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 https://doi.org/10.1186/ISRCTN17635379
Secondary identifying numbers 09/160/13
Submission date
28/02/2011
Registration date
21/06/2011
Last edited
19/02/2021
Recruitment status
No longer recruiting
Overall study status
Completed
Condition category
Circulatory System
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data

Plain English summary of protocol

Background and study aims
Heart failure is caused by the heart muscle becoming weak or stiff and failing to pump enough blood around the body. It significantly reduces quality of life and life expectancy. The costs to the NHS are high due to frequent hospitalisation and GP visits. Heart failure is a common problem in primary care, but diagnosis is difficult and GPs must decide which patients need further tests. Heart failure can be diagnosed by ultrasound (an echocardiogram) but it is expensive and limited. Therefore, GPs rely on less effective tests, resulting in under-diagnosis. Accurate diagnosis, appropriate treatment and cost−effective use of NHS resources are needed to improve quality of life and life expectancy. However, there is uncertainty in these areas. We aim to find out if a clinical decision rule (CDR) can help GPs determine which patients should be referred for an echocardiogram and if it is cost−effective. The study will tell us if a simple rule involving symptoms, physical examination and blood testing can be used for better diagnosis and targeting of further diagnostic tests for heart failure, helping to improve quality of care and save money.

Who can participate?
Patients aged 55 or over visiting their GP with new symptoms of breathlessness, lethargy (tiredness) or ankle oedema (swelling)

What does the study involve?
The GP refers all patients for chest x−ray (as usual), and then to a central research clinic. Information on symptoms and quality of life are collected, and patients undergo an electrocardiogram (measuring the electrical activity of the heart), an echocardiogram (an ultrasound scan of the heart), and provide a blood sample. We want to find out whether the CDR can correctly identify all cases with heart failure. We follow-up patients after 6 and12 months to collect medical and quality of life information.

What are the possible benefits and risks of participating?
Not provided at time of registration

Where is the study run from?
University of Oxford (UK)

When is the study starting and how long is it expected to run for?
April 2011 to June 2014

Who is funding the study?
Medical Research Council (MRC)/National Institute of Health Research (NIHR) (UK) - Efficacy and Mechanism Evaluation (EME) Programme (UK)

Who is the main contact?
Prof Richard Hobbs

Contact information

Prof Richard Hobbs
Scientific

Head of Department
General Practice
2nd Floor
23-38 Hythe Bridge Street
University of Oxford
Oxford
OX1 2ET
United Kingdom

Study information

Study designMulticentre prospective observational diagnostic validation study
Primary study designObservational
Secondary study designDiagnostic validation study
Study setting(s)GP practice
Study typeDiagnostic
Participant information sheet Not available in web format, please use the conatct details below to request a patient information sheet
Scientific titleThe 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
Study acronymREFER
Study objectivesThe 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 dependent upon the natriuretic peptide results.
Ethics approval(s)The South Birmingham Research Ethics Committee, 15/10/2009
Health condition(s) or problem(s) studiedHeart failure
InterventionThe 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)
Intervention typeOther
Primary outcome measure1. 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 measures1. 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
Overall study start date01/04/2011
Completion date01/06/2014

Eligibility

Participant type(s)Patient
Age groupAdult
SexBoth
Target number of participants500
Total final enrolment304
Key inclusion criteriaCurrent 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
Key exclusion criteriaCurrent 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
Date of first enrolment01/04/2011
Date of final enrolment01/06/2014

Locations

Countries of recruitment

  • England
  • United Kingdom

Study participating centre

University of Oxford
Oxford
OX1 2ET
United Kingdom

Sponsor information

Oxford Radcliffe Hospitals NHS Trust (UK)
Hospital/treatment centre

Heather House
Clinical Trials and Research Governance
Manor House
John Radcliffe Hospital
Headington
Oxford
OX3 9DZ
England
United Kingdom

ROR logo "ROR" https://ror.org/03h2bh287

Funders

Funder type

Government

Medical Research Council (MRC)/National Institute of Health Research (NIHR) (UK) - Efficacy and Mechanism Evaluation (EME) Programme (ref: 09/160/13)

No information available

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to shareNo
IPD sharing plan summaryNot provided at time of registration
Publication and dissemination planNot provided at time of registration
IPD sharing plan

Study outputs

Output type Details Date created Date added Peer reviewed? Patient-facing?
Protocol article protocol 30/10/2012 Yes No
Results article results 01/04/2017 19/02/2021 Yes No

Editorial Notes

19/02/2021: Publication reference and total final enrolment added.
11/04/2016: Plain English summary added.