomocysteinemia, and other factors. Carotid artery atherosclerosis is greater among patients receiving dialysis compared with controls, even after adjusting for traditional cardiovascular risk factors. In 1 study, elasticity of the walls of the carotid artery was decreased and intimal wall thickness increased in younger patients receiving hemodialysis compared with age-matched healthy subjects.26 Figure 1. Factors in CKD that may play a role in increased risk of stroke.

is associated with platelet dysfunction that improves after hemodialysis. Conversely, enhanced platelet aggregation occurs during hemodialysis, but there has been no association between this effect and clinical thrombotic events.22

Coagulation Abnormalities

Circulating concentrations of plasma fibrinogen, prothrombin, D-dimer, and thrombin-antithrombin III complex are higher in patients who have CKD compared with the general population.18 Protein C deficiency may also occur in patients with CKD and in those with ESRD receiving hemodialysis.21 Impaired thrombolysis may also play a role.23 Coagulation tendency can be further enhanced in patients who have residual kidney function and persistent proteinuria.10 This spectrum of changes may predispose patients with CKD to thrombotic events.

Role of the Endothelium The endothelium is involved in balancing the anticoagulant and procoagulant pathways. An important function is to prevent formation of thrombi through continued cell synthesis, release of prostacyclin, nitric oxide, and tissue plasminogen activator (tPA). Endothelial dysfunction or damage promotes thrombus formation. Patients with CKD and ESRD have underlying endothelial dysfunction with an inverse relationship between endothelial impairment and creatinine clearance.18

Inflammation Several observations suggest that CKD and kidney replacement therapy are associated with chronic inflammation. Plasma concentrations of C-reactive protein, fibrinogen, interleukin-6, and other inflammatory markers occur in patients with CKD and in those with ESRD.18 CKD is also associated with activation of platelet adhesion molecules and alterations in the structure and concentration of lipoproteins.18 Often chronic inflammation is associated with evidence of malnutrition, particularly in ESRD patients maintained on dialysis.24 However, because systemic inflammation is a risk factor for stroke risk in other populations, it is plausible that systemic inflammation

Homocysteine Hyperhomocysteinemia, defined as a plasma total homocysteine level greater than 12 mmol/L, occurs when the GFR falls to less than 60 mL/min. Approximately 85% to 100% of patients with ESRD have hyperhomocysteinemia.27 High homocysteine levels lead to endothelial dysfunction and accelerated atherosclerosis and is associated with atherothrombo-occlusive disease and venous thromboembolism. Impaired endothelial vasomotor responses are linked to reduced bioavailability of nitric oxide because of auto-oxidation of homocysteine in plasma, which leads to oxidative inactivation of nitric oxide.18 Elevated homocysteine levels are also an independent predictor of neurologic deterioration after acute stroke.28 The use of homocysteine-lowering therapies, however, has not consistently led to improved outcomes or lower risk of cardiovascular events. A double-blind randomized controlled trial of folic acid, vitamin B6, and vitamin B12 in veterans with advanced CKD or ESRD and elevated homocysteine levels ($15 mmol/L) was not associated with a significant decrease in mortality (HR 1.04; 95% CI 0.911.18), myocardial infarction (MI; HR 0.86; 95% CI 0.671.08), or stroke (HR 0.90; 95% CI 0.58-1.40).29

Atrial Fibrillation Patients with CKD are likely to manifest new-onset atrial fibrillation.30-33 Furthermore, subjects with AF are more likely to develop CKD.34 Even after adjusting for other variables, the incidence of AF increases with decreasing kidney function. In the Chronic Renal Insufficiency Cohort study, the prevalence of AF was 16% in patients with an eGFR of 45 mL/min or more and 20% in those with an eGFR less than 45 mL/min.30,35 In the same study, the prevalence rate of AF in patients with impaired kidney function and who were 70 years or more was 25.5%.30,35 AF is an important risk factor for stroke and negatively affects the quality of life and survival of patients with kidney disease.33 In 1 study, compared with preserved eGFR ($60 mL/min/1.73 m2) and CHADS2 score less than 2, a decreased eGFR (,60 mL/min/1.73 m2) and CHADS2 score of 2 or more was associated with higher all-cause (12.9% vs 1.4% per year, HR 6.9, P , .001) and cardiovascular (6.5% vs 0.2% per year, HR 29.7, P , .001) mortalities. The risk of stroke associated with AF is also higher in the setting of CKD. Compared

Chronic Kidney Disease and Stroke

with those without CKD, patients with CKD and AF have higher risk of ischemic stroke and thromboembolism.10,36,37 For example, compared with patients with an eGFR of 60 mL/min or more and CHADS2 score less than 2, patients with an eGFR less than 60 mL/min and an elevated stroke risk (CHADS2 score $ 2) had an 11-fold higher risk of ischemic stroke (3.6% vs 0.2% per year, HR 11.0, P , .001).38 When eGFR less than 60 mL/min was added to CHADS2 score, the new R2CHADS2 score improved the predictive value for ischemic stroke.37 In another study of patients with AF, after adjustment for other risk factors, Stage III CKD (eGFR 30-50 mL/min) remained an independent risk factor for stroke (approximate HR 1.5).39 The higher stroke risk among patients with AF is also evident among patients with severe kidney impairment and hemodialysis. In a Danish national registry of 132,372 patients with AF and CKD, the risk of stroke was nearly 2-fold higher in patients receiving dialysis or kidney transplant (HR 1.83; 95% CI 1.57-2.14).40 In the US Renal Data System, the stroke rate was 15.1% in those receiving hemodialysis compared with 9.6% in those with CKD but not receiving hemodialysis and 2.6% in matched subjects without CKD.41 CKD also increases the risk of bleeding with anticoagulants. For this reason, CKD has been incorporated in scores to estimate bleeding associated with warfarin in patients with AF such as in the widely used HAS-BLED score (a composite score of hypertension, abnormal liver/kidney function, stroke history, bleeding predisposition, labile coagulation tests, “elderly,” and drugs/alcohol use).42

Kidney Disease and Acute Stroke Treatment Intravenous Tissue Plasminogen Activator for Treatment of Stroke in Subjects With CKD It is evident that compared with the general population, patients with kidney disease are exposed to an increased risk of ischemic and hemorrhagic stroke.43 Intravenous (IV)-tPA improves outcomes in selected patients with ischemic stroke but carries a risk of symptomatic intracranial hemorrhage (sICH). Patients with kidney disease may be at an increased risk of bleeding complications after IVtPA administration because of associated platelet dysfunction and a CKD-related coagulopathy. In the alteplase (recombinant tPA) prescribing information, it is recommended to weigh the risk of treatment against the expected benefit in patients with hemostatic defects, including those resulting from severe kidney disease. The extent to which kidney function independently influences the rate of sICH after IV-tPA administration in acute stroke remains unclear. It is also not known whether a specific eGFR or creatinine cut-off can predict post-tPA outcomes or should be used as a contraindication for IVtPA treatment. Results of available studies of the association between kidney disease and the risk of sICH after IV-tPA for ischemic stroke are inconsistent: 1. Serum Cr dichotomized at 1.7 (Cr # 1.7 or .1.7 mg/dL) was not associated with the risk of sICH when tested in a model to predict sICH.44 Another study did not find

503

an association between GFR dichotomized at 60 mL/ min/1.73 m2 and risk of ICH, poor functional outcome, or death.45 2. In contrast, worsening creatinine and GFR were associated with a worse combined outcome based on the modified Rankin Score (mRS), sICH, and recurrent ischemic stroke within 3 months after IV-tPA.46 A multicenter study from Japan found that GFR less than 60 mL/min/1.73 m2 was associated with early ICH and 3-month unfavorable outcome in stroke patients receiving IV-tPA.47 In a meta-analysis, the odds of ICH after IV-tPA for acute ischemic stroke was almost double in the presence of kidney dysfunction.48 A recent observational study evaluated the association between the eGFR assessed by the CKD-Epidemiology Collaboration equation and poor 3-month outcome (mRS score 3-6), death, and sICH. Among 4780 patients treated with IV-tPA, 1217 (25.5%) had a GFR less than 60 mL/min/1.73 m2. Low GFR was independently associated with poor 3-month outcome (OR 1.32; 95% CI 1.10-1.58), death (OR 1.73; 95% CI 1.39-2.14), and sICH (OR 1.64; 95% CI 1.21-2.23) compared with normal GFR (60-120 mL/min/1.73 m2). Patients with low GFR who received thrombolysis had worse outcome than those who did not receive intravenous thrombolysis (OR 1.79; 95% CI 1.41-2.25).49 This study was conducted in European sites only. The models did not adjust for race-ethnicity, and information about the type of kidney insufficiency (ie, acute vs chronic) was not available. The inconsistent results of these studies could be because of the different methods used to ascertain kidney dysfunction, such as use of a creatinine or eGFR (Cockcroft-Gault equation, the Modification of Diet in Renal Disease Study equations, or CKD-Epidemiology Collaboration) thresholds, failure to adjust for important confounders, and differences in sample sizes and populations. Determining a cutoff of impaired kidney function that predicts complications after IV-tPA would be important to include in risk scores for sICH and potentially for informing medical decisions and the design of future clinical trials.

CKD and Secondary Stroke Prevention Anticoagulants and AF in CKD Anticoagulation therapy with warfarin or the newer anticoagulants (dabigatran, rivaroxaban, and apixaban) is indicated for patients with AF based on efficacy and safety as found in prospective randomized trials. To avoid possible complications, such as increased risk of bleeding, the major trials of anticoagulants excluded individuals with significant kidney impairment. Data pertaining to their use in CKD is based on observational studies, subgroup analyses of large randomized controlled studies, or extrapolation of pharmacodynamic data. Warfarin Warfarin is a potent vitamin K antagonist with multiple drug and food interactions. Most of the studies investigating warfarin in patients with kidney impairment and

504

El Husseini et al

AF are observational and have focused on CKD with dialysis. Conflicting evidence exists regarding the safety of warfarin in the setting CKD. For example, warfarin may accelerate cardiovascular calcification and increase the risk for the development of calcific uremic arteriolopathy.50 Some observational studies suggest that the use of warfarin may increase the risk of death and stroke among those with advanced kidney disease,36,51,52 whereas others did not find this higher risk.36,40,53,54 The efficacy and safety of warfarin in patients with ESRD have been evaluated in a small number of observational studies. One retrospective cohort study of 1671 patients with AF and CKD receiving hemodialysis found that the rate of ischemic stroke was highest in those who are also being treated with warfarin (7.1%; 95% CI 5.7-8.7) compared with those taking aspirin or clopidogrel (HR 2.79; 95% CI 1.65-4.70). This result, however, was likely because of selection bias because those receiving warfarin were at highest risk of ischemic stroke.36,52 Similarly, another study did not show a benefit from the use of warfarin in the setting of ESRD. The study was a population-based retrospective cohort of patients older than 65 years and included 1626 AF patients receiving dialysis, 46% of whom were taking warfarin.55 There was no reduction in the risk of stroke with warfarin (adjusted HR 1.14, 96% CI 0.78-1.67), and the risk of bleeding was 44% higher (adjusted HR 1.44, 95% CI 1.13-1.85).55 In contrast, several other studies found benefit of warfarin therapy in patients with AF and CKD. For example, in the 12-year Danish National Registry (vide supra), warfarin treatment was associated with a lower risk of ischemic stroke in patients with AF and CKD with kidney replacement (dialysis and kidney transplant; HR 0.44; 95% CI 0.26-0.74) and without kidney replacement (HR 0.84; 95% CI 0.69-1.01).40 The risk of warfarin-associated bleeding was increased in both groups (HR 1.36, 95% CI 1.17-1.59, for CKD vs HR 1.27, 95% CI 0.91-1.77, for CKD with kidney replacement).40 In another observational retrospective study of 399 patients with different stages of CKD and AF who were treated with warfarin (international normalized ratio between 2.0 and 3.0), warfarin compared with no warfarin was associated with a significantly lower incidence of thromboembolic stroke regardless of CKD stage.56 A different multicenter cohort study from a Swedish registry found similar results: among survivors of acute MI with AF, warfarin treatment was associated with a lower 1-year risk for the composite outcome of death, MI, and ischemic stroke without a higher risk of bleeding, independent of the severity of concurrent CKD.36 Similarly, in a subgroup analysis of the Stroke Prevention in Atrial Fibrillation III trial, warfarin reduced the relative risk of ischemic stroke and systemic embolism by 76% (95% CI 42%-90%; P , .001) compared with aspirin or low-dose warfarin without significant increase in bleeding.54 The 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society AF guideline favors anticoagulation in most nonvalvular AF patients with ESRD to prevent embolic events, but this recommendation acknowledges that anticoagulation carries significant bleeding risk in this vulnerable population.57 Warfarin

seems to be reasonable for individuals with AF and ESRD with very high-risk predictors for thromboembolism, such as known atrial thrombus, valvular/rheumatic heart disease, prosthetic heart valve, and previous transient ischemic attack or stroke.58 For less advanced stages of CKD, the benefits of anticoagulation for nonvalvular AF seem to outweigh the bleeding risks.59 CKD is associated with both decreased warfarin maintenance dose and more frequent and intensive anticoagulation clinic management.60 In a retrospective review of warfarin response in a pharmacist-managed anticoagulation clinic, subjects with CKD required a 24% lower dose of warfarin and spent less time in therapeutic range compared with controls matched for ethnicity, gender, age, body surface area, and simvastatin use. Patients with CKD had a higher proportion of clinic visits at which dose changes occurred (22% vs 12%, P , .001) and a decreased time between scheduled visits (mean of 16 vs 19.7 days, P ¼ .001).60 Novel Anticoagulants The 3 novel oral anticoagulants (NOACs) that have been introduced over the past few years are predominantly or partially excreted by the kidneys. In the setting of CKD, the NOACs have a prolonged half-life resulting in increased antithrombotic activity and augmented bleeding risk.30 For this reason, all 3 NOAC trials (the direct thrombin inhibitor dabigatran and 2 factor Xa inhibitors, apixaban and rivaroxaban) excluded patients with severe kidney impairment (estimated creatinine clearance ,30 mL/min for rivaroxaban and dabigatran, serum creatinine level .2.5 mg/dL or calculated creatinine clearance of ,25 mL/min for apixaban).61-63 The study with rivaroxaban used a reduced dose of 15 mg daily in patients with a creatinine clearance of 30 to 49 mL/min. The study with apixaban used a dose of 2.5 mg twice daily in the subset of patients with 2 or more of the following criteria: an age of at least 80 years, a body weight of no more than 60 kg, or a serum creatinine level of 1.5 mg/dL.61,62 Although the dabigatran study did not evaluate a lower dose in patients with a creatinine clearance less than 30 mL/min, the Food and Drug Administration approved a reduced dose of 75 mg twice daily in the setting of CrCl 15 to 30 mL/min.64 Dosing recommendations for patients with a CrCl less than 15 mL/ min or on dialysis cannot be provided.63 Apixaban is a factor Xa inhibitor. It is 25% renally excreted.30 Its efficacy and safety were investigated in 2 phase 3 trials. The Apixaban vs Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment trial compared apixaban with aspirin in patients with AF.65 The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial compared apixaban with warfarin in patients with AF.62 Both trials excluded patients with eGFR less than 25 mg/ mL/1.73 m2. The dose of apixaban was reduced from 5 mg twice daily to 2.5 mg twice daily in patients with a serum creatinine 1.5 to 2.5 mg/dL. Compared with aspirin, apixaban decreased the rate of stroke and systemic embolism and had a similar bleeding

Chronic Kidney Disease and Stroke

risk in subjects without and with CKD Stage 3.66 As compared with warfarin, apixaban was also more effective in preventing stroke or systemic embolism, all causemortality, and major bleeding in subjects with and without kidney impairment.67 Rivaroxaban is a factor Xa inhibitor. It is 30% renally excreted.30 Its efficacy and safety were evaluated in the phase 3 Rivaroxaban Once-Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation.61 The trial excluded subjects with CrCl less than 30 mL/min. Although there was a trend for a reduction of stroke and systemic embolism even in those with kidney impairment, bleeding events occurred more often in subjects with renal insufficiency than those without and were comparable with the rates of bleeding seen with warfarin (17.82% vs 18.28%, HR 0.98; 95% CI 0.841.14) but with less critical organ and fatal bleeding.30,61 In a secondary analysis, impaired kidney function strongly predicted new stroke or systemic embolism during follow-up.37 The risk for new stroke or systemic embolism increased by 12% for every 10 mL/min decrease in CrCl.37 Intracranial hemorrhage associated with rivaroxaban or apixaban is still less than that associated with warfarin in patients with CKD.39 Dabigatran is a direct thrombin inhibitor. It is 80% renally cleared.30 Its efficacy and safety were evaluated in the phase 3 Randomized Evaluation of Long-Term Anticoagulation Therapy trial. The trial excluded subjects with CrCl of 30 mL/min or less.63 Subgroup analysis did not reveal a significant effect of kidney function on treatment effect.63

Antiplatelet Drugs in Secondary Stroke Prevention Among Patients With CKD Antiplatelet medications are a cornerstone of therapy in the general population of patients who had a stroke, but the role of these drugs in CKD is less clear. A metaanalysis of 50 randomized controlled trials (27,139 participants) evaluated the effect of antiplatelet agents in subjects with CKD.68 Regardless of the type of antiplatelet agent or stage of CKD, antiplatelet drugs decreased the risk of MI but not all-cause mortality or stroke (11 studies; RR 1.00; 95% CI 0.58-1.72). Antiplatelet drugs increased the risk of major (RR 1.33; 95% CI 1.10-1.65) and minor bleeding (RR 1.49; 95% CI 1.12-1.97).68 Antiplatelet agents did not affect kidney outcomes such as the risk of ESRD, doubling of serum creatinine, transplant graft loss, transplant rejection, or proteinuria.68,69

Carotid Intervention for Carotid Disease in Setting of CKD Carotid artery stenosis is prevalent in the setting of CKD, but the extent to which intervention will improve clinical outcomes continues to be evaluated. Whether assessed by serum creatinine concentration or by eGFR, moderate-to-severe CKD is associated with a higher risk of major adverse events after carotid endarterectomy (CEA).70 In 1 study, higher mortality rates after CEA were found in patients with serum creatinine of 3 mg/dL or more, including among patients with asymptomatic carotid stenosis (1-month mortality of 13% in asymptomatic

505

and 28% in symptomatic patients). Subjects with ESRD who were maintained on dialysis were excluded from randomized controlled trials of carotid artery stenting and CEA. A retrospective analysis of Nationwide Inpatient Survey data compared in-hospital mortality and severe disability in subjects with dialysis dependent and nondialysis-dependent kidney failure. Both carotid artery stenosis and CEA were associated with higher rates of inhospital mortality (OR 4.3, 95% CI 2.1-9.0; P , .0001) and moderate-to-severe disability (OR 1.4; 95% CI 1.1-1.8; P ¼ .009) in those receiving dialysis.71 Based on these data, patients should be carefully selected for carotid revascularization. Patients with asymptomatic carotid disease and advanced CKD should probably avoid carotid revascularization as risks seem to outweigh potential benefits.

Statins for Secondary Stroke Prevention in Setting of CKD Statins may exert renoprotective effect in CKD. A metaanalysis of the role of statins on kidney outcome showed an association between statin therapy and GFR preservation between 1 and 3 years of use.72 A different meta-analysis, however, did not show similar benefit. The difference in the results could be because of relatively sparse data and reporting bias.73 In subgroup analyses of several large trials and in several meta-analyses, statins reduced the risk of stroke in subjects with mild-to-moderate CKD.74-76 The Study of Heart and Renal Protection trial assessed the efficacy and safety of the combination of simvastatin plus ezetimibe in patients with CKD.77 It included 9270 patients with CKD (including 3023 receiving dialysis) with no known history of MI or coronary revascularization. Subjects were randomized to simvastatin 20 mg plus ezetimibe 10 mg daily vs matching placebo.77 Statins plus ezetimibe prevented nonhemorrhagic stroke in subjects with advanced CKD not on dialysis (RR 0.75, 95% CI 0.60-0.94; P ¼ .01).77 Although statins reduce the absolute risk of cardiovascular disease in patients with mild-to-moderate CKD, the increased risk of rhabdomyolysis and the other risks associated with progressive CKD may partially offset these benefits when used for primary cardiovascular prevention.74 However, low-cost generic statins appear to be cost effective for primary prevention of cerebrovascular disease in subjects of mild-to-moderate CKD and hypertension.74 In contrast to patients with mild-to-moderate CKD, clinical trials failed to demonstrate a benefit of statins in subjects with ESRD. In a meta-analysis of 11 randomized controlled trials involving 21,295 subjects with CKD, statins in dialysis-dependent subjects with CKD did not have a significant effect on all-cause mortality and stroke (RR 1.31; 95% CI 0.90-1.89; P . .05).78 A Cochrane review found similar results in patients with ESRD on dialysis; despite reduction in cholesterol levels, statins had little or no effect on major cardiovascular events, all-cause mortality, cardiovascular mortality, or MI. Statins also had uncertain effects on stroke (RR 1.29; 95% CI 0.96 to 1.72).79 This is in contrast to nondialysis-dependent CKD, in which statins were associated with stroke reduction (RR 0.66; 95% CI 0.5-0.88; P ¼ .0022).78

506

El Husseini et al

Collaborative Care in the Management of Subjects With CKD and Cerebrovascular Disease Because of the multiple comorbidities in patients with CKD and cerebrovascular disease, patients may find themselves trying to co-ordinate the care they receive through multiple providers, or worse, end up with fragmented care. The care of cerebrovascular disease in these patients is optimized by understanding the prothrombotic and bleeding tendencies occurring with CKD, dosing considerations of prescribed medications, and hemodynamic considerations among individuals undergoing hemodialysis or those with hemodynamically significant cerebrovascular stenosis. Although it may be relatively straightforward to get simultaneous multiple inputs into the care of hospitalized patients with CKD by obtaining multiple consults, a collaborative care in an outpatient setting seems to be more complicated. A collaborative model would allow direct communication of treatment and evaluation plans within an interdisciplinary team. With interdisciplinary clinics, protocols can be put in place to assure following of evidence-based guidelines and ease the transition of these patients from inpatient to outpatient settings. These models may be particularly useful after inpatient hospitalization for stroke in the setting of advanced CKD or in the setting of complicated treatment regimen or side effects. Given the difficulty in managing traditional anticoagulants and the NOACs in CKD, these clinical issues seem likely to be best addressed with an interdisciplinary approach. A multidisciplinary clinic may benefit from a nephrologist, neurologist, pharmacist, nutrition therapist, and hematologist and would need to co-ordinate back with the primary care physician. In addition, a unified electronic medical record system may help with placing “flags” and “reminders” in care protocols. Co-ordination of care between the different specialties is important to address the multiple facets of the disease and improve treatment adherence to evidence-based guidelines.

Conclusions This review underscores the increased stroke risk associated with CKD, which seems to be gradient related, and summarizes some of the mechanisms that lead to the increased risk of stroke. CKD further affects the therapeutic effect of common medications used for treatment or prevention of stroke. For example, medications such as statins and anticoagulants have little effect or have not been rigorously studied in the setting of ESRD and dialysis. Collaborative care in managing these subjects may improve adherence to practice guideline and potentially improve outcomes.

3.

4. 5.

6.

7.

8.

9.

10.

11.

12. 13.

14.

15.

16.

17.

18. 19.

20.

References 1. Centers for Disease Control and Prevention (CDC). National Chronic Kidney Disease Fact Sheet: General Information and National Estimates on Chronic Kidney Disease in the United States, 2014. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2014. http://www.cdc.gov/diabetes/pubs/ factsheets/kidney.htm#1. Accessed September 25, 2014. 2. Muntner P, Judd SE, McClellan W, Meschia JF, Warnock DG, Howard VJ. Incidence of stroke symptoms among adults with

21. 22. 23.

chronic kidney disease: results from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Nephrol Dial Transplant. 2012;27(1):166-173. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation. 2014;129(3):e28-e292. Ninomiya T, Perkovic V, Verdon C, et al. Proteinuria and stroke: a meta-analysis of cohort studies. Am J Kidney Dis. 2009;53(3):417-425. Lee M, Saver JL, Chang KH, Liao HW, Chang SC, Ovbiagele B. Low glomerular filtration rate and risk of stroke: meta-analysis. BMJ. 2010;341:c4249. Abramson JL, Jurkovitz CT, Vaccarino V, Weintraub WS, McClellan W. Chronic kidney disease, anemia, and incident stroke in a middle-aged, community-based population: the ARIC Study. Kidney Int. 2003;64(2):610-615. Ovbiagele B, Wing JJ, Menon RS, et al. Association of chronic kidney disease with cerebral microbleeds in patients with primary intracerebral hemorrhage. Stroke. 2013;44(9):2409-2413. Bugnicourt JM, Godefroy O, Chillon JM, Choukroun G, Massy ZA. Cognitive disorders and dementia in CKD: the neglected kidneybrain axis. J Am Soc Nephrol. 2013;24(3):353-363. US Renal Data System. USRDS 2013 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2013. Go AS, Fang MC, 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(10):1363-1369. Wang HH, Hung SY, Sung JM, Hung KY, Wang JD. Risk of stroke in long-term dialysis patients compared with the general population. Am J Kidney Dis. 2014;63(4):604-611. Power A. Stroke in dialysis and chronic kidney disease. Blood Purif. 2013;36(3-4):179-183. Murray AM, Seliger S, Lakshminarayan K, Herzog CA, Solid CA. Incidence of stroke before and after dialysis initiation in older patients. J Am Soc Nephrol. 2013;24(7):1166-1173. Sozio SM, Armstrong PA, Coresh J, et al. Cerebrovascular disease incidence, characteristics, and outcomes in patients initiating dialysis: the choices for healthy outcomes in caring for ESRD (CHOICE) study. Am J Kidney Dis. 2009;54(3):468-477. Lee JG, Lee KB, Jang IM, et al. Low glomerular filtration rate increases hemorrhagic transformation in acute ischemic stroke. Cerebrovasc Dis. 2013;35(1):53-59. Bos MJ, Koudstaal PJ, Hofman A, Breteler MM. Decreased glomerular filtration rate is a risk factor for hemorrhagic but not for ischemic stroke: the Rotterdam Study. Stroke. 2007;38(12): 3127-3132. Molshatzki 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(3): 271-277. Kumai Y, Kamouchi M, Hata J, et al. Proteinuria and clinical outcomes after ischemic stroke. Neurology. 2012;78(24):1909-1915. Herzog CA, Asinger RW, Berger AK, et al. Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2011;80(6):572-586. Yahalom G, Schwartz R, Schwammenthal Y, et al. Chronic kidney disease and clinical outcome in patients with acute stroke. Stroke. 2009;40(4):1296-1303. Casserly LF, Dember LM. Thrombosis in end-stage renal disease. Semin Dial. 2003;16(3):245-256. Boccardo P, Remuzzi G, Galbusera M. Platelet dysfunction in renal failure. Semin Thromb Hemost. 2004;30(5):579-589. Sharma S, Farrington K, Kozarski R, et al. Impaired thrombolysis: a novel cardiovascular risk factor in end-stage renal disease. Eur Heart J. 2013;34(5):354-363.

Chronic Kidney Disease and Stroke

24. Rattanasompattikul M, Molnar MZ, Zaritsky JJ, et al. Association of malnutrition-inflammation complex and responsiveness to erythropoiesis-stimulating agents in long-term hemodialysis patients. Nephrol Dial Transplant. 2013;28(7):1936-1945. 25. Goldstein LB, Bushnell CD, Adams RJ, et al. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42(2):517-584. 26. Shakeri A, Abdi M, Khosroshahi HT, Fouladi RF. Common carotid artery intima-media thickness and atherosclerotic plaques in carotid bulb in patients with chronic kidney disease on hemodialysis: a case-control study. Pak J Biol Sci. 2011;14(17):844-848. 27. van Guldener C. Why is homocysteine elevated in renal failure and what can be expected from homocysteine-lowering? Nephrol Dial Transplant. 2006;21(5):1161-1166. 28. Kwon HM, Lee YS, Bae HJ, Kang DW. Homocysteine as a predictor of early neurological deterioration in acute ischemic stroke. Stroke. 2014;45(3):871-873. 29. Jamison RL, Hartigan P, Kaufman JS, et al. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. JAMA. 2007;298(10):1163-1170. 30. Reinecke H, Engelbertz C, Schabitz WR. Preventing stroke in patients with chronic kidney disease and atrial fibrillation: benefit and risks of old and new oral anticoagulants. Stroke. 2013;44(10): 2935-2941. 31. Horio T, Iwashima Y, Kamide K, et al. Chronic kidney disease as an independent risk factor for new-onset atrial fibrillation in hypertensive patients. J Hypertens. 2010;28(8):1738-1744. 32. Alonso A, Lopez FL, Matsushita K, et al. Chronic kidney disease is associated with the incidence of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 2011;123(25): 2946-2953. 33. Nelson SE, Shroff GR, Li S, Herzog CA. Impact of chronic kidney disease on risk of incident atrial fibrillation and subsequent survival in Medicare patients. J Am Heart Assoc. 2012;1(4):e002097. 34. Winkelmayer WC, Turakhia MP. Warfarin treatment in patients with atrial fibrillation and advanced chronic kidney disease: sins of omission or commission? JAMA. 2014;311(9):913-915. 35. Soliman EZ, Prineas RJ, Go AS, et al. Chronic kidney disease and prevalent atrial fibrillation: the Chronic Renal Insufficiency Cohort (CRIC). Am Heart J. 2010;159(6):1102-1107. 36. Carrero JJ, Evans M, Szummer K, et al. Warfarin, kidney dysfunction, and outcomes following acute myocardial infarction in patients with atrial fibrillation. JAMA. 2014;311(9):919-928. 37. Piccini JP, Stevens SR, Chang Y, et al. Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: validation of the R(2)CHADS(2) index in the ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (AnTicoagulation and Risk factors in Atrial fibrillation) study cohorts. Circulation. 2013;127(2):224-232. 38. Nakagawa K, Hirai T, Takashima S, et al. Chronic kidney disease and CHADS(2) score independently predict cardiovascular events and mortality in patients with nonvalvular atrial fibrillation. Am J Cardiol. 2011;107(6):912-916. 39. Hart RG, Eikelboom JW, Brimble KS, McMurtry MS, Ingram AJ. Stroke prevention in atrial fibrillation patients with chronic kidney disease. Can J Cardiol. 2013;29(suppl 7):S71-S78. 40. Olesen JB, Lip GY, Kamper AL, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med. 2012;367(7): 625-635. 41. Szeto CC, Lai KB, Kwan BC, et al. Bacteria-derived DNA fragment in peritoneal dialysis effluent as a predictor of relapsing peritonitis. Clin J Am Soc Nephrol. 2013;8(11):1935-1941.

507

42. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5):1093-1100. 43. Holzmann MJ, Aastveit A, Hammar N, Jungner I, Walldius G, Holme I. Renal dysfunction increases the risk of ischemic and hemorrhagic stroke in the general population. Ann Med. 2012;44(6): 607-615. 44. Menon BK, Saver JL, Prabhakaran S, et al. Risk score for intracranial hemorrhage in patients with acute ischemic stroke treated with intravenous tissue-type plasminogen activator. Stroke. 2012;43(9): 2293-2299. 45. Agrawal V, Rai B, Fellows J, McCullough PA. In-hospital outcomes with thrombolytic therapy in patients with renal dysfunction presenting with acute ischaemic stroke. Nephrol Dial Transplant. 2010;25(4):1150-1157. 46. Lyrer PA, Fluri F, Gisler D, Papa S, Hatz F, Engelter ST. Renal function and outcome among stroke patients treated with IV thrombolysis. Neurology. 2008;71(19):1548-1550. 47. Naganuma M, Koga M, Shiokawa Y, et al. Reduced estimated glomerular filtration rate is associated with stroke outcome after intravenous rt-PA: the Stroke Acute Management with Urgent Risk-Factor Assessment and Improvement (SAMURAI) rt-PA registry. Cerebrovasc Dis. 2011;31(2):123-129. 48. Whiteley WN, Slot KB, Fernandes P, Sandercock P, Wardlaw J. Risk factors for intracranial hemorrhage in acute ischemic stroke patients treated with recombinant tissue plasminogen activator: a systematic review and meta-analysis of 55 studies. Stroke. 2012;43(11): 2904-2909. 49. Gensicke H, Zinkstok SM, Roos YB, et al. IV thrombolysis and renal function. Neurology. 2013;81(20):1780-1788. 50. Kruger T, Brandenburg V, Schlieper G, Marx N, Floege J. Sailing between Scylla and Charybdis: oral long-term anticoagulation in dialysis patients. Nephrol Dial Transplant. 2013;28(3):534-541. 51. Wizemann V, Tong L, Satayathum S, et al. Atrial fibrillation in hemodialysis patients: clinical features and associations with anticoagulant therapy. Kidney Int. 2010;77(12):1098-1106. 52. Chan KE, Lazarus JM, Thadhani R, Hakim RM. Warfarin use associates with increased risk for stroke in hemodialysis patients with atrial fibrillation. J Am Soc Nephrol. 2009;20(10):2223-2233. 53. Winkelmayer WC, Liu J, Setoguchi S, Choudhry NK. Effectiveness and safety of warfarin initiation in older hemodialysis patients with incident atrial fibrillation. Clin J Am Soc Nephrol. 2011;6(11): 2662-2668. 54. Hart RG, Pearce LA, Asinger RW, Herzog CA. Warfarin in atrial fibrillation patients with moderate chronic kidney disease. Clin J Am Soc Nephrol. 2011;6(11):2599-2604. 55. Shah M, Avgil Tsadok M, Jackevicius CA, et al. Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis. Circulation. 2014;129(11):1196-1203. 56. Lai HM, Aronow WS, Kalen P, et al. Incidence of thromboembolic stroke and of major bleeding in patients with atrial fibrillation and chronic kidney disease treated with and without warfarin. Int J Nephrol Renovasc Dis. 2009;2:33-37. 57. January CT, Wann LS, Alpert JS, et al. 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 practice guidelines and the heart rhythm society [epub ahead of print]. Circulation. http://dx.doi.org/10.1016/j.jacc. 2014.03.021. Accessed September 30, 2014. 58. Yang F, Chou D, Schweitzer P, Hanon S. Warfarin in haemodialysis patients with atrial fibrillation: what benefit? Europace. 2010;12(12):1666-1672. 59. Culebras A, Messe SR, Chaturvedi S, Kase CS, Gronseth G. Summary of evidence-based guideline update: prevention of stroke in nonvalvular atrial fibrillation: report of the Guideline Development

508

60.

61.

62.

63.

64.

65.

66.

67.

68. 69. 70.

El Husseini et al

Subcommittee of the American Academy of Neurology. Neurology. 2014;82(8):716-724. Kleinow ME, Garwood CL, Clemente JL, Whittaker P. Effect of chronic kidney disease on warfarin management in a pharmacistmanaged anticoagulation clinic. J Manag Care Pharm. 2011;17(7): 523-530. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10): 883-891. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11): 981-992. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151. Wagner J, Jhaveri KD, Rosen L, Sunday S, Mathew AT, Fishbane S. Increased bone fractures among elderly United States hemodialysis patients. Nephrol Dial Transplant. 2014;29(1):146-151. Eikelboom JW, O’Donnell M, Yusuf S, et al. Rationale and design of AVERROES: apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment. Am Heart J. 2010;159(3): 348-353.e1. Eikelboom JW, Connolly SJ, Gao P, et al. Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease. J Stroke Cerebrovasc Dis. 2012;21(6):429-435. Hohnloser SH, Hijazi Z, Thomas L, et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J. 2012;33(22):2821-2830. Palmer SC, Di Micco L, Razavian M, et al. Antiplatelet agents for chronic kidney disease. Cochrane Database Syst Rev. 2013;2:CD008834. Floege J, Schlieper G. Chronic kidney disease: how effective and safe are antiplatelet agents in CKD? Nat Rev Nephrol. 2013;9(6):314-316. AbuRahma AF, Srivastava M, Chong B, Dean LS, Stone PA, Koszewski A. Impact of chronic renal insufficiency using serum creatinine vs glomerular filtration rate on perioperative clinical out-

71.

72.

73.

74.

75.

76.

77.

78.

79.

comes of carotid endarterectomy. J Am Coll Surgeons. 2013;216(4): 525-532. discussion 532-533. Adil M, Saeed F, Qureshi A. Carotid Artery Stent Placement and Carotid Endarterectomy in Patients with Dialysis Dependent Renal Failure. Neurology. 2014;82(suppl 10):P7. 167-P7. Nikolic D, Banach M, Nikfar S, et al. A meta-analysis of the role of statins on renal outcomes in patients with chronic kidney disease. Is the duration of therapy important? Int J Cardiol. 2013;168(6): 5437-5447. Strippoli GF, Navaneethan SD, Johnson DW, et al. Effects of statins in patients with chronic kidney disease: meta-analysis and metaregression of randomised controlled trials. BMJ. 2008;336(7645): 645-651. Erickson KF, Japa S, Owens DK, Chertow GM, Garber AM, Goldhaber-Fiebert JD. Cost-effectiveness of statins for primary cardiovascular prevention in chronic kidney disease. J Am Coll Cardiol. 2013;61(12):1250-1258. Ridker PM, MacFadyen J, Cressman M, Glynn RJ. Efficacy of rosuvastatin among men and women with moderate chronic kidney disease and elevated high-sensitivity C-reactive protein: a secondary analysis from the JUPITER (Justification for the Use of Statins in Prevention-an Intervention Trial Evaluating Rosuvastatin) trial. J Am Coll Cardiol. 2010;55(12):1266-1273. Tonelli M, Moye L, Sacks FM, et al. Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency. Ann Intern Med. 2003;138(2):98-104. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011;377(9784):2181-2192. Barylski M, Nikfar S, Mikhailidis DP, et al. Statins decrease all-cause mortality only in CKD patients not requiring dialysis therapy—a meta-analysis of 11 randomized controlled trials involving 21,295 participants. Pharmacol Res. 2013;72:35-44. Palmer SC, Navaneethan SD, Craig JC, et al. HMG CoA reductase inhibitors (statins) for dialysis patients. Cochrane Database Syst Rev. 2013;(9):CD004289.