20555822, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ehf2.13666 by Readcube (Labtiva Inc.), Wiley Online Library on [31/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License ESC HEART FAILURE STUDY DESIGN ESC Heart Failure 2021; 8: 4685–4692 Published online 28 October 2021 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.13666 Rationale and Design of the Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure Study Jeroen Dauw1,2 , Malgorzata Lelonek3 , Isabel Zegri-Reiriz4 , Cynthia P. Paredes-Paucar5 , Cornelia Zara6, Varghese George7, Marta Cobo-Marcos8, Dorit Knappe9,10, Dmitry Shchekochikhin11 , Annop Lekhakul12, Milka Klincheva13, Simone Frea14 , Òscar Miró15 , Diane Barker16, Attila Borbély17, Samer Nasr18 , Nawal Doghmi19, Rafael de la Espriella20 , Jagdeep S. Singh21 , Virginia Bovolo22, Inês Fialho23 , Noel T. Ross24 , Mieke van den Heuvel25, Riad Benkouar26, Hajo Findeisen27, Imad A. Alhaddad28, Kais Al Balbissi29, Gonzalo Barge-Caballero30 , Azmee M. Ghazi31,32, Liesbeth Bruckers33 , Pieter Martens1 and Wilfried Mullens1,34* 1 Department of Cardiology, Ziekenhuis Oost-Limburg, Schiepse Bos 6, Genk, 3600, Belgium; 2UHasselt-Hasselt University, Doctoral School for Medicine and Life Sciences, LCRC, Diepenbeek, Belgium; 3Department of Noninvasive Cardiology, Medical University of Lodz, Lodz, Poland; 4Department of Cardiology, Heart Failure and Heart Transplant Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 5Instituto Nacional de Cardiología Ignacio Chávez, Ciudad de México, Mexico; 6Theracardia Clinic, Brasov, Romania; 7Pushpagiri Institute of Medical Sciences, Tiruvalla, India; 8Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain; 9Centro de Investigación Biomédica en Red, Madrid, Spain; 10Department of Cardiology, University Heart and Vascular Center Hamburg, Hamburg, Germany; 11Department of cardiology, sonography and functional diagnostics, First Moscow State Medical University, Moscow, Russia; 12Wetchakarunrasm Hospital, Bangkok, Thailand; 13Zan Mitrev Clinic, Skopje, Macedonia; 14Division of Cardiology, Città della Salute e della Scienza University Hospital of Torino, Torino, Italy; 15Emergency Department, IDIBAPS, University of Barcelona, Barcelona, Spain; 16University Hospitals of North Midlands, Stoke on Trent, UK; 17Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; 18Department of Cardiology, Mount Lebanon Hospital-Balamand University Medical Center, Hazmiyeh, Lebanon; 19Department of Cardiology, CHU Ibn Sina, Mohammed V University, Rabat, Morocco; 20Cardiology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain; 21The Heart Centre, Royal Infirmary of Edinburgh, Edinburgh, UK; 22Department of Cardiology, Michele e Pietro Ferrero Hospital, Verduno, Italy; 23Department of Cardiology, Hospital Professor Doutor Fernando Fonseca, Amadora, Portugal; 24Kuala Lumpur General Hospital, Kuala Lumpur, Malaysia; 25Department of Cardiology, Thorax Centrum Twente, Medisch Spectrum Twente, Enschede, The Netherlands; 26Benyoucef Benkhedda Faculty of Medicine, Mustapha Pacha Hospital, University of Algiers, Algiers, Algeria; 27Department of Internal Medicine, Red Cross Hospital, Bremen, Germany; 28Jordan Hospital, Amman, Jordan; 29Department of Cardiology, Abdali Hospital, Amman, Jordan; 30Complexo Hospitalario Universitario de A Coruña (CHUAC), Servicio Galego de Saúde (SERGAS), Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain; 31Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain; 32National Heart Institute, Kuala Lumpur, Malaysia; 33I-BioStat, Data Science Institute, Hasselt University, Diepenbeek, Belgium; and 34Faculty of Medicine and Life Sciences, LCRC, UHasselt, Biomedical Research Institute, Diepenbeek, Belgium Abstract Aims Although acute heart failure (AHF) with volume overload is treated with loop diuretics, their dosing and type of admin- istration 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 furo- semide 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 conges- tion score, change in weight, in-hospital mortality, and length of hospitalization. © 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. 20555822, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ehf2.13666 by Readcube (Labtiva Inc.), Wiley Online Library on [31/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 4686 J. Dauw et al. 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. Keywords Acute heart failure; Diuretics; Urinary sodium; Decongestion; Protocol Received: 6 July 2021; Revised: 20 September 2021; Accepted: 27 September 2021 *Correspondence to: Wilfried Mullens, Department of Cardiology, Ziekenhuis Oost-Limburg, Schiepse Bos 6, 3600 Genk, Belgium. Tel: +32 89 327100; Fax: +32 89 327918. Email: wilfried.mullens@zol.be Introduction ENACT-HF study Volume overload is a hallmark symptom of heart failure (HF). Study design Haemodynamic alterations and neurohormonal activation lead to increased renal sodium avidity resulting in salt and The ENACT-HF study is an international, multicentre, non- fluid retention.1 Ultimately, patients with acute heart failure randomized, open-label, pragmatic study in AHF patients (AHF) will present with signs and symptoms of congestion ac- with volume overload, designed according to a two-phased companied by fluid accumulation. Volume overload is not a design. Objective is to enrol in at least four different mere symptom but can severely impair organ function and continents to ensure feasibility of the protocol worldwide is an important treatment target.2 For more than 50 years, (Figure 1). In the first phase of the study, all participating volume overload in AHF has been treated with loop diuretics. centres treat a group of consecutive patients according to However, despite long-term experience, their dosing and type the institution’s current standard of care, and the loop of administration are mainly based upon expert opinion. diuretic regime is left entirely at the discretion of the treating Current guidelines advise administering loop diuretics intra- physician. Subsequently, the HFA protocol is implemented for venously (IV) in AHF, using 20–40 mg of furosemide in loop the next group of consecutive patients in the second phase of diuretic naive patients and at least an equivalent to the the study. The study complies with the Declaration of Helsinki chronic oral home dose in others (class I, level of evidence and has been approved by the local ethics committees of the B).3 These recommendations are based on the Diuretic Strat- participating centres. egies in Patients with Acute Decompensated Heart Failure The ENACT-HF trial was powered for its primary endpoint: (DOSE) trial’s findings that high-dose (2.5 times the oral home natriuresis after 1 day. A recent pilot trial in AHF patients on dose) loop diuretics IV was not better in improving patients’ chronic loop diuretic therapy, similar to our study population, global assessment of symptoms after 72 h compared with reported a 24 h natriuresis of 234 ± 133 mmol in patients re- low-dose (equivalent dose to the oral home dose) IV.4 In ceiving high-dose loop diuretics twice daily.9 For sample size addition, there has been conflicting evidence from registries calculation, a similar natriuresis after 1 day was considered regarding the association between high loop diuretics doses in the standard of care group. As there are currently no data and increased mortality,5,6 suggesting to use the lowest pos- on the effect of a standardized diuretic protocol on natriure- sible loop diuretic dose that has a significant effect. Of note, sis, an increase in natriuresis of 15% was deemed both current guidelines give no specific recommendations on how achievable and clinically relevant. Considering a type I error the effect of loop diuretics should be evaluated, nor do they rate α = 0.05 and a type II error rate β = 0.20 (statistical advise on treatment strategies if the diuretic response is in- power = 80%), a sample size of 454 is defined based on a Stu- sufficient. To overcome the current gaps in evidence, the dent’s t-test. Taking a drop-out or missing data of 10% into Heart Failure Association (HFA) of the European Society of account, this renders a total study population of 500 patients. Cardiology, recently published a position paper to guide the use of diuretics in HF.7 The proposed strategy includes early IV loop diuretic administration, high dosing (one to two times Eligibility the oral home dose), and early titration of the dose based upon evaluation of diuretic response using urinary sodium The study’s inclusion and exclusion criteria are listed in concentration and/or urine output as markers. However, this Table 1. Patients are eligible for the study if they present with protocol has not been tested in clinical practice. The goal of AHF and at least one sign of volume overload (oedema, asci- the Efficacy of a Standardized Diuretic Protocol in Acute tes or pleural effusion) and have an N-terminal pro-B-type Heart Failure (ENACT-HF) study is to investigate whether natriuretic peptide (NT-proBNP) > 1000 pg/mL or a the implementation of the HFA protocol can improve decon- BNP > 250 ng/mL. Importantly, volume status will be gestion, assessed by natriuresis. determined daily by the treating physician using a predefined ESC Heart Failure 2021; 8: 4685–4692 DOI: 10.1002/ehf2.13666 20555822, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ehf2.13666 by Readcube (Labtiva Inc.), Wiley Online Library on [31/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License The ENACT-HF study 4687 Figure 1 Participating centres. Table 1 Eligibility criteria Inclusion criteria • An elective or emergency hospital admission with clinical diagnosis of acute heart failure and at least one sign of volume overload: ○ Pitting edema, assessed clinically or ○ Ascites, assessed by ultrasound or ○ Pleural effusion, assessed by ultrasound or chest x-ray • Maintenance daily loop diuretic use of ≥ 40 mg furosemide, ≥ 1 mg bumetanide, or ≥ 20 mg torsemide for ≥ 1 month • Hospital admission for IV loop diuretic administration • BNP > 250 ng/mL or NT-proBNP > 1000 pg/mL at time of screening Exclusion criteria • Cardiogenic shock or systolic blood pressure < 90 mmHg • Use of renal replacement therapy or ultrafiltration • Use or anticipated use of intravenous inotropes (dopamine, dobutamine, levosimendan, milrinone, & adrenaline) IV, intravenously; NT-proBNP, N-terminal pro-B-type natriuretic peptide. ESC Heart Failure 2021; 8: 4685–4692 DOI: 10.1002/ehf2.13666 20555822, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ehf2.13666 by Readcube (Labtiva Inc.), Wiley Online Library on [31/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 4688 J. Dauw et al. congestion score allowing a quantitative standardization of frequencies are allowed, as well as the combination of differ- congestion and decongestion (Figure 2). In addition, patients ent diuretic classes. In addition, continuous infusion or inter- should be treated with loop diuretics chronically, defined at a mittent boluses can be used. In contrast, in study Phase 2, IV dose of ≥ 40 mg of furosemide, ≥ 1 mg of bumetanide, or loop diuretic administration is performed according to the ≥ 20 mg of torsemide for ≥ 1 month prior to inclusion. HFA protocol.7 Any values that are open for interpretation Patients with cardiogenic shock, use of renal replacement are specified in the amended protocol (e.g. one to two times therapy, or ultrafiltration or patients with (expected) use of oral home dose was defined as two times oral home dose). inotropes (dopamine, dobutamine, levosimendan, milrinone, After inclusion, oral loop diuretics are stopped, and patients or adrenaline) are excluded. To enhance enrolment and in are administered two times the oral home dose IV as a bolus order to make urine collections more homogenous, it was with a maximum of 200 mg of furosemide or equivalent (con- decided that patients could only be included during working version factor 40 mg furosemide = 1 mg bumetanide = 20 mg hours (8 AM to 4 PM). This ensures the presence of research torsemide). Patients need to empty their bladder before the personnel and allows for the collection of at least 16 h of diuretic is administered. A spot urine sample to assess urinary urine during the first day. sodium concentration is taken within the first 4 h, preferably as closest to 2 h as possible. The diuretic response is reassessed after 6 h. The presence of both a urinary Study intervention sodium > 50 mmol/L in the spot urine sample and a urine output > 100 mL/h during the first 6 h is defined as a good The study flowchart is depicted in Figure 3. Every participat- diuretic response and allows the physician to repeat the ing centre is assigned to include a fixed number of 10 patients same loop diuretic dose IV, leading to a total of two bolus in study Phase 1 (routine care) before including at least a sim- doses per day. If the diuretic response is insufficient, the loop ilar number of patients in study Phase 2 (HFA protocol imple- diuretic dose should be doubled. In case the ceiling dose of mentation). The set number of patients is determined for loop diuretics was already reached, a thiazide should be each centre specifically based upon a feasibility interview added as the next step. On the morning of Day 2, diuretic re- and ranges between 20 and 40 patients (10 patients in Phase sponse is again reassessed, using urine output solely. If the 1 and 10–30 patients in Phase 2). To avoid that physicians total urine output is ≥ 3L, diuretic response is deemed suffi- would learn from the potential advantageous HFA protocol cient, and the same loop diuretic dose is repeated as an IV and change their standard of care accordingly, a centre has bolus twice daily. Otherwise, diuretic therapy should be esca- to finish Phase 1 first, before Phase 2 can be started. lated either by doubling the loop diuretic dose or addition of During Phase 1 of the study, the treatment with IV loop a thiazide in case the maximum loop diuretic dose has been diuretics will be at the physician’s discretion. All doses and reached. Again, the loop diuretic is administered as a bolus Figure 2 Congestion score. ESC Heart Failure 2021; 8: 4685–4692 DOI: 10.1002/ehf2.13666 20555822, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ehf2.13666 by Readcube (Labtiva Inc.), Wiley Online Library on [31/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License The ENACT-HF study 4689 Figure 3 Study flowchart. BID, twice daily; IV, intravenous. twice daily. If the patient is no longer volume overloaded at collection. In case of urinary incontinence, placement is man- any time of the study treatment based upon the predefined datory according to the study protocol. Special care should be congestion score (Figure 2), the protocol can be stopped. taken to ensure that all urine is collected. Physicians will be trained extensively on the details of the protocol and the congestion score. From Day 3 on, the fur- ther treatment is at the physician’s discretion in both treatment arms. To standardize fluid input, sites are Objectives and endpoints instructed to restrict daily oral intake of fluids and sodium to 1500 mL and 1.5 g, respectively. The primary objective of the ENACT-HF study is to test whether implementation of the HFA protocol can improve decongestion. Natriuresis after 1 day was set as the primary Urine collection and sampling endpoint because (i) sodium is used as a metric for loop di- uretic efficacy, (ii) the direct effect of loop diuretics is increas- Before administrating the first IV loop diuretic dose, patients ing renal sodium excretion, (iii) low natriuresis has been will be asked to void empty. From then on, loop diuretics will associated with poor outcomes, and (iv) it is an objective end- be administered and the urine collection will start. A spot point reflecting the goals of the study which is not open to urine sample will be taken within the first 4 h either directly bias.8 This will be assessed as the total renal sodium excre- from the bladder catheter or from the first void if the patient tion from the first loop diuretic administration until the does not have a bladder catheter. The first urine collection morning of Day 2. Secondary endpoints assessed after 2 days will be stopped on the morning of Day 2 between 8 and are changes in congestion score, cumulative natriuresis, 10 AM and before the first loop diuretic administration on cumulative diuresis, and change in weight (Table 2). Further, Day 2. A new 24 h urine collection will then be started until length of stay and in-hospital mortality will be additional the morning of Day 3. Insertion of a bladder catheter is rec- secondary endpoints. Doubling of serum creatinine is set as ommended but not mandatory to achieve an optimal urine a safety endpoint. ESC Heart Failure 2021; 8: 4685–4692 DOI: 10.1002/ehf2.13666 20555822, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ehf2.13666 by Readcube (Labtiva Inc.), Wiley Online Library on [31/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 4690 J. Dauw et al. Table 2 Study endpoints Primary endpoint Total natriuresis after 1 day Secondary endpoints Change in congestion score after 2 days Cumulative natriuresis after 2 days Cumulative diuresis after 2 days Change in body weight after 2 days Length of hospital stay In-hospital mortality Safety endpoint Worsening renal function, defined as a doubling of serum creatinine after 2 days Statistical plan more weight loss, and more net fluid loss. Although high-dose diuretics led to more worsening renal function, this All endpoints will be analysed according to the intention-to- was associated with improved outcomes.10 This finding is in treat principle. Given the non-randomized nature of the concordance with other studies emphasizing that creatinine study, a linear mixed model with treatment arm and baseline rises do not necessarily indicate injury nor do they impair out- factors influencing the endpoint as fixed effects and centre as comes in case of effective decongestion.11,12 Importantly, a random effect will be used to compare the primary end- only 15% of patients included in the DOSE trial were assessed point and all secondary endpoints that are on a continuous to be dry by their treating physicians at the end of the treat- scale. Data will be transformed if model assumptions are ment phase which likely explains why more than 50% of the not met (e.g. normality). In-hospital mortality will be evalu- patients were either readmitted or deceased after 3 months ated with a generalized linear mixed model for a binary out- of follow-up.4 come, using treatment arm as a fixed effect and baseline The Cardiorenal Rescue Study in Acute Decompensated differences as well as centre as a random effect. The hetero- Heart Failure trial investigated whether a step-wise pharma- geneity of the primary endpoint will be tested on cologic diuretic strategy based upon the diuretic response prespecified subgroups: (i) congestion score on admission > resulted in better decongestion in comparison with vs. < than the observed median, (ii) estimated glomerular fil- ultrafiltration.13 In the diuretic treatment arm, patients were tration rate > vs. < than the observed median, (iii) chronic treated with a step-wise loop diuretic dosing protocol using loop diuretic dose > vs. < than the observed median, (iv) continuous infusions adapted to the 24 h urine output with sex, and (v) LVEF ≥ 50% vs. < 50%. A sensitivity analysis with a of goal 3–5 L per day. In case the maximal loop diuretic dose multiple imputation of missing data will be performed for the was achieved, but response was still insufficient, a thiazide primary endpoint. In a second sensitivity analysis, the primary was added. After 96 h, protocolized diuretic treatment re- endpoint will be assessed after normalization for the duration sulted in a similar weight loss as compared with ultrafiltra- of the urine collection. All performed tests will be two-sided tion. In a post-hoc analysis, the step-wise diuretic treatment with a significance level set at P < 0.05. arm resulted in more weight loss, more net fluid loss, and slight improvement in renal function compared with standard diuretic therapy.14 Furthermore, a small single- Discussion centre study also suggested that a urine-output-guided diuretic protocol could improve decongestion and lower Although diuretics are the cornerstone treatment for volume 30 day readmissions.15 overload in AHF, there has been little evidence to guide their The direct effect of loop diuretics is reducing sodium reab- use and how to assess treatment response. The DOSE trial sorption at the loop of Henle and thus increasing natriuresis specifically addressed the question whether high-dose loop and diuresis. Weight loss and urine output are among the diuretic therapy was beneficial compared with low-dose di- most used parameters to assess diuretic response. However, uretic therapy in AHF, but also compared intermittent bo- there is rather poor correlation between both measures,16 luses with continuous infusion.4 There was no difference in and neither weight loss nor fluid loss has been associated the co-primary endpoint of patients’ global assessment of with improved outcomes.17,18 In recent years, there has symptoms and creatinine change after 72 h for either ther- been increasing interest in urinary sodium as a new and apy, but high diuretic dosages led to more dyspnoea relief, more direct measure of diuretic response. Observational ESC Heart Failure 2021; 8: 4685–4692 DOI: 10.1002/ehf2.13666 20555822, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ehf2.13666 by Readcube (Labtiva Inc.), Wiley Online Library on [31/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License The ENACT-HF study 4691 data indicate that a low urinary sodium concentration tion, there is a possibility of unbalanced patient groups. This after loop diuretic administration is associated with poor will be accounted for during statistical analysis but is never outcomes.19–21 In addition, sodium loss is a better prognosti- equivalent to randomization. cator than fluid loss.18 Based upon the aforementioned data, HFA recently designed a step-wise pharmacologic diuretic protocol,7 which will be tested in the ENACT-HF study. The pragmatic trial will Conclusions prospectively test if early evaluation of the diuretic and natri- uretic response is warranted and allows for the early intensi- The ENACT-HF study will investigate whether a step-wise fication of diuretic therapy. It will determine if analysis of pharmacologic diuretic protocol as proposed by the HFA urinary spot sodium content within the first hours of diuretic can increase natriuresis after 1 day in AHF patients on chronic administration is feasible, and if this will help the clinician to loop diuretic therapy in a safe and efficacious manner across interpret diuretic response, thereby generating the opportu- a wide spectrum of healthcare settings across the globe. nity for early intervention if sodium content is low. The strat- egy that will be tested in ENACT is important in several aspects. Firstly, persisting congestion further compromises Conflict of interest organ function. Secondly, the plasma refill rate at which fluid is mobilized from the interstitial space into the plasma com- Marta Cobo-Marcos received honorary for advisory boards partment might drop during decongestion. Thirdly, patients and lectures from Vifor, Novartis, Astra-Zeneca, and are often hospitalized in acute care units for the first days, Boehringer-Ingelheim. Diane Barker received speaker fees where intensive adaptation of therapy is more likely to occur from Astra Zeneca, Novartis, and Medtronic. Jeroen Dauw, than in a regular ward. Last, faster decongestion might be Malgorzata Lelonek, Isabel Zegri-Reiriz, Cynthia P. Paredes- especially valuable in health care systems where length of Paucar, Cornelia Zara, Varghese George, Dorit Knappe, Dmitry hospital stay needs to be short. Shchekochikhin, Annop Lekhakul, Milka Klincheva, Simone The ENACT-HF study is subject to certain limitations. Most Frea, Òscar Miró, Attila Borbély, Samer Nasr, Nawal Doghmi, importantly, it’s non-randomized open-label design raise the Rafael de la Espriella, Jagdeep S. Singh, Virginia Bovolo, Inês possibility of investigator’s altering their standard of care Fialho, Noel T Ross, Mieke van den Heuvel, Riad Benkouar, treatment to influence the endpoint. However, as stated be- Hajo Findeisen, Imad A. Alhaddad, Kais Al Balbissi, Gonzalo fore, the serial study design makes it impossible for investiga- Barge-Caballero, Azmee M Ghazi, Liesbeth Bruckers, Pieter tors to compare their standard of care with the protocol, as Martens, and Wilfried Mullens have nothing to disclose. they first have to finish Phase 1 (standard of care) before they can proceed to the standardized diuretic protocol. Investiga- tors were also clearly instructed not to change their current practice. In addition, randomization could also create bias Funding as investigators could apply methods they learned from the protocol in their own standard of care practice (e.g. using Jeroen Dauw and Wilfried Mullens are researchers for the higher diuretic boluses). Second, as there is no blinding to- Limburg Clinical Research Center (LCRC) UHasselt-ZOL-Jessa, wards the urinary sodium measurements, it is possible that supported by the foundation Limburg Sterk Merk (LSM), investigators could use this information to take therapeutic province of Limburg, Flemish government, Hasselt University, decisions during Phase 1. Last, because of lack of randomiza- Ziekenhuis Oost-Limburg, and Jessa Hospital. References 1. Mullens W, Verbrugge FH, Nijst P, Tang Platz E, Rudiger A, Ruschitzka F, 3. Ponikowski P, Voors AA, Anker SD, WHW. Renal sodium avidity in heart Schäfer A, Seferovic PM, Skouri H, Bueno H, Cleland JGF, Coats AJS, Falk failure: from pathophysiology to treat- Yilmaz MB, Mebazaa A. Organ dysfunc- V, González-Juanatey JR, Harjola VP, ment strategies. Eur Heart J 2017; 38: tion, injury and failure in acute heart Jankowska EA, Jessup M, Linde C, 1872–1882. failure: from pathophysiology to diagno- Nihoyannopoulos P, Parissis JT, Pieske 2. Harjola VP, Mullens W, Banaszewski M, sis and management. A review on behalf B, Riley JP, Rosano GMC, Ruilope LM, Bauersachs J, Brunner-La Rocca HP, of the Acute Heart Failure Committee of Ruschitzka F, Rutten FH, Van Der Meer Chioncel O, Collins SP, Doehner W, the Heart Failure Association (HFA) of P, Sisakian HS, Isayev E, Kurlianskaya Filippatos GS, Flammer AJ, Fuhrmann the European Society of Cardiology A, Mullens W, Tokmakova M, V, Lainscak M, Lassus J, Legrand M, (ESC). Eur J Heart Fail 2017; 19: Agathangelou P, Melenovsky V, Wiggers Masip J, Mueller C, Papp Z, Parissis J, 821–836. 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