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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
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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
Wali et al Efficacy of Carvedilol in Heart Failure with CKD 19

100

90

80

70

60
Cumulative %

Figure. Cumulative distribution plots of


50 eGFR at baseline and at the last
follow-up from pooled patient-level data
from COPERNICUS and CAPRICORN
40 studies. eGFR was calculated using the
4-variable Modification of Diet in Renal
Disease formula.
30

20

10

0
20 30 40 50 60 70 80 90 100
eGFR (mL/min)

Baseline PLACEBO Endpoint PLACEBO Baseline CARVEDILOL Endpoint CARVEDILOL


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This coexistence of CKD and HF could result in significant CKD.33 Although a small, randomized study demonstrated that
adverse interactive effects.17 Indeed, the presence of CKD in HF carvedilol improved survival in chronic dialysis patients with
patients is associated with an increased risk of hospitalization severe HF34 and other studies have failed to demonstrate a
and death from pump failure and all-cause mortality14 –16,18 benefit of other ␤-blockers in the dialysis population,35 there
independent of the degree of impairment in left ventricular remains a paucity of data from randomized studies evaluating
ejection fraction (LVEF)19 or the severity of heart failure the efficacy and safety of carvedilol therapy in the presence of
based on New York Heart Association (NYHA) class.20 CKD. We therefore conducted a post hoc meta-analysis of the
Conversely, HF and its treatment can also increase the rate of CKD subgroup among 4217 patients enrolled in 2 placebo-
progression in CKD.5,14,17 controlled randomized studies of carvedilol therapy in patients
The excess mortality in HF patients in the presence of with different types of systolic LVD with or without symptom-
CKD is likely to be multifactorial17 and may include low atic HF.30,31
utilization rates of currently available therapeutic options
either due to lack of proven efficacy,21,22 lack of randomized, Methods
controlled studies,11,23 or concerns over the increased rates of We analyzed the pooled patient-level data from 2 large, multicenter,
multinational, double-blind, randomized, placebo-controlled studies
adverse events, as has been demonstrated with the use of of carvedilol in systolic LVD with or without symptoms of HF.30,31
other agents such as angiotensin-converting enzyme inhibi- These studies were similar with respect to the study design, dose
tors (ACE-I),24 spironolactone,25 and nesiritide.26 Conse- titration of carvedilol, primary and secondary outcomes, and duration
quently, patients with the combination of HF and CKD are of the follow-up. Briefly, CAPRICORN (Carvedilol Post-Infarct
Survival Control in Left Ventricular Dysfunction Study) randomly
less likely to be treated with established HF therapies.21,27
assigned 1959 patients within 21 days after acute myocardial infarction
␤-Blockers are a cornerstone of therapy for HF, but their use with LVEF ⱕ0.40 with or without symptomatic HF to either carvedilol
in patients with HF and different degrees of CKD have not been (n⫽975) or placebo (n⫽984).30 In the COPERNICUS (Carvedilol
thoroughly evaluated in randomized studies.21 Carvedilol is a Prospective Randomized, Cumulative Survival) study, a total of
nonselective vasodilating ␤-adrenergic blocker with ␣1 2289 patients with LVEF ⱕ0.25 and severe chronic HF of ischemic
or nonischemic etiology while on standard therapy were randomly
adrenergic-blocking activities28,29 with established efficacy in assigned to carvedilol (n⫽1156) and to placebo (n⫽1143).31 For
decreasing mortality and morbidity in patients with mild to CAPRICORN, carvedilol was initiated at 6.25 mg twice daily within
severe chronic HF with systolic left ventricular dysfunction 21 days of the acute myocardial infarction and progressed to 12.5 mg
(LVD).30,31 Carvedilol decreases systolic and diastolic blood 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
pressure without a decrease in renal blood flow or GFR while days as tolerated. For COPERNICUS, carvedilol was initiated at
reducing renal vascular resistance.32 These hemodynamic effects 3.125 mg twice per day and titrated at intervals of no less than 2
of carvedilol could be particularly beneficial in patients with 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 versus ⱖ20%), and NYHA classification. Other covariates included
participants were already receiving conventional therapy for HF, history (yes or no) of diabetes mellitus, hypertension, coronary artery
including different doses of ACEI-I, angiotensin-receptor blockers, bypass graft, percutaneous coronary angioplasty, and stroke; and use
diuretics, spironolactone, and digitalis, as deemed necessary by the (yes or no) of ACE-I or angiotensin-receptor blockers, spironolac-
treating physician. tone, digitalis, and diuretics.
Initially for each end point, covariates were evaluated one by one,
Definition of CKD with treatment arm and study type in the model. Treatment by study
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We used the 4 variable Modification of Diet in Renal Disease and treatment by covariate interactions were explored sequentially in
formula to estimate the eGFR expressed in mL/min/1.73 m2,4 based this model. Main effects were tested at the 0.05 level and interactions
on the serum creatinine values at the time of enrollment. This at a 0.10 level. If the covariate or interaction effect was not
formula has been previously used in several HF studies.5,7,18,27,36,37 significant, it was dropped and not included in the main analysis with
CKD and non-CKD groups were defined on the basis of eGFR treatment and study effect in the CKD subgroups (parsimonious
values of ⱕ60 mL/min/1.73 m2, respectively. As a sensitivity model).
analysis, we assessed the efficacy of carvedilol in those with eGFR Additionally, to verify the robustness of the treatment effect, for
⬍45 mL/min/1.73 m2(CKD stage 3b) and eGFR ⱖ45 to 60 mL/min/ each end point, CKD subgroup analyses models were examined that
1.73 m2(CKD stage 3a). included: age (ⱕ65 versus ⬎65 years), sex, race (Caucasian, African
American, others), diabetes mellitus (yes or no), LVEF (⬍20%
Primary and Secondary Outcomes versus ⱖ20%), treatment arm, and study type. These covariates were
The primary outcome in this analysis was all-cause mortality. selected because of prior evidence suggesting their association with
Secondary outcomes were cardiovascular mortality, HF mortality, outcomes in congestive HF as well as in CKD. When compared with
first hospitalization for HF, composite of cardiovascular mortality or a parsimonious model including only treatment arm and study type,
hospitalization for HF, and sudden cardiac death. The outcomes in the treatment effect observed in these subgroup analyses models was
the present analysis were identical to those specified in the original nearly identical. As such, primary inferences in the CKD subgroup
protocols.30,31 Clinical outcomes were adjudicated by the end point analyses for these end points were based on the parsimonious
committees for the respective studies. 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
Statistical Methods
mL/min/1.73 m2 (CKD stage 3a). These sensitivity analyses models
The data from the individual patients who participated in the
included treatment arm and study type.
CAPRICORN and COPERNICUS trials were pooled for the present
All analyses were performed with SAS, version 8.2 (SAS institute,
analysis. Baseline characteristics were summarized descriptively
Inc, Cary, NC).
using summary statistics according to the variable distribution (ie,
mean and standard deviation for continuous variables; frequencies
for categorical variables). Results
Analysis of the time to each end point was performed using Cox
proportional hazards regression. For all the end points considered, Baseline Characteristics of the Cohort
the null hypothesis assumed that carvedilol therapy was similar to A total of 4217 subjects were included in this analysis. The
placebo in HF patients with concomitant CKD (eGFR ⱕ60 mL/min/ mean (⫾SD) eGFR was 57.2 (⫾18.7) mL/min/1.73 m2. The
1.73 m2). The same hypothesis was tested for the non-CKD (⬎60 eGFR values at baseline as well as at the last follow-up were
mL/min/1.73 m2) subgroup.
The following covariates were considered in the CKD subgroup similarly distributed in the carvedilol and placebo groups
analyses of these end points: baseline age (ⱖ65 versus ⬎ 65 years), (Figure). CKD was present in 2566 of 4217 (60.8%) of all
sex, race (Caucasian, African American, others), LVEF (⬍20% 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 dence interval [CI], 0.63 to 0.93; P⫽0.007); cardiovascular
1651(39.2%) non-CKD patients at baseline. Of these, 822 mortality (HR, 0.77; 95% CI, 0.62 to 0.94; P⫽0.011); HF
(49.8%) received carvedilol. mortality (HR, 0.68; 95% CI, 0.52 to 0.88; P⫽0.003); first
Baseline characteristics of the patients are summarized in hospitalization for HF (HR, 0.74; 95% CI, 0.62 to 0.88;
Table 1 and in Supplemental Table 1. In both CKD strata, P⫽0.0009); and the composite of cardiovascular mortality or
comorbidities as well as the use of medications such as hospitalization for HF (HR, 0.75; 95% CI, 0.65 to 0.87;
ACE-I or angiotensin-receptor blockers and anticoagulation P⬍0.001). However, treatment with carvedilol did not have a
therapy were similarly distributed in patients randomly as- statistically significant impact on sudden cardiac death in HF
signed to carvedilol or placebo. Conversely, patients with patients with CKD (HR, 0.76; 95% CI, 0.56 to 1.05;
CKD appeared older and to have more severe HF as assessed P⫽0.0980). The magnitude of the relative risk reduction in
by NYHA classification than non-CKD individuals. In addi- the incidence of the primary and secondary outcomes was
tion, a higher number of CKD patients were treated with a similar in the CKD and non-CKD groups. For each clinical
outcome, there were no statistically significant interactions
diuretic (84% versus 54%), digitalis (48% versus 28%), or
observed between treatment (carvedilol, placebo) and study
spironolactone (14% versus 7%).
type (CAPRICORN, COPERNICUS).
Furthermore, the robustness of the treatment effect for each
Overall Clinical Outcomes end point in the CKD subgroup remained consistent when
The median and mean (⫾SD) duration of actual follow-up other important covariates were added to the Cox models
were 13.5 months and 13.6 (⫾7.9) months, respectively. (Supplemental Table 2). The interaction between treatment
Discontinuation of carvedilol was similarly frequent in CKD and CKD group was nonsignificant for all outcomes.
and non-CKD subgroups (24% versus 22%). The patients A sensitivity analysis (Table 4) demonstrated that efficacy
with CKD had increased rates of primary as well as secondary of carvedilol was not significantly different from placebo for
outcomes on univariate analysis (Table 2) and were further the primary or secondary outcomes in the eGFR (⬍45
confirmed on multivariate analysis (data not shown). mL/min/1.73 m2, CKD stage 3b) subgroup. The overlapping
confidence intervals for these outcomes in this subgroup of
Outcomes of Carvedilol Therapy heart failure patients may be related to relatively small
Random assignment to carvedilol decreased the risks for the sample size (CKD 3b, carvedilol versus placebo: n⫽544
primary as well as all secondary outcomes in both groups of versus 572).
patients (Table 3 and Table 4). Among the CKD group, Investigator-reported adverse events were adjudicated by
treatment with carvedilol was associated with decreased risks 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 This post hoc analysis of patient-level data from 2 large,
use of carvedilol compared with placebo in patients with randomized, placebo-controlled studies with HF demon-
CKD as well as non-CKD are presented in Table 5. The strated that more than 60% of HF patients had mild to
cumulative incidence of transient changes in serum creatinine moderate CKD at the time of enrollment. Overall, treatment
in the CKD (carvedilol versus placebo) patients was 4.6% with carvedilol resulted in similar degrees of reduction in the
versus 1.8% (P⬍0.001). However, none of these patients relative risks for all-cause, cardiovascular, and HF mortality
required dialysis therapy. The use of carvedilol was associ- in the group of HF patients with CKD. As one would expect,
ated with an increase in the relative incidence of headache, this reduction translates to a greater absolute benefit with
orthostatic hypotension, hyperkalemia, and hyperglycemia in carvedilol in CKD patients.
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HF patients with CKD. The overall discontinuation rate of To our knowledge, this is the first report in which individ-
carvedilol was similar in the CKD and non-CKD subgroups ual patient data on a large cohort has been used to analyze the
(24% versus 22%). efficacy and safety of carvedilol in HF patients with concom-
itant CKD. The presence of CKD can worsen the systemic
Discussion effects of HF via adverse effects on cardiac, hemodynamic,
CKD is an independent risk factor for cardiovascular mor- and neurohormonal adaptive (or maladaptive) responses,
bidity and mortality in patients with HF.5–9 With the evolving including increased sympathetic activity, and these could
epidemic of CKD and our aging population, the prevalence of portend a poor prognosis.6,38,39 Accordingly, different degrees
patients with concomitant heart failure and CKD is increas- of CKD are independently associated with an increased risk
ing.13 Hence, it is important to understand whether current for all-cause mortality as well as HF progression.5–9 In
standard therapies have a similar degree of efficacy and safety addition, the synergism between HF and CKD could also
profiles in HF patients with different degrees of CKD.11,23 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 In this study population, the addition of carvedilol to conven-
inflammation.41 tional HF therapy was generally well tolerated. The rate of
In individuals without CKD, prolonged use of carvedilol discontinuation of carvedilol based on the investigator-
has been shown to improve symptoms of HF, increase LVEF, reported adverse events was similar in both groups of
mitigate neurohormonal activation and peripheral vasocon- patients. Changes in renal function without need for dialysis
striction, and decrease sympathetic overactivity as well as salt therapy were more frequent in the HF patients with concom-
and water retention.6,38 These events may be particularly itant CKD on treatment with carvedilol despite careful
relevant in the setting of CKD, where carvedilol therapy titration of carvedilol dose. Similar changes in kidney func-
could potentially improve renal hemodynamics and kidney tion have been reported with other types of HF therapy.24
function. Similarly, although the benefits of antioxidant However, it is essential that HF patients with CKD when
properties of carvedilol are not fully understood,42 it is treated with carvedilol should be carefully monitored and
possible that these properties may have a special role in dose optimization–tailored, based on individual patient re-
patients with a combination of HF and substantial CKD. sponses in serum creatinine and/or eGFR values during the
Wali et al Efficacy of Carvedilol in Heart Failure with CKD 25

follow-up period. In addition, CKD patients are at increased other HF-related events in patients with LVD with or without
risk for development of orthostatic hypotension, hyperkale- symptomatic HF in the presence of mild to moderate CKD.
mia, and hyperglycemia after carvedilol therapy; thus, careful The efficacy of carvedilol therapy in HF patients with
monitoring for these events is clearly warranted. advanced CKD has not been established.
These findings provide strong evidence to suggest that
addition of carvedilol to the conventional HF therapy in CKD Disclosures
patients is beneficial and safe. Ghali et al43 and Erdmann et Drs Lukas and Iyengar are employed by GlaxoSmithKline. Dr
al44 demonstrated similar benefits with metoprolol and biso- Cooper is a recipient of a research grant from GlaxoSmithKline.
prolol, respectively, in patients with HF and CKD. However,
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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.