1. health and fitness
2. disease

J Am Soc Nephrol 14: 2556–2572, 2003
DISEASE OF THE MONTH
Eberhard Ritz, Feature Editor
How to Manage the Renal Patient with Coronary Heart
Disease: The Agony and the Ecstasy of Opinion-Based
Medicine
CHARLES A. HERZOG, MD
Hennepin County Medical Center, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
The management of ischemic heart disease in patients with
chronic kidney disease (CKD) is a special challenge for clinicians. The recent heightened awareness of CKD as an important risk factor for cardiovascular death is a welcome development; the eventual outcome will be clinical trials targeting
CKD patients for prevention and treatment of coronary heart
disease and its devastating complications. The reader is urged
to consult National Kidney Foundation (NKF) task forces
dealing with cardiovascular disease in chronic renal failure
(1,2) and, most recently, lipid management (3). At the present
time, however, clinicians are often faced with a nettlesome
dilemma in their approach to renal patients with ischemic heart
disease; most of the evidence-based practice guidelines are
based on clinical trials performed in patients without CKD.
Patients with renal disease have typically been excluded from
major cardiovascular treatment trials in the past; although there
is no shortage of recent reviews on cardiovascular disease in
renal disease (4 –10), there is most certainly a paucity of good
clinical trial data in CKD patients. The application of imperfect
data to clinical practice, however, is nothing new for clinicians,
as this is common in medical practice.
It is not my intention to offer a general review on cardiovascular disease and renal disease, but rather to present my
(admittedly idiosyncratic) approach to clinical management of
coronary heart disease in renal patients distilled partly from the
literature and personal experience. This paper will focus on
cardiac disease in dialysis patients, but I will also attempt to
frame special cardiac management issues pertaining to nondialysis CKD patients.
Correspondence to Dr. Charles A. Herzog, Hennepin County Medical Center,
Department of Medicine, 701 Park Avenue – Mail Code 865A, Minneapolis,
MN 55415-1829. Phone: 612-337-8957; Fax: 612-347-5878; E-mail:
[email protected]
1046-6673/1410-2556
Journal of the American Society of Nephrology
Copyright © 2003 by the American Society of Nephrology
DOI: 10.1097/01.ASN.0000087640.94746.47
Background
Epidemiology and the Burden of Cardiovascular
Disease in ESRD Patients
Patients receiving renal replacement therapy on dialysis are
at extraordinarily high risk for death. The death rate for all US
dialysis patients in 1998 –2000 was 236/1000 patient-years
(11). Cardiac disease is the major cause of death in dialysis
patients, accounting for about 45% of all-cause mortality (12).
Approximately 20% of cardiac deaths are attributed to acute
myocardial infarction (AMI) (12). The burden of coronary
heart disease in end-stage renal disease (ESRD) patients is
projected to increase, as the greatest increase in treated ESRD
has occurred in patients with the highest risk for cardiovascular
disease, older patients and those with diabetic nephropathy.
There were an estimated 315,000 US dialysis patients in 2002
(11), with a projected number of 520,000 US dialysis patients
in 2010 (12).
The number of patients with non– dialysis-dependent renal
failure is considerably larger. In 1988 –1994, there were an
estimated 10.9 million US patients having chronic renal insufficiency with serum creatinine ⬎ 1.5 mg/dl (13). These projections raise an interesting “paradox of the missing dialysis
patients”— why is the “feeder” population of CKD more than
30 times larger than the dialysis population? It appears that the
risk of death for (nondialysis) CKD patients is considerably
greater than developing ESRD (11). A plausible explanation is
that excess cardiovascular death (including coronary heart disease) in the CKD population prevents most CKD patients from
developing ESRD; even “mild” renal insufficiency is associated with increased cardiovascular mortality (14,15). Logically, the greatest potential survival benefit from cardiac intervention in patients with renal disease would be derived from
targeting patients for CHD prevention and treatment before the
development of severe CKD.
Chronic renal failure is a condition characterized by generalized vasculopathy (16). A variety of risk factors (many of
them important in CKD patients before the development of
ESRD) contributing to accelerated cardiovascular morbidity
and mortality in renal patients include hypertension, dyslipidemia, hyperglycemia, smoking, physical inactivity, enhanced
thrombogenicity, hyperparathyroidism, hyperhomocystinemia,
increased sympathetic tone (including sleep apnea), and ele-
J Am Soc Nephrol 14: 2556–2572, 2003
vated levels of ADMA (asymmetric dimethyl arginine). The
development of left ventricular hypertrophy may be promoted
by anemia and vascular noncompliance. Aortic stiffness (assessed by aortic pulse wave velocity) is an independent predictor of cardiovascular and all-cause death in dialysis patients
(17). Premature coronary artery calcification has been detected
in young dialysis patients, and the metabolic milieu of ESRD,
including elevated calcium-phosphate product (18), and the
synergistic effect of hyperparathyroidism, and inflammation
(as reflected by levels of C-reactive protein) (19) may be
implicated. Vascular endothelial dysfunction likely contributes
to the expression of atherosclerotic disease, and even a single
hemodialysis run may adversely affect endothelial function
(20). Hyperglycemia may markedly reduce coronary vasodilator function (21) (by promoting the formation of advanced
glycation end-products, which oppose nitric oxide-mediated
endothelial-dependent relaxation) (22). The composition of
coronary plaques in patients with ESRD may be qualitatively
different, with increased media thickness and marked calcification of the affected coronary arteries (23,24). The pathophysiologic significance of coronary artery calcification in ESRD
patients, therefore, may be different from the nonrenal
population.
It is nearly impossible to accurately apportion the absolute
contribution of “obstructive” coronary artery disease to cardiovascular morbidity and mortality in ESRD patients. This may
strike some readers as pedantic, but it does have implications
for the potential magnitude of therapeutic benefit that can be
derived from coronary revascularization. Sudden cardiac death
may be implicated in 60% of all cardiac deaths in dialysis
patients. In the United States Renal Data System (USRDS)
database, “cardiac arrest, cause unknown” accounts for 47% of
all cardiac deaths, and another 13% are attributed to arrhythmia
(25). Besides obstructive coronary artery disease (CAD), factors contributing to the peculiar vulnerability of ESRD patients
to sudden death include left ventricular hypertrophy, electrolyte shifts in hemodialysis patients, and abnormalities in myocardial ultrastructure and function, including endothelial function, interstitial fibrosis, decreased perfusion reserve, and
diminished ischemia tolerance (26 –29). The nonphysiologic
nature of conventional hemodialysis schedules (usually administered thrice weekly in the United States on Monday, Wednesday, Friday or Tuesday, Thursday, Saturday) may also contribute to increased cardiac death; this hypothesis is based on a
study by Bleyer et al. (30), who found that significantly higher
cardiac mortality occurs on Mondays (and to a lesser extent,
Tuesday, the other dialysis day after the long interdialytic
weekend). It is plausible that long-duration daily hemodialysis
might lead to improved survival in ESRD patients, particularly
if maintenance of “physiologic loading conditions” is accompanied by the amelioration of left ventricular hypertrophy and
avoidance of significant electrolyte abnormalities (interdialytic
hyperkalemia and intradialytic hypokalemia).
Acute Myocardial Infarction
Acute myocardial infarction in dialysis patients is a catastrophic event associated with dismal long-term survival (31–
Ischemic Heart Disease and Renal Failure
2557
33). We have previously reported a 1-yr 59% mortality and
2-yr 73% mortality in 34,189 dialysis patients hospitalized
with AMI in the US from 1977 to 1995 (31) (Figure 1). Even
more striking is the poor outcome of patients treated in the “era
of reperfusion,” with 1-yr and 2-yr mortalities of 62% and 74%
in 1990 –95, and 2-yr mortality of 78% in 1991–97 (34). Renal
transplant recipients fare better, with a 2-yr mortality of 34%
after hospitalization for AMI in 1977–96 (35).
We have speculated that the poor outcome of these patients
may be due to a combination of underdiagnosis and undertreatment (i.e., therapeutic nihilism) (36) — “To the guy with a
hammer, everything looks like a nail.” If a dialysis patient
arrives on a Monday morning in the outpatient dialysis unit 5
kg above dry weight and complaining of dyspnea and angina,
what procedure is most likely to occur first: an electrocardiogram (ECG) or the scheduled dialysis run? Circulatory congestion attributable to the ingestion of pepperoni pizzas and
myocardial ischemia due to AMI might cause the same symptoms, and a nephrologist could easily choose dialysis as the
first procedure under these clinical circumstances, with potentially devastating results if the patient’s primary problem is
actually AMI and not pepperoni pizza. Ongoing preliminary
work at the Cardiovascular Special Studies Center of USRDS
and a recent publication by Berger et al. (36a) suggest both
underrecognition of AMI due to “atypical clinical presentations” and undertreatment.
Poor survival after AMI is a general phenomenon in patients
with CKD, and it is not restricted to dialysis patients. There is
an increasing gradient of mortality risk observed with more
severe renal dysfunction in AMI (37–39). In-hospital mortality
is correlated with renal function, and there is a strikingly
greater risk of death in patients with estimated creatinine
clearance (CrCl) ⬍ 60 ml/min. (Figure 2) One-year AMI
Figure 1. Estimated mortality of dialysis patients after acute myocardial infarction (MI). Reprinted with permission from Herzog CA, Ma
JZ, Collins AJ: Poor long-term survival after acute myocardial infarction among patients on long-term dialysis. N Engl J Med 339: 799 –
805, 1998.
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Figure 2. In-hospital mortality as a function of creatinine (Cr) clearance (P ⬍ 0.001). Reprinted with permission from Wright RS, Reeder
GS, Herzog CA, Albright RC, Williams BA, Dvorak DL, Miller WL,
Murphy JG, Kopecky SL, Jaffe AS: Acute myocardial infarction and
renal dysfunction: a high-risk combination. Ann Intern Med 137:
563–570, 2002.
mortality in elderly (ⱖ65 yr) patients enrolled in the Cooperative Cardiovascular Project (CCP) in 1994 –95 was 24% in
patients with serum creatinine ⬍1.5 mg/dl, 46% for Cr ⫽ 1.5
to 2.4 mg/dl, and 66% for Cr ⫽ 2.5 to 3.9 mg/dl (38). Similar
findings were reported by Walsh et al. (40). In a recent pooled
analysis from the Global Use of Strategies to Open Occluded
Coronary Arteries (GUSTO II-b, GUSTO-III) studies, Platelet
Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrillin Therapy (PURSUIT), and Platelet IIb/
IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network
(PARAGON-A) acute coronary syndrome trials, both ST-segment elevation and non-ST-segment elevation MI with CrCl ⬍
70 ml/min were associated with increased 1-mo and 6-mo
mortality (41).
One astounding finding in patients with CKD and AMI is
that the likelihood of receiving therapies proven to reduce
mortality in clinical trials on AMI treatment is inversely related
to the severity of renal failure (36a,37–39,42). This applies to
the use of aspirin, ␤-blockers, and reperfusion therapy. In the
study by Wright et al. (37), the use of angiotensin-converting
enzyme (ACE) inhibitors at hospital discharge was also inversely related to the degree of renal impairment. Importantly,
in these observational studies, the use of all these standard
therapies were associated with decreased mortality. In the
McCullough et al. study (42) from Henry Ford Hospital, the
age-adjusted relative risk reduction of in-hospital mortality for
patients receiving aspirin and ␤-blockers ranged from 64% to
80% across all renal function groups (compared with no treatment with either agent). In the Wright et al. study at the Mayo
Clinic, the use of aspirin and ␤-blocker therapy at discharge
and initial treatment with reperfusion therapy were independently associated with a 30% reduction in post-discharge
deaths. In the Shlipak et al. study (38) of Medicare beneficiaries in the CCP database, aspirin was associated with a 48% to
60% range of reduction in 1-mo mortality across renal function
categories, ␤-blockers were associated with a 38 to 42% reduction in 1-mo mortality, and ACE inhibitors were associated
J Am Soc Nephrol 14: 2556–2572, 2003
with a 48% to 59% reduction in 1-mo mortality. We have
reported preliminary findings on the apparent under-utilization
of thrombolytic therapy in dialysis patients. Using claims data
from USRDS, we identified 33,277 dialysis patients hospitalized for AMI in 1991–97 who did not receive coronary reperfusion therapy and suffered a 2-yr mortality rate of 78%,
compared with 176 patients receiving intravenous thrombolytic therapy with a 2-yr mortality rate of 60%. In a comorbidity-adjusted Cox model, thrombolytic therapy was associated with a 28% reduction in all-cause death risk (34). The
poor outcome of CKD patients with AMI would appear to be
partially attributable to therapeutic nihilism (and for dialysis
patients, perhaps fueled by fear of potential complications such
as hemorrhage and the unavailability of clinical trial outcome
data due to the exclusion of ESRD patients from all AMI
trials). For patients with AMI, no treatment is equivalent to bad
treatment.
The use of glycoprotein IIb/IIIa receptor antagonists as
adjunctive therapy in acute coronary syndromes and percutaneous coronary intervention (PCI) in CKD is more controversial but supported by recent data. In the Platelet Receptor
Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial of
tirofiban in acute coronary syndrome (ACS) (patients excluded
for Cr ⱖ 2.5 mg/dl), tirofiban was effective in reducing ischemic ACS complications, and there was no synergistic relationship between use of tirofiban and degree of renal impairment for the development of hemorrhagic complications (43).
Using observational data from the Michigan Cardiovascular
Outcomes and Reporting Program, Freeman et al. (44) reported
an increase in major bleeding and reduced in-hospital mortality
in patients with ACS and renal failure receiving glycoprotein
(GP) IIb/IIIa antagonists. In the Enhanced Suppression of the
Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT)
trial (eptifibatide), the beneficial effect of the agent and attributable hemorrhagic complications were not different in patients
with CrCl ⬍ 60 ml/min (mean, 48 ml/min). Jeremias et al. (45)
reported no increased risk of complications with abciximab in
patients undergoing PCI with Cr ⱖ 2.0 mg/dl (findings concordant with a recent publication by Best et al. [45a]). In
contrast, Frilling et al. (46), using the Ludwigshafen IIb/IIIaAntagonist Registry, reported a fivefold risk of any bleeding
associated with abciximab in 44 patients with impaired renal
function (Cr ⱖ 1.3 mg/dl), but the absolute number of episodes
was only 6.8%. There are a paucity of data on the use of
glycoprotein IIb/IIIa antagonists in dialysis patients, although
anecdotally, abciximab is probably the most widely used of
these agents in dialysis patients undergoing PCI. Current US
product labeling of available GP IIb/IIIa antagonists includes a
reduced dose of eptifibatide in chronic renal failure (with no
additional recommendation for Cr ⱖ 4.0 mg/dl), 50% reduction in tirofiban dose in dialysis patients, and no dose adjustment for abciximab. It should be stressed that there are currently few published data on the safety and efficacy of these
agents in dialysis patients. Prudence dictates careful clinical
observation of all dialysis patients after PCI (including ready
J Am Soc Nephrol 14: 2556–2572, 2003
availability of blood products), regardless of the particular
therapeutic strategy employed.
Anticoagulation practice in dialysis patients with PCI and/or
ACS will be limited by elimination kinetics of the drugs
(including uncertainty in dialysis patients) and the ability to
monitor therapy. During PCI, the monitoring of activated clotting time allows for dose-adjustment with unfractionated heparin. Low–molecular weight heparin has generally been
avoided in ESRD patients, partly due to safety issues (with
very prolonged half-life) and, until recently, inability to rapidly
monitor therapeutic effect. One useful anticoagulant agent in
ESRD patients undergoing PCI is bivalirudin (Angiomax), a
direct thrombin inhibitor, which is predominantly renally excreted, and (FDA-approved) appropriate adjustments for all
degrees of renal impairment, including dialysis-dependence,
are provided by the manufacturer (47).
Other untested adjunctive therapies for ACS in ESRD patients appear promising. The use of clopidogrel reduces the risk
of recurrent cardiovascular events (with an increased risk of
bleeding) in the “general population” (48). At my institution,
we have generalized the results of the Clopidogrel in Unstable
Angina to Prevent Recurrent Events (CURE) trial (48) and
applied them to ESRD patients (a practice consistent with the
application of other therapies not specifically tested in ESRD
patients but proven in the general population). In the setting of
PCI with coronary stenting, the combination of 81 to 325 mg/d
aspirin (lifelong) and clopidogrel (30 d or longer if used for
other indications) is standard therapy, including for ESRD
patients.
Patients with ESRD due to diabetic nephropathy have a 34%
increased risk of death after AMI (compared with non-DM)
(31). In diabetic patients with AMI, insulin glucose infusion
reduces long-term mortality (49,50). It has been proposed that
some of the cardioprotective benefit of insulin may derive from
myocardial effects independent of metabolic modulation (51).
Future trials in diabetic CKD patients would be appropriate.
Tables 1 to 3 summarize our general approach to the management of AMI in dialysis patients. In chronic hemodialysis
patients, the optimal timing for resumption of routine dialysis
is controversial. In our own program, we have arbitrarily
delayed routine dialysis in the first 24 h after AMI (unless
forced by metabolic derangements), a practice supported by
preliminary data from Kong et al. (52), who reported that 20%
of 45 dialysis patients with AMI suffered unexpected ventricular fibrillation during hemodialysis, with five lethal outcomes.
Medical Management of Chronic CAD in Dialysis
Patients
Table 4 summarizes our general approach to the medical
management of ischemic heart disease in dialysis patients.
Most approaches to treatment represent generalization of established therapies in non-ESRD, with a few modifications.
The maintenance of relative euvolemia is a key aspect of the
management of these patients (53). Hemodynamic target dry
weight may be a moving target in chronic dialysis patients
(particularly diabetic patients), who may lose muscle mass
over time—the same weight might denote inadequate fluid
Ischemic Heart Disease and Renal Failure
2559
Table 1. Acute myocardial infarction (AMI) in dialysis
patients: diagnostic pitfallsa
● Atypical presentations delay diagnosis.
● Symptoms of volume overload and those of AMI may be
identical. Would a hemodialysis patient with chest pain or
dyspnea receive an immediate ECG?
● Left ventricular (LV) hypertrophy with ST-segment
changes, prevalent among dialysis patients, makes ECG
diagnosis of acute MI more difficult.
● Specificity of cardiac biomarkers may be problematic
when they are present at low levels. Cardiac troponins
should be used for AMI diagnosis.
● Current troponin I assay has higher specificity for AMI
diagnosis, but troponin T is better for future prediction of
all-cause death in outpatient, asymptomatic hemodialysis
patients.
● Cardiac biomarker-based diagnosis of AMI requires timeappropriate rise and fall of the biomarker
a
Modified from reference 76a.
Table 2. Treatment of AMI in dialysis patientsa
● Antiplatelet agents (aspirin), clopidogrel.
● Anticoagulants,? bivalirudin for percutaneous coronary
intervention (PCI).
● Glycoprotein IIb/IIIa antagonists (tirofiban, abciximab)?
● Coronary reperfusion (STEMI)
● Primary PCI (hemorrhagic risk potentially lower than
that of thrombolytic therapy)
● Thrombolytics
●
●
●
●
␤-blockers.
Angiotensin-converting enzyme (ACE) inhibitors.
Nitroglycerin
Statins
a
Modified from reference 76a.
removal 2 yr later with declining lean body mass. In our
practice, we rely on echocardiography for assessment of hemodynamic dry weight and occasionally elective right heart
catheterization followed by right heart monitoring during dialysis/ultrafiltration to help determine true hemodynamic dry
weight. Anemia may exacerbate angina; adherence to Dialysis
Outcomes Quality Initiative (DOQI) anemia treatment guidelines is assumed in these patients. Hemodialysis can trigger
angina, and alterations in dialysis prescription, including prolongation of treatment time to permit decreased ultrafiltration
rate may be helpful in amelioration of dialysis-associated myocardial ischemia (54). Some nephrologists will sometimes omit
anti-anginal therapy before dialysis if it is perceived that the
agents are exacerbating unstable intradialytic hemodynamics,
but this practice is more empiric than evidence-based. Inability
to perform dialysis without hemodynamic instability or angina,
however, should prompt further cardiac investigations for as-
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Table 3. Pitfalls in the treatment of AMI in dialysis patients
Therapeutic nihilism
● Exclusion of end-stage renal disease (ESRD) patients
from clinical trials.
● Relative contraindications to thrombolytic therapy are
always present.
Volume status
● Echocardiography
● Right heart catheterization in patients undergoing
PTCA/STENT for peri-procedure dialysis management.
● Iso-osmolar radiocontrast media used for angiography.
Dialysis
● Defer routine dialysis in first 24 h?
● Acute dialysis may be forced by other therapies (for
example, hypervolemia secondary to angiography).
● Modification of dialysis runs in low-output states.
a
Modified from reference 76a.
Table 4. Medical management of chronic CAD in dialysis
patients
● Antiplatelet agents (aspirin ⫾ clopidogrel).
● ␤-blockers.
● ACE inhibitors (angiotensin receptor blockers in ACEintolerant patients).
● Long acting nitrates for angina.
● Calcium channel blockers (predominantly amlodipine) as
adjunctive therapy for angina/hypertension.
● Statins.
● Adherence to DOQI guidelines for anemia management.
● Maintenance of hemodynamic dry weight (assessed by a
variety of methods, including echocardiography).
● Alterations in dialysis prescription (e.g., prolongation of
treatment time to permit decreased ultrafiltration rate) for
amelioration of dialysis-associated myocardial ischemia.
● Intradialytic hemodynamic instability/inability to tolerate
medical therapy may be an indication for nonmedical
treatment.
sessment of left ventricular (LV) function, valvular disease,
and CAD. Obviously, inability to perform dialysis without
untoward events constitutes failure of medical therapy and
deserves further cardiac evaluation.
The treatment of dyslipidemia in chronic renal failure was
the subject of a recent DOQI task force, and the reader is urged
to consult this comprehensive document (3). Previous treatment trials in dialysis patients have essentially been large case
series and pilot studies. Statin therapy (e.g. simvastatin in
placebo-controlled randomized trial) is safe and efficacious for
treatment of hypercholesteremia in dialysis patients (55,56). It
is reasonable to treat dialysis patients (or for that matter CKD
patients) as CHD-equivalent (like diabetes) and treat to a goal
of LDL-cholesterol ⬍ 100 mg/dl. It is a bit more uncertain for
the frequent occurrence in chronic hemodialysis patients of
J Am Soc Nephrol 14: 2556–2572, 2003
“low HDL-cholesterol, normal LDL-cholesterol, and increased
triglycerides (the typical type 2 DM profile). In these patients,
we will use statins for overt CHD, but it is less clear if they
should be used for all dialysis patients. It is plausible that these
high-risk patients might all benefit from statin therapy. Hopefully, the 4-D (Die Deutsche Diabetes Dialyze Studie) trial on
the use of atorvastatin in type 2 diabetic patients will resolve
this issue in dialysis patients. On the basis of current enrollment and event rates, preliminary data may be available in
2004. In my own practice, I sometimes employ combination
therapy with statins (frequently atorvastatin) and sustainedrelease niacin (Niaspan) in patients with elevated LDL-cholesterol, decreased HDL-cholesterol, and increased triglycerides
who do not respond adequately to monotherapy with a statin.
Hepatic enzymes are monitored frequently in these patients on
combination therapy. Combination therapy with ezetimibe, an
inhibitor of intestinal brush border absorption of cholesterol,
and statins is another approach to reducing LDL-cholesterol.
The Study of Heart and Renal Protection (SHARP) trial, which
began enrollment in June 2003 will test the efficacy of ezetemide and simvastatin for the reduction of cardiovascular
events in patients with varying degrees of CKD, including
ESRD.
The cornerstone of medical therapy for CHD (and cardiomyopathy) might be ␤-blockers. Dialysis patients with dilated
cardiomyopathy benefit from ␤-blocker therapy (57–59). The
publication of a randomized, placebo-controlled trial of carvedilol in 114 Neapolitan dialysis patients with a dilated cardiomyopathy and NYHA class 2 and 3 chronic heart failure (CHF)
by Cice et al. (57) was a remarkable accomplishment, as few
clinical trials have been conducted on cardiac disease in dialysis patients. The authors reported a sustained objective improvement in LV systolic function (documented by serial echocardiography) at 1 yr, with improvement (P ⬍ 0.05) of mean
LV ejection fraction from 26 ⫾ 8% to 35 ⫾ 11% versus no
change with placebo. Nearly 30% of class 3 CHF patients
receiving carvedilol shifted to class 2 compared with no significant improvement after placebo. Cice et al. have recently
reported that the 2-yr mortality rate in the placebo group was
73% versus 52% in the carvedilol group (P ⬍ 0.01), with a
49% reduction in all-cause death risk with carvedilol and a
56% reduction in all-cause hospitalization risk (58). It has been
proposed that prophylactic ␤-blocker therapy might reduce the
cardiovascular mortality of dialysis patients (particularly diabetic patients) (59a). Given the safety of these agents and
comparatively modest cost, this would be a worthy subject for
a large-scale randomized clinical trial.
Clinical trials on antioxidant therapy in the general population have been profoundly disappointing to antioxidant vitamin
enthusiasts. In dialysis patients, the issue is less clear, as two
randomized clinical trials suggest that cardiovascular events in
dialysis patients can be reduced by antioxidant therapy: Vitamin E Secondary Prevention with Antioxidants of Cardiovascular Disease in End-Stage Renal Disease (SPACE trial) (60)
and acetylcysteine (61). The degree of oxidative stress is
greater in the dialysis population; for this reason, there may be
a special niche for antioxidant therapy. Future clinical trials
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testing the effects of anti-oxidant therapy in dialysis patients
are warranted.
Cardiac Arrest
Sudden cardiac death may be implicated in 60% of all
cardiac deaths in dialysis patients, making it potentially the
single largest cause of death in dialysis patients. Strategies to
reduce the risk of succumbing to this lethal event should
concentrate on reducing the likelihood of cardiac arrest and
increasing the probability of surviving cardiac arrest (62). The
risk of cardiac arrest increases over time after dialysis initiation
(vintage effect), with an event rate of 110 events/1000 patientyears at 2 yr, rising to 208 events/1000 patient-years 5 yr after
initiation in patients with diabetic ESRD (11). Identification of
high-risk patients by assessment of LV function, ischemic
burden, and biomarkers (particularly cardiac troponin T) might
facilitate targeted intervention in high-risk patients. Treatment
with agents known to improve cardiac survival in the general
population (e.g., aspirin, ␤-blockers, ACE inhibitors, statins,
etc) might also reduce the risk of sudden cardiac death in
ESRD patients.
The maintenance of physiologic loading conditions and
avoidance of large electrolyte shifts are specific strategies
applicable to dialysis patients. Karnik et al. (63) reported a
cardiac arrest rate of 7 per 100,000 hemodialysis sessions (with
Monday the most likely day for cardiac arrests). Cardiac arrest
was nearly twice as likely in patients dialyzed against a 0 or 1.0
mEq/L potassium dialysate on the day of cardiac arrest. Becker
et al. (64) reported on cardiac arrest outside hospitals in Seattle
and King County from 1990 to 1996 using Emergency Medical
Services (EMS) data. There were 47 cardiac arrests in dialysis
centers, with an annual incidence of 0.746.
Linda Becker has kindly shared with me the dialysis-specific
resuscitation data (47 patients), which did not appear in her
paper. There were 41 witnessed events, and bystander CPR
was administered to 41 patients. In 29 patients (62%), the
cardiac rhythm was ventricular fibrillation (VF) or ventricular
tachycardia (VT). The overall survival to hospital discharge
was 30%; of the patients with VT/VF, it was an impressive
38%. It must be acknowledged that Seattle/King County is
widely regarded for its outstanding EMS system; these survival
data reflect swift EMS response times and expert crews. These
data also make a compelling case for the availability of defibrillators in all dialysis units. The logical conclusion is that
automatic external defibrillators (AED), which are widely used
(and intended for nonmedical operators), including in all US
commercial jet aircraft, some casinos, and many public facilities, should be available in all dialysis centers. The mortality
rate is about 10% per min in the first 5 min after cardiac arrest
(including with CPR), and survival is uncommon after 10
min—-this is the reason why AED are critical, as EMS response times will always be problematic.
Unfortunately, most cardiac arrests occur at home. We have
recently presented preliminary data on the apparent striking
underutilization of implantable cardioverter defibrillators
(ICD) in cardiac arrest survivors on dialysis (65). The 1-yr
mortality of 3380 dialysis patients discharged alive from hos-
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2561
pital without ICD was 60% compared with 40% in 167 dialysis
patients receiving ICD within 30 d of cardiac arrest. In a Cox
model, there was a 47% reduction in mortality risk associated
with ICD therapy. I believe that a randomized, prospective trial
on the efficacy of ICD for the reduction of mortality in dialysis
patients would be appropriate.
Diagnosis of CAD in ESRD Patients
The identification of coronary artery disease in ESRD patients has typically focused on high-risk (predominantly diabetic) renal transplant candidates, despite the fact that a minority of ESRD patients is actually deemed to be transplant
candidates. Current practice guidelines address screening for
CAD in high-risk renal transplant candidates (66) and waitlisted patients (67), but they do not address the patients at
highest risk for cardiac death: dialysis patients not being considered for transplantation. We have previously reported that
there is an early hazard of AMI associated with dialysis initiation, as 29% of MI in dialysis patients occur within 1 yr and
52% within 2 yr of initiation of dialysis (31). I would argue that
some type of assessment of global cardiac risk would be
appropriate after dialysis initiation, provided that testing can
guide clinical management (and this is the usual Gordian knot
of clinical practice, as the evidence supporting intervention is
frequently weak or not existent).
The key issue in diagnosis/testing for CAD in ESRD patients
is how the clinician will use the resultant information. The
ability to accurately predict coronary anatomy on a noninvasive test is not equivalent to the predictive value of the test for
prognostication of future cardiac events. When renal transplant
candidates are screened for CAD by noninvasive stress imaging tests, one clinical goal is risk stratification for future
adverse cardiac events. The second goal is to actually predict
coronary anatomy, if prophylactic coronary revascularization
is solely based on angiographic findings (68). If restenosis is an
issue after PCI, the sensitivity of the stress-imaging test to
predict coronary anatomy is important, because there may be
no other clinical surrogates to identify occult restenosis.
Exercise stress electrocardiography is problematic in many
ESRD patients. Non-cardiac exercise limitations (e.g., peripheral vascular disease [PVD]) and the high prevalence of left
ventricular hypertrophy and uninterpretable stress electrocardiographic findings, make stress imaging preferable. Some
ESRD patients without PVD are able to successfully undertake
treadmill exercise for stress imaging, but the majority will
require pharmacologic stress (69).
The accuracy of pharmacologic stress nuclear imaging in
renal transplant candidates (compared with angiography) has
been disappointing in the few published series (70 –72) that
actually compared stress nuclear imaging to coronary angiography (rather than prediction of future clinical events) in the
entire study population. Marwick et al. reported 37% sensitivity and 73% specificity for detection of CAD defined as 50%
or more stenosis and 29% sensitivity for 70% or more stenosis
for dipyridamole SPECT (single-photon emission computed
tomography) thallium imaging. In Vandenberg’s series (72),
the sensitivity and specificity of pharmacologic stress thallium
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imaging in diabetic renal or pancreas transplant candidates
compared with a 75% coronary stenosis were 62% and 76%,
respectively. Boudreau et al. (71) reported better accuracy,
with 86% sensitivity and 72% specificity for detection of
coronary stenoses of more than 70% reduction in cross-sectional area by dipyridamole planar thallium imaging. Using a
novel stress protocol of combined dipyridamole-exercise thallium imaging in chronic hemodialysis patients (only 14% with
DM), Dahan et al. (73) have reported the highest level of
diagnostic accuracy for stress nuclear imaging in ESRD patients, with a sensitivity of 92% and specificity of 89% compared with coronary artery diameter stenosis ⱖ 70%. There are
few publications on dobutamine stress echocardiography in
ESRD patients employing coronary angiography in the entire
study cohort. We prospectively screened 50 renal transplant
candidates (39 DM) and performed dobutamine stress echocardiography and subsequent quantitative coronary angiography (QCA) on the entire cohort (74). The sensitivity and
specificity of the stress echo alone (not including other data
such as induction of angina) were 75% and 71%, respectively,
for QCA stenosis ⬎ 70% and 75% and 76%, respectively, for
visually estimated stenosis ⬎75% (the latter definition used in
Manske’s study on prophylactic coronary revascularization)
(68). There are few data comparing stress echo to stress nuclear
imaging in ESRD patients. We have presented preliminary data
(75) on the concordance of adenosine stress nuclear scintigraphy, dobutamine stress nuclear scintigraphy, and dobutamine
stress echocardiography in the same 33 ESRD patients. The
adenosine and dobutamine stress nuclear studies were 91%
concordant (␬ ⫽ 0.76); adenosine stress nuclear and dobutamine echo concordance was 72% (␬ ⫽ 0.43). Angiography
was performed in the 16 patients who had at least one positive
test; compared with stenosis ⬎ 70%, the sensitivity of stress
echo was 100% versus 58% for adenosine stress nuclear imaging, and 75% specificity for echo and 87% specificity for
adenosine nuclear imaging.
The utility of stress myocardial imaging studies for the
prediction of MI and cardiac death in ESRD patients evaluated
for kidney or kidney-pancreas transplantation was recently
assessed in a meta-analysis published by Rabbat et al. (76).
Although their work was limited by the relative paucity of
suitable primary data, forcing the combining of eight stress
nuclear and four echocardiographic studies to obtain an adequate sample size (and thus precluding a head-to-head echo/
nuclear comparison), it is my belief as a reviewer of this paper
that the authors accomplished the meta-analysis equivalent of
creating a silk purse from a sow’s ear. When compared with
negative tests, positive tests (which include fixed defects indicative of previous MI, but not inducible ischemia) had a
significantly increased relative risk (RR) of future MI (RR,
2.73; 95% CI, 1.25 to 5.97) and cardiac death (RR, 2.92; 95%
CI, 1.66 to 5.12). In diabetic patients, there were comparable
relative risks. Importantly, a fixed defect was not predictive of
MI, but it was strongly predictive of cardiac death (RR, 4.74;
95% CI, 2.26 to 7.94). Unfortunately, the meta-analysis did not
include the important effect of LV ejection fraction as an
independent predictor of survival. From a management per-
J Am Soc Nephrol 14: 2556–2572, 2003
spective, it would be easy for me to deal with a normal stress
imaging study (provided we also know that there is a normal
LV ejection fraction and no significant valve disease). Patients
with reversible defects (i.e., inducible ischemia) would normally receive coronary angiography. In the general population,
current practice guidelines factor in the “risk area” in clinical
management (i.e., small segments have a good prognosis and
may not need further evaluation). In the ESRD population
(particularly diabetic patients undergoing nuclear imaging), the
poor sensitivity of the testing for detection of inducible ischemia (compared with angiography) may alter the approach to
ESRD patients. In our own practice, we would usually perform
coronary angiography for any reversible defect or significant
reduction of LV ejection fraction (⬍40%) in evaluating ESRD
patients.
What do we do with fixed defects? If the imaging test were
accurate at predicting anatomy (and we knew the LV ejection
fraction), we could dispense with performing coronary angiography. The problem is that all of the non-invasive modalities
generally employed are imperfect at best, and very operatordependent. One interpretation of the paper by Rabbat et al. is
that these patients with old scars from previous MI perhaps had
an arrhythmogenic nidus for sudden cardiac death. The exclusion of other ischemic (non-infarcted) coronary artery vascular
territories is important in this setting; for this reason, our
approach is to perform angiography in these patients.
Figure 3 summarizes our current management algorithm for
cardiac evaluation of renal transplant candidates. We rely on
dobutamine stress echocardiography for noninvasive stress imaging in ESRD patients. In ESRD patients who are not transplant candidates, a similar approach is employed for symptomatic patients (dyspnea, angina, refractory CHF, hemodynamic
instability during dialysis, etc) and patients with impaired LV
systolic performance. Patient with unexplained impaired LV
systolic performance (both in the ESRD and general populations) deserve coronary angiography to rule out CAD as a
cause of cardiomyopathy.
Figure 3. Algorithm for management of coronary artery disease
(CAD) in renal transplant candidates. Reprinted with permission from
Herzog C: J Crit Illn 14:613– 621, 1999.
J Am Soc Nephrol 14: 2556–2572, 2003
There is no reliable method to predict LV ejection fraction
by physical exam, and the information is prognostically important, and cardiomyopathy is common in ESRD patients
(77), and there are proven treatments for cardiomyopathy; it is
therefore recommended that all ESRD patients be evaluated
for LV systolic function after dialysis initiation (with stable
volume status at e.g. 60 to 90 d after initiation), at the time of
renal transplant evaluation and at some arbitrary repeat frequency on dialysis (e.g., every 12 to 24 mo). The most costeffective test is an echocardiogram, because valvular disease
(e.g., aortic stenosis) and echocardiographic measures related
to volume status and cardiac function can be assessed at the
same time. Right atrial pressure can be estimated by the size
and degree of inspiratory collapse of the inferior vena cava (78)
and is routinely measured in all dialysis patients in our cardiac
ultrasound laboratory. Transplant waitlisted patients present a
special problem, and recent guidelines suggest frequent (annual) surveillance stress imaging in high-risk patients (67). Note
that our current algorithm employs surveillance stress imaging
12 to 16 wk after PCI because of the high rate of restenosis. We
hope to be able to abandon this practice after coated stents are
demonstrated to be efficacious in ESRD patients.
Other Diagnostic Testing (Noninvasive Imaging). Noninvasive imaging for detection of CAD is a rapidly evolving
field. Cardiac magnetic resonance imaging has the potential for
assessment of function, regional perfusion, metabolism, and
even coronary anatomy, including the composition of plaques
(and computerized tomography offers similar capabilities). It is
likely to play a key role in CAD assessment in the near future
in referral centers.
Coronary artery calcification in ESRD patients has attracted
increasingly more attention because of its greatly increased
prevalence in younger ESRD patients (18), its association with
metabolic abnormalities and markers of chronic inflammation
(19,79,80), and the demonstration that sevelamer attenuates the
progression of coronary artery calcification (compared with
calcium-based phosphate binders) (81). One persistent question regarding imaging of coronary calcification (by electron
beam computerized tomography or other methods) is the inability to distinguish between intimal (e.g., atherosclerotic) and
medial calcification, as these entities may represent different
diseases. In the general population, the evolving (and still
controversial) role of screening for coronary calcification is
partly risk stratification for future cardiovascular events, and it
is partly an index of atherosclerotic coronary artery disease
burden. If non-atherosclerotic disease is an important component of ESRD patient coronary artery calcification, it puts a
different spin on testing (and potential treatments). Conceptually, imaging of calcification might be equivalent to assessing
aortic pulse wave velocity, with vascular noncompliance related to calcification—very important prognostically, but
mechanistically different than obstructive CAD. At the present
time, assessment of coronary artery calcification in ESRD
patients is a promising technique that requires prospective
validation of the utility of testing for prediction of cardiovascular events (or angiographically defined obstructive CAD).
Ischemic Heart Disease and Renal Failure
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Coronary Angiography
Contrast nephropathy is a potentially serious complication of
diagnostic coronary angiography and PCI in patients with
CKD. Gruberg et al. (82) reported a 14.9% in-hospital mortality rate and 37% 1-yr mortality rate in patients with baseline Cr
ⱖ 1.8 mg/dl and ⱖ 25% increase in serum creatinine (or need
for dialysis) within 48 h after PCI, compared with a 4.9%
in-hospital mortality rate and 19% 1-yr mortality rate in patients without this degree of acute renal dysfunction. The need
for acute dialysis after PCI is associated with a marked increase
in in-hospital mortality (82– 84). There are a multiplicity of
risk factors for contrast nephropathy, including baseline renal
dysfunction, peripheral vascular disease, diabetes, CHF, cardiogenic shock, volume depletion, chronic liver disease, and
contrast volume (84-86). Freeman et al. (84) suggest a role for
the “maximum radiographic contrast dose (MRCD)” to avoid
severe contrast nephropathy requiring acute dialysis; MRCD is
calculated as 5 ml ⫻ weight (kg)/serum creatinine (mg/dl) (84)
(although one wonders whether estimated GFR would provide
a better predictive model than serum creatinine). The actual
cause of mortality in patients suffering contrast nephropathy
after coronary intervention is uncertain.
Contrast nephropathy has not been systematically investigated in dialysis patients, probably because of the perception
that “they can’t develop worsening renal failure.” Residual
renal function is important in dialysis patients (and correlates
with survival), particularly in maintenance of euvolemia. The
loss of residual renal function might compromise the ability to
perform successful chronic ambulatory peritoneal dialysis. For
this reason, we do not deny dialysis patients strategies (excluding hydration) to reduce contrast nephropathy.
In the cardiac catheterization laboratory, we routinely use
iodixanol for all coronary angiographic and PCI procedures in
patients with all stages of CKD, because it is an iso-osmolar
radiocontrast agent (minimizing volume stress in dialysis patients) and because it is less nephrotoxic (87). All patients at
risk for contrast nephropathy (including dialysis patients with
residual renal function) receive acetylcysteine for attenuation
of risk (88 –91) at a dose of 600 mg orally (two doses the day
before and two on the same day following angiography). For
emergent procedures, a single dose of 1000 mg has been
employed (92). Fasting nondialysis patients without overt CHF
are usually hydrated 6 to 12 h before the procedure with one
half normal saline at approximately 75 to 100 cc/h (and post
procedure), although a recent randomized trial comparing halfisotonic (0.45% sodium chloride plus 5% glucose) with isotonic (0.9% saline) infusion indicated that isotonic saline infusion is actually more efficacious for prevention of contrast
nephropathy (93) (and should prompt reexamination of standard hydration regimens employed before angiography). Diabetic outpatients may pose special problems if adequate preprocedure hydration is desired. In patients with questionable
volume status and/or LV dysfunction, right heart catheterization is performed first and the patient can safely receive hydration rapidly with hemodynamic monitoring (to a target
pulmonary capillary wedge pressure of 14 to 18 mmHg). We
do not administer any further hydration if the pulmonary cap-
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illary wedge pressure is ⱖ 19 mmHg. In the past, we employed
a regimen of forced osmotic diuresis with right heart monitoring similar to the methodology of the Prevention of Radiocontrast Induced Nephropathy Clinical Evaluation (PRINCE)
study (minus the dopamine), which may have a modest benefit
(94), but we abandoned this approach, primarily because it is
laborious. Similarly, the administration of fenoldopam appeared promising (and was utilized in our laboratory) on the
basis of the pilot study data (86), but recent preliminary multicenter trial data presented in April 2003 at the American
College of Cardiology sessions did not report a favorable effect
of fenoldopam on reducing contrast nephropathy.
All measures to reduce the volume of contrast administered
are appropriate. All patients should undergo complete echocardiographic examinations (including with echo contrast if LV
imaging is not ideal) before elective coronary angiography to
avoid unnecessary left ventriculograms and unpleasant surprises, such as aortic stenosis, other valvular disease, unsuspected severe cardiomyopathy, pulmonary hypertension, and to
gauge preprocedure volume status—all of which may affect the
procedure.
Nearly all patients undergoing coronary angiography are
potential candidates for PCI at the same time, making attempts
at contrast parsimony even more important in CKD patients. In
selected complex, difficult elective PCI cases, some operators
will “stage” the procedure to reduce the acute contrast load. In
dialysis patients, the risk of hemorrhage is greater during PCI,
and it is our practice to ideally have patients with preprocedure
hemoglobin values of 12 g/dl. Severely anemic patients are
transfused preprocedure on a dialysis run (to avoid hyperkalemia from the blood transfusion). All dialysis patients (with the
exception of patients opposed to transfusion) undergoing PCI
should have a current “type and screen” to facilitate crossmatching of blood for unexpected emergency transfusion.
Biomarkers
Cardiac and inflammatory biomarkers may provide an additional method of risk stratification and identification of
ESRD patients who are candidates for cardiac evaluation (and
perhaps certain therapies). In a prospective study of 663 dialysis patients, Stenvinkel et al. (95) reported the prognostic
value of different levels of C-reactive protein (CRP) for prediction of all-cause mortality. (It has been suggested that
patients with elevated CRP in the general population might be
targeted with statin therapy, but there are few data in ESRD
patients). Plasma brain natriuretic peptide (BNP), a cardiac
biomarker elevated in conditions associated with increased
cardiac filling pressures, might be helpful in following volume
status over time and for identifying dialysis patients with LV
systolic dysfunction and LVH (96,97). In my opinion, the best
prognostic biomarker is cardiac troponin T. Our group recently
published a prospective study of the predictive value of cardiac
troponin T (cTnT) and cardiac troponin I (cTnI) for subsequent
all-cause death in 733 asymptomatic patients undergoing routine outpatient hemodialysis (98). Figure 4 shows KaplanMeier survival curves by baseline troponin cutoffs for cTnT
and cTnI. Dialysis patients without detectible cTnT (⬍0.01
J Am Soc Nephrol 14: 2556–2572, 2003
Figure 4. Kaplan-Meier survival curves by baseline troponin cutoffs.
(A) Cardiac troponin T (cTnT) using the 99th percentile, 0.01 ␮g/L;
10% CV, 0.03 ␮g/L; ROC, 0.1 ␮g/L. (B) Cardiac troponin I (cTnI)
using the 99th percentile, 0.1 ␮g/L. The numbers of patients at risk at
baseline, 1 yr, 2 yr, and 2.5 yr for each cutoff are shown at the bottom
of the graphs. The 99th percentile refers to the normal reference limit.
The 10% CV refers to the lowest concentration that demonstrates a
10% total precision. The ROC cutoff refers to concentrations optimized for the sensitive and specific detection of MI. Reprinted with
permission from Apple FS, Murakami MM, Pearce LA, Herzog CA:
Predictive value of cardiac troponin I and T for subsequent death in
end-stage renal disease. Circulation 106: 2941–2945, 2002.
␮g/L) have a benign prognosis with a 2-yr mortality rate of
8.4%. In contrast, baseline cTnT levels of ⱖ 0.10 ␮g/L were
predictive of a 47% 2-yr mortality rate (with intermediate
values associated with graded risk). The presence of detectible
cardiac troponin T may reflect left ventricular mass (99) (and
perhaps cardiomyopathy) and severity of underlying CAD
(100). As concisely stated by Hamm et al. (101) in their
editorial accompanying our paper, “The data could imply that
this marker (cTnT) should enter routine clinical risk assessment in end-stage renal patients independent of any symptoms
or history of coronary artery disease. At the moment, though,
it is frustrating that the appropriate therapeutic consequences
are not yet established.”
Our study on the predictive value of cardiac troponins
J Am Soc Nephrol 14: 2556–2572, 2003
Ischemic Heart Disease and Renal Failure
2565
should help to clarify the persistently vexing clinical problem
of the interpretation of modest elevations in cardiac troponins
occurring in hospitalized dialysis patients. This finding has
previously been ascribed to false positive elevations in cardiac
troponins, as earlier publications have questioned the specificity of these biomarkers for the diagnosis of acute coronary
syndrome in dialysis patients. One frequently overlooked requirement for the diagnosis of AMI is that there should be a
time-appropriate rise and fall of the cardiac biomarker. These
elevations are not spurious; the biomarker is elevated and is a
powerful predictor of mortality. Paradoxically, the same patient’s test (which is predictive of mortality in the outpatient
setting) might be dismissed as a false positive in a hospital
setting. The potential dual role of cardiac troponin testing in
dialysis patients must be acknowledged to avoid incorrect
clinical decisions— defining acute coronary syndromes and the
prediction of mortality (complementary but discrete tasks).
Despite these issues, cardiac troponin T does reliably predict
short-term prognosis in patients with ACS in patients with
renal dysfunction (102).
Coronary Revascularization
The optimal method of coronary revascularization in dialysis
patients is controversial. PCI has a superior in-hospital or even
30 d post-procedure survival (the typical outcomes judged by
quality assurance entities) compared with coronary artery bypass (CAB) surgery. If one judges success by short-term outcome, PCI is advantageous, particularly as patients can typically be discharged from hospital within 24 h of the procedure.
There are currently two major problematic issues with PCI in
dialysis patients: higher repeat revascularization rates and
long-term mortality compared with CAB.
The accurate interpretation of studies on procedural outcome
in dialysis patients is a potentially treacherous problem if
nonfatal end points commonly employed in nonrenal patients
are used in survival analysis. In the nonrenal population, the
risk of all-cause death in the first year after PCI is low compared with the risk of restenosis, making a comparison of
restenosis risk a reasonable primary end point for a trial of
PTCA versus coronary stents. If a large number of patients die,
however, in the first 6 mo, repeat revascularization would be a
meaningless end point, because the best outcome (i.e., lowest
repeat revascularization rate) would occur in the group with the
highest death rate! In preliminary work at the Cardiovascular
Special Studies Center of USRDS, we compared the repeat
revascularization and death rates in 8724 dialysis receiving
CAB surgery, 5470 patients receiving percutaneous transluminal coronary angioplasty (PTCA) alone, and 7118 with coronary stents in the US from 1995 to 1999 identified in the
USRDS database (103). Only 21% of patients receiving stents
underwent repeat coronary revascularization of any type
(CAB, PTCA, or stent), with a repeat revascularization rate of
218/1000 patient-years. The death rate, however, was a staggering 360/1000 patient-years (in the ESRD population, allcause mortality mirrors cardiac mortality). Figures 5A and 5B
(showing diabetic patients with revascularization procedures
performed in 1995–97) demonstrate the importance of using a
Figure 5. (A) Probability of repeat coronary revascularization after an
index coronary revascularization procedure in dialysis patients with
diabetic end-stage renal disease (ESRD). (B) Probability of repeat
coronary revascularization or death after an index coronary revascularization procedure in dialysis patients with diabetic ESRD. Data
from Ma JZ, et al. The likelihood of repeated coronary revascularization procedures (CRP) after first CRP in dialysis patients. J Am Soc
Nephrol 10: 249A, 1999.
composite end point (including death) in the evaluation of
procedural outcome in these patients.
The follow-up of dialysis patients (including those waitlisted
for transplant) after PCI poses a special clinical problem.
Dialysis patients not infrequently have angina or dyspnea, and
the nephrologist’s burden is to determine whether the symptoms (if there are any) after an initially successful procedure
are related to subsequent episodes of recurrent myocardial
ischemia (either from restenosis or new obstructive CAD unrelated to the index PCI). The typical dialysis patient is preload-sensitive; due to the high prevalence of left ventricular
hypertrophy (ⱖ75%) and frequent occurrence of abnormal
diastolic function. Most US hemodialysis patients are exposed
to 1 d of increased volume stress after the long interdialytic
weekend. The accurate determination of the etiology of anginal
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Journal of the American Society of Nephrology
symptoms in a dialysis patient by subjective criteria is virtually
impossible—volume overload (i.e., circulatory congestion) and
obstructive coronary artery disease (including restenosis after
PTCA or stent) can produce identical symptoms: dyspnea or
angina. If eating a pepperoni pizza, Virginia ham, or five bags
of potato chips on a Sunday night and in-stent restenosis
produce the same symptoms (dyspnea/angina), it is plausible
that a nephrologist might choose the wrong therapy when
confronted by a dialysis patient with anginal symptoms. Alternatively, some patients truly have “silent ischemia”. For this
reason, the subsequent occurrence of anginal symptoms after
PCI cannot be used as a reliable surrogate for restenosis. In the
nonrenal population, excess death risk is not attributed to the
occurrence of restenosis. In ESRD patients, the issue is less
clear, as the rate of the competing death event is considerably
higher than the repeat revascularization rate. Finally, there
have been no large prospective angiographic series in which
the entire cohort of stent patients is restudied at time intervals
after PCI to determine the true restenosis rate and rate of new
disease progression. Recurrent episodes of myocardial ischemia may be either silent or equally probable, its clinical
recognition obscured by volume status (including the effects of
proscribed pepperoni pizza). Accordingly, in our own ESRD
program at Hennepin County Medical Center, all dialysis patients undergoing PCI with PTCA or stents have dobutamine
stress echocardiography performed at time intervals chosen to
detect occult restenosis (usually 12 to 16 wk after procedure).
As I write this section of this paper, my institution awaits the
first shipment of sirolimus-coated coronary stents. Although
the drug-coated stent trials did not enroll ESRD patients, the
early reports from the Randomized Study with the SirolimusCoated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients with De Novo Native Coronary Artery Lesions (RAVEL) trial have been extraordinary, with a 26.6%
restenosis rate at 6 mo for 118 patients receiving uncoated
stents compared with 0% in the 120 patients receiving sirolimus-coated stents for native coronary lesions (104). Preliminary data suggest that the benefit is sustained for at least 1 yr
(105). Sousa et al. (106) have reported an in-stent restenosis of
0% and target-vessel revascularization of 10% at 2 yr in 30
patients. Sirolimus-coated stents also appear promising for the
treatment of in-stent restenosis (107).
There are two key issues relating to drug-coated stents in
ESRD patients. First, will the vanishingly low restenosis rates
reported in lower-risk patients carry over to dialysis patients?
If they do, it would mean fewer repeat revascularization procedures (and we would abandon our surveillance strategy of
stress imaging at 12 to 16 wk post-PCI for diagnosis of
“occult” restenosis). The second issue is whether the long-term
survival rate will be improved by coated stents.
Coronary brachytherapy has already been established as an
adjunct to PCI in the setting of in-stent restenosis. There are
currently no data pertaining to ESRD patients, but Gruberg et
al. (108) retrospectively compared 118 chronic renal failure
(CRF) patients (mean Cr, 2.0 mg/dl) with 481 nonrenal patients
receiving intracoronary radiation and 14 CRF patients receiving placebo for treatment of in-stent restenosis. The re-resteno-
J Am Soc Nephrol 14: 2556–2572, 2003
sis rate in CRF patients was 22.6% after radiation versus 53.8%
after placebo. The re-restenosis rate was comparable in CRF
and nonrenal patients after radiation, but the 6-mo cardiac
mortality was higher in the CRF group (6.8% versus 1.5%).
Patients receiving brachytherapy currently receive longer
minimum postprocedure treatment with clopidogrel (1 mo
post-stent and 6 mo post-brachytherapy; aspirin therapy is
life-long after both). Clopidogrel may pose special problems in
a dialysis patient if they also happen to be waitlisted for
cadaveric renal transplant. Current guidelines suggest stopping
clopidogrel (but not aspirin) 1 wk before elective (usually
noncardiac) surgery, due to the excessive intraoperative bleeding that can occur in patients treated with clopidogrel. As
cadaveric renal transplants cannot be planned 7 d in advance,
it is recommended that this issue be addressed before the
ESRD patient is committed to clopidogrel therapy.
Chronic renal failure is a predictor of adverse outcome after
PCI. Azar et al. (109) in a retrospective case-control study
compared the outcome of 34 dialysis patients receiving coronary stents in 40 lesions to nonrenal controls with 80 lesions
matched for treatment site, diabetic status, lesion length, and
reference vessel diameter. Aspirin, ticlopidine, and heparin
were used in most patients. Angiographic success was
achieved in 91% of ESRD patients and 97% of controls. At
9-mo follow-up, target lesion revascularization was 35% in the
ESRD group (18% mortality) versus 16% in the controls (2%
mortality). Adverse outcomes in patients with CKD are not
limited to dialysis-dependent renal failure (110 –114). Rubenstein et al. (109) compared the immediate and long-term outcomes of 362 renal failure patients (Cr ⬎ 1.5 mg/dl; median
Cr, 1.9 mg/dl) with 2972 patients with normal renal function
undergoing PCI in 1994 –97. The in-hospital mortality was
10.8% for the renal patients and 1.1% in the controls matched
for age and gender (P ⬍ .0001). Blood transfusion occurred in
43% of renal patients versus 14% of controls. The renal group
included 27 dialysis patients with an in-hospital mortality of
11.1%. The 1-yr actuarial survival was 75% for the renal group
and 97% for the matched controls (P ⬍ 0.00001). The eventfree survival for death, AMI, or repeat coronary revascularization was 55% for the renal group and 78% for matched controls
(P ⬍ 0.00001). As shown in Figure 6, the long-term survival of
the dialysis subset was similar to the other renal failure patients. Figure 7 (111) shows the increased mortality after
successful PCI at the Mayo Clinic related to severity of renal
failure (as judged by estimated creatinine clearance).
There appears to be a relative survival advantage associated
with CAB versus PCI (PTCA or stent) in dialysis patients, and
this is consistent with earlier publications focused predominantly on the more favorable outcome of dialysis patients after
CAB compared with PTCA (115–119). Using USRDS data, we
compared the survival of dialysis patients receiving their first
coronary revascularization procedure in 1995–98: 4836 dialysis patients with PTCA, 4280 stent patients, and 6668 CAB
patients (120). The 2-yr all-cause survival was 48% in both
PCI groups and 56% after CAB. In a Cox proportional hazards
model, the risk of all-cause death was 20% lower for CAB
versus PTCA (P ⬍ 0.0001) and 6% lower for stent compared
J Am Soc Nephrol 14: 2556–2572, 2003
Figure 6. Kaplan-Meier survival curves (top) and Kaplan-Meier
event-free survival (death, AMI, or repeat coronary revascularization)
curves (bottom) of dialysis versus nondialysis patients within renal
population. Reprinted with persmission from Rubenstein MH, Harrell
LC, Sheynberg BV, Schunkert H, Bazari H, Palacios IF: Are patients
with renal failure good candidates for percutaneous coronary revascularization in the new device era? Circulation 102: 2966 –2972,
2000.
Figure 7. All-cause mortality after successful percutaneous coronary
intervention in patients. Data is based on estimated creatinine clearance. Reprinted with permission from Best PJM, Lennon R, Ting HH,
Bell MR, Rihal CS, Holmes DR, Berger PB: The impact of renal
insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions. J Am Coll Cardiol 39: 1113–1119, 2002.
with PTCA (P ⫽ 0.03). Although the in-hospital mortality is
lower for PCI (4.1% for stent, 6.4% for PTCA, and 8.6% for
CAB), the survival curves for CAB and PCI cross at 6 mo. As
shown in Figure 8, the long-term survival is more favorable
after CAB compared with PCI in dialysis patients. These data
are concordant with other clinical trials performed in nonrenal
patients, most notably the diabetic subset of the bypass angioplasty revascularization investigation (BARI) trial. In dialysis
Ischemic Heart Disease and Renal Failure
2567
Figure 8. Estimated all-cause survival of dialysis patients after
CABG, PTCA, and stenting. Bars indicate SEM. Reprinted with
permission from Herzog CA, Ma JZ, Collins AJ: Comparative survival of dialysis patients in the United States after coronary angioplasty, coronary artery stenting, and coronary artery bypass surgery
and impact of diabetes. Circulation 106: 2207–2211, 2002
patients, however, the survival advantage with surgery is not
restricted to diabetic patients.
In a subsequent preliminary analysis (121), we have reported
that the survival benefit of surgery is attributable to the utilization of internal mammary grafts (in clinical practice, this
would predominantly reflect grafting of the left internal mammary artery to the left anterior descending [LAD] coronary
artery). In patients who received surgery without internal mammary grafts, there was no relative survival advantage compared
with PCI. There are two implications to this observation: the
benefit of surgery is derived by patients who need revascularization of the LAD vascular territory and who have suitable
target vessels (i.e., not severe diffuse disease).
I believe it is possible to derive a pragmatic approach to
dialysis patient selection for coronary revascularization, based
on the small clinical series and observational studies from
administrative databases. Patients who do not need revascularization of the LAD vascular territory are appropriate candidates
for PCI (if anatomically suitable). Stents are preferable to
PTCA (predominantly for the lower restenosis risk) (122).
CAB should be considered in these patients for repeated episodes of restenosis not responsive to other available strategies
(e.g., brachytherapy, coated stents, etc). The use of repeated
PCI may be attractive in patients who are not clearly surgical
candidates, particularly because the performance of repeat PCI
does not have adverse survival consequences (123). Patients
with obstructive disease in the LAD (who are anatomically
appropriate candidates for LIMA grafts to the LAD) should be
considered for surgery as the preferred option, particularly if
there is multivessel CAD requiring revascularization. It is
prudent (when possible) to avoid placement of left arm arteriovenous fistula in patients with functioning LIMA grafts, as
hemodynamic interference (i.e., “steal” and myocardial ischemia) of upper extremity arteriovenous fistula with ipsilateral
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Journal of the American Society of Nephrology
internal mammary grafts has been reported in dialysis patients
(124). It is unknown if the survival advantage associated with
LIMA grafts is altered by the concurrent presence of ipsilateral
arteriovenous fistula in these patients. Single-vessel LAD disease management presents a special problem, as some surgeons
dislike redo coronary revascularization procedures (and valve
surgery) in patients with a patent LIMA graft (because of the
possible risk of injuring the graft with sternotomy). The rate of
progression of coronary artery disease, including multivessel
disease, may potentially be more rapid in ESRD patients (125);
a case can be made for a delaying strategy of PCI initially and
surgery if/when the patient develops multivessel disease with
LAD involvement. Hopefully, all measures to retard the progression of CAD are employed in these patients. The presence
of mild aortic stenosis (not sufficiently severe to warrant valve
replacement) might push the clinician to choose PCI as a
waiting strategy until valve replacement is indicated, as the rate
of progression of valvular aortic stenosis is likely to be greater
in ESRD patients. Dialysis patients are clearly a high-risk
surgical subset for in-hospital morbidity and mortality (126).
Patients with non– dialysis-dependent renal failure are also at
higher risk for morbidity and mortality after CAB compared
with nonrenal patients (127,128), but the postoperative recovery (127) and morbidity (including acute renal failure) may be
reduced by the use of off-pump coronary artery bypass (129).
At my own institution, off-pump CAB is also preferred, including in dialysis patients. The clinician must make an honest
appraisal of their own institutional experience, framed in the
context of expected surgical outcomes from available
databases.
There are few data on the comparative outcome of medical
therapy versus revascularization for the treatment of ischemic
heart disease in ESRD patients. Manske et al. (68) studied the
outcome of 26 angina-free diabetic renal transplant candidates
(with preserved left ventricular systolic function, no left main
disease, and at least one coronary artery stenosis in the proximal two thirds of the vessel with a visually estimated stenosis
of ⬎75% and a translesional pressure gradient of 15 mmHg)
who were randomized to either medical therapy with nifedipine
and aspirin or prophylactic coronary revascularization with
PTCA (if judged technically feasible) or CAB. Ten of thirteen
medically treated versus two (both PTCA) of 13 revascularized
patients had a prespecified cardiac end point (unstable angina,
MI, or cardiac death) at a median time of 8.4 mo after randomization (P ⫽ 0.002), and the trial was prematurely terminated. In retrospect, the medical treatment arm employed questionable therapy, as ␤-blocker therapy was not used. The
revascularization arm of the study treated the eight PTCA and
five CAB patients as receiving equivalent therapies, which is
also problematic. Noninvasive evaluation was not used in this
clinical trial.
Conclusion
I have attempted to present my perspective on the management of a special population at extraordinarily high risk for
CHD and its complications, patients with CKD. The goal of
those entrusted with promoting the health and welfare of these
J Am Soc Nephrol 14: 2556–2572, 2003
patients should be aggressive efforts to diagnose, treat, and
most importantly, prevent CHD in these patients. As a population at particularly high risk for CHD, our efforts should be
rewarded with measurable improvements in cardiovascular
outcomes in these patients.
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