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The REFer for EchocaRdiogram, clinical decision rule and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the diagnosis of heart failure
ISRCTN ISRCTN17635379
DOI 10.1186/ISRCTN17635379
ClinicalTrials.gov identifier
EudraCT number
Public title The REFer for EchocaRdiogram, clinical decision rule and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the diagnosis of heart failure
Scientific title The REFer for EchocaRdiogram, clinical decision rule and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the diagnosis of heart failure: a prospective validation study
Acronym REFER
Serial number at source 09/160/13
Study hypothesis The clinical decision rule (CDR) will discriminate between patients who have sufficiently high probability of heart failure (HF) that they should be referred for echo and those who should have a natriuretic peptide (NP) test first, with referral for echo dependant upon the natriuretic peptide results
Please note that as of 12/12/2011 the anticipated end date of this trial were modified, the initial trial dates were as follows:
Anticipated start date: 01/04/2011
Anticipated end date: 01/06/2014
Lay summary Lay summary under review 3
Ethics approval The South Birmingham Research Ethics Committee approved on 15th October 2009
Study design Multicentre prospective observational diagnostic validation study
Countries of recruitment United Kingdom
Disease/condition/study domain Heart failure
Participants - inclusion criteria Current inclusion criteria as of 12/12/2011
1. All patients 55 years of age or over presenting to their GP with new onset symptoms of breathlessness, lethargy or ankle oedema of over 48 hours duration, with no obvious recurrent, acute or self-limiting cause
2. Able to give informed consent

Previous inclusion criteria
1. All patients 55 years of age or over presenting to their GP with new onset symptoms of breathlessness, lethargy or ankle oedema of over 48 hours duration, with no obvious acute and self-limiting cause
2. Able to give informed consent
Participants - exclusion criteria Current exclusion criteria as of 12/12/2011
1. All patients with known pre-existing heart failure or left ventricular systolic dysfunction of any cause. However, patients with a pre-existing label of heart failure but without objective evidence (i.e. echocardiography) of this will not be excluded
2. Severe symptoms requiring urgent assessment or stabilisation (e.g. breathless at rest, hypotension, confusion)
3. Obvious clinically determined alternative diagnoses such as chest infection, exacerbation of chronic obstructive pulmonary disease or asthma
4. Recent acute coronary syndrome (within 60 days)
5. Major co-morbidity or other alternative diagnoses of no obvious acute and self-limiting cause (e.g. malignancy, severe respiratory disease, renal diagnosis, mental health problem)
6. Unable to provide informed consent

Previous exclusion criteria
1. All patients with known pre-existing heart failure or left ventricular systolic dysfunction of any cause. However, patients with a pre-existing label of heart failure but without objective evidence (i.e. echocardiography) of this will not be excluded
2. Severe symptoms requiring urgent assessment or stabilisation (e.g. breathless at rest, hypotension, confusion)
3. Obvious clinically determined alternative diagnoses such as chest infection, exacerbation of chronic obstructive pulmonary disease or asthma
4. Recent acute coronary syndrome (within 60 days)
5. Major co-morbidity or other alternative diagnoses of no obvious acute and self-limiting cause (e.g. active malignancy, severe respiratory disease, renal diagnosis, severe psychiatric disease)
6. Unable to provide informed consent
Anticipated start date 01/04/2011
Anticipated end date 01/06/2014
Status of trial Ongoing
Patient information material Not available in web format, please use the conatct details below to request a patient information sheet
Target number of participants 500
Interventions The general practitioner (GP) will have arranged for all patients to receive a chest x-ray when consenting patients for referral (as is usual practice). Within 7 days of referral, the research assessment clinical team will obtain written informed consent, collect baseline demographics, administer quality of life questionnaires (EQ-5D and SF12), clinically assess patients, perform a 12-lead electrocardiogram (ECG) and Echo and take blood for N-terminal pro b-type natriuretic peptide (NT-proBNP), along with creatinine for a renal dysfunction test, calculating an estimated Glomerular Filtration Rate (eGFR) (serum profile)
Primary outcome measure(s) 1. Test performance of the CDR, estimating the sensitivity and specificity, positive predictive value (PPV) and negative predictive value (NPV) of the CDR for diagnosis of HF in symptomatic patients presenting with shortness of breath, lethargy or ankle oedema of over 48 hours duration
2. Test performance of the diagnostic accuracy of NT-proBNP for diagnosis of HF in symptomatic patients, including sensitivity, specificity, PPV and NPV
3. Proportion of patients with left ventricular systolic dysfunction (LVSD) or not, (ejection fraction < 40%) and HF or not
Secondary outcome measure(s) 1. Combination of the CDR and NT-proBNP
2. Modelling of CDR test performance and epidemiological data to ascertain the most cost-effective strategy in the diagnosis of HF in primary care, incorporating data on quality of life (EQ-5D and SF12 widely used questionnaires), clinical events and health care resource use
3. Reliability of GP clinical judgment alone in diagnosing HF
4. Reliability of individual clinical features
5. Reliability of ECG interpretation
6. Estimation of the best performing cut-offs for NT-proBNP to maximise diagnostic yield and for maximising cost-effective referrals
7. Determine the use of variable echocardiographic markers of diastolic function in the diagnosis of HF with preserved ejection fraction
Sources of funding Medical Research Council (MRC)/National Institute of Health Research (NIHR) (UK) - Efficacy and Mechanism Evaluation (EME) Programme (ref: 09/160/13)
Trial website
Publications 2012 protocol in http://www.ncbi.nlm.nih.gov/pubmed/23110558
Contact name Prof  Richard  Hobbs
  Address Head of Department
General Practice
2nd Floor
23-38 Hythe Bridge Street
University of Oxford
  City/town Oxford
  Zip/Postcode OX1 2ET
  Country United Kingdom
  Email
Sponsor Oxford Radcliffe Hospitals NHS Trust (UK)
  Address Heather House
Clinical Trials and Research Governance
Manor House
John Radcliffe Hospital
Headington
  City/town Oxford
  Zip/Postcode OX3 9DZ
  Country United Kingdom
Date applied 28/02/2011
Last edited 29/07/2013
Date ISRCTN assigned 21/06/2011
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