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Managing Heart Failure in Patients on Dialysis: State-of-the-Art Review

Open AccessPublished:October 12, 2022DOI:https://doi.org/10.1016/j.cardfail.2022.09.013

      Bullet Points

      • Heart failure and end-stage kidney disease (ESKD) commonly coexist; 1 comorbidity worsens the prognosis of the other.
      • 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.
      • 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.

      Key Words

      Approximately half of the patients with heart failure (HF) have coexisting chronic kidney disease (CKD).
      • McAlister FA
      • Ezekowitz J
      • Tarantini L
      Renal dysfunction in patients with heart failure with preserved versus reduced ejection fraction impact of the new chronic kidney disease-epidemiology collaboration group formula.
      ,
      • House AA
      • Wanner C
      • Sarnak MJ
      • Piña IL
      • McIntyre CW
      • Komenda P
      • et al.
      Heart failure in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.
      Likewise, up to 70% of the patients with CKD and 36% of the patients with end-stage kidney disease (ESKD) requiring dialysis have HF.
      • Waldum-Grevbo B.
      What physicians need to know about renal function in outpatients with heart failure.
      ,
      • Bhatti NK
      • Karimi Galougahi K
      • Paz Y
      • Nazif T
      • Moses JW
      • Leon MB
      • et al.
      Diagnosis and management of cardiovascular disease in advanced and end-stage renal disease.
      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.
      • Tong J
      • Liu M
      • Li H
      • Luo Z
      • Zhong X
      • Huang J
      • et al.
      Mortality and associated risk factors in dialysis patients with cardiovascular disease.
      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.
      • McMurray JJV
      • Wheeler DC
      • Stefánsson BV
      • Jongs N
      • Postmus D
      • Correa-Rotter R
      • et al.
      Effects of dapagliflozin in patients with kidney disease, with and without heart failure.
      ,
      • Wali RK
      • Iyengar M
      • Beck GJ
      • Chartyan DM
      • Chonchol M
      • Lukas MA
      • et al.
      Efficacy and safety of carvedilol in treatment of heart failure with chronic kidney disease: a meta-analysis of randomized trials.
      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.
      K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients.
      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.
      • McDonagh TA
      • Metra M
      • Adamo M
      • Gardner RS
      • Baumbach A
      • Böhm M
      2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.
      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.
      • Pandey A
      • Golwala H
      • DeVore AD
      • Lu D
      • Madden G
      • Bhatt DL
      • et al.
      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.
      • Pandey A
      • Golwala H
      • DeVore AD
      • Lu D
      • Madden G
      • Bhatt DL
      • et al.
      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.
      More recent data from GWTG-HF from 2014 to 2019 also demonstrated less adherence to GDMT at discharge with increasing severity of CKD.
      • Patel RB
      • Fonarow G
      • Greene S
      • Zhang S
      • Alhanti B
      • DeVore A
      • et al.
      Clinical profiles, medical therapies, and outcomes among patients hospitalized for HF across the spectrum of kidney function: the GWTG-HF registry.
      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.
      • Patel RB
      • Fonarow G
      • Greene S
      • Zhang S
      • Alhanti B
      • DeVore A
      • et al.
      Clinical profiles, medical therapies, and outcomes among patients hospitalized for HF across the spectrum of kidney function: the GWTG-HF registry.
      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 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.

      Beta-Blockers

      Multiple trials demonstrate that beta-blockers reduce HF hospitalizations and cardiovascular mortality rates in patients with HFrEF.

      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

      ,
      • Dargie HJ
      • Lechat P.
      The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial.
      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.
      • Frankenfield DL
      • Weinhandl ED
      • Powers CA
      • Howell BL
      • Herzog CA
      • St. Peter WL
      Utilization and costs of cardiovascular disease medications in dialysis patients in Medicare Part D.
      There is only 1 RCT of 114 patients that evaluated the effect of beta-blockers in patients with HF and on dialysis (Table 1).
      • Cice G
      • Ferrara L
      • Di Benedetto A
      • Russo PE
      • Marinelli G
      • Pavese F
      • et al.
      Dilated cardiomyopathy in dialysis patients: beneficial effects of carvedilol: a double-blind, placebo-controlled trial.
      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.
      • Cice G
      • Ferrara L
      • Di Benedetto A
      • Russo PE
      • Marinelli G
      • Pavese F
      • et al.
      Dilated cardiomyopathy in dialysis patients: beneficial effects of carvedilol: a double-blind, placebo-controlled trial.
      Furthermore, patients receiving carvedilol rather than placebo were less likely to have NYHA functional class III or IV.
      • Cice G
      • Ferrara L
      • Di Benedetto A
      • Russo PE
      • Marinelli G
      • Pavese F
      • et al.
      Dilated cardiomyopathy in dialysis patients: beneficial effects of carvedilol: a double-blind, placebo-controlled trial.
      Table 1Completed RCTs and Key Observational Studies Evaluating HF Therapies Among HF Patients on Dialysis
      Study NameYearInterventionControlSample SizePopulationKey FindingsSafety ConcernsFollow-up (months)
      RCTs Evaluating HF Patients on Dialysis
      Cice et al.2001CarvedilolPlacebo114Patients with uremia, HFrEF (LVEF <35%) and dilated cardiomyopathy on periodic HD treatmentSignificant improvements in LVEF, LVEDV, LVESV, and NYHA functional classNo 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 arm12
      Cice et al.2003CarvedilolPlacebo114Patients with uremia, HFrEF (LVEF <35%) and dilated cardiomyopathy on periodic HD treatmentSignificant reductions in all-cause mortality, CV mortality, hospitalization for worsening HF and all-cause hospitalizationsNo 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.2010TelmisartanPlacebo332Patients with chronic HFrEF (LVEF <40%) on HD; NYHA functional class II–IIISignificant 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.2009SpironolactonePlacebo16Patients with HFrEF (LVEF <45%) and NYHA functional classes III–IV on chronic HD treatment (3 sessions/week) since at least 1 month before the studySignificant increase in LVEF and significant decrease in LV massNo significant risk of hyperkalemia (2 patients reported hyperkalemia in placebo arm only).6
      Taheri et al.2012SpironolactonePlacebo18Patients with HFrEF (LVEF≤45%) and NYHA class III or IV HF on CAPD, having a serum potassium ≤5.5 mEq/LSignificant increase in LVEFNo significant risk of hyperkalemia6
      Selectd observational studies evaluating HF patients on dialysis
      Tang et al.2016Beta-blockers, namely carvedilol, bisoprolol and metoprolol CR/XLNonusers of beta-blockers3400Patients with HF on long‐term HD (≥26 HD sessions within 3 months of commencing HD)Significant reduction in the risk of all-cause mortalityNot reportedNA
      Zhou et al.2021Beta-blockers at transitionNo beta-blockers at transition3503Patients aged ≥18 years with CKD and documented HF (5 years before dialysis initiation) on HD or PDSignificant reductions in the risk of mortality at 6 months and 12 monthsNot reported6
      Wang et al.2021ARNINA110Patients aged >18 years with HFrEF (LVEF ≤40%) and NYHA functional classes II–IV undergoing maintenance HDSignificant improvements in LVEF, LVEDD, LVESD, LAD, KCCQ scores, and NYHA functional classNot reported12
      Lee et al.2020sacubitril/valsartanNA23Patients aged >18 years with HFrEF (LVEF ≤35%) and anuric ESKD on HD or PD since more than 6 monthsSignificant 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) noted4.4
      Hsiao et al.2022ARNIACE inhibitors and ARBs1039 (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 2018Significant 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 CKDSignificant 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 patients12
      Tang et al.2013RAS blockers (ACE inhibitors and ARBs)No RAAS blockers4,771Patients 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 mortalityNot reported36
      Berger et al.2007ACE inhibitors and ARBsNA2,169Patients with chronic HF and CKD with data available for weight and serum creatinine enabling to calculate serum GFRNo significant reductions in mortality at 30 days or 1 year among dialysis patients with HFNot reported12
      Lee et al.2019MRANA3464ESKD patients on HD having HF at ESKD incidence in the USRDS between 2006–2014Significant increase in the risk of mortality; no significant effect on time to first HF admission or time to first hyperkalemia admissionNot reportedNA
      Pun et al.2015ICDno ICD303Patients 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 excludedNo significant reductions in mortality at 1 and 3 yearsNot reported56.4 (ICD registry); 34.8 (GWTG-HF registry)
      Hiremath et al.2010ICDno ICD100ESKD patients with ICD and ESKD patients with left ventricular dysfunction (LVEF <35%) on dialysis for > 3 monthsSignificant reduction in the risk of all-cause mortalityNot reportedNA
      Friedman et al.2013CRTMatched control15Patients with ESKD and HFrEF (LVEF <35%), on dialysis having NYHA functional class III or IV and QRS duration of >120 msSignificant increase in the risk of all-cause mortality and all-cause hospitalizations but no significant effect on HF hospitalizationsNot reported36
      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.
      At 2-year follow-up, patients receiving carvedilol had a 49% lower mortality rate than patients receiving placebo (HR = 0.51 [0.32 – 0.82]) (Table 1).
      • Cice G
      • Ferrara L
      • D'Andrea A
      • D'Isa S
      • Di Benedetto A
      • Cittadini A
      • et al.
      Carvedilol increases two-year survivalin dialysis patients with dilated cardiomyopathy: a prospective, placebo-controlled trial.
      In addition, patients receiving carvedilol had significant reductions in cardiovascular mortality rates (HR, 0.32 [0.18–0.57]), hospitalization for worsening HF (HR, 0.19 [0.09–0.41]) and all-cause hospitalizations (HR, 0.44 [0.25–0.77]).
      • Cice G
      • Ferrara L
      • D'Andrea A
      • D'Isa S
      • Di Benedetto A
      • Cittadini A
      • et al.
      Carvedilol increases two-year survivalin dialysis patients with dilated cardiomyopathy: a prospective, placebo-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.
      • Cice G
      • Ferrara L
      • D'Andrea A
      • D'Isa S
      • Di Benedetto A
      • Cittadini A
      • et al.
      Carvedilol increases two-year survivalin dialysis patients with dilated cardiomyopathy: a prospective, placebo-controlled trial.
      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.
      • Tang CH
      • Wang CC
      • Chen TH
      • Hong CY
      • Sue YM.
      Prognostic benefits of carvedilol, bisoprolol, and metoprolol controlled release/extended release in hemodialysis patients with heart failure: a 10-year cohort.
      ,
      • Zhou H
      • Sim JJ
      • Shi J
      • Shaw SF
      • Lee MS
      • Neyer JR
      • et al.
      β-blocker use and risk of mortality in heart failure patients initiating maintenance dialysis.
      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).
      • Tang CH
      • Wang CC
      • Chen TH
      • Hong CY
      • Sue YM.
      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).
      • Zhou H
      • Sim JJ
      • Shi J
      • Shaw SF
      • Lee MS
      • Neyer JR
      • et al.
      β-blocker use and risk of mortality in heart failure patients initiating maintenance dialysis.
      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.
      • Foley RN
      • Herzog CA
      • Collins AJ.
      Blood pressure and long-term mortality in United States hemodialysis patients: USRDS Waves 3 and 4 Study1.
      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.
      • Jin J
      • Guo X
      • Yu Q.
      Effects of beta-blockers on cardiovascular events and mortality in dialysis patients: a systematic review and meta-analysis.
      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]).
      • Jin J
      • Guo X
      • Yu Q.
      Effects of beta-blockers on cardiovascular events and mortality in dialysis patients: a systematic review and meta-analysis.
      Important factors to consider when prescribing beta-blockers to patients with HF and on dialysis are their cardioselectivity and dialyzability.
      • Hundemer GL
      • Sood MM
      • Canney M.
      β-blockers in hemodialysis: simple questions, complicated answers.
      Cardioselective beta-blockers include atenolol, bisoprolol and metoprolol; noncardioselective beta-blockers include propranolol, carvedilol, labetalol, pindolol, nadolol, and timolol.
      • Hundemer GL
      • Sood MM
      • Canney M.
      β-blockers in hemodialysis: simple questions, complicated answers.
      Highly dialyzable beta-blockers are atenolol, bisoprolol, acebutolol, nadolol, and metoprolol, whereas poorly dialyzable beta-blockers are carvedilol, labetolol and propranolol.
      • Hundemer GL
      • Sood MM
      • Canney M.
      β-blockers in hemodialysis: simple questions, complicated answers.
      There is no clear evidence of differential benefit of beta-blockers in patients with HF and ESKD.
      • Weir MA
      • Dixon SN
      • Fleet JL
      • Roberts MA
      • Hackam DG
      • Oliver MJ
      • et al.
      β-blocker dialyzability and mortality in older patients receiving hemodialysis.
      • Tieu A
      • Velenosi TJ
      • Kucey AS
      • Weir MA
      • Urquhart BL.
      β-blocker dialyzability in maintenance hemodialysis patients a randomized clinical trial.
      • Wu PH
      • Lin YT
      • Kuo MC
      • Liu JS
      • Tsai YC
      • Chiu YW
      • et al.
      β-blocker dialyzability and the risk of mortality and cardiovascular events in patients undergoing hemodialysis.
      • Assimon MM
      • Brookhart MA
      • Fine JP
      • Heiss G
      • Layton JB
      • Flythe JE.
      A comparative study of carvedilol versus metoprolol initiation and 1-year mortality among individuals receiving maintenance hemodialysis.
      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.
      • Mcmurray JJ V
      • Packer M
      • Desai AS
      • Gong J
      • Lefkowitz MP
      • Rizkala AR
      • et al.
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      ,
      • Pontremoli R
      • Borghi C
      • Perrone Filardi P
      Renal protection in chronic heart failure: focus on sacubitril/valsartan.
      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).
      • Lihua W
      • Cheng L
      • Chen H
      • Wei F
      • Jiang A.
      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).
      • Hsiao FC
      • Lin CP
      • Yu CC
      • Tung YC
      • Chu PH.
      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 NameNCT NumberPhaseNatureCurrent StatusInterventionControlEstimated Sample SizeInclusion CriteriaPrimary OutcomesSecondary OutcomesLocation
      Sacubitril/Valsartan for Dialysis Patients With CKD5 Stage Complicated With Heart Failure: a Prospective, Randomized, Controlled Multicenter StudyNCT052431994RandomizedRecruitingSacubitril/ValsartanIrbesartan600CKD 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 StudyNCT045727244Non-randomizedRecruitingSacubitril/ValsartanRAS inhibitor120Patients 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/mlCV 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 KCCQGuangdong, 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)NCT04458285NARandomizedRecruitingSacubitril/ValsartanValsartan118Patients 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 registrationChanges in LVEF at 12 weeksChanges 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)NCT05141552NARandomizedRecruitingDapagliflozinNone (standard anti-HF therapy)20Patients 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/mLHypoglycemia and UTI at 12 weeksChange in NT-proBNP at 12 weeksShanghai, 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.

      ACE Inhibitors and ARBs

      ACE inhibitors and ARBs reduce cardiovascular mortality rates and hospitalizations due to HF in patients with HFrEF according to several RCTs.

      Group* TCTS. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med. 2010;316:1429–35. https://doi.org/10.1056/NEJM198706043162301

      ,
      • Granger CB
      • McMurray JJV
      • Yusuf S
      • Held P
      • Michelson EL
      • Olofsson B
      • et al.
      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.
      • Cice G
      • Di Benedetto A
      • D'Isa S
      • D'Andrea A
      • Marcelli D
      • Gatti E
      • et al.
      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.
      In this 3-year multicenter Italian trial, telmisartan significantly reduced all-cause mortality rates (HR, 0.51 [0.32–0.82]), cardiovascular mortality (HR, 0.42 [0.38–0.61]), and hospitalization for chronic HF (HR, 0.38 [0.19–0.51]).
      • Cice G
      • Di Benedetto A
      • D'Isa S
      • D'Andrea A
      • Marcelli D
      • Gatti E
      • et al.
      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.
      • Cice G
      • Di Benedetto A
      • D'Isa S
      • D'Andrea A
      • Marcelli D
      • Gatti E
      • et al.
      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.
      • Zannad F
      • Kessler M
      • Lehert P
      • Grünfeld JP
      • Thuilliez C
      • Leizorovicz A
      • et al.
      Prevention of cardiovascular events in end-stage renal disease: results of a randomized trial of fosinopril and implications for future studies.
      Similar findings were observed in the Hemodialysis (HEMO) trial.
      • Chang TI
      • Shilane D
      • Brunelli SM
      • Cheung AK
      • Chertow GM
      • Winkelmayer WC.
      Angiotensin-converting enzyme inhibitors and cardiovascular outcomes in patients on maintenance hemodialysis.
      In fact, the use of ACE inhibitors increased the risk of hospitalization for HF (HR, 1.41 [1.11–1.80]) in the HEMO trial.
      • Chang TI
      • Shilane D
      • Brunelli SM
      • Cheung AK
      • Chertow GM
      • Winkelmayer WC.
      Angiotensin-converting enzyme inhibitors and cardiovascular outcomes in patients on maintenance hemodialysis.
      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]).
      • Liu Y
      • Ma X
      • Zheng J
      • Jia J
      • Yan T.
      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]).
      • Tang CH
      • Chen TH
      • Wang CC
      • Hong CY
      • Huang KC
      • Sue YM.
      Renin-angiotensin system blockade in heart failure patients on long-term haemodialysis in Taiwan.
      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).
      • Berger AK
      • Duval S
      • Manske C
      • Vazquez G
      • Barber C
      • Miller L
      • et al.
      Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with congestive heart failure and chronic kidney disease.
      Given that most ACE inhibitors are dialyzable, surveyed physicians prefer ARBs.
      • Liu Y
      • Ma X
      • Zheng J
      • Jia J
      • Yan T.
      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, current evidence does not offer reliable guidance regarding the use of ACE inhibitors and ARBs in patients with ESKD and HF.

      MRAs

      Prescription rates of MRAs range from 33% in patients with HFrEF in the ambulatory setting to 45% in patients at discharge post-HF hospitalization.
      • Greene SJ
      • Butler J
      • Albert NM
      • DeVore AD
      • Sharma PP
      • Duffy CI
      • et al.
      Medical therapy for heart failure with reduced ejection fraction: The CHAMP-HF Registry.
      ,
      • Greene SJ
      • Ezekowitz JA
      • Anstrom KJ
      • Demyanenko V
      • Givertz MM
      • Pina IL
      • et al.
      Medical therapy during hospitalization for heart failure with reduced ejection fraction: the VICTORIA Registry.
      Even when prescribed, titration is often limited by the associated risk of hyperkalemia.
      • Lisi F
      • Parisi G
      • Gioia MI
      • Amato L
      • Bellino MC
      • Grande D
      • et al.
      Mineralcorticoid receptor antagonist withdrawal for hyperkalemia and mortality in patients with heart failure.
      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).
      • Taheri S
      • Mortazavi M
      • Shahidi S
      • Pourmoghadas A
      • Garakyaraghi M
      • Seirafian S
      • et al.
      Spironolactone in chronic hemodialysis patients improves cardiac function.
      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).

      Taheri S, Mortazavi M, Pourmoghadas A, Seyrafian S, Alipour Z, Karimi S. A prospective double-blind randomized placebo-controlled clinical trial to evaluate the safety and efficacy of spironolactone in patients with advanced congestive heart failure on continuous ambulatory peritoneal dialysis. Saudi Journal of Kidney Diseases and Transplantation (SJKDT): Table of Contents. Accessed July 7, 2022. https://www.sjkdt.org/showcaptcha.asp?RedirectUrl=article&issn=1319-2442;year=2012;volume=23;issue=3;spage=507;epage=512;aulast=Taheri

      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.
      • Matsumoto Y
      • Mori Y
      • Kageyama S
      • Arihara K
      • Sugiyama T
      • Ohmura H
      • et al.
      Spironolactone reduces cardiovascular and cerebrovascular morbidity and mortality in hemodialysis patients.
      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]).
      • Liu J
      • Jia WY
      • Yu C.
      Safety and efficacy of spironolactone in dialysis-dependent patients: meta-analysis of randomized controlled trials.
      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]).
      • Liu J
      • Jia WY
      • Yu C.
      Safety and efficacy of spironolactone in dialysis-dependent patients: meta-analysis of randomized controlled trials.
      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.
      • Zhu Y
      • Liu Y
      • Cai R
      • Zheng D
      • Liang X
      • Tao M
      • et al.
      The safety and efficacy of low-dose mineralocorticoid receptor antagonists in dialysis patients: A meta-analysis.
      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.

      McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381):1995–2008. doi: 10.1056/NEJMOA1911303

      ,
      • Packer M
      • Anker SD
      • Butler J
      • Filippatos G
      • Pocock SJ
      • Carson P
      • et al.
      Cardiovascular and renal outcomes with empagliflozin in heart failure.
      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.
      • Zannad F
      • Ferreira JP
      • Pocock SJ
      • Zeller C
      • Anker SD
      • Butler J
      • et al.
      Cardiac and Kidney benefits of empagliflozin in heart failure across the spectrum of kidney function: insights from EMPEROR-Reduced.
      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).
      • Pun PH
      • Hellkamp AS
      • Sanders GD
      • Middleton JP
      • Hammill SC
      • Al-Khalidi HR
      • et al.
      Primary prevention implantable cardioverter defibrillators in end-stage kidney disease patients on dialysis: a matched cohort study.
      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).
      • Hiremath S
      • Punnam SR
      • Brar SS
      • Goyal SK
      • Gardiner JC
      • Shah AJ
      • et al.
      Implantable defibrillators improve survival in end-stage renal disease: results from a multi-center registry.
      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.
      • Hiremath S
      • Punnam SR
      • Brar SS
      • Goyal SK
      • Gardiner JC
      • Shah AJ
      • et al.
      Implantable defibrillators improve survival in end-stage renal disease: results from a multi-center registry.
      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]).
      • Wouter Jukema J
      • Timal RJ
      • Rotmans JI
      • Hensen LCR
      • Buiten MS
      • De Bie MK
      • et al.
      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.
      • Wouter Jukema J
      • Timal RJ
      • Rotmans JI
      • Hensen LCR
      • Buiten MS
      • De Bie MK
      • et al.
      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.
      • Pun PH
      • Parzynski CS
      • Friedman DJ
      • Sanders G
      • Curtis JP
      • Al-Khatib SM
      Trends in use and in-hospital outcomes of subcutaneous implantable cardioverter defibrillators in patients undergoing long-term dialysis.
      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).
      • Friedman DJ
      • Upadhyay GA
      • Singal G
      • Orencole M
      • Moore SA
      • Parks KA
      • et al.
      Usefulness and consequences of cardiac resynchronization therapy in dialysis-dependent patients with heart failure.
      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.
      • Friedman DJ
      • Singh JP
      • Curtis JP
      • Tang WHW
      • Bao H
      • Spatz ES
      • et al.
      Comparative effectiveness of CRT-D versus defibrillator alone in HF patients with moderate-to-severe chronic kidney disease.
      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.
      • Friedman DJ
      • Singh JP
      • Curtis JP
      • Tang WHW
      • Bao H
      • Spatz ES
      • et al.
      Comparative effectiveness of CRT-D versus defibrillator alone in HF patients with moderate-to-severe chronic kidney disease.
      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.
      • Kirklin JK
      • Naftel DC
      • Kormos RL
      • Pagani FD
      • Myers SL
      • Stevenson LW
      • et al.
      Quantifying the effect of cardiorenal syndrome on mortality after left ventricular assist device implant.
      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.
      • Bansal N
      • Hailpern SM
      • Katz R
      • Hall YN
      • Tamura MK
      • Kreuter W
      • et al.
      Outcomes associated with left ventricular assist devices among recipients with and without end-stage renal disease.
      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.
      • Ajuria M
      • Franz DD
      • Morris JT
      • Abra G
      • Hussein WF
      Peritoneal dialysis following left ventricular assist device placement and kidney recovery: a case report.
      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.
      • Sato H
      • Sakurada T
      • Kojima S
      • Okamoto T
      • Shibagaki Y
      • Ishibashi Y
      • et al.
      Transcatheter mitral valve repair with a mitraclip for severe mitral regurgitation in a patient on hemodialysis.
      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.
      • Raheja H
      • Ahuja KR
      • Nazir S
      • Saad AM
      • Gad MM
      • Chatterjee S
      • et al.
      Association of baseline kidney disease with outcomes of transcatheter mitral valve repair by MitraClip.
      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.
      • Raheja H
      • Ahuja KR
      • Nazir S
      • Saad AM
      • Gad MM
      • Chatterjee S
      • et al.
      Association of baseline kidney disease with outcomes of transcatheter mitral valve repair by MitraClip.
      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.
      • Shah B
      • Villablanca PA
      • Vemulapalli S
      • Manandhar P
      • Amoroso NS
      • Saric M
      • et al.
      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.
      • Shah B
      • Villablanca PA
      • Vemulapalli S
      • Manandhar P
      • Amoroso NS
      • Saric M
      • et al.
      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.
      • Doshi R
      • Shlofmitz E
      • Shah J
      • Meraj P.
      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.
      • Thongprayoon C
      • Lertjitbanjong P
      • Hansrivijit P
      • Crisafio A
      • Mao MA
      • Watthanasuntorn K
      • et al.
      Acute kidney injury in patients undergoing cardiac transplantation: a meta-analysis.
      ,
      • Shoji S
      • Kuno T
      • Kohsaka S
      • Amiya E
      • Asleh R
      • Alvarez P
      • et al.
      Incidence and long-term outcome of heart transplantation patients who develop postoperative renal failure requiring dialysis.
      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.
      • Shoji S
      • Kuno T
      • Kohsaka S
      • Amiya E
      • Asleh R
      • Alvarez P
      • et al.
      Incidence and long-term outcome of heart transplantation patients who develop postoperative renal failure requiring dialysis.
      Post-transplant dialysis makes these patients more susceptible to clinical complications and also increases the cost of care.
      • Hornberger J
      • Best J
      • Geppert J
      • McClellan M.
      Risks and costs of end-stage renal disease after heart transplantation.
      ,
      • Cantarovich M
      • Hirsh A
      • Alam A
      • Giannetti N
      • Cecere R
      • Carroll P
      • et al.
      The clinical impact of an early decline in kidney function in patients following 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).
      • Schaffer JM
      • Chiu P
      • Singh SK
      • Oyer PE
      • Reitz BA
      • Mallidi HR.
      Heart and combined heart-kidney transplantation in patients with concomitant renal insufficiency and end-stage heart failure.
      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.
      • Bin Hsu R
      • CI Chang
      • Tsai MK
      • Lee PH
      • Chou NK
      • Chi NH
      • et al.
      Effect of simultaneous kidney transplantation on heart-transplantation outcome in recipients with preoperative renal dysfunction.
      • Kilic A
      • Grimm JC
      • Whitman GJR
      • Shah AS
      • Mandal K
      • Conte JV
      • et al.
      The survival benefit of simultaneous heart-kidney transplantation extends beyond dialysis-dependent patients.
      • Agarwal KA
      • Patel H
      • Agrawal N
      • Cardarelli F
      • Goyal N.
      Cardiac outcomes in isolated heart and simultaneous kidney and heart transplants in the United States.
      • Gill J
      • Shah T
      • Hristea I
      • Chavalitdhamrong D
      • Anastasi B
      • Takemoto SK
      • et al.
      Outcomes of simultaneous heart-kidney transplant in the US: a retrospective analysis using OPTN/UNOS data.
      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.
      • Gill J
      • Shah T
      • Hristea I
      • Chavalitdhamrong D
      • Anastasi B
      • Takemoto SK
      • et al.
      Outcomes of simultaneous heart-kidney transplant in the US: a retrospective analysis using OPTN/UNOS data.
      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.
      • Awad MA
      • Czer LSC
      • Emerson D
      • Jordan S
      • De Robertis MA
      • Mirocha J
      • et al.
      Combined heart and kidney transplantation: clinical experience in 100 consecutive patients.
      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.
      • Melvinsdottir I
      • Foley DP
      • Hess T
      • Gunnarsson SI
      • Kohmoto T
      • Hermsen J
      • et al.
      Heart and kidney transplant: should they be combined or subsequent?.
      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.
      • Sun CY
      • Sung JM
      • Der Wang J
      • Li CY
      • Kuo YT
      • Lee CC
      • et al.
      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.
      • Sens F
      • Schott-Pethelaz AM
      • Labeeuw M
      • Colin C
      • Villar E.
      Survival advantage of hemodialysis relative to peritoneal dialysis in patients with end-stage renal disease and congestive heart failure.
      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).
      • Kunin M
      • Klempfner R
      • Beckerman P
      • Rott D
      • Dinour D.
      Congestive heart failure treated with peritoneal dialysis or hemodialysis: typical patient profile and outcomes in real-world setting.
      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.
      • Chionh CY
      • Clementi A
      • Poh CB
      • Finkelstein FO
      • Cruz DN.
      The use of peritoneal dialysis in heart failure: a systematic review.
      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]).
      • Chionh CY
      • Clementi A
      • Poh CB
      • Finkelstein FO
      • Cruz DN.
      The use of peritoneal dialysis in heart failure: a systematic review.
      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.
      • Chan C
      • Floras JS
      • Miller JA
      • Pierratos A.
      Improvement in ejection fraction by nocturnal haemodialysis in end-stage renal failure patients with coexisting heart failure.
      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]).
      • Chan CT
      • Greene T
      • Chertow GM
      • Kliger AS
      • Stokes JB
      • Beck GJ
      • et al.
      Determinants of left ventricular mass in patients on hemodialysis: the Frequent Hemodialysis Network (FHN) trials.
      ,
      • Chertow GM
      • Levin NW
      • Beck GJ
      • Daugirdas JT
      • Eggers PW
      • Kliger AS
      • et al.
      Long-term effects of frequent in-center hemodialysis.
      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.
      • Ibrahim A
      • Chan CT.
      Managing kidney failure with home hemodialysis.
      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]).
      • Trinh E
      • Chan CT.
      Intensive home hemodialysis results in regression of left ventricular hypertrophy and better clinical outcomes.
      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.
      • Lockridge R
      • Weinhandl E
      • Kraus M
      • Schreiber M
      • Spry L
      • Tailor P
      • et al.
      A systematic approach to promoting home hemodialysis during end stage kidney disease.
      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.
      • Roehm B
      • Gulati G
      • Weiner DE.
      Heart failure management in dialysis patients: many treatment options with no clear evidence.
      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).
      • Reddy YNV
      • Obokata M
      • Dean PG
      • Melenovsky V
      • Nath KA
      • Borlaug BA.
      Long-term cardiovascular changes following creation of arteriovenous fistula in patients with end stage renal disease.
      ,
      • Roca-Tey R.
      Permanent arteriovenous fistula or catheter dialysis for heart failure patients.
      ,
      • Hartley JL
      • Sharma A
      • Taha L
      • Hestletine T.
      High-output cardiac failure secondary to high-output arteriovenous fistula: investigations, management and definitive treatment.
      However, the widely acceptable “fistula-first” approach harbors important clinical complications in the setting of HF.
      • Reddy YNV
      • Obokata M
      • Dean PG
      • Melenovsky V
      • Nath KA
      • Borlaug BA.
      Long-term cardiovascular changes following creation of arteriovenous fistula in patients with end stage renal disease.
      Creation of an AVF leads to a large amount of blood’s being shunted from the left-sided circulation to the right-sided circulation.
      • Hartley JL
      • Sharma A
      • Taha L
      • Hestletine T.
      High-output cardiac failure secondary to high-output arteriovenous fistula: investigations, management and definitive treatment.
      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.
      • Reddy YNV
      • Obokata M
      • Dean PG
      • Melenovsky V
      • Nath KA
      • Borlaug BA.
      Long-term cardiovascular changes following creation of arteriovenous fistula in patients with end stage renal disease.
      Worsening RV dilation was associated with a 4-fold increased risk of mortality (HR, 3.9 [1.7–9.2]).
      • Reddy YNV
      • Obokata M
      • Dean PG
      • Melenovsky V
      • Nath KA
      • Borlaug BA.
      Long-term cardiovascular changes following creation of arteriovenous fistula in patients with end stage renal disease.
      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.
      • Reddy YNV
      • Obokata M
      • Dean PG
      • Melenovsky V
      • Nath KA
      • Borlaug BA.
      Long-term cardiovascular changes following creation of arteriovenous fistula in patients with end stage renal disease.
      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.
      • Reddy YNV
      • Obokata M
      • Dean PG
      • Melenovsky V
      • Nath KA
      • Borlaug BA.
      Long-term cardiovascular changes following creation of arteriovenous fistula in patients with end stage renal disease.
      The development of high-output HF is an underappreciated complication of AVF, which poses an important clinical dilemma.
      • Hartley JL
      • Sharma A
      • Taha L
      • Hestletine T.
      High-output cardiac failure secondary to high-output arteriovenous fistula: investigations, management and definitive treatment.
      ,
      • Stern AB
      • Klemmer PJ.
      High-output heart failure secondary to arteriovenous fistula.
      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.
      • Stern AB
      • Klemmer PJ.
      High-output heart failure secondary to arteriovenous fistula.
      Alternatively, AVF can be maintained by partial banding, in which the AVF can be constricted in 1 or more places to decrease the AVF blood flow.
      • Stern AB
      • Klemmer PJ.
      High-output heart failure secondary to arteriovenous fistula.
      Other techniques include placement of hemoclips over the venous supply, the inflow reduction procedure or the Miller procedure.
      • Stern AB
      • Klemmer PJ.
      High-output heart failure secondary to arteriovenous fistula.
      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.
      • Burton JO
      • Jefferies HJ
      • Selby NM
      • McIntyre CW.
      Hemodialysis-induced cardiac injury: determinants and associated outcomes.
      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.
      • Jefferies HJ
      • Virk B
      • Schiller B
      • Moran J
      • Mcintyre CW.
      Frequent hemodialysis schedules are associated with reduced levels of dialysis-induced cardiac injury (myocardial stunning).
      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.
      • Jefferies HJ
      • Virk B
      • Schiller B
      • Moran J
      • Mcintyre CW.
      Frequent hemodialysis schedules are associated with reduced levels of dialysis-induced cardiac injury (myocardial stunning).
      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.
      • Loutradis C
      • Papadopoulos CE
      • Sarafidis P.
      Longer dialysis sessions improve cardiac systolic function by reducing myocardial stunning.
      Other strategies include individualized-temperature HD, intradialytic exercise, dialysate cooling, and maintaining dialysate calcium ≥ 2.5 mEq/L.
      • Roehm B
      • Gulati G
      • Weiner DE.
      Heart failure management in dialysis patients: many treatment options with no clear evidence.
      ,
      • McGuire S
      • Horton EJ
      • Renshaw D
      • Chan K
      • Jimenez A
      • Maddock H
      • et al.
      Cardiac stunning during haemodialysis: the therapeutic effect of intra-dialytic exercise.
      ,
      • Jefferies HJ
      • Burton JO
      • McIntyre CW.
      Individualised dialysate temperature improves intradialytic haemodynamics and abrogates haemodialysis-induced myocardial stunning, without compromising tolerability.
      However, these studies are not specific to patients with HF on HD.

      Management of Hyperkalemia

      Patients on dialysis have an increased risk of hyperkalemia, which is often due to poor dietary adherence or, less likely, to higher catabolism rates.
      • Bansal S
      • Pergola PE.
      Current management of hyperkalemia in patients on dialysis.
      All foundational HF therapies except SGLT2 inhibitors can potentially precipitate hyperkalemia.
      • Sadjadi SA
      • McMillan JI
      • Jaipaul N
      • Blakely P
      • Hline SS.
      A comparative study of the prevalence of hyperkalemia with the use of angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers.
      ,
      • Cooper LB
      • Lippmann SJ
      • Greiner MA
      • Sharma A
      • Kelly JP
      • Fonarow GC
      • et al.
      Use of mineralocorticoid receptor antagonists in patients with heart failure and comorbid diabetes mellitus or chronic kidney disease.
      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.
      • Butler J
      • Khan MS
      • Anker SD.
      Novel potassium binders as enabling therapy in heart failure.
      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.
      • Pitt B
      • Anker SD
      • Bushinsky DA
      • Kitzman DW
      • Zannad F
      • Huang IZ.
      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.
      ,
      • Pitt B
      • Bakris GL
      • Bushinsky DA
      • Garza D
      • Mayo MR
      • Stasiv Y
      • et al.
      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.
      • Butler J
      • Anker SD
      • Siddiqi TJ
      • Coats AJS
      • Dorigotti F
      • Filippatos G
      • et al.
      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]).
      • Ferreira JP
      • Zannad F
      • Butler J
      • Filipattos G
      • Ritter I
      • Schüler E
      • et al.
      Empagliflozin and serum potassium in heart failure: an analysis from EMPEROR-Pooled.
      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.
      • Greene SJ
      • Khan MS.
      Quadruple medical therapy for heart failure: medications working together to provide the best care.
      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.
      • Sarafidis PA
      • Persu A
      • Agarwal R
      • Burnier M
      • De Leeuw P
      • Ferro CJ
      • et al.
      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).
      ,
      • Alborzi P
      • Patel N
      • Agarwal R.
      Home blood pressures are of greater prognostic value than hemodialysis unit recordings.
      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.
      • Bucharles SGE
      • Wallbach KKS
      Moraes TP de, Pecoits-Filho R. Hypertension in patients on dialysis: diagnosis, mechanisms, and management.
      ,
      • Carney EF.
      Dialysis: U-shaped associations between changes in blood pressure during dialysis and patient survival.
      ,
      • Robinson BM
      • Tong L
      • Zhang J
      • Wolfe RA
      • Goodkin DA
      • Greenwood RN
      • et al.
      Blood pressure levels and mortality risk among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study.
      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.
      • Losito A
      • Del Vecchio L
      • Del Rosso G
      • Malandra R
      Blood pressure and cardiovascular mortality in dialysis patients with left ventricular systolic dysfunction.
      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.
      • Sarafidis PA
      • Persu A
      • Agarwal R
      • Burnier M
      • De Leeuw P
      • Ferro CJ
      • et al.
      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)∗.
      ,
      • Georgianos PI
      • Agarwal R.
      Epidemiology, diagnosis and management of hypertension among patients on chronic dialysis.
      ,
      • Sarafidis PA
      • Mallamaci F
      • Loutradis C
      • Ekart R
      • Torino C
      • Karpetas A
      • et al.
      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.
      • Sarafidis PA
      • Persu A
      • Agarwal R
      • Burnier M
      • De Leeuw P
      • Ferro CJ
      • et al.
      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)∗.
      ,
      • Georgianos PI
      • Agarwal R.
      Epidemiology, diagnosis and management of hypertension among patients on chronic dialysis.
      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.
      • Agarwal R
      • Peixoto AJ
      • Santos SFF
      • Zoccali C.
      Pre- and postdialysis blood pressures are imprecise estimates of interdialytic ambulatory blood pressure.
      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.
      • Sarafidis PA
      • Persu A
      • Agarwal R
      • Burnier M
      • De Leeuw P
      • Ferro CJ
      • et al.
      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)∗.
      However, these studies are limited to patients on dialysis who did not necessarily have HF at baseline.
      Given that hypertension affects almost 70%–80% of patients on dialysis, appropriate management is key.
      • Bucharles SGE
      • Wallbach KKS
      Moraes TP de, Pecoits-Filho R. Hypertension in patients on dialysis: diagnosis, mechanisms, and management.
      The most common cause of hypertension in patients on dialysis is failure to remove enough volume effectively.
      • Sarafidis PA
      • Persu A
      • Agarwal R
      • Burnier M
      • De Leeuw P
      • Ferro CJ
      • et al.
      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.
      • Bucharles SGE
      • Wallbach KKS
      Moraes TP de, Pecoits-Filho R. Hypertension in patients on dialysis: diagnosis, mechanisms, and management.
      In addition, higher frequency, prolonged durations of dialysis and nocturnal HD are also effective measures of BP control.
      • Bucharles SGE
      • Wallbach KKS
      Moraes TP de, Pecoits-Filho R. Hypertension in patients on dialysis: diagnosis, mechanisms, and management.
      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 2
      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.
      Fig 3
      Fig. 3(Visual Take-Home Graphic). Proposed clinical approach in patients with HF and on dialysis. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; CRT, cardiac resynchronization 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.
      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.
      • Nitta K
      • Hanafusa N
      • Tsuchiya K.
      Frailty and mortality among dialysis patients.
      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.

      Tweet

      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

      Appendix. Supplementary materials

      References

        • McAlister FA
        • Ezekowitz J
        • Tarantini L
        Renal dysfunction in patients with heart failure with preserved versus reduced ejection fraction impact of the new chronic kidney disease-epidemiology collaboration group formula.
        Circ Heart Fail. 2012; 5: 309-314https://doi.org/10.1161/CIRCHEARTFAILURE.111.966242/-/DC1
        • House AA
        • Wanner C
        • Sarnak MJ
        • Piña IL
        • McIntyre CW
        • Komenda P
        • et al.
        Heart failure in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.
        Kidney Int. 2019; 95: 1304-1317https://doi.org/10.1016/J.KINT.2019.02.022
        • Waldum-Grevbo B.
        What physicians need to know about renal function in outpatients with heart failure.
        Cardiology. 2015; 131: 130-138https://doi.org/10.1159/000381012
        • Bhatti NK
        • Karimi Galougahi K
        • Paz Y
        • Nazif T
        • Moses JW
        • Leon MB
        • et al.
        Diagnosis and management of cardiovascular disease in advanced and end-stage renal disease.
        J Am Hear Assoc Cardiovasc Cerebrovasc Dis. 2016; 5: e003648https://doi.org/10.1161/JAHA.116.003648
        • Tong J
        • Liu M
        • Li H
        • Luo Z
        • Zhong X
        • Huang J
        • et al.
        Mortality and associated risk factors in dialysis patients with cardiovascular disease.
        Kidney Blood Press Res. 2016; 41: 479-487https://doi.org/10.1159/000443449
        • McMurray JJV
        • Wheeler DC
        • Stefánsson BV
        • Jongs N
        • Postmus D
        • Correa-Rotter R
        • et al.
        Effects of dapagliflozin in patients with kidney disease, with and without heart failure.
        JACC Heart Fail. 2021; 9: 807-820https://doi.org/10.1016/J.JCHF.2021.06.017
        • Wali RK
        • Iyengar M
        • Beck GJ
        • Chartyan DM
        • Chonchol M
        • Lukas MA
        • et al.
        Efficacy and safety of carvedilol in treatment of heart failure with chronic kidney disease: a meta-analysis of randomized trials.
        Circ Heart Fail. 2011; 4: 18-26https://doi.org/10.1161/CIRCHEARTFAILURE.109.932558
      1. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients.
        Am J Kidney Dis. 2005; 45: 16-153https://doi.org/10.1053/J.AJKD.2005.01.019
        • McDonagh TA
        • Metra M
        • Adamo M
        • Gardner RS
        • Baumbach A
        • Böhm M
        2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.
        Eur Heart J. 2021; 42: 3599-3726https://doi.org/10.1093/EURHEARTJ/EHAB368
        • Pandey A
        • Golwala H
        • DeVore AD
        • Lu D
        • Madden G
        • Bhatt DL
        • et al.
        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.
        JACC Hear Fail. 2016; 4: 649-661https://doi.org/10.1016/J.JCHF.2016.03.002
        • Patel RB
        • Fonarow G
        • Greene S
        • Zhang S
        • Alhanti B
        • DeVore A
        • et al.
        Clinical profiles, medical therapies, and outcomes among patients hospitalized for HF across the spectrum of kidney function: the GWTG-HF registry.
        J Am Coll Cardiol. 2021; 77: 559https://doi.org/10.1016/S0735-1097(21)01918-5
      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

        • Dargie HJ
        • Lechat P.
        The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial.
        Lancet. 1999; 353: 9-13https://doi.org/10.1016/S0140-6736(98)11181-9
        • Frankenfield DL
        • Weinhandl ED
        • Powers CA
        • Howell BL
        • Herzog CA
        • St. Peter WL
        Utilization and costs of cardiovascular disease medications in dialysis patients in Medicare Part D.
        Am J Kidney Dis. 2012; 59: 670-681https://doi.org/10.1053/J.AJKD.2011.10.047
        • Cice G
        • Ferrara L
        • Di Benedetto A
        • Russo PE
        • Marinelli G
        • Pavese F
        • et al.
        Dilated cardiomyopathy in dialysis patients: beneficial effects of carvedilol: a double-blind, placebo-controlled trial.
        J Am Coll Cardiol. 2001; 37: 407-411https://doi.org/10.1016/S0735-1097(00)01158-X
        • Cice G
        • Ferrara L
        • D'Andrea A
        • D'Isa S
        • Di Benedetto A
        • Cittadini A
        • et al.
        Carvedilol increases two-year survivalin dialysis patients with dilated cardiomyopathy: a prospective, placebo-controlled trial.
        J Am Coll Cardiol. 2003; 41: 1438-1444https://doi.org/10.1016/S0735-1097(03)00241-9
        • Tang CH
        • Wang CC
        • Chen TH
        • Hong CY
        • Sue YM.
        Prognostic benefits of carvedilol, bisoprolol, and metoprolol controlled release/extended release in hemodialysis patients with heart failure: a 10-year cohort.
        J Am Heart Assoc. 2016; 5: 1-11https://doi.org/10.1161/JAHA.115.002584
        • Zhou H
        • Sim JJ
        • Shi J
        • Shaw SF
        • Lee MS
        • Neyer JR
        • et al.
        β-blocker use and risk of mortality in heart failure patients initiating maintenance dialysis.
        Am J Kidney Dis. 2021; 77: 704-712https://doi.org/10.1053/J.AJKD.2020.07.023
        • Foley RN
        • Herzog CA
        • Collins AJ.
        Blood pressure and long-term mortality in United States hemodialysis patients: USRDS Waves 3 and 4 Study1.
        Kidney Int. 2002; 62: 1784-1790https://doi.org/10.1046/J.1523-1755.2002.00636.X
        • Jin J
        • Guo X
        • Yu Q.
        Effects of beta-blockers on cardiovascular events and mortality in dialysis patients: a systematic review and meta-analysis.
        Blood Purif. 2019; 48: 51-59https://doi.org/10.1159/000496083
        • Hundemer GL
        • Sood MM
        • Canney M.
        β-blockers in hemodialysis: simple questions, complicated answers.
        Clin Kidney J. 2021; 14: 731https://doi.org/10.1093/CKJ/SFAA249
        • Weir MA
        • Dixon SN
        • Fleet JL
        • Roberts MA
        • Hackam DG
        • Oliver MJ
        • et al.
        β-blocker dialyzability and mortality in older patients receiving hemodialysis.
        J Am Soc Nephrol. 2015; 26: 987-996https://doi.org/10.1681/ASN.2014040324
        • Tieu A
        • Velenosi TJ
        • Kucey AS
        • Weir MA
        • Urquhart BL.
        β-blocker dialyzability in maintenance hemodialysis patients a randomized clinical trial.
        Clin J Am Soc Nephrol. 2018; 13: 604-611https://doi.org/10.2215/CJN.07470717/-/DCSUPPLEMENTAL
        • Wu PH
        • Lin YT
        • Kuo MC
        • Liu JS
        • Tsai YC
        • Chiu YW
        • et al.
        β-blocker dialyzability and the risk of mortality and cardiovascular events in patients undergoing hemodialysis.
        Nephrol Dial Transplant. 2020; 35: 1959-1965https://doi.org/10.1093/NDT/GFAA058
        • Assimon MM
        • Brookhart MA
        • Fine JP
        • Heiss G
        • Layton JB
        • Flythe JE.
        A comparative study of carvedilol versus metoprolol initiation and 1-year mortality among individuals receiving maintenance hemodialysis.
        Am J Kidney Dis. 2018; 72: 337https://doi.org/10.1053/J.AJKD.2018.02.350
        • Mcmurray JJ V
        • Packer M
        • Desai AS
        • Gong J
        • Lefkowitz MP
        • Rizkala AR
        • et al.
        Angiotensin-neprilysin inhibition versus enalapril in heart failure.
        N Engl J Med. 2014; 11: 993-1004https://doi.org/10.1056/NEJMoa1409077
        • Pontremoli R
        • Borghi C
        • Perrone Filardi P
        Renal protection in chronic heart failure: focus on sacubitril/valsartan.
        Eur Hear J/Cardiovasc Pharmacother. 2021; 7: 445https://doi.org/10.1093/EHJCVP/PVAB030
        • Lihua W
        • Cheng L
        • Chen H
        • Wei F
        • Jiang A.
        Use of angiotensin receptor neprilysin inhibitor in patients on maintenance hemodialysis with reduced cardiac ejection fraction, real-world experience from a single center.
        Iran J Kidney Dis. 2021; 15: 288-299
        • Hsiao FC
        • Lin CP
        • Yu CC
        • Tung YC
        • Chu PH.
        Angiotensin receptor-neprilysin inhibitors in patients with heart failure with reduced ejection fraction and advanced chronic kidney disease: a retrospective multi-institutional study.
        Front Cardiovasc Med. 2022; 9794707https://doi.org/10.3389/FCVM.2022.794707
      3. Group* TCTS. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med. 2010;316:1429–35. https://doi.org/10.1056/NEJM198706043162301

        • Granger CB
        • McMurray JJV
        • Yusuf S
        • Held P
        • Michelson EL
        • Olofsson B
        • et al.
        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.
        Lancet. 2003; 362: 772-776https://doi.org/10.1016/S0140-6736(03)14284-5
        • Cice G
        • Di Benedetto A
        • D'Isa S
        • D'Andrea A
        • Marcelli D
        • Gatti E
        • et al.
        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.
        J Am Coll Cardiol. 2010; 56: 1701-1708https://doi.org/10.1016/J.JACC.2010.03.105
        • Zannad F
        • Kessler M
        • Lehert P
        • Grünfeld JP
        • Thuilliez C
        • Leizorovicz A
        • et al.
        Prevention of cardiovascular events in end-stage renal disease: results of a randomized trial of fosinopril and implications for future studies.
        Kidney Int. 2006; 70: 1318-1324https://doi.org/10.1038/SJ.KI.5001657
        • Chang TI
        • Shilane D
        • Brunelli SM
        • Cheung AK
        • Chertow GM
        • Winkelmayer WC.
        Angiotensin-converting enzyme inhibitors and cardiovascular outcomes in patients on maintenance hemodialysis.
        2011https://doi.org/10.1016/j.ahj.2011.05.004 (Published online)
        • Liu Y
        • Ma X
        • Zheng J
        • Jia J
        • Yan T.
        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.
        BMC Nephrol. 2017; 18: 206https://doi.org/10.1186/S12882-017-0605-7
        • Tang CH
        • Chen TH
        • Wang CC
        • Hong CY
        • Huang KC
        • Sue YM.
        Renin-angiotensin system blockade in heart failure patients on long-term haemodialysis in Taiwan.
        Eur J Heart Fail. 2013; 15: 1194-1202https://doi.org/10.1093/EURJHF/HFT082
        • Berger AK
        • Duval S
        • Manske C
        • Vazquez G
        • Barber C
        • Miller L
        • et al.
        Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with congestive heart failure and chronic kidney disease.
        Am Heart J. 2007; 153: 1064-1073https://doi.org/10.1016/J.AHJ.2007.03.017
        • Greene SJ
        • Butler J
        • Albert NM
        • DeVore AD
        • Sharma PP
        • Duffy CI
        • et al.
        Medical therapy for heart failure with reduced ejection fraction: The CHAMP-HF Registry.
        J Am Coll Cardiol. 2018; 72: 351-366https://doi.org/10.1016/J.JACC.2018.04.070
        • Greene SJ
        • Ezekowitz JA
        • Anstrom KJ
        • Demyanenko V
        • Givertz MM
        • Pina IL
        • et al.
        Medical therapy during hospitalization for heart failure with reduced ejection fraction: the VICTORIA Registry.
        J Card Fail. 2022; 14:: S1071-S9164https://doi.org/10.1016/J.CARDFAIL.2022.02.011
        • Lisi F
        • Parisi G
        • Gioia MI
        • Amato L
        • Bellino MC
        • Grande D
        • et al.
        Mineralcorticoid receptor antagonist withdrawal for hyperkalemia and mortality in patients with heart failure.
        Cardiorenal Med. 2020; 10: 145-153https://doi.org/10.1159/000505286
        • Taheri S
        • Mortazavi M
        • Shahidi S
        • Pourmoghadas A
        • Garakyaraghi M
        • Seirafian S
        • et al.
        Spironolactone in chronic hemodialysis patients improves cardiac function.
        Saudi J Kidney Dis Transplant. 2009; 20 (Accessed July 7, 2022): 392-397
      4. Taheri S, Mortazavi M, Pourmoghadas A, Seyrafian S, Alipour Z, Karimi S. A prospective double-blind randomized placebo-controlled clinical trial to evaluate the safety and efficacy of spironolactone in patients with advanced congestive heart failure on continuous ambulatory peritoneal dialysis. Saudi Journal of Kidney Diseases and Transplantation (SJKDT): Table of Contents. Accessed July 7, 2022. https://www.sjkdt.org/showcaptcha.asp?RedirectUrl=article&issn=1319-2442;year=2012;volume=23;issue=3;spage=507;epage=512;aulast=Taheri

        • Matsumoto Y
        • Mori Y
        • Kageyama S
        • Arihara K
        • Sugiyama T
        • Ohmura H
        • et al.
        Spironolactone reduces cardiovascular and cerebrovascular morbidity and mortality in hemodialysis patients.
        J Am Coll Cardiol. 2014; 63: 528-536https://doi.org/10.1016/J.JACC.2013.09.056
        • Liu J
        • Jia WY
        • Yu C.
        Safety and efficacy of spironolactone in dialysis-dependent patients: meta-analysis of randomized controlled trials.
        Front Med. 2022; 9: 663https://doi.org/10.3389/FMED.2022.828189/BIBTEX
        • Zhu Y
        • Liu Y
        • Cai R
        • Zheng D
        • Liang X
        • Tao M
        • et al.
        The safety and efficacy of low-dose mineralocorticoid receptor antagonists in dialysis patients: A meta-analysis.
        Medicine (Baltimore). 2021; 100: e24882https://doi.org/10.1097/MD.0000000000024882
      5. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381):1995–2008. doi: 10.1056/NEJMOA1911303

        • Packer M
        • Anker SD
        • Butler J
        • Filippatos G
        • Pocock SJ
        • Carson P
        • et al.
        Cardiovascular and renal outcomes with empagliflozin in heart failure.
        N Engl J Med. 2020; 383: 1413-1424https://doi.org/10.1056/NEJMOA2022190/SUPPL_FILE/NEJMOA2022190_DATA-SHARING.PDF
        • Zannad F
        • Ferreira JP
        • Pocock SJ
        • Zeller C
        • Anker SD
        • Butler J
        • et al.
        Cardiac and Kidney benefits of empagliflozin in heart failure across the spectrum of kidney function: insights from EMPEROR-Reduced.
        Circulation. 2021; 143: 310-321https://doi.org/10.1161/CIRCULATIONAHA.120.051685
        • Pun PH
        • Hellkamp AS
        • Sanders GD
        • Middleton JP
        • Hammill SC
        • Al-Khalidi HR
        • et al.
        Primary prevention implantable cardioverter defibrillators in end-stage kidney disease patients on dialysis: a matched cohort study.
        Nephrol Dial Transplant. 2015; 30: 829https://doi.org/10.1093/NDT/GFU274
        • Hiremath S
        • Punnam SR
        • Brar SS
        • Goyal SK
        • Gardiner JC
        • Shah AJ
        • et al.
        Implantable defibrillators improve survival in end-stage renal disease: results from a multi-center registry.
        Am J Nephrol. 2010; 32: 305-310https://doi.org/10.1159/000319461
        • Wouter Jukema J
        • Timal RJ
        • Rotmans JI
        • Hensen LCR
        • Buiten MS
        • De Bie MK
        • et al.
        Prophylactic use of implantable cardioverter-defibrillators in the prevention of sudden cardiac death in dialysis patients: the prospective, randomized, controlled ICD2 trial.
        Circulation. 2019; 139: 2628-2638https://doi.org/10.1161/CIRCULATIONAHA.119.039818
        • Pun PH
        • Parzynski CS
        • Friedman DJ
        • Sanders G
        • Curtis JP
        • Al-Khatib SM
        Trends in use and in-hospital outcomes of subcutaneous implantable cardioverter defibrillators in patients undergoing long-term dialysis.
        Clin J Am Soc Nephrol. 2020; 15: 1622-1630https://doi.org/10.2215/CJN.07920520
        • Friedman DJ
        • Upadhyay GA
        • Singal G
        • Orencole M
        • Moore SA
        • Parks KA
        • et al.
        Usefulness and consequences of cardiac resynchronization therapy in dialysis-dependent patients with heart failure.
        Am J Cardiol. 2013; 112: 1625-1631https://doi.org/10.1016/J.AMJCARD.2013.07.018
        • Friedman DJ
        • Singh JP
        • Curtis JP
        • Tang WHW
        • Bao H
        • Spatz ES
        • et al.
        Comparative effectiveness of CRT-D versus defibrillator alone in HF patients with moderate-to-severe chronic kidney disease.
        J Am Coll Cardiol. 2015; 66: 2618-2629https://doi.org/10.1016/J.JACC.2015.09.097
        • Kirklin JK
        • Naftel DC
        • Kormos RL
        • Pagani FD
        • Myers SL
        • Stevenson LW
        • et al.
        Quantifying the effect of cardiorenal syndrome on mortality after left ventricular assist device implant.
        J Heart Lung Transplant. 2013; 32: 1205-1213https://doi.org/10.1016/j.healun.2013.09.001
        • Bansal N
        • Hailpern SM
        • Katz R
        • Hall YN
        • Tamura MK
        • Kreuter W
        • et al.
        Outcomes associated with left ventricular assist devices among recipients with and without end-stage renal disease.
        JAMA Intern Med. 2018; 178: 204https://doi.org/10.1001/JAMAINTERNMED.2017.4831
        • Ajuria M
        • Franz DD
        • Morris JT
        • Abra G
        • Hussein WF
        Peritoneal dialysis following left ventricular assist device placement and kidney recovery: a case report.
        Kidney Med. 2021; 3: 438-441https://doi.org/10.1016/J.XKME.2020.12.009
        • Sato H
        • Sakurada T
        • Kojima S
        • Okamoto T
        • Shibagaki Y
        • Ishibashi Y
        • et al.
        Transcatheter mitral valve repair with a mitraclip for severe mitral regurgitation in a patient on hemodialysis.
        Saudi J Kidney Dis Transplant. 2021; 32: 1465https://doi.org/10.4103/1319-2442.344769
        • Raheja H
        • Ahuja KR
        • Nazir S
        • Saad AM
        • Gad MM
        • Chatterjee S
        • et al.
        Association of baseline kidney disease with outcomes of transcatheter mitral valve repair by MitraClip.
        Catheter Cardiovasc Interv. 2021; 97: E857-E867https://doi.org/10.1002/CCD.29129
        • Shah B
        • Villablanca PA
        • Vemulapalli S
        • Manandhar P
        • Amoroso NS
        • Saric M
        • et al.
        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.
        Circ Cardiovasc Interv. 2019; 12https://doi.org/10.1161/CIRCINTERVENTIONS.118.007552
        • Doshi R
        • Shlofmitz E
        • Shah J
        • Meraj P.
        Comparison of transcatheter mitral valve repair versus surgical mitral valve repair in patients with advanced kidney disease (from the national inpatient sample).
        Am J Cardiol. 2018; 121: 762-767https://doi.org/10.1016/J.AMJCARD.2017.12.015
        • Thongprayoon C
        • Lertjitbanjong P
        • Hansrivijit P
        • Crisafio A
        • Mao MA
        • Watthanasuntorn K
        • et al.
        Acute kidney injury in patients undergoing cardiac transplantation: a meta-analysis.
        Medicines. 2019; 6: 108https://doi.org/10.3390/MEDICINES6040108
        • Shoji S
        • Kuno T
        • Kohsaka S
        • Amiya E
        • Asleh R
        • Alvarez P
        • et al.
        Incidence and long-term outcome of heart transplantation patients who develop postoperative renal failure requiring dialysis.
        J Heart Lung Transplant. 2022; 41: 356-364https://doi.org/10.1016/J.HEALUN.2021.11.017
        • Hornberger J
        • Best J
        • Geppert J
        • McClellan M.
        Risks and costs of end-stage renal disease after heart transplantation.
        Transplantation. 1998; 66: 1763-1770https://doi.org/10.1097/00007890-199812270-00034
        • Cantarovich M
        • Hirsh A
        • Alam A
        • Giannetti N
        • Cecere R
        • Carroll P
        • et al.
        The clinical impact of an early decline in kidney function in patients following heart transplantation.
        Am J Transplant. 2009; 9: 348-354https://doi.org/10.1111/J.1600-6143.2008.02490.X
        • Schaffer JM
        • Chiu P
        • Singh SK
        • Oyer PE
        • Reitz BA
        • Mallidi HR.
        Heart and combined heart-kidney transplantation in patients with concomitant renal insufficiency and end-stage heart failure.
        Am J Transplant. 2014; 14: 384-396https://doi.org/10.1111/AJT.12522
        • Bin Hsu R
        • CI Chang
        • Tsai MK
        • Lee PH
        • Chou NK
        • Chi NH
        • et al.
        Effect of simultaneous kidney transplantation on heart-transplantation outcome in recipients with preoperative renal dysfunction.
        Eur J Cardio-Thoracic Surg. 2010; 37: 68-73https://doi.org/10.1016/J.EJCTS.2009.06.006
        • Kilic A
        • Grimm JC
        • Whitman GJR
        • Shah AS
        • Mandal K
        • Conte JV
        • et al.
        The survival benefit of simultaneous heart-kidney transplantation extends beyond dialysis-dependent patients.
        Ann Thorac Surg. 2015; 99: 1321-1327https://doi.org/10.1016/J.ATHORACSUR.2014.09.026
        • Agarwal KA
        • Patel H
        • Agrawal N
        • Cardarelli F
        • Goyal N.
        Cardiac outcomes in isolated heart and simultaneous kidney and heart transplants in the United States.
        Kidney Int Rep. 2021; 6: 2348-2357https://doi.org/10.1016/J.EKIR.2021.06.032
        • Gill J
        • Shah T
        • Hristea I
        • Chavalitdhamrong D
        • Anastasi B
        • Takemoto SK
        • et al.
        Outcomes of simultaneous heart-kidney transplant in the US: a retrospective analysis using OPTN/UNOS data.
        Am J Transplant. 2009; 9: 844-852https://doi.org/10.1111/J.1600-6143.2009.02588.X
        • Awad MA
        • Czer LSC
        • Emerson D
        • Jordan S
        • De Robertis MA
        • Mirocha J
        • et al.
        Combined heart and kidney transplantation: clinical experience in 100 consecutive patients.
        J Am Heart Assoc. 2019; 8: e010570https://doi.org/10.1161/JAHA.118.010570
        • Melvinsdottir I
        • Foley DP
        • Hess T
        • Gunnarsson SI
        • Kohmoto T
        • Hermsen J
        • et al.
        Heart and kidney transplant: should they be combined or subsequent?.
        ESC Hear Fail. 2020; 7: 2734-2743https://doi.org/10.1002/EHF2.12864
        • Sun CY
        • Sung JM
        • Der Wang J
        • Li CY
        • Kuo YT
        • Lee CC
        • et al.
        A comparison of the risk of congestive heart failure-related hospitalizations in patients receiving hemodialysis and peritoneal dialysis: a retrospective propensity score-matched study.
        PLoS One. 2019; 14https://doi.org/10.1371/JOURNAL.PONE.0223336
        • Sens F
        • Schott-Pethelaz AM
        • Labeeuw M
        • Colin C
        • Villar E.
        Survival advantage of hemodialysis relative to peritoneal dialysis in patients with end-stage renal disease and congestive heart failure.
        Kidney Int. 2011; 80: 970-977https://doi.org/10.1038/KI.2011.233
        • Kunin M
        • Klempfner R
        • Beckerman P
        • Rott D
        • Dinour D.
        Congestive heart failure treated with peritoneal dialysis or hemodialysis: typical patient profile and outcomes in real-world setting.
        Int J Clin Pract. 2021; 75: e13727https://doi.org/10.1111/IJCP.13727
        • Chionh CY
        • Clementi A
        • Poh CB
        • Finkelstein FO
        • Cruz DN.
        The use of peritoneal dialysis in heart failure: a systematic review.
        Perit Dial Int. 2020; 40: 527-539https://doi.org/10.1177/0896860819895198
        • Chan C
        • Floras JS
        • Miller JA
        • Pierratos A.
        Improvement in ejection fraction by nocturnal haemodialysis in end-stage renal failure patients with coexisting heart failure.
        Nephrol Dial Transplant. 2002; 17: 1518-1521https://doi.org/10.1093/NDT/17.8.1518
        • Chan CT
        • Greene T
        • Chertow GM
        • Kliger AS
        • Stokes JB
        • Beck GJ
        • et al.
        Determinants of left ventricular mass in patients on hemodialysis: the Frequent Hemodialysis Network (FHN) trials.
        Circ Cardiovasc Imaging. 2012; 5: 251https://doi.org/10.1161/CIRCIMAGING.111.969923
        • Chertow GM
        • Levin NW
        • Beck GJ
        • Daugirdas JT
        • Eggers PW
        • Kliger AS
        • et al.
        Long-term effects of frequent in-center hemodialysis.
        J Am Soc Nephrol. 2016; 27: 1830-1836https://doi.org/10.1681/ASN.2015040426
        • Ibrahim A
        • Chan CT.
        Managing kidney failure with home hemodialysis.
        Clin J Am Soc Nephrol. 2019; 14: 1268-1273https://doi.org/10.2215/CJN.13931118
        • Trinh E
        • Chan CT.
        Intensive home hemodialysis results in regression of left ventricular hypertrophy and better clinical outcomes.
        Am J Nephrol. 2016; 44: 300-307https://doi.org/10.1159/000449452
        • Lockridge R
        • Weinhandl E
        • Kraus M
        • Schreiber M
        • Spry L
        • Tailor P
        • et al.
        A systematic approach to promoting home hemodialysis during end stage kidney disease.
        Kidney. 2020; 1 (360): 993-1001https://doi.org/10.34067/KID.0003132020
        • Roehm B
        • Gulati G
        • Weiner DE.
        Heart failure management in dialysis patients: many treatment options with no clear evidence.
        Semin Dial. 2020; 33: 198-208https://doi.org/10.1111/SDI.12878
        • Reddy YNV
        • Obokata M
        • Dean PG
        • Melenovsky V
        • Nath KA
        • Borlaug BA.
        Long-term cardiovascular changes following creation of arteriovenous fistula in patients with end stage renal disease.
        Eur Heart J. 2017; 38: 1913-1923https://doi.org/10.1093/EURHEARTJ/EHX045
        • Roca-Tey R.
        Permanent arteriovenous fistula or catheter dialysis for heart failure patients.
        J Vasc Access. 2016; 17 (Suppl): S23-S29https://doi.org/10.5301/JVA.5000511
        • Hartley JL
        • Sharma A
        • Taha L
        • Hestletine T.
        High-output cardiac failure secondary to high-output arteriovenous fistula: investigations, management and definitive treatment.
        BMJ Case Rep. 2020; 13https://doi.org/10.1136/BCR-2019-233669
        • Stern AB
        • Klemmer PJ.
        High-output heart failure secondary to arteriovenous fistula.
        Hemodial Int. 2011; 15: 104-107https://doi.org/10.1111/J.1542-4758.2010.00518.X
        • Burton JO
        • Jefferies HJ
        • Selby NM
        • McIntyre CW.
        Hemodialysis-induced cardiac injury: determinants and associated outcomes.
        Clin J Am Soc Nephrol. 2009; 4: 914-920https://doi.org/10.2215/CJN.03900808
        • Jefferies HJ
        • Virk B
        • Schiller B
        • Moran J
        • Mcintyre CW.
        Frequent hemodialysis schedules are associated with reduced levels of dialysis-induced cardiac injury (myocardial stunning).
        Clin J Am Soc Nephrol. 2011; 6: 1326https://doi.org/10.2215/CJN.05200610
        • Loutradis C
        • Papadopoulos CE
        • Sarafidis P.
        Longer dialysis sessions improve cardiac systolic function by reducing myocardial stunning.
        J Card Fail. 2020; 26: 1026-1027https://doi.org/10.1016/J.CARDFAIL.2020.06.001
        • McGuire S
        • Horton EJ
        • Renshaw D
        • Chan K
        • Jimenez A
        • Maddock H
        • et al.
        Cardiac stunning during haemodialysis: the therapeutic effect of intra-dialytic exercise.
        Clin Kidney J. 2021; 14: 1335-1344https://doi.org/10.1093/CKJ/SFZ159
        • Jefferies HJ
        • Burton JO
        • McIntyre CW.
        Individualised dialysate temperature improves intradialytic haemodynamics and abrogates haemodialysis-induced myocardial stunning, without compromising tolerability.
        Blood Purif. 2011; 32: 63-68https://doi.org/10.1159/000324199
        • Bansal S
        • Pergola PE.
        Current management of hyperkalemia in patients on dialysis.
        Kidney Int Reports. 2020; 5: 779-789https://doi.org/10.1016/J.EKIR.2020.02.1028
        • Sadjadi SA
        • McMillan JI
        • Jaipaul N
        • Blakely P
        • Hline SS.
        A comparative study of the prevalence of hyperkalemia with the use of angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers.
        Ther Clin Risk Manag. 2009; 5: 547https://doi.org/10.2147/TCRM.S5176
        • Cooper LB
        • Lippmann SJ
        • Greiner MA
        • Sharma A
        • Kelly JP
        • Fonarow GC
        • et al.
        Use of mineralocorticoid receptor antagonists in patients with heart failure and comorbid diabetes mellitus or chronic kidney disease.
        J Am Hear Assoc Cardiovasc Cerebrovasc Dis. 2017; 6https://doi.org/10.1161/JAHA.117.006540
        • Butler J
        • Khan MS
        • Anker SD.
        Novel potassium binders as enabling therapy in heart failure.
        Eur J Heart Fail. 2019; 21: 550-552https://doi.org/10.1002/EJHF.1474
        • Pitt B
        • Anker SD
        • Bushinsky DA
        • Kitzman DW
        • Zannad F
        • Huang IZ.
        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.
        Eur Heart J. 2011; 32: 820-828https://doi.org/10.1093/eurheartj/ehr058
        • Pitt B
        • Bakris GL
        • Bushinsky DA
        • Garza D
        • Mayo MR
        • Stasiv Y
        • et al.
        Effect of patiromer on reducing serum potassium and preventing recurrent hyperkalaemia in patients with heart failure and chronic kidney disease on RAAS inhibitors.
        Eur J Heart Fail. 2015; 17: 1057-1065https://doi.org/10.1002/EJHF.402
        • Butler J
        • Anker SD
        • Siddiqi TJ
        • Coats AJS
        • Dorigotti F
        • Filippatos G
        • et al.
        Patiromer for the management of hyperkalaemia in patients receiving renin-angiotensin-aldosterone system inhibitors for heart failure: design and rationale of the DIAMOND trial.
        Eur J Heart Fail. 2022; 24: 230-238https://doi.org/10.1002/EJHF.2386
        • Ferreira JP
        • Zannad F
        • Butler J
        • Filipattos G
        • Ritter I
        • Schüler E
        • et al.
        Empagliflozin and serum potassium in heart failure: an analysis from EMPEROR-Pooled.
        Eur Heart J. 2022; (Published online June 10)https://doi.org/10.1093/EURHEARTJ/EHAC306
        • Greene SJ
        • Khan MS.
        Quadruple medical therapy for heart failure: medications working together to provide the best care.
        J Am Coll Cardiol. 2021; 77: 1408-1411https://doi.org/10.1016/J.JACC.2021.02.006
        • Sarafidis PA
        • Persu A
        • Agarwal R
        • Burnier M
        • De Leeuw P
        • Ferro CJ
        • et al.
        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).
        Nephrol Dial Transplant. 2017; 32: 620-640https://doi.org/10.1093/NDT/GFW433
        • Alborzi P
        • Patel N
        • Agarwal R.
        Home blood pressures are of greater prognostic value than hemodialysis unit recordings.
        Clin J Am Soc Nephrol. 2007; 2: 1228-1234https://doi.org/10.2215/CJN.02250507
        • Bucharles SGE
        • Wallbach KKS
        Moraes TP de, Pecoits-Filho R. Hypertension in patients on dialysis: diagnosis, mechanisms, and management.
        J Bras Nefrol. 2019; 41: 400-411https://doi.org/10.1590/2175-8239-JBN-2018-0155
        • Carney EF.
        Dialysis: U-shaped associations between changes in blood pressure during dialysis and patient survival.
        Nat Rev Nephrol. 2013; 9: 431https://doi.org/10.1038/NRNEPH.2013.112
        • Robinson BM
        • Tong L
        • Zhang J
        • Wolfe RA
        • Goodkin DA
        • Greenwood RN
        • et al.
        Blood pressure levels and mortality risk among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study.
        Kidney Int. 2012; 82: 570-580https://doi.org/10.1038/KI.2012.136
        • Losito A
        • Del Vecchio L
        • Del Rosso G
        • Malandra R
        Blood pressure and cardiovascular mortality in dialysis patients with left ventricular systolic dysfunction.
        Am J Hypertens. 2014; 27: 401-408https://doi.org/10.1093/AJH/HPT190
        • Sarafidis PA
        • Persu A
        • Agarwal R
        • Burnier M
        • De Leeuw P
        • Ferro CJ
        • et al.
        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)∗.
        Nephrol Dial Transplant. 2017; 32: 620-640https://doi.org/10.1093/ndt/gfw433
        • Georgianos PI
        • Agarwal R.
        Epidemiology, diagnosis and management of hypertension among patients on chronic dialysis.
        Nat Rev Nephrol. 2016; 12: 636-647https://doi.org/10.1038/nrneph.2016.129
        • Sarafidis PA
        • Mallamaci F
        • Loutradis C
        • Ekart R
        • Torino C
        • Karpetas A
        • et al.
        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.
        Nephrol Dial Transplant. 2019; 34: 1542-1548https://doi.org/10.1093/NDT/GFY147
        • Agarwal R
        • Peixoto AJ
        • Santos SFF
        • Zoccali C.
        Pre- and postdialysis blood pressures are imprecise estimates of interdialytic ambulatory blood pressure.
        Clin J Am Soc Nephrol. 2006; 1: 389-398https://doi.org/10.2215/CJN.01891105
        • Nitta K
        • Hanafusa N
        • Tsuchiya K.
        Frailty and mortality among dialysis patients.
        Ren Replace Ther. 2017; 3: 1-6https://doi.org/10.1186/S41100-017-0122-Y/FIGURES/2