Risk Stratification and Treatment of Coronary Disease in Chronic Kidney Disease and End-Stage Kidney Disease

Risk Stratification and Treatment of Coronary Disease in Chronic Kidney Disease and End-Stage Kidney Disease D1X XGautam R. Shroff, MBBS, FACC,D2X X* and D3X XTara I. Chang, MD, MSD4X†X Summary: Patients with advanced chronic kidney disease have an enormous burden of cardiovascular morbidity and mortality, but, paradoxically, their representation in randomized trials for the evaluation and management of coronary artery disease has been limited. Clinicians therefore are faced with the conundrum of synergizing evidence from observational studies, expert opinion, and extrapolation from the general population to provide care to this complex and clinically distinct patient population. In this review, we address clinical risk stratification of patients with chronic kidney disease and end-stage kidney disease using traditional cardiovascular risk factors, noninvasive functional and structural cardiac imaging, invasive coronary angiography, and cardiovascular biomarkers. We highlight the unique characteristics of this population, including the high competing risk of all-cause mortality relative to the risk of major adverse cardiac events, likely owing to important contributions from nonatherosclerotic mechanisms. We further discuss the management of coronary artery disease in patients with chronic kidney disease and endstage kidney disease, including evidence pertaining to medical management, coronary revascularization with percutaneous coronary intervention, and coronary artery bypass grafting. Our discussion includes considerations of drugeluting versus bare metal stents for percutaneous coronary intervention and off-pump versus on-pump coronary artery bypass graft surgery. Finally, we address currently ongoing randomized trials, from which clinicians are optimistic about receiving guidance regarding the best strategies to incorporate into their practice for the evaluation and management of coronary artery disease in this high-risk population. Semin Nephrol 38:582−599 Ó 2018 Elsevier Inc. All rights reserved. Keywords: Heart disease, renal disease, cardiac stress testing, revascularization, coronary artery disease, mortality

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atients with chronic kidney disease (CKD) represent a unique population with a disproportionately high burden of cardiovascular (CV) disease, including coronary artery disease (CAD), compared with the general population. Based on data obtained from the United States Renal Data System (USRDS), the prevalence of CV disease among CKD versus non-CKD patients (age, >66 y) was 66% versus 32%, respectively, in 2015.1 Similarly, the prevalence of CAD was more than two-fold higher among the CKD versus the nonCKD population (39% versus 16%). Among patients with end-stage kidney disease (ESKD) on hemodialysis, the prevalence of CV disease and CAD also is considerable, estimated at 70% and 42%, respectively. The presence of CKD is associated with higher rates of all-cause mortality as well as major adverse CV events (MACE) compared with the general population. With progressive worsening in estimated glomerular filtration rate (eGFR), Go et al showed a graded increase in the

*Division of Cardiology, Department of Medicine, Hennepin County Medical Center, University of Minnesota School of Medicine, Minneapolis, Minnesota y Division of Nephrology, Stanford University School of Medicine, Palo Alto, California Financial disclosure and conflict of interest statements: none. Address reprint requests to Gautam R. Shroff, MBBS, FACC, Division of Cardiology, Department of Medicine, Hennepin County Medical Center, 701 Park Ave S, Minneapolis, MN 55415. E-mail: [email protected] 0270-9295/ - see front matter © 2018 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.semnephrol.2018.08.004

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hazards of all-cause mortality and MACE.2 Compared with individuals with an eGFR greater than 60 mL/min/ 1.73 m2, adjusted hazard ratios (HRs) for all-cause mortality were 1.2 (95% confidence interval [CI], 1.1-1.2) for those with an eGFR of 45 to 59 mL/min/1.73 m2; 1.8 (95% CI, 1.7-1.9) for an eGFR of 30 to 44 mL/min/ 1.73 m2; and 3.2 (95% CI, 3.1-3.4) for an eGFR of 15 to 29 mL/min/1.73 m2, respectively. A similar independent, inverse, graded association also was noted between worsening eGFR and MACE.2 In a collaborative meta-analysis of 14 studies (105,872 participants), Matsushita et al3 showed that an eGFR less than 60 mL/min/1.73 m2 and proteinuria were independently and multiplicatively predictive of mortality. Compared with an eGFR of 95 mL/min/1.73 m2, the adjusted HR for all-cause mortality for an eGFR of 60 mL/min/1.73 m2 was 1.18 (95% CI, 1.05-1.32); whereas it was 1.57 (95% CI, 1.39-1.78) for an eGFR of 45 mL/min/1.73 m2 and of 3.14 (95% CI, 2.39-4.13) for an eGFR of 15 mL/min/1.73 m2. A similar graded increasing mortality hazard was noted with increasing albumin creatinine ratios.3 The presence of CKD adversely impacts survival in the context of a diagnosis of CAD. Between 2014 and 2015, 2-year survival with prevalent CAD was 76% among those with CKD compared with 87% among those without CKD.1 All-cause mortality and CV mortality peak in the ESKD population and are nearly 10-fold higher relative to the non-CKD population.4 Per USRDS data, for ESKD patients between 65 and 74 years of age in 2014, the annual adjusted mortality rates for dialysis patients were 211 to 223 per 1,000 patient-years and 60 to 66 per 1,000

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patient-years for kidney transplant recipients, compared with 18 to 27 per 1,000 patient-years for the general Medicare population.1 Approximately 48% of deaths occurring among dialysis patients are attributed to CV disease (combination of arrhythmias/sudden death, congestive heart failure, acute myocardial infarction [MI], and atherosclerotic heart disease).1 In a randomized trial of ESKD patients on hemodialysis with adjudicated clinical end points, 54% of all deaths were attributed to CV disease; of which a majority (nearly 25%) were ascribed to sudden death5: MI and heart failure/cardiogenic shock accounted for approximately 4% each, whereas non-CV causes were responsible for 46% of the total deaths. Given the strong epidemiologic association with premature advanced CV disease, CKD is considered an important risk factor for the development of CV disease.4 Indeed, patients with predialysis CKD have a higher likelihood of mortality from CV causes than eventual progression to ESKD; and, in fact, with worsening CKD, the likelihood of death is higher than MACE.6,7 The pathophysiological factors responsible for this association are not completely understood. Tangri et al8 hypothesized a multifaceted interplay between three cardinal processes: accelerated coronary atherosclerosis (intimal plaques), arteriosclerosis (including medial calcification or M€onckeberg’s sclerosis from calcium/phosphorus dysmetabolism), and left ventricular (LV) hypertrophy/dysfunction. Interestingly, an evolving body of evidence suggests that nonatherosclerotic mechanisms increasingly may be responsible for CV events with worsening kidney function.9,10 Factors responsible for the high CV mortality burden transition from predominantly atherosclerotic mechanisms in advanced CKD to predominantly nonatherosclerotic mechanisms in ESKD.10 This observation has important implications in the diagnostic evaluation and management of these high-risk patients. This review focuses on the evaluation and management of CAD in this complex population; the reader is referred to other detailed reviews11,12 regarding non-CAD contributors toward CV morbidity.

RISK STRATIFICATION FOR CAD IN CKD In an attempt to mitigate the high risk of CV events in patients with advanced CKD, clinicians continue to grapple with efforts to identify accurate methods to evaluate flowlimiting CAD, and to determine how best to manage CAD once identified. The principal tenets of risk stratification for CAD comprise clinical assessment using conventional CV risk factors, noninvasive evaluation with functional stress testing or cross-sectional/structural assessment, invasive coronary angiography (ICA), and use of CV biomarkers. Clinical Risk Stratification for CAD in CKD Risk stratification using conventional risk factors and other clinical variables is the first clinical step when

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assessing an individual’s risk of CAD. However, the contribution of traditional risk factors toward the development of atherosclerotic CAD in CKD is not well delineated. In addition, traditionally used instruments such as the Framingham risk score have been shown to have poor predictive accuracy to detect cardiac events in the context of CKD.13 Consequently, there is significant variability in societal recommendations regarding variables used for clinical risk stratification for cardiac evaluation in this population, particularly for kidney transplant candidates (Table 1). Several studies have used clinical variables to risk-stratify CKD patients into low-risk and high-risk groups, to help focus further noninvasive and invasive testing toward the higher-risk group. In their study to assess the utility of dobutamine stress echocardiography (DSE), Rakhit et al14 used three established clinical risk score schemes (Brisbane, Portland, and Framingham), which variably classified 21% to 66% of their study population as low risk. Cardiac events occurred in 2% to 10% of those stratified as low risk; the investigators concluded that DSE did not add incremental value to the risk evaluation in the low-risk subgroup. In a study of myocardial perfusion scintigraphy (MPS), Kim et al15 discerned low-risk versus highrisk groups using the following variables (age >50 y; diabetes mellitus [DM] >10 y; prior history of CAD or an abnormal electrocardiogram; decreased LV ejection fraction < 40% or regional wall motion abnormality on echocardiography; and ≥ 2 traditional CAD risk factors such as hypertension, dyslipidemia, smoking, LV hypertrophy, or family history of premature CAD). Although MPS was useful in incremental risk stratification in the high-risk group, the cardiac event rate in the low-risk group using the earlier-described criteria was low (1.2% per person-year) and did not warrant further risk stratification by imaging. Thus, clinical criteria can be used for initial risk stratification and serve as a gatekeeper to determine the need for further noninvasive or invasive testing. The 2012 guidelines by the American Heart Association/American College of Cardiology Foundation recommend consideration of noninvasive stress testing of kidney transplant candidates in the presence of three or more CAD risk factors (DM, prior CV disease, >1 year on dialysis, LV hypertrophy, age >60 years, smoking, hypertension, and dyslipidemia).16 Noninvasive Imaging for Risk Stratification for CAD in CKD The usual principles used for noninvasive imaging for CAD in the non-CKD population cannot be extrapolated routinely to the CKD population without an understanding of some key nuances. The preponderance of literature describes noninvasive testing in asymptomatic advanced CKD patients, either at onset of dialysis or as a key step in their comprehensive evaluation for candidacy for

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kidney transplantation. This constitutes a departure from the approach in the general population, wherein accuracy of stress testing generally is described in the context of symptoms concerning for CAD. It cannot be overstated that individuals identified as being potential or actual kidney transplant candidates comprise a preselected group of CKD patients; findings in this population may not be applicable to the broader CKD/ESKD population. In general, the dictum regarding noninvasive stress testing in the general population is to pursue exercise (treadmill or bike) testing when feasible, which can provide information pertaining to exertional symptoms and functional status coupled with imaging for myocardial ischemia/infarction. However, the high prevalence of exercise intolerance in the CKD population results in a higher likelihood of nondiagnostic exercise tests because of inability to achieve the age-predicted target heart rate. As a result, the noninvasive diagnostic tests studied most extensively in this population are pharmacologic stress tests (ie, MPS and DSE). Several studies have attempted to evaluate the accuracy of stress testing in this population, but were limited by widely varying estimates of sensitivity/specificity, likely reflecting inclusion of

varying patient populations with differing pretest probabilities for CAD, differences in techniques of test performance/expertise in test interpretation, and, importantly, differences in cut-off values for the determination of angiographically significant obstructive CAD. It is relevant for the reader to recognize these variables when appraising the literature for stress testing in this population. In a systematic study by Wang et al17 published in 2011, specifically comparing noninvasive cardiac testing of kidney transplant candidates with ICA, a total of 22 studies were identified. Of these studies, 11 studies of DSE (690 participants) and 7 studies of MPS (317 participants) were identified. In an updated systematic review assessing test performance of noninvasive cardiac testing in predicting hard clinical end points, Wang et al18 identified a total of 52 studies with 7,401 participants, comprising 11 studies of DSE (1,211 participants) and 25 studies of MPS (3,336 participants). Although a detailed review of all the earlier-described studies is beyond the scope of this article, we discuss representative studies that help identify salient take-home pointers for the clinician.

Table 1. Variations in Published Recommendations for Clinical Risk Stratification for Evaluation for CAD in Asymptomatic Kidney Transplant Candidates Reference

Recommendations

2012 AHA Scientific Statement

Noninvasive stress testing may be considered in kidney transplantation candidates with no active cardiac conditions on the basis of the presence of multiple CAD risk factors regardless of functional status (class IIb, Level of Evidence C) Relevant risk factors among transplantation candidates include DM, prior cardiovascular disease, >1 y on dialysis, LV hypertrophy, age >60 y, smoking, hypertension, and dyslipidemia; the specific number of risk factors that should be used to prompt testing remains to be determined, but the committee considers ≥ 3 to be reasonable No testing recommended if functional status ≥ 4 METS If functional status <4 METS or unknown, then consideration of noninvasive stress testing is recommended based on the following clinical risk factors: ischemic heart disease, compensated or prior heart failure, DM, renal insufficiency, cerebrovascular disease Recommendations for testing are stronger if ≥ 3 clinical risk factors are present but may be considered in those with 1-2 risk factors Acknowledges that there are no data establishing that screening of asymptomatic patients in itself prevents cardiac events; noninvasive and/or invasive testing should be considered in highest-risk patients with the following conditions: DM, prior cardiovascular disease, multiple cardiac risk factors (such as >1 y on dialysis, LV hypertrophy, age >60 y, smoking, hypertension, and dyslipidemia) Does not specify the number of risk factors to justify testing Noninvasive stress testing is recommended for the following: all patients with diabetes, repeat every 12 months; all patients with prior CAD; if not revascularized, repeat every 12 months; if prior PCI, repeat every 12 months; if prior CABG, repeat after first 3 years and then every 12 months; repeat every 24 months in high-risk nondiabetic patients defined as ≥ 2 traditional risk factors, known history of CAD, LVEF ≤ 40%, peripheral vascular disease Noninvasive stress testing recommended for patients at high risk, defined as renal disease from diabetes, prior history of ischemic heart disease, or ≥ 2 risk factors Coronary angiography for possible revascularization before transplantation recommended for patients with a positive stress test Revascularization before transplantation recommended for patients with critical coronary lesions Thallium scanning recommended for patients with a history of myocardial infarction or high-risk clinical features Coronary angiography recommended if thallium scanning is positive Revascularization advised if lesions are suitable

2007 ACC/AHA Perioperative Guidelines for Noncardiac Surgery

2007 Lisbon Conference

2005 NKF/KDOQI Guidelines

2001 AST Guidelines

2000 European Best Practice Guidelines

Abbreviations: ACC, American College of Cardiology; AHA, American Heart Association; AST, American Society of Transplantation; KDOQI, Kidney Disease Outcomes Quality Initiative; LVEF, left ventricular ejection fraction; METS, metabolic equivalent tasks. Adapted with permission from Lentine et al.16

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Figure 1. (A) Hazard of annual risk of cardiac death stratified by CKD (grades of eGFR) and degree of abnormality on MPS (using SSS). The trend was significantly worse for patients with CKD (P < .05 across SSS categories and between different strata of kidney function). Notably, patients with an eGFR less than 30 mL/min undergoing MPS with an SSS score of less than 4 had a 4.7% annual risk of cardiac death, compared with 1% with similar MPS results in those with an eGFR greater than 60 mL/min. Adapted with permission from Hakeem et al.21 (B) Annual hazard of cardiac death stratified by the presence of scar or ischemia on MPS and further stratified by CKD (using eGFR). The presence of ischemia, followed by scar, was strongly predictive of cardiac death compared with normal scans (P < .05). The bar diagram underscores the increasing annual risk of cardiac death despite normal MPS with a decreasing eGFR. Abbreviation: SSS, summed stress score. Adapted with permission from Hakeem et al.21

MPS in CKD MPS using single-photon emission computed tomography (SPECT) is widely used for noninvasive risk stratification for CAD worldwide. Pharmacologic agents such as adenosine, regadenoson, dipyridamole, and dobutamine can be coupled with SPECT for performing MPS. Adenosine/regadenoson lead to vasodilation of

the resistance coronary arterioles, thereby increasing coronary flow reserve (CFR) and unmasking epicardial coronary stenosis. MPS has established prognostic accuracy in multiple populations,19,20 but it often is not well appreciated that the presence of CKD affects the diagnostic and prognostic accuracy of MPS. Hakeem et al21 performed a retrospective analysis of 1,652 patients

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undergoing stress MPS (68% adenosine, 32% exercise) at a single institution. The investigators further stratified outcomes based on the strata of CKD and the extent of perfusion abnormality noted on MPS (using the summed stress score [SSS]). The prevalence of CKD (eGFR, <60 mL/min/1.73 m2) was 36%. Strikingly, patients with normal MPS and CKD had a significantly higher cardiac death rate compared with those with normal MPS without CKD (2.7% versus 0.8%; P = .001) (Fig. 1). In multivariate analysis, the presence of CKD (HR, 1.96; 95% CI, 1.29-2.95) and perfusion defects on MPS (HR, 1.9; 95% CI, 1.47-2.46) were independently predictive of cardiac death after accounting for variables such as clinical risk factors, LV dysfunction, and symptom status. Of note, the annual all-cause mortality rate was significantly higher in the CKD group versus the non-CKD group (12.5% versus 6.5%; P < .0001). In a risk-adjusted Kaplan-Meier survival analysis, patients with an eGFR less than 60 mL/min/1.73 m2 and an abnormal MPS (SSS, >4) had worse survival rates compared with all other groups (log-rank P < .001). Interestingly, the survival probability of patients with CKD/normal MPS was not different from those without CKD/abnormal MPS (log-rank P = .18). In conclusion, MPS provided incremental risk stratification across the entire spectrum of kidney function, but CKD itself was an independent predictor of cardiac death in those undergoing MPS. Bhatti et al22 performed a follow-up study to assess prognosis in patients with varying degrees of CKD with MPS using the selective A2A-receptor antagonist regadenoson. The investigators evaluated 1,107 patients; 38.4% were diagnosed with CKD (eGFR, <60 mL/min/1.73 m2) and 1.3% had ESKD. The investigators reported an incremental increase in risk of all-cause death with worsening perfusion abnormalities on MPS in the CKD as well as in the non-CKD groups. However, it was remarkable that despite a negative MPS study (SSS <4), the risk of all-cause mortality was significantly higher in the CKD versus non-CKD group (6.2% versus 1.9%). Smaller studies have evaluated the role of performing MPS in asymptomatic ESKD patients at the beginning of dialysis. Kim et al15 evaluated 215 asymptomatic patients initiating dialysis at a single institution and followed up for the development of cardiac events (cardiac death, nonfatal MI, heart failure requiring hospitalization). The population was stratified further by clinical factors such as low risk (n = 50) and high risk (n = 165). In follow-up evaluation, the high-risk group with perfusion defects on MPS (46%) had a significantly higher rate of development of future cardiac events per personyear of follow-up evaluation (15%) versus the high-risk group without perfusion defects (4.5%) versus the lowrisk group (1.2%). In the high-risk group, compared with baseline clinical data, the addition of echocardiography data improved prediction of cardiac events, and the

addition of MPS data further improved the prognostic capability. These studies indicate that MPS provides incremental prognostic data for risk stratification beyond clinical risk factors among CKD patients. Despite prognostic capability, there has been concern about the reduced overall accuracy of MPS in detecting obstructive CAD in CKD.23,24 The mechanisms underlying the relatively lower diagnostic performance of MPS in CKD compared with the general population likely are multifactorial, and hypothesized to be secondary to a higher prevalence of obstructive CAD, significant LV hypertrophy, endothelial dysfunction, and reduced coronary flow reserve.25 Although these findings could be representative of reduced sensitivity of MPS to detect future CV events, they also could be illustrative of a higher burden of nonatherosclerotic/non-CAD deaths in this population that cannot be recognized by stress testing.10 Overall, these studies exemplify the challenge for the clinician to reconcile the high risk of allcause mortality in patients with CKD despite reassuring findings on MPS. DSE in CKD

DSE harnesses the inotropic and chronotropic properties of dobutamine to identify inducible segmental or global LV dysfunction, and typically is performed with supplemental atropine. Interpretation of DSE necessitates significant expertise to ensure accurate interpretation of inducible regional dysfunction in the context of hypertrophied LV myocardium under the loading conditions of the study (tachycardia, volume fluctuations in dialysis patients, small LV cavity size). Although generally safe, DSE is associated with the risk of developing arrhythmias (including atrial fibrillation) and hypertension. Rakhit et al14 used an interesting study design by initially risk-stratifying patients with CKD (n = 244; 169 on permanent dialysis) into low-risk and high-risk categories based on conventional risk calculators before performing DSE for all patients. Patients were followed up for a duration of 20 § 14 months for the development of adverse clinical outcomes (death, MI, acute coronary syndrome). In the entire cohort, 20% of patients died and 13% had a clinical event. In the high-risk group based on the Framingham classification (37% of the cohort), a higher proportion had a cardiac event with abnormal DSE compared with normal DSE (31% versus 8%; P = .01). However, DSE was not predictive of mortality in the high-risk cohort (38% in abnormal DSE group versus 21% in the normal DSE group; P = .07). Similarly, in the low-risk group based on the Framingham classification (63% of the cohort), 30% had an abnormal DSE, which was not predictive of mortality (13% in abnormal DSE versus 16% in the normal DSE group; P = .6) or future cardiac event (15% in abnormal DSE versus 7% in normal DSE group; P = .1).

Coronary disease in CKD and ESKD

Bergeron et al7 performed a retrospective analysis of patients with CKD (creatinine level >3 mg/dL or on dialysis) who underwent DSE at a single institution. A total of 485 patients (4.6% of the total DSE studies performed over a span of 10 years) with CKD underwent DSE. During a follow-up duration of 2.3 years (§1.8 y), 39% patients died and 33% underwent kidney transplantation. In a multivariate model, the percentage of ischemic segments on DSE, peak heart rate during DSE, and resting LV ejection fraction were strong independent predictors of mortality. One-year survival varied from 88% with normal DSE to 77% with extensive ischemia. The presence of mild to moderate ischemia (<25% ischemic segments) and severe ischemia (>25%

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ischemic segments) had a significantly increased hazard of 1.58 (95% CI, 1.08-2.33; P = .02) and 2.01 (95% CI, 1.37-2.96, P < .001) compared with normal DSE, respectively. These studies show that the percentage of ischemic segments during DSE in CKD patients is independently predictive of mortality and provides prognostic information incremental to clinical data. However, these studies also exemplify the inherent challenge with this population, ie, the risk of all-cause mortality is higher than the risk of MACE, and may not be reliably predictable despite normal findings on DSE, perhaps owing to a higher proportion of nonatherosclerotic mechanisms.

Figure 2. Receiver operating characteristic curves to estimate the post-test probabilities of obstructive CAD in renal transplant candidates. DSE had a positive likelihood ratio of 6.44 (95% CI, 3.03-13.7) and a negative likelihood ratio of 0.26 (95% CI, 0.13-0.5). MPS had a positive likelihood ratio of 2.89 (95% CI, 1.39-5.99) and a negative likelihood ratio of 0.43 (95% CI, 0.23-0.8). Adapted with permission from Wang et al.24

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Comparison of MPS Versus DSE in CKD

Because a majority of the literature focuses on MPS and DSE for noninvasive stress testing in CKD, clinicians need guidance to determine which modality to choose for an individual patient. Wang et al24 performed a systematic analysis to compare the diagnostic accuracy of MPS versus DSE to detect obstructive CAD compared with ICA among potential kidney transplant recipients. In a pooled analysis, DSE had a sensitivity and specificity of 79% and 89%, respectively; whereas for MPS they were 74% and 70%, respectively. In a head-to-head comparison, the investigators reported that DSE had improved accuracy (P = .02) compared with MPS (Fig. 2); but there was no significant difference when the analysis was limited to studies in which the ICA reference was stenosis of 70% or greater (P = .09). Importantly, absence of concern regarding flow-limiting CAD on preoperative noninvasive testing did not necessarily correlate with event-free survival after transplantation. To evaluate the association of imaging studies with outcomes, Wang et al18 performed a follow-up quantitative meta-analysis involving 7,401 participants from 52 published studies. They compared the accuracy of preoperative abnormal MPS, DSE, or ICA in predicting outcomes of all-cause mortality, CV mortality, and MACE.18 When considering the risk of all-cause mortality, the predictive capability of ICA was marginally superior compared with both MPS (relative risk ratio [RRR], 0.69; 95% CI, 0.49-0.96; P = .03) and DSE (RRR, 0.72; 95% CI, 0.5-1.02; P = .06). However, in regard to the risk of CV mortality, there was no difference in the predictive capability of ICA relative to MPS (RRR, 0.89; 95% CI, 0.38-2.1; P = .78) or DSE (RRR, 1.09; 95% CI, 0.12-10.05; P = .93). Similarly, the risk of MACE did not vary significantly between those receiving ICA versus noninvasive evaluation by MPS or DSE. The investigators concluded that noninvasive imaging and ICA had similar predictive accuracy to identify future adverse CV events in advanced CKD, and that a significant proportion of transplant candidates experience adverse events despite negative tests results.

Positron Emission Tomography in ESKD

A decrease in CFR or the presence of coronary microvascular disease is a putative hypothesis to explain the high burden of CV morbidity in ESKD. To explore this hypothesis, Shah et al26 evaluated CFR noninvasively in 168 consecutive ESKD patients referred to a single center using positron emission tomography imaging. This population had an annual unadjusted mortality rate of approximately 10%. Allcause mortality was significantly higher among those with a reduced global CFR ( ≤ 1.4) compared with those with a global CFR greater than 1.4 (CFR values >2 generally are

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considered low risk in the general population). Global CFR was identified as an independent predictor of all-cause mortality in a multivariate model, and also improved the net reclassification index for predicting CV mortality. These findings suggest a potential role of quantifying global CFR using positron emission tomography imaging to risk-stratify ESKD patients at higher risk of future all-cause and CV mortality, if reproduced in larger studies. Coronary Artery Calcium and Coronary Computed Tomography Angiography in CKD

In the general population, absence of coronary artery calcium (CAC) has a high negative predictive value (NPV) for excluding significant angiographic CAD, and coronary computed tomography angiography (CCTA) has a high NPV for excluding CAD in low-intermediate−risk patients presenting with symptoms of chest discomfort. There has been skepticism about the prognostic utility of CAC monitoring in advanced CKD/ESKD patients owing to high prevalence, high scores, and rapid progression of CAC.27 The presence of significant medial calcification of coronary arteries (versus intimal calcification in typical atherosclerotic plaques) likely contributes to the high prevalence of CAC in this population. Raggi et al28 evaluated a population of 205 hemodialysis patients and reported a high prevalence of CAC (83%) with a high median score of 595; however, CAC correlated significantly with the prevalence of MI and angina. However, a small study by Sharples et al29 suggested concern about the lack of correlation of CAC with ICA. Over the past few years, a notable paradigm shift has occurred in noninvasive risk stratification of patients with CKD in the context of evaluation before kidney transplantation. The focus of the literature has transitioned from a traditional emphasis on functional modalities (ie, DSE, MPS) to structural coronary evaluation (eg, CAC, CCTA) for coronary risk stratification. Winther et al23 conducted a prospective study with a unique design in which 138 patients referred for pretransplant cardiac evaluation underwent imaging with CAC, CCTA, MPS, and ICA. Unfortunately, this study did not include an arm undergoing imaging by DSE. The overall prevalence of obstructive CAD was 22% (defined as ≥ 50% narrowing on ICA). In a patient-level analysis, the sensitivity and specificity of diagnosing obstructive CAD by noninvasive evaluation were 67% and 77% for coronary artery calcium score, 93% and 63% for CCTA, and 53% and 82% for MPS, respectively (Fig. 3). The investigators concluded that CCTA is a reliable test with a high NPV for diagnosing obstructive CAD in this population. In a follow-up publication with the same cohort, the investigators reported that receiver operating curves for CAC were higher than for conventional CV risk factors.30 They further concluded that CAC had a higher

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Figure 3. Diagnostic performance of imaging modalities in comparison with invasive coronary angiography in kidney transplant candidates. SPECT had a sensitivity of 53% and a specificity of 82%, whereas coronary CTA had a sensitivity of 93% and a specificity of 63%. The combination of coronary CTA/SPECT had a sensitivity of 67% and a specificity of 86%. Abbreviations: CACS, coronary artery calcium score; CTA, computed tomography angiography; PPV, positive predictive value; SPECT, single-photon emission computed tomography. Reprinted with permission from Winther et al.23

sensitivity than MPS and comparable specificity. Finally, to parse out the predictive capability of CV risk factors versus imaging modalities for future clinical events, Winther et al6 reported that in an average follow-up period of 3.7 years, 17.5% of patients experienced MACE whereas 20% died. Although CCTA and ICA predicted MACE, only CCTA predicted mortality, and MPS predicted neither MACE nor mortality. These investigators recommended a strategy involving CAC or CTA as the preferred modality for risk stratification for CAD among kidney transplant candidates compared with other imaging modalities or CV risk factors. Interestingly, there was no substantial increase in risk of contrast nephropathy following CCTA in this setting.31 We hope that others will prospectively compare these structural versus functional imaging modalities in future studies. Meanwhile, we hope that clinicians will need to reconcile the intriguing conclusions by this single-center study with those of large MPS studies that have shown beneficial effects in predicting MACE, including cardiac death, in this population.21,22

ICA for Risk Stratification for CAD in CKD In epidemiologic studies, the prevalence of CAD in CKD is estimated at approximately 39% to 42%, as outlined previously.1 The described prevalence of angiographic CAD in clinical studies however, is variable, and contingent upon cut-off values used for angiographic assessment and use of qualitative versus quantitative assessment. By using a cut-off criterion of 70% or greater stenosis by visual/qualitative assessment on ICA in the context of baseline CV risk factors, De Lima et al32 described an angiographic CAD prevalence of 42% among 150 kidney transplant candidates, whereas Gowdak et al33 reported a prevalence of 45% in 301 hemodialysis patients. Charytan et al34 studied a cohort of 67 asymptomatic ESKD patients, in which obstructive CAD ( ≥ 50% stenosis) was reported in 42% based on qualitative assessment. Interestingly, involvement of the proximal third of the epicardial coronary (»70% of patients) was associated with an increased mortality hazard. Marwick et al35 also reported a prevalence of 42%

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(coronary stenosis, >50%) on ICA in a series of 45 patients. Smaller studies from Japan have described a much higher prevalence of obstructive CAD in ESKD, ranging from 53% to 63%, with a high proportion of multivessel disease.36,37 In a more recent cohort of 138 kidney transplant candidates (mean age, 54 y; 43% dialysis; 46% DM), using quantitative ICA, Winther et al23 reported obstructive CAD ( ≥ 50% stenosis) in merely 22%. It bears mention that in the general population, fractional flow reserve estimation, offering both physiological and prognostic information, is the contemporary gold standard for determination of functional significance of qualitatively indeterminate coronary stenosis on ICA. Unfortunately, fractional flow reserve has not been well validated in patients with CKD, and has raised concerns about false-positive results.38 The lack of a validated method of assessing physiological/functional significance of coronary stenosis during ICA constitutes a major limitation, particularly given known shortcomings of qualitative ICA and the oculostenotic reflex. Nevertheless, owing to technical differences in adjudication of obstructive CAD, accuracy limitations in predicting future CV events,18 risks of contrast nephropathy, as well as the inherent risks of an invasive procedure (bleeding, stroke, and so forth), ICA generally is not recommended as a first-line tool for risk stratification in this high-risk population. Role of Biomarkers for Risk Stratification in CKD In patients with CKD, an increase in the cardiac-specific biomarkers troponin (Tn) and natriuretic peptides is associated with an increased risk of long-term mortality. In a meta-analysis involving 98 studies, Michos et al39 reported that elevated Tn levels were associated with an increased risk of all-cause mortality and CV mortality among dialysis patients without suspected acute coronary syndromes. Specifically, the adjusted pooled hazard for all-cause mortality with TnT increase was 3.0 (95% CI, 2.4-4.3), and for TnI increase was 2.7 (95% CI, 1.94.6). Similarly, the pooled adjusted hazards for CV mortality were 3.3 (95% CI, 1.8-5.4) for TnT and 4.2 (95% CI, 2.0-9.2) for TnI, respectively. In a meta-analysis involving 27 studies of ESKD patients, Cheng et al40 reported that an increase in B-type natriuretic peptide or N-terminal pro−B-type natriuretic peptide was associated significantly with increased all-cause mortality (odds ratio [OR], 3.85; 95% CI, 3.11-4.75) and CV mortality (OR, 4.05; 95% CI, 2.53-6.84). In the context of evaluation of kidney transplant candidates, several studies have observed an increased hazard of long-term mortality in association with an increase in pretransplant or baseline TnT levels.41-43 Hickson et al41 reported that increased TnT levels (>0.01 ng/mL) in asymptomatic patients were associated with reduced all-cause survival (HR, 1.73, 95% CI, 1.25-2.39), but not DSE or ICA.

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Similarly, Connolly et al43 reported that a baseline TnT level greater than 0.03 ng/mL was an independent predictor of mortality after adjustment for traditional CV risk factors. In a cohort of 603 kidney transplant recipients from a single institution, Hickson et al42 observed that TnT was increased (>0.01 ng/mL) in 56% of patients, and associated with reduced event-free survival (HR, 1.81; 95% CI, 1.33-2.45). The earlier-described studies exemplify the acumen of CV biomarkers in predicting long-term adverse outcomes, including mortality, in patients with CKD/ESKD. It appears promising that patients without an increase in baseline Tn levels constitute a lower-risk population, thus highlighting its role in clinical risk stratification. A practical conundrum for the clinician remains how best to mitigate the risk of future adverse CV events in an asymptomatic patient identified to be at high risk by virtue of an increase in baseline Tn levels.

RECONCILIATION OF EVIDENCE REGARDING RISK STRATIFICATION FOR CAD Rabbat et al44 performed a pooled meta-analysis to determine the prognostic significance of MPS (thallium) and DSE in kidney transplant candidates for risk stratification. The investigators identified 12 studies in which cardiac outcomes were reported (8 MPS, 4 DSE). In comparison with negative tests, positive imaging tests were associated with a significantly increased relative risk (RR) of cardiac death (RR, 2.92; 95% CI, 1.66-5.1; P < .001) and MI (RR, 2.73; 95% CI, 1.25-5.97; P = .01). The presence of both reversible and fixed defects was associated with a higher risk of cardiac death in diabetic and nondiabetic populations in this study. Hence, noninvasive tests are able to risk-stratify CKD patients/kidney transplant recipients into higher risk versus lower risk categories of future all-cause and CV mortality. The proportion of individuals at risk of adverse events after a normal test is considerably lower than that with an abnormal test. However, although abnormal noninvasive testing is successful in identifying a higher percentage of kidney transplant recipients likely to develop a future adverse CV outcome, a significant proportion of those with normal testing results remain at risk of future adverse outcomes, including mortality. As an example, Wang et al18 reported that the proportion of patients experiencing all-cause mortality was 28% versus 18.2% for abnormal versus normal MPS, 19.6% versus 9.4% for abnormal versus normal DSE, and 33.3% versus 13.4% for abnormal versus normal ICA. On the other hand, the percentage of patients who experienced CV mortality was 11.2% versus 4.4% for abnormal versus normal MPS, 16.4% versus 4.5% for abnormal versus normal DSE, and 24.9% versus 4.1% for abnormal versus normal ICA. Some may take the stance that these data fundamentally challenge the rationale of routine

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performance of cardiac testing (particularly before kidney transplantation) because all tests have modest accuracy in predicting adverse outcomes. An important lesson learned from these studies, however, is that a significant proportion of the advanced CKD population, despite reassuring testing for obstructive CAD, are at risk of future all-cause mortality (9%-18%) and CV mortality (»4%-4.5%).18 These findings most likely signify the susceptibility of these patients to nonatherosclerotic mechanisms of death, including noncoronary CV complications such as heart failure, arrhythmias, as well as non-CV complications such as sepsis and kidney failure.45 Another important factor for clinicians to consider routinely in the evaluation for CAD in this population is the high competing risk of mortality. The absence of significant CAD by CV testing does not necessarily translate into event-free survival after transplantation or in the long term.24

TREATMENT OF CAD IN CKD Once the diagnosis of CAD has been established, the optimal treatment for patients with concomitant CKD is unclear because few trials have focused specifically on this patient population. Most of the evidence available to guide clinical practice is derived from post hoc subgroup analyses or from retrospective observational cohort studies. Comparison across studies also is complicated by the fact that different studies often defined CKD in different ways. Optimal Medical Therapy Patients with advanced CKD are at higher risk of adverse side effects from medications owing to differences in drug metabolism and elimination. Moreover, although a substantial body of evidence has shown that medications such as aspirin, b-blockers, angiotensin-converting enzyme inhibitors (ACEI) or angiotensin-receptor blockers (ARBs), and statins46 reduce CV morbidity and mortality in patients with preserved kidney function, the evidence in patients with advanced CKD or ESKD is less well established. For example, the Heart Outcomes Prevention Evaluation (HOPE) study helped to establish the benefit of ACEI in reducing the rates of death, MI, and stroke among patients with CAD or DM,47 but patients with overt nephropathy were excluded from that trial. Studies of ACEI or ARBs that specifically enrolled patients with established CKD, such as the African American Study of Kidney Disease and Hypertension,48 were designed to examine the progression of CKD rather than the effect on CV outcomes. Although a post hoc analysis of the African American Study of Kidney Disease and Hypertension (AASK) showed no benefit of ramipril over metoprolol or amlodipine on CV outcomes,49 that analysis may have been underpowered to detect any significant differences. Similarly, a randomized trial in patients with

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ESKD on dialysis50 that was designed to examine fatal and nonfatal CV events showed no benefit of fosinopril over placebo (RR, 0.93; 95% CI, 0.68-1.26), but may have been underpowered because the observed event rates were much lower than what had been anticipated. Statins serve as another example of how medication efficacy can differ in patients with advanced CKD compared with patients without CKD. The Study of Heart and Renal Protection (SHARP)51 showed that reduction of low-density lipoprotein cholesterol with simvastatin 20 mg plus ezetimibe 10 mg/d reduced the incidence of atherosclerotic events among patients with CKD (plasma creatinine level, >1.7 mg/dL in men or >1.5 mg/dL in women). However, three well-conducted randomized clinical trials of statins in patients with ESKD on dialysis (ie, the German Diabetes and Dialysis [4D] Study, A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events [AURORA] and a prespecified subgroup of SHARP 51-53) showed no benefit of statins in reducing CV events or death, despite decreasing serum low-density lipoprotein levels. There is even a concern that statins may hasten the already accelerated process of vascular calcification in ESKD.54 Given the relative paucity of data to suggest otherwise, the use of aspirin, ACEI/ARBs, and b-blockers as part of medical therapy for CAD is reasonable in patients with CKD/ESKD, with careful monitoring for adverse events such as hyperkalemia or acute-on-chronic kidney injury. In regard to lipid management, current Kidney Disease: Improving Global Outcomes guidelines55 recommend treating all patients age 50 years and older with an eGFR less than 60 mL/min/1.73 m2 who are not yet on dialysis with statins or a statin/ezetimibe combination, but do not recommend initiating statins for patients on dialysis. However, they suggest continuing statins in patients with CKD who progress to ESKD while receiving them, based on level C (low-quality) evidence. Coronary Revascularization in Patients With CKD Current American College of Cardiology/American Heart Association guidelines46,56 provide detailed recommendations for proceeding with coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI), depending on the anatomic setting (eg, unprotected left main disease), number of involved vessels, and clinical scenario (eg, survivors of sudden cardiac death with presumed ischemia-mediated ventricular tachycardia). However, much like the randomized clinical trials of optimal medical therapy as noted earlier, few, if any, patients with advanced CKD were included in trials of coronary revascularization, and patients with ESKD were excluded.

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Comparison of Coronary Revascularization With Optimal Medical Therapy

Current evidence on the relative effectiveness of coronary revascularization versus optimal medical therapy in advanced CKD is derived from post hoc analyses of randomized trials or from observational studies. For example, the Clinical Outcomes Utilization Revascularization and Aggressive Drug Evaluation (COURAGE) trial found no difference in death and nonfatal MI among 2,287 patients with myocardial ischemia and stable CAD randomized to undergo PCI with optimal medical therapy (metoprolol succinate, amlodipine, and isosorbide mononitrate, alone or in combination; ACEI or ARB; and statin § ezetimibe) or optimal medical therapy alone (HR, 1.05; 95% CI, 0.98-1.27).57 A post hoc analysis of the 320 COURAGE participants with baseline CKD (defined as an eGFR <60 mL/min/1.73 m2) showed similar results (HR, 1.05; 95% CI, 0.09-1.16) to the main trial results.58 Similarly, a re-analysis of the Medical, Angioplasty or Surgery Study (MASS) II, which randomized patients with multivessel CAD, stable angina, and preserved LV function to optimal medical therapy, PCI, or CABG, found no differences in survival or CV events among the three treatment groups in patients with CKD (n = 150; defined as an eGFR <60 mL/min/ 1.73 m2).59 However, with the small sample size in that cohort, the analysis likely was underpowered. An observational study examined patients with documented CAD undergoing cardiac catheterization from a single center in the United States, and compared outcomes among patients treated with medical therapy only, CABG, or PCI.60 That analysis found that for patients with creatinine clearance (CrCl) of 30 to 59 mL/min (N = 917), revascularization with CABG or PCI was associated with better survival than medical therapy alone (HR, 0.43; 95% CI, 0.33-0.55; HR, 0.75; 95% CI, 0.58-1.74, respectively). For patients with more advanced CKD (CrCl, 15-29 mL/min; N = 107), PCI was no better than medical therapy (HR, 1.00; 95% CI, 0.581.74), but CABG was associated with a very large survival benefit (HR, 0.45; 95% CI, 0.27-0.74). A similar beneficial association of CABG (but not PCI) over medical treatment alone in patients with CKD (defined as serum creatinine level >2.3 mg/dL; N = 750) was reported in an observational study using a Canadian database.61 Although both analyses included careful statistical adjustments, as with all observational studies, residual selection bias remains a concern in the absence of randomized treatment assignment. The ongoing International Study of Comparative Health Effectiveness with Medical and Invasive Approaches—Chronic Kidney Disease (ISCHEMIACKD) trial (Clinicaltrials.gov identifier: NCT01985360) promises to provide more insight into decisions

regarding coronary revascularization versus medical therapy in patients with CKD.62 This trial will evaluate the best management strategy for patients with advanced CKD (eGFR, <30 mL/min or receiving dialysis), stable ischemic heart disease, and at least moderate ischemia on noninvasive testing. The randomized comparators include an invasive arm (cardiac catheterization followed by revascularization with PCI or CABG as determined by the local heart team) versus optimal medical therapy only. The primary outcome is CV death or nonfatal MI. Comparison of CABG With PCI

In general, CABG is associated with higher perioperative and short-term mortality and stroke compared with PCI, but better long-term outcomes among patients with multivessel CAD and preserved kidney function. For example, a meta-analysis of individual patient data from 10 randomized trials comparing CABG with PCI showed similar long-term mortality for patients without diabetes, but lower mortality rates associated with CABG versus PCI for patients with diabetes and for patients older than the age of 65 years63; CABG also was associated with lower rates of MI and repeat revascularization. Similar findings were observed in a separate meta-analysis of 10 randomized trials focused on patients with stages 3 to 5 CKD: CABG conferred better MI-free survival (HR, 0.49; 95% CI, 0.29-0.82) and repeat-revascularization free-survival (HR, 0.21; 95% CI, 0.11-0.39) than PCI, but overall mortality rates did not differ (HR, 0.99; 95% CI, 0.67-1.46). Importantly, many randomized trials did not provide information on baseline kidney function, and of those included in the meta-analysis, the total number of patients with CKD (defined as eGFR <60 mL/min/1.73 m2) was relatively small (N = 425), and only 137 patients had more advanced CKD (defined as an eGFR <45 mL/min/1.73 m2).64 There have been several retrospective observational studies on outcomes with CABG compared with PCI in patients with CKD. Older studies have shown mixed results, but these studies had relatively small sample sizes, which may have led to limited statistical power,6567 or were from the prestent68 or bare-metal stent60,69 era. For example, a post hoc analyses of the Arterial Revascularization Therapies Study67 found no significant difference in mortality in participants with baseline CKD randomized to CABG or PCI (HR, 0.98; 95% CI, 0.402.42; P = .97),69 but the cohort only had 290 patients. In contrast, the study discussed earlier60 showed a survival benefit associated with CABG versus PCI in patients with a CrCl 30 to 59 and 15 to 29 mL/min (N = 917 and 107, respectively). Larger, more recent, observational studies have shown a more consistent beneficial association of CABG

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Figure 4. Adjusted hazard ratios for specified outcomes comparing CABG with PCI as initial treatment for multivessel coronary artery disease by eGFR category (in mL/min/1.73 m2) in propensity score-matched patients. Models adjusted for age, sex, race, Hispanic ethnicity, baseline history of acute MI or unstable angina, medications, smoking status, comorbid conditions, dipstick proteinuria, high-density lipoprotein, low-density lipoprotein, year of procedure, and local health care facility. Abbreviation: ACS, Acute coronary syndrome. Adapted with permission from Chang et al.72

compared with PCI on long-term clinical outcomes in patients with CKD. For example, an analysis using data from a New York state PCI registry of 11,305 patients70 with CKD (defined as an eGFR <60 mL/min/1.73 m2) showed lower associated risks of death, stroke, and repeat revascularization in the short term (30 days) with PCI, but lower risks of MI and repeat revascularization with CABG in the long term. The American College of Cardiology Foundation (ACCF) and The Society of Thoracic Surgeons (STS) Database Collaboration on the Comparative Effectiveness of Revascularization Strategies (ASCERT) showed that in patients 65 years of age or older with multivessel CAD, CABG was associated with lower long-term mortality (RR, 0.79; 95% CI, 0.76-0.82); these results were consistent across eGFR stages.71 Similarly, using a propensity-matched cohort (n = 8,172) from a large integrated health care system with CKD72 (defined as an eGFR <60 mL/min/1.73 m2) and multivessel CAD, CABG was associated with a lower adjusted rate of death than PCI across strata of kidney function (HR, 0.73; 95% CI, 0.56-0.95 for an eGFR of 45-59 mL/min/1.73 m2; and HR, 0.87; 95% CI, 0.67-1.14 for an eGFR <45 mL/min/ 1.73 m2) (Fig. 4). CABG also was associated with significantly lower risks of acute coronary syndrome and repeat revascularization at all levels of eGFR compared with multivessel PCI. For patients with ESKD treated with dialysis, the only available evidence on the comparative effectiveness of

CABG versus PCI comes from observational studies, which generally have favored CABG. In the analysis using the New York state registry data as noted earlier,70 the subgroup of patients on dialysis showed a benefit of CABG compared with PCI for the outcomes of death, MI, and repeat revascularization. An analysis using data from the USRDS of 21,981 patients with ESKD on maintenance dialysis found that multivessel CABG was associated with higher short-term risk of death, but with a significantly lower risk of death compared with multivessel PCI (HR, 0.87; 95% CI, 0.84-0.90) and death or MI (HR, 0.88; 95% CI, 0.86-0.91)73 in the long term. A separate analysis that also used USRDS data similarly found higher in-hospital mortality with CABG, but superior long-term survival and lower risk for repeat revascularization compared with PCI74 in patients with ESKD on dialysis. Comparison of Bare Metal Stents and Drug-Eluting Stents

Numerous clinical trials in patients with preserved kidney function have shown that drug-eluting stents (DES) reduce the use of repeat revascularization compared with bare metal stents (BMS), but the comparative efficacy on the risk of MI and mortality have been less consistent.75,76 For example, a meta-analysis of 76 randomized clinical trials comparing DES and BMS showed that the short-term risk of MI was lower with PCI using DES

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Figure 5. Forest plot adapted from a meta-analysis of 39 studies comparing drug-eluting stents with bare metal stents in patients with CKD. The outcome of major adverse cardiovascular events was stratified by clinically important variables. Adapted with permission from Lu et al.80

relative to BMS, but there was no benefit on short-term mortality.75 For patients with CKD, limited evidence from randomized clinical trials indicated that DES is superior to BMS. A meta-analysis of three randomized clinical trials of sirolimus-eluting stents versus BMS found that patients with CKD (defined as CrCl <60 mL/ min) treated with DES had lower rates of 8-month re-stenosis (9.7% versus 39.7%; P < .001) and 1-year target vessel revascularization rates (5.5% versus 26.9; P < .001); rates of death and MI were not significantly different between the DES and BMS groups.76 However,

patients with serum creatinine levels greater than 3 mg/dL were excluded from those trials. The Randomized Comparison of Xience V and MultiLink Vision Coronary Stents in the Same Multivessel Patient with Chronic Kidney Disease (RENAL-DES) trial enrolled 215 patients with a CrCl less than 60 mL/min, including patients with ESKD on dialysis, and multivessel CAD to receive a DES or BMS.77 The mean CrCl was 47 mL/min, with 10% of the cohort (N = 22) on dialysis. Results from RENAL-DES showed that the incidence of ischemia-driven target vessel

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revascularization at 12 months was 8.7% lower in the DES versus BMS group (2.7% versus 11.4%; P < .001). Differences were even larger for patients with advanced CKD, which included patients with CrCl less than 30 mL/min or who were on dialysis (BMS, 24.2%; DES, 3.1%; absolute risk reduction, 21.1%; P = .005). However, the annual death rate in the RENAL-DES cohort was exceptionally low at only 3.7%, which is much lower than the annual death rates for the general population of patients with CKD and CAD.78 A contemporary retrospective observational study of patients with end-stage renal disease on dialysis using data from the USRDS examined 1-year outcomes among 36,117 patients receiving DES or BMS. By using propensity score matching, the study showed that receipt of DES was associated with an 18% (95% CI, 14%-22%) lower risk of death; a 16% (95% CI, 13%-19%) lower risk of death or MI; and a 13% (95% CI, 9%-16%) lower risk of death, MI, or repeat revascularization compared with BMS.79 Given the nonrandomized nature of that study and ensuing concerns about residual selection bias, Chang et al79 also conducted a temporal analysis that leveraged changes in the prevalence of DES use over different study time periods (transitional, 56% use: April 23, 2003 to June 30, 2004; liberal, 85% use: July 1, 2004 to December 31, 2006; and selective, 62% use: January 1, 2007 to December 31, 2010). Outcomes for PCI with DES were improved significantly from the transitional to the liberal era, but remained similar in the selective era; these observations likely are reflective of greater operator expertise, and beneficial effects of newer-generation DES. Finally, a recent meta-analysis of 38 studies involving 123,396 patients with CKD (including patients with ESKD) found that DES (compared with BMS) was

associated with lower odds of MACE (pooled OR, 0.75; 95% CI, 0.62-0.88), all-cause mortality (OR, 0.81; 95% CI, 0.73-0.90), MI (OR, 0.80; 95% CI, 0.67-0.95), target-lesion revascularization, and target-vessel revascularization.80 Similar results were found among patients with predialysis CKD and ESKD on dialysis (Fig. 5). In conclusion, the use of DES for PCI appears to be effective and safe in patients with CKD/ESKD, and consistently associated with improved outcomes relative to PCI with BMS. Comparison of Off-Pump Versus On-Pump CABG

The practice of performing CABG without the use of a heart−lung bypass (pump) remains a controversial topic among cardiothoracic surgeons. Three randomized clinical trials in the general population81-83 of off-pump versus on-pump CABG showed similar rates of death, stroke, and acute kidney injury requiring dialysis at 30 days, but a higher likelihood of incomplete revascularization with off-pump CABG. Studies on long-term outcomes have shown conflicting results, perhaps owing to differences in surgeon experience and technical skills. Nonetheless, some studies have indicated that patients at higher risk of adverse outcomes may derive a greater benefit from off-pump CABG,84 a group to which patients with CKD and ESKD certainly would belong. Shroff et al85 conducted a large study comparing the effectiveness of off-pump versus on-pump CABG in patients with ESKD on dialysis. By using data from the USRDS, they showed that among 13,085 patients on dialysis undergoing CABG, 17.8% were performed offpump. Off-pump CABG was associated with a lower risk of death from any cause (HR, 0.92; 95% CI, 0.860.99). However, the survival difference was no longer

Figure 6. The uncertainties inherent in the process of screening renal transplant candidates using stress testing or angiography and downstream management. Abbreviations: angio, angiography; revasc, revascularize. Adapted with permission from Hart et al.89

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significant after 2 years, and no differences in in-hospital or cardiac mortality were noted. The use of internal mammary artery (IMA) grafts was an independent predictor of survival after CABG. Decisions about on-pump versus off-pump CABG, therefore, remain patient- and surgeon-specific and need to be individualized. Coronary Revascularization in Kidney Transplant Candidates

In patients with advanced CKD/ESKD who are potential kidney transplant candidates, coronary revascularization appears to be a seemingly logical approach aimed at mitigating CV risk to tailor a limited resource (organs for donation) to a population most suitable for it. However, this approach is predicated on an as-yet-unproven assumption that preoperative coronary revascularization for obstructive CAD prevents downstream major adverse CV events, and therefore remains heavily debated (Fig. 6). The lone randomized controlled trial on this topic was published several decades ago,86 and enrolled only 26 asymptomatic patients with insulin-dependent DM randomized to angiography/revascularization compared with medical therapy alone. In this trial, 2 of 13 randomized patients who underwent coronary revascularization (coronary stenosis, >75% on ICA) had MACE versus 10 of 13 patients on medical therapy; 4 subjects in the medical therapy arm died. Limitations of this trial included its small sample size and inadequate background medical therapy (aspirin, calcium channel blocker) compared with contemporary standards. The ongoing Canadian-Australian Randomised Trial of Screening Kidney Transplant Candidates for Coronary Artery Disease (CARSK) will provide much-needed evidence on this important topic. This trial has been enrolling since 2016 and is registered with the Australian New Zealand Clinical Trials Registry (trial ID: ACTRN12616000736448). The study will enroll patients with ESKD on dialysis who are being considered for kidney transplant or who already are active on the kidney transplant waiting list, and who are expected to require further screening for CAD before transplantation. Patients will be randomized to an arm that will have no routine CAD screening while waitlisted or to an arm that will have routine CAD screening while wait-listed as determined by the local transplant center. Patients will be followed up for 12 months after kidney transplantation for the primary outcome of MACE (composite of CV mortality, MI, emergency revascularization, and hospitalization for unstable angina).

A PRAGMATIC APPROACH TO CAD MANAGEMENT IN ADVANCED CKD Decisions pertaining to coronary revascularization for the advanced CKD patient are incredibly complex and

necessitate a thoughtful and deliberate multidisciplinary approach.87 Patients with advanced CKD/ESKD have several reasons for higher levels of complexity: incidentally detected CAD in asymptomatic patients (often in the context of renal transplant evaluation) in whom the benefit of coronary revascularization has not been shown prospectively; a higher prevalence of nonatherosclerotic mechanisms contributing to mortality; risk of procedural acute kidney injury hastening the development of ESKD in predialysis patients; and higher short-term and long-term risks compared with the general population with coronary revascularization using either surgical or percutaneous modalities. Hence, before embarking on coronary revascularization, there is a need for a thorough appraisal of the coronary anatomy to determine coronary lesion complexity, and specifically to estimate risks of stent thrombosis versus in-stent restenosis/repeat revascularization and the suitability of placement of an IMA graft. In addition, thorough clinical vetting is necessary for risks of bleeding and stroke, as well as assessment of the comorbidity profile to assess shortterm and long-term risks of morbidity and mortality. We strongly advocate a team approach wherein input is sought from the cardiologist, nephrologist, and from the cardiothoracic surgeon in the context of multivessel disease. In multivessel CAD, if the short-term risk and comorbidity profile are acceptable, and if the anatomy is conducive to placement of an IMA graft, the existing literature favors a surgical approach owing to a demonstrated long-term survival advantage as well as completeness of revascularization. However, if the short-term risks based on the comorbidity profile are believed to be too high to pursue surgical revascularization, percutaneous revascularization may be the preferred option. If percutaneous revascularization is pursued, the evidence favors DES compared with BMS placement, with up-front consideration of the minimum duration of dual-antiplatelet therapy in patients who also may be kidney transplant candidates. In case of surgical revascularization, the multidisciplinary team approach should continue to be pursued postoperatively to collaborate collectively to mitigate the high risk of in-hospital mortality and morbidity. Finally, we underscore the fact that much of the uncertainty regarding CAD evaluation and management stems from the limited randomized data regarding patients with advanced CKD/ESKD. Studies such CARSK and ISCHEMIA-CKD represent important steps in the right direction, and we echo the call88 to the academic community to continue to design trials with an eye toward representing patients with advanced CKD/ ESKD in future trials of CAD outcomes.

REFERENCES 1. Saran R, Robinson B, Abbott KC, et al. US Renal Data System 2016 Annual Data Report: epidemiology of kidney disease in the United States. Am J Kidney Dis. 2017;69(Suppl 1):A7-8.

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2. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-305. 3. Matsushita K, van der Velde M, Astor BC, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010;375:2073-81. 4. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation. 2003;108:2154-69. 5. Wheeler DC, London GM, Parfrey PS, et al. Effects of cinacalcet on atherosclerotic and nonatherosclerotic cardiovascular events in patients receiving hemodialysis: the EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) trial. J Am Heart Assoc. 2014;3:e001363. 6. Winther S, Svensson M, Jørgensen HS, et al. Prognostic value of risk factors, calcium score, coronary CTA, myocardial perfusion imaging, and invasive coronary angiography in kidney transplantation candidates. JACC Cardiovasc Imaging. 2018;11:842-54. 7. Bergeron S, Hillis GS, Haugen EN, Oh JK, Bailey KR, Pellikka PA. Prognostic value of dobutamine stress echocardiography in patients with chronic kidney disease. Am Heart J. 2007;153:385-91. 8. Tangri N, Komenda PV, Rigatto C. Chronic kidney disease and heart disease: after 179 years, do we yet understand the link? Kidney Int. 2015;88:11-3. 9. Bittencourt MS, Hulten EA, Ghoshhajra B, et al. Incremental prognostic value of kidney function decline over coronary artery disease for cardiovascular event prediction after coronary computed tomography. Kidney Int. 2015;88:152-9. 10. Herzog CA, Shroff GR. Atherosclerotic versus nonatherosclerotic evaluation: the yin and yang of cardiovascular imaging in advanced chronic kidney disease. JACC Cardiovasc Imaging. 2014;7:729-32. 11. Bansal N. Evolution of cardiovascular disease during the transition to end-stage renal disease. Semin Nephrol. 2017;37:120-31. 12. Makar MS, Pun PH. Sudden cardiac death among hemodialysis patients. Am J Kidney Dis. 2017;69:684-95. 13. Weiner DE, Tighiouart H, Elsayed EF, et al. The Framingham predictive instrument in chronic kidney disease. J Am Coll Cardiol. 2007;50:217-24. 14. Rakhit DJ, Armstrong KA, Beller E, Isbel NM, Marwick TH. Risk stratification of patients with chronic kidney disease: results of screening strategies incorporating clinical risk scoring and dobutamine stress echocardiography. Am Heart J. 2006;152:363-70. 15. Kim JK, Kim SG, Kim HJ, Song YR. Cardiac risk assessment by gated single-photon emission computed tomography in asymptomatic end-stage renal disease patients at the start of dialysis. J Nucl Cardiol. 2012;19:438-47. 16. Lentine KL, Costa SP, Weir MR, et al. Cardiac disease evaluation and management among kidney and liver transplantation candidates: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. J Am Coll Cardiol. 2012;60:434-80. 17. Wang LW, Fahim MA, Hayen A, et al. Cardiac testing for coronary artery disease in potential kidney transplant recipients: a systematic review of test accuracy studies. Am J Kidney Dis. 2011;57:476-87. 18. Wang LW, Masson P, Turner RM, et al. Prognostic value of cardiac tests in potential kidney transplant recipients: a systematic review. Transplantation. 2015;99:731-45. 19. Hachamovitch R, Berman DS, Shaw LJ, et al. Incremental prognostic value of myocardial perfusion single photon emission

20.

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22.

23.

24.

25.

26.

27.

28.

29.

30.

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35.

36.

computed tomography for the prediction of cardiac death: differential stratification for risk of cardiac death and myocardial infarction. Circulation. 1998;97:535-43. Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Berman DS. Stress myocardial perfusion single-photon emission computed tomography is clinically effective and cost effective in risk stratification of patients with a high likelihood of coronary artery disease (CAD) but no known CAD. J Am Coll Cardiol. 2004;43:200-8. Hakeem A, Bhatti S, Dillie KS, et al. Predictive value of myocardial perfusion single-photon emission computed tomography and the impact of renal function on cardiac death. Circulation. 2008;118:2540-9. Bhatti S, Hakeem A, Dhanalakota S, et al. Prognostic value of regadenoson myocardial single-photon emission computed tomography in patients with different degrees of renal dysfunction. Eur Heart J Cardiovasc Imaging. 2014;15:933-40. Winther S, Svensson M, Jørgensen HS, et al. Diagnostic performance of coronary CT angiography and myocardial perfusion imaging in kidney transplantation candidates. JACC Cardiovasc Imaging. 2015;8:553-62. Wang LW, Fahim MA, Hayen A, et al. Cardiac testing for coronary artery disease in potential kidney transplant recipients. Cochrane Database Syst Rev. 2011;(12):CD008691. Golzar Y, Doukky R. Stress SPECT myocardial perfusion imaging in end-stage renal disease. Curr Cardiovasc Imaging Rep. 2017;10. Shah NR, Charytan DM, Murthy VL, et al. Prognostic value of coronary flow reserve in patients with dialysis-dependent ESRD. J Am Soc Nephrol. 2016;27:1823-9. Goodman WG, Goldin J, Kuizon BD, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. 2000;342:1478-83. Raggi P, Boulay A, Chasan-Taber S, et al. Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease. J Am Coll Cardiol. 2002;39:695-701. Sharples EJ, Pereira D, Summers S, et al. Coronary artery calcification measured with electron-beam computerized tomography correlates poorly with coronary artery angiography in dialysis patients. Am J Kidney Dis. 2004;43:313-9. Winther S, Bøttcher M, Jørgensen HS, et al. Coronary calcium score may replace cardiovascular risk factors as primary risk stratification tool before kidney transplantation. Transplantation. 2016;100:2177-87. Winther S, Svensson M, Jørgensen HS, et al. Repeated contrast administration is associated with low risk of postcontrast acute kidney injury and long-term complications in patients with severe chronic kidney disease. Am J Transplant. 2016;16:897-907. De Lima JJ, Sabbaga E, Vieira ML, et al. Coronary angiography is the best predictor of events in renal transplant candidates compared with noninvasive testing. Hypertension. 2003;42:263-8. Gowdak LH, de Paula FJ, Cesar LA, et al. Screening for significant coronary artery disease in high-risk renal transplant candidates. Coron Artery Dis. 2007;18:553-8. Charytan D, Kuntz RE, Mauri L, DeFilippi C. Distribution of coronary artery disease and relation to mortality in asymptomatic hemodialysis patients. Am J Kidney Dis. 2007;49:409-16. Marwick TH, Steinmuller DR, Underwood DA, et al. Ineffectiveness of dipyridamole SPECT thallium imaging as a screening technique for coronary artery disease in patients with end-stage renal failure. Transplantation. 1990;49:100-3. Joki N, Hase H, Nakamura R, Yamaguchi T. Onset of coronary artery disease prior to initiation of haemodialysis in patients with end-stage renal disease. Nephrol Dial Transplant. 1997;12:718-23.

598

37. Ohtake T, Kobayashi S, Moriya H, et al. High prevalence of occult coronary artery stenosis in patients with chronic kidney disease at the initiation of renal replacement therapy: an angiographic examination. J Am Soc Nephrol. 2005;16:1141-8. 38. Ukaigwe AC, Gilchrist IC. Not just a FREAK finding, but perhaps an important insight. Catheter Cardiovasc Interv. 2016;88:562-4. 39. Michos ED, Wilson LM, Yeh HC, et al. Prognostic value of cardiac troponin in patients with chronic kidney disease without suspected acute coronary syndrome: a systematic review and metaanalysis. Ann Intern Med. 2014;161:491-501. 40. Cheng YJ, Yao FJ, Liu LJ, et al. B-type natriuretic peptide and prognosis of end-stage renal disease: a meta-analysis. PLoS One. 2013;8:e79302. 41. Hickson LJ, Cosio FG, El-Zoghby ZM, et al. Survival of patients on the kidney transplant wait list: relationship to cardiac troponin T. Am J Transplant. 2008;8:2352-9. 42. Hickson LJ, Hickson LT, El-Zoghby ZM, et al. Patient survival after kidney transplantation: relationship to pretransplant cardiac troponin T levels. Am J Transplant. 2009;9:1354-61. 43. Connolly GM, Cunningham R, McNamee PT, Young IS, Maxwell AP. Troponin T is an independent predictor of mortality in renal transplant recipients. Nephrol Dial Transplant. 2008;23:1019-25. 44. Rabbat CG, Treleaven DJ, Russell JD, Ludwin D, Cook DJ. Prognostic value of myocardial perfusion studies in patients with endstage renal disease assessed for kidney or kidney-pancreas transplantation: a meta-analysis. J Am Soc Nephrol. 2003;14:431-9. 45. Foley RN. Clinical epidemiology of cardiac disease in dialysis patients: left ventricular hypertrophy, ischemic heart disease, and cardiac failure. Semin Dial. 2003;16:111-7. 46. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/ AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2012;60:e44-164. 47. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145-53. 48. Wright Jr JT, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002;288:2421-31. 49. Norris K, Bourgoigne J, Gassman J, et al. Cardiovascular outcomes in the African American Study of Kidney Disease and Hypertension (AASK) Trial. Am J Kidney Dis. 2006;48:739-51. 50. Zannad F, Kessler M, Lehert P, et al. Prevention of cardiovascular events in end-stage renal disease: results of a randomized trial of fosinopril and implications for future studies. Kidney Int. 2006;70:1318-24. 51. 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;377:2181-92. 52. Fellstr€om BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009;360:1395-407. 53. Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005;353:238-48.

G.R. Shroff and T.I. Chang

54. De Vriese AS. Should statins be banned from dialysis? J Am Soc Nephrol. 2017;28:1675-6. 55. Kidney Disease: Improving Global Outcomes (KDIGO) Lipid Work Group. KDIGO clinical practice guideline for lipid management in chronic kidney disease. Kidney Int Suppl. 2013;3:259-305. 56. Fihn SD, Blankenship JC, Alexander KP, et al. 2014 ACC/AHA/ AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2014;64:1929-49. 57. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356:1503-16. 58. Sedlis SP, Jurkovitz CT, Hartigan PM, et al. Optimal medical therapy with or without percutaneous coronary intervention for patients with stable coronary artery disease and chronic kidney disease. Am J Cardiol. 2009;104:1647-53. 59. Lopes NH, da Silva Paulitsch F, Pereira A, et al. Mild chronic kidney dysfunction and treatment strategies for stable coronary artery disease. J Thorac Cardiovasc Surg. 2009;137:1443-9. 60. Reddan DN, Szczech LA, Tuttle RH, et al. Chronic kidney disease, mortality, and treatment strategies among patients with clinically significant coronary artery disease. J Am Soc Nephrol. 2003;14:2373-80. 61. Hemmelgarn BR, Southern D, Culleton BF, Mitchell LB, Knudtson ML, Ghali WA. Survival after coronary revascularization among patients with kidney disease. Circulation. 2004;110:1890-5. 62. Stone GW, Hochman JS, Williams DO, et al. Medical therapy with versus without revascularization in stable patients with moderate and severe ischemia: the case for community equipoise. J Am Coll Cardiol. 2016;67:81-99. 63. Hlatky MA, Boothroyd DB, Bravata DM, et al. Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised trials. Lancet. 2009;373:1190-7. 64. Charytan DM, Desai M, Mathur M, et al. Reduced risk of myocardial infarct and revascularization following coronary artery bypass grafting compared with percutaneous coronary intervention in patients with chronic kidney disease. Kidney Int. 2016;90:411-21. 65. Ashrith G, Lee VV, Elayda MA, Reul RM, Wilson JM. Short- and long-term outcomes of coronary artery bypass grafting or drug-eluting stent implantation for multivessel coronary artery disease in patients with chronic kidney disease. Am J Cardiol. 2010;106:348-53. 66. Wang ZJ, Zhou YJ, Liu YY, et al. Comparison of drug-eluting stents and coronary artery bypass grafting for the treatment of multivessel coronary artery disease in patients with chronic kidney disease. Circ J. 2009;73:1228-34. 67. Serruys PW, Unger F, Sousa JE, et al. Comparison of coronaryartery bypass surgery and stenting for the treatment of multivessel disease. N Engl J Med. 2001;344:1117-24. 68. Szczech LA, Reddan DN, Owen WF, et al. Differential survival after coronary revascularization procedures among patients with renal insufficiency. Kidney Int. 2001;60:292-9. 69. Ix JH, Mercado N, Shlipak MG, et al. Association of chronic kidney disease with clinical outcomes after coronary revascularization: The arterial revascularization therapies study (ARTS). Am Heart J. 2005;149:512-9. 70. Bangalore S, Guo Y, Samadashvili Z, Blecker S, Xu J, Hannan EL. Revascularization in patients with multivessel coronary artery

Coronary disease in CKD and ESKD

71.

72.

73.

74.

75.

76.

77.

78.

disease and chronic kidney disease: everolimus-eluting stents versus coronary artery bypass graft surgery. J Am Coll Cardiol. 2015;66:1209-20. Weintraub WS, Grau-Sepulveda MV, Weiss JM, et al. Comparative effectiveness of revascularization strategies. N Engl J Med. 2012;366:1467-76. Chang TI, Leong TK, Kazi DS, Lee HS, Hlatky MA, Go AS. Comparative effectiveness of coronary artery bypass grafting and percutaneous coronary intervention for multivessel coronary disease in a community-based population with chronic kidney disease. Am Heart J. 2013;165:800-8. 808 e801-2. Chang TI, Shilane D, Kazi DS, Montez-Rath ME, Hlatky MA, Winkelmayer WC. Multivessel coronary artery bypass grafting versus percutaneous coronary intervention in ESRD. J Am Soc Nephrol. 2012;23:2042-9. Shroff GR, Solid CA, Herzog CA. Long-term survival and repeat coronary revascularization in dialysis patients after surgical and percutaneous coronary revascularization with drug-eluting and bare metal stents in the United States. Circulation. 2013;127:1861-9. Bangalore S, Kumar S, Fusaro M, et al. Short- and long-term outcomes with drug-eluting and bare-metal coronary stents: a mixedtreatment comparison analysis of 117 762 patient-years of followup from randomized trials. Circulation. 2012;125:2873-91. Garg P, Charytan DM, Novack L, et al. Impact of moderate renal insufficiency on restenosis and adverse clinical events after sirolimus-eluting and bare metal stent implantation (from the SIRIUS trials). Am J Cardiol. 2010;106:1436-42. Tomai F, Ribichini F, De Luca L, et al. Randomized comparison of Xience V and Multi-Link Vision Coronary Stents in the Same Multivessel Patient With Chronic Kidney Disease (RENAL-DES) study. Circulation. 2014;129:1104-12. Saran R, Li Y, Robinson B, et al. US Renal Data System 2014 Annual Data Report: Epidemiology of Kidney Disease in the United States. Am J Kidney Dis. 2015;66(1 Suppl 1):S1-305.

599

79. Chang TI, Montez-Rath ME, Tsai TT, Hlatky MA, Winkelmayer WC. Drug-eluting versus bare-metal stents during PCI in patients with end-stage renal disease on dialysis. J Am Coll Cardiol. 2016;67:1459-69. 80. Lu R, Tang F, Zhang Y, et al. Comparison of drugeluting and bare metal stents in patients with chronic kidney disease: an updated systematic review and metaanalysis. J Am Heart Assoc. 2016;5. 81. Shroyer AL, Grover FL, Hattler B, et al. On-pump versus off-pump coronary-artery bypass surgery. N Engl J Med. 2009;361:1827-37. 82. Lamy A, Devereaux PJ, Prabhakaran D, et al. Off-pump or onpump coronary-artery bypass grafting at 30 days. N Engl J Med. 2012;366:1489-97. 83. Diegeler A, Borgermann J, Kappert U, et al. Off-pump versus onpump coronary-artery bypass grafting in elderly patients. N Engl J Med. 2013;368:1189-98. 84. Puskas JD, Thourani VH, Kilgo P, et al. Off-pump coronary artery bypass disproportionately benefits high-risk patients. Ann Thorac Surg. 2009;88:1142-7. 85. Shroff GR, Li S, Herzog CA. Survival of patients on dialysis having off-pump versus on-pump coronary artery bypass surgery in the United States. J Thorac Cardiovasc Surg. 2010;139: 1333-8. 86. Manske CL, Wang Y, Rector T, Wilson RF, White CW. Coronary revascularisation in insulin-dependent diabetic patients with chronic renal failure. Lancet. 1992;340:998-1002. 87. Shroff GR, Herzog CA. Coronary revascularization in patients with CKD stage 5D: pragmatic considerations. J Am Soc Nephrol. 2016;27:3521-9. 88. Granger CB, Chertow GM. A pint of sweat will save a gallon of blood: a call for randomized trials of anticoagulation in end-stage renal disease. Circulation. 2014;129:1190-2. 89. Hart A, Weir MR, Kasiske BL. Cardiovascular risk assessment in kidney transplantation. Kidney Int. 2015;87:527-34.