Condition category
Circulatory System
Date applied
28/02/2011
Date assigned
21/06/2011
Last edited
11/04/2016
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

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

Trial website

Contact information

Type

Scientific

Primary contact

Prof Richard Hobbs

ORCID ID

Contact details

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

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

09/160/13

Study information

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

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 dependent upon the natriuretic peptide results.

Ethics approval

The South Birmingham Research Ethics Committee, 15/10/2009

Study design

Multicentre prospective observational diagnostic validation study

Primary study design

Observational

Secondary study design

Diagnostic validation study

Trial setting

GP practices

Trial type

Diagnostic

Patient information sheet

Not available in web format, please use the conatct details below to request a patient information sheet

Condition

Heart failure

Intervention

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)

Intervention type

Other

Phase

Not Applicable

Drug names

Primary outcome measures

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 measures

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

Overall trial start date

01/04/2011

Overall trial end date

01/06/2014

Reason abandoned

Eligibility

Participant 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

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

500

Participant 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

Recruitment start date

01/04/2011

Recruitment end date

01/06/2014

Locations

Countries of recruitment

United Kingdom

Trial participating centre

University of Oxford
Oxford
OX1 2ET
United Kingdom

Sponsor information

Organisation

Oxford Radcliffe Hospitals NHS Trust (UK)

Sponsor details

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

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Government

Funder name

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

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

2012 protocol in: http://www.ncbi.nlm.nih.gov/pubmed/23110558

Publication citations

  1. Protocol

    Tait L, Roalfe AK, Mant J, Cowie MR, Deeks JJ, Iles R, Barton PM, Taylor CJ, Derit M, Hobbs FD, The REFER (REFer for EchocaRdiogram) protocol: a prospective validation of a clinical decision rule, NT-proBNP, or their combination, in the diagnosis of heart failure in primary care. Rationale and design., BMC Cardiovasc Disord, 2012, 12, 97, doi: 10.1186/1471-2261-12-97.

Additional files

Editorial Notes

11/04/2016: Plain English summary added.