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Reprint requests: Gregg C. Fonarow, MD. Ahmanson-UCLA Cardiomyopathy Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA; Tel: 310 206-9112
Heart failure and end-stage kidney disease (ESKD) commonly coexist; 1 comorbidity worsens the prognosis of the other.
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Although patients with ESKD compose an extremely high-risk population, they have been excluded from landmark clinical trials in heart failure, and there is, thus, a paucity of data regarding the management of heart failure in patients on dialysis.
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Trial-level evidence is warranted in the future to endorse the efficacy and safety of therapeutic interventions in patients with heart failure and on dialysis. Collaborations between cardiologists and nephrologists are needed to devise an optimal treatment strategy for these patients.
ABSTRACT
Heart failure (HF) and end-stage kidney disease (ESKD) frequently coexist; 1 comorbidity worsens 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 available 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 optimize the management of HF in these high-risk patients.
Renal dysfunction in patients with heart failure with preserved versus reduced ejection fraction impact of the new chronic kidney disease-epidemiology collaboration group formula.
The prognosis of patients with both conditions is substantially worse than those with either condition alone. Cardiovascular disease, including HF, accounts for approximately 50% of the deaths in patients undergoing dialysis.
Beta-blockers, angiotensin receptor neprilysin inhibitors (ARNIs), renin-angiotensin-aldosterone system (RAAS) inhibitors, mineralocorticoid receptor antagonists (MRAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce mortality rates in patients with HF with reduced ejection fraction (HFrEF). However, patients with HF and ESKD have been excluded from landmark trials of all these therapies. Guideline-directed medical therapy (GDMT) in patients with HFrEF who are on dialysis is often withheld or not uptitrated to recommended target doses due to safety and tolerability concerns and lack of available clinical trial data. Similarly, patients with HF and ESKD are not eligible for initiation of multiple GDMTs according to current practice guidelines.
Although some randomized clinical trials (RCTs) have evaluated the efficacy of GDMT in patients with HF and CKD, data regarding the management of HF in patients with ESKD who are undergoing dialysis remain very limited.
The current evidence is mostly observational, and guidelines reflect this dearth of evidence. The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative guidelines note that left ventricular (LV) systolic dysfunction and LV hypertrophy are independent predictors of poor survival rates in patients undergoing dialysis and recommend consistent maintenance of euvolemia as a cornerstone of HF treatment in patients undergoing dialysis, with a likely need to alter dosage of therapeutic drugs in accordance with hemodialysis (HD) schedules.
The 2021 European Society of Cardiology guidelines offer a class IIa recommendation for the usage of renal-replacement therapy in patients with ESKD and refractory volume overload as a treatment option for HF.
However, guidelines offer little direction regarding other specific HF management in these patients.
Given the lack of evidence and guidelines, it is not surprising that patients with HFrEF who are on dialysis are less likely to receive GDMT in observational registries. In a cohort of 3124 patients with HF and on dialysis from the Get With The Guidelines-Heart Failure (GWTG-HF) registry, Pandey et al. showed that patients with HFrEF and on dialysis received GDMT less commonly than patients with normal renal function and those with impaired renal function but not on dialysis.
Trends in the use of guideline-directed therapies among dialysis patients hospitalized with systolic heart failure: findings from the American Heart Association Get With The Guidelines-Heart Failure program.
Although there was a significant increase in the adherence to GDMT and HF-specific process-of-care measures over time, improvement in clinical outcomes remained significantly lower than that in patients with normal renal function.
Trends in the use of guideline-directed therapies among dialysis patients hospitalized with systolic heart failure: findings from the American Heart Association Get With The Guidelines-Heart Failure program.
The differences observed in the use of GDMT for HF were most pronounced in patients with estimated glomerular filtration rates (eGFRs) < 30 mL/min/1.73m2 and those on dialysis.
In this context, the goal of this state-of-the-art review is to discuss the available evidence for each of the foundational HF therapies in ESKD, to review current challenges and barriers to managing patients with HF on dialysis and to outline the future directions to optimize the management of HF in these high-risk patients.
Evidence for GDMT in Patients With HF and ESKD
The evidence regarding the use of differing HF therapies for patients on dialysis is summarized in Fig. 1.
Fig. 1Summary 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, cardiovascular; eGFR, estimated glomerular filtration rate; HF, heart failure; ICD, implantable cardioverter defibrillator; IV, intravenous; 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.
Packer M, Coats AJS, Fowler MB, Katus HA, Krum H, Mohacsi P, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:1651–8. doi: 10.1056/NEJM200105313442201
Although beta-blockers are the most commonly prescribed cardiovascular medications (64% of all prescriptions) for patients on dialysis, their efficacy and safety remain uncertain in patients with HF and on dialysis.
Patients receiving carvedilol demonstrated significant improvements in left ventricular ejection fraction (LVEF) and reduced left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV) compared with placebo at both 6-month and 12-month follow-ups.
Table 1Completed RCTs and Key Observational Studies Evaluating HF Therapies Among HF Patients on Dialysis
Study Name
Year
Intervention
Control
Sample Size
Population
Key Findings
Safety Concerns
Follow-up (months)
RCTs Evaluating HF Patients on Dialysis
Cice et al.
2001
Carvedilol
Placebo
114
Patients with uremia, HFrEF (LVEF <35%) and dilated cardiomyopathy on periodic HD treatment
Significant improvements in LVEF, LVEDV, LVESV, and NYHA functional class
No significant safety concerns; however, hypotension, bradycardia, acute myocardial infarction, and second-degree heart block were seen in carvedilol arm, and worsening HF, sudden death, acute myocardial infarction, and death due to refractory hyperpotassemia were seen in placebo arm
12
Cice et al.
2003
Carvedilol
Placebo
114
Patients with uremia, HFrEF (LVEF <35%) and dilated cardiomyopathy on periodic HD treatment
Significant reductions in all-cause mortality, CV mortality, hospitalization for worsening HF and all-cause hospitalizations
No significant safety concerns; however, hypotension, bradycardia, acute myocardial infarction, and second-degree heart block were seen in carvedilol arm; and worsening HF, sudden death, acute myocardial infarction, and death due to refractory hyperpotassemiwere seen in placebo arm.
24
Cice et al.
2010
Telmisartan
Placebo
332
Patients with chronic HFrEF (LVEF <40%) on HD; NYHA functional class II–III
Significant reductions in all-cause mortality, CV mortality, and hospitalization for chronic HF. Improvements were noted in LVEF and NYHA functional class.
Adverse events leading to discontinuations were higher in telmisartan arm. Most common safety concern was hypotension; other concerns noted were increase in plasma potassium, diarrhea, back pain, sore throat, and dizziness.
35.5
Taheri et al.
2009
Spironolactone
Placebo
16
Patients with HFrEF (LVEF <45%) and NYHA functional classes III–IV on chronic HD treatment (3 sessions/week) since at least 1 month before the study
Significant increase in LVEF and significant decrease in LV mass
No significant risk of hyperkalemia (2 patients reported hyperkalemia in placebo arm only).
6
Taheri et al.
2012
Spironolactone
Placebo
18
Patients with HFrEF (LVEF≤45%) and NYHA class III or IV HF on CAPD, having a serum potassium ≤5.5 mEq/L
Significant increase in LVEF
No significant risk of hyperkalemia
6
Selectd observational studies evaluating HF patients on dialysis
Tang et al.
2016
Beta-blockers, namely carvedilol, bisoprolol and metoprolol CR/XL
Nonusers of beta-blockers
3400
Patients with HF on long‐term HD (≥26 HD sessions within 3 months of commencing HD)
Significant reduction in the risk of all-cause mortality
Not reported
NA
Zhou et al.
2021
Beta-blockers at transition
No beta-blockers at transition
3503
Patients aged ≥18 years with CKD and documented HF (5 years before dialysis initiation) on HD or PD
Significant reductions in the risk of mortality at 6 months and 12 months
Not reported
6
Wang et al.
2021
ARNI
NA
110
Patients aged >18 years with HFrEF (LVEF ≤40%) and NYHA functional classes II–IV undergoing maintenance HD
Significant improvements in LVEF, LVEDD, LVESD, LAD, KCCQ scores, and NYHA functional class
Not reported
12
Lee et al.
2020
sacubitril/valsartan
NA
23
Patients aged >18 years with HFrEF (LVEF ≤35%) and anuric ESKD on HD or PD since more than 6 months
Significant increase in LVEF and significant reductions in high‐sensitive troponin T and soluble ST2; only 2/23 patients were hospitalized for HF, and no CV deaths were noted.
Symptomatic hypotension (4/23) and dizziness (1/23) noted
4.4
Hsiao et al.
2022
ARNI
ACE inhibitors and ARBs
1039 (618 on dialysis)
Patients with HFrEF (LVEF <40%) and advanced CKD (2 consecutive records of eGFR ≤30 mL/min/1.73 m2 in the previous year) in the Chang Gung Research Database between 2016 to 2018
Significant increase in the risk of HF hospitalization and composite of hospitalization for HF and all-cause death; no significant effect on composite outcome of all-cause mortality and hospitalization for HF, reverse cardiac remodeling, and progression to ESKD in patients with HFrEF and advanced CKD
Significant increase in the risk of hyperkalemia with ARNI usage in patients with HFrEF and advanced CKD (but not on dialysis); safety concerns not reported specifically in dialysis patients
12
Tang et al.
2013
RAS blockers (ACE inhibitors and ARBs)
No RAAS blockers
4,771
Patients with HF on long-term HD (≥ 26 HD sessions within 3 months after initiating HD)
Significant reductions in the risk of all-cause and cardiovascular mortality
Not reported
36
Berger et al.
2007
ACE inhibitors and ARBs
NA
2,169
Patients with chronic HF and CKD with data available for weight and serum creatinine enabling to calculate serum GFR
No significant reductions in mortality at 30 days or 1 year among dialysis patients with HF
Not reported
12
Lee et al.
2019
MRA
NA
3464
ESKD patients on HD having HF at ESKD incidence in the USRDS between 2006–2014
Significant increase in the risk of mortality; no significant effect on time to first HF admission or time to first hyperkalemia admission
Not reported
NA
Pun et al.
2015
ICD
no ICD
303
Patients aged ≥65 years with HFrEF (LVEF ≤35%) and documented cardiomyopathy receiving chronic dialysis treatment; patients with NYHA class IV symptoms, CABG 90 days before implant, new-onset HF (<3 months) and MI 40 days before implant were excluded
No significant reductions in mortality at 1 and 3 years
Not reported
56.4 (ICD registry); 34.8 (GWTG-HF registry)
Hiremath et al.
2010
ICD
no ICD
100
ESKD patients with ICD and ESKD patients with left ventricular dysfunction (LVEF <35%) on dialysis for > 3 months
Significant reduction in the risk of all-cause mortality
Not reported
NA
Friedman et al.
2013
CRT
Matched control
15
Patients with ESKD and HFrEF (LVEF <35%), on dialysis having NYHA functional class III or IV and QRS duration of >120 ms
Significant increase in the risk of all-cause mortality and all-cause hospitalizations but no significant effect on HF hospitalizations
Not reported
36
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, peritoneal dialysis; RAS, rennin angiotensin-system; RCT, randomized controlled trial.
However, the generalizability of the trial is questionable because it included a small sample, and 13.6% of the patients were excluded during the run-in phase due to hypotension, bronchospasm, worsening HF, or bradycardia.
In contrast to the relative scarcity of RCT data, multiple observational studies have evaluated the association between beta-blocker use and outcomes in patients with HF and on dialysis.
Prognostic benefits of carvedilol, bisoprolol, and metoprolol controlled release/extended release in hemodialysis patients with heart failure: a 10-year cohort.
In a nationwide retrospective cohort study in Taiwan, including 3400 patients with HF on long-term HD, beta-blocker therapy was associated with a 20% reduction in all-cause mortality (HR, 0.80 [0.72–0.90]) (Table 1).
Prognostic benefits of carvedilol, bisoprolol, and metoprolol controlled release/extended release in hemodialysis patients with heart failure: a 10-year cohort.
Similarly, in another retrospective cohort study of 3503 patients on HD or peritoneal dialysis (PD), carvedilol was associated with a 21% reduction in mortality rates at 6 and 12 months (HR, 0.79 [0.65–0.91] HR, 0.79 [0.65–0.94], respectively).
Moreover, in about 11,000 patients from the US Renal Data System (USRDS) registry, beta-blockers were the only antihypertensive drugs independently associated with substantial survival benefit (HR 0.84 [0.75–0.93]), though only 39% of patients in this study had HF.
Although not a dedicated HF study, a large meta-analysis evaluated the effectiveness of beta-blockers in more than 120,000 patients on dialysis, irrespective of HF status.
The included RCTs (n = 3) showed that beta-blockers significantly reduced all-cause mortality (risk ratio [RR], 0.73 [0.54–0.97]) cardiovascular mortality (RR, 0.44 [0.29–0.68]), and hospitalizations (RR, 0.61 [0.48–0.78]) in patients on dialysis, and the included observational studies (n = 9) also demonstrated significant reductions in all-cause mortality (RR, 0.86 [0.80–0.92]).
Cardioselective beta-blockers include atenolol, bisoprolol and metoprolol; noncardioselective beta-blockers include propranolol, carvedilol, labetalol, pindolol, nadolol, and timolol.
Highly dialyzable beta-blockers are atenolol, bisoprolol, acebutolol, nadolol, and metoprolol, whereas poorly dialyzable beta-blockers are carvedilol, labetolol and propranolol.
Thus, the choice of evidence-based beta-blocker in patients with HF and ESKD (bisoprolol, carvedilol or sustained-release metoprolol) should be based on tolerability and availability rather than on clinical-trial evidence.
Angiotensin Receptor Neprilysin Inhibitors
In post hoc or observational analyses, sacubitril/valsartan is effective and well tolerated in patients with eGFRs 30–60 mL/min/1.73 m2.
A single-center observational study of 110 patients with HF on HD noted that patients taking sacubitril/valsartan had improved improved LVEF (baseline, 35.1%; 12 months, 49.8%), left ventricular mass index (baseline, 167.8 g/m; 12 months, 154.9 g/m), left ventricular end diastolic diameter (baseline, 52.2 mm; 12 months, 51.5 mm), and LVESD (baseline, 35.9 mm; 12 months, 36.9 mm), as well as in Kansas City Cardiomyopathy Questionnaire (KCCQ) scores and New York Heart Association (NYHA) functional classes (Table 1).
Use of angiotensin receptor neprilysin inhibitor in patients on maintenance hemodialysis with reduced cardiac ejection fraction, real-world experience from a single center.
However, the safety and long-term efficacy of sacubitril/valsartan in patients with HF and ESKD and those on dialysis has not been evaluated in any RCT to date.
In contrast to these analyses demonstrating a beneficial effect of ARNIs in patients with HF and ESKD, a subgroup analysis of a retrospective multicenter study of 618 dialysis patients with HFrEF in Taiwan demonstrated that ARNIs were associated with increased risk of hospitalization for HF (HR, 1.97 [1.36–2.85]) and composite of hospitalization for HF and all-cause death (HR, 1.73 [1.23–2.44]) compared with ACE inhibitors/ARBs (Table 1).
Angiotensin receptor-neprilysin inhibitors in patients with heart failure with reduced ejection fraction and advanced chronic kidney disease: a retrospective multi-institutional study.
The lack of reliable evidence regarding the efficacy and safety of ARNI treatment in patients with HF and ESKD requiring dialysis warrants future investigation and, fortunately, there are 3 ongoing trials to assess the safety and efficacy of sacubitril/valsartan in patients with HF and on dialysis: NCT05243199 (Sacubitril/Valsartan for Dialysis Patients With CKD5 Stage Complicated With Heart Failure: A Prospective, Randomized, Controlled Multicenter Study); NCT04572724 (The Effect of Sacubitril/Valsartan on Cardiovascular Events Outcome in Maintenance Dialysis Patients With Heart Failure and Efficacy Prediction of Baseline LVEF Value: A Prospective Cohort Study); and NCT04458285 (Efficacy and Safety of Sacubitril/Valsartan in Maintenance Hemodialysis Patients With Heart Failure [ESARHD-HF]) (Table 2). Importantly, 2 of these trials (NCT05243199 and NCT04572724) have important clinical endpoints (cardiovascular death and hospitalization for HF) as primary outcomes.
Table 2Ongoing Trials Evaluating the Effect of Various HF Therapies in Patients on Dialysis
Study Name
NCT Number
Phase
Nature
Current Status
Intervention
Control
Estimated Sample Size
Inclusion Criteria
Primary Outcomes
Secondary Outcomes
Location
Sacubitril/Valsartan for Dialysis Patients With CKD5 Stage Complicated With Heart Failure: a Prospective, Randomized, Controlled Multicenter Study
NCT05243199
4
Randomized
Recruiting
Sacubitril/Valsartan
Irbesartan
600
CKD stage 5 patients with HF initiating regular HD or PD for more than 1 month, NT-proBNP ≥2000 pg/mL.
Hospitalization for worsening HF, death due to CV or other causes (at 1 year)
Rate of blood pressure compliance, improvement in residual renal function (at 1 year)
Shanghai, China
The Effect of Sacubitril/Valsartan on Cardiovascular Events Outcome in Maintenance Dialysis Patients With Heart Failure and Efficacy Prediction of Baseline LVEF Value:A Prospective Cohort Study
NCT04572724
4
Non-randomized
Recruiting
Sacubitril/Valsartan
RAS inhibitor
120
Patients with stable HF (NYHA class II, III or IV), typical HF symptoms, and structural and/or functional cardiac abnormality under maintenance HD or PD for more than 1 year, NT-proBNP ≥600 pg/ml
CV death and HHF (at least 18 months)
Composite of death from CV diseases or first unplanned HHF (at least 18 months), change from baseline to 12 months in the NT-proBNP, change from baseline to 1 month, 6 month, and 18 months in the CSS on KCCQ
Guangdong, China
A Multi-center, Randomized, Open-label, Active-controlled, 12-week Study to Evaluate the Efficacy and Safety of Sacubitril/Valsartan in Maintenance Hemodialysis Patients With Heart Failure (ESARHD-HF)
NCT04458285
NA
Randomized
Recruiting
Sacubitril/Valsartan
Valsartan
118
Patients with chronic HFrEF (LVEF ≤ 50%, NYHA class ≥ II) and ESKD (eGFR <15mL/min/1.73m²) receiving HD 3 times/week for at least 12 weeks before registration
Changes in LVEF at 12 weeks
Changes in NT-proBNP, LVEDV, LAV, E/E', pulmonary artery pressure, Concentration of high-sensitivity serum troponin T, NYHA functional classification, Minnesota Heart Failure Quality of Life Questionnaire (LiHFe), SBP, DBP, concentration of potassium, ECG, eGFR, incidence of angioedema, Concentration of alanine aminotransferase or aspartate aminotransferase (at 12 weeks)
Guangdong, China
The Safety of Dapagliflozin in Hemodialysis Patients With Heart Failure (SDHF)
NCT05141552
NA
Randomized
Recruiting
Dapagliflozin
None (standard anti-HF therapy)
20
Patients with chronic HF (NYHA class II–IV) undergoing maintenance blood purification 2 or 3 times (including HD, hemoperfusion, hemofiltration) 2 or 3 times a week, NT-proBNP >11500 pg/mL or BNP >500 pg/mL
Hypoglycemia and UTI at 12 weeks
Change in NT-proBNP at 12 weeks
Shanghai, China
BNP, brain natriuretic peptide; CKD, chronic kidney disease; CSS, clinical summary score; CV, cardiovascular; DBP, diastolic blood pressure; ECG, electrocardiogram; eGFR, estimated glomerular 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-type natriuretic peptide; NYHA, New York Heart Association; PD, peritoneal dialysis; RAS, rennin angiotensin-system; SBP, systolic blood pressure.
Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial.
However, their use in patients with HF and on dialysis has stayed limited due to conflicting findings and the paucity of reliable evidence in this population (Table 1). There is 1 RCT of ARB use in 332 patients with HFrEF and ESKD.
Effects of telmisartan added to angiotensin-converting enzyme inhibitors on mortality and morbidity in hemodialysis patients with chronic heart failure: a double-blind, placebo-controlled trial.
Effects of telmisartan added to angiotensin-converting enzyme inhibitors on mortality and morbidity in hemodialysis patients with chronic heart failure: a double-blind, placebo-controlled trial.
However, telmisartan was not well tolerated and was more likely than placebo to be discontinued (16.3% vs 10.7%), most often due to hypotension or hyperkalemia.
Effects of telmisartan added to angiotensin-converting enzyme inhibitors on mortality and morbidity in hemodialysis patients with chronic heart failure: a double-blind, placebo-controlled trial.
Although not specific to patients with HF, RCTs evaluating ACE inhibitors in patients receiving dialysis have produced mixed findings. In the Fosinopril in Dialysis (FOSIDIAL) trial of 397 patients with left ventricular hypertrophy (LVH) on HD, fosinopril failed to reduce the risk of the primary endpoint of composite of cardiovascular death, nonfatal myocardial infarction, unstable angina, stroke, revascularization, or hospitalization due to HF.
The lack of benefit of ACE inhibitors and ARBs in patients with dialysis was confirmed in a meta-analysis of 11 studies including 1856 patients, though a subgroup analysis revealed that ARBs reduced the risk of HF events by 33% (RR, 0.67 [0.47–0.93]).
Effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on cardiovascular events and residual renal function in dialysis patients: a meta-analysis of randomised controlled trials.
However, it must be emphasized that these studies comprised patients on dialysis, and HF was not required for study entry.
Observational studies including HF patients on dialysis have also yielded conflicting results. A nationwide survey and propensity analysis including 4771 Taiwanese patients with chronic HF and on dialysis showed that ACE inhibitors and ARBs reduced all-cause (HR, 0.80 [0.72–0.89]) and cardiovascular mortality (HR, 0.76 [0.64–0.90]).
Conversely, a retrospective analysis of 2169 patients from the Minnesota Heart Survey showed that ACE inhibitors or ARBs did not confer any survival benefits at 30 days or 1 year in patients on dialysis and hospitalized with HF (Table 1).
Effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on cardiovascular events and residual renal function in dialysis patients: a meta-analysis of randomised controlled trials.
These concerns are heightened in patients with HF and on dialysis. Two small RCTs have been conducted to assess the efficacy and safety of MRAs in patients with HFrEF on dialysis. In 16 patients with HFrEF on HD, spironolactone (25 mg/day) significantly increased mean LVEF and decreased mean LV mass without increasing the risk of hyperkalemia (reported in only 2 patients in the placebo group) (Table 1).
Similarly, in 18 patients with HFrEF and ESKD undergoing continuous ambulatory PD, spironolactone vs placebo resulted in significant improvement in the mean LVEF with the use of spironolactone without significantly raising the risk of hyperkalemia (Table 1).
These pilot results support the use of MRAs in patients with HFrEF on dialysis, but they are limited by small sample sizes, low event rates and lack of ascertainment of hard clinical endpoints. Other trials in patients on dialysis (not necessarily having HF at baseline) have similarly revealed that MRA use is effective and does not increase the risk of clinically significant hyperkalemia.
In contrast to these small RCTs of patients with HF and ESKD, an observational study based on the USRDS (2006–2014) of 3464 patients with HF and ESKD and on HD noted that MRAs were associated with significantly greater risk of mortality (HR, 1.35 [1.25–1.46]) (Table 1). However, the mechanism of death was not clear; there was no difference in the risk of time to first admission due to HF (HR, 1.03 [0.93-1.15]) or time to first admission due to hyperkalemia (HR, 0.98 [0.86--1.12]). In contrast, a meta-analysis of 15 studies in patients on HD with no HF requirement showed that spironolactone reduced all-cause mortality (RR, 0.42 [0.28–0.62]).
Although spironolactone was associated with higher serum potassium (mean difference, 0.22 [0.12–0.31]), there was no increased risk of significant hyperkalemia (RR, 1.21, [0.83–1.77]).
Similarly, in a another meta-analysis of 1128 patients on dialysis, low-dose MRA use reduced cardiovascular mortality by 54% (RR, 0.46 [0.28–0.76]) and all-cause mortality by 52% (RR, 0.48 [0.33–0.72]) but did not significantly increase the risk of moderate (RR, 1.29, [0.87–1.91]) to severe (RR, 1.85, [0.90–3.80]) hyperkalemia.
The lack of significant hyperkalemia risk in patients with HF and ESKD requiring dialysis is promising and may be related to MRA dosage. Concomitant usage of novel potassium binders, such as patiromer and sodium zirconium silicate, may help to alleviate the associated hyperkalemia risk if it is unable to be managed with HD therapy alone, although there is no current evidence to support their use.
Two large ongoing RCTs, Aldosterone Blockade for Health Improvement EValuation in End-stage Renal Disease (ACHIEVE) (NCT03020303) and ALdosterone Antagonist Chronic HEModialysis Interventional Survival Trial (ALCHEMIST) (NCT01848639) are being conducted to establish the effects of MRAs in patients undergoing chronic hemodialysis. However, these trials are not specific to patients with HF requiring dialysis.
SGLT2 Inhibitors
SGLT2 inhibitors reduce cardiovascular mortality rates and hospitalizations due to HF in patients with HFrEF accoding to several RCTs.
Currently, there is a lack of trial-level and observational evidence regarding the ue and effectiveness of SGLT2 inhibitors in patients with HF and on dialysis. However, recent RCTs have provided reassuring results that indicate the possible renoprotection benefits associated with SGLT2 inhibitors in patients with HF and CKD.
Evidence from the ongoing Safety of Dapagliflozin in Hemodialysis Patients with Heart Failure (SDHF) trial (NCT05141552) in the future will enable appropriate assessment of the usage of SGLT2 inhibitors in patients with HF and on HD (Table 2). In addition, the ongoing DAPA-HD (NCT05179668) trial will provide additional information regarding the effects of SGLT2 inhibition by dapagliflozin in diabetic and nondiabetic patients on HD. Although this trial is not focused exclusively on patients with HF and on dialysis, the subgroup analysis of patients with HF in this trial may be informative.
Implantable Cardioverter Defibrillators
Implantable cardioverter defibrillators (ICDs) have been shown to reduce mortality rates and morbidity in patients with HFrEF. However, their benefit in dialysis-dependent patients with HF remains unclear owing to exclusions of such patients from pivotal trials. Evidence from RCTs for ICD usage in patients with HF and on dialysis is lacking. However, some observational studies have evaluated the efficacy of ICDs in patients with HFrEF and on dialysis. In a matched cohort study including 303 patients on dialysis, no significant survival benefits (HR, 0.87 [0.66–1.13]) were noted with ICD use among dialysis patients with HFrEF at follow-ups of both 1 (ICD, 42.2%; no ICD, 38.1%) and 3 years (ICD, 68.6%; no ICD, 75.7%), and the results were consistent on propensity-matching as well (HR, 0.94 [0.67–1.31]) (Table 1).
In contrast, results from a multicenter registry study by Hiremath et al. that included 100 patients on dialysis and with LV dysfunction showed that ICD use significantly reduced the incidence of all-cause mortality (HR, 0.40 [0.19–0.82]) compared to patients not having ICDs (Table 1).
In a subgroup analysis specific to patients with LVEF < 35% (n = 91), ICD use significantly reduced the risk of all-cause mortality (HR, 0.32 [0.15–0.71]) as well.
No safety concerns were reported in either of these studies.
The recent ICD2 trial aimed to evaluate the effect of prophylactic ICD use in patients on dialysis but without significant LV dysfunction (LVEF > 35%). Although relatively healthy patients on dialysis were recruited in this trial so as to attain significant survival benefit, the trial was terminated early due to futility. ICD usage did not reduce the incidence of sudden cardiac death (HR, 1.32 [0.53–3.29]) or all-cause mortality (HR, 1.02 [0.69–1.52]).
Prophylactic use of implantable cardioverter-defibrillators in the prevention of sudden cardiac death in dialysis patients: the prospective, randomized, controlled ICD2 trial.
In fact, more than 50% of the patients died during the follow-up period. Interestingly, the major cause of death was found to be infections (ICD, 15/97; control, 14/91) followed by sudden cardiac death.
Prophylactic use of implantable cardioverter-defibrillators in the prevention of sudden cardiac death in dialysis patients: the prospective, randomized, controlled ICD2 trial.
Although this trial was not specific to patients with HF, it provides important insights regarding the risks and benefits of ICD therapy in patients on dialysis.
Subcutaneous ICD implantation has been found to reduce the risk of infections associated with transvenous ICD implantation in patients on dialysis and is likely to be a safer alternative.
However, current literature has conflicting evidence regarding the efficacy and safety of ICD therapy in patients with HF and on dialysis, and its usage should generally be avoided until further evidence is available.
Cardiac Resynchronization Therapy
The effectiveness of CRT in patients with HFrEF and on dialysis remains questionable owing to the lack of pertinent RCTs and the exclusions of these high-risk patients from landmark clinical trials. Few observational studies have evaluated the effectiveness of CRT in patients with HF and on dialysis. A case-control study evaluating the effectiveness and safety of CRT in 15 patients on dialysis and with HF demonstrated that CRT increased the risk of all-cause mortality (CRT, 73%; control, 44%; P= 0.038) and all-cause hospitalizations (CRT, 100%; control, 76%; P= 0.047), but it did not significantly affect hospitalizations due to HF (CRT, 31%; control, 45%; P= 0.39) when compared with matched controls (Table 1).
In contrast, a large retrospective analysis based on almost 11,000 patients with HFrEF and advanced CKD (stages 3–5), including those on dialysis, showed that the use of CRT with defibrillators significantly reduced the risk of mortality (CRT-D, 2936/9525; ICD, 569/1421; HR, 0.84 [0.76–0.94]) and hospitalizations due to HF(CRT-D, 2722/9525; ICD, 529/1421; HR, 0.81 [0.72–0.91]) when compared with ICD.
The clinical benefits yielded were sustained across all classes of CKD. Overall complication rates (in-hospital: CRT-D, 6.0% vs ICD, 5.8%; 30-day: CRT-D, 5.0% vs ICD, 4.7%; 90-day: CRT-D, 0.3% vs ICD, 0.4%) and rates for individual complications such as hematoma (in-hospital: CRT-D, 2.5% vs ICD, 2.3%; 30-day: CRT-D, 3.2% vs ICD, 3.0%), pneumothorax or hemothorax (in-hospital: CRT-D, 0.9% vs ICD, 1.1%; 30-day: CRT-D, 1.1% vs ICD, 1.2%), cardiac tamponade or pericardial effusion requiring pericardiocentesis (in-hospital: CRT-D, 0.6% vs ICD, 0.9%; 30-day: CRT-D, 0.9% vs ICD, 1.1%), and device-related infections (90-day: CRT-D, 0.3% vs ICD, 0.4%) were also similar in the CRT-D and ICD groups.
However, patients with HF and on dialysis were not evaluated separately in this study.
Given the paucity of evidence and the presence of conflicting findings regarding the usefulness of CRT in patients on dialysis and with HF, no definitive conclusions can be reached unless further evidence specific to patients on dialysis and with HF is generated.
Left Ventricular Assist Devices
Dialysis-dependent patients with advanced CKD or ESKD are often not recommended for left ventricular assist device (LVAD) implantation due to concerns about poor patient prognosis and increased mortality rates (> 60%) owing to LVAD implantation-related complications. Moreover, dialysis centers have typically avoided accepting high-risk patients with LVADs. In a retrospective analysis by Kirklin et al. that included 4917 patients from Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS), continuous-flow LVAD implantation was associated with a 22% mortality rate at a 3-month follow-up in patients with HF on dialysis and those with eGFRs < 30 mL/min/1.73 m2.
Similarly, an 11-year-long observational study by Bansan et al. showed that most of the patients (81.9%) with ESKD died during follow-up after LVAD implantation, with the median time to death being only 16 days for patients with ESKD compared with 2125 days for those without ESKD. However, this study was not specific to patients with HF and on dialysis.
LVAD implantation complicates the management of patients receiving maintenance dialysis; the risks are more pronounced in patients on HD compared with those on PD. Lack of a pulsatile blood pressure in patients with continuous-flow LVAD implants may result in ventricular arrythmias due to low ventricular volumes and pressures caused by ultrafiltration during dialysis. The slower ultrafiltration rate among patients on PD confers greater stability in these patients. In addition, patients on HD are less likely to preserve residual renal function and more likely to have bacteremia and other infections. A recent case report by Ajuria et al. showed that transitioning to PD from HD improved kidney function significantly for an obese woman with nonischemic HFrEF and hypertension.
In addition, PD was found to be safer and more well tolerated compared with HD. Interestingly, studies have also displayed survival and clinical benefits associated with chronic intermittent HD. Although current evidence indicates worsening of patient prognosis and poor survival rates in patients with HF and on dialysis receiving LVAD implantation, the use of PD or intermittent HD may be a safer alternative for these high-risk patients.
Transcatheter Mitral Valve Repair
Clinical trials and observational studies evaluating the usage of MitraClip in patients with HF and on dialysis are lacking. In a case report of a patient with HF and on HD by Sato et al., transcatheter mitral valve replacement (TMVR) using MitraClip significantly reduced mitral regurgitation and improved NYHA functional class from II to I without any postoperative complications.
However, non-HF-specific observational studies evaluating patients on dialysis have revealed potential futility regarding the use of MitraClip in this high-risk patient cohort. In a large retrospective study (n = 13,563) using the Nationwide Readmissions Database (NRD), Raheja et al. showed that patients with ESKD on dialysis (n = 476) undergoing TMVR had significantly higher rates of in-hospital mortality (7.2% vs 2.5% vs 2.0%; P< 0.001), greater incidence of bleeding (16.6% vs 10.3% vs 10.0%; P= 0.003), blood transfusions (19.7% vs 8.1% vs 6.0; P< 0.001), and 30-day all-cause readmission (22.7% vs 15.6% vs 13.7%; P< 0.001) compared with patients with CKD or no CKD, respectively.
Although this study was not specific to patients with HF, a large proportion of patients had HF at baseline in all the 3 groups (ESKD, 80.2%; CKD, 87.1%; no CKD, 74.5%), and chronic HF was found to be the most common cause of hospital readmission post MitraClip placement.
Similarly, Shah et al. showed that patients on dialysis (n = 154) were at an almost 5-fold increase in risk of primary composite outcome of all-cause mortality, stroke and new requirement for dialysis (OR, 4.93 [2.33–10.5]) compared to patients with a creatinine clearance > 60 mL/min.
Outcomes after transcatheter mitral valve repair in patients with renal disease: insights from the Society of Thoracic Surgeons/American College of Cardiology national cardiovascular data registry, transcatheter valve therapy registry.
Upon multivariable adjustment, patients on dialysis were significantly associated with a higher risk of any bleeding event at 1 year (HR, 2.11 [1.31–3.41]) and all-cause mortality, both at 30-day (HR, 3.31 [1.79–6.13]) and 1-year (2.44 [1.66–3.57]) follow-ups when compared with patients with creatinine clearances > 60 mL/min.
Outcomes after transcatheter mitral valve repair in patients with renal disease: insights from the Society of Thoracic Surgeons/American College of Cardiology national cardiovascular data registry, transcatheter valve therapy registry.
In contrast, a large national study (n = 2197) by Doshi et al. showed that TMVR significantly reduced in-hospital mortality rates (OR, 0.06 [0.01–0.56]) and stroke (OR, 0.05 [0.03—0.07]) in patients with ESKD (n = 1,628) when compared with surgical mitral valve replacement.
Comparison of transcatheter mitral valve repair versus surgical mitral valve repair in patients with advanced kidney disease (from the national inpatient sample).
However, few patients had HF at baseline in this study. In the future, clinical trials and observational studies specific to patients with HF and on dialysis need to be conducted to evaluate the efficacy of transcatheter therapeutics in this population of high-risk patients.
Heart and Kidney Transplantation
Patients with concomitant advanced HF and ESKD on dialysis constitute an extremely high-risk population and are more susceptible to complications after transplantation. The incidence of dialysis-dependent acute renal failure post heart transplantation remains an important clinical issue.
A recent analysis by Shoji et al. revealed a 5-fold greater risk in the incidence of all-cause mortality (HR, 5.2 [4.7–5.7]) in patients receiving dialysis after heart transplantation.
Therefore, simultaneous heart and kidney transplant (SHKT) is generally recommended in patients with concomitant end-stage HF and ESKD on dialysis.
In a retrospective analysis of the United Network for Organ Sharing database, Schaffer et al. showed that patients with end-stage HF on dialysis receiving SHKT had better post-transplant survival rates than propensity-matched heart transplant alone (HTA) patients (1 year, 84% vs 69%; 5 years, 73% vs 51%; P < 0.001).
In addition, multiple non-HF-specific observational studies have shown that SHKT offers greater survival rates and clinical benefits than HTA in patients with ESKD.
Prior studies (although not HF-specific) have also shown that patients undergoing SHKT have a lower risk of acute rejection compared with patients receiving HTA.
Another study has demonstrated that the effectiveness of SHKT over HTA is sustained across various age groups (≥ 60 and < 60 years) and in both dialysis-dependent and nondialysis-dependent patients with renal insufficiency.
In contrast, a recent observational analysis by Melvinsdottir et al. included 845 patients with end-stage heart and kidney failure and revealed a 4.7-fold increase in the risk of mortality (HR, 4.77 (2.41–9.44]) when compared with patients who underwent kidney transplant after heart transplant.
However, not all patients included in this study were on dialysis. Nonetheless, this mode of subsequent transplantation needs to be assessed further in comparison with simultaneous dual-organ transplantation.
Dialysis in HF
Dialysis Modality Preference
Multiple observational studies have compared HD to PD in patients with HF. A retrospective propensity score-matched study in 2019 included 65,899 patients and showed that HD was associated with higher incidence rates of HF (HR, 1.45 [1.23–1.70]) compared with PD.
A comparison of the risk of congestive heart failure-related hospitalizations in patients receiving hemodialysis and peritoneal dialysis: a retrospective propensity score-matched study.
However, in patients with established HF, evidence is conflicting, although it is overall in favor of HD. An observational study of 3468 patients on HD and 933 patients on HD showed that PD significantly increased the risk of overall and cardiovascular mortality compared with HD.
In contrast, a smaller retrospective cohort study of 69 patients on PD and 195 patients on HD revealed no difference in overall survival, although deaths due to cardiovascular cause were significantly increased with PD (PD, 64.4%; HD, 37.9%; P= 0.001).
Although observational studies of patients with HF and ESKD seem to favor HD for clinical endpoints, there is some evidence of favorable surrogate endpoints and functional status with PD. A systematic review and meta-analysis of 31 studies showed that PD significantly increased LVEF (mean difference, 3.76% [2.24–5.27]) and NYHA functional class.
Patients with HF on PD also had a reduced frequency of hospitalization or length of stay after PD was introduced (mean difference, −26.9, [−36.9 to −16.83]).
Given the limitations of observational analysis, clear recommendations concerning the use of PD vs HD in patients with HF cannot be offered. Factors impacting the decision include patient preferences for lifestyle and for participating in the dialysis process and the recommendations of the collaborating nephrologist.
Modifications in Dialysis Procedure
In a small study including ESKD patients with concomitant HF (n = 6), conversion to frequent nocturnal HD significantly increased the LVEF (from 28%–42%; P= 0.01), reduced the systolic (138 mmHg–120 mmHg; P= 0.04) and mean arterial BP (99 mmHg to 86 mmHg; P= 0.01), and decreased the number of prescribed cardiovascular medications (from 2.2%–0.7%; P= 0.02) when compared with conventional HD at baseline.
Cardiovascular benefits of intensive HD were also noted in the Frequent Hemodialysis Network Daily Trial (n = 245), where 6 times-weekly, in-center HD significantly reduced left ventricular mass (mean change, −13.1 [−21.3, −5.0]; P= 0.002) and the risk of mortality (HR, 0.54 [0.31–0.93]).
However, this trial was not specific to patients with HF.
Home HD is another potential alternative that has multiple clinical benefits, including blood pressure and extracellular volume control, reduction in LV hypertrophy and improvements in LVEF.
In a retrospective cohort study (n = 144) by Trinh et al., LV hypertrophy regression due to home HD was significantly associated with a decrease in the risk of mortality (HR 0.24 [0.08–0.77]).
Home HD can possibly alleviate the hemodynamic shifts by reducing interdialytic gaps and decreasing the intensity of ultrafiltration associated with thrice-weekly conventional HD, but there is a dearth of evidence specific to patients with HF.
Although conventional HD is subject to increased risks due to greater ultrafiltration rates and relative lack of preservation of residual renal function, modifications in HD have proven to be beneficial. For instance, cooled dialysate, extracorporeal ultrafiltration, higher levels of dialysate sodium and calcium and use of midodrine have yielded significant improvements in the efficacy and safety of the HD procedure.
However, current literature lacks evidence for the efficacy of these modifications in patients with HF and on dialysis.
Management of Arteriovenous Fistula
The arteriovenous fistula (AVF) is the preferred vascular access for patients on chronic HD, compared with arteriovenous graft (AVG) (which have shorter secondary patency following successful cannulation) and tunneled central venous catheter (which are susceptible to an increased risk of infections, thrombosis, hospitalizations, and mortality).
The resulting extra demand on cardiac output due to AVF creation can worsen the progression of HF.
In a retrospective cohort study including 137 patients on HD, AVF/AVG creation significantly increased the risk of RV dilation, RV dysfunction and left atrial dilation.
Patients developing incident HF had significantly greater increments in left atrial volume and worsening of both RV dilation and dysfunction compared with patients who did not develop incident HF.
A subgroup analysis of 35 patients who underwent AVF ligation revealed reductions in left ventricular end diastolic diameter and LV mass index and stability or improvement in RV function, but there were no significant changes in LV systolic or diastolic function nor any significant reverse RV remodeling.
The ideal approach may be the prevention of worsening HF while maintaining AVF access, but balancing them simultaneously is often not possible, and AVF may have to be ligated, causing loss of vascular access.
However, these are proposed approaches for the management of high-output HF, and current literature lacks evidence of their efficacy and safety in patients with HF. Although the use of a central venous catheter is the least desirable form of vascular access, the risk of infection, morbidity and mortality should be weighed against the risk of increasing HF progression and should be compared with AVF in patients with HF. The aggravating progression of HF with AVF can possibly render PD as a preferred modality over HD in patients with HF.
Myocardial Stunning
Myocardial stunning is a well-established complication of HD and is more commonly observed in patients receiving thrice-weekly HD. HD-induced myocardial stunning has been found to be associated with an increased risk of mortality at 12 months and may even lead to the incidence of HF.
In a small cross-sectional study including patients (n = 46) with a mean LVEF 30%–40%, all patients receiving thrice-weekly conventional HD were found to have myocardial stunning compared with 92% of patients receiving more frequent HD, 5--6 times/week, 75% of patients receiving frequent home HD, and 50% of patients receiving home nocturnal HD.
Patients on more frequent HD schedules had lower volumes and rates of ultrafiltration, decreased markers of inflammation and less myocardial intracellular damage; hence, they were less likely to develop dialysis-induced myocardial stunning compared with conventional thrice-weekly HD.
Prolonged dialysis sessions (median 24 hours/week) have also been found to be associated with improved cardiac systolic function by reduction in LV mass index and improvements in LVEF.
Individualised dialysate temperature improves intradialytic haemodynamics and abrogates haemodialysis-induced myocardial stunning, without compromising tolerability.
There are several ways to mitigate this concern. Given that the kidneys are the main source for K+ excretion mainly, limiting food sources rich in potassium may reduce serum potassium levels. The usage of novel potassium binders, such as patiromer or sodium zirconium silicate, may offer an effective strategy to prevent hyperkalemia while allowing for optimization of foundational therapies for HF.
The potassium binder patiromer was associated with a reduction in serum potassium and lesser discontinuations of RAAS inhibitors in the 4-week PEARL-HF (Evaluation of Patiromer in Heart Failure Patients) and 12-week OPAL-HK (A Two-Part, Single-Blind, Phase 3 Study Evaluating the Efficacy and Safety of Patiromer for the Treatment of Hyperkalemia) trials.
Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a double-blind, placebo-controlled study in patients with chronic heart failure (the PEARL-HF) trial.
Effect of patiromer on reducing serum potassium and preventing recurrent hyperkalaemia in patients with heart failure and chronic kidney disease on RAAS inhibitors.
In the DIAMOND (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAAS inhibitor Medications for the Treatment of Heart Failure) trial, patiromer was associated with a reduced the incidence of severe hyperkalemia (> 5.5 mEq/L) and enabled optimization of guideline-directed medical doses of RAAS inhibitors in 85% of the included patients with HFrEF.
Patiromer for the management of hyperkalaemia in patients receiving renin-angiotensin-aldosterone system inhibitors for heart failure: design and rationale of the DIAMOND trial.
Nonetheless, it must be emphasized that there is no current evidence to support the use of novel potassium binders in patients on dialysis; further investigation is needed.
SGLT2 inhibitors reduce the risk of hyperkalemia while enabling optimization of GDMT in patients with HF. In a recent analysis of the EMPEROR-Pooled (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure--EMPEROR-Reduced and EMPEROR-Preserved combined) HF population, empagliflozin reduced the rates of hyperkalemia compared with placebo (serum potassium > 5.5 mmol/L: HR, 0.85 [0.74, 0.97]; serum potassium > 6.0 mmol/L: HR, 0.62 [0.48, 0.81]) without significantly increasing the incidence of hypokalemia (investigator-reported HR, 1.20 [0.91, 1.57]; serum potassium < 3.0 mmol/L: HR, 1.35 [0.75, 2.45]).
Although these findings are not directly applicable to patients with HF on dialysis, SGLT2 inhibitors can potentially enable the continuation and optimization of other HF therapies in patients with HF on dialysis as well.
Another approach to managing hyperkalemia in patients with HF on dialysis includes reduction of the dialysate K+ concentration. Close monitoring of electrolyte levels is required to allow for effective management of hyperkalemia in these high-risk patients.
Management of Blood Pressure
Blood pressure (BP) control in patients on dialysis remains challenging. In fact, BP in patients on dialysis is often measured incorrectly, and readings taken at dialysis units hold less prognostic value.
Hypertension in dialysis patients: a consensus document by the European Renal and Cardiovascular Medicine (EURECA-m) working group of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and the Hypertension and the Kidney working group of the European Society of Hypertension (ESH).
Evidence has suggested that BP taken the morning, after dialysis, is most accurate and reliable. Multiple observational studies have shown a U-shaped relationship between pre-HD systolic BP (SBP) and mortality in patients on dialysis.
Postdialysis SBP > 180 mmHg and diastolic BP (DBP) > 90 mmHg are associated with an increased risk of cardiovascular mortality. In patients with HFrEF and on dialysis, in particular, predialysis BP values of < 120 mmHg, considered to be within the normal range, increased the risk of cardiovascular mortality more than higher BP values.
In fact, lower predialysis SBP and mean arterial pressure were associated with increased mortality rates, whereas higher postdialysis SBP and mean arterial pressure were associated with increased mortality rates. Whether this represents association vs causation is not clear.
It is important to note that predialysis and postdialysis BP are subject to several limitations and cannot be used as reliable metrics for diagnosing hypertension or assessing long-term cardiovascular risk in patients on dialysis.
Hypertension in dialysis patients: a consensus document by the European Renal and Cardiovascular Medicine (EURECA-m) working group of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and the Hypertension and the Kidney working group of the European Society of Hypertension (ESH)∗.
Prevalence and control of hypertension by 48-h ambulatory blood pressure monitoring in haemodialysis patients: a study by the European Cardiovascular and Renal Medicine (EURECA-m) working group of the ERA-EDTA.
The white-coat effect, masked hypertension, limited time for patient relaxation before or after the dialysis procedure, and variability in volume status during the intra- and interdialytic periods render this method imprecise for BP management in dialysis patients.
Hypertension in dialysis patients: a consensus document by the European Renal and Cardiovascular Medicine (EURECA-m) working group of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and the Hypertension and the Kidney working group of the European Society of Hypertension (ESH)∗.
A meta-analysis has shown that both pre- and postdialysis BP measurements give inaccurate estimates of the mean interdialytic BP measured by ambulatory BP monitoring, with the predialysis diastolic BP overestimating the ambulatory BP (ABP) and the postdialysis systolic and diastolic BP underestimating the ABP.
Ambulatory BP monitoring is considered the gold standard for diagnosing hypertension in patients on dialysis and has been found to predict all-cause and cardiovascular mortality better than peridialytic BP.
Hypertension in dialysis patients: a consensus document by the European Renal and Cardiovascular Medicine (EURECA-m) working group of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and the Hypertension and the Kidney working group of the European Society of Hypertension (ESH)∗.
Hypertension in dialysis patients: a consensus document by the European Renal and Cardiovascular Medicine (EURECA-m) working group of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and the Hypertension and the Kidney working group of the European Society of Hypertension (ESH).
Given that PD is a better way to remove fluid than HD, it is likely that patients on PD have better BP control and, hence, do better, even in the setting of concomitant HF. Nonpharmacological measures for reducing hypertension include control of dietary sodium intake, attainment of dry weight and reduction in dialysate sodium concentration.
Antihypertensive medications, however, remain the cornerstone treatment for hypertension in patients with HF and on dialysis. It is imperative that in these instances, antihypertensive medications, which are not life-prolonging, such as clonidine and nifedipine, be switched to foundational HF therapies that are effective in controlling blood pressure and potentially prolonging survival as well.
In the future, studies specific to patients with HF and on dialysis should be conducted to evaluate the relationship of BP with important clinical outcomes and to ascertain the U-shaped paradoxical association between BP and mortality. Research focused on determining the ideal BP range for patients with HF and on dialysis is also needed. Based on the current dearth of evidence, the BP control in patients with HF on dialysis should be guided toward avoiding symptomatic hypotension and hypotension limiting effective dialysis, particularly for patients receiving HD.
Challenges and Future Directions
Fig. 2 summarizes the barriers to and possible solutions for patients with HF and on dialysis. One of the major reasons for the undertreatment of HF in patients on dialysis is the lack of reliable evidence from well-powered RCTs. Few to no RCTs specific to patients with HF and on dialysis have been conducted; the majority of evidence to date is derived from observational studies, which are inherently subject to confounding and biases. Moreover, exclusions of these high-risk patients from landmark RCTs of drug and device interventions for HF make it even more difficult to ascertain the efficacy and safety of these therapeutic agents in dialysis-dependent patients with HF. Conflicting findings from observational studies further complicate the assessment, consequently, leaving the important drug efficacy and safety questions unanswered for these high-risk patients. In addition, perceived concerns regarding the safety and tolerability of GDMT for HF in dialysis-dependent patients have led to discontinuations of therapies, thereby compromising the management of HF in these patients. Fig. 3 gives an overview of the proposed clinical approach in patients with HF on dialysis (Visual Take Home Graphic).
Fig. 2Current 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.
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 cardiovascular outcome trials that that have confirmed the efficacy of therapies in nondialysis patients with HF, patients with HF and on dialysis are generally frailer, older and have poorer prognoses.
Thus, the degree to which the safety and efficacy seen in the prior landmark trials of HF therapies generalize to patients with ESKD and on dialysis are generally uncertain. It may be feasible to answer these research questions with pragmatic RCTs, leveraging the benefits of randomization to determine cause-effect relationships while potentially maximizing application to the generally multimorbid ESKD population encountered in routine practice.
Conclusion
In patients with HF who are receiving dialysis, despite being at substantially higher risk for morbidity and mortality, there is a critical lack of reliable evidence to guide management and inform best practice. Owing to perceived concerns about the effectiveness and safety of conventional therapies for HF, clinicians have been reluctant to prescribe these medications. Trial-level evidence is warranted in the future to endorse the efficacy and safety of therapeutic HF interventions in patients on dialysis. Collaborations between the cardiologists and nephrologists are needed to devise an optimal treatment strategy for these patients.
Brief Lay Summary
Heart failure (HF) and end-stage kidney disease (ESKD) frequently coexist, with 1 comorbidity worsening the prognosis of the other. Some randomized clinical trials have evaluated the efficacy of therapies in patients with HF and chronic kidney disease, but data regarding the management of HF in patients with ESKD and undergoing dialysis remain very limited. Trial-level evidence is warranted in the future to endorse the efficacy and safety of therapeutic interventions in patients with HF and on dialysis. Collaborations between the cardiologists and nephrologists are needed to devise an optimal treatment strategy for these patients.
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There is a paucity of data regarding the management of heart failure in patients on dialysis. Trial-level evidence is warranted in the future to endorse the efficacy and safety of therapeutic interventions for heart failure in patients on dialysis, and collaborations between the cardiologists and nephrologists are needed. @ShahzebKhanMD; @gcfmd
Renal dysfunction in patients with heart failure with preserved versus reduced ejection fraction impact of the new chronic kidney disease-epidemiology collaboration group formula.
Trends in the use of guideline-directed therapies among dialysis patients hospitalized with systolic heart failure: findings from the American Heart Association Get With The Guidelines-Heart Failure program.
Packer M, Coats AJS, Fowler MB, Katus HA, Krum H, Mohacsi P, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:1651–8. doi: 10.1056/NEJM200105313442201
Prognostic benefits of carvedilol, bisoprolol, and metoprolol controlled release/extended release in hemodialysis patients with heart failure: a 10-year cohort.
Use of angiotensin receptor neprilysin inhibitor in patients on maintenance hemodialysis with reduced cardiac ejection fraction, real-world experience from a single center.
Angiotensin receptor-neprilysin inhibitors in patients with heart failure with reduced ejection fraction and advanced chronic kidney disease: a retrospective multi-institutional study.
Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial.
Effects of telmisartan added to angiotensin-converting enzyme inhibitors on mortality and morbidity in hemodialysis patients with chronic heart failure: a double-blind, placebo-controlled trial.
Effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on cardiovascular events and residual renal function in dialysis patients: a meta-analysis of randomised controlled trials.
Prophylactic use of implantable cardioverter-defibrillators in the prevention of sudden cardiac death in dialysis patients: the prospective, randomized, controlled ICD2 trial.
Outcomes after transcatheter mitral valve repair in patients with renal disease: insights from the Society of Thoracic Surgeons/American College of Cardiology national cardiovascular data registry, transcatheter valve therapy registry.
Comparison of transcatheter mitral valve repair versus surgical mitral valve repair in patients with advanced kidney disease (from the national inpatient sample).
A comparison of the risk of congestive heart failure-related hospitalizations in patients receiving hemodialysis and peritoneal dialysis: a retrospective propensity score-matched study.
Individualised dialysate temperature improves intradialytic haemodynamics and abrogates haemodialysis-induced myocardial stunning, without compromising tolerability.
Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a double-blind, placebo-controlled study in patients with chronic heart failure (the PEARL-HF) trial.
Effect of patiromer on reducing serum potassium and preventing recurrent hyperkalaemia in patients with heart failure and chronic kidney disease on RAAS inhibitors.
Patiromer for the management of hyperkalaemia in patients receiving renin-angiotensin-aldosterone system inhibitors for heart failure: design and rationale of the DIAMOND trial.
Hypertension in dialysis patients: a consensus document by the European Renal and Cardiovascular Medicine (EURECA-m) working group of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and the Hypertension and the Kidney working group of the European Society of Hypertension (ESH).
Hypertension in dialysis patients: a consensus document by the European Renal and Cardiovascular Medicine (EURECA-m) working group of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and the Hypertension and the Kidney working group of the European Society of Hypertension (ESH)∗.
Prevalence and control of hypertension by 48-h ambulatory blood pressure monitoring in haemodialysis patients: a study by the European Cardiovascular and Renal Medicine (EURECA-m) working group of the ERA-EDTA.
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