I. Chronic Kidney Disease: What every physician needs to know.

The presence of chronic kidney disease (CKD) is a major risk factor for developing coronary artery disease (CAD). Clinicians should be aware that the risk of dying from cardiovascular causes in patients with CKD is significantly higher than developing end-stage renal disease.

Moreover, the presence of CKD is an independent risk factor for poor outcomes, including myocardial infarction (MI) and cardiovascular death in patients with CAD. CKD is frequently associated with diabetes and anemia, and all three conditions are independent predictors of adverse outcomes in patients undergoing coronary revascularization. Furthermore, rates of restenosis following percutaneous coronary intervention (PCI) are worse in patients with advanced renal failure as compared to those with early stages of CKD or patients with normal kidney function.

The mechanisms by which CKD promotes coronary atherosclerosis are likely multifactorial. Decreased glomerular filtration rate (GFR) is a key component of the development of accelerated atherosclerosis, perhaps mediated by impaired clearance of pro-atherogenic cytokines and hormones by the kidney.

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II. Diagnostic Confirmation: Are you sure your patient has Chronic Kidney Disease?

Both decreased GFR and proteinuria increase the risk of cardiovascular disease. It is important to obtain estimates of GFR rather than relying on creatinine measurements alone. Creatinine may be in the normal range despite significantly decreased GFR, especially in women, smaller patients, and older patients.

Common risk factors for CAD such as diabetes, dyslipidemia, and hypertension overlap as risk factors for CAD, making it important to monitor GFR and screen for albuminuria on a periodic basis in patients with CAD. However, recommendations about strategies to screen for CKD in CAD patients have not been clearly established since measurement of GFR and albumin excretion provides additional risk estimation only for renal outcomes, while it does not significantly improve the prognostic value of a traditional model for risk stratification in CAD.

A. History Part I: Pattern Recognition

The clinical manifestations of CAD may be altered in patients with CKD. The initial presentation of CAD in patients with advanced stages of CKD is commonly acute clinical syndrome (ACS), particularly non-ST segment elevation, as well as ST segment elevation MI, as opposed to stable exertional angina, which is more commonly found as the first sign of CAD in less advanced CKD.

This is particularly important when the GFR is lower than 45 ml/min/1.73 m2. In addition, silent ischemia is more common in CKD patients compared to patients with normal renal function in part explained by a higher rate of diabetic neuropathy, which may correlate with the degree of renal failure.

But even nondiabetic patients with CKD, particularly those with advanced stages, also have a higher prevalence of uremic neuropathy contributing to atypical or silent presentation of CAD. This has prognostic importance since silent ischemia in patients with CKD and CAD is associated with a higher frequency of serious arrhythmias, sudden cardiac death, and heart failure and a significantly higher 10-year mortality.

Consequently clinicians should have a high index of suspicion for CAD in patients with CKD who present with an angina equivalent, such as fatigue or dyspnea. Complicating matters, clinicians must also take into account that these symptoms might also be secondary to volume overload due to impaired kidney function.

Another important consideration in terms of clinical presentation of CAD in patients with CKD is related to the hemodynamic variations that occur during dialysis. Fluid shifts with secondary hypotension and tachycardia might induce transient ischemia with subsequent angina, syncope, arrhythmias, or sudden cardiac death during or after dialysis. It is thus important to closely monitor patients with history of cardiac events or prior documented ischemia during dialysis to minimize cardiac complications.

B. History Part 2: Prevalence

It is estimated that 17% to 48% of patients with CAD have at least some degree of renal dysfunction. Patients with CKD have an increased prevalence of coronary atherosclerosis and tend to have severe disease. For example, approximately half of elderly patients with CKD carry the concomitant diagnosis of heart failure indicative of the advanced stage of their cardiovascular disease.

C. History Part 3: Competing diagnoses that can mimic Chronic Kidney Disease

CKD is a laboratory diagnosis as detailed below in the section on laboratory studies and is not easily confused with other conditions. Occasionally severe dehydration, nephrotoxic drugs, or other acute causes of kidney injury can lead to a reversible decrease in GFR, but such acute kidney injury is more common in patients with some degree of preexisting though mild CKD. Similarly, elevations in cardiac enzymes, including CK, CK-MB, and cardiac troponins might be seen in patients with renal failure but without myocardial ischemia. This will be discussed in detail in the following sections.

D. Physical Examination Findings

Hypertension, often severe, is very common in patients with CKD due to altered vascular homeostasis and activation of the renin-angiotensin-aldosterone system. Similarly, widening of the pulse pressure is frequently found as a result of peripheral vascular stiffness.

These vascular changes might be prominent and easily detected during examination of the peripheral pulses. Other frequent findings are S3 and S4 gallops as a manifestation of systolic or diastolic dysfunction secondary to chronic hypertension, ischemic cardiomyopathy, or both.

In the setting of ACS, acute ischemia might contribute to abnormal filling patterns in the left ventricle by stiffening the myocardium leading to a more prominent S4. Finally, due to valvular calcification from a process similar to the one observed in the vascular wall, it is also common to find cardiac murmurs compatible with either aortic sclerosis or aortic stenosis in patients with CKD.

E. What diagnostic tests should be performed?

The diagnosis of CKD in patients with CAD is based on criteria established by the National Kidney Foundation/Kidney Disease Outcomes Quality Initiative (NKF/KDOQI) for the general population, including those individuals with and without CAD. These criteria include: (1) Kidney damage for more than 3 months manifested by pathologic abnormalities or markers of kidney damage in the blood and urine, or on imaging with or without decreased GFR; or (2) a GFR <60 mL/min/1.73m2 for > 3 months with or without kidney damage. Once the diagnosis has been established the NKF/KDOQI recommends classification in 5 stages according to the GFR level (stage 1 kidney damage with GFR ≥ 90 mL/min/1.73 m2, stage 2 GFR 60-89 m:/min/1.73 m2, stage 3 GFR 30-59 mL/min/1.73 m2, stage 4 GFR 15-29 mL/min/1.73 m2, stage 5 GFR <15 mL/min/1.73 m2 or dialysis.

A meta-analysis that included more than 105,000 subjects demonstrated that all-cause mortality, as well as cardiovascular mortality, inversely correlated with GFR at 8-years follow-up. This study also demonstrated that higher levels of proteinuria either by urine dipstick or albumin/creatinine ratio were associated with higher cardiovascular and all-cause mortality.

Newer markers of kidney function, such as Cystatin C, beta-trace protein, and beta-2-microglobulin are more sensitive than creatinine for detecting kidney injury. Notably, estimated GFR by Cystatin-C levels has been shown to have a stronger association with cardiovascular outcomes than creatinine-based GFR estimation.

Nonetheless, these findings should be interpreted with caution as Cystatin-C levels might be elevated due to factors not directly related to kidney failure, such as inflammation and cardiovascular disease itself. In addition to this, Cystatin-C levels are not routinely measured in clinical settings.

Other laboratory tests that might be considered in the evaluation of patients with CKD and CAD include C-reactive protein (CRP) and asymmetric dimethylarginine (ADMA), which have a prognostic value in these subjects. Elevated CRP reflects a higher inflammatory burden related to the presence of CAD in CKD patients, which might have a synergistic effect in determining outcomes related to increased cardiovascular morbidity and mortality.

Similarly, ADMA, which is an endogenous inhibitor of nitric oxide synthase, is a marker of endothelial dysfunction. This molecule has displayed an association with a modest increase in cardiovascular, as well as all-cause mortality, particularly in nondiabetic patients with CKD stages 3 or 4. Another serum marker of cardiovascular risk is serum total homocysteine. When elevated, this molecule increases the risk of cardiovascular events in patients with CKD and in those with kidney transplant.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Diagnosis of ACS in patients with CKD

The diagnosis of ACS in patients with CKD is based on the combination of clinical presentation, electrocardiographic changes suggestive of acute ischemia ,and elevation of cardiac biomarkers. However, the interpretation of biomarkers in patients with impaired renal function must be done carefully.

Elevations in serum troponins are common among patients with renal failure who do not have clinical evidence of myocardial damage. These elevations are not completely understood but may be secondary to left ventricular hypertrophy due to chronic volume and pressure overload leading to release of free cytosolic troponin from cardiac myocytes and impaired renal clearance of these markers.

Although new troponin assays seem to have a better specificity to detect myocardial damage, their interpretation is also limited in patients with CKD, particularly when measuring Troponin T (cTnT). This subtype of troponin is more commonly elevated than Troponin I (cTnI) because there is a higher amount of unbound cTnT in the cytosol than cTnI and because its higher molecular weight limits its clearance by the kidneys.

Notably troponin elevations in asymptomatic patients with CKD have prognostic significance, as they are associated with worse clinical outcomes, particularly at long term, as well as decreased survival time from postischemic changes or stunning after dialysis. Troponin measurement is useful in CKD patients with suspected ACS.

Sensitivity and specificity for the detection of myocardial ischemia is higher for cTnI (94% and 100%) than for CK-MB (44% and 56%) and troponin elevations are prognostic for both short- and long-term outcomes in CKD patients with ACS. It has been found that the most accurate biomarker of myocardial injury in patients with CKD and suspected ACS is cTnI followed by cTnT and then by CK-MB, with myoglobin providing less accurate information.

Also, an important way to correctly identify myocardial damage in CKD patients is to perform serial troponin measurements, particularly cTnI, to detect progressive sequential elevation resulting from true myocardial injury instead of the steady increased levels seen with impaired renal clearance.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

What diagnostic tests should be performed

The main objective of diagnosing CAD in patients with CKD is to identify individuals whose prognosis could be improved by optimizing medical therapies or by coronary revascularization. It is assumed that strategies for secondary prevention have already been implemented in patients with CKD.

In patients undergoing dialysis, CAD should be suspected by physical examination signs; new symptoms, such as angina or angina equivalents; change in symptom patterns; new or recurrent hypotension before, during, or after dialysis; and new onset heart failure or heart failure that does not respond to changes in dry weight. These patients should be initially evaluated with electrocardiogram and echocardiogram.

Cardiac risk factors such as lipid values and blood pressure should be measured. However, it is important to understand that the interaction between these traditional risk factors and cardiovascular outcomes, based on traditional risk factor models, such as the Framingham/ATP III criteria has not been clearly established for dialysis patients as it has been for the general population or for patients with less severe stages of CKD.

After the initial evaluation, stress testing might be indicated in patients with changes in symptoms or clinical status that could be related to ischemic heart disease. This is particularly important for patients with an ejection fraction lower than 40%, history of prior coronary revascularization with CABG at least 3 years before or PCI at least 1 year before, and in those with high a Framingham risk score, especially if they are part of a transplant waiting list.

The diagnostic accuracy of stress testing in patients with CKD faces several limitations. First CKD might induce abnormalities in the electrocardiogram from LVH and electrolyte abnormalities. Similarly, the altered metabolic homeostasis might impair the interpretation of radionuclide scintigraphy. In addition to this, patients with CKD often have physical limitations interfering with their ability to exercise.

In terms of selection of noninvasive stress tests for the evaluation of CAD in CKD patients, dobutamine stress echocardiography seems to have the highest sensitivity, which is about 75%, when compared to other tests, including vasodilator-induced ischemia nuclear stress test. Notably, both dobutamine stress echocardiography and nuclear stress test provide important prognostic information in patients with CAD in the setting of CKD.

When positive for ischemia, the risk of myocardial infarction and cardiovascular death significantly increases when compared with negative studies. Currently, despite the growing data on coronary CT angiography and a calcium score in the assessment for CAD, the role of this imaging modality in the evaluation of patients with CKD is limited by the high incidence of abnormal vascular calcification that might not be necessarily associated with coronary stenosis, as well as the nephrotoxicity of intravenous contrast.

III. Management.

The decision to perform coronary angiography is often difficult in patients with CKD and is a key decision point in patient management. The risks and potential benefits must be carefully balanced and the possible need for dialysis after the procedure must be discussed with the patient. It is necessary to minimize the amount of contrast used during coronary angiography and to use iso-osmolar or low osmolar radiocontrast media as recommended by the NKF/KDOQI.

A. Immediate management.

The frequently acute presentation of CAD in patients with CKD makes immediate management an important challenge for physicians caring for this high-risk population. Higher vascular calcification, increased inflammation, higher platelet reactivity and thrombogenicity, along with a more extensive distribution of disease makes CKD patients more prone to cardiovascular events and bleeding complications.

Notably however, studies have shown that an early invasive strategy for ACS is associated with a significant decrease in mortality, MI, and rehospitalization for ACS at 30 days and 6 months in patients with CKD independent of the stage or degree of kidney damage. Such differences are less apparent at 1-year follow-up. Interestingly, the beneficial effect of revascularization, either by CABG or PCI, over medical therapy might be more significant in terms of survival for stage 5 patients but not for those patients with CKD not on dialysis according to a prospective Canadian registry that included more than 41,000 patients.

In terms of device selection, there might be some small difference in terms of occurrence of major adverse cardiovascular events (MACE) at 12 months between different types of drug eluting stents (DES), particularly driven by newer versus older generation DES. A recent retrospective study that included 2,400 patients with CKD (GFR <60 mL/min/1.73m2) who presented with STEMI showed that the rates of MACE were significantly different with Everolimus Eluting Stents (2.6%) when compared to Zotarolimus Eluting Stents (5.5%), Sirolimus Eluting Stents (8.6%), Paclitaxel Eluting Stents (9.8%), and bare metal stents (BMS) (8.3%). However there was no significant difference in survival, and the results must be interpreted with caution given the nonrandomized retrospective nature of the study.

B. Physical Examination Tips to Guide Management.

There are no data in terms of treatment response for acute or chronic treatment of CAD specifically applicable to patients with CKD. We recommend that clinicians follow standard definitions for successful revascularization with angiographic, electrocardiographic, laboratory, and clinical criteria derived from trials in patients with normal renal function.

C. Long-term management.

Medical therapy for CAD in CKD patients

A major drawback of the literature analyzing therapeutic approaches for CAD in patients with CKD is the lack of randomized controlled trials. Similarly, the implementation of subgroup analysis from major cardiovascular trials to study such interventions is not always possible as patients with CKD are systematically excluded from these trials.

Statins: Despite the fact that subgroup analysis from large randomized trials have shown that statins are associated with improved cardiovascular outcomes in patients with renal failure, results from randomized trials assessing the effect of statins in patients undergoing hemodialysis, such as the 4-D, A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA), and Study of Heart and Renal Protection (SHARP) trials failed to show efficacy.

The SHARP trial included 9,270 patients who were randomized to receive an ezetimibe and simvastatin combination, simvastatin alone or a placebo, with a compliance rate of about 71% for all treatment groups. At 4.9-year follow-up, the risk of major atherosclerotic events was reduced by 17% in patients treated with both simvastatin and ezetimibe, which translated into a reduction of 20 to 40 events per 1,000 patients who were treated for 5 years.

Similarly, subanalysis from the AURORA and the 4-D trials demonstrated that statin use was beneficial in patients undergoing dialysis who were diabetic or who had LDL above 145 mg/dl. Two meta-analyses have shown conflicting results, with one suggesting a modest benefit of statin therapy on atherosclerotic events, and the other showing no benefit in mortality, cardiovascular, and all-cause and major cardiovascular events.

The differences between these results and those in patients with normal kidney function or with mild to moderate CKD could be secondary to disparities in the pathophysiology of adverse cardiovascular events in each of these populations. For example, it is known that cardiovascular deaths occurring in patients on dialysis are commonly due to cardiac arrhythmias from myocardial abnormalities, including hypertrophy and nonischemic fibrosis where coronary atherosclerosis might not play a causative role. It is therefore recommended that the results from these trials of statins in dialysis patients should not be applied to patients with milder degrees of CKD.

Aspirin: Large observational studies suggest increased rates of cardiovascular events, including cardiovascular death in dialysis patients treated with aspirin, while the rates of stroke were lower in those patients. The randomized trial UK-HARP-1 that studied the safety of simvastatin and aspirin versus a placebo among patients with different degrees of renal failure failed to confirm the safety of aspirin in CKD patients. Thus the current recommendation from the NKF/KDOQI is that low dose aspirin (81 mg/day) might be given to patients with CKD; however ,this decision should be made on an individual basis taking into account individual risks, potential benefits, and patient preferences.

The avoidance of aspirin in dialysis patients might be reasonable due to the potential increased risk of bleeding and unproven cardiovascular benefit. Prospective randomized trials evaluating the benefit-to-risk ratio for aspirin in patients with CKD, including those on dialysis, are needed to establish clear management guidelines.

Other therapies: The evidence supporting the use of other cardiovascular medications for the treatment of CAD, including beta blockers, angiotensin converting-enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB), nitrates, and calcium blockers is limited in CKD patients and studies specifically done to test cardiovascular outcomes with these drugs in CKD patients are lacking.

Some of the available evidence addressing cardiovascular drugs in CKD patients comes from studies analyzing sudden cardiac death. A small study reported that carvedilol was effective in decreasing all-cause mortality in patients on dialysis, with a trend toward reduction of sudden cardiac death.

Similar findings were reported in the Dialysis Outcomes and Practice Patterns Study. In terms of ACE-I, retrospective data suggest a positive effect on survival rates; however, a prospective study did not report any improvement in cardiovascular events with fosinopril. On the other hand, candesartan seems to have a beneficial effect on mortality, cardiovascular, and sudden cardiac death when compared in a randomized fashion to no therapy. Again, large, prospective, randomized and placebo controlled trials are needed in order to establish the safety and efficacy of these medications in patients with CAD and CKD.

The effects of treatments other than cardiovascular medications on cardiovascular events have also been studied in CKD patients. However, most of these interventions have proved not to be beneficial. For instance, it has been reported that normalization of hematocrit with agents that stimulate erythropoiesis is associated with increased mortality, higher cardiovascular event rates, and thrombosis of the vascular access site in dialysis patients.

Similarly, higher-dose dialysis and high-flux dialysis failed to reduce cardiovascular events and improve mortality and quality of life. More recently, the EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) trial studied the effects of Cinacalcet, a calcimimetic agent used to treat hyperparathyroidism in renal failure, on cardiovascular endpoints in dialysis patients. the authors reported a 7% reduction that was not statistically significant in the risk of the primary composite endpoint of MI, hospitalization for unstable angina, heart failure, or a peripheral vascular event. Once again, these results suggest that further research is warranted in order to identify effective therapies for CAD in patients with CKD.

Optimal medical therapy versus coronary revascularization

An important body of evidence about the role of optimal medical therapy (OMT) and coronary revascularization by PCI comes from a post-hoc analysis of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial. This study evaluated the role of OMT versus PCI (predominantly BMS) as an initial therapeutic approach in patients with stable CAD.

The endpoints assessed included risk of death and nonfatal MI as primary outcomes with stroke, heart failure, hospitalization for unstable angina and freedom from angina. One important aspect of this trial is that the presence of CKD was not an exclusion criterion and creatinine levels did not determine who could be included or not.

Patients who were randomized to PCI also received intense medical therapy. ACE-I were used as antihypertensive therapy, especially for patients with diabetes and proteinuria and for patients post-MI. ARBs were used for ACE-I intolerant patients.

Lifestyle modification was also promoted among subjects included in the trial, with counseling on exercise, weight loss, nutrition, and smoking cessation. Target LDL cholesterol levels were between 60 and 80 mg/dL, while the blood pressure target was less than 130/80 for CKD patients.

The subgroup of patients with CKD from the COURAGE cohorts was composed of 320 patients (14% of the total). All had at least stage 3 CKD, but only 16 had stage 4 or worse CKD and none were on dialysis.

The degree of effective OMT was similar in patients with and without CKD. Compliance with >80% of recommended therapy was achieved in 94% of the patients with CKD. Interestingly, 77% of patients with CKD were treated with ACE-I or ARBs compared to 75% of those with normal renal function. There was no difference in terms of antiplatelet medications, beta-blockers, and statins between patients with or without CKD. There were no significant differences in terms of achieving exercise goals, blood pressure targets, and lipid goals between patients with or without CKD, and at 3-years follow-up, there were fewer smokers in the CKD group.

Despite compliance with and the ability to tolerate OMT, outcomes were far worse for the CKD patients than for those with normal kidney function, and CKD was an independent predictor of poor outcome. At follow-up, death and MI was significantly higher with an almost twofold increase in patients with CKD as compared to those with normal kidney function.

Similarly, new onset of heart failure was more commonly seen in CKD patients. PCI had no effect on these outcomes and had no significant effect on angina. At 3 years, freedom from angina was achieved in 76% of the PCI group and 70% of the OMT group.

As in the overall COURAGE study, crossover to PCI was required in approximately one third of the OMT patients, was well tolerated, and provided symptomatic relief. Importantly, the rate of restenosis was no higher in CKD patients than in those with normal kidney function. Thus an initial strategy of OMT for CKD patients with stable CAD is safe and effective, and can be supplemented with PCI if symptoms are not adequately controlled with medication alone.

PCI and Coronary Artery Bypass Grafting (CABG) in patients with CKD

A retrospective study that included a cohort of Medicare patients with CKD who underwent CABG (n = 4,547) or PCI (n = 8,620), compared outcomes in terms of progression to stage 5 CKD and death between revascularization strategies. Need for dialysis was less common than death for all patients.

Long-term mortality and the combination of death and need for dialysis were both less common with CABG. A similar retrospective study of 22,000 dialysis patients also found better survival with CABG. Such retrospective studies are subject to selection bias and sicker patients may not be deemed surgical candidates and undergo PCI instead. Nevertheless, the advanced nature and anatomic complexity of CAD in many dialysis patients often makes CABG the preferred means of revascularization if feasible.

D. Common Pitfalls and Side-Effects of Management

One of the mainstays of therapy for ACS is the administration of antiplatelet agents. However, in patients with CKD, the efficacy and safety, as well as the short- and long-term outcomes for this therapy are not clear.

Unfortunately, the studies analyzing antiplatelet and antithrombotic treatment in patients with CKD are usually low quality, mostly based on subgroup analyses from larger trials, with a lack of standardized definitions for outcomes—in particular for bleeding outcomes—and with high variability in the duration, population, and methodological design, which are factors that significantly limit their interpretation. In addition, almost all trials exclude patients with stage 4 and 5 CKD.

There are data showing that antiplatelet drugs, in particular glycoprotein IIb/IIIa antagonists, when given in addition to standard treatment do not decrease mortality, recurrence of MI, or revascularization in patients with CKD undergoing PCI even in the setting of high-risk PCI for ACS, but they can increase the rates of serious bleeding, especially if given in combination with clopidogrel. There might be a potential benefit of the newer antiplatelet agents, particularly if not metabolized by the kidney, when used as adjunctive therapy in patients with ACS. A substudy of the PLATelet inhibition and patient Outcomes (PLATO) trial showed reduced mortality and fewer major cardiovascular events with ticagrelor as compared to clopidogrel in the prespecified cohort with CKD.

A prospective nonrandomized registry of STEMI patients that included 1,457 patients with CKD compared the rates of major bleeding and in-hospital complications, as well as adverse cardiac events, including death, MI, stent thrombosis, and target lesion revascularization in patients treated with a clopidogrel loading dose of 300 mg versus 600 mg and failed to find any difference in either cardiac events or bleeding. This may reflect a lack of statistical power, and we recommend a clopidogrel loading dose of 600 mg for ACS cases.

A meta-analysis comparing heparin with bivalirudin in PCI patients found lower bleeding rates with bivalirudin in patients with normal kidney function and in those with mild to moderate CKD. The number of patients with stage 4 and 5 CKD was very small, but in this cohort there also appeared to be less bleeding with bivalirudin, and we recommend that bivalirudin be used for PCI in patients on dialysis or with severe CKD.

IV. Management with Co-Morbidities

Common co-morbid conditions include hypertension, dyslipidemia, diabetes mellitus, vascular disease, and anemia. Each of these conditions will require individualization of therapy, especially in the setting of severe CKD.

For example, in dialysis patients, insulin doses must be adjusted to avoid hypoglycemia; blood pressure goals need to be revised to avoid hypotension and normalization of hematocrit must be avoided to prevent cardiovascular events, thrombosis of vascular access sites, and increased mortality.

The COURAGE trial has shown that it is feasible to achieve blood pressure and lipid goals in patients with stage 3 CKD. Achieving similar results in patients with advanced CKD is more challenging and the benefits are less clear cut.

Thiazide diuretics may not be effective for blood pressure control in stage 4 and 5 CKD. ACE-I and ARBs are effective for blood pressure control in advanced CKD, but may not be safe to use in the setting of hyperkalemia. Statins do lower lipid levels in patients with stage 5 CKD, but as noted before, this may not be associated with clinical benefit.

V. Patient Safety and Quality Measures

A. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Despite the high prevalence of hypertension, diabetes, and dyslipidemia in CKD patients, risk factors that should be controlled in such a population are usually not optimally treated. Though the COURAGE study has shown that OMT is feasible, in practice less than 10% of patients with CAD and CKD reach target levels for risk factor control. Use of statins and ACE-I is particularly low in patients with stage 4 CKD.

B. What's the Evidence for specific management and treatment recommendations?

Current ACC/AHA guidelines give a Class IIa recommendation for an invasive management strategy for ACS in patients with mild to moderate CKD, but give no recommendations for stage 4 and 5 CKD given the paucity of data in this population. The NKF/KDOQI recommends that low dose aspirin (81 mg/day might be given to patients with CKD but the decision must be individualized.


Sarnak, MJ, Levey, AS, Schoolwerth, AC. “Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association councils on kidney disease in cardiovascular disease, high blood pressure research, clinical cardiology, and epidemiology and prevention”. Circulation. vol. 108. 2003. pp. 2154-69. (This statement from the National Kidney Foundation (NKF) Task Force on Cardiovascular Disease in Chronic Renal Disease and the American Heart Association emphasizes the high risk of cardiovascular disease in patients with chronic renal failure. It is relevant to the clinician as it documents the increased mortality risk due to CVD in CKD and recommends that patients with CKD be considered in the “highest risk group” for subsequent CVD.)

Herzog, CA. “How to manage the renal patient with coronary heart disease: the agony and the ecstasy of opinion-based medicine”. J Am Soc Nephrol. vol. 14. 2003. pp. 2556This is important paper by a leading authority in the field summarizes the data on management of cardiovascular disease in patients on dialysis.

Best, PJ, Lennon, R, Ting, HH. “The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions”. J Am Coll Cardiol. vol. 39. 2002. pp. 1113-9. (This study from the Mayo Clinic registry of over 5,000 patients with CKD undergoing PCI shows that CKD is a strong predictor of death and subsequent cardiac events independent of all other measured variables.)

Strippoli, GF, Navaneethan, SD, Johnson, DW. “Effects of statins in patients with chronic kidney disease: meta-analysis and meta-regression of randomised controlled trials”. BMJ.. vol. 336. 2008. pp. 645-51. (This large meta-analysis includes 50 trials and over 30,000 patients comparing different statins with a placebo for cholesterol reduction and cardiovascular endpoints shows that statins significantly reduce lipid concentrations and cardiovascular end points in patients with chronic kidney disease, irrespective of the stage of the disease. Nonetheless, the authors found no benefit on all-cause mortality or any role for statins in primary prevention of CV endpoints in patients with CKD.)

Palmer, SC, Di Micco, L, Razavian, M. “Effects of antiplatelet therapy on mortality and cardiovascular and bleeding outcomes in persons with chronic kidney disease”. Ann Intern Med. vol. 156. 2012. pp. 445-59.

Angiolillo, DJ, Bernardo, E, Capodanno, D. ” Impact of chronic kidney disease on platelet function profiles in diabetes mellitus patients with coronary artery disease taking dual antiplatelet therapy”. J Am Coll Cardiol. vol. 55. 2010. pp. 1139-46. (The two aforementioned references provide valuable information about the lower efficacy of antiplatelet medications in patients with CKD. The first is a meta-analysis with 9 trials (unfortunately of low quality evidence) showing that glycoprotein IIb/IIIa inhibitors or clopidogrel plus standard care compared with standard care alone had little or no effect on all-cause or cardiovascular mortality or on myocardial infarction but increased serious bleeding. Compared with a placebo or no treatment in persons with stable or no cardiovascular disease, antiplatelet agents prevented myocardial infarction but had uncertain effects on mortality and increased minor bleeding. The second paper is a longitudinal observational study that demonstrated the reduced antiplatelet effects of clopidogrel in patients with DM and CKD when assessed by platelet function tests.)

Kersting, S, Grumann, T, Hummel, J. “Impact of chronic kidney disease on long-term clinical outcomes after percutaneous coronary intervention with drug-eluting or bare-metal stents”. Crit Pathways Cardiol. vol. 11. 2012. pp. 152-9.

Chang, TI, Shilane, D, Kazi, DS, Montez-Rath, ME, Hlatky, MA, Winkelmayer, WC. “Multivessel coronary artery bypass grafting versus percutaneous coronary intervention in ESRD”. J Am Soc Nephrol. vol. 23. 2012. pp. 2042-9. (The two aforementioned references provide information about coronary revascularization in patients with CKD. The first is a retrospective study that included a cohort of over 12,000 patients with CKD who underwent CABG or PCI and showed that the incidence of cardiovascular death was higher than the incidence of developing ESRD with need of dialysis. The second is a retrospective study over 22,000 patients and assesses mortality in patients undergoing CABG who are already on dialysis.

Boden, WE, O’Rourke, RA, Teo, KK. “Optimal medical therapy with or without PCI for stable coronary disease”. N Engl J Med. vol. 356. 2007. pp. 1503-16. (The COURAGE trial provides valuable data comparing the role of OMT versus PCI as an initial therapeutic approach in patients with stable CAD. Notably, this trial did not exclude patients with CKD.)

Sedlis, SP, Jurkovitz, CT, Hartigan, PM. “Optimal medical therapy with or without percutaneous coronary intervention for patients with stable coronary artery and chronic kidney disease”. Am J Cardiol. vol. 104. 2009. pp. 647-53. (This is a post-hoc analysis of data from the COURAGE trial from patients with CKD. Importantly the comparator arms were protocol driven and randomly assigned, making it more rigorous in terms of methodological design than observational studies. This study shows that similar levels of control of blood pressure and lipid parameters in patients can be achieved in patients with CKD as without CKD. In addition, PCI in combination with OMT in patients with CKD appears to be safe and does not increase or reduce mortality, MI, or heart failure, when compared to OMT alone.