REFER (REFer for EchocaRdiogram) - A Prospective Validation of a Clinical Decision Rule, NT-proBNP, or their combination, in the Diagnosis of Heart Failure in Primary Care

cardiographHeart failure (HF) dramatically reduces quality and length of life. Additionally this life-threatening condition is very costly to treat. Most patients with HF will go to see their GP first, but HF is commonly misdiagnosed in the primary care setting. Diagnostic strategies can vary between GPs if a case of HF is suspected, but the most appropriate strategy is unclear.

One reliable diagnostic tool is echocardiography (Echo), however performing Echo on all suspected HF patients would be costly as many patients test negative. A key dilemma facing GPs is deciding which patients to refer for Echo and when.

Research has been done on alternative methods of diagnosing HF. Evidence suggests that a potentially successful alternative could be B-type natriuretic peptides (NPs) tests.

There is uncertainty about the best cut-off levels of NPs in primary care and the cost-effectiveness/benefit has not been established. Using NP tests as a diagnostic tool for HF alone is likely to be unreliable, as factors such as age, gender and current medication complicate results. However the addition of NP testing to the standard clinical assessment is a suggested alternative approach. The cost-effectiveness of NPs versus standard diagnostic triage is not established, and neither is the optimal combination of clinical assessment and NP test features. These two areas therefore require investigation.

Previous research by us has identified key features of a Clinical Decision Rule (CDR) for diagnosing HF. CDRs are evidence-based clinical tools designed to help clinician decision-making in a standardised and cost-effective manner. The purpose of the REFER study is to perform a rigorous evaluation of the clinical validity and diagnostic utility of the CDR we have developed. In addition, we will assess the value of combining clinical information and NP testing. This will be done in a primary care patient population.

We aim to prospectively validate the CDR in this study but GPs will not apply the CDR (applying the rule would be appropriate in an implementation study); GPs will refer all patients suspected of having HF and not previously diagnosed with Echo and we shall collect data on how well the CDR predicts the diagnosis of HF. The CDR’s impact potential will be demonstrated by evaluating whether its sensitivity and specificity is superior to that of GPs’ (unaided) decisions.

Aim of study

The primary aim of this study is to prospectively validate a CDR, a natriuretic peptide assay, or a combination of both, in the diagnosis of suspected HF in primary care.

Secondary aims are i) to determine if the CDR or assay can be used in routine clinical practice to establish referral on for echocardiography in patients presenting with symptoms suggestive of HF; and ii) to quantify the most reliable cut-off level of the natriuretic peptide assay in symptomatic patients.


The study will be conducted in 30 urban and rural primary care practices in Birmingham, West Midlands, England.

Target population

All adult primary care patients aged 55 years or over presenting to their GP with recent new onset symptoms of breathlessness, lethargy or ankle oedema of over 48 hours duration, with no obvious acute and self-limiting cause, will be enrolled.

All consenting patients meeting the eligibility criteria are entered into the study. All patients will undergo a structured clinical assessment, as we have done previously in our ECHOES (2) study and our ongoing follow-up ECHOES-X study. GPs will refer all eligible patients, whether or not they believe HF is a likely diagnosis, to a research team led clinic, where all clinical assessments will be performed up to seven days later.