Journal of the American College of Cardiology

2011 by the American College of Cardiology Foundation

Published by Elsevier Inc.

Vol. 58, No. 9, 2011

ISSN 0735-1097/$36.00
doi:10.1016/j.jacc.2011.05.024

STATE-OF-THE-ART PAPER

Device Therapy in Heart Failure Patients

With Chronic Kidney Disease
Leon A. Cannizzaro, MD,* Jonathan P. Piccini, MD, MHS* Uptal D. Patel, MD,*
Adrian F. Hernandez, MD*
Durham, North Carolina
Heart failure (HF) and chronic kidney disease (CKD) both carry significant risk for sudden cardiac death, hospitalization, and mortality; when combined, however, they markedly increase the risk of morbidity and mortality. Device therapies such as implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy (CRT)
are treatments proven to have significant benefit on clinical outcomes in select patients with HF. However, the
majority of studies supporting the use of these devices have limited data on patients with CKD or end-stage renal disease. In this review, we discuss the intersection of HF and CKD as it relates to progressive HF and the risk
of sudden death. Although these disorders are common and have a poor prognosis, the evidence available for
guiding treatment decisions for the use of ICD and CRT devices in these patients is lacking. Given this lack of
clear evidence, pragmatic clinical trials and comparative effectiveness studies are needed to help identify the
appropriate use of ICD and CRT devices in this high-risk population of patients with HF and CKD. (J Am Coll
Cardiol 2011;58:88996) 2011 by the American College of Cardiology Foundation

Heart failure (HF) and chronic kidney disease (CKD) are

each major health problems with an increasing prevalence.
More than 5 million adults currently have HF, and at 40
years of age, the lifetime risk for developing HF is approximately 20% (1). Similarly, the prevalence of CKD, defined
by the presence of either reduced estimated glomerular
filtration rate (eGFR) or albuminuria, is approximately 16%,
with more than 8% classified as stage 3 or greater (eGFR
60 ml/min/1.73 m2) (2). Currently, there are more than
500,000 people living in the U.S. with end-stage renal
disease (ESRD), which represents a doubling in prevalence
over each of the last 2 decades (2). The growth and severity
of HF and CKD will continue with the prevalence of HF
increasing and the progression of CKD to ESRD continuing to steadily rise due to the aging population, increasing
rate of diabetes, and patient survival from initial cardiac
insults such as acute coronary syndrome.

From the *Department of Medicine, Duke University Medical Center, Durham,

North Carolina; Division of Cardiology, Duke University Medical Center, Durham,
North Carolina; Duke Clinical Research Institute, Duke University Medical Center,
Durham, North Carolina; and the Division of Nephrology, Duke University
Medical Center, Durham, North Carolina. Dr. Cannizzaro has reported that he has
no relationships relevant to the contents of this paper to disclose. Dr. Piccini has
received grants for clinical research from Johnson & Johnson, Bayer Healthcare, and
Boston Scientific. Dr. Patel has received research support from Luitpold Pharmaceuticals, Inc., and the American Society of Nephrology. Dr. Hernandez has received
research support from Johnson & Johnson, Merck & Co., and Proventys; and
honoraria from AstraZeneca, Amgen, Corthera, and Medtronic.
Manuscript received February 14, 2011; revised manuscript received April 26,
2011, accepted May 24, 2011.

Unfortunately, the prevalence of HF complicated by

CKD is growing. Multiple studies have demonstrated that
nearly one-third of patients with HF have concomitant
stage 3 or greater CKD (3,4). CKD also carries a significant
risk for the development of HF. Patients with an eGFR
60 ml/min/1.73 m2 have a 3-fold higher risk for HF
compared with patients without CKD (5). Even worse,
more than 50% of patients starting renal replacement
therapy will develop symptomatic HF or left ventricular
(LV) dysfunction later in life (6).
Although a number of independent risk factors are
common to both HF and CKD, the combination of these
diseases amplifies the risk of poor outcomes (4,7). Patients
with HF and significant renal dysfunction have nearly 3
times the mortality risk when compared with patients
without significant kidney disease. Patients with ESRD
carry a 6- to 9-fold increase in death attributable to sudden
cardiac death (SCD) or malignant arrhythmias (Fig. 1) (2).
Although there are multiple pathways for LV dysfunction
and arrhythmogenesis in the general HF population, the
combination of HF and CKD leads to a perfect storm of
clinical risk for worsening HF and SCD. Much of the
decision making regarding device therapy in this subgroup
seems to be primarily based on expert opinion rather than
conclusive evidence (8). The goal of this review is to
summarize existing knowledge regarding the role of implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy (CRT) in the prevalent, growing

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Cannizzaro et al.
Device Therapy in HF, CKD, and ESRD

Abbreviations
and Acronyms
CKD chronic kidney
disease
CRT cardiac
resynchronization therapy
eGFR estimated
glomerular filtration rate

population of patients with both

CKD and HF and to stimulate
future investigations.
Pathophysiology
Leading to Poor Outcomes

Multiple mechanisms lead patients with HF to develop kidney

ESRD end-stage renal
disease. The decreased function
disease
of the heart compromises stroke
HF heart failure
volume, leading to adverse renal
ICD implantable
hemodynamics. In addition, concardioverter-defibrillator
gestion and increased central veLV left ventricular
nous pressure limit renal perfuLVRR left ventricular
sion pressure and contribute to
reverse remodeling
worsening renal function (9).
SCD sudden cardiac
One
mechanism frequently prodeath
posed to explain worsening renal
function in patients with HF is
overall reduced renal perfusion. However, HF patients with
preserved ejection fraction have similar eGFR when compared with patients with reduced ejection fraction (10).
Furthermore, this mechanism was assessed in the Evaluation Study of Congestive Heart Failure and Pulmonary
Artery Catheterization Effectiveness trial, which concluded
that poor forward flow did not account for the development
of worsening CKD in decompensated HF, and increased
right atrial pressure, which may indicate renal congestion,
was the only hemodynamic parameter that was significantly
correlated with impaired renal function (11). Others have
also noted that venous congestion is among the most

Figure 1

JACC Vol. 58, No. 9, 2011

August 23, 2011:88996

important hemodynamic factors driving worsening renal

function (12). Neurohormonal factors, anemia, medications,
and natriuretic peptides are among other contributors to
worsening CKD in patients with HF (9).
The complications associated with CKD have the potential to negatively affect many of the stages of the classic
cardiovascular continuum leading to a more rapid progression to HF and an increased risk of SCD. Early in the renal
disease process, renovascular hypertension can lead to worsening LV hypertrophy, atherosclerosis, and conduction
disturbances such as bundle branch blocks. Anemia of CKD
can worsen the progression of HF as a result of ineffective
blood volume and the adverse effects of inflammatory
cytokines on cardiomyocytes (13). Furthermore, the various
electrolyte abnormalities observed in renal dysfunction,
including hyperkalemia, uremia, and metabolic acidosis,
contribute through multiple mechanisms to worsening cardiovascular disease and increased risk of malignant arrhythmias. CKD is frequently also associated with hypercalcemia,
and renal function is inversely associated with coronary
artery calcification, which significantly increases the risk for
adverse cardiovascular events (14). Many of these proarrhythmic factors are even more arrhythmogenic in the
presence of scar tissue after myocardial infarction, which at
least partially explains why patients with CKD are at high
risk for SCD. A retrospective study evaluating patients with
CKD undergoing cardiac catheterization found that every
10 ml/min/1.73 m2 decline in eGFR below 60 ml/min/
1.73 m2 was independently associated with a hazards ratio
(HR) of 1.11 for SCD (15). Thus, there are multiple
pathophysiological mechanisms to explain the heightened

Mortality and Sudden Cardiac Death Across the Spectrum of Chronic Kidney Disease

Estimates of all-cause mortality (ACM) and sudden cardiac death (SCD) across the spectrum of chronic kidney disease (CKD)
and glomerular filtration rate (GFR) (background shaded curve) (2,15,40).

Cannizzaro et al.
Device Therapy in HF, CKD, and ESRD

JACC Vol. 58, No. 9, 2011

August 23, 2011:88996

risk of SCD in this patient population. In addition, both

HF and CKD are independently associated with multiple
risk factors known to decrease survival (Fig. 2).
As patients develop ESRD, they accumulate even more
risk factors for SCD (Table 1). Prior studies have shown
that myocardial perfusion decreases during hemodialysis
and that SCDs have a temporal relation to hemodialysis
sessions (16). However, there are other factors beyond
dialysis itself associated with the increased risk of SCD. A
study evaluating the frequency of arrhythmias in 3 subgroups of patients (pre-dialysis renal failure, hemodialysis,
and renal transplant) without known cardiac disease failed
to demonstrate a statistically significant difference in the
frequency of arrhythmias and complex ectopic activity
between the 3 groups despite the correction of uremia by
successful transplant, indicating that myocardial dysfunction
was a more important determinant of complex arrhythmia
than dialysis or uremia in patients with CKD (17). Worsening LV hypertrophy has been shown to be the strongest
predictor of SCD in patients undergoing hemodialysis (18).
The Evidence Base for ICD Therapy
Randomized clinical trials of ICD therapy in patients with
HF provide limited data regarding patients with CKD. In
most trials, those with renal dysfunction were either excluded or renal function was not reported (Table 2). The
most applicable data comes from a retrospective subgroup
analysis of patients enrolled in the Multicenter Automatic
Defibrillator Implantation TrialII, in which for each

Figure 2

Risk Factors Common to Heart Failure and

Chronic Kidney Disease for Cardiovascular
Disease and Outcomes

Risk factors common to both heart failure and chronic kidney disease
contributing to arrhythmogenesis, disease progression, and death (6,41,42).

891

Patients
Risk
Factors
With
for
ESRD
SCD
(16,18,23,43)
in for SCD in
Risk
Factors
Table 1
Patients With ESRD (16,18,23,43)
Primary Difference in
ESRD Patients
Cardiac structural
abnormalities

Potential Cause for Increased

Risk of Arrhythmias and SCD
Reduced LVEF
LV hypertrophy
Increased prevalence of CAD
Narrowed coronary arteries

Dialysis procedure

Myocardial ischemia/stunning
Atheroma formation/progression
Induced interstitial fibrosis and
vascular endothelial
dysfunction
Rapid electrolyte changes

Alteration in cardiac
autonomic function

Prolonged QT appearance of
late potentials
Sympathetic overactivity

Other

Arterial hypertension
Increased rates of infection

CAD coronary artery disease; ESRD end-stage renal disease; LV left ventricular; LVEF left
ventricular ejection fraction; SCD sudden cardiac death.

10 ml/min/1.73 m2 reduction in eGFR, the risk of all-cause

mortality and SCD increased significantly by 16%
(p 0.005) and 17% (p 0.03), respectively (19). Among
those with an eGFR 35 ml/min/1.73 m2, ICD therapy
was associated with a significant survival benefit (overall risk
reduction for all-cause mortality 32% and for SCD 66%).
However, no survival benefit was observed with ICD
therapy among patients with an eGFR 35 ml/min/1.73 m2
(HR: 1.09; p 0.84).
As stated, patients with CKD and HF have poor longterm outcomes when compared with the general population.
Multiple studies have confirmed that this finding remains
present despite ICD implantation (20). A study by Turakhia et al. (21) evaluating 507 patients for the association of
pre-ICD implant renal function on all-cause mortality
demonstrated that for every 10 ml/min/1.73 m2 decrease in
eGFR, the adjusted hazard of death increased significantly
by 12%. A meta-analysis performed to evaluate the role of
ICD therapy in dialysis patients concluded that despite
having ICDs, patients receiving dialysis had a 2.7-fold
higher mortality compared with those not receiving dialysis.
However, comparing patients receiving dialysis and those
with CKD but not receiving dialysis, there was no significant difference in mortality (relative risk: 1.62; 95% CI: 0.84
to 3.14) (22). Robin et al. (23) also concluded that survival
was significantly shorter for patients with ESRD compared
with non-ESRD patients (3.2 years vs. 7.4 years). Although
these studies did not compare patients without ICD therapy, they confirm the risk of mortality with severe renal
dysfunction and the need to better elucidate the net-clinical
benefit of ICD therapy in these patients.
To the best of our knowledge, there are no randomized
controlled trials to adequately address the efficacy and safety
of ICD implantation in patients undergoing dialysis. A
recent retrospective cohort study by Hiremath et al. (24)

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Device Therapy in HF, CKD, and ESRD

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Major
Supporting
Use in Patients
Heart Failure
and Reported
Renal
Characteristics
TableTrials
2 Major
TrialsICD
Supporting
ICD UseWith
in Patients
With Heart
Failure and
Reported
Renal Characteristics

Trial (Ref. #)
AVID (44)

n
1,016

Inclusion Criteria

Intervention

Baseline Renal Function

Renal Subgroup
Analysis

Patients resuscitated from nearfatal VF or had cardioversion

from sustained VT

ICD vs.
antiarrhythmic
agents

NA

CAT (45)

104

Recent onset of DCM (9 months)

and an EF 30%

ICD vs. control

subjects

NA

DEFINITE (46)

458

NIDCM, LVEF 36%, and PVCs or

NSVT

ICD vs. medical

treatment

NA

MADIT-I (47)

196

NYHA I, II, or III with prior MI;

LVEF 35%; NSVT; and
inducible, nonsuppressible VT
on EP study

ICD vs. medical

treatment

43 patients (22%) with BUN 25 mg/dl;

ESRD excluded

MADIT-II (48)

1,232

Prior MI and LVEF 30%

ICD vs. medical

treatment

61 patients (5%) with BUN 25 mg/dl,

estimated GFR 68.8 23.9 ml/min/1.73 m2;
ESRD excluded

Yes (19), no significant

difference in 2-yr allcause mortality for GFR
35 ml/min/1.73 m2

704

Prior MI; asymptomatic NSVT;

LVEF 40%; and inducible
sustained VT

ICD antiarrhythmic
agents

NA

2,521

LVEF 35% and NYHA II or III

ICD vs. amiodarone

vs. placebo

MUSTT (49)

SCD-HeFT (50)

Mean creatinine 1.1 mg/dl

(IQR: 0.91.3 mg/dl)

No

No

AVID Antiarrhythmics Versus Implantable Defibrillators; BUN blood urea nitrogen; CAT Cardiomyopathy Trial; DCM dilated cardiomyopathy; DEFINITE Defibrillators in Non-Ischemic
Cardiomyopathy Treatment Evaluation; EF ejection fraction; EP electrophysiology; ESRD end-stage renal disease; GFR glomerular filtration rate; ICD implantable cardioverter-defibrillator; IQR
interquartile range; LV left ventricular; MADIT Multicenter Automatic Defibrillator Implantation Trial; MI myocardial infarction; MUSTT Multicenter Unsustained Tachycardia Trial; NA not available;
NIDCM nonischemic dilated cardiomyopathy; NSVT nonsustained ventricular tachycardia; NYHA New York Heart Association; PVC premature ventricular complex; SCD-HeFT Sudden Cardiac
Death in Heart Failure Trial; VF ventricular fibrillation; VT ventricular tachycardia.

comparing ESRD patients with LV dysfunction (defined as

ejection fraction 35%) who either did or did not undergo
ICD placement concluded that the ICD group had significantly less all-cause mortality when compared with the noICD group (HR: 0.40), with a median survival in the ICD
group of 8.0 years compared with 3.1 years in the no-ICD
group.
A retrospective study by Herzog et al. (25) used a
propensity model to compare ESRD patients who presented
with ventricular fibrillation/cardiac arrest and did or did not
receive ICD placement for secondary prevention within 30
days. They found a significant survival benefit in the ICD
group. They estimated that in the ICD group, 1-, 2-, 3-, 4-,
and 5-year survival rates were 71%, 53%, 36%, 25%, and
22%, respectively; in the no-ICD group, they were 49%,
33%, 23%, 16%, and 12% (p 0.0001), respectively. ICD
implantation was independently associated with a 42%
reduction in mortality risk. This study supports the use of
ICDs in secondary prevention of SCD in patients undergoing dialysis; however, uncertainty remains in defining the
use of ICD placement for primary prevention in these
patients.
ICD implantation also carries periprocedural risk, especially in patients with HF and CKD. Patients with an
eGFR 60 ml/min/1.73 m2 were shown to have a 4.8-odd
higher risk for device infection when compared with control
subjects (26). As technology improves, future devices may
mitigate this risk; an example would be the use of entirely
subcutaneous devices without intracardiac lead placement.
Another study to evaluate the risk profile of patients with
ESRD after undergoing ICD placement compared with

patients without ESRD found that ESRD patients had a

nearly 5 times higher risk of in-hospital mortality after ICD
placement (1.9% vs. 0.4%; p 0.0001) (27). ESRD patients
were also more likely than non-ESRD patients to have
major complications, including hematoma, vein thrombosis,
and lead dysfunction requiring revision (29% vs. 5%; p 0.03).
Decision models have been developed to address the
concerns on the uncertain balance of risk and benefits for
ICD implantation in patients with CKD. For example,
Amin et al. (28) proposed a decision model analysis to help
guide the placement of ICDs for primary prevention in
patients with CKD. Their simulation favored ICD implantation at age 80 years for eGFR 30 to 59 ml/min/1.73 m2,
age 75 years for eGFR 15 to 29 ml/min/1.73 m2, and age
65 years for eGFR 15 ml/min/1.73 m2 or hemodialysis.
Although these results seem promising in guiding clinical
decisions, the empirical data on which the assumptions were
based are very limited. Furthermore, studies on costeffectiveness in this population, especially those with
ESRD, are even more limited, and prior calculations on
cost-effectiveness may be less applicable to this patient
subpopulation (29).
The Evidence Base for CRT
Most of the major randomized controlled trials designed to
investigate the benefit of CRT in patients with HF were not
designed (or powered) to assess the effects of renal dysfunction on outcomes (Table 3). In the CARE-HF (Cardiac
Resynchronization Therapy in Heart Failure) trial, a predefined analysis found that baseline eGFR was a significant

Cannizzaro et al.
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August 23, 2011:88996

893

Major
Supporting
Use in Patients
Heart Failure
and Reported
Renal
Characteristics
TableTrials
3 Major
TrialsCRT
Supporting
CRT UseWith
in Patients
With Heart
Failure and
Reported
Renal Characteristics

Trial (Ref. #)
CARE-HF (51)

n
813

Inclusion Criteria

Intervention

Baseline Renal Function

Renal Subgroup
Analysis

NYHA III or IV; QRS 120

ms with standard
pharmacological
treatment

Medical treatment CRT

Median estimated GFR 61 ml/min/1.73 m2

(IQR: 46773 ml/min/1.73 m2)

Yes (30), no change in

the benefit of CRT for
the primary outcome
if GFR 60 or
60 ml/min/1.73 m2
Yes (32), HR: 1.69 for
SCD in patients with
renal dysfunction

COMPANION (33)

1,520

NYHA III or IV; ICM or NICM;

QRS 120 ms

Medical treatment vs. medical

treatment ICD vs.
medical treatment
ICD/CRT

Not reported; 22% with renal

dysfunction (not specified)

MADIT-CRT (52)

1,820

NYHA I or II; ICM or NICM;

EF 30%; QRS 130 ms

ICD CRT

24% with baseline BUN 26 mg/dl;

baseline creatinine 1.2 0.4 mg/dl;
ESRD excluded

No

MIRACLE (53)

453

NYHA III or IV; EF 35%;

QRS 130 ms

CRT vs. control subjects

Not reported; excluded creatinine

3 mg/dl

MIRACLE ICD (54)

369

NYHA II or IV; EF 35%;

QRS 130 ms

All received ICD/CRT;

CRT inactivated in 182

Not reported; excluded creatinine

3 mg/dl

1,798

NYHA II or III; EF 30%;

QRS 120 ms or
paced QRS 200 ms

ICD CRT

GFR 30 ml/min/1.73 m2: 120 (7%);

GFR 3059 ml/min/1.73 m2:
781 (43%);
GFR 60 ml/min/1.73 m2:
881 (49%)

No significant difference
between GFR 60 or
60 ml/min/1.73 m2;
no further analysis

NYHA I or II; EF 40%;

QRS 120 ms

All received CRT device

(defibrillator);
CRT inactive in 191

CRT inactive: GFR 89.6 36.4 ml/min/

1.73 m2 CRT active: GFR 84.2 31.3
ml/min/1.73 m2

No significant difference
between GFR 82.7
ml/min/1.73 m2 or
82.7; no further
analysis

RAFT (55)

REVERSE (56)

610

Yes (31), CRT improved

GFR if baseline GFR
between 30 and 60
ml/min/1.73 m2;
mortality not reported
No

CARE-HF Cardiac Resynchronization Therapy in Heart Failure; COMPANION Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure; CRT cardiac resynchronization therapy; HR
hazard ratio; ICM ischemic cardiomyopathy; MADIT-CRT Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy; MIRACLE Multicenter InSync Randomized
Clinical Evaluation study; NICM nonischemic cardiomyopathy; RAFT Resynchronization/Defibrillation for Ambulatory Heart Failure Trial; REVERSE Resynchronization Reverses Remodeling in Systolic
Left Ventricular Dysfunction trial; SCD sudden cardiac death; other abbreviations as in Table 2.

predictor of outcome. Despite this association, no differential benefit of the composite primary endpoint of all-cause
mortality or unplanned hospitalization for a major cardiovascular event was observed relative to renal function (/
median eGFR 60.3 ml/min/1.73 m2) (30). A retrospective
subgroup analysis of the Multicenter InSync Randomized
Clinical Evaluation study found that in patients with an
eGFR between 30 and 60 ml/min/1.73 m2, CRT improved
eGFR when compared with the non-CRT group (6.4 2.4
ml/min/1.73 m2 vs. 1.1 1.5 ml/min/1.73 m2; p
0.008) (31). No difference was observed in patients with
eGFR 60 ml/min/1.73 m2, and there were too few
patients with eGFR 30 ml/min/1.73 m2 to draw any
meaningful conclusions. This subgroup analysis was the first
large placebo-controlled trial to report an improvement in
eGFR with the use of CRT in patients with impaired renal
function. Another retrospective subgroup analysis of the
COMPANION (Comparison of Medical Therapy, Pacing,
and Defibrillation in Heart Failure) trial concluded that in
CRT candidates, the risk for SCD was significantly increased
by renal dysfunction (HR: 1.69; 95% CI: 1.06 to 2.69; p
0.03) (32,33). These findings are consistent with previously
identified increased risk of SCD in renal dysfunction.
Fung et al. (34) were among the first to identify a potential
association between impaired renal function and worse clinical

outcome among patients treated with CRT. They retrospectively evaluated echocardiographic assessment and renal function tests before and 3 months after CRT in 85 consecutive
patients. Mean baseline eGFR was reported to be 56.9 19.7
ml/min/1.73 m2. Successful left ventricular reverse remodeling
(LVRR), which they defined as a reduction of LV end-systolic
volume of 10%, was observed in 52% of patients after CRT.
They reported a small but significant improvement in eGFR in
those with LVRR when compared with those without at
3-month follow-up (2.5 7.0 ml/min/1.73 m2 vs. 13.1
11.9 ml/min/1.73 m2; p 0.001). Of significance, they also
demonstrated a marked deterioration in eGFR in those who
did not have LVRR (61.9 17 ml/min/1.73 m2 vs. 48.8
13.0 ml/min/1.73 m2; p 0.001). Change in eGFR after
CRT was significantly correlated with the changes in LV
end-systolic volumes, end-diastolic volumes, ejection fraction,
and mortality. Successful LVRR was the only independent
predictor of preservation of renal function after CRT. This
study indicated that changes in eGFR at 3 months after CRT
might clarify long-term prognosis in these patients. In addition, lack of significant LVRR after CRT may indicate a
high-risk group with potential for rapid decline in renal
function (34).
As for the role of CRT alone (without defibrillator
capacity) in patients with ESRD, there is not enough

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Key
Questions
to ICD
and/or
Placement
Patients With
HF and With
CKD HF and CKD
Table
4 KeySpecific
Questions
Specific
to CRT
ICD and/or
CRTinPlacement
in Patients
1. What is the comparative effectiveness and safety in overall mortality across the strata of CKD patients who undergo ICD and/or CRT placement compared with those
who do not receive device therapy?
2. Is there a difference in the rates of sudden cardiac death by CKD status overall? If so, will the overall benefit improve with advancement in device therapy technology,
including less invasive devices?
3. What pharmacotherapies are most effective for reducing the risk of arrhythmic death in patients with HF and CKD?
4. Do any current or emerging renal protective therapies influence the risk of arrhythmic death in patients with HF?
5. What is the optimal timing of ICD or CRT-D implantation in patients with CKD?
6. Do current patterns of practice vary with regards to device therapy in this population and why?
7. What is the cost-effectiveness of ICD and/or CRT in patients with CKD and symptomatic HF?
8. How does device therapy affect quality of life in this population?
9. Can risk stratification models or risk scores facilitate device implantation decisions, particularly in terms of competing risks for mortality?
10. How can infectious risks and vascular access concerns be optimally addressed in patients with CKD and HF who undergo device implantation?
CKD chronic kidney disease; CRT cardiac resynchronization therapy; CRT-D cardiac resynchronization therapy defibrillator; HF heart failure; ICD implantable cardioverter-defibrillator.

evidence to judge whether it is beneficial. As with the ICD

group, cost-effectiveness and safety are also issues in the
CRT group, including increased risk of infection and
procedural complications in patients with CKD. In a study
published in 2004 evaluating patients with HF, CRT was
associated with a median incremental cost of $107,800 per
quality-adjusted life-year gained (35). However, as expected, this benefit varied according to the presence of
comorbid illness, indicating that careful consideration
should be given to patients with shortened life expectancy,
such as those with CKD.
Adequate recommendations regarding the use of CRT in
patients with renal dysfunction cannot easily be made on the
basis of the literature available. Additional studies are
needed in this area to better evaluate the appropriate use and
effect of CRT on morbidity and mortality in such patients.
Future Directions
Potential future directions of research will likely require
multiple different study designs, including comparative effectiveness studies using existing observational data as well
as pragmatic randomized controlled trials. Leveraging representative national databases with sufficiently large sample
sizes to examine device therapy and outcomes in patients
with HF and CKD will be useful in understanding the
scope of issues and potential areas of focus. Registries that
collect data and are linked to longitudinal outcomes may
allow further understanding of effectiveness and safety of
ICD/CRT placement accounting for baseline cardiac and
renal function as well as standard demographic and medical
background information. Furthermore, short-term procedural complications, rehospitalization rates, and long-term
mortality rates may allow a better understanding of appropriate utilization of these interventions in the HF/CKD
population. Because of the limitations of using observational
data even with the use of methods to adjust for selection bias
and confounding, clinical trials remain an important area for
growth to improve the evidence base. As health care evolves,
allowing integration of electronic health records into everyday practice, use of observational data for comparative

effectiveness studies as well as pragmatic clinical trials in the

real-world setting becomes more feasible. Although questions remain on whether the population of patients with
HF/CKD can be adequately studied, others are proving that
it is possible. For example, the ICD2 (Implantable Cardioverter Defibrillators in Dialysis Patients) trial, which has
been approved in the Netherlands, aims to determine
whether ICD therapy in dialysis patients age 55 to 80 years
results in a significant reduction in primary SCD rates when
compared with no ICD therapy (36). Regardless of the
method, additional evidence is needed to adequately guide
decision making.
Conclusions
The population of patients with both HF and CKD,
including ESRD, is already significant in size and is steadily
growing. These patients have an increased mortality risk
compared with other patients, making it even more essential
to identify the appropriate use of therapies that can improve
their overall survival, comorbidities, and quality of life. The
majority of the literature available regarding the use of
device therapy in this group of patients is based on retrospective data, which are subject to a myriad of biases,
particularly selection bias, which is not easily overcome even
with large datasets and multiple methods for adjustment.
Due to the paucity of evidence, neither the American
College of Cardiology/American Heart Association nor the
European Society of Cardiology guidelines for HF adequately address this issue (37,38). Until more definitive
evidence is available, the management of such patients
should follow currently available American College of Cardiology/American Heart Association guidelines for HF.
However, as with many therapies without clearly defined
guidelines, one must assess the risk/benefit ratio of device
therapy on an individual basis, particularly in ESRD patients with known HF, a subgroup that has been shown to
have a 2-year survival rate as low as 50% (39). Further
investigational studies are needed to help provide guidance
for the proper use of device therapy in this high-risk,
prevalent population (Table 4).

Cannizzaro et al.
Device Therapy in HF, CKD, and ESRD

JACC Vol. 58, No. 9, 2011

August 23, 2011:88996

Reprint requests and correspondence: Dr. Adrian F. Hernandez,

Duke Clinical Research Institute, Room 0311 Terrace Level, 2400
Pratt Street, Durham, North Carolina 27705. E-mail: adrian.
hernandez@duke.edu.

20.

21.
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Key Words: cardiac resynchronization therapy y chronic kidney disease
y end-stage renal disease y heart failure y implantable cardioverter
defibrillators y SCD.