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....................................................................................................................................................................... are similar, if not greater, than in the patients with normal renal function.206,471,741,742 Beta-blockers reduce mortality in HFrEF patients with moderate (eGFR 4559 mL/min/1.73 m2) and moderately severe (eGFR 3044 mL/min/1.73 m2) renal dysfunction, whereas limited evidence is available regarding patients with severe renal impairment (eGFR <30 mL/min/1.73 m2).743 Sacubitril/valsartan, compared with enalapril, led to a slower decline in renal function, despite a slight increase in the urinary albumin/creatinine ratio, and improved CV outcomes to a similar extent in patients with CKD vs. the others in PARADIGM-HF.127 SGLT2 inhibitors lead to a slower decline in renal function, compared with placebo, both in patients with HFrEF and in those with CKD.108,109,737,738,744 The improvement in cardiac output after CRT or LVAD implantation may be associated with, at least, a transient improvement in renal function.471,745,746 The benefits of ICDs may be reduced in patients with severe renal dysfunction because of the competing risk of nonarrhythmic causes of death.747749

There is little direct evidence to support any recommendations for treatment of HF patients with severe CKD as to date, RCTs excluded patients with advanced stages of CKD, i.e. eGFR <30 mL/ min/1.73 m2 (Supplementary Table 23). Cut-off values for inclusion were lower in recent trials: 25 mL/min/1.73 m2 in DAPA-CKD, 20 mL/min/1.73 m2 in EMPEROR-Reduced and GALACTIC-HF, and 15 mL/min/1.73 m2 in VICTORIA, respectively.109,141,737,738,750 Despite differences in baseline characteristics between patients with severely impaired renal function and the others, no interaction between drug effects and renal function was noted in subgroup analysis of these trials.109,141,738,750

13.7 Electrolyte disorders: hypokalaemia, hyperkalaemia, hyponatraemia, hypochloraemia Electrolyte disturbances are frequent in patients with HF and may often be iatrogenic.751 Serum potassium levels have a U-shaped relation with mortality with the lowest risk of death within a relatively narrow range of 4 to 5 mmol/L.752758 Hypokalaemia is defined as serum potassium <3.5 mmol/L and may occur in up to 50% of patients with HF.759 Hypokalaemia is often induced by loop and thiazide diuretic administration. It may cause lethal ventricular arrhythmias and increase CV mortality. Its treatment includes the use of RAAS inhibitors, potassium-sparing diuretics, and prescription of oral potassium supplements (i.e. potassium chloride tablets). When oral administration is not possible, potassium supplementation by infusion may be necessary (20 to 40 mmol of potassium in 2501000 mL of normal saline). Potassium-rich solution should be infused at slow rate through a large vein using a venous catheter. Hyperkalaemia is defined as serum potassium >5 mmol/L and can be classified as mild (>5.0 to <5.5 mmol/L), moderate (5.5 to 6.0 mmol/L), or severe (>6.0 mmol/L).760 It is associated with an increased risk of hospitalization and death.752,753,755,756,761,762 Hyperkalaemia can be associated with the administration of RAAS inhibitors, CKD and increased absorption.760 Among patients with HF, the prevalence of hyperkalaemia at any given time among patients with HF appears to be less than 5%,757 but the incidence is much higher, at up to 40% in chronic HF and 73% in CKD over follow-up durations of approximately 1 year.753,756,757,763765 In PARADIGM- HF, treatment with sacubitril/valsartan was associated with lower risk of severe hyperkalaemia, compared with enalapril.128 Life-threatening hyperkalaemia requires immediate treatment with a combination of calcium carbonate and/or sodium bicarbonate, insulin, with or without glucose, and beta adrenoceptor agonists [e.g. salbutamol, offlabel use in some European Union (EU) countries]. These agents favour potassium entry into the cells and do not increase potassium excretion. Thus, they only provide temporary benefit and rebound hyperkalaemia can occur after few hours. Loop diuretics can be administered to facilitate potassium loss.

Potassium binders bind to potassium in the gastrointestinal tract reducing its absorption. They can be used for acute and chronic potassium lowering. They include sodium polystyrene sulfonate, calcium polystyrene sulfonate, and the much better tolerated patiromer sorbitex calcium and sodium zirconium cyclosilicate (SZC). Sodium polystyrene sulfonate is still indicated in anuric or severely oliguric patients, but it should not be used in the medium or long term as it may cause severe gastrointestinal side effects, including bowel necrosis.760 Patiromer or SZC increase faecal potassium excretion and act mainly in the colon. Both compounds are effective in normalizing elevated potassium levels, maintaining normokalaemia over time and preventing the recurrence of hyperkalaemia and can be considered for treatment of hyperkalaemia766768 (see Supplementary Table 24). Renal dysfunction and hyperkalaemia are the major causes of underuse of RAAS inhibitors, particularly MRA, in clinical practice.342,753,758,769771 Administration of the potassium-lowering agents, patiromer or SZC, may allow their initiation or uptitration in a larger proportion of patients. This hypothesis was tested in doubleblind, placebo-controlled, randomized trials with patiromer or placebo administration to patients with CKD and hyperkalaemia, or discontinuation of RAAS inhibitors for hyperkalaemia, and with an indication for spironolactone for HF and/or resistant hypertension. Patiromer was more likely to lower serum potassium and decreased episodes of hyperkalaemia than spironolactone initiation and uptitration.772775 The ongoing RCT DIAMOND (NCT03888066) is testing the impact on clinical outcomes of a strategy based on patiromer administration, compared with placebo, in patients with HFrEF who are hyperkalaemic while on RAAS inhibitors or with a history of hyperkalaemia with subsequent reduction or discontinuation of a RAAS inhibitor776,777 (see Supplementary text 13.1). Hyponatraemia is defined as a serum sodium concentration lower than 136 mmol/L. It is common in HF and may be present in up to 30% of patients admitted to hospital with HF. It reflects neurohormonal activation and is a powerful independent marker of poor outcomes in patients with acute or chronic HF.778,779 Severe hyponatraemia may cause neurologic symptoms (seizures, obtundation, delirium) due to cerebral oedema and may require immediate treatment with hypertonic saline with serum sodium increases by 12 mmol/L per hour, though less than 8 mmol/L in 24 h as a more rapid correction increases the risk of myelinolysis. Intravenous treatment is not required when hyponatraemia is less Downloaded from academic.oup.com/eurheartj/article/42/36/3599/6358045 by guest on 07 October 2026