JACC: HEART FAILURE
5, 2019
ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER
MINI-FOCUS ISSUE: THE INTERSECTION OF THE KIDNEY AND THE HEART
STATE-OF-THE-ART REVIEW
Medical Management of Heart Failure
With Reduced Ejection Fraction in
Patients With Advanced Renal Disease
Aaron M. Hein, BS,a Julia J. Scialla, MD, MHS,a,b Daniel Edmonston, MD,a,b Lauren B. Cooper, MD, MHS,a,c
Adam D. DeVore, MD, MHS,a,b Robert J. Mentz, MDa,b
JACC: HEART FAILURE CME/MOC/ECME
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VOL. 7, NO.
CME/MOC/ECME Objectives for This Article: Upon completion of this
activity, the learner should be able to: 1) discuss the current use of guide-
line-directed medical therapy in patients with heart failure with reduced
ejection fraction (HFrEF) and advanced chronic kidney disease (CKD); 2)
select appropriate management options for patients with HFrEF and
advanced CKD; and 3) identify potential adverse effects and monitoring
considerations in patients with HFrEF and advanced CKD.
CME/MOC/ECME Editor Disclosure: Editor-in-Chief Christopher M.
O’Connor, MD, has received consultant fees/honoraria from AbbVie, Inc.,
Actelion Pharmaceuticals Ltd., Bayer, Bristol-Myers Squibb, Cardiorentis,
Merck & Co., Inc., ResMed, and Roche Diagnostics; and has ownership
interest in Biscardia, LLC.ExecutiveEditorMona Fiuzat,PharmD, has
receivedresearch support from ResMed, Gilead, Critical Diagnostics,
Otsuka, and Roche Diagnostics. Tariq Ahmad, MD, MPH, has received a
travel scholarship from Thoratec. Abhinav Sharma, MD, has received
support from Bayer-Canadian Cardiovascular Society, Alberta Innovates
Health Solution, Roche Diagnostics, and Takeda. Mitchell Psotka, MD,
PhD, and Kishan Parikh, MD, have no relationships relevant to the
contents of this paper to disclose.
Author Disclosures: Dr. Scialla has received research support from Na-
tional Institute of Diabetes and Digestive and Kidney Diseases grant
R01DK111952, GlaxoSmithKline, and Sanofi. Dr. Cooper has received
research support from Abbott Laboratories. Dr. DeVore has received
research support from Amgen, the American Heart Association, the Na-
tional Heart, Lung, and Blood Institute, and Novartis; and is a consultant
for Novartis. Dr. Mentz has received research support from National In-
stitutes of Health grants U01HL125511-01A1, U10HL110312, and
R01AG045551-01A1; has received funding from Akros, Amgen,
AstraZeneca, Bayer, GlaxoSmithKline, Gilead, Luitpold, Medtronic, Merck
Sharp & Dohme, Novartis, Otsuka, and ResMed; has received honoraria
from Abbott Laboratory, Amgen, AstraZeneca, Bayer, Janssen, Luitpold
Pharmaceuticals, Medtronic, Merck Sharp & Dohme, Novartis, and
ResMed; and serves on advisory boards for Amgen, Luitpold, Merck
Sharp & Dohme, and Boehringer Ingelheim. All other authors have
reported that they have no relationships relevant to the contents of this
paper to disclose. Barry Greenberg, MD, served as Guest Editor for this
paper.
Medium of Participation: Print (article only); online (article and quiz).
CME/MOC/ECME Term of Approval
Issue date: May 2019
Expiration date: April 30, 2020
https://doi.org/10.1016/j.jchf.2019.02.009
372 Hein et al. JACC: HEART FAILURE VOL. 7, NO. 5, 2019

Heart Failure Therapy and Advanced Renal Disease MAY 2019:371–82

Medical Management of Heart Failure With

Reduced Ejection Fraction in Patients With
Advanced Renal Disease
Aaron M. Hein, BS,a Julia J. Scialla, MD, MHS,a,b Daniel Edmonston, MD,a,b Lauren B. Cooper, MD, MHS,a,c
Adam D. DeVore, MD, MHS,a,b Robert J. Mentz, MDa,b

HIGHLIGHTS

Patients with HF and advanced chronic kidney disease constitute a substantial population
that experiences poor outcomes.

Evidence for HF therapies in this population is limited by study exclusion and nonstandard
definitions.

Renin-angiotensin system inhibitors and beta-blockers have yielded some promising
results, whereas mineralocorticoid receptor antagonists should generally be avoided.

Directed trials and well-powered studies are needed to examine the potential risk-benefit
balance of HF therapies.

ABSTRACT

Large randomized clinical trials (RCT) supporting guidelines for the management of heart failure with reduced ejection
fraction (HFrEF) have typically excluded patients with advanced chronic kidney disease (CKD). Patients with concomitant
advanced CKD and HFrEF experience poor cardiovascular outcomes and mortality relative to either disease in isolation
and have been shown to consistently receive lower rates of HFrEF guideline-directed medical therapy (GDMT).
This review evaluated recent evidence for the use of GDMT in patients with HFrEF and advanced CKD approaching
dialysis from RCTs and observational cohorts. The authors also discuss the limitations and challenges inherent in the
evidence for GDMT in this population, and offer guidance to clinicians for proper clinical use and future research
directions. (J Am Coll Cardiol HF 2019;7:371–82) © 2019 by the American College of Cardiology Foundation.

P atients with heart failure (HF) experience sig-

nificant morbidity and mortality associated
with chronic kidney disease (CKD). In patients
with HF with reduced ejection fraction (HFrEF),
the prevalence of CKD greater than stage $G4
(Table 1) is approximately 10% (1,2). Pre-existing HF
predisposes patients to acute kidney injury (AKI),
development of CKD, and end-stage renal disease
due to impaired renal hemodynamics (3,4). Similarly,
patients with impaired renal function are prone to so-
dium and fluid retention and thus are more likely to
develop HF (5). Comorbid CKD is an independent pre-
dictor of both short-term and long-term cardiovascu-
lar outcomes and death in patients with HF, with

From the aDepartment of Medicine, Duke University School of Medicine, Durham, North Carolina; bDuke Clinical Research
Institute, Durham, North Carolina; and the cInova Heart and Vascular Institute, Falls Church, Virginia. Dr. Scialla has received
research support from National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK111952, GlaxoSmithKline, and
Sanofi. Dr. Cooper has received research support from Abbott Laboratories. Dr. DeVore has received research support from Amgen,
the American Heart Association, the National Heart, Lung, and Blood Institute, and Novartis; and is a consultant for Novartis. Dr.
Mentz has received research support from National Institutes of Health grants U01HL125511-01A1, U10HL110312, and
R01AG045551-01A1; has received funding from Akros, Amgen, AstraZeneca, Bayer, GlaxoSmithKline, Gilead, Luitpold, Medtronic,
Merck Sharp & Dohme, Novartis, Otsuka, and ResMed; has received honoraria from Abbott Laboratory, Amgen, AstraZeneca,
Bayer, Janssen, Luitpold Pharmaceuticals, Medtronic, Merck Sharp & Dohme, Novartis, and ResMed; and serves on advisory
boards for Amgen, Luitpold, Merck Sharp & Dohme, and Boehringer Ingelheim. All other authors have reported that they have no
relationships relevant to the contents of this paper to disclose. Barry Greenberg, MD, served as Guest Editor for this paper.

Manuscript received January 27, 2019; accepted February 20, 2019.

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JACC: HEART FAILURE VOL. 7, NO. 5, 2019 Hein et al. 373
MAY 2019:371–82 Heart Failure Therapy and Advanced Renal Disease

more advanced renal disease conferring a worse prog- advanced CKD or observational studies with ABBREVIATIONS

nosis (6,7). Patients with HFrEF particularly experi- inherent limitations, as reviewed here. AND ACRONYMS

ence a greater increase in morbidity and mortality Many completed trials, subgroup analyses,
ACE = angiotensin-converting
when advanced CKD is present relative to other HF and observational studies in advanced CKD enzyme
subtypes (6). and HFrEF used serum creatinine (sCr) cutoff
ARB = angiotensin receptor
Despite the high prevalence of concomitant HFrEF values to define levels of renal insufficiency. blocker
and CKD, routine guideline-directed medical therapy Although the use of sCr is a common clinical CKD = chronic kidney disease
(GDMT) of this cohort is often lower than in the approach, sCr alone is an imperfect mea- GDMT = guideline-directed
general HFrEF population (8,9). There remains an surement of kidney function, influenced by medical therapy

unmet need to characterize challenges and recent demographic and patient-specific character- HF = heart failure
therapeutic advances from clinical trials in the HF istics such as age, sex, race, and muscle mass, HFrEF = heart failure with
population, including those with CKD, and to eval- and is used to derive direct estimates of kid- reduced ejection fraction

uate real-world evidence from registries and obser- ney function such as estimated glomerular RCT = randomized controlled

vational cohorts that can inform routine practice. filtration rate (eGFR). With widespread trial

This study evaluated contemporary published adoption of eGFR reporting and increasing aware-
research of pharmacological management of patients ness, recent observational studies and trials largely
with HFrEF and advanced CKD, defined as those with have incorporated eGFR, but challenges remain in
CKD $G4 who are not receiving renal replacement older studies.
therapy. MEDLINE papers published between January Similarly, there is increasing recognition of the
1985 and August 2018 were searched using Medical importance of proteinuria/albuminuria in the evalu-
Subject Headings (MESH) and key words, focusing on ation of kidney dysfunction in patients with HFrEF.
relevant terms for this topic (Online Appendix). We Recent studies have identified that even modest in-
also manually searched reference lists of pertinent creases in proteinuria/albuminuria are independently
reviews and studies to find any relevant citations. All associated with the development of HFrEF and with
citations were screened and evaluated by 1 reviewer morbidity and mortality in those with HFrEF (11–13).
(A.M.H.) to select relevant studies. Unfortunately, many previous studies evaluating
This review discusses the limitations of the current GDMT in patients with advanced CKD, who experi-
evidence and future research directions and offers ence increased proteinuria relative to the general
clinicians guidance regarding the safe use of GDMT in population, do not account for or report data for
this high-risk population. Discussion focuses on proteinuria. Further research should determine the
pharmacotherapy using renin-angiotensin system risk and benefits of GDMT when proteinuria is present
(RAS) inhibitors, angiotensin receptor blockers/ in those with advanced CKD.
neprilysin inhibitors (ARNIs), mineralocorticoid re- Lack of universal outcome definitions represent
ceptor antagonists (MRAs), and beta-blockers and another key limitation. For instance, AKI is a common
briefly considers device therapy in this population.
There is little to no evidence for other HF pharma-
T A B L E 1 Chronic Kidney Disease Categories
cological therapies, such as isosorbide dinitrate and
ivabradine, in advanced CKD, so these therapies were eGFR
eGFR Stages (ml/min per 1.73 m2) Terms
not included in this review. Detailed characteristics
G1 >90 Normal or high
and outcomes for relevant studies are outlined in
G2 60–89 Mildly decreased
Table 2, with studies of note highlighted in the body
G3a 45–59 Mildly to moderately decreased
of the text.
G3b 30–44 Moderately to severely decreased
G4 15–29 Severely decreased
LIMITATIONS OF CURRENT EVIDENCE IN G5 <15 Kidney failure
PATIENTS WITH HFrEF AND ADVANCED CKD Albumin-to-Creatinine Ratio

Albuminuria Albumin Excretion

Many pivotal clinical trials for guideline-directed Categories Rate (mg/24 h) (mg/mmol) (mg/g) Terms

HFrEF therapies excluded patients with severe kid- A1 <30 <3 <30 Normal to mildly increased

ney disease, resulting in limited evidence for A2 30–300 3–30 30–300 Moderately increased
A3 >300 >30 >300 Severely increased
contemporary GDMT in those with advanced CKD and
HFrEF (Central Illustration) (10). Dedicated clinical In the absence of evidence of kidney damage, neither eGFR stage G1 nor G2 fulfill the criteria for CKD. The terms
trials in advanced CKD and HFrEF are uncommon; G2 and A2 are relative to young adult levels. Adapted with permission from the Kidney Disease Improving Global
Outcomes Guidelines (2).
thus, recommendations often rely upon extrapolation eGFR ¼ estimated glomerular filtration rate.
from populations with low numbers or without

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374 Hein et al. JACC: HEART FAILURE VOL. 7, NO. 5, 2019

Heart Failure Therapy and Advanced Renal Disease MAY 2019:371–82

T A B L E 2 Outcomes for HF Therapies in Patients with HFrEF and CKD

Follow-Up Exams (n), Population

First Author, Year (Ref. #) Design Time Period and Subgroup Renal Criteria

Renin-angiotensin system inhibitors

Swedberg et al., 1990 (24) PC-RCT* SG analysis 253, 6 months NYHA functional classes IV HFrEF, sCr <3.4 mg/dl; 12% estimated
SG: sCr >1.39 mg/dl with CKD G4
Hillege et al., 2006 (25) PC-RCT SG analysis 2,680, 37.7 median Age >18 yrs, NYHA functional classes sCr <3.0 mg/dl
months II–IV, (LVEF #40%, n ¼ 1,656),
SG: eGFR #45 ml/min per 1.73 m2
Edner et al., 2015 (26) CE-OC 1,204, 1 yr LVEF #39% CKD G4–5 or sCr >2.5 mg/dl
Masoudi et al., 2004 CE-OC 1,258, 1 yr Age $65 yrs, LVEF <40%, after HF sCr >2.5 mg/dl
(Online Ref. 1) hospitalization
Berger et al., 2007 (19) CE-OC 381, 1 yr Age 35–84 yrs, with HF exacerbation CKD G4, n ¼ 238; CKD G5, n ¼ 143
(n ¼ 137 with LVEF <35%)
McAlister et al., 2004 CE-OC 754, 2.5 median yrs Outpatients with HF (57% with CKD $G3; n ¼ 118 with CKD G4–5
(Online Ref. 2) LVEF #35%)
Ahmed et al., 2012 CE-OC 541, 8 yrs Medicare cohort, LVEF #45% eGFR #38.5 ml/min per 1.73 m2
(Online Ref. 3) after HF hospitalization n ¼ 541
Angiotensin receptor blocker/
neprilysin inhibitors
Damman et al., 2018 (31) CER-RCT SG analysis 2,745 NYHA functional classes II–IV, CKD G3–4
LVEF #40%
Solomon et al., 2016 (32) Meta-analysis 14,472 IMPRESS, OVERTURE, -
PARADIGM-HF trial participants
Mineralocorticoid receptor
antagonists
Lu et al., 2016 (41) Meta-analysis 4,935 Adults with CKD CKD G1–5

Inampudi et al., 2014 (42) CE-OC 1,140, 1 yr Hospitalized patients with HF eGFR <45 ml/min per 1.73 m2
and LVEF <45%
Cooper et al., 2017 (43) CE-OC 16,848, 3 yrs Age > 65 yrs, HF hospitalization sCr >2.0 mg/dl or type 2 diabetes
mellitus (mean 1.9 mg/dl)

Beta-blockers
Ghali et al., 2009 (49) PC-RCT SG analysis 493 Age 40-80 yrs, NYHA functional II–IV, CKD $G3b (mean eGFR 36.6 ml/min
LVEF <40% per 1.73 m2)

Erdmann et al., 2001 PC-RCT SG analysis 63, 1.3 yrs NYHA functional classes III–IV, CKD G4–5
(Online Ref. 4) LVEF #35% on ACE inhibitor therapy
Castagno et al., 2010 (50) PC-RCT SG analysis 450, 1.3 yrs NYHA functional classes III–IV, CKD $G3b
LVEF #35% on ACE inhibitor therapy (mean 38.4 ml/min per 1.73 m2)
Badve et al., 2011 (51) Meta-analysis 5,972 Patients with chronic HFrEF CKD $G3

Wali et al., 2011 Meta-analysis 1,116 Patients with systolic left CKD $G3b
(Online Ref. 5) ventricular dysfunction
Nagatomo et al., 2017 (52) CE-RCT 360, 3.8 yrs Age 20–80 yrs, NYHA functional classes Stratification at eGFR 60 ml/min per
II–III, LVEF <40% 1.73 m2
Chang et al., 2013 (9) CE-OC, 2.4 median yrs 668 Age >18 yrs, newly diagnosed HFrEF, CKD $3 or proteinuria, nondialysis;
LVEF <40% 6.3% CKD G4-5
McAlister et al., 2004 CE-OC 419, 2.5 median yrs Outpatients with HF (57% with CKD $G3; n ¼ 118 with CKD G4–5
(Online Ref. 2) LVEF #35%)

The table lists trials and observational studies investigating medical therapies in patients with HFrEF and CKD. Studies not cited in the body of the text are listed in the Online References.
ACE ¼ angiotensin-converting enzyme; ACM ¼ all-cause mortality; ARNI ¼ angiotensin receptor blocker/neprilysin inhibitor; CE-OC ¼ comparative effectiveness observational cohort; CE-RCT ¼
comparative effectiveness randomized controlled trial; CI ¼ confidence interval; eGFR ¼ estimated glomerular filtration rate; G4–5 ¼ stage G4 to G5; HF ¼ heart failure; HR ¼ hazard ratio;
IMPRESS ¼ Inhibition of Metalloprotease by Omapatarilat in Randomized Exercise and Symptoms Study of Heart Failure; LVEF ¼ left ventricular ejection fraction; MACE ¼ major adverse cardiac events;
MRA ¼ mineralocorticoid receptor antagonist; NYHA ¼ New York Heart Association class; OR ¼ odds ratio; OVERTURE ¼ Omapatrilat versus Enalapril Randomized Trial of Utility in Reducing Events;
PARADIGM-HF ¼ Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure; PC-RCT ¼ placebo-controlled randomized controlled trial; RR ¼ risk ratio;
RAS ¼ renin-angiotensin system inhibitor; sCr ¼ serum creatinine; SG ¼ subgroup.

Continued on the next page

feature of decompensated HFrEF, often evaluated as must be sustained or confirmed on repeat testing.
an adverse effect or study outcome. Definitions of the Recent international guidelines in kidney disease
degree of decline, acuity, or timeframe of the change may provide standardized outcome criteria that could
in kidney function vary, and whether the changes reduce this variation in future studies (14).

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JACC: HEART FAILURE VOL. 7, NO. 5, 2019 Hein et al. 375
MAY 2019:371–82 Heart Failure Therapy and Advanced Renal Disease

T A B L E 2 Continued

Outcome(s) of Interest
Adjustment Intervention, Comparison Primary Outcome HR/RR (95% CI)

— Enalapril vs. placebo ACM 30% vs. 55%; p ¼ 0.004

— Candesartan vs. placebo Cardiovascular death, unplanned No significant interaction among candesartan, sCr, and primary
readmission, or ACM outcome (p ¼ 0.84)

Propensity matched
Multivariable regression
Risk adjustment models
Multiple logistic regression
Propensity matched
RAS inhibitor vs. no RAS inhibitor
prescription at discharge
ACE inhibitor vs. no ACE inhibitor
prescription at discharge
RAS-I vs. no RAS inhibitor prescription
in-hospital
ACE inhibitor vs. no ACE inhibitor at
discharge
RAS inhibitor at target dose vs. no RAS
inhibitor prescription at discharge
ACM HR ¼ 0.76 (0.67–0.86)
ACM RR ¼ 0.65 (0.51–0.80)
30-day ACM CKD G4: 9.4% vs. 18.5%; p ¼ 0.008
CKD G5: 11.9% vs. 22.8%; p ¼ 0.03
1-yr ACM OR ¼ 0.46 (0.26–0.82)
ACM HR ¼ 0.82 (0.70–1.00); reduced ACM for those at target doses

— Valsartan/sacubitril vs. enalapril Cardiovascular death and HF HR ¼ 0.79 (0.69–0.90)

hospitalization
ARNI vs. single RAS inhibitor therapy Adverse events Increased symptomatic hypotension, but decreased serum
potassium elevation and renal impairment

— MRA vs. non-MRA treatment
Propensity-matched
Inverse probability-weighted
proportional models
Spironolactone vs. no spironolactone
at discharge
MRA vs. no MRA prescription at
discharge
ACM, MACE, hyperkalemia
1-yr all-cause readmission
ACM (30-day, 1-yr, 3-yrs)
ACM: RR ¼ 0.78 (0.62–0.97)
MACE: RR ¼ 0.65 (0.50–0.83)
Hyperkalemia: RR ¼ 2.32 (1.83–2.94)
Not significant in patients with HF
HR ¼ 1.36 (1.13–1.63)
eGFR <15 ml/min per 1.73 m2: HR ¼ 4.75 (1.84–12.28)
No differences in any ACM;
3-yr all-cause readmission: HR ¼ 0.94 (0.89–0.98)
Long-term hyperkalemia readmission: HR ¼ 1.30 (95% CI: 1.11–
1.53)

— Metoprolol succinate vs. placebo ACM, HF mortality, all-cause ACM: HR ¼ 0.41 (95% CI: 0.25–0.68)
hospitalization HF mortality: HR ¼ 0.25 (0.10–0.62)
All-cause hospitalization: HR ¼ 0.61 (0.47–0.79)
— Bisoprolol vs. placebo ACM RR ¼ 0.59 (0.30–1.18)l more permanent treatment
withdrawals in eGFR <30 ml/min per 1.73 m2
— Bisoprolol vs. placebo ACM, composite of ACM or HF HR ¼ 0.71 (0.48–1.05)
hospitalization ACM or HF hospitalization: HR ¼ 0.72 (0.53–0.99)
— Beta-blocker vs. placebo ACM RR ¼ 0.72 (0.64–0.80)
Cardiovascular mortality: RR ¼ 0.66 (0.49–0.89)
— Carvedilol vs. placebo ACM HR ¼ 0.94 (0.72–1.23)
HF mortality: HR ¼ 0.86 (0.61–1.21)
— 2.5 mg vs. 5 mg vs. 20 mg Change in LVEF No difference in LVEF increase between eGFR >60 ml/min per
carvedilol 1.73 m2 and eGFR <60 ml/min per 1.73 m2 for all groups
Nested covariable models New user of beta-blocker vs. ACM HR ¼ 0.75 (0.51–1.12)
no beta-blocker Death or HF hospitalization: HR ¼ 0.67 (0.51–0.88)
Multiple logistic regression Beta-blocker vs. no beta-blocker 1-yr ACM OR ¼ 0.40 (0.23–0.70)
prescription at discharge

Furthermore, worsening renal function suggestive of
AKI may not reflect true kidney injury in decom-
pensated HFrEF or during initiation of RAS inhibitor
therapy (15,16). Conversely, improving measurements
of function during decompensated HFrEF have been
associated with poor outcomes, reflecting the uncer-
tainty surrounding renal function measurement in
this clinical setting (17).
Importantly, many results from observational
studies are limited by potential confounding, as the
sickest, most fragile patients, already at increased
risk for poor outcomes, may be less likely to receive
GDMT due to concerns for adverse effects. This reality
may result in attribution of morbidity and mortality
benefit to GDMT in an observational cohort that is
truly due to unaccounted factors in participant

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376 Hein et al.
Heart Failure Therapy and Advanced Renal Disease
baseline status. Circumventing this limitation is
challenging and requires high-quality data sources
with capture of relevant clinical variables and
rigorous analytic techniques including new-user de-
signs, propensity scoring, and marginal structural
models, among others.
Several medications can cause adverse effects in
advanced CKD that affect the risk-benefit calculation.
For instance, RAS inhibitor therapies may result in or
exacerbate hyperkalemia or precipitate AKI in this
vulnerable population. Due to renal clearance of
many medications used in HFrEF, dose adjustments
and monitoring may vary greatly based on the degree
of renal impairment, as outlined in Figure 1. Concerns
for adverse events and polypharmacy often shift the
cost-benefit ratio of medication prescription for these
patients.
Thus, it is known that those with CKD and HFrEF
experience worse outcomes on average, and unsur-
prisingly, they receive lower rates of GDMT. A recent
national registry study of patients with end-stage
renal disease found 40% of patients approaching
dialysis were receiving an angiotensin-converting
enzyme (ACE) inhibitor or an angiotensin receptor
blocker (ARB), regardless of HFrEF history, and 60%
to 75% of those with HFrEF were receiving a beta-
blocker (9). Other studies in outpatients with
advanced CKD and HF found prescription rates of
50% to 70%, often 20% lower than their non-CKD
counterparts (18,19). Studies have shown that GDMT
improves after initiation of dialysis (19). Given the
limited life expectancy and comorbid conditions
often experienced by these patients, in combination
with limited clinical trial evidence for efficacy in this
group, clinicians may be dissuaded from initiating
GDMT.
RENIN-ANGIOTENSIN SYSTEM INHIBITORS
ACE inhibitors and ARBs in large randomized
controlled trials (RCTs) have decreased cardiovascu-
lar events, HF hospitalizations, and mortality, while
improving quality of life in those with HFrEF (20,21).
However, many RCTs that established ACE inhibitors
and ARBs as integral therapies excluded patients with
advanced CKD (10). Although subgroup analyses of
many major trials suggested benefit in those with
CKD $G3 similar to or greater than that in the larger
trial (22,23), data for those with advanced CKD are
scarce.
Of the RAS inhibitor RCTs, only a small proportion
of 2 trials included patients with advanced CKD. In a
subgroup analysis of the CONSENSUS (Cooperative
North Scandinavian Enalapril Survival Study),
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JACC: HEART FAILURE VOL. 7, NO. 5, 2019
MAY 2019:371–82
enalapril significantly reduced all-cause mortality in
patients with sCr >1.39 mg/dl compared with placebo
but did not have a significant effect in those with
sCr <1.39 mg/dl (24). A post hoc CHARM (Candesartan
in Heart Failure-Assessment of Reduction in Mortal-
ity and Morbidity; NCT00634400) analysis found no
interaction between renal function and the cardio-
vascular benefits of candesartan in those with HF and
CKD $G3b. Candesartan resulted in a greater
absolute risk reduction in those with significant
renal dysfunction who experienced overall worse
outcomes (25).
Only observational data have been reported for the
population with advanced CKD and HFrEF. In a
propensity-matched cohort study of patients with
HFrEF and CKD $G4, RAS inhibitor therapy was
associated with increased 1-year survival compared
with nonusers, with efficacy similar to that seen in
patients without CKD, particularly in those with New
York Heart Association functional class III symptoms
(26). Another cohort study found RAS inhibitor ther-
apy during HF hospitalization was associated with
decreased 30-day all-cause mortality in patients with
CKD G4 to G5. That study did not independently
evaluate patients with HFrEF, however (19). Other
studies have demonstrated improved outcomes and a
potentially higher absolute risk reduction in this
population using RAS inhibitor therapy (Table 2).
Although the aforementioned studies suggest
therapeutic benefit for RAS inhibitor therapy in those
with HFrEF and advanced CKD, concern for increased
adverse renal outcomes and electrolyte disturbances
are substantial. In a subgroup of patients with un-
specified HF from a population-based study, those
with “moderate-to-severe” CKD had a higher risk of
an increase of >30% in sCr relative to that in other
groups, and this adverse event conferred an increased
risk of death in those with comorbid HF (27).
Furthermore, a meta-analysis of patients with
CKD $G3, in which HF history was unspecified, found
a roughly doubled risk of hyperkalemia with RAS in-
hibitor monotherapy relative to that of placebo or
active controls, although RAS inhibitor monotherapy
also reduced all-cause mortality (28). However, in an
outpatient cohort with HFrEF and CKD G3 to G4,
chronic RAS inhibitor therapy or up-titration was not
associated with worsened renal outcomes or hyper-
kalemia after 1 year, although that study may have
excluded participants with previous adverse effects
related to RAS inhibitor administration (29).
Recently, ARNIs have been shown to effectively
reduce HFrEF hospitalizations and mortality (30).
However, the tolerability and safety of this new class
of medications in patients with comorbid advanced
JACC: HEART FAILURE VOL. 7, NO. 5, 2019 Hein et al. 377
MAY 2019:371–82 Heart Failure Therapy and Advanced Renal Disease

C ENTR AL I LL U STRA T I ON Limitations in the Evidence for Patients With HFrEF and Advanced CKD

Hein, A.M. et al. J Am Coll Cardiol HF. 2019;7(5):371–82.

Current challenges affecting the paucity of evidence in patients with HFrEF and advanced CKD contributing to reduced utilization of medical therapy in this vulnerable
population. CKD ¼ chronic kidney disease; HFrEF ¼ heart failure with reduced ejection fraction.

CKD is unclear. A PARADIGM (Prospective Compari-
son of ARNI with ACEI to Determine Impact on
Global Mortality and Morbidity in Heart Failure;
NCT01035255) trial subgroup analysis found patients
with CKD G3 receiving sacubitril/valsartan had
decreased rates of cardiovascular mortality and HF
hospitalization compared to those receiving enalapril
in addition to reductions in all-cause mortality,
noting a higher absolute risk reduction than those
without CKD (30,31). Furthermore, the rate of CKD
progression was reduced in those treated with sacu-
bitril/valsartan compared with those receiving ena-
lapril, although those patients also experienced an
increase in urinary albumin/creatinine ratio. Notably,
the increase in albuminuria did not affect the 30-day
risk of cardiovascular mortality or HF hospitalization
(31). Despite these encouraging findings, the study
excluded patients with CKD G4 to G5, leaving its
applicability to patients with advanced CKD untested.
Regarding adverse events, 1 meta-analysis found
rates of renal impairment and hyperkalemia were
decreased in patients receiving ARNI therapy relative
to those in patients with HFrEF taking ACE inhibitor
therapy, although ARNI therapy resulted in increased
rates of symptomatic hypotension (32).
RECOMMENDATIONS AND
FUTURE RESEARCH DIRECTIONS
Given the weak evidence base for ACE inhibitor/ARBs
in this population, current American College of Car-
diology Foundation/American Heart Association
(ACCF/AHA) guidelines suggest caution in using RAS
inhibitor therapy in those with comorbid CKD $G4

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378 Hein et al. JACC: HEART FAILURE VOL. 7, NO. 5, 2019

Heart Failure Therapy and Advanced Renal Disease MAY 2019:371–82

F I G U R E 1 Recommended Dosage Adjustments and Monitoring Considerations in Patients With HFrEF and CKD Stages G4 to G5

Dosage adjustments and monitoring adjustments are shown for patients with HFrEF and CKD stages G4 to G5. Adjustments refer to initial dosage with titration as
tolerated based on safety. Dosing adjustments primarily derived from manufacturer labeling and package insert data when possible. †Reduced rate of titration
recommended for captopril. ‡Use with caution. §Twice daily dosing. ACE-Is ¼ angiotensin-converting enzyme inhibitor; ARNI ¼ angiotensin receptor blocker/neprilysin
inhibitor; eGFR ¼ estimated glomerular filtration rate; HFrEF ¼ heart failure with reduced ejection fraction; MRA ¼ mineralocorticoid receptor antagonist.

(33). Kidney Disease: Improving Global Outcomes
(KDIGO) guidelines recommend specialist supervision
for the use of RAS inhibitor in patients with CKD $G4,
a reduced starting dose for those with CKD $G3b,
eGFR monitoring, and serum potassium measure-
ment within 1 week of initiation; KDIGO guidelines
also advise against routine discontinuation once
eGFR reaches <30 ml/min/1.73 m 2 (2,34). However,
many of the included studies suggest a survival
benefit with the use of RAS inhibitor therapy in this
population, and the introduction of therapies to pre-
vent hyperkalemia may lessen safety concerns (35).
Robust trials with adequate safeguards are needed to
confirm the potential benefits in patients with HFrEF
and advanced CKD.
Current guidelines do not comment on the use of
ARNI therapy in those with CKD but suggest the po-
tential for renal insufficiency with this medication
(33). Although the present evidence is reassuring for
ARNI therapy in those with CKD G3, further studies
are needed to elucidate whether these beneficial ef-
fects extend to those with comorbid CKD $G4.
MINERALOCORTICOID RECEPTOR
ANTAGONISTS
In major RCTs, MRAs have consistently improved
symptoms while hospitalizations and
have been reduced in patients with HFrEF (36,37).
Although subanalyses of major RCTs showed cardio-
vascular benefits in those with mild to moderate CKD
and HFrEF (10,38,39), concern for adverse effects,
notably the heightened risk of hyperkalemia observed
after the completion of the Randomized Aldactone
Evaluation Study (40), resulted in the exclusion of
patients with advanced CKD and HFrEF from major
trials. Although a meta-analysis of 12 studies reported
use of MRA in a general population of patients with
CKD $G3 was associated with reduced all-cause
mortality, these mortality benefits were not signifi-
cant in studies incorporating an HF subanalysis (41).
Observational studies of MRA use in patients with
HFrEF and advanced CKD have also been scant, but
mainly raise concerns about adverse effects without
clear evidence of benefit. A propensity-matched
analysis of the Alabama Heart Failure registry found
MRA prescription at discharge for hospitalized pa-
tients with HFrEF and CKD $G3b was associated with
increased readmission rates, as well as the combined
endpoint of 1-year all-cause mortality or readmission;
the risk of 1-year all-cause readmission was greatly
increased in those with CKD G5 not receiving dialysis
(42).
A study incorporating the Get With The Guidelines-
HF registry and Medicare claims found MRA
discharge prescription, after adjustment for patient
mortality characteristics and concomitant medication use, was
not associated with differences in 30-day, 1-year, or

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JACC: HEART FAILURE VOL. 7, NO. 5, 2019
MAY 2019:371–82
3-year mortality for hospitalized patients with HF
and comorbid diabetes mellitus type 2 or an sCr
>2.0 mg/dl. In contrast, MRA therapy was associated
with modest decreases in 1-year and 3-year all-cause
readmissions. Increased risk of short- and long-term
hyperkalemia readmissions was also observed (43).
RECOMMENDATIONS AND FUTURE
RESEARCH DIRECTIONS
ACCF/AHA guidelines recommend against using MRA
therapy in men with sCr >2.5 mg/dl and in women
with sCr >2.0 mg/dl due to concern for hyperkalemia,
AKI, and inadequate evidence from RCTs (44). KDIGO
guidelines suggest a reduced starting dose for those
with CKD $G3b, eGFR monitoring, and serum potas-
sium measurement within 1 week of initiation but
advise against routine discontinuation once eGFR
reaches <30 ml/min/1.73 m 2 (2). The reviewed studies
suggest that results of MRA therapy in those with
HFrEF and advanced CKD raise valid safety concerns
without clear benefit independent of concomitant use
of RAS inhibitor therapy.
NOVEL POTASSIUM BINDERS AS
ADJUNCT THERAPY
The emergence of novel potassium binders such as
patiromer and sodium zirconium cyclosilicate may
mitigate the hyperkalemia associated with RAS in-
hibitor agents, particularly in vulnerable CKD pop-
ulations (35). In a recent trial, patients with CKD G3 to
G4 receiving RAS inhibitors who experienced
elevated serum potassium levels received either
patiromer or placebo. In the HF subgroup, patiromer
therapy resulted in a significant decrease in serum
potassium levels and hyperkalemia recurrence (45).
Patiromer therapy may also decrease the risk of life-
threatening hyperkalemia in those treated with
MRAs and recently has been tolerated in CKD patients
up-titrated on spironolactone therapy (46). Adjunc-
tive use of these therapies may help shift the feasi-
bility of the use of RAS inhibitors in this group.
However, these therapies also require consideration
of potential adverse events, such as binding of con-
current oral medications, gastrointestinal upset, hy-
pomagnesemia with patiromer, and worsening edema
from an increased sodium load with sodium zirco-
nium cyclosilicate (35).
BETA-BLOCKERS
Beta-blockers have consistently reduced morbidity
and mortality in patients with HFrEF (47,48). Large
RCTs evaluating beta-blocker use in HFrEF often
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Hein et al. 379
Heart Failure Therapy and Advanced Renal Disease
included more patients with advanced CKD than in
RAS inhibitor trials, likely due to decreased safety
concerns with initiation (10). Multiple subgroup ana-
lyses support the benefits of beta-blockers in those
with advanced CKD. Analysis of MERIT-HF (Meto-
prolol CR/XL Randomised Intervention Trial in
Congestive Heart Failure) found participants with
CKD $G3b who received metoprolol had significant
decreases in all-cause mortality, HF mortality, and
all-cause hospitalization (49). One analysis of the
CIBIS-II (Cardiac Insufficiency Bisoprolol Study II)
trial likewise found patients with CKD $G3b had
decreased risk of either all-cause mortality or HF
hospitalization, with a lower number needed to treat
due to poor outcomes in this subgroup (50).
In a large meta-analysis, beta-blocker therapy in
patients with CKD $G3a reduced all-cause and car-
diovascular mortality risk but increased the risk of
bradycardia and hypotension; no differences in
hyperkalemia were noted (51). The effect of increased
LVEF with carvedilol treatment seen overall after 56
weeks was not blunted for patients with CKD $G3a in
the Japanese congestive heart failure trial, which
randomized patients with HFrEF to receive 3
different doses of carvedilol (52). Each of those
studies suffered from few included participants with
CKD G4 to G5, some below 10%, which limits the
generalizability to those with advanced CKD.
Observational studies involving beta-blocker ther-
apy in patients with CKD and HFrEF have also been
hindered by small proportions of patients with
advanced CKD and have reported mixed results for
mortality benefits. For example, in a retrospective
study of 668 patients with HFrEF and CKD $G3, beta-
blocker therapy was not associated with decreased
all-cause mortality, but it was associated with a
decreased risk of the composite outcome of death or
HF hospitalization. There were only 47 patients with
CKD G4 to G5 in that study, however (53).
RECOMMENDATIONS AND
FUTURE RESEARCH DIRECTIONS
Beta-blockers in HFrEF patients have often shown
beneficial effects on morbidity and mortality in those
with CKD. ACCF/AHA guidelines support beta-blocker
therapy in patients with comorbid CKD and HF, and
KDIGO guidelines, while recommending beta-blocker
therapy, suggest dose reduction by 50% for those
with CKD G4 to G5 (2,34,44). However, although
many findings from subgroup analyses of RCTs are
promising, there is conflicting observational evidence
for efficacy in those with advanced CKD, primarily
due to a low number of participants included. Careful
380 Hein et al. JACC: HEART FAILURE VOL. 7, NO. 5, 2019

Heart Failure Therapy and Advanced Renal Disease MAY 2019:371–82

monitoring for side effects such as bradyarrhythmia CONCLUSIONS

and hypotension is suggested with beta-blocker
initiation in this population. The lack of high-quality evidence for GDMT in pa-
tients with HFrEF and advanced CKD leaves little
IMPLANTABLE DEVICE THERAPY
guidance for the management of this vulnerable
population. GDMT in this population can yield
Device therapy in patients with HFrEF and advanced
dangerous side effects, but overall poor outcomes
CKD is another area of continued controversy, as
may result in a greater absolute therapeutic benefit.
multiple trials have shown benefit in patient pop-
Although RAS inhibitor therapy in patients with
ulations with HFrEF, but application to the advanced
HFrEF and advanced CKD has generally shown posi-
CKD population is less clear. The risk of sudden car-
tive outcomes, the role of MRAs is less clear. ARNI
diac death increases with worsening kidney
therapy requires thorough evaluation in CKD but may
dysfunction (54), suggesting patients with advanced
promise decreased safety concerns compared with
CKD may benefit from device therapy with an
ACE inhibitor/ARB therapy. Potassium binding ther-
implantable cardioverter-defibrillator (ICD). Howev-
apies may prove beneficial as adjunctive therapy to
er, a meta-analysis of 3 primary prevention ICD RCTs
RAS inhibitor therapies in patients with CKD experi-
found no survival benefit from ICD therapy in pa-
encing hyperkalemia. Beta-blockers, although often
tients with CKD $G3 (55). Also, a secondary analysis
beneficial in populations with comorbid CKD-HFrEF,
of the Multicenter Automatic Defibrillator Implanta-
require careful monitoring for side effects, particu-
tion Trial-II found ICD therapy was not associated
larly in patients nearing dialysis. Finally, consider-
with decreased mortality in patients with eGFR <35
2 ation of benefit from device therapy in this
ml/min per 1.73 m (54). Another meta-analysis of 4
population must weigh the elevated risks of device
primary prevention ICD trials found the therapeutic
placement, life expectancy, and comorbidity burden.
benefit was attenuated with increasing comorbidity
Clearly, adequately powered clinical trials with care-
burden (56). Although 1 study showed eGFR
ful adverse event monitoring and follow-up are
improvement with cardiac resynchronization therapy
required to evaluate the benefits of these therapies.
in those with CKD G3 (57), no studies specifically
evaluated the benefit of cardiac resynchronization
therapy in advanced CKD (58). In this population, ADDRESS FOR CORRESPONDENCE: Dr. Robert J.
factors such as life expectancy and periprocedural Mentz, Duke Clinical Research Institute, 2301 Erwin
risk must be balanced when considering the potential Road, P.O. Box 17969, Durham, North Carolina 27715.
benefit of device therapy. E-mail: robert.mentz@duke.edu.

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