Rationale and Design of the Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure Study

Abstract

Aims Although acute heart failure (AHF) with volume overload is treated with loop diuretics, their dosing and type of administration are mainly based upon expert opinion. A recent position paper from the Heart Failure Association (HFA) proposed a step‐wise pharmacologic diuretic strategy to increase the diuretic response and to achieve rapid decongestion. However, no study has evaluated this protocol prospectively. Methods and results The Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure (ENACT‐HF) study is an international, multicentre, non‐randomized, open‐label, pragmatic study in AHF patients on chronic loop diuretic therapy, admitted to the hospital for intravenous loop diuretic therapy, aiming to enrol 500 patients. Inclusion criteria are as follows: at least one sign of volume overload (oedema, ascites, or pleural effusion), use ≥ 40 mg of furosemide or equivalent for >1 month, and a BNP > 250 ng/L or an N‐terminal pro‐B‐type natriuretic peptide > 1000 pg/L. The study is designed in two sequential phases. During Phase 1, all centres will treat consecutive patients according to the local standard of care. In the Phase 2 of the study, all centres will implement a standardized diuretic protocol in the next cohort of consecutive patients. The protocol is based upon the recently published HFA algorithm on diuretic use and starts with intravenous administration of two times the oral home dose. It includes early assessment of diuretic response with a spot urinary sodium measurement after 2 h and urine output after 6 h. Diuretics will be tailored further based upon these measurements. The study is powered for its primary endpoint of natriuresis after 1 day and will be able to detect a 15% difference with 80% power. Secondary endpoints are natriuresis and diuresis after 2 days, change in congestion score, change in weight, in‐hospital mortality, and length of hospitalization. Conclusions The ENACT‐HF study will investigate whether a step‐wise diuretic approach, based upon early assessment of urinary sodium and urine output as proposed by the HFA, is feasible and able to improve decongestion in AHF with volume overload.

Renal effects of guideline‐directed medical therapies in heart failure: a consensus document from the Heart Failure Association of the European Society of Cardiology

“…Such approach helps to identify patients with good diuretic response (UNa >50–70 mmol/L after 2 h or UO >600 ml after 6 h). The ongoing PUSH‐HF trial and ENACT‐HF study are assessing the feasibility and safety of protocol‐driven diuretic administration in acute HF and determine whether such approach is associated with better clinical outcome 122,123 …”

“…The ongoing PUSH-HF trial and ENACT-HF study are assessing the feasibility and safety of protocol-driven diuretic administration in acute HF and determine whether such approach is associated with better clinical outcome. 122,123 In the chronic HF setting, observational data indicate that higher doses of loop diuretics are associated with a more rapid decline in GFR over time. However, such observational data are heavily influenced by selection bias as the sickest patients with intrinsic more rapid decline in GFR are often prescribed the highest doses of loop diuretics.…”

Assessing intrinsic renal sodium avidity in acute heart failure: implications in predicting and guiding decongestion

“…Indeed, in the proposed algorithm (which is also endorsed by the 2021 ESC heart failure guidelines), early measurement of diuretic response could identify patients in which the current used loop diuretic dose is insufficient to attain complete decongestion 31 . Currently, two studies are testing as to whether the employment of such a natriuretic response‐guided treatment algorithm leads to better decongestive response 15,16 . These studies will provide a valuable insight into the use of well‐timed post‐diuretic UNa samples in titrating decongestive therapies.…”

“…Numerous studies have tried to estimate diuretic efficiency or decongestive efficacy in post‐hoc analyses of AHF trials, but the problem with metrics such as weight change after 72–96 h or cumulative urine output over a certain amount of days, is that these metrics are only available near the time of discharge and therefore not practical in the individual patient management 7–14 . As a result, natriuretic response measured via the urinary sodium (UNa) concentration in a urine spot sample 1–2 h after loop diuretic administration has gained popularity as a metric used for early assessment of diuretic response 1,15,16 . However, collecting a well‐timed UNa sample 1–2 h after diuretic administration can be challenging in numerous scenarios and care settings.…”

Role of Early Assesment of Diuresis and Natriuresis in Detecting In-Hospital Diuretic Resistance in Acute Heart Failure

“…At this time, two other studies are evaluating the performance of this diagnostic strategy, the ENACT-HF trial (Rationale and Design of the Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure Study) ( Dauw et al, 2021 ), and the PUSH-HF trial (Natriuresis-guided therapy in acute heart failure: rationale and design of the Pragmatic Urinary Sodium-based treatment algoritHm in Acute Heart) ( Maaten et al, 2022 ).…”