Efficacy and Safety of Carvedilol in Treatment of Heart

Failure with Chronic Kidney Disease

A Meta-Analysis of Randomized Trials
Ravinder K. Wali, MD; Malini Iyengar, PhD; Gerald J. Beck, PhD; David M. Chartyan, MD, MSc;
Michel Chonchol, MD; Mary Ann Lukas, MD; Christopher Cooper, MD; Jonathan Himmelfarb, MD;
Matthew R. Weir, MD; Tomas Berl, MD; William L. Henrich, MD; Alfred K. Cheung, MD

Background—The safety and efficacy of different types of ␤-blocker therapy in patients with non– dialysis-dependent
chronic kidney disease (CKD) and systolic heart failure (HF) are not well described. We assessed whether treatment of
systolic HF with carvedilol is efficacious and safe in adults with CKD.
Methods and Results—We performed a post hoc analysis of pooled individual patient data (n⫽4217) from 2 multinational,
double-blinded, placebo-controlled, randomized trials, CAPRICORN (Carvedilol Postinfarct Survival Control in Left
Ventricular Dysfunction Study) and COPERNICUS (Carvedilol Prospective Randomized, Cumulative Survival study).
Primary outcome was all-cause mortality. Secondary outcomes included cardiovascular mortality, HF mortality, first HF
hospitalization, the composite of cardiovascular mortality or first HF hospitalization, and sudden cardiac death.
Non– dialysis-dependent CKD was defined by estimated glomerular filtration rate ⱕ60 mL/min/1.73 m2, using the
abbreviated Modification of Diet in Renal Disease equation. CKD was present in 2566 of 4217 (60.8%) of the cohort,
50.4% of whom were randomly assigned to carvedilol therapy. Within the CKD group, treatment with carvedilol
decreased the risks of all-cause mortality (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.63 to 0.93;
P⫽0.007), cardiovascular mortality (HR, 0.76; 95% CI, 0.62 to 0.94; P⫽0.011), HF mortality (HR, 0.68; 95% CI, 0.52
to 0.88; P⫽0.003), first hospitalization for HF (HR, 0.74; 95% CI, 0.61 to 0.88; P⫽0.0009), and the composite of
cardiovascular mortality or HF hospitalization (HR, 0.75; 95% CI, 0.65 to 0.87; P⬍0.001) but was without significant
effect on sudden cardiac death (HR, 0.76; 95% CI, 0.56 to 1.05; P⫽0.098). There was no significant interaction between
Downloaded from http://ahajournals.org by on February 14, 2019

treatment arm and study type. Carvedilol was generally well tolerated by both groups of patients, with an increased
relative incidence in transient increase in serum creatinine without need for dialysis and other electrolyte changes in the
CKD patients. However, in a sensitivity analysis among HF subjects with estimated glomerular filtration rate ⬍45
mL/min/1.73 m2 (CKD stage 3b), the efficacy of carvedilol was not significantly different from placebo.
Conclusions—This analysis suggests that the benefits of carvedilol therapy in patients with systolic left ventricular dysfunction
with or without symptoms of HF are consistent even in the presence of mild to moderate CKD. Whether carvedilol therapy
is similarly efficacious in HF patients with more advanced kidney disease requires further study. (Circ Heart Fail.
2011;4:18-26.)
Key Words: chronic heart failure 䡲 meta-analysis 䡲 carvedilol 䡲 chronic kidney disease

C hronic heart failure (HF) is associated with an increased

risk of morbidity and mortality.1–3 Chronic kidney dis-
ease (CKD)4 defined by estimated glomerular filtration rate
the US population estimated to be 20 million10 –12 and 6
million,1,2,13 respectively. Not unexpectedly, the prevalence
of concomitant CKD in patients with HF is also high.9,14 –16
(eGFR) ⱕ60 mL/min/1.73 m2 is a powerful risk factor for
cardiovascular adverse outcomes in patients with HF.5–9 Both
Clinical Perspective on p 26
CKD and chronic HF are common, with prevalence rates in

Received December 28, 2009; accepted October 15, 2010.

From the University of Maryland School of Medicine (R.K.W., M.R.W.), Baltimore, Md; GlaxoSmithKline (M.I., M.A.L.), King of Prussia, Pa; the
Cleveland Clinic Foundation (G.J.B.), Department of Quantitative Health Sciences, Cleveland, Ohio; Brigham and Women’s Hospital (D.M.C.), Harvard
Medical School, Boston, Mass; the University of Colorado Health Science Center (M.C., T.B.), Renal Diseases and Hypertension, Denver, Colo; the
University of Toledo (C.C.), Toledo, Ohio; the University of Washington School of Medicine (J.H.), Seattle, Wash; the University of Texas Health
Science Center (W.L.H.), San Antonio, Tex; Veterans Affairs Salt Lake City Healthcare Systems and University of Utah School of Medicine (A.K.C.),
Salt Lake City, Utah; and the Kidney Disease Research Consortium.
Guest Editor for this article was Emily B. Levitan, PhD.
The online-only Data Supplement is available at http://circheartfailure.ahajournals.org/cgi/content/full/CIRCHEARTFAILURE.109.932558/DC1.
Correspondence to Ravinder K. Wali, MD, Inova Transplant Center, 8503 Arlington Boulevard, Fairfax, VA 22031. E-mail ravinder.wali@inova.org
© 2011 American Heart Association, Inc.
Circ Heart Fail is available at http://circheartfailure.ahajournals.org DOI: 10.1161/CIRCHEARTFAILURE.109.932558

18

100
90
80
70
60
Cumulative %
50
40
30
20
10
0
20 30 40 50 60
eGFR (mL/min)
Baseline PLACEBO Endpoint PLACEBO
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This coexistence of CKD and HF could result in significant
adverse interactive effects.17 Indeed, the presence of CKD in HF
patients is associated with an increased risk of hospitalization
and death from pump failure and all-cause mortality14 –16,18
independent of the degree of impairment in left ventricular
ejection fraction (LVEF)19 or the severity of heart failure
based on New York Heart Association (NYHA) class.20
Conversely, HF and its treatment can also increase the rate of
progression in CKD.5,14,17
The excess mortality in HF patients in the presence of
CKD is likely to be multifactorial17 and may include low
utilization rates of currently available therapeutic options
either due to lack of proven efficacy,21,22 lack of randomized,
controlled studies,11,23 or concerns over the increased rates of
adverse events, as has been demonstrated with the use of
other agents such as angiotensin-converting enzyme inhibi-
tors (ACE-I),24 spironolactone,25 and nesiritide.26 Conse-
quently, patients with the combination of HF and CKD are
less likely to be treated with established HF therapies.21,27
␤-Blockers are a cornerstone of therapy for HF, but their use
in patients with HF and different degrees of CKD have not been
thoroughly evaluated in randomized studies.21 Carvedilol is a
nonselective vasodilating ␤-adrenergic blocker with ␣1
adrenergic-blocking activities28,29 with established efficacy in
decreasing mortality and morbidity in patients with mild to
severe chronic HF with systolic left ventricular dysfunction
(LVD).30,31 Carvedilol decreases systolic and diastolic blood
pressure without a decrease in renal blood flow or GFR while
reducing renal vascular resistance.32 These hemodynamic effects
of carvedilol could be particularly beneficial in patients with
Wali et al Efficacy of Carvedilol in Heart Failure with CKD 19
Figure. Cumulative distribution plots of
eGFR at baseline and at the last
follow-up from pooled patient-level data
from COPERNICUS and CAPRICORN
studies. eGFR was calculated using the
4-variable Modification of Diet in Renal
Disease formula.
70 80 90 100
Baseline CARVEDILOL Endpoint CARVEDILOL
CKD.33 Although a small, randomized study demonstrated that
carvedilol improved survival in chronic dialysis patients with
severe HF34 and other studies have failed to demonstrate a
benefit of other ␤-blockers in the dialysis population,35 there
remains a paucity of data from randomized studies evaluating
the efficacy and safety of carvedilol therapy in the presence of
CKD. We therefore conducted a post hoc meta-analysis of the
CKD subgroup among 4217 patients enrolled in 2 placebo-
controlled randomized studies of carvedilol therapy in patients
with different types of systolic LVD with or without symptom-
atic HF.30,31
Methods
We analyzed the pooled patient-level data from 2 large, multicenter,
multinational, double-blind, randomized, placebo-controlled studies
of carvedilol in systolic LVD with or without symptoms of HF.30,31
These studies were similar with respect to the study design, dose
titration of carvedilol, primary and secondary outcomes, and duration
of the follow-up. Briefly, CAPRICORN (Carvedilol Post-Infarct
Survival Control in Left Ventricular Dysfunction Study) randomly
assigned 1959 patients within 21 days after acute myocardial infarction
with LVEF ⱕ0.40 with or without symptomatic HF to either carvedilol
(n⫽975) or placebo (n⫽984).30 In the COPERNICUS (Carvedilol
Prospective Randomized, Cumulative Survival) study, a total of
2289 patients with LVEF ⱕ0.25 and severe chronic HF of ischemic
or nonischemic etiology while on standard therapy were randomly
assigned to carvedilol (n⫽1156) and to placebo (n⫽1143).31 For
CAPRICORN, carvedilol was initiated at 6.25 mg twice daily within
21 days of the acute myocardial infarction and progressed to 12.5 mg
twice per day within 3 to 10 days, with further escalation to the target
dose of 25 mg twice per day (maximum dose) within another 5 to 10
days as tolerated. For COPERNICUS, carvedilol was initiated at
3.125 mg twice per day and titrated at intervals of no less than 2
weeks to 12.5 mg twice daily with further escalation to the target
 20 Circ Heart Fail January 2011

Table 1. Baseline Characteristics of CKD Versus Non-CKD Patients at the Time of Random
Assignment to Carvedilol Versus Placebo
CKD Group, Non-CKD Group,
eGFR ⱕ60 mL/min/1.73 m2 eGFR ⬎60 mL/min/1.73 m2

Carvedilol Placebo Carvedilol Placebo

Description (n⫽1293) (n⫽1273) (n⫽822) (n⫽829)
Serum creatinine, ␮mol/L*
Mean⫾SD 140.3⫾33.9 140.4⫾33.6 94.6⫾14.1 94.9⫾14.7
Median 133 131.7 96 97
eGFR, mL/min/1.73 m2†
Mean⫾SD 45.7⫾9.7 45.3⫾9.5 74.8⫾12.8 75.7⫾15.6
Median 47.1 46.3 71 72
eGFR categories,‡ n (%)
ⱖ90 0 0 103 (13) 123 (15)
60–89 3 (0.2) 1 (0.1) 719 (88) 706 (88)
30–60 1184 (91) 1180 (92)
15–30 105 (8) 92 (7)
⬍15 1 (0.1) 0
Age, y
Mean⫾SD 65.3⫾10.5 66.2⫾10.4 58.5⫾11.3 57.6⫾11.4
Sex, n (%)
Male 920 (71) 892 (70) 701 (85) 727 (88)
Race, n (%)
Caucasian 1209 (94) 1194 (94) 760 (93) 747 (90)
Black 39 (3) 35 (3) 29 (4) 35 (4)
Other 45 (3) 44 (3) 33 (4) 47 (6)
Weight, kg 77.7⫾15.3 76.9⫾15.2 78.5⫾14.9 79.5⫾15.0
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History of diabetes mellitus, n (%) 324 (25) 340 (26) 183 (22) 171 (21)
History of hypertension, n (%) 632 (49) 608 (48) 330 (40) 318 (38)
History of hypotension,§ n (%) 98 (7) 73 (6) 58 (7) 58 (7)
History of AMI, n (%) 212 (16) 183 (15) 163 (20) 161 (19)
History of PTCA, n (%) 23 (1.8) 28 (3) 21 (3) 17 (2)
History of CABG, n (%) 45 (4) 42 (4) 18 (2.2) 3 (0.4)
History of stroke, n (%) 74 (6) 80 (6) 38 (5) 22 (3)
History of PVD, n (%) 67 (5) 77 (6) 53 (6) 44 (5)
Hematocrit,㛳 n (%)
⬍30% 9 (0.7) 12 (0.9) 8 (1) 5 (0.6)
31% to 39% 185 (14) 178 (14) 165 (20) 159 (19)
⬎40% 211 (16) 225 (18) 316 (38) 318 (38)
Missing 333 (41) 347 (42)
LVEF, %
Mean⫾SD 24⫾8 24⫾8 28⫾8 28⫾8
Median 23 23 30 28
LVEF categories, n (%)
ⱕ10% 34 (3) 31 (3) 12 (1.5) 13 (1.6)
11% to 20% 426 (33) 435 (34) 178 (22) 174 (21)
21% to 30% 530 (41) 510 (40) 252 (31) 284 (34)
31% to 40% 299 (23) 293 (23) 378 (46) 356 (43)
NYHA class,¶ n (%)
I 139 (11) 151 (12) 288 (35) 281 (34)
II 184 (14) 194 (15) 189 (23) 198 (24)
III 72 (6) 62 (5) 31 (4) 25 (3)
IV 0 2 1
(Continued)
 Wali et al Efficacy of Carvedilol in Heart Failure with CKD 21

Table 1. Continued
CKD Group, Non-CKD Group,
eGFR ⱕ60 mL/min/1.73 m2 eGFR ⬎60 mL/min/1.73 m2

Carvedilol Placebo Carvedilol Placebo

Description (n⫽1293) (n⫽1273) (n⫽822) (n⫽829)
Baseline medications, n (%)
ACE-I 1180 (92) 1167 (92) 791 (96) 796 (96)
ARB 97 (8) 90 (7) 33 (4) 26 (3)
Diuretics 1088 (84) 1057 (83) 449 (55) 445 (54)
Digitalis 627 (49) 594 (47) 241 (29) 223 (27)
Spironolactone 180 (14) 179 (14) 59 (7) 61 (8)
Anticoagulants 1080 (84) 1063 (84) 731 (89) 736 (89)
AMI indicates acute myocardial infarction; PTCA, percutaneous coronary angioplasty; CABG, coronary artery bypass
grafting; PVD, peripheral vascular disease; and ARB, angiotensin receptor blockers.
*To convert serum creatinine values to mg/dL, divide serum creatinine (␮mol/L) by 88.4.
†Estimated GFR by abbreviated (4-variable) Modification of Diet Renal Disease formula.
‡eGFR categories: According to KDOQI, CKD stages 3, 4, and 5 are based on Modification of Diet Renal Disease
formula– derived eGFR values (mL/min/1.73 m2) of ⬎30 to 60; ⬎15 to 30; and ⬍15, respectively.
§Hypotension defined as systolic blood pressure ⬍100 mm Hg.
㛳Hematocrit values were available only in patients enrolled in the CAPRICORN study.
¶NYHA classification was not captured for the patients enrolled in the COPERNICUS study. Hence, this classification
is given for the cohort of CAPRICORN study participants.

dose of 25 mg twice daily (maximum dose) as tolerated. The study
participants were already receiving conventional therapy for HF,
including different doses of ACEI-I, angiotensin-receptor blockers,
diuretics, spironolactone, and digitalis, as deemed necessary by the
treating physician.
Definition of CKD
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versus ⱖ20%), and NYHA classification. Other covariates included
history (yes or no) of diabetes mellitus, hypertension, coronary artery
bypass graft, percutaneous coronary angioplasty, and stroke; and use
(yes or no) of ACE-I or angiotensin-receptor blockers, spironolac-
tone, digitalis, and diuretics.
Initially for each end point, covariates were evaluated one by one,
with treatment arm and study type in the model. Treatment by study

We used the 4 variable Modification of Diet in Renal Disease
formula to estimate the eGFR expressed in mL/min/1.73 m2,4 based
on the serum creatinine values at the time of enrollment. This
formula has been previously used in several HF studies.5,7,18,27,36,37
CKD and non-CKD groups were defined on the basis of eGFR
values of ⱕ60 mL/min/1.73 m2, respectively. As a sensitivity
analysis, we assessed the efficacy of carvedilol in those with eGFR
⬍45 mL/min/1.73 m2(CKD stage 3b) and eGFR ⱖ45 to 60 mL/min/
1.73 m2(CKD stage 3a).
Primary and Secondary Outcomes
The primary outcome in this analysis was all-cause mortality.
Secondary outcomes were cardiovascular mortality, HF mortality,
first hospitalization for HF, composite of cardiovascular mortality or
hospitalization for HF, and sudden cardiac death. The outcomes in
the present analysis were identical to those specified in the original
protocols.30,31 Clinical outcomes were adjudicated by the end point
committees for the respective studies.
Statistical Methods
The data from the individual patients who participated in the
CAPRICORN and COPERNICUS trials were pooled for the present
analysis. Baseline characteristics were summarized descriptively
using summary statistics according to the variable distribution (ie,
mean and standard deviation for continuous variables; frequencies
for categorical variables).
Analysis of the time to each end point was performed using Cox
proportional hazards regression. For all the end points considered,
the null hypothesis assumed that carvedilol therapy was similar to
placebo in HF patients with concomitant CKD (eGFR ⱕ60 mL/min/
1.73 m2). The same hypothesis was tested for the non-CKD (⬎60
mL/min/1.73 m2) subgroup.
The following covariates were considered in the CKD subgroup
analyses of these end points: baseline age (ⱖ65 versus ⬎ 65 years),
sex, race (Caucasian, African American, others), LVEF (⬍20%
and treatment by covariate interactions were explored sequentially in
this model. Main effects were tested at the 0.05 level and interactions
at a 0.10 level. If the covariate or interaction effect was not
significant, it was dropped and not included in the main analysis with
treatment and study effect in the CKD subgroups (parsimonious
model).
Additionally, to verify the robustness of the treatment effect, for
each end point, CKD subgroup analyses models were examined that
included: age (ⱕ65 versus ⬎65 years), sex, race (Caucasian, African
American, others), diabetes mellitus (yes or no), LVEF (⬍20%
versus ⱖ20%), treatment arm, and study type. These covariates were
selected because of prior evidence suggesting their association with
outcomes in congestive HF as well as in CKD. When compared with
a parsimonious model including only treatment arm and study type,
the treatment effect observed in these subgroup analyses models was
nearly identical. As such, primary inferences in the CKD subgroup
analyses for these end points were based on the parsimonious
models.
Finally, a sensitivity analysis was performed in the subgroups with
eGFR ⬍45 mL/min/1.73 m2 (CKD stage 3b) and eGFR ⱖ45 to 60
mL/min/1.73 m2 (CKD stage 3a). These sensitivity analyses models
included treatment arm and study type.
All analyses were performed with SAS, version 8.2 (SAS institute,
Inc, Cary, NC).
Results
Baseline Characteristics of the Cohort
A total of 4217 subjects were included in this analysis. The
mean (⫾SD) eGFR was 57.2 (⫾18.7) mL/min/1.73 m2. The
eGFR values at baseline as well as at the last follow-up were
similarly distributed in the carvedilol and placebo groups
(Figure). CKD was present in 2566 of 4217 (60.8%) of all
patients enrolled in these 2 trials. Among individuals with
 22 Circ Heart Fail January 2011

Table 2. Clinical Outcomes During the Follow-Up Period in the CKD and Non-CKD Groups After Random Assignment to Carvedilol
Versus Placebo
CKD, Non-CKD,
Entire Cohort eGFR ⱕ60 mL/min/1.73 m2 eGFR ⬎60 mL/min/1.73 m2
(n⫽4217) (n⫽2566) (n⫽1651)

Outcomes Carvedilol Placebo Carvedilol Placebo Carvedilol Placebo

Randomized Groups (n⫽2115) (n⫽2102) (n⫽1293) (n⫽1273) (n⫽822) (n⫽829)
Duration of follow-up, mo, mean⫾SD 13.6⫾7.9 13.3⫾7.8 12.9⫾7.8 13.0⫾7.8 14.6⫾7.9 13.9⫾7.8
Target dose titration of carvedilol, n (%) 1485 (71) ... 867 (68) ... 618 (76) ...
Discontinuation of carvedilol therapy, n (%) 480 (23) ... 300 (24) ... 180 (22) ...
*Follow-up serum creatinine, ␮mol/L
Mean⫾SD 126⫾51 124⫾46 144⫾57 138⫾51 100⫾22 102⫾24
Median 115.31 114.92 129.24 129.24 100.00 100.00
Follow-up eGFR, mL/min/1.73 m2
Mean⫾SD 58⫾22 57⫾19 48⫾18 48⫾14 73⫾19 72⫾17
Median 55.67 54.88 47.75 47.55 69.96 54.88
Range 6.10–337.52 4.70–149.44 6.10–337.52 4.70–130.92 31.78–211.39 4.70–149.44
Event rates for primary and secondary outcomes
All-cause mortality, n (%) 244 (12) 336 (16) 181 (14) 233 (18) 63 (8) 103 (13)
Cardiovascular mortality, n (%) 218 (11) 301 (14) 162 (13) 209 (17) 56 (7) 92 (11)
HF mortality, n (%) 118 (6) 174 (8) 97 (8) 139 (11) 21 (3) 35 (4.2)
First hospitalizations for HF, n (%) 312 (15) 393 (18) 216 (17) 280 (22) 96 (12) 113 (14)
Composite of cardiovascular mortality 453 (22) 573 (27) 315 (25) 401 (32) 138 (17) 172 (21)
or hospitalization for HF, n (%)
Sudden cardiac death, n (%) 96 (5) 136 (7) 67 (6) 87 (7) 29 (4) 49 (6)
*Follow-up serum creatinine values were available for 1632 of 4217 (39%) of total patients.

CKD, 1293 (50.4%) were randomly assigned to carvedilol of all-cause mortality (hazard ratio [HR], 0.76; 95% confi-
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therapy and 1273 (49.6%) to placebo. There were
1651(39.2%) non-CKD patients at baseline. Of these, 822
(49.8%) received carvedilol.
Baseline characteristics of the patients are summarized in
Table 1 and in Supplemental Table 1. In both CKD strata,
comorbidities as well as the use of medications such as
ACE-I or angiotensin-receptor blockers and anticoagulation
therapy were similarly distributed in patients randomly as-
signed to carvedilol or placebo. Conversely, patients with
CKD appeared older and to have more severe HF as assessed
by NYHA classification than non-CKD individuals. In addi-
tion, a higher number of CKD patients were treated with a
diuretic (84% versus 54%), digitalis (48% versus 28%), or
spironolactone (14% versus 7%).
Overall Clinical Outcomes
The median and mean (⫾SD) duration of actual follow-up
were 13.5 months and 13.6 (⫾7.9) months, respectively.
Discontinuation of carvedilol was similarly frequent in CKD
and non-CKD subgroups (24% versus 22%). The patients
with CKD had increased rates of primary as well as secondary
outcomes on univariate analysis (Table 2) and were further
confirmed on multivariate analysis (data not shown).
Outcomes of Carvedilol Therapy
Random assignment to carvedilol decreased the risks for the
primary as well as all secondary outcomes in both groups of
patients (Table 3 and Table 4). Among the CKD group,
treatment with carvedilol was associated with decreased risks
dence interval [CI], 0.63 to 0.93; P⫽0.007); cardiovascular
mortality (HR, 0.77; 95% CI, 0.62 to 0.94; P⫽0.011); HF
mortality (HR, 0.68; 95% CI, 0.52 to 0.88; P⫽0.003); first
hospitalization for HF (HR, 0.74; 95% CI, 0.62 to 0.88;
P⫽0.0009); and the composite of cardiovascular mortality or
hospitalization for HF (HR, 0.75; 95% CI, 0.65 to 0.87;
P⬍0.001). However, treatment with carvedilol did not have a
statistically significant impact on sudden cardiac death in HF
patients with CKD (HR, 0.76; 95% CI, 0.56 to 1.05;
P⫽0.0980). The magnitude of the relative risk reduction in
the incidence of the primary and secondary outcomes was
similar in the CKD and non-CKD groups. For each clinical
outcome, there were no statistically significant interactions
observed between treatment (carvedilol, placebo) and study
type (CAPRICORN, COPERNICUS).
Furthermore, the robustness of the treatment effect for each
end point in the CKD subgroup remained consistent when
other important covariates were added to the Cox models
(Supplemental Table 2). The interaction between treatment
and CKD group was nonsignificant for all outcomes.
A sensitivity analysis (Table 4) demonstrated that efficacy
of carvedilol was not significantly different from placebo for
the primary or secondary outcomes in the eGFR (⬍45
mL/min/1.73 m2, CKD stage 3b) subgroup. The overlapping
confidence intervals for these outcomes in this subgroup of
heart failure patients may be related to relatively small
sample size (CKD 3b, carvedilol versus placebo: n⫽544
versus 572).
Investigator-reported adverse events were adjudicated by
the end point committee and the rates of cardiac, neurologi-
 Wali et al Efficacy of Carvedilol in Heart Failure with CKD 23

Table 3. Adjusted Risk (Hazard Ratios) for Primary and Secondary Outcomes in
HF Patients Within CKD and Non-CKD Groups, Based on Treatment With
Carvedilol
CKD, eGFR ⱕ60 mL/ Non-CKD, eGFR ⬎60 mL/
min/1.73 m2 min/1.73 m2
(Carvedilol Versus (Carvedilol Versus
Placebo) (n⫽1293 Placebo) (n⫽822
Versus 1273) Versus 829)

Outcome HR* 95% CI HR* 95% CI

All-cause mortality 0.76 0.63– 0.93 0.59 0.43– 0.81
Cardiovascular mortality 0.77 0.62–0.94 0.59 0.42–0.82
HF mortality 0.68 0.52–0.88 0.58 0.34–0.99
First hospitalization for HF 0.74 0.62–0.88 0.83 0.63–1.09
Composite of cardiovascular 0.75 0.65–0.87 0.78 0.63–0.98
mortality or hospitalization
for HF
Sudden cardiac death 0.76 0.56–1.05 0.58 0.37–0.92
*HR is based on the Cox model after adjusting for treatment arm and study type.
There was no significant interaction of treatment and CKD/non-CKD for any of the outcomes.

cal, vascular, and other miscellaneous adverse events with the
use of carvedilol compared with placebo in patients with
CKD as well as non-CKD are presented in Table 5. The
cumulative incidence of transient changes in serum creatinine
in the CKD (carvedilol versus placebo) patients was 4.6%
versus 1.8% (P⬍0.001). However, none of these patients
required dialysis therapy. The use of carvedilol was associ-
ated with an increase in the relative incidence of headache,
orthostatic hypotension, hyperkalemia, and hyperglycemia in
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This post hoc analysis of patient-level data from 2 large,
randomized, placebo-controlled studies with HF demon-
strated that more than 60% of HF patients had mild to
moderate CKD at the time of enrollment. Overall, treatment
with carvedilol resulted in similar degrees of reduction in the
relative risks for all-cause, cardiovascular, and HF mortality
in the group of HF patients with CKD. As one would expect,
this reduction translates to a greater absolute benefit with
carvedilol in CKD patients.

HF patients with CKD. The overall discontinuation rate of
carvedilol was similar in the CKD and non-CKD subgroups
(24% versus 22%).
Discussion
CKD is an independent risk factor for cardiovascular mor-
bidity and mortality in patients with HF.5–9 With the evolving
epidemic of CKD and our aging population, the prevalence of
patients with concomitant heart failure and CKD is increas-
ing.13 Hence, it is important to understand whether current
standard therapies have a similar degree of efficacy and safety
profiles in HF patients with different degrees of CKD.11,23
To our knowledge, this is the first report in which individ-
ual patient data on a large cohort has been used to analyze the
efficacy and safety of carvedilol in HF patients with concom-
itant CKD. The presence of CKD can worsen the systemic
effects of HF via adverse effects on cardiac, hemodynamic,
and neurohormonal adaptive (or maladaptive) responses,
including increased sympathetic activity, and these could
portend a poor prognosis.6,38,39 Accordingly, different degrees
of CKD are independently associated with an increased risk
for all-cause mortality as well as HF progression.5–9 In
addition, the synergism between HF and CKD could also
potentiate other risk factors frequently associated with mild to

Table 4. Adjusted Risk (Hazard Ratios) for Primary and Secondary Outcomes in HF Patients Within Different
eGFR Groups, Based on Treatment With Carvedilol
eGFR ⬍45 mL/min/ eGFR ⬎60 mL/min/
1.73 m2 (CKD Stage eGFR ⱖ45–60 mL/min/ 1.73 m2 (Non-CKD),
3b), Carvedilol 1.73 m2 (CKD Stage 3a), Carvedilol Versus
Versus Placebo Carvedilol Versus Placebo Placebo (n⫽822
(n⫽544 Versus 572) (n⫽749 Versus 701) Versus 829)

Outcome HR* 95% CI HR* 95% CI HR* 95% CI

All-cause mortality 0.94 0.72–1.23 0.63 0.47– 0.84 0.59 0.43– 0.81
HF mortality 0.86 0.61–1.21 0.52 0.35–0.77 0.58 0.34–0.99
Composite of 0.92 0.75–1.13 0.62 0.50–0.77 0.78 0.63–0.98
cardiovascular mortality
or hospitalization for HF
Sudden cardiac death 1.04 0.64–1.71 0.62 0.41–0.94 0.58 0.37–0.92
*Hazard ratio is based on the Cox model after adjusting for treatment arm and study type.
There was no significant interaction of treatment and CKD/non-CKD for any of the outcomes.
 24 Circ Heart Fail January 2011

Table 5. Cumulative Incidence of Investigator-Reported Adverse Events While on Therapy in

the CKD and Non-CKD Patients After Random Assignment to Carvedilol Versus Placebo
CKD, Non-CKD,
eGFR ⱕ60 mL/min/1.73 m2 eGFR ⬎60 mL/min/1.73 m2

Carvedilol Placebo Carvedilol Placebo

Type of Event, n (%) (n⫽1293) (n⫽1273) P Value* (n⫽822) (n⫽829) P Value*
Any event 896 (69%) 350 (27%) ⬍0.0001 581 (71%) 412 (50%) ⬍0.0001
Any serious event 368 (28%) 197 (15%) ⬍0.0001 274 (33%) 224 (27%) ⬍0.0001
Cardiac events
Any cardiac event† 442 (34) 210 (16) ⬍0.0001 284 (34) 234 (28) ⬍0.0066
Angina pectoris 64 (5) 51 (4) 0.289 64 (8) 57 (7) 0.538
Unstable angina 39 (3) 29 (2) 0.297 33 (4) 37 (4) 0.741
Myocardial infarction 13 (1) 25 (2) 0.064 22 (2) 39 (5) 0.04
Cardiogenic shock 5 (⬍1) 3 (⬍1) . . .‡ 1 (⬍1) 0 . . .‡
Bradycardia 110 (9) 21 (2) ⬍0.0001 45 (5) 14 (2) ⬍0.001
Atrial fibrillation 16 (1) 25 (2) 0.190 9 (1) 14 (2) 0.412
Ventricular tachycardia 8 (⬍1) 10 (⬍1) 0.787 4 (⬍1) 10 (1) 0.184
Atrioventricular block 8 (⬍1) 2 (⬍1) . . .‡ 8 (1) 3 (⬍1) . . .‡
Neurological events
Any event 353 (27) 81 (6) ⬍0.0001 192 (23) 90 (11) ⬍0.0001
Dizziness 253 (20) 43 (3) ⬍0.0001 118 (14) 49 (6) ⬍0.0001
Syncope 69 (5) 4 (⬍1) ⬍0.0001 26 (3) 2 (⬍1) ⬍0.0001
Headache 40 (3) 11 (⬍1) 0.0001 30 (4) 21 (3) 0.242
Stroke 11 (⬍1) 9 (1) 0.849 5 (⬍1) 3 (⬍1) . . .‡
Vascular events
Any vascular event 250 (19) 83 (7) ⬍0.0001 169 (20) 87 (10) ⬍0.0001
Hypotension 156 (12) 30 (2) ⬍0.0001 101 (12) 42 (5) ⬍0.0001
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Hypertension 40 (3) 25 (2) 0.09 31 (4) 25 (3) 0.47

Orthostatic hypotension 24 (2) 3 (⬍1) 0.0001 12 (1) 4 (⬍1) 0.075
Renal events
Changes in serum creatinine 60 (4.6) 23 (1.8) ⬍0.001 1 (⬍1) 1 (⬍1) . . .‡
(cumulative incidence)
Hyperkalemia 27 (2) 4 (⬍1) ⬍0.0001 6 (⬍1) 2 (⬍1) . . .‡
Hypokalemia 14 (1) 5 (⬍1) 0.076 5 (⬍1) 1 (⬍1) . . .‡
Miscellaneous events
Any event 270 (21) 101 (8) ⬍0.0001 206 (25) 128 (15) ⬍0.0001
Asthenia 93 (7) 16 (1) ⬍0.0001 41 (5) 10 (1) ⬍0.0001
Fatigue 11 (⬍1) 10 (⬍1) 0.971 14 (2) 13 (2) 0.982
Peripheral edema 106 (9) 9 (1) ⬍0.0001 38 (5) 11 (1) ⬍0.0001
Hyperglycemia 37 (3) 10 (1) 0.0002 8 (⬍1) 3 (⬍1) 0.220
*P values are based on ␹2 test.
†Any cardiac event is the cumulative event rate except those described in the primary and secondary outcomes.
‡P values are not available because of small counts.

moderate degrees of CKD such as anemia36,40 and chronic
inflammation.41
In individuals without CKD, prolonged use of carvedilol
has been shown to improve symptoms of HF, increase LVEF,
mitigate neurohormonal activation and peripheral vasocon-
striction, and decrease sympathetic overactivity as well as salt
and water retention.6,38 These events may be particularly
relevant in the setting of CKD, where carvedilol therapy
could potentially improve renal hemodynamics and kidney
function. Similarly, although the benefits of antioxidant
properties of carvedilol are not fully understood,42 it is
possible that these properties may have a special role in
patients with a combination of HF and substantial CKD.
In this study population, the addition of carvedilol to conven-
tional HF therapy was generally well tolerated. The rate of
discontinuation of carvedilol based on the investigator-
reported adverse events was similar in both groups of
patients. Changes in renal function without need for dialysis
therapy were more frequent in the HF patients with concom-
itant CKD on treatment with carvedilol despite careful
titration of carvedilol dose. Similar changes in kidney func-
tion have been reported with other types of HF therapy.24
However, it is essential that HF patients with CKD when
treated with carvedilol should be carefully monitored and
dose optimization–tailored, based on individual patient re-
sponses in serum creatinine and/or eGFR values during the
 Wali et al
follow-up period. In addition, CKD patients are at increased
risk for development of orthostatic hypotension, hyperkale-
mia, and hyperglycemia after carvedilol therapy; thus, careful
monitoring for these events is clearly warranted.
These findings provide strong evidence to suggest that
addition of carvedilol to the conventional HF therapy in CKD
patients is beneficial and safe. Ghali et al43 and Erdmann et
al44 demonstrated similar benefits with metoprolol and biso-
prolol, respectively, in patients with HF and CKD. However,
in a sensitivity analysis of HF patients with advanced CKD
(stage 3b), the efficacy of carvedilol was not different from
placebo. Whether this reflects a lack of sufficient power due
to the relatively small sample size in the subgroup with
advanced CKD or a different biological response to carve-
dilol in the setting of more advanced CKD cannot be
determined in this post hoc analysis and merits additional
studies.
This study has several limitations: First, almost all serum
creatinine– based estimating equations for GFR are inherently
imprecise, and this is specifically true when serum creatinine
is measured in different laboratories or in those with lower
than expected muscle mass. This is an important concern in
patients with HF who may have lower muscle mass than
those in the general population. Conversely, HF itself or
therapy with ACE-I and diuretics may result in transient
changes in GFR without concomitant changes in the under-
lying kidney function.16 These issues could potentially have
resulted in overestimation or underestimation of eGFR with
misclassification of CKD stages.45 Second, our analysis is a
Downloaded from http://ahajournals.org by on February 14, 2019
post hoc analysis of the original studies. We had the ability to
analyze individual-level data from 2 randomized, double-
blind, placebo-controlled studies, with similar homogeneity
in the study design, dose titration of carvedilol, and rigorous
uniform definitions as well as rigorous ascertainment of
prespecified outcomes. Nevertheless, our results should still
be considered hypothesis forming and must be extrapolated
cautiously to those with advanced CKD or severe HF. Third,
this meta-analysis involved a homogenous population of
systolic HF with a relatively low number of African Ameri-
cans. Our population may not accurately represent the HF
patient population in the community, and our results should
be generalized cautiously to those not well represented in our
analysis.46
A number of strengths of our analysis are also worth
noting. We analyzed a large number of patients with CKD
and thus provide the most robust evidence to date to suggest
that carvedilol therapy has beneficial effects in patients with
mild to moderate CKD and HF. An additional randomized
study with adequate sample size is needed to determine
whether the benefits of carvedilol therapy extend to individ-
uals with advanced CKD (eGFR ⬍45 mL/min/1.73 m2).
Additionally, we analyzed results of treatment with carvedilol
in both ischemic and nonischemic HF patients; hence, these
results are generalizable to CKD patients with LVD of either
etiology.
Conclusion
The results of this meta-analysis support treatment with
carvedilol to reduce rates of all-cause mortality as well as
Efficacy of Carvedilol in Heart Failure with CKD 25
other HF-related events in patients with LVD with or without
symptomatic HF in the presence of mild to moderate CKD.
The efficacy of carvedilol therapy in HF patients with
advanced CKD has not been established.
Disclosures
Drs Lukas and Iyengar are employed by GlaxoSmithKline. Dr
Cooper is a recipient of a research grant from GlaxoSmithKline.
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CLINICAL PERSPECTIVE
Chronic heart failure is a clinical syndrome associated with increased rates of morbidity, frequent hospitalizations, and
increased utilization of health care costs as well as all-cause mortality. Similarly, chronic kidney disease (CKD) increases
the risk for adverse cardiovascular outcomes in the general population as well as in those with underlying heart failure.
There is a paucity of evidence whether therapeutic interventions that are effective for the treatment of heart failure in the
general population are also effective in those heart failure patients with concomitant CKD. Consequently, clinicians may
be reluctant to use these evidence-based therapies in the presence of CKD. We performed a post hoc meta-analysis of
individual patient-level data from 2 large, randomized, controlled trials (CAPRICORN and COPERNICUS) of carvedilol
in patients with ischemic or nonischemic left ventricular dysfunction. The data were categorized for the presence or absence
of CKD, based on the estimated glomerular filtration rate (⬍60 or ⱖ60 mL/min/1.73 m2, respectively), using the Modified
Diet Renal Disease equation from the serum creatinine values obtained at the time of enrollment. Our study demonstrates
that carvedilol therapy leads to similar benefits in the presence of CKD as in those heart failure patients without CKD.
However, the effect of carvedilol therapy in heart failure patients with advanced CKD (estimated glomerular filtration rate
⬍45 mL/min/1.73 m2) was not different from placebo. This hypothesis-generating finding that carvedilol may not be
efficacious in very advanced stages of CKD must be confirmed by future studies. We also observed that the use of
carvedilol therapy in the presence of CKD can lead to transient fluctuations in renal function and increases the risk for
orthostatic hypotension and other electrolyte abnormalities. Hence, patients with heart failure with concomitant CKD
should have careful dose titration as well as judicious monitoring of kidney function, blood pressure, and electrolytes when
treated with carvedilol.