Background: The use of urinary sodium to guide diuretics in acute heart failure is recommended by experts and the most recent European Society of Cardiology guidelines. However, there are limited data to support this recommendation. The ENACT-HF study (Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure) investigated the feasibility and efficacy of a standardized natriuresis-guided diuretic protocol in patients with acute heart failure and signs of volume overload. Methods: ENACT-HF was an international, multicenter, open-label, pragmatic, 2-phase study, comparing the current standard of care of each center with a standardized diuretic protocol, including urinary sodium to guide therapy. The primary end point was natriuresis after 1 day. Secondary end points included cumulative natriuresis and diuresis after 2 days of treatment, length of stay, and in-hospital mortality. All end points were adjusted for baseline differences between both treatment arms. Results: Four hundred one patients from 29 centers in 18 countries worldwide were included in the study. The natriuresis after 1 day was significantly higher in the protocol arm compared with the standard of care arm (282 versus 174 mmol; adjusted mean ratio, 1.64; P <0.001). After 2 days, the natriuresis remained higher in the protocol arm (538 versus 365 mmol; adjusted mean ratio, 1.52; P <0.001), with a significantly higher diuresis (5776 versus 4381 mL; adjusted mean ratio, 1.33; P <0.001). The protocol arm had a shorter length of stay (5.8 versus 7.0 days; adjusted mean ratio, 0.87; P =0.036). In-hospital mortality was low and did not significantly differ between the 2 arms (1.4% versus 2.0%; P =0.852). Conclusions: A standardized natriuresis-guided diuretic protocol to guide decongestion in acute heart failure was feasible, safe, and resulted in higher natriuresis and diuresis, as well as a shorter length of stay.

Mortality and re-admission rates for decompensated acute heart failure (AHF) is increasing overall and risk stratification might be challenging. We sought to evaluate the prognostic role of systemic venous ultrasonography in patients hospitalized for AHF. We prospectively recruited 74 AHF patients with a NT-proBNP level above 500 pg/mL. Then, multi-organ ultrasound assessments (lung, inferior vena cava (IVC), pulsed-wave Doppler (PW-Doppler) of hepatic, portal, intra-renal and femoral veins) were performed at admission, discharge, and follow-up (for 90 days). We also calculated the Venous Excess Ultrasound System (VExUS), a new score of systemic congestion based on IVC dilatation and pulsed-wave Doppler morphology of hepatic, portal and intra-renal veins. An intra-renal monophasic pattern (area under the curve (AUC) 0.923, sensitivity (Sn) 90%, specificity (Sp) 81%, positive predictive value (PPV) 43%, and negative predictive value (NPV) 98%), a portal pulsatility > 50% (AUC 0.749, Sn 80%, Sp 69%, PPV 30%, NPV 96%) and a VExUS score of 3 corresponding to severe congestion (AUC 0.885, Sn 80%, Sp 75%, PPV 33%, and NPV 96%) predicted death during hospitalization. An IVC above 2 cm (AUC 0.758, Sn 93.l% and Sp 58.3) and the presence of an intra-renal monophasic pattern (AUC 0. 834, sensitivity 0.917, specificity 67.4%) in the follow-up visit predicted AHF-related re-admission. Additional scans during hospitalization or the calculation of a VExUS score probably adds unnecessary complexity to the assessment of AHF patients. In conclusion, VExUS score does not contribute to the guidance of therapy or the prediction of complications, compared with the presence of an IVC greater than 2 cm, a venous monophasic intra-renal pattern or a pulsatility > 50% of the portal vein in AHF patients. Early and multidisciplinary follow-up visits remain necessary for the improvement of the prognosis of this highly prevalent disease.

Mineralocorticoid receptor antagonists (MRA) improve outcomes in patients with heart failure and reduced ejection fraction (HFrEF) but are underused in clinical practice. Observational data suggest that hyperkalemia is the leading obstacle for the suboptimal use of MRA. We evaluated the effects of sodium zirconium cyclosilicate (SZC) in optimizing use of spironolactone among participants with HFrEF and hyperkalemia. REALIZE-K (NCT04676646) was a prospective, double-blind, randomized- withdrawal trial in participants with HFrEF (NYHA II-IV; left ventricular ejection fraction ≤40%), optimal guideline-directed therapy (except MRA), and prevalent or incident MRA- induced hyperkalemia. During open-label run-in, participants underwent spironolactone titration (target: 50 mg/daily); those with hyperkalemia started SZC. Participants with normokalemia (potassium 3.5-5.0 mEq/L) on SZC and spironolactone ≥25 mg/daily were randomized to continued SZC or placebo for 6 months. The primary endpoint was optimal treatment response (normokalemia on spironolactone ≥25 mg/daily without rescue therapy for hyperkalemia [months 1-6]). The five key secondary endpoints were tested hierarchically. Exploratory endpoints included a composite of adjudicated cardiovascular death or worsening HF events (hospitalizations and urgent visits). Overall, 203 participants were randomized (SZC 102, placebo 101). Higher percentage of SZC- versus placebo-treated participants had optimal response (71% vs 36%; OR 4.45 [95% CI 2.89-6.86]; p<0.001). SZC (versus placebo) improved the first four key secondary endpoints: normokalemia on randomization dose of spironolactone and without rescue therapy (58% vs 23%; OR 4.58 [2.78-7.55]; p<0.001), receiving spironolactone ≥25 mg/daily (81% vs 50%; OR 4.33 [2.50-7.52]; p<0.001), time to hyperkalemia (HR 0.51 [0.37-0.71]; p<0.001), time to decrease/discontinuation of spironolactone due to hyperkalemia (HR 0.37 [0.17-0.73]; p=0.006). There was no between-group difference in KCCQ-CSS at 6 months (-1.01 points [-6.64-4.63]; p=0.72). Adverse events (64% vs 63%) and serious adverse events (23% vs 22%) were balanced between SZC and placebo, respectively. Composite of CV death or worsening HF occurred in 11 (11%) participants in the SZC group (1 with CV death, 10 with HF events) and 3 (3%) participants in the placebo group (1 with CV death, 2 with HF events; log-rank nominal p=0.034). In participants with HFrEF and hyperkalemia, SZC led to large improvements in the percentage of participants with normokalemia while on optimal spironolactone dose, and reduced risk of hyperkalaemia and down-titration/discontinuation of spironolactone. Although underpowered for clinical outcomes, more participants had HF events with SZC than placebo, which should be factored into the clinical decision making.

Worsening kidney function (WKF) is common in patients with acute heart failure (AHF) syndromes. Although WKF has traditionally been associated with worse outcomes on a population level, serum creatinine concentrations vary greatly during episodes of worsening heart failure, with substantial individual heterogeneity in terms of their clinical meaning. Consequently, interpreting such changes within the appropriate clinical context is essential to unravel the pathophysiology of kidney function changes and appropriately interpret their clinical meaning. This article aims to provide a critical overview of WKF in AHF, aiming to provide physicians with some tips and tricks to appropriately interpret kidney function changes in the context of AHF.

The population with concomitant heart and kidney disease (often termed ‘cardiorenal’ disease) is expected to grow, significantly impacting public health and healthcare utilization. Moreover, the cardiorenal nexus encompasses a bidirectional relationship that worsens prognosis and may complicate pharmacological management in often elderly and frail patients. Therefore, a more cohesive multidisciplinary team approach aiming to provide holistic, coordinated and specialized care would be a positive shift towards improving patient outcomes and optimizing healthcare resources. This article aims to define the organizational aspects and key elements for setting up a multidisciplinary cardiorenal clinical program as a potential healthcare model adapted to the particular characteristics of patients with cardiorenal disease.