Chronic kidney disease (CKD) affects approximately 26 million people in the US.1 CKD is considered a coronary risk equivalent and also a risk factor for progression of cardiovascular disease (CVD).2 Cardiovascular death rates are 10–30 times higher in dialysis patients than in the general population.3 This increase in CKD patients is multifactorial and is now mainly considered via two pathways: pump failure and arrhythmias.4 The uremia-related non-traditional cardiac risk modifiers include cardiomyocyte dysfunction, defective iron re-utilization and erythropoietin deficient anemia, abnormal calcium–phosphate homeostasis with phosphate retention and hyperparathyroidism, inflammation, hyperhomocysteinemia, and hypervolemia; these all contribute to the increased risks observed in CKD patients.5 In addition, the dialysis procedure (peritoneal or hemodialysis) itself likely contributes to CVD morbidity. Due to the under-representation of CKD patients in controlled trials of CVD6, there is a limited body of evidence for treatment modalities specific to this population. Most of the current evidence suggests that with appropriate monitoring, cardiovascular medications and interventional strategies can be applied safely and provide a benefit in patients with renal impairment.7
To increase awareness of CKD, an American Heart Association (AHA) science advisory for the detection of CKD in patients with, or at increased risk for, CVD was recently developed in collaboration with the National Kidney Foundation. The advisory recommends that all patients with CVD be screened for evidence of kidney disease by estimating glomerular filtration rate (GFR) and testing for microalbuminuria by measuring the albumin:creatinine ratio (Class IIa, Level of Evidence: C).8 A GFR less than 60 ml/min/1.73 m2 of body surface area should be regarded as abnormal (Class I, Level of Evidence: B). Furthermore, the albumin:creatinine ratio should be used to screen for the presence of kidney damage in adult patients with CVD, with values greater than 30 mg albumin per 1 g creatinine regarded as abnormal (Class IIa, Level of Evidence: B). It has been shown that urine microalbuminuria will detect CKD in younger populations while estimated GFR (eGFR) is the major identifier in older age groups.9
The Kidney Early Evaluation Program (KEEP) is a free community-based health screening program that targets populations 18 years and older at high risk of kidney disease.10 For screening patients for CKD, KEEP now employs the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation instead of the Modification of Diet in Renal Disease (MDRD) equation.11 The use of the CKD-EPI equation results in a higher eGFR for a given creatinine level compared with the MDRD study equation for most people younger than 75 years. Therefore, the use of the CKD-EPI equation led to a lower estimated prevalence of CKD in the National Health and Nutrition Examination Survey (NHANES) at 11.1 %, compared with 13.2 % using the MDRD study equation. When analyzed with respect to CVD risk factors, researchers found that net reclassification showed a 15.9 % improvement (p<0.001) in the association of eGFR with mortality. Therefore, the CKD-EPI equation is now considered the preferred eGFR equation when providing prognostic information concerning CVD and mortality.
Cardiovascular Disease in Patients with Chronic Kidney Disease
A history of CKD should be considered more than a coronary risk equivalent, and patients should receive equally intensive risk factor intervention as those with clinically apparent coronary heart disease (Level of Evidence: A).3 The risk of cardiovascular mortality in patients with moderate CKD was as high as that in patients with a history of myocardial infarction (MI) or diabetes mellitus (DM).12
The most common initial manifestation of ischemic heart disease is chronic stable angina, occurring in almost half of patients.13,14 Even patients with mild anginal symptoms may have severe coronary artery disease (CAD).15–17 Initial evaluation in all patients suspected of symptomatic CVD, including those with CKD, includes a thorough history and physical examination, as well as a baseline electrocardiogram (ECG). Further risk stratification for CVD in patients with a higher index of suspicion should be done with exercise or pharmacologic stress echocardiography or nuclear scintigraphy.
Coronary Artery Calcification in Chronic Kidney Disease
Coronary artery calcification (CAC), a marker for atherosclerosis, is more common in CKD than in the general population. Although elevated CAC can occur without significant obstructive atherosclerosis, evidence suggests a predictive trend, even in CKD, of elevated CAC with obstructive atherosclerosis.18 Coronary computed tomography angiography (CCTA) is useful especially due to its negative predictive ability to exclude obstructive CAD.19,20
Historically, patients with CKD and those on dialysis have largely been excluded from trials involving CCTA due to the high coronary artery calcium burden, which may interfere with CCTA evaluation, as well as the high contrast volume load, which raises safety concerns for contrast-induced acute kidney injury. The change on coronary calcium scoring on serial CCTA should not be considered a valid endpoint in clinical trials or a measure of response to anti-atherosclerotic therapies, since osteoblastic transformation of vascular smooth muscle cells is a late-stage, stabilizing feature of fibrous plaques.21–24
Importance of Optimal Blood Pressure Control
The Joint National Committee VII (JNC VII) guidelines recommend a tighter control of blood pressure in the CKD patient, with a goal of less than 130/80 mmHg.25 The risk of cardiovascular events and cardiovascular deaths could be reduced by almost one-third among dialysis patients if they all received blood pressure-lowering agents.26 Optimal management of CKD requires coordination of antihypertensive therapy with other therapies, such as smoking cessation, lipid-lowering therapy, management of diabetes, and other dietary and lifestyle modifications.27 The most important lifestyle change is to restrict sodium to <2 g/day, which will result in lower blood pressure, less soft tissue edema, and greater responsiveness to oral antihypertensive therapy. For hypertensive patients with well-established CAD, it is useful to add blood pressure medication as tolerated, treating initially with beta-blockers and/or angiotensin-converting enzyme (ACE) inhibitors, with the addition of other drugs as needed to achieve target blood pressure (Class IC recommendation).27 The cardiovascular protective benefit of ACE inhibitors has been demonstrated by the Heart outcomes prevention evaluation (HOPE) trial as well as several smaller studies.28 Therefore, in CKD patients, ACE inhibitors should be started and continued indefinitely in all patients with left ventricular ejection fraction less than or equal to 40 %, as well as those with hypertension or diabetes (Class IA recommendation).27 Despite the benefits of blood pressure control, compliance still remains a barrier; one-third of CKD patients have low adherence to antihypertensive medication, contributing to poor blood pressure control.29
Pharmacologic Interventions Recommended for Chronic Coronary Disease
Pharmacologic treatment of patients with chronic stable angina in the presence of CKD includes aspirin, beta-blockers, ACE inhibitors, nitrates, and statin therapy, with ranolazine used as adjunctive therapy (see Table 1). Aspirin reduces mortality in patients with stable known or suspected coronary heart disease.30 Aspirin should be started and continued indefinitely at a dose of 75–100 mg/day in all patients unless contraindicated.27 There are no particular recommendations for the change in dosing of aspirin in CKD patients; however, they are recognized to be at increased risk of bleeding with all antiplatelet agents, given uremic platelet dysfunction. Beta-blockers have been shown to reduce mortality in all patients, and have similar benefits in CKD patients. Selective beta-1 adrenergic blockers such as metoprolol and combination alpha- and beta-blockers such as carvedilol should be generally favored because of studies demonstrating cardiovascular protection with these agents, particularly in patients with heart failure.31,32 Metoprolol and atenolol are dialyzable agents, and require supplementation after dialysis.33 Metoprolol, primarily excreted by the liver, does not need dosage adjustment in dialysis patients.33 Atenolol, acebutolol, and nadolol, however, are renally excreted and may require dosage adjustment in dialysis patients.34 There is weak evidence that some beta-blockers may hinder peritoneal transport in patients on peritoneal dialysis (PD)35 but this evidence is not sufficient to warrant withholding the use of beta-blockers in dialysis patients when they are clearly indicated. In patients with previous MI or with well-established CAD, beta-blockers should be the preferred antihypertensive agent.
Angiotensin receptor blockers (ARBs) should be initiated in those patients that are intolerant to ACE inhibitors.27 ARBs are also recommended for use in post-MI patients without significant renal dysfunction (creatinine <2.5 mg/dl in men and <2.0 mg/dl in women) or hyperkalemia (potassium <5.0 mEq/l) who are already receiving therapeutic doses of an ACE inhibitor and a beta-blocker, and have a left ventricular ejection fraction less than or equal to 40 % (Class IA Recommendation).27
Nitrates have commonly been shown to decrease anginal symptoms in patients. The use of nitrates results in a relaxation of vascular smooth muscle, and a decrease in systemic arterial blood pressure.36 Therefore, caution should be exercised when using nitrates in dialysis patients. Hemodialysis creates a transient low-preload state (i.e. hypovolemia at the end of a hemodialysis session), and this may potentiate the hypotensive effect of the drug.37
A history of CKD also confers an increased risk of dyslipidemia characterized by impaired reverse cholesterol transport and reduced lipolysis. In NHANES III, participants with CKD (GFR <60 ml/min/1.73 m2) had higher levels of apolipoprotein B and lower levels of apolipoprotein A than those with normal renal function (p=0.003 and 0.021, respectively).38 Multiple trials in CKD subgroups have demonstrated that lipid-lowering therapy with pravastatin and atorvastatin reduces cardiovascular events.39–41 The Study of heart and renal protection (SHARP) demonstrated a 17 % reduction in the rate of atherosclerotic events in CKD patients using simvastatin and ezetimibe when compared with placebo.42 Therefore, we recommend the administration of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors and ezetimibe as lipid-lowering agents in CKD patients, but note that the benefits may not translate into reductions in mortality.43
Ranolazine, a piperazine derivative that exerts anti-ischemic actions without a clinically significant effect on heart rate or blood pressure, is an adjunctive therapy for chronic stable angina.44,45 The Monotherapy assessment of ranolazine in stable angina (MARISA) trial demonstrated a dose-dependent benefit of ranolazine compared with placebo in improving exercise duration.45 However, due to an association with a modest prolongation of the QT interval, certain patients could be more prone to torsades de pointes.44 Ranolazine in non-ST-elevation (non-STE) acute coronary syndrome (ACS) does not show a clear mortality benefit, but has been shown to have an adequate safety profile.46 Pharmacokinetically, ranolazine has a 73 % excretion through urine.47 Reduced glomerular filtration has been shown to increase, up to twofold, the area under the concentration time curve (AUC) between 0 and 12 hours after the dosing of ranolazine.48 Despite the higher serum levels of ranolazine in CKD patients, no serious adverse events have been observed. In the light of these findings, dose reduction of ranolazine may be needed depending on the severity of renal dysfunction.
Risk Assessment in Acute Coronary Syndromes
Among patients presenting with chest discomfort to the emergency department, patients with CKD have an approximate 40 % chance of MI, heart failure, or death.49 Across the spectrum of confirmed ACS, patients with chronic renal insufficiency have more extensive CAD, a worse risk profile, more atypical and delayed presentations, and are less likely to receive evidence-based therapy.50
Of the eight variables used in the Global Registry of Acute Coronary Events (GRACE) risk model, which predicts in-hospital mortality in patients with unstable angina (UA), non-ST-segment MI (NSTEMI), or ST-segment MI (STEMI), serum creatinine level demonstrated a 1.2-fold greater risk of mortality per 1 mg/dl increase.51,52 The severity of renal dysfunction is associated in a graded fashion with short- and long-term mortality.53,54 Patients with renal dysfunction experience increased bleeding risk, have higher rates of heart failure and arrhythmias, have been under-represented in cardiovascular trials, and may not enjoy the same magnitude of benefit with therapies compared with patients with normal renal function.6 The medical history, physical examination, ECG, assessment of renal function, and cardiac biomarker measurements in patients with symptoms suggestive of ACS at the time of initial presentation are essential in estimating the risk of death and non-fatal cardiac ischemic events which, as indicated above, are clearly higher than in those without CKD.3,55–58
When evaluating a patient with suspected ACS, the diagnostic role of cardiac troponins, consisting of Troponin I (cTnI), Troponin T (cTnT), and Troponin C (cTnC) subunits, is complicated by renal insufficiency. Although troponins accurately identify myocardial necrosis, they do not inform as to the causes of necrosis; these can be multiple,59 including renal insufficiency.60 In patients with renal dysfunction, cTnI assessment appears to have a specific role.61 Among patients with end-stage renal disease and no clinical evidence of acute myocardial necrosis, 15–53 % show increased cTnT, but fewer than 10 % have increased cTnI; dialysis generally increases cTnT and, to a lesser extent, cTnI. The exact reasons for the high rates of elevation of cardiac troponins, especially cTnT, in renal failure are not clear; they can be related to myocardial damage, differential clearance, or to other biochemical or metabolic abnormalities.61 It is plausible that the elevation in serum cardiac troponins in asymptomatic dialysis patients is a reflection of silent ischemic heart disease or non-ischemic cardiomyopathy; troponin levels have also been shown to be related to left ventricular (LV) mass.62 In almost 7,000 patients enrolled in the Global use of strategies to open occluded coronary arteries (GUSTO IV) trial with suspected ACS, TnT level was an independent predictor of risk across the entire spectrum of renal function.63 A sequential change in cardiac troponin levels in the first 24 hours of observation for a suspected ACS supports new myocardial injury, whereas unchanging levels are more consistent with a chronic disease state without ACS.3
Treatment of Acute Coronary Syndromes
Patients presenting with STEMI should be taken to a percutaneous coronary intervention (PCI) center and undergo primary PCI with stenting within 90 minutes. In addition, thrombolysis may be an initial reperfusion strategy for patients presenting outside of a 90 minute door-to-balloon time for percutaneous intervention in the setting of STEMI. Patients with STEMI and kidney disease do not receive thrombolytic therapy as quickly as those without kidney disease.64 Newsome et al. found that of 109,169 Medicare patients with MI (mean age 77), fewer patients with kidney disease received thrombolytic therapy, and patients with the worst kidney disease waited the longest for therapy. The disparity may arise from the concern about thrombolytic-associated bleeding in patients with kidney disease, yet Newsome et al. demonstrated the adjusted odds ratio (OR) for bleeding events was lower in patients on dialysis versus patients with normal kidney function (OR 1.84 versus 2.28). There are no formal dose adjustment recommendations for the use of streptokinase, alteplase, reteplase, or tenecteplase in patients with CKD. The post-reperfusion care of STEMI patients largely follows a similar set of guidance to that of NSTEMI patients. Once a patient with suspected non-STE ACS is admitted to the hospital, standard medical therapy should be initiated, consisting of aspirin, beta-blocker, anticoagulant therapy, possibly a glycoprotein (GP) IIb/IIIa antagonist or abciximab, and a thienopyridine, unless there is a specific contraindication.3 In the untreated state, patients with CKD have greater tendencies to blood clotting given excessive generation of thrombin and potential losses of protein C in the urine. However, in the setting of anticoagulants, given the presence of a greater number of circulating thrombin–antithrombin complexes, all forms of indirect thrombin and factor Xa inhibitors (heparin, low molecular weight heparin [LMWH], fondaparinux) have a more potent effect on the coagulation system, and hence have greater rates of major bleeding complications. Intravenous bivalirudin, a direct thrombin inhibitor, has been associated with the lowest bleeding risk and best cardiovascular endpoint outcomes in patients with CKD.65
The American College of Cardiology (ACC)/AHA guidelines for ACS give additional detail on the issue of PCI in non-STE ACS.3 Mild to moderate kidney disease is considered high-risk in UA/NSTEMI, and an invasive strategy is preferred to conservative medical management.66 However, for patients undergoing dialysis or those with end-stage renal disease, the data are not sufficient to recommend catheterization, and may even suggest harm.66 Although CKD patients are less likely to be offered coronary angiography in ACS, they still benefit from revascularization and have a reduction in six-month mortality.67,68
The choice for primary PCI in CKD has been questioned in recent studies.69 The Swedish web-system for enhancement and development of evidence-based care in heart disease evaluated according to recommended therapies (SWEDEHEART) showed that in 23,262 consecutive cases of non-STE MI, as eGFR declined there was a lesser use of coronary angiography and revascularization.70 In patients with eGFR <30 ml/min/1.73 m2, fewer than one-third are selected for an early invasive management approach for ACS. This group, however, had a 33.7 % relative risk reduction in mortality compared with those managed conservatively (41.5 % all-cause mortality).71 Patients with CKD with or without diabetes who undergo angiography are at higher risk of contrast-induced acute kidney injury. This risk, however, is not compounded by the choice of the contrast agent used for angiography. The 2009 ACC/AHA guidelines for PCI recommend that for patients with CKD undergoing angiography who are not undergoing chronic dialysis, either an iso-osmolar contrast medium (Level of Evidence: A) or a low molecular weight contrast medium other than ioxaglate or iohexol is indicated (Level of Evidence: B).72,73 The 2011 ACC/AHA guidelines denote less emphasis on specific types of contrast agents, and more emphasis on the volume of contrast used during PCI.66 In addition, it is recommended that patients should be adequately hydrated prior to undergoing angiography.
As mentioned previously, all patients, including those with CKD, should receive aspirin and beta-blockers unless otherwise contraindicated. In UA/NSTEMI patients where beta-blockers are contraindicated, a non-dihydropyridine calcium channel blocker should be given as initial therapy in the absence of clinically significant LV dysfunction or other contraindications (Level of Evidence: B).74 Thienopyridines are indicated in the setting of ACS, and can be used in CKD patients. Clopidogrel is approved in the general population for the secondary prevention of atherosclerotic CVD events, including CAD. Most dialysis patients would theoretically be candidates for long-term clopidogrel therapy. The 2011 ACC/AHA guidelines add prasugrel to the list.66 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 conservative, non-invasive management. In patients managed non-invasively, 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 one month.
Prasugrel may also be used in this clinical scenario, with a class IIB recommendation. Following PCI, both clopidogrel and prasugrel should be given for at least 12 months. The 2011 ACC/AHA guidelines recommend the use of GP IIb/IIIa inhibitors in high-risk UA/NSTEMI patients already taking aspirin and a thienopyridine and who are selected for an invasive strategy.66 However, they note that in UA/NSTEMI patients at low risk of ischemic events, such as those with a thrombolysis in MI (TIMI) risk score <2 or those at high risk of bleeding, who are already treated with aspirin and clopidogrel, the upstream use of GP IIb/IIIa inhibitors is not recommended (see Table 2). In addition, those with elevated cardiac troponins also benefit from GP IIb/IIIa inhibitors. Abciximab and tirofiban have both been shown to reduce death or non-fatal MI in patients with cTnT elevation75,76 and should also be considered as adjunctive therapy in ACS in dialysis patients. Abciximab is the preferred agent for PCI, and the clearance of the drug is not altered in dialysis patients. Tirofiban requires a 50 % dose reduction for eGFR <30 ml/min. Eptifibatide, also a platelet GP IIb/IIIa inhibitor, is renally cleared and requires a 50 % dose reduction for eGFR <50 ml/min. Its use is not recommended in dialysis patients because of increased bleeding risk.77 Despite increased bleeding events, reduced in-hospital mortality in CKD patients with ACS treated with IIb/IIIa antagonists has been shown.78 The 2008 American College of Chest Physicians (ACCP) non-STE ACS guidelines recommend anticoagulation in all patients with unfractionated heparin (UFH), LMWH, bivalirudin, or fondaparinux over no anticoagulation (see Table 3).79 In patients selected for an invasive strategy, both UFH and an LMWH, such as enoxaparin, are Class IA recommendations in the 2011 ACC/AHA UA/NSTEMI guidelines.66 Whether managed invasively or conservatively, fondaparinux, a direct Factor Xa inhibitor, is also an option with a Class IB recommendation, and is preferred in those with an increased risk of bleeding. Bivalirudin, a direct thrombin inhibitor, is a Class IB recommendation only in patients selected for an invasive strategy. When choosing these agents in patients with renal dysfunction, it should be noted that UFH is not renally cleared, and can be used in CKD and dialysis patients.80 LMWH has long shown clear benefits in patients with elevated cardiac troponins suspected of UA and NSTEMI.81,82 However, enoxaparin, a renally cleared LMWH, should be used with caution in patients with renal insufficiency, due to the increased risk of bleeding complications.
It is not recommended in dialysis patients for this reason.83,84 Fondaparinux is also cleared renally, and is contraindicated in patients with a creatinine clearance <30 ml/min. Bivalirudin, cleared with partial renal excretion, is currently only recommended for use in patients selected for an invasive strategy, and requires dosage adjustment in patients with renal dysfunction.85 Of note, bivalirudin is also dialyzable.
Atrial Fibrillation is a common comorbidity in patients with ACS and CKD.86 Dabigatran, an oral direct thrombin inhibitor, was recently approved by the Food and Drug Administration for anticoagulation in patients with non-valvular atrial fibrillation.87 For patients with renal dysfunction, the 75 mg twice daily dose was approved for a creatinine clearance of 15-30 ml/min. In dialysis patients or those with a creatinine clearance <15 ml/min, it is contraindicated at this time.88 Currently, dabigatran is being studied for the secondary prevention of cardiac events in patients with prior coronary events, and we await the results to help define its role. Another newly available agent is rivaroxaban, an oral factor Xa inhibitor. It is currently being studied in the setting of ACS, via the ongoing Anti-Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with ACS (ATLAS ACS) 2-TIMI 51 trial, the results of which will help determine its benefit in this setting.
CKD is a high-risk condition in the evaluation and treatment of patients with coronary atherosclerosis. 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, pre-dialysis CKD patients should preferentially undergo an early invasive strategy, consisting of coronary angiography for further risk assessment and classification. This recommendation does not include patients undergoing hemodialysis or PD, where additional research is needed.