Management of Coronary Atherosclerosis and Acute Coronary Syndromes in Patients With Chronic Kidney Disease

Management of Coronary Atherosclerosis and Acute Coronary Syndromes in Patients With Chronic Kidney Disease Karthiek R. Narala, MD, Sohail Hassan, MD, Thomas A. LaLonde, MD, and Peter A. McCullough, MD, MPH Abstract: Atherosclerosis of the coronary arteries is common, extensive, and more unstable among patients with chronic renal impairment or chronic kidney disease (CKD). The initial presentation of coronary disease is often acute coronary syndrome (ACS) that tends to be more complicated and has a higher risk of death in this population. Medical treatment of ACS includes antianginal agents, antiplatelet therapy, anticoagulants, and pharmacotherapies that modify the natural history of ventricular remodeling after injury. Revascularization, primarily with percutaneous coronary intervention and stenting, is critical for optimal outcomes in those at moderate and high risk for reinfarction, the development of heart failure, and death in predialysis patients with CKD. The benefit of revascularization in ACS may not extend to those with endstage renal disease because of competing sources of all-cause mortality. In stable patients with CKD and multivessel coronary artery disease, observational studies have found that bypass surgery is associated with a reduced mortality as compared with percutaneous coronary intervention when patients are followed for several years. This article will review the guidelines-recommended therapeutic armamentarium for K.R.N. and P.A.M. researched data for the article and wrote the manuscript. All the authors provided substantial contribution to discussion of content and reviewed and edited the manuscript before submission. Curr Probl Cardiol 2013;38:165-206. 0146-2806/$ – see front matter http://dx.doi.org/10.1016/j.cpcardiol.2012.12.004

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the treatment of stable coronary atherosclerosis and ACS and give specific guidance on benefits, hazards, dose adjustments, and caveats concerning patients with baseline CKD. (Curr Probl Cardiol 2013;38:165-206.) he prevalence of chronic kidney disease (CKD) is approximately 26 million in the United States.1 CKD, commonly defined as an estimated glomerular filtration rate (eGFR) of ⬍60 mL/min/1.73 m2 or evidence of kidney damage with biomarkers (spot urine albumin: creatinine ratio ⬎30 mg/g) or by imaging, is considered a coronary risk equivalent and also a risk factor for progression of cardiovascular disease.2 At the most extreme end of the spectrum of CKD, dialysis recipients have cardiovascular mortality rates that are 10-30 times higher than in the general population.3 Although rates of myocardial infarction (MI) and stroke are higher in patients with CKD than in the general population, the increase in cardiovascular mortality in these patients is considerably driven by 2 important pathways: pump failure and arrhythmias.4 The term “uremia” implies urine in the blood and is recognized by elevations in blood urea nitrogen, uric acid, and a host of protein and electrolyte disturbances that have been associated with cardiomyocyte dysfunction, decreased myocardial capillary density, increased left ventricular mass, impaired iron reutilization, erythropoietin deficiency, anemia, abnormal calcium–phosphate homeostasis with phosphate retention and hyperparathyroidism, inflammation, hyperhomocysteinemia, and hypervolemia. These modifiers all contribute to myocardial dysfunction and fibrosis observed in patients with CKD.5 Thus, in the setting of acute coronary syndromes (ACS), CKD patients are more likely to develop arrhythmias and left ventricular dysfunction leading to death than are patients without CKD.4 For patients with end-stage renal disease (ESRD), hemodialysis itself may add to cardiovascular morbidity by markedly increasing levels of cytokines, promoting activation of tissue enzymes, and causing transient cardiac ischemia.

T

Bernard J. Gersh. The increased cardiovascular risk in patients with CKD is a function of the prevalence of traditional risk factors in these patients, such as hypertension, diabetes, dyslipidemia, older age, left ventricular hypertrophy, and the metabolic syndrome. In addition, there is an increased prevalence of nontraditional risk factors such as uremic toxins, anemia, calcium uptake, abnormalities in bone mineral metabolism, and in “a chronic inflammatory state.” The direct association with these variables and coronary artery disease (CAD) is, however, unclear. 166

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Many patients with chronic renal failure have other risk factors for bleeding that complicate invasive management, both percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). This is particularly the case in patients on dialysis receiving high-dose heparin and platelet inhibitors, and many of these patients were not included in the randomized trial. There is an excellent discussion of these issues by the authors later in this monograph.

Potential subjects with CKD are commonly excluded from clinical trials involving either stable atherosclerosis or ACS. As a result,6 limited evidence exists for specific treatment modalities tested in this population. In general, with appropriate monitoring, most cardiovascular therapies can be used safely and provide a benefit in patients with renal impairment.7 The American Heart Association (AHA) and the National Kidney Foundation recommend early detection of CKD in patients with, or at increased risk of, cardiovascular disease.8 Specifically all patients with cardiovascular disease should be screened for evidence of kidney disease by calculating the eGFR and testing for microalbuminuria by measuring the albumin-to-creatinine ratio (Class IIa, Level of Evidence C).8 An eGFR of ⬍60 mL/min/1.73 m2 should be regarded as abnormal (Class I, Level of Evidence B) and confers increased cardiovascular risk.9 Furthermore, the albumin-to-creatinine ratio should be used to screen for the presence of kidney damage in adult patients with cardiovascular disease, with values ⬎30 mg/g on a spot urine specimen being regarded as abnormal (Class IIa, Level of Evidence B). It has been shown that urine microalbuminuria will detect CKD in younger populations (aged ⬍46 years), whereas eGFR is more likely to detect CKD in older age-groups (aged ⱖ46 years).10 The risk of cardiovascular events increases with both decreasing eGFR and increasing microalbuminuria, and both factors should therefore be considered in the same patient when assessing risk of cardiovascular disease (Fig 1). Bernard J. Gersh. A recent study of ⬎ 2 million participants dispels the myth that a low eGFR in older patients is simply a function of aging. This study pointed out that absolute mortality differences by eGFR actually increased with advancing age (JAMA 2012;308:2349-60). Other markers of kidney function such as plasma cystatin-C concentrations are under evaluation as markers of cardiovascular risk. Some studies have suggested that cystatin-C may be a more accurate measure of cardiovascular risk than elevated plasma creatinine concentrations, but others have emphasized the nonrenal determinants of cystatin-C levels, such as increased inflammation.

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Fig 1. Relative risks of cardiovascular death according to eGFR and microalbuminuria (urine ACR) from the CKD Prognosis Consortium. Blue indicates lowest risk and red indicates highest risk. ACR, albumin-to-creatinine ratio; eGFR, estimated glomerular filtration rate. Reproduced with permission from van der Velde et al.11

The Kidney Early Evaluation Program (KEEP) is a free communitybased health screening program for adults at high risk for CKD.12 When screening patients for CKD, KEEP now uses the Chronic Kidney Disease–Epidemiology Collaboration (CKD–EPI) equation instead of the Modification of Diet in Renal Disease (MDRD) equation.13 The use of the CKD–EPI equation results in a higher eGFR for a given creatinine value than does the MDRD study equation for most persons ⬍75 years old. The CKD–EPI equation yielded a lower prevalence (11.1%) of CKD in the National Health and Nutrition Examination Survey (NHANES) database, compared with 13.2% using the MDRD study equation13; reclassification of persons using CKD–EPI was associated with a 15.9% improvement in the association of eGFR with mortality (P ⬍ 0.001). Thus, the CKD–EPI equation is now considered the preferred eGFR equation as a prognostic aid in understanding the future risk of cardiovascular disease and mortality. In this review, the authors discuss the clinical characterization of CKD, which can be applied in risk prediction, triage, and management of patients presenting with suspected ACS.

Risk Assessment in ACS As CKD worsens, patients are more likely to present with acute MI than with stable exertional angina (Fig 2).14 In a study by McCullough et al.,15 168

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Re ela
ve Rissk of AMII Presentta
on

4.00 3 50 3.50 3.00 2.50 2.00 1.50 1.00 0.50 0.00

130-90

89-60

59-45

<45

eGFR (ml/min/1.73 m2) Fig 2. Relative risk of AMI when presenting with suspected ACS according to baseline eGFR.13 ACS, acute coronary syndromes; AMI, acute myocardial infarction; eGFR, estimated glomerular filtration rate; RR, relative risk. Reproduced with permission from Go et al.14

CKD patients presenting with chest pain to the emergency department had an approximate 40% risk of MI, heart failure, or death. The presence of CKD can be considered more than a coronary risk equivalent, and patients with CKD should therefore receive at least equally intensive risk factor modification as those with clinically recognized coronary heart disease (Level of Evidence A).3 Despite these recommendations, a study by Wattanakit et al.16 questioned whether the history of CKD was equivalent to a history of MI in determining cardiovascular risk. The investigators found that patients with a history of CKD had a higher incidence of cardiovascular disease and mortality rates than did those without a history of CKD or MI. However, the incidence of cardiovascular disease and mortality rates were even higher in those with a history of MI. It is important to note that Wattanakit et al.’s study population did not include patients with a glomerular filtration rate of ⬍30 mL/min/1.73 m2, which may have excluded the sickest patients with CKD. The risk of cardiovascular mortality in patients with moderate CKD is similar to those with a previous MI or diabetes mellitus.17 In ACS, patients with CKD have more extensive CAD; have higher risk for reinfarction, heart failure, and death; have more atypical and delayed presentations; and are less likely to receive evidence-based therapy than are patients without CKD.18 As 1 of 8 variables in the Global Registry of Acute Coronary Events (GRACE) risk model for predicting in-hospital mortality in patients with unstable angina, non-ST-segment elevation myocardial infarction (NSTEMI), or ST-segment elevation myocardial Curr Probl Cardiol, May 2013

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infarction (STEMI), serum creatinine level is associated with a 1.2-fold increased risk of mortality per 1 mg/dL (88.4 ␮mol/L) increase.19,20 The severity of renal disease is associated in a graded fashion with short- and long-term mortality after ACS.21,22 At the time of presentation with symptoms suggestive of ACS, the patient’s medical history, physical findings, electrocardiogram, eGFR and CKD status, and cardiac biomarker measurements are essential to identify risk of mortality and nonfatal cardiac ischemic events.3,23-26 When evaluating a patient with suspected ACS, the diagnostic role of cardiac troponin is complicated by CKD. Although elevated levels of troponins accurately identify myocardial necrosis, they do not point to the causes, which can be multiple27 and include renal insufficiency.28 The exact reasons for the higher rates of elevated cardiac troponin concentrations in patients with CKD are not clear. These increases can reflect myocardial damage, decreased renal clearance, skeletal muscle expression of cardiac-specific epitopes, or other metabolic abnormalities.29 It is plausible that the elevation in serum cardiac troponin levels in asymptomatic patients on dialysis is a reflection of silent ischemic heart disease or accelerated myocyte apoptosis. Troponin levels are also associated with increased left ventricular mass in patients with ESRD.30 Highsensitivity cardiac troponin T measured in stable patients with ESRD, preferably before the midweek dialysis session, has been cleared by the Food and Drug Administration (FDA) as a prognostic aid for assessing risk of mortality in these patients. Thus, when evaluating a patient with CKD with suspected ACS, a baseline troponin above the 99% percentile value for the normal population is common, so one must see a further characteristic rise and fall consistent with MI to secure this part of the diagnostic criteria. Additionally, there must be at least 1 piece of supportive clinical evidence, such as symptoms consistent with ischemia, new or presumed new ST-T wave changes or new left bundle branch block, development of pathologic Q-waves, imaging evidence of new loss of viable myocardium or new wall motion abnormality, or identification of coronary thrombus by angiography or at autopsy. In 7800 patients with suspected ACS enrolled in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO IV) trial, blood troponin T was an independent predictor of risk of death across the entire spectrum of renal function.31 Thus, a characteristic rise in serial cardiac troponin levels in the first 24 hours for patients with suspected ACS supports new cardiac injury, whereas chronically elevated levels indicate either unstable angina or a chronic disease state.3 170

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Bernard J. Gersh. A recent consensus document from the American College of Cardiology (ACC) Foundation emphasized that troponin elevations in the diagnosis of MI need to take into account the clinical setting, including symptoms, electrocardiographic changes, and a typical rise and fall in troponin levels (JACC 2012;60:2427-63).

Management of ACS Patients presenting with STEMI should undergo primary PCI with stenting within 90 minutes (door-to-balloon time). In addition, reperfusion with thrombolysis can be an initial strategy for patients presenting outside the 90-minute window or in those with a prolonged transport time. There appears to be a delay in treatment for STEMI in patients with CKD that may be due to either difficulty in early recognition or confusion on the risks and benefits of treatment.32 In a study by Newsome et al.,33 investigators found that of 109,169 Medicare patients with MI, fewer patients with kidney disease received thrombolytic therapy, and those with the worst kidney disease (serum creatinine level ⬎1.6 mg/dL [⬎141.4 ␮mol/L]) waited the longest for therapy. It is possible that some clinicians have a concern about thrombolysis-associated bleeding in patients with kidney disease, yet Newsome et al. demonstrated that the adjusted odds ratio (OR) for bleeding events was lower in ESRD than in patients with normal kidney function (OR 1.84 vs 2.28, respectively). There are no formal dose adjustment recommendations for the use of streptokinase, alteplase, reteplase, or tenecteplase in patients with CKD. After reperfusion, medical management of STEMI largely follows a similar course of therapy to that of patients with NSTEMI. Once a patient with suspected unstable angina or NSTEMI is diagnosed, standard medical therapy should include aspirin, a ␤-adrenergic receptor blocker, anticoagulant therapy, possibly a glycoprotein IIb/IIIa antagonist, and a thienopyridine, unless a specific contraindication exists (Tables 1–3).3 Untreated CKD patients have greater tendencies for thrombosis as a result of excessive generation of thrombin and reduced levels of protein C, either owing to decreased production or excess losses in the urine, particularly in those with proteinuria.45,46 However, because there are a greater number of circulating thrombin–antithrombin complexes in patients with CKD, all forms of indirect thrombin and factor Xa inhibition (such as heparin, low-molecular-weight heparin [LMWH], and fondaparinux) have a more profound anticoagulation effect, and hence have increased rates of major and minor bleeding events.45 Compared with Curr Probl Cardiol, May 2013

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TABLE 1. Acute and chronic treatments for ACS in patients with CKD Medication Antiplatelet Aspirin

Antiplatelet (ADP receptor antagonists) Clopidogrel

Prasugrel

Ticagrelor

ACE inhibitors E.g., captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, fosinopril

ARBs E.g., losartan, irbesartan, olmesartan, candesartan, valsartan, telmisartan

CCBs Dihydropyridines, eg, amlodipine, felodipine, nicardipine, nifedipine, nimodipine, nitrendipine Nondihyrdropyridines, eg, diltiazem, verapamil

172

Normal dose Acute MI: 160-325 mg by mouth as soon as possible MI prophylaxis: 81-162 mg by mouth once daily. PCI: 325 mg by mouth 2 h presurgery, then 160-325 mg by mouth maintenance UA: 75-162 mg by mouth once daily

UA/NSTEMI: 300-600 mg initial loading dose, followed by 75 mg by mouth once daily with aspirin. STEMI: 75 mg by mouth once daily with aspirin 75162 mg/d Recent MI: 75 mg by mouth once daily ACS: Loading dose: 60 mg by mouth once Maintenance dose: 10 mg by mouth once daily with aspirin 81-325 mg/d; bleeding risk may increase if weight ⬍60 kg; consider 5 mg by mouth once daily (efficacy/safety not established) ACS with PCI and stent: Starting dose: 180 mg by mouth once Maintenance dose: 90 mg by mouth twice daily To be given for 1 y with aspirin as an alternative option for dual antiplatelet therapy Indicated for the treatment of hypertension, prevention of cardiovascular events, including heart failure in those at risk, reduction in the progression of type 1 diabetic nephropathy, and reduction in cardiovascular events in patients post MI with left ventricular dysfunction or heart failure. Also indicated for the treatment of heart failure Indicated for treatment of hypertension, to reduce the progression of type 2 diabetic nephropathy, and reduce cardiovascular events in patients post-MI with left ventricular dysfunction or heart failure Indicated for heart failure in those intolerant to ACE inhibitors

In UA/NSTEMI, if ␤-blockers are contraindicated, a nondihydropyridine CCB should be chosen in the absence of clinically significant left ventricular dysfunction or other contraindications36

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TABLE 1. Continued CKD population

Pharmacology

No specific dosing adjustments in patients with CKD Meta-analysis involving patients on dialysis demonstrated a benefit of aspirin therapy on cardiovascular outcomes33

Metabolism: liver, microsomal enzyme system Renal clearance: 80%-100% 24-72 h Excretion: principally in urine (80%-100%), sweat, saliva, feces

No specific dosing adjustments in patients with CKD.

Metabolism: CYP3A4, CYP2C19 (predominantly), and others to generate active metabolite; also by esterase to an inactive metabolite Excretion: urine and feces Metabolism: liver; CYP450, CYP2B6, CYP2C9/CYP2C19 (minor), CYP3A4 substrate; CYP2B6 (weak) inhibitor Excretion: urine (68%) and feces (27%)

No specific dose adjustments in patients with CKD

No specific dose adjustments in patients with CKD

Metabolism: hepatic CYP450 Excretion: bile primarily, urine ⬍1%

The dosing schedules may need to be individualized for each dialysis session to avoid intradialytic hypotension

Elimination: mainly renal with an elimination half-life of 12.6 h in healthy individuals In patients with impaired renal function (CrCl ⱕ30 mL/min), a longer half-life, and accumulation have been observed without clinical consequences

As first-line treatment in most patients with CKD, we recommend the use of ACE inhibitors or ARBs; both have been shown to reduce LVH in patients on hemodialysis34,35 Levels of ARBs do not change significantly during hemodialysis

Losartan has 88% hepatic and 12% renal clearance

No specific dose adjustments for patients with CKD The management of chronic CAD in patients on dialysis should follow that of the general population and use of CCBs as indicated

Amlodipine has renal elimination as the major route of excretion, with about 60% cleared in the urine Diltiazem undergoes primary liver metabolism

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TABLE 1. Continued Medication

Nitrates Nitroglycerin

Antianginal Ranolazine

Normal dose

2% ointment Angina: 0.5-2 inches applied in morning and 6 h later to truncal skin Heart failure: 1.5 inches, increase by 0.5-1 inch up to 4 inches, every 4 h Sublingual: 0.4 mg for relief of chest pain in ACS Sublingual: 0.3-0.6 mg every 5 min Maximum: 3 doses within 15 min 500-1000 mg by mouth twice daily Max: 2000 mg/d

ACE, angiotensin-converting enzyme; ACS, acute coronary syndromes; ADP, adenosine diphosphate; ARB, angiotensin-receptor blocker; CAD, coronary artery disease; CCB, calciumchannel blocker; CKD, chronic kidney disease; CrCl, creatinine clearance; LVH, left ventricular hypertrophy; MI, myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction; UA, unstable angina.

heparin, the intravenous direct thrombin inhibitor bivalirudin has been associated with lower bleeding risk and better cardiovascular outcomes in patients with CKD.47 The ACC/AHA guidelines for ACS provide some additional guidance on the use of PCI in patients with unstable angina or NSTEMI.3 Mild to moderate CKD is considered a risk for major complications in patients with unstable angina or NSTEMI, and an early invasive strategy is preferred to conservative medical management.48 However, these guidelines note that for patients with ESRD or those undergoing dialysis, data are not supportive of catheterization, which may even cause harm, including the development of heart failure, loss of residual renal function, and death.48 Although patients with predialysis CKD are less likely to be offered coronary angiography in the setting of ACS, observational studies suggest they benefit from revascularization and with a reduction in 6-month mortality.49,50 Primary PCI for NSTEMI in ESRD, however, has been questioned.51 The Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated Ac174

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TABLE 1. Continued CKD population

Pharmacology

The hemodynamic and electrophysiological effects of CCBs are markedly different from each other and should be evaluated when selecting a suitable therapy No specific dose adjustments for patients with CKD Care must be used to avoid hypotension in low-volume states, such as dialysis sessions

Metabolism: mainly in liver, extrahepatic sites such as vascular wall, red blood cells Excretion: urine

No specific dose adjustments for patients with CKD Prolongs QTc interval Recommend close monitoring

Excretion: urine 73%-75%, feces 25%

cording to Recommended Therapies (SWEDEHEART) reported in 23,262 consecutive cases of NSTEMI, that the utilization of coronary angiography and revascularization decreased as eGFR declined.52 In patients with an eGFR of ⬍30 mL/min, less than one-third were selected for an early invasive approach likely due to advanced age, perceived risks (bleeding, contrast-induced acute kidney injury [CI-AKI]), questions regarding benefit, and possibly patient preference. In SWEDEHEART, the benefits of an early invasive strategy on 1-year mortality seen in patients with mild and moderate CKD were not observed in patients on dialysis. Because all-cause mortality is so high in ESRD, it is likely that competing mortality from other sources, including infection, non-ischemia-related arrhythmias, thromboembolism, and neurodegenerative diseases, works to reduce any measured benefit of primary PCI for acute MI in ESRD. However, Wong et al.53 showed a benefit with revascularization even in those with severe CKD. In-hospital revascularization was independently associated with a lower 1-year mortality irrespective of the eGFR (adjusted OR: 0.52, 95% CI: 0.36-0.77, P ⫽ 0.001). The benefit of Curr Probl Cardiol, May 2013

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TABLE 2. ␤-adrenergic receptor blockers for ACS in patients with CKD* Medication

Normal dose

Metoprolol Acute MI Metoprolol tartrate: 2.5-5 mg rapid IV every 2-5 min, up to 15 mg over 10-15 min, then 15 min after last IV and receiving 15 mg IV or 50 mg by mouth every 6 h for 48 h, then 50-100 mg by mouth twice daily Angina Metoprolol tartrate: initially 50 mg by mouth twice daily, then titrated to 200 mg by mouth twice daily. Metoprolol succinate: 100 mg by mouth once daily, no more than 400 mg/d Esmolol Immediate control For intraoperative treatment, give an 80 mg (approximately 1 mg/kg) bolus dose over 30 sec followed by a 150 ␮g/kg/ min infusion, if needed. Maximum infusion rate: 300 ␮g/kg/min Gradual control For postoperative treatment, give loading dosage infusion of 500 ␮g/kg/min over 1 min followed by a 4 min infusion of 50 ␮g/kg/min If no effect within 5 min, repeat loading dose and follow with infusion increased to 100 ␮g/kg/min Carvedilol Hypertension and post-MI protection: 6.25-25 mg by mouth twice daily Start at 6.25 mg by mouth twice daily, then increase every 3-14 d to 12.5 mg by mouth twice daily, then 25 mg by mouth twice daily

CKD population

Pharmacology

No specific dose adjustments for patients with CKD Recommend close monitoring for adverse effects

Dialyzable: yes Metabolism: hepatic CYP2D6 Metabolites: inactive Excretion: urine 95%

No specific dose Metabolism: adjustments for patients extensively with CKD metabolized by esterase in cytosol of red blood cells Metabolites: major acid metabolite (ASL-8123), methanol (inactive) Excretion: urine ⬍1%-2%

No specific dose Elimination: mainly adjustments for patients biliary with CKD Excretion: primarily In a small study of patients through feces on dialysis with dilated cardiomyopathies, carvedilol improved left ventricular function and decreased hospitalization, cardiovascular deaths, and total mortality37

*Hemodialysis reduces blood levels of atenolol, acebutolol, and nadolol; by contrast, levels of carvedilol and labetalol do not change significantly.

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TABLE 3. Lipid-lowering therapy for primary and secondary prevention in patients with CKD Medication

Normal dose

CKD population

Pharmacology

Simvastatin

Cardiovascular event protection: 20 mg by mouth once daily combined with ezetimibe, 10 mg by mouth once daily Maximum dose: 40 mg by mouth given at hour of sleep Cardiovascular event protection: 10 mg by mouth once daily.

Consider starting dose at 5 mg in the evening in patients with CKD In SHARP, lipid lowering with statin ⫹ ezetimibe was beneficial in patients with CKD38 In HPS, simvastatin reduced the renal decline in patients with CKD39 No specific dose adjustments for patients with CKD Atorvastatin 10 mg in patients with CKD revealed a significantly lower risk of the primary end point (nonfatal MI or cardiac death) when compared with placebo40 With the TNT and GREACE studies, atorvastatin showed improvement in renal function in patients with CKD41 No specific dose adjustments for patients with CKD Caution for increased risk of rhabdomyolysis A multicenter, randomized, double-blind, placebocontrolled trial of fluvastatin was conducted in kidney transplant recipients42 Fluvastatin reduced LDL cholesterol levels by 32%. Although the primary end point did not achieve statistical significance, secondary analysis showed that the fluvastatin group experienced fewer cardiac deaths and nonfatal MI than did the placebo group.43 Coronary intervention procedures were not significantly different between the two groups

Metabolism: liver, CYP450 Excretion: bile primarily, urine ⬍2%

Atorvastatin

Fluvastatin

Cardiovascular event protection: 40 mg by mouth twice daily Extended-release: 80 mg by mouth once daily

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Metabolism: liver, CYP450 Excretion: bile primarily, urine ⬍2%

Excretion: feces 90%, urine 5%

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TABLE 3. Continued Medication

Normal dose

CKD population

Pharmacology

Pravastatin

Cardiovascular event protection: Start: 40 mg by mouth once daily, may adjust dose every 4 wks Maximum dose: 80 mg by mouth once daily

Start at 10 mg by mouth once daily in patients with CKD A randomized trial of pravastatin vs placebo in patients with previous MI and CKD44 Secondary analysis showed coronary death or nonfatal MI was lower in patients receiving pravastatin, suggesting that pravastatin is effective for secondary prevention of cardiovascular events in patients with CKD

Excretion: feces 70%, urine 20%

ACS, acute coronary syndromes; CKD, chronic kidney disease; MI, myocardial infarction; HPS, Heart Protection Study; TNT, Treating to New Targets.

early revascularization in patients with CKD was also demonstrated by Charytan and colleagues.54 All of these studies are heavily influenced by selection bias. Thus, the real benefit of revascularization in persons with CKD and ACS remains uncertain. Bernard J. Gersh. The competing risk concept is important, and in many patients, the cardiovascular risk is greater than the risk of requiring renal replacement therapy, but this varies with age, other risk factors, and the severity of kidney dysfunction, and clinical decisions must be individualized.

Patients with CKD who undergo angiography are at increased risk of CI-AKI. The 2009 ACC/AHA guidelines for PCI recommend that either an iso-osmolar contrast medium or a low-molecular-weight low-osmolar contrast medium (other than ioxaglate or iohexol) be used for patients with predialysis CKD who are undergoing angiography.55,56 The 2011 ACC/AHA guidelines now place less emphasis on specific types of contrast agents, and more on limiting the volume of contrast used during the procedure.48 Furthermore, the guidelines recommend that patients should be adequately hydrated with intravenous isotonic crystalloid before undergoing angiography to reduce the risk of CI-AKI. As mentioned previously, all patients, including those with CKD, should be treated with aspirin and ␤-adrenergic receptor blockers, unless 178

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otherwise contraindicated. In patients with unstable angina or NSTEMI where ␤-blockers are contraindicated, a nondihydropyridine calciumchannel blocker can be given for angina in patients without clinically significant left ventricular dysfunction or other contraindications (Level of Evidence B).36 Thienopyridines are indicated in the setting of ACS and can be used in patients with CKD; however, there is an increased risk of bleeding in this population. Clopidogrel is also approved in the general population for the secondary prevention of atherosclerotic cardiovascular events in those who cannot take aspirin; most patients on dialysis would theoretically be candidates for long-term clopidogrel therapy in the case of aspirin intolerance. The 2011 ACC/AHA guidelines added prasugrel to the list of recommended agents.48 Prasugrel is recommended at the time of decision for PCI (Class IA recommendation). However, the guidelines note that it is not recommended for patients undergoing initially conservative medical management. In non-ST-elevation ACS patients with CKD undergoing urgent PCI, clopidogrel administered as an initial loading dose followed by a maintenance dose should be started as soon as possible after admission and given for at least 1 month for patients receiving bare metal stents. Prasugrel may also be used in this clinical scenario, with a Class IIB recommendation. After PCI with drug-eluting stents, clopidogrel or prasugrel should be given for at least 12 months for patients receiving drug-eluting stents. The 2012 American College of Chest Physicians guidelines for primary and secondary prevention of cardiovascular disease add ticagrelor, in addition to aspirin, as an option for dual antiplatelet therapy for patients undergoing PCI with stent placement (Class IB recommendation).57 At the time of this writing, there are now published articles evaluating the risks and benefits of ticagrelor in persons with CKD. The 2011 ACC/AHA guidelines recommend the use of glycoprotein IIb/IIIa inhibitors in patients with elevated troponin levels and those at high risk of reinfarction or death with unstable angina or NSTEMI already taking aspirin and a thienopyridine and who are selected for urgent PCI.48 However, in patients with unstable angina or NSTEMI who are at low risk of ischemic events, including those with a Thrombolysis In Myocardial Infarction (TIMI) risk score ⬍2 or those at high risk of bleeding already treated with aspirin and clopidogrel, the upstream use of glycoprotein IIb/IIIa inhibitors is not recommended (Table 4). Thus, most troponin-negative patients with CKD already at an elevated bleeding risk from aspirin and thienopyridine therapy would not be good candidates for glycoprotein IIb/IIIa inhibitors. Abciximab and tirofiban have both been shown to reduce rates of death or nonfatal MI in patients with elevated Curr Probl Cardiol, May 2013

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TABLE 4. Intravenous glycoprotein IIb/IIIa inhibitors for unstable angina/NSTEMI and STEMI Agent Abciximab

Normal dose

CKD population*

Adjunct to PCI: 0.25 mg/kg No specific dose IV bolus over at least 1 adjustments for patients min 10-60 min before with CKD start of PCI, then 0.125 Abciximab should also be ␮g/kg/min (not to considered as adjunctive exceed 10 ␮g/min) therapy in patients with continuous IV infusion ACS on dialysis for 12 h In CKD, safety of abciximab Unstable angina with PCI has been shown for planned within 24 h: creatinine levels ⬎ 0.25 mg/kg IV bolus 152.5 ␮mol/L58 although over at least 1 min, then increased bleeding with 0.125 ␮g/kg/min (not to abciximab in patients exceed 10 ␮g/min) IV with CKD has been infusion for 18-24 h reported,59 other studies concluding 1 h after PCI have shown no increase in bleeding for CKD vs no CKD for abciximab in PCI60 Eptifibatide ACS: 180 ␮g/kg IV bolus, creatinine clearance ⬍ 50 then 2 ␮g/kg/min IV for mL/min and ACS: 180 up to 72 h ␮g/kg IV, then PCI: 180 ␮g/kg IV, then a continuous infusion 1 continuous infusion at 2 ␮g/kg/min ␮g/kg/min with another Safety and use during 180 ␮g/kg IV bolus 10 hemodialysis is not min after first bolus established Continue infusion for at least 12 h Tirofiban In patients undergoing PCI, Creatinine clearance ⬍ 30 tirofiban is not mL/min and ACS: reduce recommended as an dose to 50% of normal alternative to rate abciximab56 Safety and use during ACS: 0.4 ␮g/kg/min IV for hemodialysis not 30 min, then 0.1 ␮g/kg/ established min IV for 48-108 h PCI: continue 0.1 ␮g/kg/ min IV through procedure and for 12-24 h after

Pharmacology Metabolism: unknown, but likely by the reticuloendothelial system CYP450: unknown involvement Excretion: urine

Metabolism: other, minimal CYP450: unknown involvement Excretion: urine 50%

Excretion: urine 65% (primarily unchanged), feces 25% (primarily unchanged)

ACS, acute coronary syndromes; CKD, chronic kidney disease; IV, intravenous; NSTEMI, non-ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction. *When a glycoprotein IIb/IIIa antagonist is used, abciximab and tirofiban should be considered preferred agents, as no dosing changes are required for abciximab, and dialysis-specific dosing recommendations are available for tirofiban. Increased bleeding but reduced in-hospital mortality in CKD patients with ACS treated with glycoprotein IIb/IIIa antagonists has also been shown.61

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troponin concentration62,63 and should also be considered as adjunctive therapy for ACS in patients on dialysis. Abciximab is the preferred agent for PCI, and the clearance of the drug is not altered in patients on dialysis. Tirofiban requires a 50% dose reduction in patients with an eGFR of ⬍30 mL/min. Eptifibatide is renally cleared and requires a 50% dose reduction in patients with an eGFR of ⬍50 mL/min. It is not recommended in patients on dialysis due to an increased risk of bleeding.64 Despite increased bleeding events, glycoprotein IIb/IIIa antagonists have been associated with reduced in-hospital mortality in CKD patients with ACS.61 Although many trials favor antiplatelet agents in patients undergoing PCI, more recent data suggest otherwise. A meta-analysis of antiplatelet agents in patients with CKD by Palmer et al.65 demonstrated low- or very low-quality evidence, indicating little or no benefit of antiplatelet agents during PCI on all-cause mortality (relative risk [RR]: 0.86, 95% CI: 0.69-1.07). However, in patients with stable cardiovascular disease or those at risk for ACS, moderate-quality evidence demonstrated that antiplatelet therapy reduced the risk of MI (RR: 0.66, 95% CI: 0.51-0.87), and low-quality evidence showed uncertain effects on allcause mortality (RR: 0.87, 95% CI: 0.61-1.24) and cardiovascular mortality (RR: 0.91, 95% CI: 0.60-1.36).

Antithrombotic Therapy In 2008, American College of Chest Physicians guidelines for unstable angina and NSTEMI recommend anticoagulation in all patients with unfractionated heparin, LMWH, bivalirudin or fondaparinux (Table 5).66 When an invasive strategy is selected, both unfractionated heparin and an LMWH, such as enoxaparin, are Class IA recommendations (2011 ACC/AHA unstable angina/NSTEMI guidelines).48 Bivalirudin, a direct thrombin inhibitor, is a Class IB recommendation only in patients selected for an invasive strategy and, as aforementioned, has been associated with favorable outcomes in CKD compared with unfractionated heparin, provided there is renal dose adjustment.67 Of note, bivalirudin is dialyzable. When choosing these agents in patients with renal dysfunction, it should be noted that unfractionated heparin has partial dependence on renal function for its metabolism but can be used in patients with CKD and in those on dialysis.68 In clinical trials, LMWH has been shown to be superior to unfractionated heparin in patients with elevated levels of cardiac troponin and either unstable angina or NSTEMI.69,70 Enoxaparin, however, is a renally cleared LMWH and should be used with caution in patients with decreased renal filtration function owing to the increased risk of bleeding complications. This agent is not recommended in patients Curr Probl Cardiol, May 2013

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TABLE 5. Antithrombotic agents for unstable angina/NSTEMI and STEMI Agent Indirect factor Xa inhibitors Unfractionated heparin

Low-molecularweight heparin (eg, enoxaparin)

182

Normal dose

CKD population

Pharmacology

Recommended dosage and desired aPTT values as per institutional protocol PCI: 60-100 units/kg IV given once Target ACT 250-350 sec In patients receiving glycoprotein IIb/IIIa inhibitor, give 50-70 units/kg IV to target ACT 200 sec STEMI, adjunct treatment, streptokinase use: 800 units/h when ⬍ 80 kg body weight or 1000 U/ h when ⬎ 80 kg body weight Start: 5000 units IV, adjust dose to target aPTT 50-75 sec NSTEMI: 12-15 units/kg/h IV Start: 60-70 units/kg IV; Max 5000 units bolus, max rate 1000 U/h Adjust dose to target aPTT 50-75 sec Unstable angina, non-Q-wave myocardial infarction: 1 mg/kg subcutaneously twice daily. STEMI, aged ⬍ 75 years: 30 mg IV bolus plus 1 mg/kg subcutaneously, then 1 mg/kg subcutaneously every 12 h. PCI: additional 0.3 mg/kg IV bolus if last subcutaneous administration given ⬎ 8 h before balloon inflation STEMI, aged ⬎ 75 years: 0.75 mg/kg subcutaneously every 12 h (no IV bolus)

In patients with CKD, suggested starting dose of heparin is 50 IU/kg bolus, then 18 IU/kg/h Monitor aPTT level and adjust accordingly as per institutional protocol

Metabolism: liver (partial) metabolites: none Excretion: urine

CrCl ⬍ 30 mL/min STEMI, aged ⬍ 75 years: 30 mg IV bolus plus 1 mg/kg subcutaneously, then 1 mg/kg subcutaneously once a day. STEMI, aged ⬎ 75 years: 1 mg/kg subcutaneously once a day

Excretion: urine 40%

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TABLE 5. Continued Agent Direct factor Xa inhibitor Fondaparinux

Direct thrombin inhibitors Bivalirudin

Dabigatran

Normal dose

CKD population

Pharmacology

Unstable angina/NSTEMI Conservative strategy: 2.5 mg subcutaneously once daily Suring PCI: add unfractionated heparin, 50-60 units kg⫺1 IV bolus for prophylaxis of catheter thrombosis61

CrCl 30-50 mL/min: Excretion: urine use with caution (primarily CrCl ⬍ 30 mL/min: not unchanged) indicated

Intended for use with aspirin 300-325 mg/d 0.75 mg/kg IV bolus initially, followed by continuous infusion at rate of 1.75 mg/kg/h for duration of procedure Perform ACT 5 min after bolus dose Administer additional 0.3 mg/kg bolus, if necessary May continue infusion after PCI beyond 4 h (optional post-PCI, at discretion of treating health-care provider) initiated at rate of 0.2 mg/kg/h for up to 20 h, as needed Indicated for prevention of stroke and thromboembolism associated with nonvalvular atrial fibrillation CrCl ⬎ 30 mL/min: 150 mg by mouth twice daily

CrCl 10-29 mL/min: usual bolus dose, then initial infusion of 1 mg/kg/h IV up to 4 h Hemodialysis: usual bolus dose, then initial infusion of 0.25 mg/kg/h IV up to 4 h Bivalirudin is a direct thrombin inhibitor with specific dosing adjustments for patients on dialysis and should be preferentially considered

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Dialyzable: with 25% reduction in levels Excretion: urine

CrCl 15-30 mL/min: 75 Excretion: urine mg by mouth twice 7%, feces 86% daily CrCl ⬍ 15 mL/min or hemodialysis: not indicated For patients currently taking dabigatran, wait 12 h (CrCl ⱖ 30 mL/min) or 24 h (CrCl ⬍ 30 mL/min) after the last dose of dabigatran before initiating treatment with a parenteral anticoagulant

183

TABLE 5. Continued Agent

Rivaroxaban

Normal dose

Indicated for prevention of stroke and thromboembolism associated with nonvalvular atrial fibrillation CrCl ⬎ 50 mL/min: 20 mg by mouth at hour of sleep

CKD population

Pharmacology

If possible, discontinue dabigatran, 1-2 d (CrCl ⱖ 50 mL/min) or 3-5 d (CrCl ⬍ 50 mL/min) before invasive or surgical procedures because of increased risk of bleeding CrCl 15-50 mL/min: 15 Metabolism: liver mg by mouth at hour CYP450 of sleep Excretion: urine CrCl ⬍ 15 mL/min: not 66%, feces indicated 28% Half-life: 5-9 h or 11-13 h in elderly

ACT, activated clotting time; aPTT, activated partial thromboplastin time; CKD, chronic kidney disease; CrCl, creatinine clearance; IV, intravenous; NSTEMI, non-ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction.

undergoing dialysis.71,72 Fondaparinux, an indirect factor Xa inhibitor, is also cleared renally and is contraindicated in patients with a creatinine clearance (CrCl) of ⬍30 mL/min. Bernard J. Gersh. The difference between ACS and stroke prevention in patients with atrial fibrillation needs to be emphasized. The window of opportunity in ACS is much narrower because the risk of bleeding on anticoagulants in patients, many of whom have received stents and already are on dual antiplatelet therapy, is much increased. Moreover, the benefits in terms of reducing ischemic risk may be somewhat less in a patient population with a high incidence of revascularization. It should be noted that in a prescribed analysis of the ARISTOTLE trial of patients with atrial fibrillation, apixaban was superior to warfarin in preventing the primary outcome of stroke or systemic thromboembolism, and in addition, patients with kidney disease had the greatest reduction in bleeding risk with apixaban compared with warfarin (Eur Heart J 2012;33:2821-30).

Therapies to Reduce Rates of Reinfarction After ACS, patients remain at increased risk of recurrent cardiovascular events. Prolonged treatment with fondaparinux and bivalirudin led to a decrease in bleeding events and a reduction in ischemic events and 184

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mortality in the OASIS-5 (Fifth Organization to Assess Strategies in Ischemic Syndromes73 and HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction trials.74,75 Therefore, the use of oral anticoagulation for secondary prevention in patients after ACS was studied with apixaban in APPRAISE-2 (Apixaban for Prevention of Acute Ischemic Events 2.76 In addition to aspirin and clopidogrel, a significant increase in major bleeding was observed in patients with STEMI or unstable angina/NSTEMI according to the TIMI criteria using apixaban, and the trial was therefore terminated early. At the time of writing this review, this drug still awaits review by the FDA for its role in nonvalvular atrial fibrillation. There are currently no data concerning the use of apixaban in CKD patients for the prevention of ischemic cardiac events. The ESTEEM (Efficacy and Safety of the oral Thrombin inhibitor ximelagatran in combination with aspirin, in patiEnts with rEcent Myocardial damage)77 and RE-DEEM (Dose Finding Study for Dabigatran Etexilate in Patients With Acute Coronary Syndrome)78 trials studied the oral direct thrombin inhibitors ximelagatran and dabigatran, respectively. In phase II trials, both drugs showed an increase in major bleeding events without any benefit in cardiovascular event reduction. Therefore, these agents were not studied beyond phase II trials. Dabigatran, however, was recently approved by the FDA for anticoagulation in patients with nonvalvular atrial fibrillation.79 Atrial fibrillation is a common background condition in patients with ACS and CKD that clinicians will invariably face in practice.80 In patients with CKD, the 75-mg twice-daily dose was approved for patients with a CrCl of 15-30 mL/min. In patients on dialysis or those with a CrCl of ⬍15 mL/min, dabigatran is contraindicated at this time.81

Bernard J. Gersh. These recommendations are based on pharmacodynamic monitoring and not trial data. It is important to regularly reassess renal function in patients on the novel anticoagulants, as this may mandate dosage reduction.

Rivaroxaban is a novel factor Xa inhibitor recently approved for stroke prevention in nonvalvular atrial fibrillation, replacing warfarin. Results of its use were reported in the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with ACS (ATLAS ACS 2-TIMI 51) trial.82 The 2.5-mg twice-daily dose of rivaroxaban was associated with decreased cardiovascular events, death from cardiovasCurr Probl Cardiol, May 2013

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cular causes, and death from any cause compared with placebo. Rivaroxaban did, however, lead to an increase in bleeding events and intracranial hemorrhage compared with placebo, without a significant increase in fatal bleeding (0.3% vs 0.2%, P ⫽ 0.66). It should be noted, however, that the 2.5-mg twice-daily dosing used in this trial was much lower than the 20-mg total daily dose approved by the FDA that most patients received in demonstrating benefits of rivaroxaban in nonvalvular atrial fibrillation.83 Rivaroxaban relies on the kidneys for 65% of its metabolism. The recommended dose for those with CKD and CrCl of 15-50 mL/min is 15 mg orally daily. For those with CrCl of ⬍15 mL/min and patients on dialysis, rivaroxaban is contraindicated. Although further studies will guide the optimal dose of rivaroxaban for secondary prevention of MI in patients with CKD, we must emphasize that care must be taken in the setting of patients with CKD on dual antiplatelet therapy. Addition of anticoagulation in this setting could adversely increase bleeding risk, especially in the setting of platelet P2Y12 subtype adenosine diphosphate receptor inhibitors.65 These interactions remain to be further studied.

Therapy for Chronic Coronary Disease Medical management of patients with coronary disease in the presence of CKD commonly includes aspirin, ␤-adrenergic receptor blockers, angiotensin-converting-enzyme (ACE) inhibitors, nitrates, and statin therapy, with ranolazine used as adjunctive therapy for chronic stable angina (Tables 1–3). Aspirin reduces mortality in patients with stable known or suspected coronary heart disease presumably by reducing the chances of significant thrombus formation with plaque rupture.84 Aspirin should be initiated and continued indefinitely at a dose of 75-100 mg/d in all patients, including those with CKD, unless contraindicated.85 No particular recommendations exist for dosing adjustment of aspirin in patients with CKD; however, these patients are recognized to be at increased risk of bleeding with all antiplatelet agents because of decreased platelet aggregation secondary to uremia. As a class, ␤-adrenergic receptor blockers have been shown to reduce mortality in patients with CKD and ESRD after an MI.37 Selective ␤1-adrenergic receptor blockers such as metoprolol and combination ␣-blockers and ␤-blockers such as carvedilol are favored, as studies have demonstrated cardiovascular protection with these agents, particularly in patients with heart failure.86,87 Metoprolol and atenolol are removed with dialysis, and may require dose supplementation after dialysis.37 Metoprolol undergoes primarily hepatic metabolism and does not necessarily need specific 186

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dosage adjustment in patients on dialysis,51 whereas atenolol, acebutolol, and nadolol are renally cleared and may require dosage adjustment in patients on dialysis.88 It has been suggested that ␤-adrenergic receptor blockers may hinder peritoneal transport of fluid and electrolytes in patients on peritoneal dialysis,89 but this notion is not sufficient to warrant withholding ␤-adrenergic receptor blockers in dialysis patients when they are clearly indicated. In patients with previous MI, angina, or with well-established CAD with high-risk anatomy, ␤-blockers should be the preferred antihypertensive agent in patients with CKD.86 Angiotensin-receptor blockers (ARBs) should be considered in CKD patients who are intolerant to ACE inhibitors.85 The addition of ARBs should be considered after MI in patients without marked renal impairment (creatinine concentration ⬍2.5 mg/dL [221 ␮mol/L] in men and ⬍2.0 mg/dL [176.8 ␮mol/L] in women) or without hyperkalemia (potassium ⬍5.0 mmol/L) who are already on therapeutic doses of an ACE inhibitor and a ␤-adrenergic receptor blocker, and have a left ventricular ejection fraction ⱕ 40%, and have diabetes mellitus or heart failure (Class IA recommendation).85 Use of mineralocorticoid-receptor-blocking agents (such as spironolactone and eplerenone) has been shown to reduce blood pressure, improve edema, and reduce the rates of rehospitalization or death in patients after MI with reduced ejection fraction or in those with class II–IV heart failure.90-92 As seen with ACE inhibitors and ARBs, the main caveat is hyperkalemia, which increases in frequency when the baseline eGFR is ⬍45 mL/min or with a potassium level of ⬎4.5 mmol/L. Until there is clear evidence, ACE plus ARB should not be used in CKD patients, as there are more expected serious safety events without a proven cardiovascular or renal benefit. If spironolactone or eplerenone is used in such patients, a repeat potassium level should be checked after 3-5 doses.

Bernard J. Gersh. Aldactone and eplerenone have been major additions to our therapeutic armamentarium in patients with congestive heart failure and left ventricular dysfunction. The caveat, as the authors point out, is hyperkalemia, and one needs to remain constantly aware of this as renal function declines over time.

Both short- and long-term nitrates decrease anginal symptoms in patients with chronic coronary disease. Nitrates relax vascular smooth muscle (in coronary arterial and both systemic arterial and venous beds) resulting in a decrease in systemic arterial blood pressure.93 These effects Curr Probl Cardiol, May 2013

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Fig 3. Primary outcome from the Study of Heart and Renal Protection testing simvastatin 20 mg plus ezetimibe 10 mg po qd versus placebo. The primary outcome was time until first major atherosclerotic event (nonfatal myocardial infarction or coronary death, nonhemorrhagic stroke, or any arterial revascularization procedure). Reproduced with permission from Baigent et al.38

should be kept in mind when using nitrates in patients during hemodialysis where hypovolemia at the end of a session may potentiate the hypotensive effect of the drug.94 A history of CKD confers a common dyslipidemia characterized by impaired reverse cholesterol transport and reduced lipolysis. In NHANES III, participants with CKD had higher levels of apolipoprotein B and lower levels of apolipoprotein A than did those with normal renal filtration function (P ⫽ 0.003 and P ⫽ 0.021, respectively).95 Multiple trials in subgroups of patients with CKD have demonstrated that lipidlowering therapy with the hydroxymethylglutaryl-coenzyme A reductase inhibitors pravastatin and atorvastatin was associated with reduced rates of cardiovascular events.44,96,97 The Study of Heart and Renal Protection (SHARP) demonstrated a 17% reduction in the rate of atherosclerotic events in patients with CKD using simvastatin and ezetimibe compared with placebo (Fig 3).38 Furthermore, analysis from the Heart Protection Study (HPS)39 showed a reduction in worsening renal function in patients with CKD on simvastatin. Both the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE),98 and Treating to New Targets (TNT)41 showed an increase in GFR with administration of atorvastatin in patients with CKD. Therefore, owing to protective effects on both cardiovascular events and possibly renal function, we recommend the administration of statins and ezetimibe as lipid-lowering agents in 188

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patients with CKD. It should be noted that the benefits of statins might not translate into a reduction in all-cause mortality in patients on dialysis;99 in A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA), there was no significant benefit of statin therapy on all-cause mortality in patients on dialysis, despite a lowering of low-density lipoprotein levels. Another neutral statin trial was Die Deutsche Diabetes Dialyse (4D) study,100 involving atorvastatin in patients with type 2 diabetes mellitus on maintenance hemodialysis. Atorvastatin yielded a nonsignificant 8% reduction in the primary outcome of cardiovascular death, nonfatal MI, and stroke. Bernard J. Gersh. Most of the data on statins emanate from trials enrolling older patients with comorbidities such as smoking, diabetes, or hypertension. Whether statin therapy would be beneficial in younger patients who have CKD due to primary kidney disease without traditional cardiovascular risk factors or evidence of cardiovascular disease is unclear.

Ranolazine, a late sodium channel blocker, has anti-ischemic effects without a clinically significant reduction in heart rate or blood pressure and is used an adjunctive therapy for chronic stable angina.101,102 The Monotherapy Assessment of Ranolazine in Stable Angina (MARISA) trial demonstrated a dose-dependent benefit of ranolazine compared with placebo on the outcome of exercise treadmill time.103 Given a modest prolongation of the QT interval using ranolazine, patients with baseline QT prolongation could be more prone to torsades de pointes.101 Ranolazine in non-ST-elevation ACS did not reduce mortality but did have an adequate safety profile.103 Ranolazine has 73% of its clearance through the urine.104 Reduced GFR has been shown to increase the area under the ranolazine concentration time curve between 0 and 12 hours by 2-fold.105 Despite presumed higher serum levels of ranolazine in patients with CKD, no serious adverse events have been reported in this population. Nevertheless, a dose reduction of ranolazine may be needed depending on the severity of renal dysfunction (remaining at 500 mg orally twice daily).

Optimal Blood Pressure Control The Joint National Committee VII guidelines recommended a target blood pressure of ⬍130/80 mm Hg in patients with CKD.106 This goal is supported by subsequent analyses of clinical trials in patients with CKD and cardiovascular disease.107 In fact, further reduction of blood pressure Curr Probl Cardiol, May 2013

189

Fig 4. Optimal blood pressure targets for patients with CKD and CVD. Reproduced with permission from Khouri et al.109

parameters (systolic 120-130 mm Hg and diastolic 70-80 mm Hg) has been recommended in those patients with CKD and proteinuria of ⬎1 g/d. However, a meta-analysis found that there was no difference in adverse events in nondiabetic patients with CKD with a blood pressure goal of 140/90 mm Hg compared with those with a goal of 130/80 mm Hg.108 By contrast, lower-quality evidence showed tighter blood pressure control may be beneficial in patients with proteinuria of ⬎0.3-1 g/d (Fig 4).106 Furthermore, in an analysis of KEEP (n ⫽ 16,129 with eGFR ⬍60 mL/min), Peralta et al.110 found that the risk for progression to ESRD or death began to increase at a systolic blood pressure of ⬎140 mm Hg. Among those with ESRD, the risk of cardiovascular events and cardiovascular deaths, in theory, could be reduced by almost one-third with uniform blood pressure control,111 although no formal blood pressure goals exist. In addition, the removal of fluid during hemodialysis alters hemodynamics and makes the evaluation of hypertension challenging. Agarwal and Lewis propose a predialysis blood pressure of ⬎150/85 mm Hg to have 80% sensitivity in monitoring hypertension in patients on dialysis.112 The effects of low blood pressure should also be highlighted as a U-shaped relationship exists between mortality and blood pressure, demonstrating that low blood pressure is associated with worse outcomes.113 190

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Optimal management of blood pressure in CKD requires coordination of antihypertensive therapy with other therapies, such as antilipidemics, glycemic control, smoking cessation, and lifestyle modifications.85 The most important lifestyle change is dietary sodium restriction to ⬍2 g/d, which lowers blood pressure, lessens soft-tissue edema, and allows a greater response to antihypertensive therapy. For hypertensive patients with established CAD, we recommend initial treatment with ␤-adrenergic receptor blockers and/or ACE inhibitors or ARBs, with the addition of other drugs to achieve target blood pressure levels (Class IC recommendation).85 The cardiovascular protective benefit of ACE inhibitors has been demonstrated by the Heart Outcomes Prevention Evaluation (HOPE) trial as well as by several smaller studies with CKD subgroups.114 Accordingly, in patients with CKD, ACE inhibitors are indicated in all patients with hypertension, diabetes mellitus, and in those with a left ventricular ejection fraction of ⱕ40% (Class IA recommendation).85 ARBs may also be used, and several studies have shown a delay in progression to ESRD in patients with type 2 diabetes mellitus with proteinuria.115,116 Despite the benefits of blood pressure control, compliance with sodium restriction and multiple oral agents remains a barrier, as one-third of patients with CKD have low adherence resulting in poor blood pressure control.117 Bernard J. Gersh. As the response to ACE/ARB in patients with cardiovascular and presumably renovascular disease is unpredictable, it is mandatory to monitor blood pressure and renal function carefully during the initiation of these therapies.

Modification of Vascular Calcification Atherosclerotic calcification begins as early as the second decade of life, just after fatty streak formation in human arteries.118 Coronary artery lesions of young adults have revealed small aggregates of crystalline calcium within the necrotic lipid core of a plaque demonstrated on histopathology and by electron microscopy. Calcium phosphate (hydroxyapatite, Ca3[-PO4] 2-xCa[OH]2) contains 40% calcium by weight and precipitates in diseased coronary arteries by a mechanism similar to that found in osteogenesis and bone formation. Hydroxyapatite is secreted in vesicles that pinch off from transformed vascular smooth muscle cells that are histopathologically and functionally similar to osteoblasts in lamellar bone. Coronary artery calcification (CAC) seems to occur exclusively in atherosclerotic arteries and is absent in normal vessel wall. Curr Probl Cardiol, May 2013

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Thus, the finding of calcification on human imaging studies implies the anatomic presence of atherosclerosis and relates to CAD risk.119 When the eGFR is ⬍60 mL/min/1.73 m2, there is a reduction in the filtration and elimination of phosphorus. Approximately 70% of the ingested phosphorus, mainly in the form of protein, is cleared by the kidneys each day. Thus, subtle degrees of hyperphosphatemia combined with a relative hypocalcemia and deficiency of vitamin D trigger the release of parathyroid hormone (PTH), which in turn liberates calcium from bone, potentially accelerating the vascular calcification process. Patients with ESRD have the greatest absolute values and rates of accumulation of CAC. A variety of stimuli can induce vascular smooth muscle cells to assume osteoblast-like functions, including handling of phosphorus, oxidized low-density lipoprotein cholesterol (LDL-C), vascular calcification factor, PTH, and vascular calcification factor. Clinical studies in ESRD suggest that vascular calcification is influenced by the age, length of time on dialysis, and dyslipidemia.120 A systematic review of the literature concerning CKD and ESRD (n ⫽ 2919) found 31 studies that were split on either finding or not finding significance of serum calcium (Ca), serum phosphate (PO4), calcium–phosphorus product, PTH, or treatments for calcium–phosphorus balance, including phosphate binders, calcium, and vitamin D analogs. When considered, the lipid profiles (primarily reduced high-density lipoprotein cholesterol, elevated triglycerides, elevated LDL-C, and elevated total cholesterol) were the most predictive factors for CAC in ESRD.120,121 There have been multiple randomized trials comparing non-calciumbased phosphate binders (eg, sevelamer, a gastrointestinal phosphate binder with a similar structure to the bile acid-binding resin colesevelam) and calcium-based binders (calcium carbonate or calcium acetate), measuring the change in CAC by computed tomography scans done at baseline and at 52 weeks.122 In general, no specific strategy has been shown to change the annual rate of increase in CAC score, which has been pooled from 10 trials to be 16.9% and 18.4% in general and CKD populations, respectively.122 This study found no association between the degree of LDL-C reduction or blood pressure control and CAC progression, despite having a reduction in the rates of cardiovascular events. Cinacalcet, a calcimimetic agent that modifies the calcium-sensing receptor on parathyroid cells and is used as a treatment of secondary hyperparathyroidism, and vitamin D analogs that reduce nuclear transcription of PTH have been tested as agents to reduce the rate of CAC. The ADVANCE study (A randomiseD VAscular calcificatioN study to evaluate the effects of CinacalcEt) randomized hemodialysis patients with 192

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PTH ⬎300 pg/mL or PTH 150-300 pg/mL with calcium–phosphorus product ⬎50 mg2/dL2 while receiving calcium-based phosphate binders to cinacalcet (30-180 mg/d) plus low-dose calcitriol or vitamin D analog (ⱕ 2 ␮g paricalcitol equivalent/dialysis session), vs flexible vitamin D therapy.123 The median CAC scores increased 24% in the cinacalcet group and 31% in the flexible vitamin D group (P ⫽ 0.07). The EVOLVE (EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events) trial randomized 3883 ESRD patients with secondary hyperparathyroidism to cinacalcet vs placebo, and despite lowering PTH, there was no difference in the primary composite of all-cause mortality or first nonfatal cardiovascular event, including MI, hospitalization for unstable angina, heart failure, or peripheral vascular event; however, when adjusting for baseline factors, including age, cinacalcet had a modest reduction in the relative hazard for the primary composite end point of 0.88 (95% CI: 0.79-0.97; P ⫽ 0.008).124 Unfortunately, CAC was not evaluated in this trial. Thus, at the time of this writing, there are no strategies that manipulate calcium–phosphorus balance or treat secondary hyperparathyroidism that influence the progression of coronary calcification or significantly decrease the rates cardiovascular events in patients with ESRD.

Coronary Revascularization in Stable Coronary Disease Patients With CKD Patients with CKD, as discussed previously, have more extensive coronary atherosclerosis, which tends to be considerably more calcified than similar patients with normal renal function. The spatial distribution of the lesions tends to be more proximal and longer in length, as shown in Fig 5.125 There are limited data on outcomes in the modern era of coronary stenting and use of off-pump bypass surgery. The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial reported that in the predialysis CKD subgroup, n ⫽ 320 (14%), after adjustment for baseline differences, CKD was an independent predictor of death or nonfatal MI, but PCI had no effect on these outcomes.126 At 36 months, a similar percentage of patients with CKD treated with optimal medical therapy (70%) and PCI plus optimal medical therapy (76%) were angina-free compared with patients without CKD. In a registry of both ACS and stable CAD patients, the Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH), survival was reported in 662 dialysis patients (1.6%) and 750 non-dialysis-dependent kidney disease patients (1.8%).127 Adjusted 8-year survival rates were 45.9% for CABG, 32.7% for PCI, and 29.7% Curr Probl Cardiol, May 2013

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Fig 5. Spatial geometry of CAD in patients with significant CAD demonstrating the tendency for more proximal and longer coronary lesions than in those with normal renal function. Reproduced with permission from Mukherjee.125

for medical therapy alone in the nondialysis kidney disease group (P ⬍ 0.001 for CABG vs no revascularization; P ⫽ 0.48 for PCI vs no revascularization) and 44.8% for CABG, 41.2% for PCI, and 30.4% for no revascularization (P ⫽ 0.003 for CABG vs no revascularization; P ⫽ 0.03 for PCI vs no revascularization) (Fig 6). Charytan et al.128 reported on Medicare recipients with CKD undergoing PCI (n ⫽ 8620) or CABG (n ⫽ 4547). The 3-year cumulative incidence of progression to ESRD was lower (PCI: 5.4%, CABG: 6.8%) than death (PCI: 32.8%, CABG: 28.3%). The adjusted hazard ratio of death was greater during the first 3 194

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A

1 CABG

Survival Rate

0.8

PCI No revasc

0.6 0.4 0.2 0 0

1

2

3

4

5

6

7

8

Time since coronary angiography (years)

B

1

Survival Rate

0.8 0.6 CABG

0.4

PCI No revasc

0.2 0 0

1

2

3

4

5

6

7

8

Time since coronary angiography (years)

C

1

Survival Rate

0.8 0.6 CABG

0.4

PCI

0.2

No revasc

0 0

1

2

3

4

5

6

7

8

Time since coronary angiography (years) Fig 6. Long-term survival in patients with CAD and CKD or ESRD with medical therapy, PCI, and CABG. Adapted with permission from Hemmelgarnet et al.127

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months after CABG than after PCI (1.25, 95% CI: 1.12-1.40; P ⬍ 0.001), but less from 6 months onward (0.61, 95% CI: 0.55-0.69). In one small (n ⫽ 100) study from Korea, patients with predialysis CKD and multivessel CAD were compared according to those who received PCI or CABG.129 Both groups had similar baseline characteristics. At 3 years, the death rate (PCI: 18.8% vs CABG: 19.2%, P ⫽ 0.94) was similar between the PCI and CABG groups, but the major adverse cardiac event rate (PCI: 47.9% vs CABG: 21.2%, P ⫽ 0.006) was higher in the PCI group compared with the CABG group, largely driven by repeat revascularization (PCI: 12.5% vs CABG: 1.9%, P ⫽ 0.05). In the Arterial Revascularization Therapies Study (ARTS) trial, 292 (25%) had predialysis CKD, 151 and 139 received PCI and CABG, respectively.130 No difference was observed in the rates of death, MI, or stroke with CABG or PCI. However, CABG was associated with a 72% reduced risk for repeat revascularization (P ⬍ 0.01). In a meta-analysis of 16 studies, with 32,350 ESRD patients undergoing revascularization, with PCI or CABG, surgery was associated with a 10% risk reduction for mortality beyond 1 year, a 36% reduction in MI, and a 78% reduction in repeat revascularization, despite having a higher risk for early mortality (RR: 1.98, 95% CI: 1.51-2.60).131 Studies of off-pump CABG have demonstrated significantly lesser changes in microalbuminuria, fractional excretion of sodium, free water clearance, N-acetyl-beta-D-glucosaminidase (marker of renal injury), and free hemoglobin compared with operation done with cardiopulmonary bypass.132 A recent randomized trial of off-pump surgery vs bypass found lower rates of acute kidney injury (Cr rise ⱖ 0.3 mg/dL, 28.0 vs 32.1%, P ⫽ 0.01) but no differences in the use of dialysis or death with off-pump surgery.133 Thus, it appears that in patients with more severe CAD and CKD, revascularization, particularly CABG when possible, despite the early hazards, confers a long-term survival benefit.

Conclusions CKD is a high-risk condition that must be considered in the evaluation and treatment of patients with coronary atherosclerosis and in those presenting with ACS. Treatment in this patient population should consist of therapies proven to improve symptoms and reduce morbidity and mortality. Certain medications require dosing adjustment based on renal clearance. In the setting of ACS, patients with predialysis CKD should preferentially undergo an early invasive strategy, consisting of coronary angiography and PCI or surgical revascularization, if there is amenable coronary anatomy. This recommendation does not extend to patients undergoing hemodialysis or peritoneal dialysis, where additional research 196

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is needed. In stable CAD, multiple medical interventions that result in reduction in LDL-C and blood pressure are associated with reduced rates of major cardiac events. When stable angina is present, and coronary lesions are amenable to revascularization, there appears to be a survival benefit with revascularization compared with medical therapy alone. In patients with multivessel disease, CABG is associated with reduced long-term mortality compared with PCI, despite the early hazards of surgical complications. Bernard J. Gersh. This is an excellent summary of an important and complex topic. Both the text and the comprehensive tables will provide a valuable source of reference for those of us who treat these patients with combined cardiovascular and chronic renal disease. The link between CKD and cardiovascular disease is strong and is being increasingly recognized. Not only is CKD a risk factor for cardiovascular disease, but its presence and severity are powerful adverse prognostic factors. Moreover, in the presence of an acute coronary number of therapeutic options, the presence of CKD introduces an additional layer of complexity. In this respect, this review is particularly helpful in identifying differences between standard therapeutic approaches and those in patients with CKD. The interrelationship between these 2 conditions is further highlighted by the indisputable fact that cardiovascular disease is the single best predictor of mortality in patients with ESRD and, in some series, accounts for almost 50% of the deaths. It is clear, therefore, that an assessment of the presence and extent of CKD is an integral part of the evaluation of patients with cardiovascular disease and has a major impact on the choice of therapies and prognosis. This monograph is timely and provides a contemporary overview of the management of both acute and chronic CAD in patients with CKD.

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