Managing Heart Failure in Patients On Dialysis
Managing Heart Failure in Patients On Dialysis
Managing Heart Failure in Patients On Dialysis
1 2023
Review Article
Managing Heart Failure in Patients on Dialysis:
State-of-the-Art Review
MUHAMMAD SHAHZEB KHAN, MD, MSC,1 AYMEN AHMED, MBBS,2 STEPHEN J. GREENE, MD,1,3 MONA FIUZAT, PharmD,1
MICHELLE M. KITTLESON, MD, PhD,4 JAVED BUTLER, MD, MPH, MBA,5,6 GEORGE L. BAKRIS, MD,7 AND
GREGG C. FONAROW, MD8
Durham, Los Angeles, Jackson, Dallas, and Chicago, USA; and Karachi, Pakistan
ABSTRACT
Heart failure (HF) and end-stage kidney disease (ESKD) frequently coexist; 1 comorbidity wor-
sens the prognosis of the other. HF is responsible for almost half the deaths of patients on
dialysis. Despite patients’ with ESKD composing an extremely high-risk population, they have
been largely excluded from landmark clinical trials of HF, and there is, thus, a paucity of data
regarding the management of HF in patients on dialysis, and most of the available evidence is
observational. Likewise, in clinical practice, guideline-directed medical therapy for HF is often
down-titrated or discontinued in patients with ESKD who are undergoing dialysis; this is due
to concerns about safety and tolerability. In this state-of-the-art review, we discuss the avail-
able evidence for each of the foundational HF therapies in ESKD, review current challenges
and barriers to managing patients with HF on dialysis, and outline future directions to opti-
mize the management of HF in these high-risk patients. (J Cardiac Fail 2023;29:87 107)
Key Words: Heart failure, dialysis, chronic kidney disease, end-stage kidney disease.
Approximately half of the patients with heart disease (ESKD) requiring dialysis have HF.3,4 The
failure (HF) have coexisting chronic kidney disease prognosis of patients with both conditions is sub-
(CKD).1,2 Likewise, up to 70% of the patients with stantially worse than those with either condition
CKD and 36% of the patients with end-stage kidney alone. Cardiovascular disease, including HF,
accounts for approximately 50% of the deaths in
patients undergoing dialysis.5 Beta-blockers, angio-
From the 1Division of Cardiology, Duke University School of
Medicine, Durham, NC, USA; 2Division of Medicine, Dow Univer- tensin receptor neprilysin inhibitors (ARNIs), renin-
sity of Health Sciences, Karachi, Pakistan; 3Duke Clinical Research angiotensin-aldosterone system (RAAS) inhibitors,
Institute, Durham, NC, USA; 4Department of Cardiology, Smidt mineralocorticoid receptor antagonists (MRAs) and
Heart Institute-Cedars Sinai Medical Center, Los Angeles, CA,
USA; 5Department of Medicine, University of Mississippi Medical sodium-glucose cotransporter-2 (SGLT2) inhibitors
Center, Jackson, Mississippi, USA; 6Baylor Scott and White reduce mortality rates in patients with HF with
Research Institute, Dallas, TX, USA; 7Department of Medicine, reduced ejection fraction (HFrEF). However,
University of Chicago Medicine, Chicago, IL and 8Ahmanson-
UCLA Cardiomyopathy Center, David Geffen School of Medicine, patients with HF and ESKD have been excluded
University of California Los Angeles, Los Angeles, CA, USA. from landmark trials of all these therapies. Guide-
Manuscript received July 10, 2022; revised manuscript received line-directed medical therapy (GDMT) in patients
August 28, 2022; revised manuscript accepted September 20,
2022. with HFrEF who are on dialysis is often withheld or
Reprint requests: Gregg C. Fonarow, MD. Ahmanson-UCLA not uptitrated to recommended target doses due
Cardiomyopathy Center, David Geffen School of Medicine, to safety and tolerability concerns and lack of avail-
University of California Los Angeles, Los Angeles, CA; Tel: 310
206-9112 E-mail: [email protected] able clinical trial data. Similarly, patients with HF
1071-9164/$ - see front matter and ESKD are not eligible for initiation of multiple
© 2022 The Author(s). Published by Elsevier Inc. This is an open GDMTs according to current practice guidelines.
access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/) Although some randomized clinical trials (RCTs)
https://doi.org/10.1016/j.cardfail.2022.09.013 have evaluated the efficacy of GDMT in patients
87
88 Journal of Cardiac Failure Vol. 29 No. 1 January 2023
Fig. 1. Summary of current evidence regarding the use of various HF therapies for patients with HF and on dialysis. ACE,
angiotensin-converting enzyme; ARB, angiotensin receptor blockers; ARNI, angiotensin receptor neprilysin inhibitor; BNP,
brain natriuretic peptide; CABG, coronary artery bypass grafting; CRT, cardiac resynchronization therapy; CV, cardiovascu-
lar; eGFR, estimated glomerular filtration rate; HF, heart failure; ICD, implantable cardioverter defibrillator; IV, intrave-
nous; LVEDD, left ventricular end diastolic diameter; LVEDV, left ventricular end diastolic volume; LVEF, left ventricular
ejection fraction; LVESV, left ventricular end systolic volume; MI, myocardial infarction; MRA, mineralocorticoid receptor
antagonists; NYHA, New York Heart Association; RCT, randomized controlled trial; SGLT2, sodium-glucose cotransporter-2.
mortality (risk ratio [RR], 0.73 [0.54 0.97]) cardiovas- blockers in patients with HF and ESKD.22 25 Thus,
cular mortality (RR, 0.44 [0.29 0.68]), and hospital- the choice of evidence-based beta-blocker in
izations (RR, 0.61 [0.48 0.78]) in patients on dialysis, patients with HF and ESKD (bisoprolol, carvedilol or
and the included observational studies (n = 9) also sustained-release metoprolol) should be based on
demonstrated significant reductions in all-cause tolerability and availability rather than on clinical-
mortality (RR, 0.86 [0.80 0.92]).20 trial evidence.
Important factors to consider when prescribing
beta-blockers to patients with HF and on dialysis are
Angiotensin Receptor Neprilysin Inhibitors
their cardioselectivity and dialyzability.21 Cardiose-
lective beta-blockers include atenolol, bisoprolol In post hoc or observational analyses, sacubitril/
and metoprolol; noncardioselective beta-blockers valsartan is effective and well tolerated in patients
include propranolol, carvedilol, labetalol, pindolol, with eGFRs 30 60 mL/min/1.73 m2.26,27 A single-cen-
nadolol, and timolol.21 Highly dialyzable beta-block- ter observational study of 110 patients with HF on
ers are atenolol, bisoprolol, acebutolol, nadolol, and HD noted that patients taking sacubitril/valsartan
metoprolol, whereas poorly dialyzable beta-blockers had improved improved LVEF (baseline, 35.1%; 12
are carvedilol, labetolol and propranolol.21 There is months, 49.8%), left ventricular mass index (base-
no clear evidence of differential benefit of beta- line, 167.8 g/m; 12 months, 154.9 g/m), left
90 Journal of Cardiac Failure Vol. 29 No. 1 January 2023
Table 1. Completed RCTs and Key Observational Studies Evaluating HF Therapies Among HF Patients on Dialysis
Sample Follow-up
Study Name Year Intervention Control Size Population Key Findings Safety Concerns (months)
Sample Follow-up
Study Name Year Intervention Control Size Population Key Findings Safety Concerns (months)
Taheri et al. 2012 Spironolactone Placebo 18 Patients with HFrEF Significant increase in No significant risk of 6
(LVEF45%) and NYHA LVEF hyperkalemia
class III or IV HF on
CAPD, having a serum
potassium 5.5 mEq/L
Selectd observational studies evaluating HF patients on dialysis
Tang et al. 2016 Beta-blockers, Nonusers of beta- 3400 Patients with HF on long- Significant reduction Not reported NA
namely carvedi- blockers term HD (26 HD ses- in the risk of all-
Sample Follow-up
Study Name Year Intervention Control Size Population Key Findings Safety Concerns (months)
Tang et al. 2013 RAS blockers (ACE No RAAS blockers 4,771 Patients with HF on long- Significant reductions Not reported 36
inhibitors and term HD ( 26 HD ses- in the risk of all-
ARBs) sions cause and cardiovas-
within 3 months after cular mortality
initiating HD)
Berger et al. 2007 ACE inhibitors and NA 2,169 Patients with chronic HF No significant reduc- Not reported 12
ARBs and CKD with data tions in mortality at
available for weight and 30 days or 1 year
serum creatinine among dialysis
enabling to calculate patients with HF
serum GFR
Lee et al. 2019 MRA NA 3464 ESKD patients on HD hav- Significant increase in Not reported NA
ing HF at ESKD inci- the risk of mortality;
dence in the USRDS no significant effect
between 2006 2014 on time to first HF
admission or time to
first hyperkalemia
admission
Pun et al. 2015 ICD no ICD 303 Patients aged 65 years No significant reduc- Not reported 56.4 (ICD registry);
with HFrEF (LVEF 35%) tions in mortality at 34.8 (GWTG-HF
and documented car- 1 and 3 years registry)
diomyopathy receiving
chronic dialysis treat-
ment; patients with
NYHA class IV symp-
toms, CABG 90 days
before implant, new-
onset HF (<3 months)
and MI 40 days before
implant were excluded
Hiremath et al. 2010 ICD no ICD 100 ESKD patients with ICD Significant reduction Not reported NA
and ESKD patients with in the risk of all-
left ventricular dysfunc- cause mortality
tion (LVEF <35%) on
dialysis for > 3 months
Friedman et al. 2013 CRT Matched control 15 Patients with ESKD and Significant increase in Not reported 36
HFrEF (LVEF <35%), on the risk of all-cause
dialysis having NYHA mortality and all-
functional class III or IV cause hospitaliza-
and QRS duration of tions but no signifi-
>120 ms cant effect on HF
hospitalizations
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blockers; ARNI, angiotensin receptor neprilysin inhibitor; CABG, coronary artery bypass grafting; CAPD, continuous
ambulatory peritoneal dialysis; CKD, chronic kidney disease; CRT, cardiac resynchronization therapy; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; GWTG-HF,
Get with the Guidelines-Heart Failure; HD, hemodialysis; HF, heart failure; ICD, implantable cardioverter defibrillator; KCCQ, Kansas City Cardiomyopathy Questionnaire; LAD, left atrial
diameter; LVEDD, left ventricular end diastolic diameter; LVEDV, left ventricular end diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end systolic volume; MI,
myocardial infarction; MRA, mineralocorticoid receptor antagonists; NA, not applicable; NT-proBNP, N-terminal pro b-type natriuretic peptide; NYHA, New York Heart Association; PD, peri-
toneal dialysis; RAS, rennin angiotensin-system; RCT, randomized controlled trial.
Managing Heart Failure in Patients on Dialysis: State-of-the-Art KHAN et al 93
ventricular end diastolic diameter (baseline, 52.2 Although not specific to patients with HF, RCTs
mm; 12 months, 51.5 mm), and LVESD (baseline, evaluating ACE inhibitors in patients receiving dialy-
35.9 mm; 12 months, 36.9 mm), as well as in Kansas sis have produced mixed findings. In the Fosinopril
City Cardiomyopathy Questionnaire (KCCQ) scores in Dialysis (FOSIDIAL) trial of 397 patients with left
and New York Heart Association (NYHA) functional ventricular hypertrophy (LVH) on HD, fosinopril
classes (Table 1).28 However, the safety and long- failed to reduce the risk of the primary endpoint of
term efficacy of sacubitril/valsartan in patients with composite of cardiovascular death, nonfatal myocar-
HF and ESKD and those on dialysis has not been dial infarction, unstable angina, stroke, revasculari-
evaluated in any RCT to date. zation, or hospitalization due to HF.33 Similar
In contrast to these analyses demonstrating a ben- findings were observed in the Hemodialysis (HEMO)
eficial effect of ARNIs in patients with HF and ESKD, trial.34 In fact, the use of ACE inhibitors increased
a subgroup analysis of a retrospective multicenter the risk of hospitalization for HF (HR, 1.41
study of 618 dialysis patients with HFrEF in Taiwan [1.11 1.80]) in the HEMO trial.34 The lack of benefit
demonstrated that ARNIs were associated with of ACE inhibitors and ARBs in patients with dialysis
increased risk of hospitalization for HF (HR, 1.97 was confirmed in a meta-analysis of 11 studies
[1.36 2.85]) and composite of hospitalization for HF including 1856 patients, though a subgroup analysis
and all-cause death (HR, 1.73 [1.23 2.44]) compared revealed that ARBs reduced the risk of HF events by
with ACE inhibitors/ARBs (Table 1).29 33% (RR, 0.67 [0.47 0.93]).35 However, it must be
The lack of reliable evidence regarding the effi- emphasized that these studies comprised patients
cacy and safety of ARNI treatment in patients with on dialysis, and HF was not required for study entry.
HF and ESKD requiring dialysis warrants future Observational studies including HF patients on
investigation and, fortunately, there are 3 ongoing dialysis have also yielded conflicting results. A
trials to assess the safety and efficacy of sacubitril/ nationwide survey and propensity analysis including
valsartan in patients with HF and on dialysis: 4771 Taiwanese patients with chronic HF and on
NCT05243199 (Sacubitril/Valsartan for Dialysis dialysis showed that ACE inhibitors and ARBs
Patients With CKD5 Stage Complicated With Heart reduced all-cause (HR, 0.80 [0.72 0.89]) and cardio-
Failure: A Prospective, Randomized, Controlled Mul- vascular mortality (HR, 0.76 [0.64 0.90]).36 Con-
ticenter Study); NCT04572724 (The Effect of Sacubi- versely, a retrospective analysis of 2169 patients
tril/Valsartan on Cardiovascular Events Outcome in from the Minnesota Heart Survey showed that ACE
Maintenance Dialysis Patients With Heart Failure inhibitors or ARBs did not confer any survival bene-
and Efficacy Prediction of Baseline LVEF Value: A fits at 30 days or 1 year in patients on dialysis and
Prospective Cohort Study); and NCT04458285 (Effi- hospitalized with HF (Table 1).37 Given that most
cacy and Safety of Sacubitril/Valsartan in Mainte- ACE inhibitors are dialyzable, surveyed physicians
nance Hemodialysis Patients With Heart Failure prefer ARBs.35 However, current evidence does not
[ESARHD-HF]) (Table 2). Importantly, 2 of these trials offer reliable guidance regarding the use of ACE
(NCT05243199 and NCT04572724) have important inhibitors and ARBs in patients with ESKD and HF.
clinical endpoints (cardiovascular death and hospi-
talization for HF) as primary outcomes.
MRAs
Prescription rates of MRAs range from 33% in
ACE Inhibitors and ARBs
patients with HFrEF in the ambulatory setting to
ACE inhibitors and ARBs reduce cardiovascular 45% in patients at discharge post-HF
mortality rates and hospitalizations due to HF in hospitalization.38,39 Even when prescribed, titration
patients with HFrEF according to several RCTs.30,31 is often limited by the associated risk of hyperkale-
However, their use in patients with HF and on dialy- mia.40 These concerns are heightened in patients
sis has stayed limited due to conflicting findings and with HF and on dialysis. Two small RCTs have been
the paucity of reliable evidence in this population conducted to assess the efficacy and safety of MRAs
(Table 1). There is 1 RCT of ARB use in 332 patients in patients with HFrEF on dialysis. In 16 patients with
with HFrEF and ESKD.32 In this 3-year multicenter HFrEF on HD, spironolactone (25 mg/day) signifi-
Italian trial, telmisartan significantly reduced all- cantly increased mean LVEF and decreased mean LV
cause mortality rates (HR, 0.51 [0.32 0.82]), cardio- mass without increasing the risk of hyperkalemia
vascular mortality (HR, 0.42 [0.38 0.61]), and hospi- (reported in only 2 patients in the placebo group)
talization for chronic HF (HR, 0.38 [0.19 0.51]).32 (Table 1).41 Similarly, in 18 patients with HFrEF and
However, telmisartan was not well tolerated and ESKD undergoing continuous ambulatory PD, spiro-
was more likely than placebo to be discontinued nolactone vs placebo resulted in significant improve-
(16.3% vs 10.7%), most often due to hypotension or ment in the mean LVEF with the use of
hyperkalemia.32 spironolactone without significantly raising the risk
94 Journal of Cardiac Failure Vol. 29 No. 1 January 2023
of hyperkalemia (Table 1).42 These pilot results sup- is a lack of trial-level and observational evidence
port the use of MRAs in patients with HFrEF on dialy- regarding the ue and effectiveness of SGLT2 inhibi-
sis, but they are limited by small sample sizes, low tors in patients with HF and on dialysis. However,
event rates and lack of ascertainment of hard clinical recent RCTs have provided reassuring results that
endpoints. Other trials in patients on dialysis (not indicate the possible renoprotection benefits associ-
necessarily having HF at baseline) have similarly ated with SGLT2 inhibitors in patients with HF and
revealed that MRA use is effective and does not CKD.48 Evidence from the ongoing Safety of Dapa-
increase the risk of clinically significant gliflozin in Hemodialysis Patients with Heart Failure
hyperkalemia.43 (SDHF) trial (NCT05141552) in the future will enable
In contrast to these small RCTs of patients with HF appropriate assessment of the usage of SGLT2 inhib-
and ESKD, an observational study based on the itors in patients with HF and on HD (Table 2). In
USRDS (2006 2014) of 3464 patients with HF and addition, the ongoing DAPA-HD (NCT05179668) trial
ESKD and on HD noted that MRAs were associated will provide additional information regarding the
with significantly greater risk of mortality (HR, 1.35 effects of SGLT2 inhibition by dapagliflozin in dia-
[1.25 1.46]) (Table 1). However, the mechanism of betic and nondiabetic patients on HD. Although this
death was not clear; there was no difference in the trial is not focused exclusively on patients with HF
risk of time to first admission due to HF (HR, 1.03 and on dialysis, the subgroup analysis of patients
[0.93-1.15]) or time to first admission due to hyper- with HF in this trial may be informative.
kalemia (HR, 0.98 [0.86–1.12]). In contrast, a meta-
analysis of 15 studies in patients on HD with no HF
Implantable Cardioverter Defibrillators
requirement showed that spironolactone reduced
all-cause mortality (RR, 0.42 [0.28 0.62]).44 Implantable cardioverter defibrillators (ICDs) have
Although spironolactone was associated with higher been shown to reduce mortality rates and morbidity
serum potassium (mean difference, 0.22 in patients with HFrEF. However, their benefit in
[0.12 0.31]), there was no increased risk of signifi- dialysis-dependent patients with HF remains unclear
cant hyperkalemia (RR, 1.21, [0.83 1.77]).44 Simi- owing to exclusions of such patients from pivotal tri-
larly, in a another meta-analysis of 1128 patients on als. Evidence from RCTs for ICD usage in patients
dialysis, low-dose MRA use reduced cardiovascular with HF and on dialysis is lacking. However, some
mortality by 54% (RR, 0.46 [0.28 0.76]) and all- observational studies have evaluated the efficacy of
cause mortality by 52% (RR, 0.48 [0.33 0.72]) but ICDs in patients with HFrEF and on dialysis. In a
did not significantly increase the risk of moderate matched cohort study including 303 patients on dial-
(RR, 1.29, [0.87 1.91]) to severe (RR, 1.85, ysis, no significant survival benefits (HR, 0.87
[0.90 3.80]) hyperkalemia.45 [0.66 1.13]) were noted with ICD use among dialysis
The lack of significant hyperkalemia risk in patients with HFrEF at follow-ups of both 1 (ICD,
patients with HF and ESKD requiring dialysis is prom- 42.2%; no ICD, 38.1%) and 3 years (ICD, 68.6%; no
ising and may be related to MRA dosage. Concomi- ICD, 75.7%), and the results were consistent on pro-
tant usage of novel potassium binders, such as pensity-matching as well (HR, 0.94 [0.67 1.31])
patiromer and sodium zirconium silicate, may help (Table 1).49 In contrast, results from a multicenter
to alleviate the associated hyperkalemia risk if it is registry study by Hiremath et al. that included 100
unable to be managed with HD therapy alone, patients on dialysis and with LV dysfunction showed
although there is no current evidence to support that ICD use significantly reduced the incidence of
their use. all-cause mortality (HR, 0.40 [0.19 0.82]) compared
Two large ongoing RCTs, Aldosterone Blockade to patients not having ICDs (Table 1).50 In a sub-
for Health Improvement EValuation in End-stage group analysis specific to patients with LVEF < 35%
Renal Disease (ACHIEVE) (NCT03020303) and ALdo- (n = 91), ICD use significantly reduced the risk of all-
sterone Antagonist Chronic HEModialysis Interven- cause mortality (HR, 0.32 [0.15 0.71]) as well.50 No
tional Survival Trial (ALCHEMIST) (NCT01848639) are safety concerns were reported in either of these
being conducted to establish the effects of MRAs in studies.
patients undergoing chronic hemodialysis. However, The recent ICD2 trial aimed to evaluate the effect
these trials are not specific to patients with HF of prophylactic ICD use in patients on dialysis but
requiring dialysis. without significant LV dysfunction (LVEF > 35%).
Although relatively healthy patients on dialysis were
recruited in this trial so as to attain significant sur-
SGLT2 Inhibitors
vival benefit, the trial was terminated early due to
SGLT2 inhibitors reduce cardiovascular mortality futility. ICD usage did not reduce the incidence of
rates and hospitalizations due to HF in patients with sudden cardiac death (HR, 1.32 [0.53 3.29]) or all-
HFrEF accoding to several RCTs.46,47 Currently, there cause mortality (HR, 1.02 [0.69 1.52]).51 In fact,
Table 2. Ongoing Trials Evaluating the Effect of Various HF Therapies in Patients on Dialysis
Estimated
Current Sample Inclusion Secondary
Study Name NCT Number Phase Nature Status Intervention Control Size Criteria Primary Outcomes Outcomes Location
Sacubitril/Valsartan for NCT05243199 4 Randomized Recruiting Sacubitril/ Irbesartan 600 CKD stage 5 patients with Hospitalization Rate of blood pres- Shanghai,
Dialysis Patients With Valsartan HF initiating regular HD for worsening sure compliance, China
CKD5 Stage Compli- or PD for more than 1 HF, death due to improvement in
cated With Heart Fail- month, NT-proBNP CV or other residual renal
ure: a Prospective, 2000 pg/mL. causes (at 1 function (at 1
Randomized, Con- year) year)
trolled Multicenter
BNP, brain natriuretic peptide; CKD, chronic kidney disease; CSS, clinical summary score; CV, cardiovascular; DBP, diastolic blood pressure; ECG, electrocardiogram; eGFR, estimated glo-
merular filtration rate; ESKD, end-stage kidney disease; HD, hemodialysis; HF, heart failure; HFrEF, HF with reduced ejection fraction; KCCQ, Kansas City Cardiomyopathy Questionnaire;
LAV, left atrial volume; LVEDV, left ventricular end diastolic volume; LVEF, left ventricular ejection fraction; NA, not applicable; NCT, national clinical trial; NT-proBNP, N-terminal pro b-
more than 50% of the patients died during the fol-
Shanghai,
low-up period. Interestingly, the major cause of
Location
China
death was found to be infections (ICD, 15/97; con-
trol, 14/91) followed by sudden cardiac death.51
Although this trial was not specific to patients with
HF, it provides important insights regarding the risks
proBNP at 12
Hypoglycemia and Change in NT-
type natriuretic peptide; NYHA, New York Heart Association; PD, peritoneal dialysis; RAS, rennin angiotensin-system; SBP, systolic blood pressure.
HF and on dialysis, and its usage should generally be
avoided until further evidence is available.
Patients with chronic HF
perfusion, hemofiltra-
tion) 2 or 3 times a
(NYHA class II IV)
week, NT-proBNP
tion 2 or 3 times
20
Table 2 (Continued)
dard
Given the paucity of evidence and the presence of dialysis are lacking. In a case report of a patient with
conflicting findings regarding the usefulness of CRT HF and on HD by Sato et al., transcatheter mitral
in patients on dialysis and with HF, no definitive con- valve replacement (TMVR) using MitraClip signifi-
clusions can be reached unless further evidence spe- cantly reduced mitral regurgitation and improved
cific to patients on dialysis and with HF is generated. NYHA functional class from II to I without any post-
operative complications.58 However, non-HF-specific
Left Ventricular Assist Devices observational studies evaluating patients on dialysis
have revealed potential futility regarding the use of
Dialysis-dependent patients with advanced CKD or
MitraClip in this high-risk patient cohort. In a large
ESKD are often not recommended for left ventricular
retrospective study (n = 13,563) using the Nation-
assist device (LVAD) implantation due to concerns
wide Readmissions Database (NRD), Raheja et al.
about poor patient prognosis and increased mortality
showed that patients with ESKD on dialysis (n = 476)
rates (> 60%) owing to LVAD implantation-related
undergoing TMVR had significantly higher rates of
complications. Moreover, dialysis centers have typi-
in-hospital mortality (7.2% vs 2.5% vs 2.0%; P<
cally avoided accepting high-risk patients with
0.001), greater incidence of bleeding (16.6% vs
LVADs. In a retrospective analysis by Kirklin et al. that
10.3% vs 10.0%; P= 0.003), blood transfusions
included 4917 patients from Interagency Registry for
(19.7% vs 8.1% vs 6.0; P< 0.001), and 30-day all-
Mechanically Assisted Circulatory Support (INTER-
cause readmission (22.7% vs 15.6% vs 13.7%; P<
MACS), continuous-flow LVAD implantation was
0.001) compared with patients with CKD or no CKD,
associated with a 22% mortality rate at a 3-month
respectively.59 Although this study was not specific
follow-up in patients with HF on dialysis and those
to patients with HF, a large proportion of patients
with eGFRs < 30 mL/min/1.73 m2.55 Similarly, an 11-
had HF at baseline in all the 3 groups (ESKD, 80.2%;
year-long observational study by Bansan et al.
CKD, 87.1%; no CKD, 74.5%), and chronic HF was
showed that most of the patients (81.9%) with ESKD
found to be the most common cause of hospital
died during follow-up after LVAD implantation, with
readmission post MitraClip placement.59 Similarly,
the median time to death being only 16 days for
Shah et al. showed that patients on dialysis (n = 154)
patients with ESKD compared with 2125 days for
were at an almost 5-fold increase in risk of primary
those without ESKD. However, this study was not
composite outcome of all-cause mortality, stroke
specific to patients with HF and on dialysis.56
and new requirement for dialysis (OR, 4.93
LVAD implantation complicates the management
[2.33 10.5]) compared to patients with a creatinine
of patients receiving maintenance dialysis; the risks
clearance > 60 mL/min.60 Upon multivariable adjust-
are more pronounced in patients on HD compared
ment, patients on dialysis were significantly associ-
with those on PD. Lack of a pulsatile blood pressure
ated with a higher risk of any bleeding event at 1
in patients with continuous-flow LVAD implants may
year (HR, 2.11 [1.31 3.41]) and all-cause mortality,
result in ventricular arrythmias due to low ventricular
both at 30-day (HR, 3.31 [1.79 6.13]) and 1-year
volumes and pressures caused by ultrafiltration dur-
(2.44 [1.66 3.57]) follow-ups when compared with
ing dialysis. The slower ultrafiltration rate among
patients with creatinine clearances > 60 mL/min.60
patients on PD confers greater stability in these
In contrast, a large national study (n = 2197) by
patients. In addition, patients on HD are less likely to
Doshi et al. showed that TMVR significantly reduced
preserve residual renal function and more likely to
in-hospital mortality rates (OR, 0.06 [0.01 0.56])
have bacteremia and other infections. A recent case
and stroke (OR, 0.05 [0.03—0.07]) in patients with
report by Ajuria et al. showed that transitioning to
ESKD (n = 1,628) when compared with surgical
PD from HD improved kidney function significantly
mitral valve replacement.61 However, few patients
for an obese woman with nonischemic HFrEF and
had HF at baseline in this study. In the future, clinical
hypertension.57 In addition, PD was found to be safer
trials and observational studies specific to patients
and more well tolerated compared with HD. Interest-
with HF and on dialysis need to be conducted to
ingly, studies have also displayed survival and clinical
evaluate the efficacy of transcatheter therapeutics
benefits associated with chronic intermittent HD.
in this population of high-risk patients.
Although current evidence indicates worsening of
patient prognosis and poor survival rates in patients
with HF and on dialysis receiving LVAD implantation, Heart and Kidney Transplantation
the use of PD or intermittent HD may be a safer alter-
Patients with concomitant advanced HF and ESKD
native for these high-risk patients.
on dialysis constitute an extremely high-risk popula-
tion and are more susceptible to complications after
Transcatheter Mitral Valve Repair
transplantation. The incidence of dialysis-dependent
Clinical trials and observational studies evaluating acute renal failure post heart transplantation
the usage of MitraClip in patients with HF and on remains an important clinical issue.62,63 A recent
98 Journal of Cardiac Failure Vol. 29 No. 1 January 2023
analysis by Shoji et al. revealed a 5-fold greater risk Although observational studies of patients with
in the incidence of all-cause mortality (HR, 5.2 HF and ESKD seem to favor HD for clinical endpoints,
[4.7 5.7]) in patients receiving dialysis after heart there is some evidence of favorable surrogate end-
transplantation.63 Post-transplant dialysis makes points and functional status with PD. A systematic
these patients more susceptible to clinical complica- review and meta-analysis of 31 studies showed that
tions and also increases the cost of care.64,65 There- PD significantly increased LVEF (mean difference,
fore, simultaneous heart and kidney transplant 3.76% [2.24 5.27]) and NYHA functional class.76
(SHKT) is generally recommended in patients with Patients with HF on PD also had a reduced frequency
concomitant end-stage HF and ESKD on dialysis. of hospitalization or length of stay after PD was
In a retrospective analysis of the United Network introduced (mean difference, 26.9, [ 36.9 to
for Organ Sharing database, Schaffer et al. showed 16.83]).76
that patients with end-stage HF on dialysis receiving Given the limitations of observational analysis,
SHKT had better post-transplant survival rates than clear recommendations concerning the use of PD vs
propensity-matched heart transplant alone (HTA) HD in patients with HF cannot be offered. Factors
patients (1 year, 84% vs 69%; 5 years, 73% vs 51%; P impacting the decision include patient preferences
< 0.001).66 In addition, multiple non-HF-specific for lifestyle and for participating in the dialysis pro-
observational studies have shown that SHKT offers cess and the recommendations of the collaborating
greater survival rates and clinical benefits than HTA nephrologist.
in patients with ESKD.67 70 Prior studies (although
not HF-specific) have also shown that patients
Modifications in Dialysis Procedure
undergoing SHKT have a lower risk of acute rejec-
tion compared with patients receiving HTA.70 In a small study including ESKD patients with con-
Another study has demonstrated that the effective- comitant HF (n = 6), conversion to frequent noctur-
ness of SHKT over HTA is sustained across various nal HD significantly increased the LVEF (from
age groups ( 60 and < 60 years) and in both dialy- 28% 42%; P= 0.01), reduced the systolic (138
sis-dependent and nondialysis-dependent patients mmHg 120 mmHg; P= 0.04) and mean arterial BP
with renal insufficiency.71 In contrast, a recent obser- (99 mmHg to 86 mmHg; P= 0.01), and decreased the
vational analysis by Melvinsdottir et al. included 845 number of prescribed cardiovascular medications
patients with end-stage heart and kidney failure (from 2.2% 0.7%; P= 0.02) when compared with
and revealed a 4.7-fold increase in the risk of mortal- conventional HD at baseline.77 Cardiovascular bene-
ity (HR, 4.77 (2.41 9.44]) when compared with fits of intensive HD were also noted in the Frequent
patients who underwent kidney transplant after Hemodialysis Network Daily Trial (n = 245), where 6
heart transplant.72 However, not all patients times-weekly, in-center HD significantly reduced left
included in this study were on dialysis. Nonetheless, ventricular mass (mean change, 13.1 [ 21.3, 5.0];
this mode of subsequent transplantation needs to P= 0.002) and the risk of mortality (HR, 0.54
be assessed further in comparison with simultaneous [0.31 0.93]).78,79 However, this trial was not specific
dual-organ transplantation. to patients with HF.
Home HD is another potential alternative that has
Dialysis in HF multiple clinical benefits, including blood pressure
and extracellular volume control, reduction in LV
Dialysis Modality Preference
hypertrophy and improvements in LVEF.80 In a retro-
Multiple observational studies have compared HD spective cohort study (n = 144) by Trinh et al., LV
to PD in patients with HF. A retrospective propensity hypertrophy regression due to home HD was signifi-
score-matched study in 2019 included 65,899 cantly associated with a decrease in the risk of mor-
patients and showed that HD was associated with tality (HR 0.24 [0.08 0.77]).81 Home HD can possibly
higher incidence rates of HF (HR, 1.45 [1.23 1.70]) alleviate the hemodynamic shifts by reducing inter-
compared with PD.73 However, in patients with dialytic gaps and decreasing the intensity of ultrafil-
established HF, evidence is conflicting, although it is tration associated with thrice-weekly conventional
overall in favor of HD. An observational study of HD, but there is a dearth of evidence specific to
3468 patients on HD and 933 patients on HD showed patients with HF.82
that PD significantly increased the risk of overall and Although conventional HD is subject to increased
cardiovascular mortality compared with HD.74 In risks due to greater ultrafiltration rates and relative
contrast, a smaller retrospective cohort study of 69 lack of preservation of residual renal function, modi-
patients on PD and 195 patients on HD revealed no fications in HD have proven to be beneficial. For
difference in overall survival, although deaths due instance, cooled dialysate, extracorporeal ultrafiltra-
to cardiovascular cause were significantly increased tion, higher levels of dialysate sodium and calcium
with PD (PD, 64.4%; HD, 37.9%; P= 0.001).75 and use of midodrine have yielded significant
Managing Heart Failure in Patients on Dialysis: State-of-the-Art KHAN et al 99
improvements in the efficacy and safety of the HD with AVF in patients with HF. The aggravating pro-
procedure.83 However, current literature lacks evi- gression of HF with AVF can possibly render PD as a
dence for the efficacy of these modifications in preferred modality over HD in patients with HF.
patients with HF and on dialysis.
Myocardial Stunning
Management of Arteriovenous Fistula Myocardial stunning is a well-established compli-
cation of HD and is more commonly observed in
The arteriovenous fistula (AVF) is the preferred
patients receiving thrice-weekly HD. HD-induced
vascular access for patients on chronic HD, compared
myocardial stunning has been found to be associ-
with arteriovenous graft (AVG) (which have shorter
ated with an increased risk of mortality at 12 months
secondary patency following successful cannulation)
and may even lead to the incidence of HF.88 In a
and tunneled central venous catheter (which are
small cross-sectional study including patients (n = 46)
susceptible to an increased risk of infections, throm-
with a mean LVEF 30% 40%, all patients receiving
bosis, hospitalizations, and mortality).84,85,86 How-
thrice-weekly conventional HD were found to have
ever, the widely acceptable “fistula-first” approach
myocardial stunning compared with 92% of patients
harbors important clinical complications in the set-
receiving more frequent HD, 5–6 times/week, 75%
ting of HF.84 Creation of an AVF leads to a large
of patients receiving frequent home HD, and 50%
amount of blood’s being shunted from the left-
of patients receiving home nocturnal HD.89 Patients
sided circulation to the right-sided circulation.86 The
on more frequent HD schedules had lower volumes
resulting extra demand on cardiac output due to
and rates of ultrafiltration, decreased markers of
AVF creation can worsen the progression of HF.
inflammation and less myocardial intracellular dam-
In a retrospective cohort study including 137
age; hence, they were less likely to develop dialysis-
patients on HD, AVF/AVG creation significantly
induced myocardial stunning compared with con-
increased the risk of RV dilation, RV dysfunction and
ventional thrice-weekly HD.89 Prolonged dialysis ses-
left atrial dilation.84 Worsening RV dilation was
sions (median 24 hours/week) have also been found
associated with a 4-fold increased risk of mortality
to be associated with improved cardiac systolic func-
(HR, 3.9 [1.7 9.2]).84 Patients developing incident
tion by reduction in LV mass index and improve-
HF had significantly greater increments in left atrial
ments in LVEF.90 Other strategies include
volume and worsening of both RV dilation and dys-
individualized-temperature HD, intradialytic exer-
function compared with patients who did not
cise, dialysate cooling, and maintaining dialysate cal-
develop incident HF.84 A subgroup analysis of 35
cium 2.5 mEq/L.83,91,92 However, these studies are
patients who underwent AVF ligation revealed
not specific to patients with HF on HD.
reductions in left ventricular end diastolic diameter
and LV mass index and stability or improvement in
Management of Hyperkalemia
RV function, but there were no significant changes
in LV systolic or diastolic function nor any significant Patients on dialysis have an increased risk of
reverse RV remodeling.84 hyperkalemia, which is often due to poor dietary
The development of high-output HF is an under- adherence or, less likely, to higher catabolism
appreciated complication of AVF, which poses an rates.93 All foundational HF therapies except
important clinical dilemma.86,87 The ideal approach SGLT2 inhibitors can potentially precipitate
may be the prevention of worsening HF while main- hyperkalemia.94,95 There are several ways to miti-
taining AVF access, but balancing them simulta- gate this concern. Given that the kidneys are the
neously is often not possible, and AVF may have to main source for K+ excretion mainly, limiting food
be ligated, causing loss of vascular access.87 Alterna- sources rich in potassium may reduce serum potas-
tively, AVF can be maintained by partial banding, in sium levels. The usage of novel potassium binders,
which the AVF can be constricted in 1 or more places such as patiromer or sodium zirconium silicate, may
to decrease the AVF blood flow.87 Other techniques offer an effective strategy to prevent hyperkalemia
include placement of hemoclips over the venous while allowing for optimization of foundational
supply, the inflow reduction procedure or the Miller therapies for HF.96
procedure.87 However, these are proposed The potassium binder patiromer was associated
approaches for the management of high-output HF, with a reduction in serum potassium and lesser dis-
and current literature lacks evidence of their efficacy continuations of RAAS inhibitors in the 4-week
and safety in patients with HF. Although the use of a PEARL-HF (Evaluation of Patiromer in Heart Failure
central venous catheter is the least desirable form of Patients) and 12-week OPAL-HK (A Two-Part, Single-
vascular access, the risk of infection, morbidity and Blind, Phase 3 Study Evaluating the Efficacy and
mortality should be weighed against the risk of Safety of Patiromer for the Treatment of Hyperkale-
increasing HF progression and should be compared mia) trials.97,98 In the DIAMOND (Patiromer for the
100 Journal of Cardiac Failure Vol. 29 No. 1 January 2023
symptomatic hypotension and hypotension limiting patients with HF on dialysis (Visual Take Home
effective dialysis, particularly for patients receiving Graphic).
HD. Future RCTs are needed to assess the effectiveness
of well-established HF therapies in patients with HF
and on dialysis. As compared with the initial cardio-
Challenges and Future Directions
vascular outcome trials that that have confirmed the
Fig. 2 summarizes the barriers to and possible sol- efficacy of therapies in nondialysis patients with HF,
utions for patients with HF and on dialysis. One of patients with HF and on dialysis are generally frailer,
the major reasons for the undertreatment of HF in older and have poorer prognoses.112 Thus, the
patients on dialysis is the lack of reliable evidence degree to which the safety and efficacy seen in the
from well-powered RCTs. Few to no RCTs specific to prior landmark trials of HF therapies generalize to
patients with HF and on dialysis have been con- patients with ESKD and on dialysis are generally
ducted; the majority of evidence to date is derived uncertain. It may be feasible to answer these
from observational studies, which are inherently research questions with pragmatic RCTs, leveraging
subject to confounding and biases. Moreover, exclu- the benefits of randomization to determine cause-
sions of these high-risk patients from landmark RCTs effect relationships while potentially maximizing
of drug and device interventions for HF make it application to the generally multimorbid ESKD pop-
even more difficult to ascertain the efficacy and ulation encountered in routine practice.
safety of these therapeutic agents in dialysis-depen-
dent patients with HF. Conflicting findings from
Conclusion
observational studies further complicate the assess-
ment, consequently, leaving the important drug In patients with HF who are receiving dialysis,
efficacy and safety questions unanswered for these despite being at substantially higher risk for morbid-
high-risk patients. In addition, perceived concerns ity and mortality, there is a critical lack of reliable
regarding the safety and tolerability of GDMT for evidence to guide management and inform best
HF in dialysis-dependent patients have led to discon- practice. Owing to perceived concerns about the
tinuations of therapies, thereby compromising the effectiveness and safety of conventional therapies
management of HF in these patients. Fig. 3 gives an for HF, clinicians have been reluctant to prescribe
overview of the proposed clinical approach in these medications. Trial-level evidence is warranted
Fig. 2. Current barriers and possible solutions for managing HF in patients on dialysis. CKD, chronic kidney disease; ESKD,
end-stage kidney disease; HF, heart failure; OS, observational studies; RCT, randomized controlled trial.
102 Journal of Cardiac Failure Vol. 29 No. 1 January 2023
Fig. 3. (Visual Take-Home Graphic). Proposed clinical approach in patients with HF and on dialysis. ACE, angiotensin-con-
verting enzyme; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; CRT, cardiac resynchro-
nization therapy; CV, cardiovascular; GDMT, guideline-directed medical therapy; HF, heart failure; ICD, implantable cardiac
defibrillator; LVAD, left ventricular assist device; MRA, mineralocorticoid receptor antagonist; SGLT2, sodium-glucose
cotransporter 2.
in the future to endorse the efficacy and safety of but data regarding the management of HF in
therapeutic HF interventions in patients on dialysis. patients with ESKD and undergoing dialysis remain
Collaborations between the cardiologists and neph- very limited. Trial-level evidence is warranted in the
rologists are needed to devise an optimal treatment future to endorse the efficacy and safety of thera-
strategy for these patients. peutic interventions in patients with HF and on dial-
ysis. Collaborations between the cardiologists and
nephrologists are needed to devise an optimal treat-
Brief Lay Summary
ment strategy for these patients.
Heart failure (HF) and end-stage kidney disease
(ESKD) frequently coexist, with 1 comorbidity wors-
Tweet
ening the prognosis of the other. Some randomized
clinical trials have evaluated the efficacy of thera- There is a paucity of data regarding the manage-
pies in patients with HF and chronic kidney disease, ment of heart failure in patients on dialysis. Trial-
Managing Heart Failure in Patients on Dialysis: State-of-the-Art KHAN et al 103
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