Sage Journals: Discover world-class research

Abstract

The population with chronic kidney disease (CKD) is unique in the sense that they are more prone to heart failure and ischemic heart disease. This is mainly due to the presence of hypertension, anemia, and associated fluid overload, which is common to them. Managing heart failure in this cohort of patients is challenging as treatment of heart failure leads to worsening of kidney parameters.

Keywords

AKI CKD diuretics heart failure

Chronic kidney disease (CKD) is increasingly prevalent in patients with heart failure (HF), and HF is one of the leading causes of hospitalization, morbidity, and mortality in patients with an impaired renal function. There is a significant co-occurrence of HF and CKD—it is reported that almost half of patients with HF have a degree of renal impairment, and HF is prevalent in 17%–50% of patients with CKD, depending on the stage of the CKD and age of the patients.^{1, 2} In addition, the prevalence and mortality of HF increase with worsening renal failure.³ Renal function is an independent predictor for inpatient mortality of patients with acute HF, length of hospital stay, and re-admission rate.³

With improving survival in both patients with HF and those with CKD, it is likely that the numbers of patients presenting with both these conditions will continue to rise.

Case 1: A 56-year-old man is admitted to the hospital with worsening dyspnea and 8 kg weight gain and is diagnosed with acute decompensated heart failure (ADHF). He has a history of hypertension, type 2 diabetes, coronary artery disease, chronic kidney disease (CKD), glomerular filtration rate (GFR) category 3b and albuminuria category 2 (G3bA2), and ischemic cardiomyopathy with an ejection fraction of 30%. He is adherent to prescribed medications, including losartan, furosemide (40 mg twice daily), atorvastatin, and insulin. His blood pressure (BP) is 162/92 mm Hg and heart rate is 104 beats per minute. Physical examination reveals an S3 gallop, bilateral crackles, and pitting edema (3+). Admission laboratory data include serum sodium level of 132 mEq/L, serum potassium level of 5.2 mEq/ L, serum urea nitrogen level of 63 mg/dL, and serum creatinine (Scr) level of 2.1 mg/dL (baseline, 1.4 mg/dL).

Question 1: Which of the following is the next best step in management?

Prescribe furosemide intravenous (IV) infusion

Prescribe metolazone

Prescribe dapagliflozin

Prescribe isolated ultrafiltration

Discontinue losartan

Volume overload is defined as excess total body sodium and water with expansion of extracellular fluid volume. Volume overload characterizes several common disorders, including congestive heart failure (CHF), cirrhosis or end-stage liver disease (ESLD), CKD (including kidney failure), and nephrotic syndrome. Diuretics are the cornerstone of therapy for volume overload. There are several classes of diuretics, whose mechanisms of action, pharmacokinetics, and clinical use constitute basic principles of nephrology. The patient in case 1 presents with ADHF associated with resistance to oral furosemide. The best next step in management is changing furosemide from oral to IV dosing, thereby bypassing slowed absorption from gastrointestinal (GI) edema. Additionally, most contemporary guidelines suggest using 2–2.5 times the home dose (here, 80–100 mg IV). Alternatively, furosemide could be changed to an equivalent dose of bumetanide or torsemide; some small studies have shown better intermediate outcomes with torsemide for symptomatic decongestion, but large outcome studies conflict as to whether loop diuretic choice affects long-term outcomes, including mortality. Metolazone could be added to block distal tubule sodium reabsorption in conjunction with, but not in place of, IV furosemide. Dapagliflozin improves outcomes in CHF but would not replace an IV loop diuretic for prompt decongestion. Isolated ultrafiltration removes fluid as effectively as furosemide but is associated with more frequent adverse events. Stopping losartan may be necessary if acute kidney injury (AKI) or hyperkalemia worsen, but these conditions frequently improve with diuresis alone. So, the correct answer to question 1 is (a).

Case 1, continued: Furosemide 40 mg IV followed by an infusion of 5 mg/h is administered, and urine output increases to 2.4 l/d. After 2 days, the patient’s dyspnea and peripheral edema have improved, and BP has decreased to 146/84 mm Hg. Scr has also decreased from 2.1 to 1.7 mg/dL. Preparing the patient for discharge, the inpatient team converts medications from IV to oral dosing and schedules primary care follow-up within 1 week.

Question 2: Which of the following is the most appropriate diuretic regimen for discharge?

Furosemide 120 mg twice daily and metolazone 10 mg/d

Furosemide 80 mg twice daily

Furosemide 160 mg/d

Bumetanide 4 mg twice daily

Bumetanide 4 mg/d

Pharmacokinetics describe how a drug is absorbed, distributed, metabolized, and eliminated by the body. For example, furosemide is absorbed similarly in the stomach and duodenum, although gastric absorption is slow and includes first-pass metabolism. This effect may account for the lower (50%–60%) bioavailability of furosemide compared with other loop diuretics such as bumetanide and torsemide (>80%). Such differences in bioavailability have implications for IV-to-oral dosing conversions: generally, the furosemide dose should be doubled when making this change, whereas bumetanide and torsemide doses should stay the same, although these rules are only approximations. Ultimately, the effective dose is determined by the urine output response. GI tract edema decreases the velocity but not the total amount of furosemide absorbed. However, this slowed absorption may prevent orally administered furosemide from reaching its threshold plasma concentration (Figure 1(A)). Finally, the dose-response curve for loop diuretic agents is sigmoidal and logarithmic, so exponential dose increases may be needed for patients who do not show a response to an algorithmic or empirical dose (Figure 1(B)). Conversely, doses that yield plasma concentrations greater than the ceiling may increase toxicity without increasing the response. Once absorbed, most diuretics bind to serum albumin for distribution, followed by metabolism and elimination by the liver and kidneys. Hypoalbuminemia and impaired renal blood flow (as in AKI and CKD) decrease diuretic delivery, so albumin and loop diuretic coinfusion has been proposed to improve drug response, but this practice has not been beneficial in critically ill adult patients. Furosemide is metabolized completely by the kidneys (35% furosemide glucuronide and 65% parent molecule excretion), whereas torsemide is metabolized mainly by the liver. Triamterene is a prodrug that requires hepatic activation to hydroxytriamterene, so it is relatively ineffective in ESLD. Routes of diuretic metabolism and elimination may be important considerations for patients with kidney or liver disease (Table 1). Peak serum concentrations of loop diuretics occur within 0.5–2 hours, even though drug effects may last for 6–8 hours, especially with impaired kidney, heart, or liver function. The short elimination half-life (t1/2) of most loop diuretics, except possibly torsemide, means they are typically dosed at least twice daily. Despite this short t1/2, more frequent administration than twice daily is usually unnecessary because sodium intake is zero during sleep. Conversely, if loop diuretics are prescribed only once daily, the kidneys are diuretic free for many hours, allowing considerable rebound sodium reabsorption in most cases. On the contrary, thiazide and distal diuretics have much longer t1/2 values and may be given daily. A new extended-release preparation of torsemide has been approved by the US Food and Drug Administration (FDA) for the treatment of edema from heart and kidney failure. In case 1, the patient was initially prescribed a furosemide loading dose of 80 mg IV to rapidly achieve a therapeutic serum level, followed by a maintenance dose of 5 mg/h (120 mg/d) IV to maintain a steady state; this management strategy has effectively achieved decongestion. This dose is equivalent to 240 mg/d orally, which should be given as 120 mg twice daily to avoid postdiuretic sodium reabsorption. However, because this patient’s signs and symptoms of ADHF and AKI resolved and 2.4 L/d urine output is no longer necessary, a lower oral dose of furosemide, such as 80 mg twice daily, may be appropriate. Furosemide 120 mg twice daily with metolazone 10 mg/d would further increase diuresis and could cause hypovolemia and/or hypokalemia. Similarly, bumetanide 4 mg orally twice daily, which is equivalent to furosemide 160 mg IV twice daily or 320 mg orally twice daily, would also risk hypovolemia. Unless sodium intake can be severely restricted, neither furosemide nor bumetanide should be dosed once daily. The correct answer to question 2 is (b).⁴

Figure 1.

Source: https://doi.org/10.2215/cjn.09630818 (with permission of the copyright holder).

Table 1.

Pharmacok inetics of Diuretics.

Diuretic	Bioavailability	Equivalent Dose, mg	Metabolism (Kidney/Liver)	Elimination t1/2, h
Diuretic	Bioavailability	Equivalent Dose, mg	Metabolism (Kidney/Liver)	Normal	CKD	CHF	ESLD
Loop
Furosemide	50%–60%(10%–100%)	40	100%/0%	1.5–2	2.6–2.8	2.7	2.5
Bumetanide	80%–100%	1	50%/50%	1	1.6	1.3	2.3
Torsemide	68%–100%	20	20%/80%	3–4	4–5	6	8
Thiazide
HCTZ	65%–75%	25	100%/0%	6–15	↑	↔	↔
Chlorthalidone	60%–72%	12.5	100%/0%	40–60	↑	↔	↔
Metolazone	65%–90%	2.5	70%–95%/5–30%	14–20	↑	↔	↔
Distal
Amiloride	50%–60%(10%–100%)	10	50%/—	6–26	100	?	↔
Triamterene	52%–80%	100	20%/80%	2–5	↑	?	–
Spironolactone	>90%	25	0%/100%	>15	↔	?	↔

Case 1, continued: He is adherent to prescribed medications, including losartan, furosemide (80 mg twice daily), atorvastatin, and insulin. His BP is 162/92 mm Hg and heart rate is 104 beats per minute. What should be the next step for better management ?

Recommendation for Beta Blockers
COR	LOE	Recommendation
1	A	1. In patients with heart failure with reduced ejection fraction (HFrEF), with current or previous symptoms, use of 1 of the 3 beta blockers proven to reduce mortality (e.g., bisoprolol, carvedilol, sustained-release metoprolol succinate) is recommended to reduce mortality and hospitalizations.^1–3
Valve statement: High value (A)		2. In patients with HFrEF, with current or previous symptoms, beta-blocker therapy provides a high economic value.^4–8

Treatment with beta blockers reduces the risk of death and the combined risk of death and hospitalization in patients with HFrEF.^5–7 In addition, this treatment can improve LVEF, lessen the symptoms of HF, and improve clinical status.^5–10 Clinical trials have shown that beta blockers should be prescribed to all patients when HFrEF is diagnosed, including in-hospital, unless contraindicated or not tolerated.^5–10 These benefits of beta blockers were observed in patients with or without CAD, and in patients with or without diabetes, in older patients, as well as in women and across racial and ethnic groups but not in patients with AF.^5–7,9–11 Even if symptoms do not improve, long-term treatment should be maintained to reduce the risk of major cardiovascular events. Beta blockers should be initiated at low doses, and every effort should be made to achieve the target doses of the beta blockers shown to be effective in major clinical trials, as tolerated.^1–8

Three beta blockers have been shown to be effective in reducing the risk of death in patients with HFrEF: bisoprolol, sustained-release metoprolol (succinate), and carvedilol.^5–7 The favorable findings with these three agents, however, should not be considered a beta-blocker class effect in HFrEF. Other beta blockers are not included in this recommendation for use.^12–14 Even when asymptomatic, or when symptoms are mild or improve with other therapies, beta-blocker therapy is important and should not be delayed until symptoms return or disease progression is documented.¹⁵

The Metoprolol CR/XL Randomized Intervention Trial in Chronic HF (MERIT-HF) randomized patients with symptomatic HFrEF to metoprolol or placebo and included many patients with eGFR < 45 ml/min per 1.73 m². The hazard ratio for total mortality was 0.41 in favor of metoprolol for the CKD subgroup and demonstrated higher risk reduction than did the reference group with eGFR > 60 ml/min per 1.73 m².¹⁶

A similar analysis was performed in the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), which included patients having a serum creatinine level up to 300 mmol/l (3.4 mg/dl) and demonstrated sustained benefit of bisoprolol with worsening kidney function.¹⁷

A small study of carvedilol in patients with dialysis-dependent CKD and HFrEF also conferred a mortality benefit.¹⁸ Therefore, it seems reasonable to use beta blockers for managing HFrEF in patients with CKD, except for beta blockers that have significant renal excretion and have the potential for overexposure, such as atenolol, nadolol, or sotalol.¹⁹ Atenolol can be used as part of the management approach for hypertension and coronary disease if given 3 times per week in ESKD during hemodialysis.²⁰ Consideration should be given to the potential for dialyzability of certain beta blockers, as a 1.4-fold increased mortality risk was observed in the group treated with highly dialyzable beta blockers such as metoprolol.²¹

Case 1, continued: The patient is adherent to prescribed medications including losartan, furosemide (80 mg twice daily), atorvastatin, insulin, and beta blockers. His BP is 162/92 mm Hg and heart rate is 104 beats per minute.

Which is better to continue, ACEi, ARB, or ARNi?

Renin-angiotensin System Inhibition with ACEi or ARB or ARNi

Inhibition of the renin-angiotensin system is recommended to reduce morbidity and mortality for patients with HFrEF, and ARNi, ACEi, or ARB is recommended as a first-line therapy.^22–39 If patients have chronic symptomatic HFrEF with NYHA class II or III symptoms and they tolerate an ACEi or ARB, they should be switched to an ARNi because of improvement in morbidity and mortality.^22–26 An ARNi is recommended as a de novo treatment in hospitalized patients with acute HF before discharge, given there is improvement in health status, reduction in the prognostic biomarker NT-proBNP, and improvement in LV remodeling parameters compared with ACEi/ARB. Although data are limited, the use of an ARNi may be efficacious as a de novo treatment in patients with symptomatic chronic HFrEF to simplify management. ARB may be used as an alternative to ACEi in the setting of intolerable cough or as an alternative to ACEi and ARNi in patients with a history of angioedema. If patients are switched from an ACEi to an ARNi or vice versa, there should be at least 36 hours’ gap between ACEi and ARNi doses.

In the Prospective Comparison of ARNi with ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, an RCT that compared the first approved ARNi, sacubitril-valsartan, with enalapril in symptomatic patients with HFrEF tolerating an adequate dose of either ACEi or ARB, sacubitril-valsartan significantly reduced the composite endpoint of cardiovascular death or HF hospitalization by 20% relative to enalapril.²²

Dosage recommendations for ARNi in CKD⁷³
Conditions Treated with ARNi			Initial Dose	Target Dose
Patients with	Heart failure	eGFR ≥ 60 ml/min/1.73 m²	50 mg BID	200 mg BID
non-dialysis CKD		eGFR < 0 ml/min/1.73 m²	25–50 mg BID

	Hypertension	eGFR ≥ 60ml/min/1.73 m²	200 mg QD or	400 mg QD or
			100 mg BID	200 mg BID
		EGFR 15–60 ml/min/1.73 m²	100 mg QD or
			50 mg BID
Patients with CKD undergoing maintenance dialysis: Heart failure or hypertension			25–50 mg QD	100–150 mg QD to BID

Recommendations for Renin-angiotensin System Inhibition with ACEi or ARB or ARNi
COR	LOE	Recommendations
1	A	1. In patients with HFrEF and NYHA class II to III symptoms, the use of ARNi is recommended to reduce morbidity and mortality.^1–5
1	A	2. In patients with previous or current symptoms of chronic HFrEF, the use of ACEi is beneficial to reduce morbidity and mortality when the use of ARNi is not feasible.^6–13
1	A	3. In patients with previous or current symptoms of chronic HFrEF who are intolerant to ACEi because of cough or angioedema and when the use of ARNi is not feasible, the use of ARB is recommended to reduce morbidity and mortality.^14–18
Value statement: high value (A)		4. In patients with previous or current symptoms of chronic HFrEF, in whom ARNi is not feasible, treatment with an ACEi or an ARB provides a high economic value.^19–25
1	B-R	5. In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACEi or an ARB, replacement with an ARNi is recommended to further reduce morbidity and mortality.^1–5
Value statement: high value (A)		6. In patients with chronic symptomatic HFrEF, treatment with an ARNi instead of an ACEi provides high economic value.^26–29
3: Harm	B-R	7. ARNi should not be administered concomitantly with ACEi or within 36 hours of the last dose of an ACEi.
3: Harm	C-LD	8. ARNi should not be administered to patients with any history of angioedema.
3: Harm	C-LD	9. ACEi should not be administered to patients with any history of angioedema.

Case 1, continued: The patient is prescribed sacubitril-valsartan in place of losartan, furosemide (80 mg twice daily), atorvastatin, and insulin. His BP is 162/92 mm Hg and heart rate is 104 beats per minute. This patient has a creatinine of 1.7 mg% (eGFR 47 ml/min).

How to monitor renal functions when a patient is on ARNi/ACEi/ARB?

Renin-angiotensin-aldosterone System Inhibitor Therapy in Patients with Heart Failure with Reduced Ejection Fraction and CKD

Randomized controlled trials have shown improvement of survival in patients with HF with the use of ACEi (or ARB) and mineralocorticoid receptor antagonists. Most of these studies included patients with mild-to-moderate (i.e., stages 1–3) CKD.⁴⁰ Patients with severe CKD have been excluded from most ACEi studies.

The use of ACEi and mineralocorticoid receptor antagonists, particularly in patients with CKD, is often associated with hyperkalemia and rising creatinine. Rising creatinine of up to 40% has been observed in ACEi trials, without significant effects on long-term outcomes.^{41, 42} A rise of up to 30% can be viewed as resulting from hemodynamic changes owing to RAASis.⁴³ In fact, such a change may be beneficial and is named permissive AKI as opposed to true AKI due to other reasons in patients with HFrEF, which requires careful history taking and physical examination. RAASis should be stopped when kidney blood flow autoregulation is necessary in a patient, for example, with diarrhea causing volume depletion.

A large randomized controlled trial of dual angiotensin receptor and neprilysin inhibitor therapy excluded patients with an eGFR of 30 ml/min per 1.73 m² (see Figure 1, Table 1) but included patients with only mild CKD.⁴⁴ A randomized controlled trial of angiotensin receptor neprilysin inhibitors, including patients with eGFR as low as 20 ml/min per 1.73 m², demonstrated safety and efficacy similar to irbesartan.⁴⁵ More recently, angiotensin receptor and neprilysin inhibitor therapy has been shown to slow the progression of CKD in patients with HF with preserved ejection fraction (HFpEF) more effectively than valsartan.⁴⁶ The recommended starting dosage for patients with an eGFR of 60 ml/min per 1.73 m² is 24 mg sacubitril and 26 mg valsartan, administered twice per day, at least 36 hours after stopping ACEi or ARB; the dose is then increased, with careful monitoring of creatinine, potassium, and BP.

Drug		Starting Dose	Max Daily Dose	Kidney Impairment
ACE inhibitors	Benazepril	10 mg once daily	80 mg	CrCl ≥ 30 ml/min: No dosage adjustment needed.CrCl < 30 ml/min: Reduce initial dose to 5 mg PO once daily for adults.Patient compound not removed by hemodialysis.
	Captopril	12.5–25 mg 2 to 3 times daily	Usually 50 mg 3 times daily (may go up to 450 mg/d)	Half-life is increased in patients with kidney impairment.CrCl 10–50 ml/min: administered 75% of normal dose every 12–18 hours. CrCl < 10 ml/min. Administer 50% of normal dose every 24 hours.Hemodialysis: administer after dialysis. About 40% drug is removed by hemodialysis.
	Enalapril	5 mg once daily	40 mg	CrCl ≤ 30 ml/min: In adult patients, reduce initial dose to 2.5 mg PO once daily 2.5 mg PO after hemodialysis on dialysis days, dosage on nondialysis days should be adjusted based on clinical response.
	Fosinopril	10 mg once daily	40 mg	No dosage adjustment necessary. Poorly removed by hemodialysis.
	Lisinopril	10 mg once daily	40 mg	CrCl 10–30 ml/min: Reduce initial recommended dose by 50% for adults. Max: 40 mg/d. CrCl < 10 ml/min: Reduce initial dosage to 2.5 mg PO once daily. Max: 40 mg/d.
	Perindopril	2 mg once daily	8 mg	Use is not recommended when CrCl < 30 ml/min. Perindopril and its metabolites are removed by hemodialysis.
	Quinapril	10 mg once daily	80 mg	CrCl 61–89 ml/min: start at 10 mg once daily; CrCl 30–60 ml/min: start at 5 mg once daily; CrCl 10–29 ml/min: start at 2.5 mg once daily; CrCl < 10 ml/min: insufficient data for dosage recommendation about 12% of patient compound removed by hemodialysis.
	Ramipril	2.5 mg OD	20 mg	Administer 25% of normal dose when CrCl < 40 ml/min; minimally removed by hemodialysis.
	Trandolapril	1 mg OD	4 mg	CrCl < 30 ml/min: reduce initial dose to 0.5 mg/d.
Angiotensin receptor blockers	Azilsartan	20–80 mg OD	80 mg	Dose adjustment is not required in patients with mild to severe kidney impairment or kidney failure.
	Candesartan	16 mg OD	32 mg	In patients with CrCl <30 ml/min, AUC and C_max were approximately doubled with repeated dosing. Not removed by hemodialysis.
	Irbesartan	150 mg OD	300 mg	No dosage adjustment necessary. Not removed by hemodialysis.
	Losartan	50 mg OD	100 mg	No dosage adjustment necessary. Not removed by hemodialysis.
	Olmesartan	20 mg OD	40 mg	AUC is increased threefold in patients with CrCl <20 ml/min. No initial dosage adjustment is recommended for patients with moderate to marked kidney impairment (CrCl < 40 ml/min). Has not been studied in dialysis patients.
	Telmisartan	40 mg OD	80 mg	No dosage adjustment necessary. Not removed by hemodialysis.
	Valsartan	80 mg OD	320 mg	No dosage adjustment available for CrCl < 30 mil/min—to be used with caution. Not removed significantly by hemodialysis.

Patients are referred back and forth, between nephrologists and cardiologists, with RAASi-induced changes in creatinine and potassium, resulting in multiple hospital attendances and, often, discontinuation of RAASi. An analysis of 194,456 patient records showed up to 30% increase in the frequency of hyperkalemia in patients with CKD stages 4 and 5 if measured more than 4 times a year and discontinuation of ACEi/ARB in 24% of patients.⁴⁷ Nephrologists traditionally have managed hyperkalemia with judicious use of diuretics and correction of acidosis, but oral potassium binders such as patiromer or sodium zirconium cyclosilicate may be useful.⁴⁸ Randomized controlled studies of new potassium binders for maximization of RAASi therapy in patients with advanced CKD and heart failure are necessary. A close collaboration between nephrologists and cardiologists is necessary for successful initiation and continuation of RAASi in patients with CKD and HF.

Case 1, continued: This patient’s creatinine was repeated 2 weeks after starting ARNi. His creatinine jumped to 2.4 mg% (eGFR 31 ml/min). Should ARNi be continued or not?

As 30% rise in creatinine is expected after starting ARNi. We continued ARNi with frequent monitoring of renal functions.

Recommendation for SGLT2i
COR	LOE	Recommendation
1	A	1. In patients with symptomatic chronic HFrEF, SGLT2i are recommended to reduce hospitalizations for HF and cardiovascular mortality, irrespective of the presence of type 2 diabetes
Value statement: intermediate value (A)		2. In patients with symptomatic chronic HFrEF, SGLT2i therapy provides intermediate economic value.

Several RCTs in patients with type 2 diabetes and either established CVD or high risk for CVD have shown that SGLT2i prevent HF hospitalizations compared with placebo.^49–51

The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial and EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure with Reduced ejection fraction (EMPEROR-Reduced) showed the benefit of SGLT2i (dapagliflozin and empagliflozin, respectively) versus placebo on outcomes (median follow-up, 16–18 months).^{49, 52} Patients who enrolled had symptomatic chronic HFrEF (LVEF ≤ 40%, NYHA class II to IV, and elevated natriuretic peptides) and were already on GDMT. Important exclusions were eGFR < 20 ml/min (EMPEROR-Reduced) < 30 ml/min (DAPA-HF), type 1 diabetes, or lower SBP.

In the DAPA-HF and EMPEROR-Reduced trials, SGLT2i compared with placebo reduced the composite of cardiovascular death or HF hospitalization by approximately 25%.^{50, 52–54} The benefit in reduction of HF hospitalization was greater (30%) in both trials.⁹ Risk of cardiovascular death was significantly lowered (18%) with dapagliflozin, as was risk of all-cause mortality (17%).

Recommendations for Mineralocorticoid Receptor Antagonists (MRAs)
COR	LOE	Recommendations
1	A	1. In patients with HFrEF and NYHA class II to IV symptoms, an MRA (spironolactone or eplerenone) is recommended to reduce morbidity and mortality, if eGFR > 30 ml/min/ 1.73 m² and serum potassium < 5.0 mEq/l. Careful monitoring of potassium renal function and diuretic dosing should be performed at initiation and closely monitored thereafter to minimize the risk of hyperkalemia and renal insufficiency.
Value statement: high Value (A)		2. In patients with HFrEF and NYHA class II to IV symptoms, MRA therapy provides a high economic value.
3: Harm	B-NR	3. In patients taking MRA whose serum potassium cannot be maintained at < 5.5 mEq/l, MRA should be discontinued to avoid life-threatening hyperkalemia.

MRA (also known as aldosterone antagonists or anti-mineralocorticoids) show consistent improvements in all-cause mortality, HF hospitalizations, and SCD across a wide range of patients with HFrEF.^55–57

Clinical trials taken on MRA together—Randomized Aldactone Evaluation Study (RALES), which randomized highly symptomatic patients with LVEF ≤ 35%; Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), which randomized patients post-MI with LVEF ≤ 40%; and Eplerenone in Mild Patient Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF), which randomized patients with mild symptoms and LVEF ≤ 30%—suggest a benefit of MRA across the spectrum of HFrEF, inclusive of a wide range of etiologies and disease severities. Initiation in the ambulatory or hospital setting is appropriate.⁵⁸ The starting dose of spironolactone and eplerenone is 25 mg orally daily, increased to 50 mg daily orally after a month; for eGFR 31–49 m;/min/1.73 m², dosing should be reduced by half. Regular checks of serum potassium levels and renal function should be performed according to clinical status, approximately 1 week, then 4 weeks, then every 6 months after initiating or intensifying MRA, with more frequent testing for clinical instability.

Spironolactone and eplerenone are partially excreted through the kidneys, raising concerns about safety when eGFR ≤ 30 ml/min/1.73 m².^{59, 60} Spironolactone and eplerenone decrease renal potassium excretion, raising the risk of hyperkalemia, particularly when MRA is initiated at serum potassium ≥ 5.0 mEq/L and continued at serum potassium ≥ 5.5 mEq/L. Evidence around the use of any MRA in patients with HF and CKD stages 4–5 is lacking (ECR).

Vasodilators

Two RCTs, Vasodilator Heart Failure Trial (V-HeFT I) and African American Heart Failure Trial (A-HeFT), established the benefit of the combination of hydralazine-isosorbide dinitrate in self-identified African Americans.^{61, 62}

In a large-scale trial that compared the vasodilator combination with placebo, the use of hydralazine and isosorbide dinitrate reduced mortality in patients with HF treated with digoxin and diuretics but not an ACEi or beta blocker.⁴ However, in two other trials that compared the vasodilator combination with an ACEi, the ACEi produced more favorable effects on survival.⁶³

There are insufficient data to guide the use of hydralazine-isosorbide dinitrate with ARNi. In patients with HFrEF who cannot receive first-line agents such as ARNi, ACEi, or ARB, referral to a HF specialist can provide guidance for further management because the use of hydralazine and isosorbide dinitrate in these patients is uncertain.

Ivabradine

The ivabradine and outcomes in chronic heart failure (SHIFT) study demonstrated improved hospitalization and deaths owing to HF with ivabradine treatment in patients with HFrEF with a heart rate > 70 beats per minute despite beta-blocker therapy, which included patients with creatinine 2.5 mg/dl. The study included 1,589 patients with CKD stage 3, and benefits in patients with CKD were similar to those in patients without CKD.⁶⁴ Ivabradine is metabolized by the CYP3A4 enzyme in the liver and gut, and elimination by kidneys is minimal. The dosage is 2.5–7.5 mg twice per day and does not require dose adjustment with creatinine clearance of 15 ml/min.

Recommendation for the Management of Stage C HF: Ivabradine
COR	LOE	Recommendation
2a	B-R	1. For patients with symptomatic (NYHA class II to III) stable chronic HFrEF (LVEF ≤ 35%) who are receiving GDMT, including a beta blocker at the maximum tolerated dose, and who are in sinus rhythm with a heart rate of ≥ 70 bpm at rest, ivabradine can be beneficial to reduce HF hospitalizations and cardiovascular death.

Management of Iron Deficiency and Anemia in Patients with Heart Failure with Reduced Ejection Fraction and CKD

Nephrologists have been using intravenous iron for the past three decades to treat anemia in patients with CKD, both before and during dialysis. In the United Kingdom, a recent study in patients receiving dialysis has shown benefits of high-dose intravenous iron in reducing mortality and morbidity, together with HF hospitalizations by 44%.⁶⁵ A previous trial of benefits of intravenous iron in patients with HFrEF included patients with early stages of CKD.⁶⁶ A collaboration between cardiologists and nephrologists may assist the management of iron deficiency in patients with HFrEF and CKD.

RRT

CKD is a progressive disease with declining kidney function over time, causing frequent episodes of fluid overload and hyperkalemia, further complicated by episodes of AKI. With an eGFR of 20 ml/min per 1.73 m², decisions need to be made, in discussion with the patient, about indications, appropriateness, and modality of KRT. Careful consideration of factors such as patient expectations, comorbidities, frailty, and quality of life is necessary to consider when starting KRT. Patients with HF on dialysis have very poor prognosis, with a five-year survival rate of 12.5%.⁶⁷ There may be symptomatic relief and fewer hospitalizations with peritoneal dialysis in carefully selected patients.⁶⁸ In a study of 118 patients with HF and CKD, peritoneal dialysis was associated with improvement in quality of life and New York Heart Association class.⁶⁹ A meta-analysis of 23 studies demonstrated benefits of peritoneal dialysis in patients with HF and CKD, with improved hospitalization rates and heart function.⁷⁰ In patients with refractory HF, overnight ultrafiltration with icodextrin solution improved quality of life, heart function, and New York Heart Association class.⁷¹ Hemodialysis may be tricky in patients with low BP, but more frequent dialysis and longer nocturnal dialysis may be useful for fluid removal. However, creation of arteriovenous fistula or graft for hemodialysis may cause dilation of left atrium and right ventricle and associated HF.⁷² For patients with acute HF and low BP, slow ultrafiltration with continuous KRT may be useful.

The Way Forward

To achieve appropriate therapy and the best possible outcome, combined cardiology–nephrology clinics are necessary, which manage kidney and heart care, together with intravenous iron and advice on dialysis therapy.⁴⁹ Patients appreciate the multiple benefits from a single visit and provide excellent feedback. The multidisciplinary “one-stop shop” clinic is very patient centered and helps with decision making regarding RAASi, device therapy, and intravenous iron administration but requires proper resources, including the presence of a nephrologist, cardiologist, and nurse and appropriate space (Figure 2). With improved knowledge among cardiologists and nephrologists and multidisciplinary approach, evidence-based therapy can be implemented in patients with early-to-moderate CKD. However, we recognize that more studies are necessary to strengthen the evidence base in patients with advanced CKD.

Figure 2.

Note: ACEi, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; AKI, acute kidney injury; ARB, angiotensin II receptor blocker; ARNi, angiotensin receptor neprilysin inhibitor; CKD-MBD, chronic kidney disease–mineral bone disorder; CRT, cardiac resynchronization therapy; CRRT, continuous renal replacement therapy; ESKD, end-stage kidney disease; H-isdn, hydralazine–isosorbide dinitrate; ICD, implantable cardioverter–defibrillator; NSAID, nonsteroidal anti-inflammatory drug; RAASi, rennin-angiotensin–aldosterone system inhibitor.

Prognosis of CKD by GFR and Albuminuria Categories: KDIGO 2012				Persistent Albuminuria Categories (Description and Range)
				A1	A2	A3
				Normal to mildly increased	Moderately increased	Severely increased
				<30 mg/g–<3 mg/mmol	30–300 mg/g to 3–30 mg/mmol	>300 mg/d >30 mg/mmol
GFR categories (ml/min per 1.73 m²) Description and range	G1	Normal or high	≥90		Monitor	Refer
	G2	Mildly decreased	60–89		Monitor	Refer
	G3a	Mildly to moderately decreased	40–59	Monitor	Monitor	Refer
	G3b	Moderately to severely decreased	30–44	Monitor	Monitor	Refer
	G4	Severely decreased	15–29	Refer	Refer	Refer
	G5	Kidney failure	<15	Refer	Refer	Refer
	Low risk (if no other markers of kidney disease, no CKD
	Moderately increased risk
	High risk
	Very high risk

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval and Informed Consent

The ethical clearance and patient consent were obtained for the study.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Rajasekara Chakravarthi Madarasu

References

Kottgen

, Russell

, Loehr

, . Reduced kidney function as a risk factor for incident heart failure: the Atherosclerosis Risk In Communities (ARIC) study. J Am Soc Nephrol . 2007;18:1307–1315.

Saran

, Robinson

, Abbott

, . US Renal Data System 2019 annual data report: epidemiology of kidney disease in the United States. Am J Kidney Dis . 2020;75(Suppl 1):A6–A7.

House

, Wanner

, Sarnak

, . Heart failure in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) controversies conference. Kidney Int . 2019;95:1304–1317.

Novak

, Ellison

DH.

Diuretics in states of volume overload: core curriculum 2022. Am J Kidney Dis . 2022;80(2):264–276. https://doi.org/10.1053/j.ajkd.2021.09.029

Investigators CIBIS-II Study Committees. The Cardiac Insufficiency Bisoprolol (CIBIS-II): a randomised trial. Lancet . 1999;353(9146):9–13.

MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet . 1999;353:2001–2007.

Packer

, Fowler

, Roecker

, . Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study. Circulation . 2002;106:2194–2199.

Bristow

, Gilbert

, Abraham

, . Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators. Circulation . 1996;94:2807–2816.

Cleland

JGF

, Bunting

, Flather

, . Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials. Eur Heart J . 2018;39:26–35.

10.

Hjalmarson

, Goldstein

, Fagerberg

, . Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). JAMA . 2000;283:1295–1302.

11.

Kotecha

, Holmes

, Krum

, . Efficacy of beta blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis. Lancet . 2014;384:2235–2243.

12.

Flather

, Shibata

, Coats

, . Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J . 2005;26:215–225.

13.

Beta-Blocker Investigators Evaluation of Survival Trial, Eichhorn EJ, Domanski MJ, et al. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med . 2001;344:1659–1667.

14.

Poole-Wilson

, Swedberg

, Cleland

, . Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet . 2003;362:7–13.

15.

Willenheimer

, van Veldhuisen

, Silke

, . Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite sequence: results of the randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III. Circulation . 2005;112:2426–2435.

16.

Ghali

, Wikstrand

, Van Veldhuisen

, . The influence of renal function on clinical outcome and response to beta-blockade in systolic heart failure: insights from Metoprolol CR/XL Randomized Intervention Trial in Chronic HF (MERIT-HF). J Card Fail . 2009;15:310–318.

17.

CIBIS-II Investigators. The Cardiac Insufficiency Bisoprolol Study II (CIBISII): a randomised trial. Lancet . 1999;353:9–13.

18.

Cice

, Ferrara

, D’Andrea

, . Carvedilol increases two-year survival in dialysis patients with dilated cardiomyopathy: a prospective, placebo-controlled trial. J Am Coll Cardiol . 2003;41:1438–1444.

19.

McDevitt

DG.

Comparison of pharmacokinetic properties of betaadrenoceptor blocking drugs. Eur Heart J . 1987;8 (Suppl M):9–14.

20.

Agarwal

, Sinha

, Pappas

, . Hypertension in hemodialysis patients treated with atenolol or lisinopril: a randomized controlled trial. Nephrol Dial Transplant . 2014;29:672–681.

21.

Weir

, Dixon

, Fleet

, . b-Blocker dialyzability and mortality in older patients receiving hemodialysis. J Am Soc Nephrol . 2015;26:987–996.

22.

McMurray

, Packer

, Desai

, . Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med . 2014;371:993–1004.

23.

Wachter

, Senni

, Belohlavek

, . Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study. Eur J Heart Fail . 2019;21:998–1007.

24.

Velazquez

, Morrow

, DeVore

, . Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med . 2019;380:539–548.

25.

Desai

, Solomon

, Shah

, . Effect of sacubitril-valsartan vsenalapril on aortic stiffness in patients with heart failure and reduced ejection fraction: a randomized clinical trial. JAMA . 2019;322:1077–1084.

26.

Wang

, Zhou

, Lu

, . Effects of the angiotensin-receptor neprilysin inhibitor on cardiac reverse remodeling: meta-analysis. J Am Heart Assoc . 2019;8:e012272.

27.

Consensus Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med . 1987;316:1429–1435.

28.

SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med . 1991;325:293–302.

29.

ATLAS Study Group Packer

, Poole-Wilson

, . Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation . 1999;100:2312–2318.

30.

The SAVE Investigators Pfeffer

, Braunwald

, . Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement Trial. N Engl J Med . 1992;327:669–677.

31.

The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet . 1993;342:821–828.

32.

Trandolapril Cardiac Evaluation (TRACE) Study Group Køber

, Torp-Pedersen

, . A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med . 1995;333:1670–1676.

33.

Collaborative Group on ACE Inhibitor Trials, Garg

, Yusuf

Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA. 1995;273:1450–1456.

34.

Woodard-Grice

, Lucisano

, Byrd

, . Sex-dependent and race-dependent association of XPNPEP2 C–2399A polymorphism with angiotensin-converting enzyme inhibitor-associated angioedema. Pharmacogenet Genomics . 2010;20:532–536.

35.

Cohn

, Tognoni

Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med . 2001;345:1667–1675.

36.

Pfeffer

, McMurray

, Velazquez

, . Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med . 2003;349:1893–1906 [published correction appears in N Engl J Med. 2004;350:203].

37.

HEAAL Investigators Konstam

, Neaton

, . Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet . 2009;374:1840–1848.

38.

ONTARGET Investigators Yusuf

, Teo

, . Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med . 2008;358:1547–1559.

39.

Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators Yusuf

, Teo

, . Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet . 2008;372:1174–1183.

40.

McCallum

, Tighiouart

, Ku

, . Acute declines in estimated glomerular filtration rate on enalapril and mortality and cardiovascular outcomes in patients with heart failure with reduced ejection fraction. Kidney Int . 2019;96:1185–1194.

41.

Bowling

, Sanders

, Allman

, . Effects of enalapril in systolic heart failure patients with and without chronic kidney disease: insights from the SOLVD Treatment trial. Int J Cardiol . 2013;167:151–156.

42.

Clark

, Kalra

, Petrie

, . Change in renal function associated with drug treatment in heart failure: national guidance. Heart . 2019;105:904–910.

43.

McCallum

, Tighiouart

, Ku

, . Trends in kidney function outcomes following RAAS inhibition in patients with heart failure with reduced ejection fraction. Am J Kidney Dis . 2020;75:21–29.

44.

Chang

, Sang

, Leddy

, . Antihypertensive medications and the prevalence of hyperkalemia in a large health system. Hypertension . 2016;67:1181–1188.

45.

Patiromer–204 Investigators Pitt

, Bushinsky

, . Evaluation of an individualized dose titration regimen of patiromer to prevent hyperkalaemia in patients with heart failure and chronic kidney disease. ESC Heart Fail . 2018;5:257–266.

46.

McCausland

, Lefkowitz

, Claggett

, . Angiotensin-neprilysin inhibition and renal outcomes in heart failure with preserved ejection fraction. Circulation . 2020;142:1236–1245.

47.

McMurray

JJV

, Solomon

, Inzucchi

, . Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med . 2019;381:1995–2008.

48.

Packer

, Anker

, Butler

, . Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med . 2020;383:1413–1424.

49.

PARADIGM-HF Investigators Committees McMurray

, Packer

, . Angiotensinneprilysin inhibition versus enalapril in heart failure. N Engl J Med . 2014;371:993–1004.

50.

Haynes

, Judge

, Staplin

, . Effects of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease. Circulation . 2018;138:1505–1514.

51.

Wiviott

, Raz

, Bonaca

, . Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med . 2019;380:347–357.

52.

Zinman

, Wanner

, Lachin

, . Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med . 2015;373:2117–2128.

53.

Zannad

, Ferreira

, Pocock

, . SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet . 2020;396:819–829.

54.

Neal

, Perkovic

, Mahaffey

, . Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med . 2017;377:644–657.

55.

Randomized Aldactone Evaluation Study Investigators Pitt

, Zannad

, . The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med . 1999;341:709–717.

56.

Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators Pitt

, Remme

, . Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med . 2003;348:1309–1321.

57.

Zannad

, McMurray

, Krum

, . Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med . 2011;364:11–21.

58.

FDA Aldactone label 2008. Accessed June 28, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/012151s062lbl.pdf

59.

FDA INSPRA label 2008. Accessed June 28, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021437s006lbl.pdf

60.

Cohn

, Archibald

, Ziesche

, . Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med . 1986;314:1547–1552.

61.

Butler

, Anstrom

, Felker

, . Efficacy and safety of spironolactone in acute heart failure: the ATHENA-HF Randomized Clinical Trial. JAMA Cardiol . 2017;2:950–958.

62.

Taylor

, Ziesche

, Yancy

, . Combination of isosorbidedinitrate and hydralazine in blacks with heart failure. N Engl J Med . 2004;351:2049–2057.

63.

Cohn

, Johnson

, Ziesche

, . A comparison of enalapril with hydralazine-isosorbidedinitrate in the treatment of chronic congestive heart failure. N Engl J Med . 1991;325:303–310.

64.

Investigators

SHIFT

, Voors

, van Veldhuisen

, . The effect of heart rate reduction with ivabradine on renal function in patients with chronic heart failure: an analysis from SHIFT. Eur J Heart Fail . 2014;16:426–434.

65.

PIVOTAL Investigators and Committees Macdougall

, White

, . Intravenous iron in patients undergoing maintenance hemodialysis. N Engl J Med . 2019;380:447–458 [published correction appears in N Engl J Med. 2019;380:502. https://doi.org/10.1056/NEJMx180044

66.

FAIR-HF Trial Investigators Anker

, Comin

, . Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med . 2009;361:2436–2448.

67.

Banerjee

, Ma

, Collins

, . Long-term survival of incident hemodialysis patients who are hospitalized for congestive heart failure, pulmonary edema, or fluid overload. Clin J Am Soc Nephrol . 2007;2:1186–1190.

68.

Nunez

, Gonzalez

, Minana

, . Continuous ambulatory peritoneal dialysis as a therapeutic alternative in patients with advanced congestive heart failure. Eur J Heart Fail . 2012;14:540–548.

69.

Koch

, Haastert

, Kohnle

, . Peritoneal dialysis relieves clinical symptoms and is well tolerated in patients with refractory heart failure and chronic kidney disease. Eur J Heart Fail . 2012;14:530–539.

70.

, Mucino-Bermejo

, Ribeiro

, . Peritoneal dialysis in patients with refractory congestive heart failure: a systematic review. Cardiorenal Med . 2015;5:145–156.

71.

Wojtaszek

, Grzejszczak

, Niemczyk

, . Peritoneal ultra filtration in the long-term treatment of chronic heart failure refractory to pharmacological therapy. Front Physiol . 2019;10:310.

72.

Reddy

YNV

, Obokata

, Dean

, . Long-term cardiovascular changes following creation of arteriovenous fistula in patients with end stage renal disease. Eur Heart J . 2017;38:1913–1923.

73.

Gan

, Lyu

, Yang

, . Application of angiotensin receptor–neprilysin inhibitor in chronic kidney disease patients: Chinese expert consensus. Front Med . 2022 July 19;9. https://doi.org/10.3389/fmed.2022.877237

Heart Failure in CKD Population

Abstract

Keywords

Pharmacok inetics of Diuretics.

Renin-angiotensin System Inhibition with ACEi or ARB or ARNi

Renin-angiotensin-aldosterone System Inhibitor Therapy in Patients with Heart Failure with Reduced Ejection Fraction and CKD

Vasodilators

Ivabradine

Management of Iron Deficiency and Anemia in Patients with Heart Failure with Reduced Ejection Fraction and CKD

RRT

The Way Forward

Footnotes

Declaration of Conflicting Interests

Ethical Approval and Informed Consent

Funding

ORCID iD

References