Journal of the American College of Cardiology

2011 by the American College of Cardiology Foundation

Published by Elsevier Inc.

Vol. 58, No. 11, 2011

ISSN 0735-1097/$36.00
doi:10.1016/j.jacc.2011.04.041

Cardiovascular Pharmacology

Effects of Beta-Adrenergic Antagonists

in Patients With Chronic Kidney Disease
A Systematic Review and Meta-Analysis
Sunil V. Badve, MBBS, MD, DNB,* Matthew A. Roberts, MBBS, PHD,
Carmel M. Hawley, MBBS, MMEDSCI,* Alan Cass, BA, MBBS, GRAD DIP CLIN EPI, PHD,*#
Amit X. Garg, MD, MA, PHD,** Henry Krum, MBBS, PHD, Andrew Tonkin, MBBS, MD,
Vlado Perkovic, MBBS, PHD*#
Brisbane, Melbourne, and Sydney, Australia; and London, Ontario, Canada
Objectives

The aim of this systematic review was to study the benefits and risks of beta-adrenergic antagonists (betablockers) in patients with chronic kidney disease (CKD).

Background

There is an excess burden of cardiovascular disease and death in people with CKD. Despite their potential benefits, the effects of beta-blockers in this population are uncertain.

Methods

CENTRAL (Cochrane Central Register of Controlled Trials), Medline (Medical Literature Analysis and Retrieval
System Online), and Embase (Excerpta Medical Database) were searched for randomized controlled trials with at
least 3 months of follow-up in patients with CKD stages 3 to 5 that reported mortality outcomes. Summary estimates of effect were obtained using a random effects model.

Results

Eight trials met criteria for review: 6 placebo-controlled trials involving 5,972 participants with chronic systolic heart failure and 2 angiotensin-converting enzyme inhibitorcomparator trials involving 977 participants not known to have heart failure. In CKD patients with heart failure, compared with placebo, betablocker treatment reduced the risk of all-cause (risk ratio [RR]: 0.72, 95% confidence interval [CI]: 0.64 to
0.80) and cardiovascular mortality (RR: 0.66, 95% CI: 0.49 to 0.89), but increased the risk of bradycardia
(RR: 4.92, 95% CI: 3.20 to 7.55) and hypotension (RR: 5.08, 95% CI: 3.48 to 7.41). Quantitative metaanalysis was not performed for the nonheart failure studies due to substantial clinical diversity or lack of
informative data.

Conclusions

Treatment with beta-blockers improved all-cause mortality in patients with CKD and chronic systolic heart failure. There is insufficient evidence to conclude whether people with CKD who are not known to have heart failure
derive benefit from beta-blockers. (J Am Coll Cardiol 2011;58:115261) 2011 by the American College
of Cardiology Foundation

From the *Australasian Kidney Trials Network, School of Medicine, The University
of Queensland, Brisbane, Queensland, Australia; Department of Nephrology,
Princess Alexandra Hospital, Brisbane, Queensland, Australia; Department of
Nephrology, Austin Health, Melbourne, Victoria, Australia; Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia; Clinical Pharmacology Unit, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia; Cardiovascular Research Unit, Department of
Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria,
Australia; #Renal Division, The George Institute for Global Health, Sydney, New
South Wales, Australia; and the **Division of Nephrology, University of Western
Ontario, London, Ontario, Canada. Dr. Badve has reported that he has no
relationships relevant to the contents of this paper to disclose. Dr. Roberts is
supported by a National Health and Medical Research Council Training Fellowship.
Dr. Hawley has received speakers honoraria from Shire Australia, Genzyme Australia, Roche Products Pty Ltd, Amgen Pty Ltd, and Fresenius Medical Care, as well as
research grants from Roche Products Pty Ltd, Abbott Laboratories, Amgen Pty Ltd,

Janssen Cilag Pty Ltd., Bayer HealthCare, Gambro Pty Ltd, Baxter Healthcare Pty Ltd,
Shire Australia, and Fresenius Medical Care. Dr. Cass is supported by a National Health
and Medical Research Council Senior Research Fellowship and has received speakers
honoraria from Roche Products Pty Ltd and Servier Laboratories Pty Ltd, as well as a
research grant from Roche Products Pty Ltd. Dr. Garg has received a research grant from
Roche Products Pty Ltd. Dr. Krum has served as a consultant for Roche Products Pty
Ltd, GlaxoSmithKline Pharmaceuticals, Merck KGaA, and CSL Limited. Dr. Tonkin
has served as consultant for AstraZeneca Pty Ltd and CSL Limited and has received
speakers honoraria from AstraZeneca Pty Ltd. Dr. Perkovic has served as a consultant for
Abbott Laboratories; has received speakers honoraria from Roche Products Pty Ltd,
Servier Laboratories Pty Ltd, AstraZeneca Pty Ltd, and Abbott Laboratories; and has
received research grants from Johnson and Johnson Pharmaceutical Research & Development, L.L.C., Roche Products Pty Ltd, Novartis Pharmaceuticals Corporation, and
Baxter Healthcare Pty Ltd.
Manuscript received February 3, 2011; revised manuscript received April 19, 2011,
accepted April 21, 2011.

Badve et al.
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September 6, 2011:115261

Chronic kidney disease (CKD), defined as an estimated

glomerular filtration rate (eGFR) reduced to 60 ml/min/
1.73 m2 or excess proteinuria (250 mg/day or urine
albumin-creatinine ratio 30 mg/g), is a major public
health problem affecting 8% to 12% of adults in industrialized countries (1,2). Compared with the general population,
See page 1162

people with CKD, including those receiving dialysis, are at

greater risk of death (35). A cardiac cause accounts for 35%
to 40% of all deaths in patients with end-stage renal disease
on dialysis (6 8). In CKD patients who are not yet on
dialysis (nondialysis CKD patients), the risk of having a
cardiovascular event is inversely proportional to eGFR
(3,4,9 12). Results of a collaborative meta-analysis of general population cohorts consisting of more than 1.2 million
people showed that eGFR 60 ml/min/1.73 m2 was an
independent predictor of all-cause and cardiovascular mortality (13). Furthermore, there was an exponential increase
in the risk of death at lower eGFR levels.
Beta-adrenergic receptor antagonists (beta-blockers)
reduce mortality in patients following myocardial infarction and in patients with chronic systolic heart failure
(14,15). Evidence-based treatment guidelines recommend their use in such patients unless contraindicated or
not tolerated (16,17). However, randomized controlled
trials (RCTs) providing this evidence have generally
excluded individuals with CKD, including end-stage
renal disease patients requiring dialysis (18,19). Ischemic
heart disease, congestive heart failure, arrhythmias, left
ventricular hypertrophy, and increased sympathetic nervous system activity are highly prevalent in people with
advanced CKD, and this population could theoretically
derive large benefits from beta-blockers (7,8,20 25).
Observational studies in patients with CKD have demonstrated better survival and cardiovascular outcomes in
those treated with beta-blockers (26 28). Despite this,
the use of beta-blockers in patients receiving dialysis
varies considerably, ranging from as few as 10% of
patients in Japan to approximately 60% in the United
States (29,30). In a study of nondialysis CKD patients
who had a myocardial infarction, the frequency of betablocker use diminished as eGFR declined (3). In the
United States, 61% and 73% of all dialysis patients with
congestive heart failure and acute myocardial infarction,
respectively, were prescribed beta-blockers (30). The
variable rates of utilization of beta-blockers in dialysis
patients may be due to uncertainty regarding potential
benefits in this population, as well as the possibility of
hemodynamic side effects in patients subjected to wide
fluctuations in extracellular fluid volume. Several investigators have called for an increased use of beta-blockers
in dialysis patients while awaiting RCTs (3134).

Therefore, the aim of this systematic review was to determine

the effects of beta-blockers on
clinical endpoints in patients
with CKD stages 3 to 5 including those on dialysis.
Methods

1153

Abbreviations
and Acronyms
CI confidence interval(s)
CKD chronic kidney
disease
eGFR estimated
glomerular filtration rate
GFR glomerular filtration
rate

A systematic review was underLVEF left ventricular

taken in accordance with the
ejection fraction
PRISMA (Preferred Reporting
RCT randomized
Items for Systematic Reviews
controlled trial
and Meta-Analyses) Statement
RR risk ratio
(35).
Search strategy, study selection,
and data extraction. Studies were eligible for inclusion if
they: 1) were randomized controlled trials; 2) included
participants with CKD stages 3 to 5 (eGFR 60 ml/min/
1.73 m2), including those on dialysis therapy, who were
randomized to an oral beta-blocking agent compared with
placebo, a cardiovascular agent of another class, or no
treatment; 3) followed patients for at least 3 months
post-randomization; and 4) reported mortality outcomes.
Trials performed in kidney transplant patients were excluded.
Relevant studies were identified through electronic
searches of Medline (Medical Literature Analysis and Retrieval System Online) via Ovid (from inception to October
2010), Embase (Excerpta Medical Database) (from inception to October 2010), and the CENTRAL (Cochrane
Central Register of Controlled Trials) (Issue 4, 2010)
without any language restriction. In addition, reference lists
of relevant review articles, systematic reviews, treatment
guidelines, textbook chapters, conference proceedings, and
online trial registries were searched. Missing, incomplete, or
unpublished data from clinical trials were requested from
the respective investigators/authors by e-mail. (See the
Online Appendix for complete search strategy.)
The following data were extracted using a standardized
form: patient demographic details, study design and conduct, rates of outcome events, and adverse events. The
methodological quality of each included study was assessed
using the risk of bias assessment tool developed by the
Cochrane Bias Methods Group (36). The following 6 items
were assessed: 1) random sequence generation; 2) allocation
concealment; 3) blinding; 4) incomplete outcome data;
5) selective outcome reporting; and 6) any other bias (e.g.,
insufficient rationale, study design).
Outcomes assessed. The primary outcome assessed in this
meta-analysis was all-cause mortality. In addition, all other
reported clinical outcomes such as cardiovascular mortality,
sudden death, all-cause hospitalization, hospitalization for
worsening of heart failure, and adverse events were assessed.
Statistical analysis. For dichotomous outcomes, the results
were expressed as risk ratios (RRs) with 95% confidence
intervals (CIs). Summary estimates were obtained by ran-

1154

Badve et al.
Beta-Blockers in Chronic Kidney Disease

dom effects model using the DerSimonian and Laird

method (37). Heterogeneity across the studies was estimated using the I-square test (38). I-square values of 25%,
50%, and 75% correspond to low, moderate, and high levels
of heterogeneity (39). Meta-analysis results were reported
only if the I-square value was lower than 75%. We analyzed
trials that only included participants with heart failure
separately to those with a broader range of participants
(non heart failure studies) because there were substantial
differences in cardiovascular morbidity, comparator, and
duration of follow-up. If sufficient data were available,
subgroup analysis was performed according to severity of
kidney disease (nondialysis CKD and end-stage renal disease requiring dialysis). The statistical analyses were done
with Stata/SE (version 10.1, Stata Corp., College Station,
Texas).
Results
Selection and description of studies. Nine reports of 8
trials involving 6,949 patients were included in the systematic review (Fig. 1). Six trials were performed in 5,972
patients with chronic systolic heart failure (40 44). Data
from 2 of these trials were obtained from a previously
published patient-level meta-analysis (44). Data on the

Figure 1

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number of events in the individual trial arms were not

available in 1 report (43) and, hence, were extracted from
the previous publication of the same trial (45). The remaining 2 trials were conducted in 977 patients without heart
failure (46,47) (Table 1). One additional trial included
patients receiving dialysis and reported clinical endpoints in
abstract form (48), but we were unable to obtain the
necessary data required for inclusion.
Patients undergoing dialysis were included in only 1 of 6
chronic systolic heart failure studies (114 patients, all on
hemodialysis) (40). The remaining 5 trials were post hoc
analyses reporting on the subgroup of nondialysis CKD
patients within a larger study evaluating beta-blockers in
patients with chronic systolic heart failure (41 44). One of
these trials was restricted to elderly patients (age 70 years)
(41). The major distinction from the non heart failure
studies was that all 6 trials compared a beta-blocker with a
placebo.
None of the 2 non heart failure studies included dialysis
patients (Table 1) (46,47). A beta-blocker was used as an
active comparator to an angiotensin-converting enzyme
inhibitor in both of these trials, which had a primary
objective to study the effect of an angiotensin-converting
enzyme inhibitor on the progression of CKD (46,47).

PRISMA Flow Diagram Showing Selection of Studies

Eight trials were included in the systematic review. Of these, 6 trials involving chronic systolic heart failure were included in the meta-analysis.
CKD chronic kidney disease; PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RCT randomized controlled trial.

First Author (Study)

(Ref. #) (Location)

Inclusion Criteria

Active Treatment

Control

LVEF (%),
Mean (SD)

GFR* or Type
of Dialysis,
Mean (SD)

Follow-Up

Age (yrs),
Mean (SD)

All HD

24 months

55 (7.6)

Men
(%)

Concomitant
DM MI ACE Inhibition
(%) (%)
(%)

Heart Failure Studies

Cice (39,48)
(Italy)

ESRD

114

LVEF 35%

Carvedilol

Placebo

26 (8)

62

NR

70

100

66

14

70

95

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Characteristics
of Included Studies
Table 1 Characteristics
of Included Studies

(3.12525 mg BD)

Symptomatic heart failure

(NYHA IIIII)
GFR* 60

1,119

(CIBIS-II) (42,44)

LVEF 35%

450 (eGFR45)

(Multinational)

Symptomatic heart failure

(NYHA IIIIV)

669 (eGFR 4560)

Castagno

GFR* 60

1,469

(MERIT-HF) (41)

LVEF 40%

493 (eGFR45)

(Multinational)

Symptomatic heart failure

(NYHA IIIV)

976 (eGFR 4560)

Ghali

Cohen-Solal

GFR* 60

(SENIORS) (40)

Age 70 yrs

(Multinational)

Symptomatic heart failure

(NYHA IIIV) defined as
LVEF 35% or prior
hospitalization for heart
failure in the previous
year

Wali

GFR* 60

704

Bisoprolol (1.2510
mg daily)

Placebo

NR

NR

1.3 yrs

NR

28 (22.7, 32) 38.4 (32.9, 42.1)

71 (66, 75)

28 (23, 32)

52.4 (48.9, 56.2)

67 (61, 72)

27 (7)

47.7 (9.5)

27 (7)

36.6 (6.8)

27 (7)

53.3 (4.4)

Metoprolol CR/XL
(25200 mg
daily)

Placebo

Nebivolol

Placebo

34.2 (12.1)

Placebo

24 (8)

1 yr

68.1 (8.2)

68

29

55

95

43.5 (8.9)

21 months

77.4 (5)

59

29

46

NR

45.5 (9.6)

13 months

65.7 (10.5)

71

26

15

99

51 (2.2)

53

Ex

Ex

NA

54.7 (10.6)

61

Ex

NR

NA

(1.2510 mg
daily)

2,566

CAPRICORN trial:

CAPRICORN trial:
Symptomatic heart failure
Post-acute MI

(Multinational)

LVEF 40%
COPERNICUS trial:
Symptomatic or
asymptomatic
heart failure
LVEF 25%

197 (eGFR 1530)

1 (eGFR 15)

Hannedouche (46)
(France)

Creatinine
200400 mol/l

100

Acebutolol (400 mg
daily) or atenolol
(100 mg daily)

Wright
(AASK) (45)

GFR* 20 to 65
Hypertensive

877

Metoprolol (50200
mg/day)

Carvedilol
(6.2525 mg
BD)
2,364 (eGFR 3060) COPERNICUS trial:

NR
NR
NR

NR
NR
NR

Enalapril (510 mg daily)

NR

Inulin clearance
25.7 (10.5)

Ramipril (2.510 mg/day)

NR

Carvedilol
(3.12525 mg
BD)

45.6 (13.1)

3 yrs

4.1 yrs

(United States)

1155

*Expressed as ml/min/1.73 m2. Expressed as median (interquartile range).

AASK African American Study of Kidney Disease and Hypertension; ACE angiotensin-converting enzyme; BD twice daily; CAPRICORN Carvedilol Post-Infarct Survival Controlled Evaluation; CIBIS-II The Cardiac Insufficiency Bisoprolol Study II; COPERNICUS
Effect of Carvedilol on Survival in Severe Chronic Heart Failure; DM diabetes mellitus; eGFR estimated glomerular filtration rate; ESRD end-stage kidney disease; Ex excluded; GFR glomerular filtration rate; HD hemodialysis; LVEF left ventricular ejection
fraction; MERIT-HF Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure; MI myocardial infarction; NA not applicable; NR not reported; NYHA New York Heart Association; SENIORS Study of Effects of Nebivolol Intervention on Outcomes
and Rehospitalization in Seniors With Heart Failure.

Badve et al.
Beta-Blockers in Chronic Kidney Disease

(Pooled data from

CAPRICORN and
COPERNICUS trials) (43)

1156

Figure 2

Badve et al.
Beta-Blockers in Chronic Kidney Disease

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Summary of Risk of Bias Assessment

The risk of bias assessment was performed using a tool developed by the Cochrane Bias Methods Group. Allocation concealment was adequate in 4 trials.
Blinding of outcome assessors was adequate in 5 trials.

Figure 2 summarizes the risk of bias assessment of the

individual studies. Allocation concealment was adequate in
only 4 trials. The only trial involving dialysis patients with
heart failure was a double-blind protocol during the
initial 12 months (40), but became an open-label protocol
after 12 months, and the investigators reported mortality
after the second 12-month period in a subsequent publication (49).
Effects of intervention. HEART FAILURE STUDIES. Compared with placebo, treatment with beta-blockers reduced
the risk of all-cause mortality (6 trials; risk ratio [RR]: 0.72,
95% confidence interval [CI]: 0.64 to 0.80, p 0.001; test
for heterogeneity I-square 0%, p 0.601) (Fig. 3). The
p values testing for an interaction between CKD status and
the effect of beta-blockers on all-cause mortality were
nonsignificant in each of the 5 post-hoc CKD subgroup
analyses of larger trials, indicating that the treatment effect
was similar in CKD patients and those without CKD. Data
on cardiovascular mortality were reported from 4 trials (n
3,384) with results that again favored beta-blockers (RR:
0.66, 95% CI: 0.49 to 0.89, p 0.006) (Fig. 4), although
moderate level heterogeneity was present (I-square
64.2%, p 0.045).
Only 1 trial included dialysis patients (40), and the overall
results were not significantly changed by exclusion of this
study for mortality (RR: 0.72, 95% CI: 0.64 to 0.81, p
0.001; test for heterogeneity: I-square 0%, p 0.435),
whereas the effects on cardiovascular mortality became more
clearly beneficial and consistent (3,270 nondialysis patients;

3 trials; RR: 0.76, 95% CI: 0.64 to 0.90, p 0.001; test for
heterogeneity: I-square 0%, p 0.92).
The risk of sudden death was also reduced by betablockers (4 trials; RR: 0.70, 95% CI: 0.55 to 0.89, p
0.004; test for heterogeneity: I-square 0%, p 0.491)
(Online Fig. 1), whereas beta-blockers did not significantly
affect the risk of all-cause hospitalization (2 trials; RR: 0.75,
95% CI: 0.52 to 1.08, p 0.121; test for heterogeneity:
I-square 67.1%, p 0.050). Summary statistics for
hospitalization for worsening of heart failure are not reported due to the presence of high-level heterogeneity (4
trials; I-square 82.5%, p 0.003).
NONHEART FAILURE STUDIES. There were substantial differences in the baseline eGFR and blood pressure target
between the 2 non heart failure studies (46,47). Due to the
relatively larger sample size and number of mortality events,
the AASK (African American Study of Kidney Disease and
Hypertension) trial (46) dominated the pooled estimates
with a weighting of 96.3%. Therefore, a quantitative metaanalysis is not reported. Data on cardiovascular mortality
was only reported in 1 trial, so meta-analysis was not
possible.
Adverse effects. HEART FAILURE STUDIES. There was inadequate reporting of rates of study medication discontinuation due to adverse events in 3 trials (43,44). In the
remaining 3 trials, discontinuation of study medication in
the beta-blocker arm was comparable to the control arm (3
trials RR: 1.17, 95% CI: 0.66 to 2.09, p 0.585; I-square

Badve et al.
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Figure 3

1157

Forest Plot: All-Cause Mortality

Compared with placebo, treatment with beta-blockers reduced the risk of all-cause mortality in chronic kidney disease patients with heart failure. The report by Wali et al.
(44) includes pooled data from 2 trialsCAPRICORN (Carvedilol Post-Infarct Survival Controlled Evaluation) and COPERNICUS (Effect of Carvedilol on Survival in Severe
Chronic Heart Failure). CI confidence interval; RR risk ratio; SENIORS Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors
With Heart Failure.

59.2%, p 0.086) (Fig. 5) (40 42). Compared with

placebo, treatment with beta-blockers was associated with
increased risk of bradycardia (4 trials; RR: 4.92, 95% CI:
3.20 to 7.55, p 0.001; I-square 0%, p 0.838) and
hypotension (4 trials; RR: 5.08, 95% CI: 3.48 to 7.41, p
0.001; I-square 0%, p 0.941) (Fig. 5) (40,41,44). The
risk of hyperkalemia was similar in the 2 groups (3 trials;
RR: 2.16, 95% CI: 0.12 to 37.92, p 0.6; I-square 68.2%,
p 0.076) (Fig. 5) (40,44). Data on hyperglycemia was
reported in 1 trial only, hence a meta-analysis was not
possible.

Figure 4

Data on study medication

discontinuation due to adverse events (47) and hyperkalemia
(46) was reported in 1 trial each, so meta-analysis not possible
for these adverse events. Neither of the trials reported data on
bradycardia, hypotension, and hyperglycemia.

NONHEART FAILURE STUDIES.

Discussion
This meta-analysis has demonstrated a 28% and 34%
relative reduction in all-cause and cardiovascular mortality,
respectively, with beta-blocker therapy in patients with

Forest Plot: Cardiovascular Mortality

Compared with placebo, treatment with beta-blockers reduced the risk of cardiovascular mortality in chronic kidney disease patients with
heart failure. The report by Wali et al. (44) includes pooled data from 2 trialsCAPRICORN and COPERNICUS. Abbreviations as in Figure 3.

1158

Figure 5

Badve et al.
Beta-Blockers in Chronic Kidney Disease

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Forest Plot: Adverse Events

The risk of discontinuation of study medication due to adverse events was comparable between beta-blockers and placebo. The report by Wali et al. (44) includes pooled
data from 2 trialsCAPRICORN and COPERNICUS. MERIT-HF Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure; other abbreviations as in Figure 3.

heart failure and CKD. Compared with placebo, there was

an increased risk of bradycardia and hypotension with
beta-blocker therapy in patients with heart failure. Only 1
trial assessing major clinical outcomes was designed to
include patients receiving dialysis. There is a paucity of data
on the effect of beta-blockers on patient-level clinical
outcomes in CKD patients without heart failure.
The excess burden of cardiovascular disease in patients
with CKD contributes to their poor survival (6 8). This is
likely partly due to traditional cardiovascular risk factors
such as hypertension, older age, dyslipidemia, and diabetes,
as these are highly prevalent in CKD patients (13,50). In

addition, a combination of nontraditional risk factors

including anemia, hyperphosphatemia, chronic inflammation, oxidative stress, volume overload, medial vascular
calcification, and sympathetic nervous system overactivity
have been identified in this patient population. These risk
factors are also likely to contribute to elevated cardiovascular
risk (25,51). Randomized controlled trials assessing standard cardiovascular therapies in CKD patients have often
yielded disappointing results (5254), possibly due to the
multifactorial nature of cardiovascular disease in CKD.
Given the high prevalence of heart failure (31% to 40%),
ischemic heart disease (33% to 39%), and arrhythmia (7% to

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31%) in CKD patients (7,55), particular those requiring

dialysis (8), it is possible that CKD patients may derive
benefit from beta-blocker therapy that is similar to or
perhaps greater than that observed in other populations
(14,15). In this systematic review, data regarding nondialysis CKD patients was obtained exclusively from post hoc
subgroup analyses of RCTs in patients with heart failure.
Although these studies were not specifically designed to
assess effects in people with CKD, the absence of an
interaction suggests that the benefits for all-cause and
cardiovascular mortality in nondialysis CKD patients are
similar to those in people who do not have CKD. Given that
patients with CKD have a higher frequency of cardiovascular
events than patients with GFR 60 ml/min/1.73 m2 do, the
absolute risk reduction with beta-blocker therapy should be
much greater in this group.
This systematic review also highlights the absence of specific
evidence that beta-blockers reduce all-cause or cardiovascular
mortality in the individuals with CKD who do not have heart
failure, particularly those undergoing dialysis. Such individuals
may still have ischemic heart disease or arrhythmias and thus
may derive benefit from beta-blockers. However, in patients
undergoing hemodialysis, the hypotensive side effects of betablockers may be exacerbated by marked fluctuations in extracellular fluid volume. Only 1 trial reported clinical outcomes in
dialysis patients (40,49), and this included only 114 patients
with symptomatic heart failure, contributing less than 15% of
the weight for the mortality outcome. The small sample size
and the lack of blinding during the second 12-month period of
the study (when most events occurred) suggest that more
studies are required.
Study limitations. The limitations of this systematic review include the relatively small number of eligible studies,
the post hoc nature of analyses of the largest studies, the
difficulties in defining symptomatic heart failure in patients with CKD, and the lack of systematic data on adverse
effects. In this systematic review, data regarding nondialysis
CKD patients was obtained exclusively from post hoc
subgroup analyses of RCTs in patients with heart failure
that defined CKD as an eGFR 60 ml/min/1.73 m2.
Because patients with advanced CKD were excluded from
these 5 heart failure studies, the majority of participants in
the CKD subgroups had relatively mild CKD. For example,
60% and 66% of participants from the CKD cohort of the
CIBIS-II (Cardiac Insufficiency Bisoprolol Study II) (43)
and MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure) (42) studies, respectively, had an eGFR between 45 and 60 ml/min/1.73 m2
at baseline. In the combined cohort of CAPRICORN
(Carvedilol Post-Infarct Survival Controlled Evaluation)
and COPERNICUS (Effect of Carvedilol on Survival in
Severe Chronic Heart Failure) studies, only 8% of all CKD
participants had eGFR 30 ml/min/1.73 m2 (44). Therefore, the application of these results to patients with very
low levels of GFR (particularly 30 ml/min/1.73 m2) is

1159

limited by the smaller number of participants with such low

GFR in these studies.
The definition of heart failure in terms of presence and
severity of symptoms was not uniform across the studies and
almost all studies defined patients as symptomatic based on
the New York Heart Association functional classification of
symptoms. Patients with CKD may report symptoms of heart
failure, such as fatigue or dyspnea, even in the absence of heart
failure. This was demonstrated in an analysis of 2,883 CKD
patients without heart failure, in which 25% of the cohort had
the modified Kansas City Cardiomyopathy Questionnaire
score 75, a threshold suggestive of moderate burden of heart
failure symptoms (56). However, as described in Table 1, all
studies were uniformly composed of participants with low left
ventricular ejection fraction (LVEF). Hence, the findings of
this systematic review apply to patients with CKD and heart
failure with decreased LVEF, but not to patients with heart
failure and preserved LVEF.
Conclusions
This systematic review demonstrates that treatment with betablockers decreased all-cause and cardiovascular mortality in
patients with CKD who have heart failure and low LVEF,
suggesting these individuals will obtain similar or greater
benefits than people with heart failure who do not have CKD.
The widespread use of beta-blockers to reduce cardiovascular events and improve patient-level outcomes in patients
with CKD who do not have heart failure or those with
symptomatic heart failure and a normal LVEF cannot be
recommended based on existing RCT evidence. The need
for adequately powered prospective RCTs assessing the
effects of beta-blockers in a broader population of individuals with advanced CKD are supported by the demonstrated
effects in people with CKD and heart failure, as well as by
the known cardiovascular pathophysiology that has been
described in this patient population. Such trials should
provide a clear demonstration of the benefits and risks
associated with beta-blockers in patients with advanced
CKD, particularly those receiving dialysis, and inform
potential use of a treatment to reduce the burden of death
and disability suffered by this patient population.
Acknowledgments

The authors are grateful to Dr. Jalal K. Ghali and Dr. John
Wikstrand for providing data.
Reprint requests and correspondence: Dr. Sunil V. Badve,
Princess Alexandra Hospital, Level 2, ARTS Building, Woolloongabba, Queensland 4102, Australia. E-mail: Sunil_Badve@
health.qld.gov.au.
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Key Words: beta-adrenergic antagonists y cardiovascular disease y

chronic kidney disease y heart failure y meta-analysis.
APPENDIX

For the complete search strategy,

please see the online version of this article.