Discussion
AHF, euvolemia, NRPE, congestion, Decompensated Heart Failure
ADVERSE EVENTS, CONGESTION, EVENTS, BLIND
In PUSH-AHF, natriuresis-guided diuretic therapy in patients with AHF significantly improved natriuresis and diuresis up to 48 h without impacting all-cause mortality and/or HF hospitalization at 180 days. There are several other key findings that deserve consideration in interpreting these results. First, in the natriuresis-guided treatment group, intensification of diuretic therapy occurred in the majority of patients, and this resulted in substantially higher doses of loop diuretics being administered. Second, the urinary sodium-based diuretic treatment algorithm was safe and did not result in renal or electrolyte perturbations despite much higher cumulative loop diuretic doses used. Third, the effect of natriuresis-guided therapy on 24 h natriuresis was consistent across a broad spectrum of patients reflecting a contemporary, all-comer, AHF population. The results of PUSH-AHF provide the first randomized evidence supporting the use of natriuresis-guided therapy to improve natriuresis in patients with AHF.Over the past decades, diuretic treatment of AHF has been largely based on expert opinion and local practices using generally unreliable surrogate measures of response. Therefore, even nowadays, there is great variation in decongestive approaches and the use of diuretic therapy across centers and countries. This observation is even more important in the perspective of relatively recent data showing that impaired response to diuretics is common in patients with AHF and associated with persistent congestion and poor clinical outcomes, including high rates of HF rehospitalizationTo reduce congestion, loop diuretics are administered that inhibit the sodium-chloride–potassium co-transporter in the ascending loop of Henle resulting in potent natriuresis and subsequent diuresisFollowing from the observation that early assessment of spot urinary sodium within 1–2 h after initiation of intravenous loop diuretic treatment was shown to be an accurate marker of subsequent 6 h natriuretic response, a natriuretic response prediction equation (NRPE) was developedThe achieved natriuresis in the PUSH-AHF trial was much higher, also in the SOC group compared with previous observations from ENACT even in the active arm, and also from a subanalysis from the Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) study, where addition of acetazolamide resulted in total natriuresis of 258 ± 133 mmol in 24 h (refs. In contrast to the Diuretic Optimization Strategies Evaluation trial where the high-dose strategy was associated with greater diuresis but also with transient worsening of renal function, no increased risk of worsening of renal function was observed in the natriuresis-guided groupThere was no effect of natriuresis-guided treatment on the combined endpoint of 180 day all-cause mortality and HF rehospitalization. It has been proven difficult to improve outpatient clinical outcome in patients with AHF, with the exception of some treatments that were continued after hospitalization. For PUSH-AHF, where the intervention was only administered during the first 36 h of admission, a direct effect may not be possible to observe. It would be tempting to speculate that there might have been an effect if the treatment algorithm was maintained until patients had reached euvolemia. There are currently multiple ongoing trials studying the effect of natriuresis-guided therapy that will provide additional data. A combined analysis with an ongoing randomized controlled trial studying the effect of protocolized diuretic therapy guided by spot urine chemistry using the NRPE to improve outcomes (ESCALATE; We acknowledge the limitations of the single-center nature, as well as open-label design of this study. Given the design of the study, requiring adjustments based on urinary sodium levels, with our limited funding, it was unfortunately not feasible to perform this trial in a double-blind fashion including the pharmacist to blind the treating physicians to both the urinary sodium values as the necessity and dose of additional diuretics. We furthermore intentionally chose to design this study as a pragmatic trial to enroll a generalizable, all-comer, AHF population and allow for swift enrollmentIn summary, the PUSH-AHF trial is the first randomized clinical trial to show that natriuresis-guided diuretic therapy improves natriuresis and diuresis in patients with AHF. These findings could be directly and easily implementable as spot urinary sodium values are easy to obtain, inexpensive and available in most centers around the world. Additionally, the studied treatment algorithm involves medication that are widely available, and is therefore easily implementable. An important observation from the PUSH-AHF trial is that natriuresis-guided diuretic therapy was safe and did not result in more (serious) adverse events or prespecified renal events. The PUSH-AHF study provides a first step towards a personalized natriuresis-guided approach in patients with AHF.