This retrospective study will take advantage of an existing EU-funded dataset, the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF), which was designed to identify biomarkers related to the response to guideline directed medical therapy, and coordinated by UMCG.

The availability of this comprehensive dataset of patients with severe HFrEF, prospectively and consistently collected, with the possibility to access a biobank to re-assay samples with novel biomarkers, provides a unique opportunity to derive preliminary data about the interaction between biomarkers of congestion and diuretic doses, that were prescribed based on clinical judgement, and therefore derive a machine learning-based algorithm than could be tested to guide the management of diuretic therapy

This is a retrospective study based on the index and the validation cohorts of the BIOSTAT-CHF project. The index cohort consists of a prospectively enrolled series of 2516 patients from 69 centres in 11 European countries recruited between December 2010 and December 2012 and with a median follow-up of 21 months [interquartile range (IQR) 15 - 27 months]. Validation cohort was designed as well as a multicentre, prospective, observational study, which included 1738 patients from six centres in Scotland, United Kingdom.

BIOSTAT-CHF samples and data will be re-analysed to include additional congestion biomarkers, to obtain the BIOTOOL-CHF DISCO dataset. The latter has been used to derive a predictive model for congestion-related adverse events, priming the design of a prospective randomized study (the BIOTOOL-CHF VALID study).

Preliminary analysis reported advanced age, higher blood urea nitrogen and N-terminal pro-B-type natriuretic peptide (NT-proBNP), lower haemoglobin, and failure to prescribe a beta-blocker as the five strongest predictors of mortality. Moreover, the five strongest predictors of hospitalisation due to decompensated HF were more advanced age, previous hospitalisation owing to HF, presence of oedema, lower systolic blood pressure and lower estimated glomerular filtration rate.

Capitalizing from these preliminary results, the BIOTOOL-CHF VALID study will test the score derived from the analysis of the BIOTOOL-CHF DISCO dataset, in order to guide therapy management in HF patients.

Inclusion Criteria:

In order to have been included to participate in the index trial, a subject must have met all of the following criteria:

• age >=18 years with symptoms of new-onset or worsening heart failure;
• objective evidence of cardiac dysfunction documented either by left ventricular ejection fraction <=40% or plasma concentrations of brain natriuretic peptide (BNP) >400 pg/mL and/or NT-proBNP >2000 pg/mL;
• treatment with either oral or intravenous furosemide >=40 mg/day or equivalent at the time of inclusion; not previously treated with evidence-based therapies (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and beta-blockers) or receiving <=50% of target doses of these drugs at the time of inclusion; anticipated initiation or up-titration of ACE inhibitors or ARBs and/or beta-blockers by the treating physician.

For the validation cohort, patients had to fulfil the following inclusion criteria:

• age >=18 years;
• diagnosis of heart failure with a previous documented admission requiring diuretic treatment;
• treatment with furosemide >=20 mg/day or equivalent;
• not previously treated or receiving <=50% of target doses of ACE inhibitors or ARBs and/or beta-blockers;
• anticipated initiation or up-titration of ACE inhibitors or ARBs and/or beta-blockers. In both trials, patients could be enrolled as inpatients or from outpatient clinics.

Exclusion Criteria:

A potential subject who meets any of the following criteria will be excluded from participation in this study:

- known diagnosis of septicaemia, known diagnosis of acute myocarditis or hypertrophic obstructive, restrictive, or constrictive cardiomyopathy, heart transplant recipient or admitted for cardiac transplantation or left ventricular assist device surgery, anticipated need for surgery or any cardiovascular intervention, except implantable cardioverter defibrillator and-or cardiac resynchronization therapy, within 4 weeks, current known inability to follow instructions or comply with follow-up procedures, and treatment with medications or devices not approved in Europe.

Patients with concomitant pulmonary disease, even if severe, valvular disease, acute coronary syndrome or stroke, could be included when the primary diagnosis for admission to hospital or outpatient clinic visit was heart failure, rather than the concomitant condition

The study population will be patients with congestive HF previously enrolled in the BIOSTAT-CHF cohorts. The index cohort consists of a prospectively enrolled series of 2516 patients from 69 centres in 11 European countries recruited between December 2010 and December 2012 and with a median follow-up of 21 months [interquartile range (IQR) 15 - 27 months]. Validation cohort was designed as well as a multicentre, prospective, observational study, which included 1738 patients from six centres in Scotland, United Kingdom