Cardiovascular Pharmacology
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.
Beta-Blockers in Chronic Kidney Disease
1153
Abbreviations
and Acronyms
CI confidence interval(s)
CKD chronic kidney
disease
eGFR estimated
glomerular filtration rate
GFR glomerular filtration
rate
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Badve et al.
Beta-Blockers in Chronic Kidney Disease
Figure 1
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.
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
(%) (%)
(%)
ESRD
114
LVEF 35%
Carvedilol
Placebo
26 (8)
62
NR
70
100
66
14
70
95
Characteristics
of Included Studies
Table 1 Characteristics
of Included Studies
(3.12525 mg BD)
1,119
(CIBIS-II) (42,44)
LVEF 35%
450 (eGFR45)
(Multinational)
Castagno
GFR* 60
1,469
(MERIT-HF) (41)
LVEF 40%
493 (eGFR45)
(Multinational)
Ghali
Cohen-Solal
GFR* 60
(SENIORS) (40)
Age 70 yrs
(Multinational)
Wali
GFR* 60
704
Bisoprolol (1.2510
mg daily)
Placebo
NR
NR
1.3 yrs
NR
71 (66, 75)
28 (23, 32)
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%
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
NR
Inulin clearance
25.7 (10.5)
NR
Carvedilol
(3.12525 mg
BD)
45.6 (13.1)
3 yrs
4.1 yrs
(United States)
1155
Badve et al.
Beta-Blockers in Chronic Kidney Disease
1156
Figure 2
Badve et al.
Beta-Blockers in Chronic Kidney Disease
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.
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.
Beta-Blockers in Chronic Kidney Disease
Figure 3
1157
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.
Figure 4
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
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
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.
Badve et al.
Beta-Blockers in Chronic Kidney Disease
1159
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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Beta-Blockers in Chronic Kidney Disease
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