INTRODUCTION — Chronic kidney disease (CKD) is an independent risk factor for the development of coronary artery disease, and for more severe coronary heart disease (CHD) [1-5]. CKD is also associated with adverse outcomes in those with existing cardiovascular disease [6-8]. This includes increased mortality after an acute coronary syndrome, after percutaneous coronary intervention (PCI) with or without stenting [9-16], and after coronary artery bypass. In addition, patients with CKD are more likely to present with atypical symptoms, which may delay diagnosis and adversely affect outcomes [17,18].
An overview of CKD and CHD is presented in this topic review. Issues related to CHD in patients with end-stage kidney disease (ESKD) and general discussions of risk factors for cardiovascular disease and interventions for secondary prevention are presented separately:
●(See "Risk factors and epidemiology of coronary heart disease in end-stage kidney disease (dialysis)".)
●(See "Overview of established risk factors for cardiovascular disease".)
CHRONIC KIDNEY DISEASE AS AN INDEPENDENT RISK FACTOR FOR CHD — Both decreased glomerular filtration rate (GFR) and increased proteinuria increase the risk of cardiovascular disease. These associations have been shown in both community-based populations (ie, cohorts that were not selected specifically to enroll individuals with CKD or cardiovascular disease), and in populations of patients at high cardiovascular risk (ie, cohorts in which patients with preexisting cardiovascular disease or cardiovascular disease risk factors were specifically recruited).
Association between CKD and CHD in community-based populations — Numerous observational studies have shown that a reduced GFR and proteinuria are both independently associated with an increased risk of cardiovascular events in community-based populations of patients who were not selected based upon the presence of known kidney or cardiovascular disease [1,6,19-55]. In addition, the association between CKD and cardiovascular events may be stronger among Black individuals as compared with White individuals [33,37,54].
The best data come from a meta-analysis of general population cohorts that included 105,872 participants with urine albumin-to-creatinine ratio (ACR) measurements and 1,128,310 participants with urine protein dipstick measurements; all had documented baseline estimated GFR [22]. Compared with participants whose estimated GFR was 95 mL/min/1.73 m2, hazard ratios (HR) for all-cause mortality during 7.9 years of follow-up were 1.18 (95% CI 1.05-1.32), 1.57 (95% CI 1.39-1.78), and 3.14 (95% CI 2.39-4.13) for estimated GFRs of 60, 45, and 15 mL/min per 1.73 m2, respectively. Similar outcomes were observed for cardiovascular mortality, and similar results were obtained in older and younger individuals (age greater than 65 years versus 65 years or less). A higher risk for all-cause mortality was observed at estimated GFRs greater than 105 mL/min per 1.73 m2; however, this association may reflect either reduced muscle mass from ill health leading to a lower creatinine value, or a high prevalence of individuals with diabetes or obesity causing hyperfiltration and a low creatinine [56].
Proteinuria was independently associated with increased all-cause and cardiovascular mortality in this study [22]. Compared with an albumin-to-creatinine ratio (ACR) of 0.6 mg/mmol (6 mg/g), the adjusted hazard ratio for all-cause mortality was 1.20 (95% CI 1.15-1.26); 1.63 (95% CI 1.50-1.77); and 2.20 (95% CI 1.97-2.51) for ACRs of 1.1 (10 mg/g); 3.4 (30 mg/g); and 33.9 mg/mmol (300 mg/g), respectively. Similar findings were observed for cardiovascular mortality. An ACR greater than 3.4 mg/mmol (30 mg/g) was associated with a greater than twofold mortality risk for all levels of estimated GFR except the lowest (<30 mL/min per 1.73 m2). Among participants with dipstick determination of proteinuria, a trace urine positive dipstick was also associated with increased all-cause and cardiovascular mortality for all levels of kidney function, although large heterogeneity was present between studies that provided only dipstick measurement of protein.
Given that CKD alone appears to increase the risk of CHD in the general population, it is not surprising that the Framingham risk score, the traditional method to analyze future cardiovascular risk among individuals without CKD, provides poor overall accuracy in predicting cardiovascular events in patients with CKD [57,58], while inclusion of estimated GFR and ACR with traditional cardiovascular risk factors improves the ability to forecast events [59]. This may be partly due to the markedly increased cardiac event rate and overall death rate among such patients. Attempts have been made to improve the predictive accuracy of the Framingham risk equations by including kidney parameters. Such efforts have been successful in some but not all populations [57,60,61], suggesting that new prediction equations must be developed to help predict future events among patients with CKD.
Despite the preponderance of evidence in favor of an increase in risk with CKD alone, a few studies have found that less severe kidney disease is not an independent risk factor for adverse cardiovascular outcomes [62,63].
Association between CKD and CHD among those at high cardiovascular risk — Numerous secondary analyses of studies that enrolled patients with known risk factors for cardiovascular disease (such as hypertension and diabetes), or preexisting cardiovascular disease, have shown that the presence or development of various degrees of kidney dysfunction is independently associated with cardiovascular events [20,52,53,59,64-74]. In addition, accounting for estimated GFR and ACR in conjunction with traditional risk factors improves the ability to predict cardiovascular events in patients at high cardiovascular risk [59].
The magnitude of the association of kidney function, albuminuria, and outcomes was illustrated in a collaborative meta-analysis of 10 cohorts with 266,975 patients who had hypertension, diabetes, cardiovascular disease, or a combination of these disorders [64]. Compared with a reference estimated GFR of 95 mL/min per 1.73 m2, the hazard ratios for cardiovascular mortality were 1.11 for an estimated GFR of 60 mL/min per 1.73 m2, 1.73 for an estimated GFR of 45 mL/min per 1.73 m2, and 3.08 for an estimated GFR of 15 mL/min per 1.73 m2. Similar findings were noted for all-cause mortality, and the associations were similar in younger and older patients. A monotonic association between higher ACR and risk of both cardiovascular and all-cause mortality was also noted.
CKD as a CHD risk equivalent — The above evidence that mild to moderate CKD is associated with an adverse cardiovascular prognosis led both the National Kidney Foundation and the American College of Cardiology/American Heart Association to recommend in older guidelines that CKD be considered a CHD risk equivalent [1,75-78]. Consistent with this, the number of cardiovascular events attributable to CKD in the Alberta Kidney Disease Network and Atherosclerosis Risk In Communities (ARIC) studies were comparable to the number of events attributable to diabetes, another factor considered to be a CHD risk equivalent [37,79].
In addition, the nine-year rates of cardiovascular death among 1899 individuals in the Cardiovascular Health Study (CHS) were as follows (CKD was defined as an estimated GFR less than 60 mL/min per 1.73 m2) [80]:
●History of myocardial infarction, but no diabetes or CKD: 15.7 percent
●History of diabetes, but no myocardial infarction or CKD: 15.8 percent
●History of CKD, but no myocardial infarction or diabetes: 13 percent
Although CKD was a powerful risk factor for cardiovascular disease in these and other studies, the generalization that CKD is a CHD risk equivalent for all persons with CKD may not be warranted for several reasons:
●Some studies contradict the concept that CKD is a CHD risk equivalent. In the Alberta Kidney Disease Network cohort, for example, the four-year incidence of myocardial infarction was nearly threefold higher among those who had a prior history of myocardial infarction (7.7 percent) compared with those without a prior history of myocardial infarction but who had CKD (2.8 percent) [79]. The incidence of myocardial infarction among those who had a prior history of myocardial infarction but no diabetes and no CKD was more than twice the incidence among those with CKD but not prior myocardial infarction. Similarly, a secondary analysis from the ARIC study suggested that the risk associated with CKD was not comparable to the risk associated with a prior myocardial infarction [81].
●The risk of heart disease in those with CKD appears to vary based upon absolute level of kidney function and degree of proteinuria, as well as the rate at which these factors change. The simultaneous presence of both decreased kidney function and increased proteinuria further enhance the risk for cardiovascular disease compared with the risk associated with either problem alone [21-23,64,79]. In addition, the rate of decline of kidney function and the rate of increase of proteinuria also correlate with varying risks of adverse cardiovascular events [82-84].
●Even patients with the same degree of kidney dysfunction may not have the same risk of cardiovascular disease since the risk of cardiovascular disease in a patient with CKD is in part related to the presence and extent of significant comorbidities. As an example, the overall risk for a 25-year-old nonsmoking man with moderate CKD due to IgA nephropathy is not the same as that of a 65-year-old man with a similar degree of CKD but with a long history of smoking, hypertension, and elevated serum cholesterol levels. Thus, the proper assessment of overall cardiovascular risk in patients with CKD requires an adequate assessment for the presence and severity of the other major risk factors for cardiovascular disease. (See "Overview of established risk factors for cardiovascular disease".)
The concept of CHD risk equivalency was developed by expert panels as a means to help clinicians make decisions about how aggressively to treat their patients to prevent CHD [85]. As an example, while it is fairly simple to identify a patient who has diabetes or CKD, and thus institute aggressive therapy for secondary prevention of CHD, it is more cumbersome to calculate every patient's 10-year cardiovascular risk. Approximately half of adults in the United States with CKD have another CHD risk equivalent, specifically a prior history of myocardial infarction or stroke, diabetes, angina, or a calculated Framingham 10-year CHD risk greater than 20 percent [86]. Thus, the question of whether CKD is a CHD risk equivalent is germane to whether millions of additional patients with CKD should receive aggressive therapy to lower their LDL cholesterol and blood pressure, and whether they should receive antiplatelet therapy. In general, many expert panels are moving away from the concept of "risk equivalency" and are, instead, basing their recommendations for preventative therapies upon the predicted 10-year CHD risk. These issues are discussed in detail below. (See 'Reduction of CHD risk in patients with CKD' below.)
Limitations of the data — One possible limitation in nearly all of the above reports is that kidney function was indirectly estimated. Since the various estimates provide results that may differ from each other, the association between kidney function and cardiovascular risk is affected by the method selected to estimate kidney function. The association may be further compromised because some of the formulas utilized are based directly upon variables linked with cardiovascular risk, such as age, weight, and body mass index.
This difficulty was shown using data from 8592 participants in the PREVEND study, in which the association between various cardiovascular risk factors and kidney function was examined [87,88]. Kidney function was estimated using creatinine clearance (based upon two 24-hour urine collections), and the Cockcroft-Gault and Modification of Diet in Renal Disease (MDRD) formulas [87]; the various cardiovascular risk factors examined included blood pressure, serum cholesterol and glucose levels, age, sex, weight, waist-to-hip ratio, and body mass index. (See "Assessment of kidney function".)
Markedly different relationships emerged when each method for estimating kidney function was plotted against each cardiovascular risk factor. These varied relationships were most pronounced for age, weight, and body mass index, and less pronounced (but still statistically significant) for blood pressure, and serum cholesterol and glucose levels. As a result, caution must be exercised when studying the relationships among cardiovascular risk factors, indirect estimates of kidney function, and cardiovascular risk.
Cystatin C and other markers of kidney function — Another potential limitation of kidney function estimates in the vast majority of studies mentioned above is that level of GFR may not be accurately assessed using creatinine-based equations, particularly in those with estimated GFR values greater than 60 mL/min/1.73 m2. In these individuals, cystatin C and other markers of kidney function (such as beta-trace protein and beta-2-microglobulin) may be more sensitive measures of decreased GFR, and also more strongly associated with fatal and nonfatal cardiovascular events, than creatinine and creatinine-based estimates of GFR [43-50,89,90]. As an example, the risk of death relative to the cystatin C concentration increased in a dose-response fashion in one study [43]. Relative to the first quintile, the adjusted hazard ratio of cardiovascular death for the third, fourth, and fifth quintiles (the fifth quintile further subdivided into thirds) of cystatin C levels were 1.93, 1.99, and 2.48 to 2.83, respectively. In contrast, a significant association with adverse outcomes was only observed among those in the lowest quintile of GFR estimated from the plasma creatinine concentration. In addition, compared with creatinine-based estimation of GFR, estimation using a cystatin C-based equation improves risk stratification for mortality, cardiovascular events, and end-stage kidney disease (ESKD) [90]. (See "Assessment of kidney function".)
These results suggest that elevated plasma cystatin C concentration may be a more accurate measure of cardiovascular risk than elevated plasma creatinine concentration. However, some have postulated that non-renal determinants of cystatin C levels, such as increased inflammation and other cardiovascular factors, may underlie this association. In addition, cystatin C is not as yet routinely measured.
PRESENCE OF TRADITIONAL AND NONTRADITIONAL CARDIOVASCULAR RISK FACTORS IN CKD — Patients with CKD often have numerous traditional and nontraditional risk factors for the development of cardiovascular disease. Traditional risk factors appear to be associated with much larger absolute increases in risk in comparison with nontraditional risk factors in the earlier stages of CKD [91].
Traditional risk factors — Traditional cardiovascular risk factors, such as hypertension (which may be accompanied by left ventricular hypertrophy), smoking, diabetes, dyslipidemia and older age, are highly prevalent in CKD populations [1,92,93]. The number of cardiovascular risk factors appears to correlate with the severity of kidney dysfunction [93]. These are discussed in greater detail elsewhere. (See "Overview of hypertension in acute and chronic kidney disease" and "Overview of established risk factors for cardiovascular disease".)
Patients with CKD are also more likely to have the metabolic syndrome, which could contribute to the increase in cardiovascular risk [3,94]. This syndrome is defined as some combination of insulin resistance, dyslipidemia, elevated serum glucose, abdominal obesity, and hypertension. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)".)
Nontraditional risk factors — Possible risk factors that are relatively unique to patients with moderate to severe CKD include retention of uremic toxins, anemia, elevated levels of certain cytokines, positive calcium balance, abnormalities in bone mineral metabolism, and/or an "increased inflammatory-poor nutrition" state [4,95]. How these risk factors may lead to cardiovascular disease is unclear. As an example, disorders of bone mineral metabolism in patients with CKD have often been linked to coronary artery calcification. However, while there is a consistent association between CKD and a higher burden of coronary artery calcification [96-98], the associations among phosphorus, calcium, and parathyroid hormone with coronary artery calcification in these patients is inconsistent [99-101]. (See "Risk factors and epidemiology of coronary heart disease in end-stage kidney disease (dialysis)" and "Inflammation in patients with kidney function impairment" and "Coronary artery calcium scoring (CAC): Overview and clinical utilization".)
Elevated levels of C-reactive protein (CRP) and asymmetric dimethylarginine, both of which are typically found in patients with CKD, were both independently associated with an increased risk of all-cause and cardiovascular mortality in the Modification of Diet in Renal Disease (MRDR) study [102,103], although a similar relation between CRP and cardiovascular disease was not observed in the Irbesartan for Diabetic Nephropathy trial [104]. Hyperhomocysteinemia has also been inconsistently associated with increased cardiovascular risk [105-107].
There is also a relationship between cardiovascular disease and moderately increased albuminuria (formerly called "microalbuminuria") among nondiabetic patients with normal estimated GFR. However, some disagree with the KDOQI and KDIGO working groups that isolated moderately increased albuminuria (ie, without a reduction in GFR or some other kidney abnormality) necessarily reflects kidney disease among nondiabetic patients [75]. It correlates best with generalized endothelial dysfunction and is associated with an increase in cardiovascular risk. (See "Overview of the management of chronic kidney disease in adults", section on 'Definition and classification' and "Moderately increased albuminuria (microalbuminuria) and cardiovascular disease".)
COMPETING RISKS OF CARDIOVASCULAR AND END-STAGE KIDNEY DISEASE — Morbidity and mortality from cardiovascular disease among those with CKD is high. The risk of death, particularly due to cardiovascular disease, is typically higher than the risk of eventually requiring kidney replacement therapy. However, this risk varies with age and other factors. In many studies, older patients with less severe CKD and lower levels of proteinuria are more likely to die (usually due to cardiovascular disease) before needing kidney replacement therapy, while younger patients with proteinuria and diseases localized to the kidney are more likely to ultimately need kidney replacement therapy [20,55,71,108-112]. This is illustrated by the following examples:
●The following three studies largely include older patients identified through Medicare participation or through the Veteran's Affairs Network:
•In a study of over 1,000,000 individuals enrolled in the Medicare program in the United States, outcomes were reported for several groups, including those with CKD but no diabetes (2.2 percent) and both CKD and diabetes (1.6 percent) [20]. After two years of follow-up, the rates for requiring kidney replacement therapy were 1.6 and 3.4 per 100 patient-years for patients with CKD alone and those with both disorders, respectively; by comparison, the death rates were 17.7 and 19.9 per 100 patient-years. In addition, rates for atherosclerotic vascular disease for these two groups were 35.7 and 49.1, while heart failure rates were 30.7 and 52.3, respectively.
•A longitudinal follow-up of nearly 30,000 older patients with estimated glomerular filtration rates (GFR) of less than 90 mL/min per 1.73 m2 reported the rate of kidney replacement and death at five years [108]. The rate of kidney replacement therapy in those with stage 2, 3, or 4 disease was 1.1, 1.3, and 19.9 percent, respectively; by comparison, the mortality rate was 19.5, 24.3, and 45.7 percent. A higher incidence of coronary artery disease, heart failure, diabetes mellitus, and anemia was noted in those who died.
•In a report of over 12,000 older patients with diabetes, 48 percent had CKD defined as GFR less than 60 mL/min per 1.73 m2, or proteinuria [109]. After three years of follow-up, mortality rates were 6, 10, 20 and 30 percent for patients with CKD stages 2, 3, 4 and 5, respectively, compared to 5 percent for those with preserved kidney function at baseline. Rates of progression to end-stage kidney disease (ESKD) were much lower, less than 1 percent for stages 2 and 3, and 14 percent for stage 4.
●The nondiabetic patients in the MDRD study included a broad range of ages, causes of kidney disease, baseline GFR, and baseline protein excretion. After nearly 12 years of follow-up, 936 patients (56 percent) developed ESKD, and 369 (22 percent) died [113]. Death prior to ESKD was more likely to occur in older as compared with younger individuals. In those patients older than 65 years, for example, 42 percent developed ESKD and 22 percent died before developing ESKD. However, in those 45 years or younger, 65 percent developed ESKD and less than 1 percent died before developing ESKD.
●The following are two studies with long-term observations from two cohorts of younger individuals with type 1 diabetes and nephropathy:
•The rate of ESKD incidence was substantially greater than the mortality rate (35.5 versus 9.5 percent) in a cohort of 592 young (median age 42 years) patients with type 1 diabetes followed for 10 years [110]. All patients in this study had at least 300 mg/day of proteinuria, and 60 percent of patients had an estimated GFR less than 60 mL/min per 1.73 m2.
•Similar results were observed in a cohort of 423 young (median age 39 years) patients with type 1 diabetes, at least 300 mg/day of proteinuria, and a median baseline estimated GFR of 66 mL/min per 1.73 m2 [111]. During 15 years of follow-up, 41 percent of patients developed ESKD, while 7 percent died without developing ESKD.
Although these data suggest that age differences determine whether or not patients with CKD will develop ESKD before dying, this observation may be biased by study design. Patients enrolled into studies of cardiovascular disease tend to be older and have less severe kidney disease than patients enrolled into studies of kidney disease. In addition, older patients with severe kidney dysfunction are more likely to develop ESKD before dying, as was observed in 3228 older individuals with type 2 diabetes and nephropathy (mean age 59 years, estimated GFR 44 mL/min per 1.73 m2, and mean urine albumin-to-creatinine ratio 1.37 g/g) [114].
REDUCTION OF CHD RISK IN PATIENTS WITH CKD — In patients without CKD, risk factor modification and beneficial lifestyle changes can substantially decrease morbidity and mortality in those with coronary, cerebrovascular, or peripheral artery disease. These modalities include therapy with statins, control of hypertension, cessation of smoking, maintaining ideal body weight and an active lifestyle, glycemic control in diabetes, and the use of aspirin. A review of the data supporting these interventions is presented in detail separately. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)
In the past, patients with CKD were largely excluded from clinical trials of patients with coronary artery disease. A 2006 survey of the published literature noted that 75 percent of coronary artery disease trials excluded patients with CKD and only 7 percent reported baseline kidney function [115]. Similar observations were reported in a contemporaneous survey [116,117]. However, randomized trials have subsequently been performed specifically in patients with CKD, particularly regarding statin therapy. (See 'CKD as a CHD risk equivalent' above.)
As noted above, we do not agree with the generalization that CKD is a CHD risk equivalent for all persons with CKD. Our approach is instead based upon the available data and an assessment of future cardiovascular risk. This evidence, which is presented below, supports the following approach to reduce the risk of atherosclerotic cardiovascular disease in most patients with CKD not requiring dialysis:
●Statin therapy. (See 'Statin therapy' below.)
●In patients with albuminuric CKD (defined as albuminuria greater than 300 mg/day), we recommend angiotensin blockade as part of the antihypertensive regimen. Goal blood pressure in patients with CKD is presented elsewhere. (See 'Blood pressure control' below and "Goal blood pressure in adults with hypertension" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Treatment of hypertension in patients with diabetes mellitus".)
●Low-dose aspirin therapy. (See 'Antiplatelet therapy' below.)
●In all patients, smoking cessation, maintenance of an ideal body weight, an active lifestyle, and, in patients with diabetes, glycemic control. (See 'Other issues' below.)
The KDIGO guidelines also consider persistent proteinuria, including moderately increased albuminuria (formerly called "microalbuminuria"), to be part of CKD and therefore associated with increased CHD risk even if estimated glomerular filtration rate (GFR) is normal. We do not agree with applying this paradigm to all patients. As an example, it is unknown whether a 25-year-old nonsmoker with IgA nephropathy, normal serum creatinine concentration, and normal blood pressure is at increased cardiovascular risk in the absence of progressive disease. Such patients should clearly be followed carefully and patient values should be taken into account when considered how aggressively one would modify coronary risk factors. Issues related to moderately increased albuminuria are discussed separately. (See "Moderately increased albuminuria (microalbuminuria) and cardiovascular disease".)
Secondary prevention of cardiovascular disease in patients with end-stage kidney disease (ESKD) on maintenance dialysis or those with a kidney transplant are discussed elsewhere:
●(See "Secondary prevention of cardiovascular disease in end-stage kidney disease (dialysis)".)
●(See "Hypertension after kidney transplantation".)
●(See "Lipid abnormalities after kidney transplantation".)
Statin therapy — Most evidence for the use of statins in patients with mild to moderate CKD comes from post-hoc subgroup analyses of randomized trials that were not intended to include patients with decreased kidney function. (See "Lipid management in patients with nondialysis chronic kidney disease".) One randomized trial, the Study of Heart and Renal Protection (SHARP) trial, specifically evaluated cholesterol lowering with a statin to prevent major vascular events in patients with CKD.
The findings from the SHARP trial echoed the observations made in CKD subgroups from other randomized trials: treatment of patients with CKD not requiring dialysis with a statin leads to a significant reduction in cardiovascular events. Patients who received statin therapy in SHARP also received ezetimibe, although it is not clear if ezetimibe contributed to the clinical benefit. A detailed discussion of these findings and recommendations regarding statin use in CKD are presented elsewhere. (See "Lipid management in patients with nondialysis chronic kidney disease".)
However, these trials mainly enrolled older patients with various comorbid conditions such as smoking, diabetes, and hypertension. Whether statin therapy would be beneficial in younger patients who have CKD due to primary kidney disease (such as IgA nephropathy or autosomal dominant polycystic kidney disease) rather than a systemic disease (such as diabetes) is unclear. We would initiate statin therapy in most patients who have an estimated GFR less than 60 mL/min per 1.73 m2; detailed recommendations are presented elsewhere. (See "Lipid management in patients with nondialysis chronic kidney disease", section on 'Treatment'.)
A related issue is whether statins provide cardiovascular protection due in part to their pleiotropic effects that are independent of lipid lowering in patients with and without CKD. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease".)
There are as yet no trials that have compared cardiovascular outcomes among patients with dyslipidemia who were randomly assigned to specific target lipid levels rather than specific statin doses. When the results of multiple trials are considered, each using a fixed atorvastatin dose, the rate of major cardiovascular events falls linearly with the reduction in LDL cholesterol [118]. However, there is as yet no good evidence that titrating statin therapy to achieve specific target LDL levels in patients at increased cardiovascular risk is associated with improved cardiovascular outcomes. Hence, the Kidney Disease Improving Global Outcomes (KDIGO) guidelines on management of dyslipidemia in CKD did not base their suggestions upon target levels of LDL cholesterol. Rather, they recommend standard doses based upon cardiovascular risk and level of estimated GFR. (See "Lipid management in patients with nondialysis chronic kidney disease", section on 'Treatment' and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)
Although the evidence is weak, there are also data suggesting that lipid lowering with statins may be associated with a slower rate of loss of GFR in patients with mild to moderate CKD.
Blood pressure control — Numerous trials of patients with primary hypertension (formerly called "essential" hypertension) have shown that blood pressure control improves cardiovascular outcomes. Goal blood pressure, including in patients with chronic kidney disease and those at high risk for cardiovascular events, is presented in detail separately. (See "Goal blood pressure in adults with hypertension" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Treatment of hypertension in patients with diabetes mellitus".)
Post-hoc analyses of CKD subgroups from cardiovascular trials suggest that antihypertensive therapy reduces the risk of cardiovascular events [65,72,119,120]. However, no specific antihypertensive drug (eg, angiotensin-converting enzyme [ACE] inhibitors) provides preferential cardiovascular benefit, at least in patients with non-proteinuric CKD. As an example, a meta-analysis examined the cardiovascular outcomes and mortality of 30,295 patients with an estimated GFR <60 mL/min/1.73 m2 from 26 randomized hypertension trials; 93 percent of patients were non-proteinuric [119]. Follow-up of these patients for approximately four to five years yielded the following findings:
●Compared with placebo, both ACE inhibitors (3.2 percent absolute decrease) and calcium channel antagonists (2.1 percent absolute decrease) reduced the incidence of cardiovascular events (stroke, myocardial infarction, heart failure) and mortality. Trials comparing diuretics or beta blockers with placebo were not included in the meta-analysis.
●In drug versus drug trials, the incidence of cardiovascular events and mortality were similar comparing angiotensin inhibitors with either diuretics or beta blockers (18 versus 19 percent) or with calcium channel antagonists (23 versus 24 percent).
In contrast to patients with non-proteinuric CKD, there is some evidence of benefit from specific antihypertensive drugs (ie, ACE inhibitors) in patients with proteinuria (defined as more than 500 to 1000 mg/day). In such patients, ACE inhibitors and may reduce the progression of kidney disease. These issues are discussed in detail elsewhere. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Treatment of hypertension in patients with diabetes mellitus".)
Antiplatelet therapy — Long-term aspirin therapy reduces the risk of subsequent myocardial infarction (MI), stroke, and vascular death among patients without CKD, but with a wide range of prior manifestations of cardiovascular disease. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)
There are fewer data related to the effectiveness and safety of antiplatelet therapy in patients with CKD [121,122]. The best data come from a meta-analysis of 27,139 patients with CKD who participated in 50 randomized trials that tested the efficacy of antiplatelet agents (mostly aspirin) for prevention of CVD [121]. Antiplatelet therapy significantly reduced the incidence of fatal or nonfatal myocardial infarction as compared with either placebo or no therapy (6.7 versus 7.0 percent, or 3 myocardial infarctions prevented for every 1000 patients treated). However, antiplatelet therapy also significantly increased the rate of major bleeding (4.4 versus 2.9 percent, or 15 additional major bleeding events for every 1000 patients treated). Antiplatelets had no effect on stroke or mortality. The results were similar in patients of all CKD stages.
Based upon these data, we suggest that decisions about antiplatelet therapy to prevent cardiovascular disease in patients with CKD be individualized depending upon the patient's overall risk for CHD (for example, a prior history of myocardial infarction) and for bleeding, and also upon their preferences. This suggestion is broadly consistent with guidelines made by the Kidney Disease Improving Global Outcomes (KDIGO) report on the management of CKD [123]. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)
In addition to cardiovascular disease, aspirin therapy may reduce the risk of cancer incidence. This should also be considered in the decision about whether or not to use aspirin in patients with CKD. (See "Aspirin in the primary prevention of cardiovascular disease and cancer".)
The prescription of low-dose aspirin is probably safe in most patients with CKD. The KDOQI clinical practice guidelines for controlling the epidemic of CV disease in CKD, as well as other KDOQI guidelines, can be accessed through the National Kidney Foundation's web site at www.kidney.org/professionals/kdoqi/guidelines.cfm.
Other issues — In general, similar considerations apply to patients with and without kidney dysfunction concerning interventions for cessation of smoking, maintaining ideal body weight and an active lifestyle, and glycemic control in diabetes. Recommendations concerning these issues are presented separately. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)
Measures aimed at correcting other nontraditional cardiovascular risk factors in those with CKD, such as anemia, calcium-phosphate disorders, systemic inflammation, and increased oxidative stress, may also improve cardiovascular outcomes. This is also discussed separately:
●(See "Treatment of anemia in nondialysis chronic kidney disease".)
●(See "Hyporesponse to erythropoiesis-stimulating agents (ESAs) in chronic kidney disease".)
●(See "Management of hyperphosphatemia in adults with chronic kidney disease".)
●(See "Overview of the management of chronic kidney disease in adults".)
TREATMENT OF CORONARY HEART DISEASE — Patients with CKD require drug dose adjustments and have a higher risk of drug-related adverse effects. Despite the increased risk of adverse effects, the treatments used for established CHD and acute coronary syndrome that are used in patients with normal kidney function (eg, revascularization, medical therapy) usually have similar benefits in patients with CKD [124,125]. (See "Chronic coronary syndrome: Indications for revascularization" and "Chronic coronary syndrome: Overview of care" and "Overview of the acute management of non-ST-elevation acute coronary syndromes" and "Overview of the acute management of ST-elevation myocardial infarction" and "Initial evaluation and management of suspected acute coronary syndrome (myocardial infarction, unstable angina) in the emergency department" and "Overview of the nonacute management of unstable angina and non-ST-elevation myocardial infarction" and "Non-ST-elevation acute coronary syndromes: Selecting an approach to revascularization" and "Coronary artery bypass graft surgery in patients with acute ST-elevation myocardial infarction".)
Multiple studies have reported that medical therapy commonly used in patients without CKD is employed significantly less frequently in patients with CKD [13,14,126-132]. As an example, a study of 889 patients with an acute coronary syndrome (ACS) evaluated the association between kidney dysfunction, defined as an estimated glomerular filtration rate (GFR) below 60 mL/min per 1.73 m2, and in-hospital management and outcomes [14]. Kidney dysfunction was associated with a lower likelihood of receiving percutaneous coronary intervention, and a reduction in the use of a GP IIb/IIIa inhibitor, although the frequency of coronary artery bypass grafting was similar in those with and without kidney dysfunction. Less frequent utilization of angiography, revascularization, and standard medical therapy (eg, angiotensin-converting enzyme inhibitors, beta blockers) in CKD patients after ACS has also been observed in other studies [126,131,132].
However, not all of the usual treatments used in patients with normal kidney function should be universally applied in patients with CKD. As an example, a meta-analysis of 9969 CKD patients who were having an ACS or percutaneous coronary intervention found that the use of glycoprotein IIb/IIIa inhibitors or clopidogrel increased major bleeding episodes without preventing cardiovascular events or death [122]. In addition, automated implantable defibrillators may not provide a survival advantage in patients with CKD [133-135].
PROGNOSIS OF CORONARY HEART DISEASE IN PATIENTS WITH CKD — A pervasive finding among patients who suffer coronary events or who have coronary interventions is that those with impaired kidney function have a worse prognosis. The mechanisms which underlie the poor prognosis in patients with CKD are not entirely clear.
One possibility is that patients who have a coronary event and abnormal kidney function are more likely to have other predictors of adverse outcomes such as older age, hypotension, and lower body weight; these factors may confound the associations observed in the various studies despite statistical adjustment. A second potential explanation is that the adverse outcome (eg, death, recurrent vascular event) ascribed to worse kidney function may instead reflect a more severe acute coronary syndrome (ACS). Because only baseline creatinine values (at the time of presentation with an ACS) were used in most studies to define the presence of CKD, patients with hemodynamic compromise would have been more likely to be defined as having CKD. The formulas used to estimate glomerular filtration rate (GFR) based upon serum creatinine are predicated on there being a stable creatinine concentration. (See "Assessment of kidney function".)
Prognosis after acute coronary syndrome — An adverse association between mild to moderate kidney dysfunction and cardiovascular prognosis in patients with ACS has been reported, both in patients with ST elevation myocardial infarction and non-ST elevation ACS. This is discussed in detail elsewhere. (See "Risk factors for adverse outcomes after non-ST elevation acute coronary syndromes", section on 'Chronic kidney disease' and "Risk factors for adverse outcomes after ST-elevation myocardial infarction", section on 'Chronic kidney disease'.)
Prognosis after CABG — Although there are some reports of equivalent outcomes [136], most studies demonstrate that decreased kidney function at the time of coronary artery bypass grafting (CABG) is associated with higher risk of adverse outcomes [127,137]. As a consequence, kidney function is included in a commonly used risk prediction algorithm for cardiac surgical mortality (table 1). (See "Operative mortality after coronary artery bypass graft surgery", section on 'Chronic kidney disease'.)
In-hospital complication rates and in-hospital as well as long-term mortality are highest among patients on dialysis [138-141].
Patients with CKD who develop acute kidney injury after CABG may require temporary or permanent dialysis. This issue is discussed elsewhere. (See "Early noncardiac complications of coronary artery bypass graft surgery", section on 'Acute kidney injury'.)
Prognosis after PCI — The presence of even mild CKD appears to predict an adverse prognosis after percutaneous coronary intervention (PCI) with or without stenting [15,16,142-145], and kidney function is incorporated into a commonly used risk score that predicts one-year mortality following PCI in patients with acute myocardial infarction (table 2). (See "Primary percutaneous coronary intervention in acute ST elevation myocardial infarction: Determinants of outcome", section on 'Other risk factors' and "Intracoronary stent restenosis", section on 'Clinical factors'.)
The observation that revascularization for restenosis is required less frequently when stents are deployed has been made in patients with CKD as it has in patients with normal kidney function [146]. In addition, CKD does not appear to mitigate the angiographic benefits observed with drug-eluting stents [147,148]. (See "Percutaneous coronary intervention with intracoronary stents: Overview".)
A separate issue is whether the presence of CKD is associated with higher rates of restenosis. While some studies have found an increased risk of restenosis in patients with CKD [145,149], other studies have reported that CKD is not associated with increased restenosis [142,147].
PCI versus CABG in patients with CKD — No trials have compared outcomes with PCI versus CABG specifically in patients with moderate to severe CKD. The relative efficacies of PCI with stenting and CABG in patients with mild CKD was addressed in a subgroup analysis from the ARTS trial, which compared multivessel PCI with bare metal stenting to CABG in patients with stable angina. Among the 1205 patients, 290 had CKD as defined by an estimated creatinine clearance ≤60 mL/min (mean 50 mL/min) [143]. A more complete description of this study is discussed elsewhere. (See "Revascularization in patients with stable coronary artery disease: Coronary artery bypass graft surgery versus percutaneous coronary intervention".)
After three years of follow-up, the rate of the primary composite end point of death, myocardial infarction, or stroke was similar with PCI and CABG (adjusted hazard ratio 0.93) but, as in the patients without CKD, CABG was associated with a much lower risk of subsequent revascularization (RR 0.28, 95% CI 0.14-0.54) [143]. This difference persisted at five years, as the rate of a second revascularization procedure remained higher with PCI than CABG (19 versus 8 percent) [150].
However, the applicability of the findings in ARTS to current practice is uncertain given the widespread use of drug-eluting stents. Uncontrolled observations from ARTS II suggested that outcomes with drug-eluting stents approached those with CABG but data in patients with CKD are not available. (See "Percutaneous coronary intervention with intracoronary stents: Overview" and "Revascularization in patients with stable coronary artery disease: Coronary artery bypass graft surgery versus percutaneous coronary intervention".)
INCREASED SERUM CARDIAC ENZYMES AND ACUTE CORONARY EVENTS — Cardiac troponins are the preferred marker for the diagnosis of myocardial injury among patients with normal kidney function because of their increased specificity compared with CK-MB and other markers. (See "Troponin testing: Clinical use".)
Cardiac troponins are also used in the diagnosis of myocardial infarction in patients with CKD and a suspected acute coronary syndrome, although minor chronic elevations in serum troponins are commonly observed in patients with CKD who do not have clinical evidence of a myocardial infarction. These issues are discussed in detail separately. (See "Cardiac troponins in patients with kidney disease".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)
SUMMARY
●Both decreased glomerular filtration rate (GFR) and increased proteinuria increase the risk of cardiovascular disease. These associations have been shown in both community-based populations (ie, cohorts that were not selected specifically to enroll individuals with chronic kidney disease [CKD] or cardiovascular disease) and in populations of patients at high cardiovascular risk (ie, cohorts in which patients with preexisting cardiovascular disease or cardiovascular disease risk factors were specifically recruited). (See 'Chronic kidney disease as an independent risk factor for CHD' above.)
●Patients with CKD often have numerous traditional and nontraditional risk factors for the development of cardiovascular disease. Traditional risk factors (hypertension, smoking, diabetes, dyslipidemia, and older age) appear to be more important risk factors during the earlier stages of CKD. Nontraditional risk factors include uremic toxins, anemia, elevated levels of certain cytokines, an increased calcium load, abnormalities in bone mineral metabolism, and/or an increased inflammatory-poor nutrition state. (See 'Presence of traditional and nontraditional cardiovascular risk factors in CKD' above.)
●Among those with CKD, the risk of death, particularly due to cardiovascular disease, is typically higher than the risk of eventually requiring kidney replacement therapy. However, this risk varies with age and other factors. In many studies, older patients with less severe CKD and lower levels of proteinuria are more likely to die (usually due to cardiovascular disease) before needing kidney replacement therapy, while younger patients with proteinuria and diseases localized to the kidney are more likely to ultimately need kidney replacement therapy. (See 'Competing risks of cardiovascular and end-stage kidney disease' above.)
●Our general approach to reduce the risk of atherosclerotic cardiovascular disease in most patients with CKD not requiring dialysis includes the following (see 'Reduction of CHD risk in patients with CKD' above):
•Statin therapy. (See 'Statin therapy' above.)
•In patients with proteinuric CKD (defined as proteinuria greater than 500 to 1000 mg/day), we recommend angiotensin blockade as part of the antihypertensive regimen. Goal blood pressure is discussed elsewhere. (See 'Blood pressure control' above and "Goal blood pressure in adults with hypertension" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Treatment of hypertension in patients with diabetes mellitus".)
•Individualized decisions about antiplatelet therapy. (See 'Antiplatelet therapy' above.)
•In all patients, smoking cessation, maintenance of an ideal body weight, an active lifestyle, and, in patients with diabetes, glycemic control. (See 'Other issues' above.)
●Patients with CKD require drug dose adjustments and have a higher risk of drug-related adverse effects. Despite the increased risk of adverse effects, the treatments used for established coronary heart disease (CHD) and acute coronary syndrome that are used in patients with normal kidney function (eg, revascularization) may have similar benefits in patients with CKD. (See 'Treatment of coronary heart disease' above.)
●Patients with CKD who suffer an acute coronary syndrome or who have coronary interventions (ie, coronary artery bypass grafting, percutaneous coronary intervention [PCI]) have a worse prognosis than patients with normal kidney function who have similar events or procedures (table 1 and table 2). The mechanisms which underlie the poor prognosis in patients with CKD are not entirely clear. (See 'Prognosis of coronary heart disease in patients with CKD' above.)
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