Mini Forum for AMI
Acta Cardiol Sin 2013;29:132-141
Contemporary Management of Coronary Artery Disease and Acute Coronary Syndrome in Patients with Chronic Kidney Disease and End-Stage Renal Disease Chin-Chou Huang and Jaw-Wen Chen
Chronic kidney disease (CKD) and end-stage renal disease (ESRD) have emerged as a worldwide public health problem. Due to the remarkably higher incidence and prevalence of this chronic disease in Taiwan than in other countries, CKD/ESRD has contributed to a significant health burden in Taiwan. Patients with CKD/ESRD have an increased risk of coronary artery disease (CAD) and acute coronary syndrome (ACS) compared to the normal population. Patients with ACS alone can present differently than patients with ACS and CKD/ESRD. Also, due to the lower prevalence of chest pain and ST-segment elevation, CKD/ESRD patients were more difficult to diagnose than other patients. Furthermore, whether advances in ACS management with medical therapy and an early invasive approach could improve patient outcomes with CKD/ESRD is not known. The use of antiplatelets such as aspirin and other antithrombotic agents might reduce the incidence of ACS or stroke in CKD patients. However, such use could also increase bleeding risk and even increase the likelihood of mortality, especially in dialysis patients. While recent clinical data suggest the potential benefit of aggressive management with coronary intervention for CAD and ACS in this category of patients, further clinical studies are still indicated for the proper medical strategy and revascularization therapy to improve the outcomes of CAD and ACS in CKD/ESRD patients, both in Taiwan and worldwide.
Key Words:
Acute coronary syndrome · Chronic kidney disease · Coronary artery disease · Diagnosis · End-stage renal disease · Management
INTRODUCTION
demic levels of diabetes mellitus and obesity, as well as the rapidly aging population. 3,4 It causes a huge economic burden worldwide. Health costs of treating people with CKD are nearly 3-fold higher than those for people without CKD, and the cost of treating ESRD is 10-fold higher.5 There is an increased risk of coronary artery disease (CAD) and acute coronary syndrome (ACS) in these patients. Due to the poor clinical outcomes, the diagnosis and management of CAD and ACS are particularly important for patients with CKD/ESRD.
Chronic kidney disease (CKD) has emerged as a worldwide public health problem. 1-3 The size of the global population suffering from CKD and end-stage renal disease (ESRD) continues to increase because of epi-
Received: December 3, 2012 Accepted: February 6, 2013 Department of Medical Research and Education, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital; Cardiovascular Research Center and Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan. Address correspondence and reprint requests to: Dr. Jaw-Wen Chen, Department of Medical Research and Education, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, Taiwan. Tel: 886-2-2871-2121 ext. 3793; Fax: 886-2-2871-1601; E-mail: jwchen@ vghtpe.gov.tw
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EPIDEMIOLOGY DATA OF CKD AND ESRD IN TAIWAN Abundant clinical evidence indicates that there is a
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remarkably higher incidence and prevalence of CKD and ESRD in Taiwan than in other countries6-9 Hsu et al.7 reported a prevalence rate of 6.9% of CKD stage 3-5 in subjects over 20 years of age in the Taiwanese Survey on Blood Sugar, Blood Lipids and Blood Pressure (TW3H). Kuo et al. 8 reported that the prevalence of CKD increased from 1.99% in 1996 to 9.83% in 2007 by using disease code analysis from the dataset of National Health Insurance (NHI). Wen et al. 9 later reported an overall prevalence of 11.93% of CKD stage 1-5 in a cohort consisting of 462,293 individuals who participated in a standard medical screening program in Taiwan.
rate of ACS when compared with the general population, but lower than that of similar cohorts in the United States. The increased prevalence of prior cardiovascular disease and coexisting conditions with ESRD may interact to increase the risk of ACS in dialysis patients.
THE PRESENTATION OF ACS IN PATIENTS WITH CKD AND ESRD Many earlier studies have demonstrated the atypical presentation of ACS in patients with renal disease.22-27 Sosnov et al.22 reported that patients with renal disease experiencing acute myocardial infarction (AMI) were significantly less likely to report chest pain. Shroff et al.24 reported that only 40% of advanced CKD patients with AMI complained of chest pain as the presenting symptom. In contrast, shortness of breath was the index symptom for most of these patients,22 which was likely not recognized by clinicians as an “anginal equivalent.” Similar findings have also been reported in the dialysis population. 23 The possible explanations would be that kidney disease may alter the clinical presentation of AMI. Furthermore, the higher prevalence of diabetes in this population may also mask the “typical” symptoms of AMI. Therefore, a routine survey of those CKD patients with the presentation of shortness of breath may be needed to most effectively identify the possibility of ACS. There was also a noteworthy difference in electrocardiographic findings for patients with and without significant renal disease. ST-segment elevation was present in only 15.9% of advanced CKD patients presenting with AMI, compared with 32.5% of non-CKD patients.24 Using a combination of ST-segment elevation and left bundle branch block (LBBB), 25.8% of advanced CKD patients met the criteria for STEMI compared with 37.9% of non-CKD patients. The proportions of advanced CKD and dialysis patients with ST-segment elevation/LBBB on initial ECG were identical. 23 According to the ACTION registry, Fox et al.25 estimated that nearly 30% of patients with ST-segment elevation myocardial infarction (STEMI) and 43% with non-STEMI had CKD stage 3 or higher (eGFR < 60 mL/min/ 1.73 m2). Similarly, Szummer et al.26 reported moderate or higher incidence of CKD (eGFR < 60 mL/min/1.73 m2) in approximately 24% of
THE RISK OF ACS IN PATIENTS WITH CKD AND ESRD CKD is closely associated with a higher risk of cardiovascular disease (CVD).10-16 Even in early-stage CKD, the risk for premature CVD is increased by 25% to 30%,10 and is more than 30- to 50-fold higher in patients with ESRD.16 Wen et al.9 have reported that patients with CKD in Taiwan may have 83% higher mortality for all-cause and 100% higher for CVD. Chien et al.17 reported that the deterioration of renal function could be related to cardiovascular and all-cause death mortality based on the data from healthy adults in Taiwan. Furthermore, the effect was additive with the presence of metabolic syndrome components. Hwang et al.18 also reported that late-stage CKD is a significant risk factor for mortality in elderly Taiwanese, especially due to cardiovascular and renal diseases, which is according to the data in the Elderly Health Examination Program (EHEP), an observational cohort study in Kaohsiung City, Taiwan. Compared with a reference group with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min per 1.73 m2, adjusted HR for all-cause mortality was 1.5, 2.1 and 2.6 for groups with eGFR of 30-44, 15-29 and less than 15 mL/min per 1.73 m2, respectively.18 Recently, Chou et al.19 reported that the incidence of ACS in the Taiwanese Chinese population under dialysis was 1.780/100-person-years. Another nationwide analysis of ACS patients in Taiwan showed that peak incidence was up to 9/1000 in males and 8/1000 in females.20 In the United States Renal Data System Wave 2 study,21 the incidence of ACS over 2.2 years was 10.2%. Dialysis patients in Taiwan had a higher 133
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non-ST-segment elevation myocardial infarction (NSTEMI) patients from the SWEDEHEART registry. In the GRACE study, Gurm et al.27 reported that dialysis patients presented less typically and were most likely to manifest with a NSTEMI when compared to nondialysis patients. Due to the lower prevalence of chest pain and ST-segment elevation, the diagnosis of ACS is difficult in CKD/ESRD patients, which may likely contribute to the poor outcomes of this population. However, the related data is insufficient, and future prospective investigation is indicated to clarify the above issue in Taiwan. In addition to the symptom of chest pain and electrocardiographic findings, detection of a rise and/or fall of cardiac biomarkers is essential to the diagnosis of AMI. The preferred biomarker is cardiac troponin (I or T), which has high myocardial tissue specificity as well as high clinical sensitivity. In the third universal definition of myocardial infarction by the ESC/ACCF/AHA/WHF task force,28 an increased cardiac troponin concentration is defined as a value exceeding the 99th percentile of a normal reference population [upper reference limit (URL)]. For patients with ESRD, the National Academy of Clinical Biochemistry guidelines29 have recommended a change in the cardiac troponin concentration of ³ 20% for the diagnosis of AMI in those who present with elevated cardiac troponin, 6-9 h after presentation, as indicative of a relevant concentration change. Recently, in a cohort of asymptomatic patients with ESRD, a troponin concentration exceeding the 99th percentile value using the new highly sensitive cardiac troponin T assay was found in 100% of patients.30
and left ventricular dysfunction were associated with escalating hazards of future cardiovascular events and death. Best et al.39 reported CKD as a powerful predictor of adverse outcomes after percutaneous coronary intervention (PCI) and coronary artery bypass surgery (CABG). The occurrence of ACS increases the risk of inhospital heart failure and sudden cardiac death in patients with CKD/ESRD.24,25,38 Shroff et al.24 reported that in-hospital heart failure rates were significantly higher in advanced CKD patients (41% vs. 25.8% in dialysis and 21.1% in non-CKD patients). Fox et al.25 reported about a 3-fold higher likelihood of developing in-hospital heart failure in stage 4 CKD patients than in non-CKD patients. Pun et al.38 reported a progressive increase in the rate of sudden cardiac death associated with worsening eGFR values in a cohort of 19,440 patients undergoing cardiac catheterization. There are also some reports about the poor prognosis of patients with CKD/ESRD in Taiwan.19,20,40,41 Chien et al.40 reported that poor renal function was a poor prognostic factor for patients after ACS events in Taiwan. Chen et al.41 reported that metabolic syndrome was associated with a higher probability of CAD, cardiac death, and major cardiac events in Taiwanese patients with ESRD complicated by ACS. Recently, Hsieh et al. 20 reported that CKD increased the risk of in-hospital mortality [odds ratio, 2.0; 95% confidence interval (CI), 1.8-2.1] in a total of 97,220 patients with ACS during 2004 to 2008 from the national health insurance database in Taiwan. From the same database, Chou et al.19 reported the overall in-hospital mortality rate in dialysis patients with ACS was 9.7%. Male gender, age of ³ 65 years, and associated comorbidities were independent risk factors for ACS.19
THE PROGNOSIS OF ACS IN CKD AND ESRD PATIENTS POSSIBLE MECHANISMS RELATED TO THE POOR PROGNOSIS IN CKD/ESRD PATIENTS
Patients with CKD, particularly those on maintenance dialysis, have poor outcomes after the occurrence of ACS.31-38 Herzog et al.36 reported that mortality rates for AMI in dialysis patients were 26% in 1998 and 21.6% in 2007. Fox et al.25 reported a higher mortality rate for those with STEMI compared with those NSTEMI (31.8% vs.12.4%) in ESRD patients. Wright et al.37 reported that AMI in patients with non-dialysis-dependent advanced CKD was also associated with poor long-term cardiovascular outcomes and survival. Anavekar et al.31 reported that minor reductions in eGFR in CKD patients with AMI Acta Cardiol Sin 2013;29:132-141
There are several potential factors associated with poor outcomes after ACS in patients with CKD/ESRD. First, these patients usually have excess comorbidities such as hypertension, diabetes, and so on.42-45 Second, the presence of impaired renal function can lead to activation of the renin-angiotensin system, oxidative stress, elevated asymmetric dimethylarginine, low-grade inflammation with increased circulating cytokines and 134
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ESRD could be less likely to receive traditional evidencebased inpatient and outpatient treatment, including medical therapy and revascularization.24,25,37,42,49-52 Furthermore, it is also not known whether advances in ACS management such as aggressive medical therapy and an early invasive approach may improve the prognosis of patients with CKD/ESRD. Patients with CKD were excluded from 75% of the published CAD trials.53 Despite optimal contemporary medical therapy and revascularization, the prognosis of patients with CKD and, in particular, of patients undergoing dialysis, remains poor.51 There have been serial studies about the management of CKD and ESRD patients with CAD or ACS (Table 1). However, most of the study designs are retrospective or sub-analysis of the data. Even the study about the management of CKD and ESRD patients in Taiwan was in and of itself rare.19 The American College of Cardiology
dyslipidemia, which may promote the development and progression of clinical atherosclerosis diseases.43 Third, structural and functional abnormalities of the heart in these patients may also contribute to excess cardiovascular risk.42,46,47 Fourth, while platelet dysfunction is frequently associated with the presence of CKD, the use of antiplatelet and antithrombotic agents can increase the risk of bleeding contributing to the increased mortality in CKD patients.48 Finally, it is reported that the use of evidence-based pharmacologic and interventional therapies could be reduced in this population.24,25,37,42,49-52
THE MANAGEMENT OF CAD AND ACS IN PATIENTS WITH CKD/ESRD Accumulated data indicated that patients with CKD/
Table 1. Findings from the studies about managing chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients with coronary artery disease (CAD) or acute coronary syndrome (ACS) Study Medical therapy Berger et al.
Design
Retrospective study
Patient size
Patient characteristics
N = 1,025 AMI
N = 595
Renal status
ESRD
Sciahbasi et al.
Retrospective study
AMI
Whole spectrum of renal dysfunction ESRD
DOPPS study
Retrospective N = 28,320 Patients with or study without CAD
OASIS 5 trial
Sub-analysis
N = 19,979 NSTE-ACS
Whole spectrum of renal dysfunction
HOT study
Sub-analysis
N = 18,597 Diastolic hypertension
CURE trial
Sub-analysis
N = 12,253 NSTE-ACS
Whole spectrum of renal dysfunction Whole spectrum of renal dysfunction
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Major findings
Ref
There are benefits on 30-day mortality 52 among ESRD patients (aspirin: RR 0.64; 95% CI 0.50 to 0.80; beta-blocker: RR 0.78; 95% CI 0.60 to 0.99; ACE inhibitor: RR 0.58; 95% CI 0.42 to 0.77). 63 Chronic aspirin and statin therapy has a cardioprotective role that is evident also in patients with CKD Aspirin was associated with decreased risk of stroke (RR, 0.82; p < 0.01) and increased risk of myocardial infarction (RR, 1.21; p = 0.01) and cardiac event (RR, 1.08; p < 0.01) in all patients, with similar results for patients with CAD. Lower rates of the composite end point (death, myocardial infarction, refractory ischemia, and major bleeding) in patients with fondaparinux than with enoxaparin among patients with a GFR less than 58 2 mL/min per 1.73 m . Aspirin therapy produces greater absolute reduction in major cardiovascular events and mortality in hypertensive patients with CKD than with normal kidney function. Clopidogrel was beneficial and safe in patients with and without CKD.
64
49
56
66
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Chin-Chou Huang et al. Table 1. Continued PLATO trial
Sub-analysis
Antithrombotic Trialists’ Collaboration
Meta-analysis N = 212,000 Patients at high annual risk of vascular events
Palmer et al.
CKD Meta-analysis N = 21,670 ACS or were undergoing PCI (N = 9,969) and stable or no cardiovascular disease (N = 11,701)
Coronary intervention therapy Chou et al.
Herzog et al.
Szummer et al.
N = 15,202 ACS
Whole spectrum of renal dysfunction
Whole spectrum of renal dysfunction
Retrospective N = 19,974 Patients with or study without CAD
ESRD
Retrospective N = 15,784 Patients undergoing ESRD study coronary revascularization procedures Retrospective N = 23,262 NSTEMI Whole study spectrum of renal dysfunction
Szczech et al.
Retrospective N = 59,576 Patients undergoing Whole study CABG or PCI spectrum of renal dysfunction Koyanagi et al. Retrospective N = 43 Patients undergoing Whole spectrum of study CABG patients or renal coronary dysfunction angioplasty ACS I, ACS II, and Prospective, N = 11,377 NSTE-ACS Whole GRACE study spectrum of multi-centre, renal observational studies dysfunction
67 In ACS patients with CKD, ticagrelor compared with clopidogrel significantly reduces ischemic end points and mortality without a significant increase in major bleeding but with numerically more nonprocedure-related bleeding. Aspirin (or another oral antiplatelet drug) is 55 protective in most types of patient at increased risk of occlusive vascular events, including those with an AMI or ischemic stroke, unstable or stable angina, previous myocardial infarction, stroke or cerebral ischaemia, peripheral arterial disease, or atrial fibrillation. 68 Benefits for antiplatelet therapy among persons with CKD are uncertain and are potentially outweighed by bleeding hazards.
Dialysis patients with PCI for ACS may have a reduced risk of mortality than those with medical treatment only. Dialysis patients had better long-term survival after CABG surgery than after PCI.
Early invasive therapy is associated with greater 1-year survival in patients with NSTEMI and mild-to-moderate renal insufficiency, but the benefit declines with lower renal function, and is less certain in those with renal failure or on dialysis. There was a survival benefit among patients with ESRD undergoing CABG surgery as compared with PCI.
19
36
50
79
80 CABG surgery in chronic renal dialysis patients can be accomplished with a better short- and long-term outcome than coronary angioplasty. 81 In-hospital revascularization was independently associated with improved survival, irrespective of eGFR.
ACE, angiotensin converting enzyme; ACS, acute coronary syndrome; AMI, acute myocardial infarction; CAD, coronary artery disease; CI, confidence interval; CKD, chronic kidney disease; Cr, creatinine; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; RR, relative risk. Acta Cardiol Sin 2013;29:132-141
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hemodialysis. On the other hand, although b-blockers and ACE inhibitors are commonly used in this population, randomized data of these drugs in dialysis patients are also absent.65 Accordingly, medical treatment seems helpful in stable CKD patients. An antiplatelet such as aspirin may reduce the incidence of AMI, ACS, or stroke but also increase the bleeding risk in patients with CKD. It may even be harmful and should be carefully used, particularly in dialysis patients.
(ACC) and American Heart Association (AHA) guidelines for management of ACS clearly acknowledge the lack of sufficient studies so as to make specific recommendations for patients with CKD.54
Medical therapy for stable CAD in CKD patients Antiplatelet agents are widely used to prevent cardiovascular events by inhibiting intravascular thrombosis. It has been shown that antiplatelet drugs reduce vascular deaths by 15% and serious cardiovascular events by 20% in persons at high risk for a vascular event.55 However, extrapolating these benefits of antiplatelet therapy to persons with CKD/ESRD is problematic because nonatherosclerotic conditions (cardiac failure, sudden cardiac death, and arrhythmia) are more common causes of CVD in persons with CKD than in the general population.55,56 On the other hand, uremia is associated with prolongation of bleeding time and abnormal platelet aggregation and adhesion due to intrinsic and extrinsic factors.57 Therefore, the bleeding risk of antiplatelet agents may be elevated.24,49,58-62 Previous studies showed that low eGFR values are associated with an increased risk of bleeding.60,61 Holden et al.62 reported the substantially higher baseline risk for bleeding in persons with CKD (approximately 2.5% per year compared with 1% in other at-risk populations),55 suggesting that absolute bleeding risks with antiplatelet therapy might be at least doubled in patients with CKD than in those patients without CKD. Berger et al.52 reported that there were benefits of medical therapy on 30-day mortality among ESRD patients [aspirin: relative risk (RR) 0.64; 95% CI 0.50 to 0.80; beta-blocker: RR 0.78; 95% CI 0.60 to 0.99; ACE inhibitor: RR 0.58; 95% CI 0.42 to 0.77]. In a post-hoc subgroup analysis of HOT study,56 aspirin therapy produced a greater absolute reduction in major cardiovascular events and mortality in hypertensive patients with CKD than in those patients with normal kidney function. Sciahbasi et al.63 reported that the chronic use of aspirin or statins was independently associated with the decreased probability of STEMI (odds ratio, 0.5; 95% CI, 0.2-1.0, p = 0.05) in patients with CKD. In the DOPPS study, 64 however, aspirin was associated with a decreased risk of stroke (RR, 0.82; p < 0.01) but increased risk of myocardial infarction (RR, 1.21; p = 0.01) and cardiac event (RR, 1.08; p < 0.01) in patients with
Medical therapy for ACS in CKD patients In the sub-analysis of the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial,66 the beneficial effect of adding clopidogrel to standard treatment in non-ST-segment elevation ACS was observed in all three tertiles of renal function [lower third RR = 0.89 (95% CI 0.76-1.05); medium third RR = 0.68 (95% CI 0.56-0.84); upper third RR = 0.74 (95% CI 0.60-0.93)] in spite of the significantly increased risk of minor bleeding in all tertiles of renal function. Furthermore, recent subgroup data from the PLATO (Platelet Inhibition and Patient Outcomes) trial67 indicated that ticagrelor, an oral purinergic receptor inhibitor cleared by extrarenal mechanisms, reduced mortality and major cardiovascular events better than clopidogrel among persons with CKD and ACS. Finally, a recent meta-analysis68 indicated that antiplatelet agents reduced myocardial infarction in persons with CKD but had uncertain effects on stroke and mortality, and may increase bleeding hazards. However, glycoprotein IIb/IIIa inhibitors or clopidogrel given in addition to standard care had little or no effect on death, myocardial infarction, or coronary revascularization, and may increase major bleeding in persons with CKD and ACS or those having high-risk coronary artery intervention. Taken together, aspirin is still essential in CKD patients with ACS. However, it is not known whether other antiplatelets might be helpful in this particular group of patients. Statins use in CKD patients Recently, the efficacy of statin therapy in patients with CKD has drawn much attention. Strippoli et al.69 reported that statins decreased the risk of cardiovascular events and cardiovascular mortality in CKD patients, irrespective of the stage of disease (pre-dialysis, dialysis, and transplant). Another systematic review and metaanalysis70 showed that lipid-lowering therapy decreased 137
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or ESRD had better long-term survival after CABG surgery than after PCI.36,79,80 However, most of these studies were retrospective designed. Future prospective randomized study may be indicated to clarify if aggressive strategy with PCI or CABG should be routinely applied to the management of ACS in patients with CKD/ESRD. On the other hand, patients with CKD/ESRD continue to be treated more conservatively, with an associated worse outcome.25,34,81 Fox et al.25 noted that non-STEMI patients with stage 4 CKD were least likely to undergo coronary revascularization (40% less likely than non-CKD patients), followed by patients with stage 5 CKD or on dialysis (20% less likely). Among dialysis patients treated with an invasive approach, there may be concerns about excess bleeding related in part to the use of antiplatelet and antithrombotic agents. 24,49,58-62,66 The long-term safety and efficacy of antiplatelet and antithrombotic agents and the technical challenge of intervening in heavily calcified coronary vessels may potentially influence physicians’ choices with respect to coronary revascularization in this particular patient cohort.82
cardiac death and atherosclerosis-mediated cardiovascular events in persons with CKD. However, Slinin et al.71 reported that statin therapy was not effective for reducing all-cause mortality or stroke in individuals with type 2 diabetes and CKD. When focusing on the patients with ESRD, the data was still controversial and not of sufficient power. In the Dialysis Outcomes and Practice Patterns Study, statins were shown to reduce mortality in HD patients.72 In the Die Deutsche Diabetes Dialyse Studies (the 4D study), atorvastatin did not reduce the composite primary end point (including cardiovascular death, nonfatal myocardial infarction, and stroke) in diabetic patients undergoing HD.73 In the post hoc analysis of the 4D study,74 however, treatment with atorvastatin in diabetic patients undergoing HD significantly reduced the risk of fatal and nonfatal cardiac events and death from any cause if pretreatment LDL-cholesterol was > 145 mg/dL (3.76 mmol/L). In the AURORA trial,75 rosuvastatin didn’t reduce the combined end point of myocardial infarction, stroke, or death from cardiovascular causes in patients undergoing HD. In the post hoc analysis of the AURORA trial,76 however, treatment with rosuvastatin in diabetic patients undergoing HD reduced atherosclerotic coronary events by 32%. In the SHARP (Study of Heart and Renal Protection) trial,77 treatment with simvastatin and ezetimibe could reduce major atherosclerotic events in a wide range of patients with advanced CKD. However, the study didn’t have sufficient power to assess the effects on major atherosclerotic events separately in HD and non-HD patients. Further study is still needed to clarify the impacts of statins in patients with CKD and ESRD, especially those with ACS.
CONCLUSIONS There is a remarkably high incidence and prevalence of CKD/ESRD in Taiwan. The CKD/ESRD patients may be at higher risk of ACS when compared to the normal population. Due to the lower prevalence of chest pain and ST-segment elevation, the diagnosis of ACS could be difficult in these patients. They are less likely to receive traditional evidence-based treatment. Until now, there was still lack of sufficient evidence for the proper treatment of CAD/ACS in these patients. While recent clinical data suggest the potential benefit of aggressive management with coronary intervention for CAD and ACS in this category of patients, further prospective randomized clinical studies are still indicated for the proper medical strategy and revascularization therapy to improve the outcomes of CAD and ACS in CKD/ESRD patients in Taiwan as well as worldwide.
Coronary revascularization therapy Coronary revascularization therapy including PCI and CABG is being applied to a widening spectrum of patients, including those with CKD.19,36,50,78-80 A more recent multicenter observational study demonstrated an independent association between in-hospital coronary revascularization and improved one-year survival in patients with ACS, irrespective of eGFR.81 Chou et al.19 also reported that in Taiwan, dialysis patients with PCI for ACS may have a reduced risk of mortality than those with medical treatment only. When comparing different strategies of coronary revascularization, patients with CKD Acta Cardiol Sin 2013;29:132-141
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Chin-Chou Huang et al. 30. Jacobs LH, van de Kerkhof J, Mingels AM, et al. Haemodialysis patients longitudinally assessed by highly sensitive cardiac troponin T and commercial cardiac troponin T and cardiac troponin I assays. Ann Clin Biochem 2009;46:283-90. 31. Anavekar NS, McMurray JJ, Velazquez E, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 2004;351:1285-95. 32. Keough-Ryan TM, Kiberd BA, Dipchand CS, et al. Outcomes of acute coronary syndrome in a large Canadian cohort: impact of chronic renal insufficiency, cardiac interventions, and anemia. Am J Kidney Dis 2005;46:845-55. 33. Melloni C, Peterson ED, Chen AY, et al. Cockcroft-gault versus modification of diet in renal disease: importance of glomerular filtration rate formula for classification of chronic kidney disease in patients with non-ST-segment elevation acute coronary syndromes. J Am Coll Cardiol 2008;51:991-6. 34. Han JH, Chandra A, Mulgund J, et al. Chronic kidney disease in patients with non-ST-segment elevation acute coronary syndromes. Am J Med 2006;119:248-54. 35. Santopinto JJ, Fox KA, Goldberg RJ, et al. Creatinine clearance and adverse hospital outcomes in patients with acute coronary syndromes: findings from the Global Registry of Acute Coronary Events (GRACE). Heart 2003;89:1003-8. 36. Herzog CA, Ma JZ, Collins AJ. Comparative survival of dialysis patients in the United States after coronary angioplasty, coronary artery stenting, and coronary artery bypass surgery and impact of diabetes. Circulation 2002;106:2207-11. 37. Wright RS, Reeder GS, Herzog CA, et al. Acute myocardial infarction and renal dysfunction: a high-risk combination. Ann Intern Med 2002;137:563-70. 38. Pun PH, Smarz TR, Honeycutt EF, et al. Chronic kidney disease is associated with increased risk of sudden cardiac death among patients with coronary artery disease. Kidney Int 2009;76:652-8. 39. Best PJ, Lennon R, Ting HH, et al. The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions. J Am Coll Cardiol 2002;39:1113-9. 40. Chien KL, Lin HJ, Hsu HC, et al. Lipid-related residual risk and renal function for occurrence and prognosis among patients with first-event acute coronary syndrome and normal LDL cholesterol. Lipids Health Dis 2011;10:215. 41. Chen HH, Wu CJ, Chen YC, et al. Metabolic syndrome is associated with severe coronary artery disease and poor cardiac outcome in end-stage renal disease patients with acute coronary syndrome. Coron Artery Dis 2006;17:593-6. 42. McCullough PA. Why is chronic kidney disease the “spoiler” for cardiovascular outcomes? J Am Coll Cardiol 2003;41:725-8. 43. Amann K, Wanner C, Ritz E. Cross-talk between the kidney and the cardiovascular system. J Am Soc Nephrol 2006;17:2112-9. 44. Ford ML, Tomlinson LA, Chapman TP, et al. Aortic stiffness is independently associated with rate of renal function decline in chronic kidney disease stages 3 and 4. Hypertension 2010;55: 1110-5. 45. Tonelli M, Wiebe N, Culleton B, et al. Chronic kidney disease and Acta Cardiol Sin 2013;29:132-141
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mortality risk: a systematic review. J Am Soc Nephrol 2006;17: 2034-47. Rodriguez-Iturbe B, Correa-Rotter R. Cardiovascular risk factors and prevention of cardiovascular disease in patients with chronic renal disease. Expert Opin Pharmacother 2010;11:2687-98. Zoccali C, Benedetto FA, Tripepi G, et al. Left ventricular systolic function monitoring in asymptomatic dialysis patients: a prospective cohort study. J Am Soc Nephrol 2006;17:14605. Alexander KP, Chen AY, Roe MT, et al. Excess dosing of antiplatelet and antithrombin agents in the treatment of non-STsegment elevation acute coronary syndromes. JAMA 2005;294: 3108-16. Fox KA, Bassand JP, Mehta SR, et al. Influence of renal function on the efficacy and safety of fondaparinux relative to enoxaparin in non ST-segment elevation acute coronary syndromes. Ann Intern Med 2007;147:304-10. Szummer K, Lundman P, Jacobson SH, et al. Influence of renal function on the effects of early revascularization in non-ST-elevation myocardial infarction: data from the Swedish web-system for enhancement and development of evidence-based care in heart disease evaluated according to recommended therapies (SWEDEHEART). Circulation 2009;120:851-8. Bonello L, De Labriolle A, Roy P, et al. Impact of optimal medical therapy and revascularization on outcome of patients with chronic kidney disease and on dialysis who presented with acute coronary syndrome. Am J Cardiol 2008;102:535-40. Berger AK, Duval S, Krumholz HM. Aspirin, beta-blocker, and angiotensin-converting enzyme inhibitor therapy in patients with end-stage renal disease and an acute myocardial infarction. J Am Coll Cardiol 2003;42:201-8. Charytan D, Kuntz RE. The exclusion of patients with chronic kidney disease from clinical trials in coronary artery disease. Kidney Int 2006;70:2021-30. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction). J Am Coll Cardiol 2007;50:652-726. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86. Jardine MJ, Ninomiya T, Perkovic V, et al. Aspirin is beneficial in hypertensive patients with chronic kidney disease: a post-hoc subgroup analysis of a randomized controlled trial. J Am Coll Cardiol 2010;56:956-65. Washam JB, Adams G. Risks and benefits of antiplatelet therapy in uremic patients. Adv Chronic Kidney Dis 2008;15:370-7. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000;321:1183-7.
Acute Coronary Syndrome in Renal Disease 59. Remuzzi G. Bleeding in renal failure. Lancet 1988;1:1205-8. 60. Mehran R, Pocock SJ, Nikolsky E, et al. A risk score to predict bleeding in patients with acute coronary syndromes. J Am Coll Cardiol 2010;55:2556-66. 61. Subherwal S, Bach RG, Chen AY, et al. Baseline risk of major bleeding in non-ST-segment-elevation myocardial infarction: the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) Bleeding Score. Circulation 2009;119: 1873-82. 62. Holden RM, Harman GJ, Wang M, et al. Major bleeding in hemodialysis patients. Clin J Am Soc Nephrol 2008;3:105-10. 63. Sciahbasi A, Arcieri R, Quarto M, et al. Impact of chronic aspirin and statin therapy on presentation of patients with acute myocardial infarction and impaired renal function. Prev Cardiol 2010; 13:18-22. 64. Ethier J, Bragg-Gresham JL, Piera L, et al. Aspirin prescription and outcomes in hemodialysis patients: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2007;50: 602-11. 65. Wetmore JB, Shireman TI. The ABCs of cardioprotection in dialysis patients: a systematic review. Am J Kidney Dis 2009;53: 457-66. 66. Keltai M, Tonelli M, Mann JF, et al. Renal function and outcomes in acute coronary syndrome: impact of clopidogrel. Eur J Cardiovasc Prev Rehabil 2007;14:312-8. 67. James S, Budaj A, Aylward P, et al. Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation 2010;122:1056-67. 68. Palmer SC, Di Micco L, Razavian M, et al. Effects of antiplatelet therapy on mortality and cardiovascular and bleeding outcomes in persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med 2012;156:445-59. 69. 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; 336:645-51. 70. Upadhyay A, Earley A, Lamont JL, et al. Lipid-lowering therapy in persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med 2012;157:251-62.
71. Slinin Y, Ishani A, Rector T, et al. Management of hyperglycemia, dyslipidemia, and albuminuria in patients with diabetes and CKD: a systematic review for a KDOQI clinical practice guideline. Am J Kidney Dis 2012;60:747-69. 72. Mason NA, Bailie GR, Satayathum S, et al. HMG-CoA reductase inhibitor use is associated with mortality reduction in hemodialysis patients. Am J Kidney Dis 2005;45:119-26. 73. Wanner C, Krane V, März W, et al. German Diabetes and Dialysis Study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;353:23848. 74. März W, Genser B, Drechsler C, et al. German Diabetes and Dialysis Study Investigators. Atorvastatin and low-density lipoprotein cholesterol in type 2 diabetes mellitus patients on hemodialysis. Clin J Am Soc Nephrol 2011;6:1316-25. 75. Fellström BC, Jardine AG, Schmieder RE, et al. AURORA Study Group. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009;360:1395-407. 76. Holdaas H, Holme I, Schmieder RE, et al. AURORA Study Group. Rosuvastatin in diabetic hemodialysis patients. J Am Soc Nephrol 2011;22:1335-41. 77. Baigent C, Landray MJ, Reith C, et al. SHARP Investigators. 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. 78. Le Feuvre C. Angioplasty and stenting in patients with renal disease. Heart 2000;83:7-8. 79. 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. 80. Koyanagi T, Nishida H, Kitamura M, et al. Comparison of clinical outcomes of coronary artery bypass grafting and percutaneous transluminal coronary angioplasty in renal dialysis patients. Ann Thorac Surg 1996;61:1793-6. 81. Wong JA, Goodman SG, Yan RT, et al. Temporal management patterns and outcomes of non-ST elevation acute coronary syndromes in patients with kidney dysfunction. Eur Heart J 2009; 30:549-57. 82. Ziada KM. Coronary revascularization in end-stage renal disease. Curr Cardiol Rep 2007;9:389-95.
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Acta Cardiol Sin 2013;29:132-141
Contemporary Management of Coronary Artery Disease and Acute Coronary Syndrome in Patients with Chronic Kidney Disease and End-Stage Renal Disease Chin-Chou Huang and Jaw-Wen Chen
Chronic kidney disease (CKD) and end-stage renal disease (ESRD) have emerged as a worldwide public health problem. Due to the remarkably higher incidence and prevalence of this chronic disease in Taiwan than in other countries, CKD/ESRD has contributed to a significant health burden in Taiwan. Patients with CKD/ESRD have an increased risk of coronary artery disease (CAD) and acute coronary syndrome (ACS) compared to the normal population. Patients with ACS alone can present differently than patients with ACS and CKD/ESRD. Also, due to the lower prevalence of chest pain and ST-segment elevation, CKD/ESRD patients were more difficult to diagnose than other patients. Furthermore, whether advances in ACS management with medical therapy and an early invasive approach could improve patient outcomes with CKD/ESRD is not known. The use of antiplatelets such as aspirin and other antithrombotic agents might reduce the incidence of ACS or stroke in CKD patients. However, such use could also increase bleeding risk and even increase the likelihood of mortality, especially in dialysis patients. While recent clinical data suggest the potential benefit of aggressive management with coronary intervention for CAD and ACS in this category of patients, further clinical studies are still indicated for the proper medical strategy and revascularization therapy to improve the outcomes of CAD and ACS in CKD/ESRD patients, both in Taiwan and worldwide.
Key Words:
Acute coronary syndrome · Chronic kidney disease · Coronary artery disease · Diagnosis · End-stage renal disease · Management
INTRODUCTION
demic levels of diabetes mellitus and obesity, as well as the rapidly aging population. 3,4 It causes a huge economic burden worldwide. Health costs of treating people with CKD are nearly 3-fold higher than those for people without CKD, and the cost of treating ESRD is 10-fold higher.5 There is an increased risk of coronary artery disease (CAD) and acute coronary syndrome (ACS) in these patients. Due to the poor clinical outcomes, the diagnosis and management of CAD and ACS are particularly important for patients with CKD/ESRD.
Chronic kidney disease (CKD) has emerged as a worldwide public health problem. 1-3 The size of the global population suffering from CKD and end-stage renal disease (ESRD) continues to increase because of epi-
Received: December 3, 2012 Accepted: February 6, 2013 Department of Medical Research and Education, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital; Cardiovascular Research Center and Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan. Address correspondence and reprint requests to: Dr. Jaw-Wen Chen, Department of Medical Research and Education, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, Taiwan. Tel: 886-2-2871-2121 ext. 3793; Fax: 886-2-2871-1601; E-mail: jwchen@ vghtpe.gov.tw
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EPIDEMIOLOGY DATA OF CKD AND ESRD IN TAIWAN Abundant clinical evidence indicates that there is a
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remarkably higher incidence and prevalence of CKD and ESRD in Taiwan than in other countries6-9 Hsu et al.7 reported a prevalence rate of 6.9% of CKD stage 3-5 in subjects over 20 years of age in the Taiwanese Survey on Blood Sugar, Blood Lipids and Blood Pressure (TW3H). Kuo et al. 8 reported that the prevalence of CKD increased from 1.99% in 1996 to 9.83% in 2007 by using disease code analysis from the dataset of National Health Insurance (NHI). Wen et al. 9 later reported an overall prevalence of 11.93% of CKD stage 1-5 in a cohort consisting of 462,293 individuals who participated in a standard medical screening program in Taiwan.
rate of ACS when compared with the general population, but lower than that of similar cohorts in the United States. The increased prevalence of prior cardiovascular disease and coexisting conditions with ESRD may interact to increase the risk of ACS in dialysis patients.
THE PRESENTATION OF ACS IN PATIENTS WITH CKD AND ESRD Many earlier studies have demonstrated the atypical presentation of ACS in patients with renal disease.22-27 Sosnov et al.22 reported that patients with renal disease experiencing acute myocardial infarction (AMI) were significantly less likely to report chest pain. Shroff et al.24 reported that only 40% of advanced CKD patients with AMI complained of chest pain as the presenting symptom. In contrast, shortness of breath was the index symptom for most of these patients,22 which was likely not recognized by clinicians as an “anginal equivalent.” Similar findings have also been reported in the dialysis population. 23 The possible explanations would be that kidney disease may alter the clinical presentation of AMI. Furthermore, the higher prevalence of diabetes in this population may also mask the “typical” symptoms of AMI. Therefore, a routine survey of those CKD patients with the presentation of shortness of breath may be needed to most effectively identify the possibility of ACS. There was also a noteworthy difference in electrocardiographic findings for patients with and without significant renal disease. ST-segment elevation was present in only 15.9% of advanced CKD patients presenting with AMI, compared with 32.5% of non-CKD patients.24 Using a combination of ST-segment elevation and left bundle branch block (LBBB), 25.8% of advanced CKD patients met the criteria for STEMI compared with 37.9% of non-CKD patients. The proportions of advanced CKD and dialysis patients with ST-segment elevation/LBBB on initial ECG were identical. 23 According to the ACTION registry, Fox et al.25 estimated that nearly 30% of patients with ST-segment elevation myocardial infarction (STEMI) and 43% with non-STEMI had CKD stage 3 or higher (eGFR < 60 mL/min/ 1.73 m2). Similarly, Szummer et al.26 reported moderate or higher incidence of CKD (eGFR < 60 mL/min/1.73 m2) in approximately 24% of
THE RISK OF ACS IN PATIENTS WITH CKD AND ESRD CKD is closely associated with a higher risk of cardiovascular disease (CVD).10-16 Even in early-stage CKD, the risk for premature CVD is increased by 25% to 30%,10 and is more than 30- to 50-fold higher in patients with ESRD.16 Wen et al.9 have reported that patients with CKD in Taiwan may have 83% higher mortality for all-cause and 100% higher for CVD. Chien et al.17 reported that the deterioration of renal function could be related to cardiovascular and all-cause death mortality based on the data from healthy adults in Taiwan. Furthermore, the effect was additive with the presence of metabolic syndrome components. Hwang et al.18 also reported that late-stage CKD is a significant risk factor for mortality in elderly Taiwanese, especially due to cardiovascular and renal diseases, which is according to the data in the Elderly Health Examination Program (EHEP), an observational cohort study in Kaohsiung City, Taiwan. Compared with a reference group with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min per 1.73 m2, adjusted HR for all-cause mortality was 1.5, 2.1 and 2.6 for groups with eGFR of 30-44, 15-29 and less than 15 mL/min per 1.73 m2, respectively.18 Recently, Chou et al.19 reported that the incidence of ACS in the Taiwanese Chinese population under dialysis was 1.780/100-person-years. Another nationwide analysis of ACS patients in Taiwan showed that peak incidence was up to 9/1000 in males and 8/1000 in females.20 In the United States Renal Data System Wave 2 study,21 the incidence of ACS over 2.2 years was 10.2%. Dialysis patients in Taiwan had a higher 133
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Chin-Chou Huang et al.
non-ST-segment elevation myocardial infarction (NSTEMI) patients from the SWEDEHEART registry. In the GRACE study, Gurm et al.27 reported that dialysis patients presented less typically and were most likely to manifest with a NSTEMI when compared to nondialysis patients. Due to the lower prevalence of chest pain and ST-segment elevation, the diagnosis of ACS is difficult in CKD/ESRD patients, which may likely contribute to the poor outcomes of this population. However, the related data is insufficient, and future prospective investigation is indicated to clarify the above issue in Taiwan. In addition to the symptom of chest pain and electrocardiographic findings, detection of a rise and/or fall of cardiac biomarkers is essential to the diagnosis of AMI. The preferred biomarker is cardiac troponin (I or T), which has high myocardial tissue specificity as well as high clinical sensitivity. In the third universal definition of myocardial infarction by the ESC/ACCF/AHA/WHF task force,28 an increased cardiac troponin concentration is defined as a value exceeding the 99th percentile of a normal reference population [upper reference limit (URL)]. For patients with ESRD, the National Academy of Clinical Biochemistry guidelines29 have recommended a change in the cardiac troponin concentration of ³ 20% for the diagnosis of AMI in those who present with elevated cardiac troponin, 6-9 h after presentation, as indicative of a relevant concentration change. Recently, in a cohort of asymptomatic patients with ESRD, a troponin concentration exceeding the 99th percentile value using the new highly sensitive cardiac troponin T assay was found in 100% of patients.30
and left ventricular dysfunction were associated with escalating hazards of future cardiovascular events and death. Best et al.39 reported CKD as a powerful predictor of adverse outcomes after percutaneous coronary intervention (PCI) and coronary artery bypass surgery (CABG). The occurrence of ACS increases the risk of inhospital heart failure and sudden cardiac death in patients with CKD/ESRD.24,25,38 Shroff et al.24 reported that in-hospital heart failure rates were significantly higher in advanced CKD patients (41% vs. 25.8% in dialysis and 21.1% in non-CKD patients). Fox et al.25 reported about a 3-fold higher likelihood of developing in-hospital heart failure in stage 4 CKD patients than in non-CKD patients. Pun et al.38 reported a progressive increase in the rate of sudden cardiac death associated with worsening eGFR values in a cohort of 19,440 patients undergoing cardiac catheterization. There are also some reports about the poor prognosis of patients with CKD/ESRD in Taiwan.19,20,40,41 Chien et al.40 reported that poor renal function was a poor prognostic factor for patients after ACS events in Taiwan. Chen et al.41 reported that metabolic syndrome was associated with a higher probability of CAD, cardiac death, and major cardiac events in Taiwanese patients with ESRD complicated by ACS. Recently, Hsieh et al. 20 reported that CKD increased the risk of in-hospital mortality [odds ratio, 2.0; 95% confidence interval (CI), 1.8-2.1] in a total of 97,220 patients with ACS during 2004 to 2008 from the national health insurance database in Taiwan. From the same database, Chou et al.19 reported the overall in-hospital mortality rate in dialysis patients with ACS was 9.7%. Male gender, age of ³ 65 years, and associated comorbidities were independent risk factors for ACS.19
THE PROGNOSIS OF ACS IN CKD AND ESRD PATIENTS POSSIBLE MECHANISMS RELATED TO THE POOR PROGNOSIS IN CKD/ESRD PATIENTS
Patients with CKD, particularly those on maintenance dialysis, have poor outcomes after the occurrence of ACS.31-38 Herzog et al.36 reported that mortality rates for AMI in dialysis patients were 26% in 1998 and 21.6% in 2007. Fox et al.25 reported a higher mortality rate for those with STEMI compared with those NSTEMI (31.8% vs.12.4%) in ESRD patients. Wright et al.37 reported that AMI in patients with non-dialysis-dependent advanced CKD was also associated with poor long-term cardiovascular outcomes and survival. Anavekar et al.31 reported that minor reductions in eGFR in CKD patients with AMI Acta Cardiol Sin 2013;29:132-141
There are several potential factors associated with poor outcomes after ACS in patients with CKD/ESRD. First, these patients usually have excess comorbidities such as hypertension, diabetes, and so on.42-45 Second, the presence of impaired renal function can lead to activation of the renin-angiotensin system, oxidative stress, elevated asymmetric dimethylarginine, low-grade inflammation with increased circulating cytokines and 134
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ESRD could be less likely to receive traditional evidencebased inpatient and outpatient treatment, including medical therapy and revascularization.24,25,37,42,49-52 Furthermore, it is also not known whether advances in ACS management such as aggressive medical therapy and an early invasive approach may improve the prognosis of patients with CKD/ESRD. Patients with CKD were excluded from 75% of the published CAD trials.53 Despite optimal contemporary medical therapy and revascularization, the prognosis of patients with CKD and, in particular, of patients undergoing dialysis, remains poor.51 There have been serial studies about the management of CKD and ESRD patients with CAD or ACS (Table 1). However, most of the study designs are retrospective or sub-analysis of the data. Even the study about the management of CKD and ESRD patients in Taiwan was in and of itself rare.19 The American College of Cardiology
dyslipidemia, which may promote the development and progression of clinical atherosclerosis diseases.43 Third, structural and functional abnormalities of the heart in these patients may also contribute to excess cardiovascular risk.42,46,47 Fourth, while platelet dysfunction is frequently associated with the presence of CKD, the use of antiplatelet and antithrombotic agents can increase the risk of bleeding contributing to the increased mortality in CKD patients.48 Finally, it is reported that the use of evidence-based pharmacologic and interventional therapies could be reduced in this population.24,25,37,42,49-52
THE MANAGEMENT OF CAD AND ACS IN PATIENTS WITH CKD/ESRD Accumulated data indicated that patients with CKD/
Table 1. Findings from the studies about managing chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients with coronary artery disease (CAD) or acute coronary syndrome (ACS) Study Medical therapy Berger et al.
Design
Retrospective study
Patient size
Patient characteristics
N = 1,025 AMI
N = 595
Renal status
ESRD
Sciahbasi et al.
Retrospective study
AMI
Whole spectrum of renal dysfunction ESRD
DOPPS study
Retrospective N = 28,320 Patients with or study without CAD
OASIS 5 trial
Sub-analysis
N = 19,979 NSTE-ACS
Whole spectrum of renal dysfunction
HOT study
Sub-analysis
N = 18,597 Diastolic hypertension
CURE trial
Sub-analysis
N = 12,253 NSTE-ACS
Whole spectrum of renal dysfunction Whole spectrum of renal dysfunction
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Major findings
Ref
There are benefits on 30-day mortality 52 among ESRD patients (aspirin: RR 0.64; 95% CI 0.50 to 0.80; beta-blocker: RR 0.78; 95% CI 0.60 to 0.99; ACE inhibitor: RR 0.58; 95% CI 0.42 to 0.77). 63 Chronic aspirin and statin therapy has a cardioprotective role that is evident also in patients with CKD Aspirin was associated with decreased risk of stroke (RR, 0.82; p < 0.01) and increased risk of myocardial infarction (RR, 1.21; p = 0.01) and cardiac event (RR, 1.08; p < 0.01) in all patients, with similar results for patients with CAD. Lower rates of the composite end point (death, myocardial infarction, refractory ischemia, and major bleeding) in patients with fondaparinux than with enoxaparin among patients with a GFR less than 58 2 mL/min per 1.73 m . Aspirin therapy produces greater absolute reduction in major cardiovascular events and mortality in hypertensive patients with CKD than with normal kidney function. Clopidogrel was beneficial and safe in patients with and without CKD.
64
49
56
66
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Chin-Chou Huang et al. Table 1. Continued PLATO trial
Sub-analysis
Antithrombotic Trialists’ Collaboration
Meta-analysis N = 212,000 Patients at high annual risk of vascular events
Palmer et al.
CKD Meta-analysis N = 21,670 ACS or were undergoing PCI (N = 9,969) and stable or no cardiovascular disease (N = 11,701)
Coronary intervention therapy Chou et al.
Herzog et al.
Szummer et al.
N = 15,202 ACS
Whole spectrum of renal dysfunction
Whole spectrum of renal dysfunction
Retrospective N = 19,974 Patients with or study without CAD
ESRD
Retrospective N = 15,784 Patients undergoing ESRD study coronary revascularization procedures Retrospective N = 23,262 NSTEMI Whole study spectrum of renal dysfunction
Szczech et al.
Retrospective N = 59,576 Patients undergoing Whole study CABG or PCI spectrum of renal dysfunction Koyanagi et al. Retrospective N = 43 Patients undergoing Whole spectrum of study CABG patients or renal coronary dysfunction angioplasty ACS I, ACS II, and Prospective, N = 11,377 NSTE-ACS Whole GRACE study spectrum of multi-centre, renal observational studies dysfunction
67 In ACS patients with CKD, ticagrelor compared with clopidogrel significantly reduces ischemic end points and mortality without a significant increase in major bleeding but with numerically more nonprocedure-related bleeding. Aspirin (or another oral antiplatelet drug) is 55 protective in most types of patient at increased risk of occlusive vascular events, including those with an AMI or ischemic stroke, unstable or stable angina, previous myocardial infarction, stroke or cerebral ischaemia, peripheral arterial disease, or atrial fibrillation. 68 Benefits for antiplatelet therapy among persons with CKD are uncertain and are potentially outweighed by bleeding hazards.
Dialysis patients with PCI for ACS may have a reduced risk of mortality than those with medical treatment only. Dialysis patients had better long-term survival after CABG surgery than after PCI.
Early invasive therapy is associated with greater 1-year survival in patients with NSTEMI and mild-to-moderate renal insufficiency, but the benefit declines with lower renal function, and is less certain in those with renal failure or on dialysis. There was a survival benefit among patients with ESRD undergoing CABG surgery as compared with PCI.
19
36
50
79
80 CABG surgery in chronic renal dialysis patients can be accomplished with a better short- and long-term outcome than coronary angioplasty. 81 In-hospital revascularization was independently associated with improved survival, irrespective of eGFR.
ACE, angiotensin converting enzyme; ACS, acute coronary syndrome; AMI, acute myocardial infarction; CAD, coronary artery disease; CI, confidence interval; CKD, chronic kidney disease; Cr, creatinine; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; RR, relative risk. Acta Cardiol Sin 2013;29:132-141
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hemodialysis. On the other hand, although b-blockers and ACE inhibitors are commonly used in this population, randomized data of these drugs in dialysis patients are also absent.65 Accordingly, medical treatment seems helpful in stable CKD patients. An antiplatelet such as aspirin may reduce the incidence of AMI, ACS, or stroke but also increase the bleeding risk in patients with CKD. It may even be harmful and should be carefully used, particularly in dialysis patients.
(ACC) and American Heart Association (AHA) guidelines for management of ACS clearly acknowledge the lack of sufficient studies so as to make specific recommendations for patients with CKD.54
Medical therapy for stable CAD in CKD patients Antiplatelet agents are widely used to prevent cardiovascular events by inhibiting intravascular thrombosis. It has been shown that antiplatelet drugs reduce vascular deaths by 15% and serious cardiovascular events by 20% in persons at high risk for a vascular event.55 However, extrapolating these benefits of antiplatelet therapy to persons with CKD/ESRD is problematic because nonatherosclerotic conditions (cardiac failure, sudden cardiac death, and arrhythmia) are more common causes of CVD in persons with CKD than in the general population.55,56 On the other hand, uremia is associated with prolongation of bleeding time and abnormal platelet aggregation and adhesion due to intrinsic and extrinsic factors.57 Therefore, the bleeding risk of antiplatelet agents may be elevated.24,49,58-62 Previous studies showed that low eGFR values are associated with an increased risk of bleeding.60,61 Holden et al.62 reported the substantially higher baseline risk for bleeding in persons with CKD (approximately 2.5% per year compared with 1% in other at-risk populations),55 suggesting that absolute bleeding risks with antiplatelet therapy might be at least doubled in patients with CKD than in those patients without CKD. Berger et al.52 reported that there were benefits of medical therapy on 30-day mortality among ESRD patients [aspirin: relative risk (RR) 0.64; 95% CI 0.50 to 0.80; beta-blocker: RR 0.78; 95% CI 0.60 to 0.99; ACE inhibitor: RR 0.58; 95% CI 0.42 to 0.77]. In a post-hoc subgroup analysis of HOT study,56 aspirin therapy produced a greater absolute reduction in major cardiovascular events and mortality in hypertensive patients with CKD than in those patients with normal kidney function. Sciahbasi et al.63 reported that the chronic use of aspirin or statins was independently associated with the decreased probability of STEMI (odds ratio, 0.5; 95% CI, 0.2-1.0, p = 0.05) in patients with CKD. In the DOPPS study, 64 however, aspirin was associated with a decreased risk of stroke (RR, 0.82; p < 0.01) but increased risk of myocardial infarction (RR, 1.21; p = 0.01) and cardiac event (RR, 1.08; p < 0.01) in patients with
Medical therapy for ACS in CKD patients In the sub-analysis of the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial,66 the beneficial effect of adding clopidogrel to standard treatment in non-ST-segment elevation ACS was observed in all three tertiles of renal function [lower third RR = 0.89 (95% CI 0.76-1.05); medium third RR = 0.68 (95% CI 0.56-0.84); upper third RR = 0.74 (95% CI 0.60-0.93)] in spite of the significantly increased risk of minor bleeding in all tertiles of renal function. Furthermore, recent subgroup data from the PLATO (Platelet Inhibition and Patient Outcomes) trial67 indicated that ticagrelor, an oral purinergic receptor inhibitor cleared by extrarenal mechanisms, reduced mortality and major cardiovascular events better than clopidogrel among persons with CKD and ACS. Finally, a recent meta-analysis68 indicated that antiplatelet agents reduced myocardial infarction in persons with CKD but had uncertain effects on stroke and mortality, and may increase bleeding hazards. However, glycoprotein IIb/IIIa inhibitors or clopidogrel given in addition to standard care had little or no effect on death, myocardial infarction, or coronary revascularization, and may increase major bleeding in persons with CKD and ACS or those having high-risk coronary artery intervention. Taken together, aspirin is still essential in CKD patients with ACS. However, it is not known whether other antiplatelets might be helpful in this particular group of patients. Statins use in CKD patients Recently, the efficacy of statin therapy in patients with CKD has drawn much attention. Strippoli et al.69 reported that statins decreased the risk of cardiovascular events and cardiovascular mortality in CKD patients, irrespective of the stage of disease (pre-dialysis, dialysis, and transplant). Another systematic review and metaanalysis70 showed that lipid-lowering therapy decreased 137
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or ESRD had better long-term survival after CABG surgery than after PCI.36,79,80 However, most of these studies were retrospective designed. Future prospective randomized study may be indicated to clarify if aggressive strategy with PCI or CABG should be routinely applied to the management of ACS in patients with CKD/ESRD. On the other hand, patients with CKD/ESRD continue to be treated more conservatively, with an associated worse outcome.25,34,81 Fox et al.25 noted that non-STEMI patients with stage 4 CKD were least likely to undergo coronary revascularization (40% less likely than non-CKD patients), followed by patients with stage 5 CKD or on dialysis (20% less likely). Among dialysis patients treated with an invasive approach, there may be concerns about excess bleeding related in part to the use of antiplatelet and antithrombotic agents. 24,49,58-62,66 The long-term safety and efficacy of antiplatelet and antithrombotic agents and the technical challenge of intervening in heavily calcified coronary vessels may potentially influence physicians’ choices with respect to coronary revascularization in this particular patient cohort.82
cardiac death and atherosclerosis-mediated cardiovascular events in persons with CKD. However, Slinin et al.71 reported that statin therapy was not effective for reducing all-cause mortality or stroke in individuals with type 2 diabetes and CKD. When focusing on the patients with ESRD, the data was still controversial and not of sufficient power. In the Dialysis Outcomes and Practice Patterns Study, statins were shown to reduce mortality in HD patients.72 In the Die Deutsche Diabetes Dialyse Studies (the 4D study), atorvastatin did not reduce the composite primary end point (including cardiovascular death, nonfatal myocardial infarction, and stroke) in diabetic patients undergoing HD.73 In the post hoc analysis of the 4D study,74 however, treatment with atorvastatin in diabetic patients undergoing HD significantly reduced the risk of fatal and nonfatal cardiac events and death from any cause if pretreatment LDL-cholesterol was > 145 mg/dL (3.76 mmol/L). In the AURORA trial,75 rosuvastatin didn’t reduce the combined end point of myocardial infarction, stroke, or death from cardiovascular causes in patients undergoing HD. In the post hoc analysis of the AURORA trial,76 however, treatment with rosuvastatin in diabetic patients undergoing HD reduced atherosclerotic coronary events by 32%. In the SHARP (Study of Heart and Renal Protection) trial,77 treatment with simvastatin and ezetimibe could reduce major atherosclerotic events in a wide range of patients with advanced CKD. However, the study didn’t have sufficient power to assess the effects on major atherosclerotic events separately in HD and non-HD patients. Further study is still needed to clarify the impacts of statins in patients with CKD and ESRD, especially those with ACS.
CONCLUSIONS There is a remarkably high incidence and prevalence of CKD/ESRD in Taiwan. The CKD/ESRD patients may be at higher risk of ACS when compared to the normal population. Due to the lower prevalence of chest pain and ST-segment elevation, the diagnosis of ACS could be difficult in these patients. They are less likely to receive traditional evidence-based treatment. Until now, there was still lack of sufficient evidence for the proper treatment of CAD/ACS in these patients. While recent clinical data suggest the potential benefit of aggressive management with coronary intervention for CAD and ACS in this category of patients, further prospective randomized clinical studies are still indicated for the proper medical strategy and revascularization therapy to improve the outcomes of CAD and ACS in CKD/ESRD patients in Taiwan as well as worldwide.
Coronary revascularization therapy Coronary revascularization therapy including PCI and CABG is being applied to a widening spectrum of patients, including those with CKD.19,36,50,78-80 A more recent multicenter observational study demonstrated an independent association between in-hospital coronary revascularization and improved one-year survival in patients with ACS, irrespective of eGFR.81 Chou et al.19 also reported that in Taiwan, dialysis patients with PCI for ACS may have a reduced risk of mortality than those with medical treatment only. When comparing different strategies of coronary revascularization, patients with CKD Acta Cardiol Sin 2013;29:132-141
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