Heart failure (HF) is a life-threatening, costly condition . It affects at least 2.3% of adults over 45, rising to 4% in over 75 year olds . HF markedly reduces quality and length of life , and treatment costs are high, second only to stroke and mainly due to high admission rates ; estimated to consume almost 2% (£751 million) of total NHS expenditure . HF is a diagnostic challenge, as symptoms are non-specific and physical signs can be subtle [6–9]. Because outcomes in HF are linked to stage of disease and evidence-based treatments alter natural history as well as improve symptoms and prognosis [10–12], accurate early diagnosis and treatment is essential to reduce morbidity and mortality. As most patients with suspected HF are seen initially by GPs [6, 13], the need for early and accurate diagnosis in primary care is essential to ensure optimum management and appropriate treatment is initiated rapidly.
Specialist review of symptoms and signs plus objective investigations, including echocardiography (Echo), is the established ‘gold standard’ for diagnosing left ventricular systolic dysfunction (LVSD) and increasingly suspected HF with a preserved ejection fraction (HFpEF) . Diagnosing HF requires objective estimation of cardiac function (i.e. Echo) since determining the aetiology and stage of HF leads to different management choices such as initiation of angiotensin-converting enzyme (ACE) inhibitors , ß-blockers  and aldosterone antagonists in most patients with LVSD , cardiac resynchronization therapy for those with LVSD and broad QRS complex , or surgery where significant valve disease exists. These therapies improve symptoms, prognosis and quality of life, and can reduce healthcare utilisation and NHS costs. However, a difficulty is that performing Echo on all suspected HF patients would be costly as many patients are found not to have HF.
Diagnostic strategies can vary between GPs if a case of HF is suspected, but the most appropriate strategy is unclear. These include an initial clinical assessment of patient signs and symptoms using physical examination, and investigations such as lab blood tests or chest x-ray. Additionally, screening tests, such as electrocardiogram (ECG) and natriuretic peptide (NP) tests, where available, have been recommended by NICE as potential ‘rule out’ tests for HF to limit unnecessary referrals to echocardiography [16, 17]. Routine clinical assessment takes place over multiple consultations, due mainly to diagnostic uncertainty and delays that occur in the referral pathway.
Diagnostic uncertainty in clinical practice, difficulties diagnosing HF and local organisational factors such as limited availability of diagnostic services, or delays inherent in the current referral system, create barriers to the early and accurate diagnosis of HF. Access to Echo is variable, often delayed, and limited by the significant skill shortage of trained Echocardiographers [14, 16, 18, 19]. As a consequence, many GPs rely solely on, often inaccurate, unstructured clinical assessment [7, 8, 18, 20]. However, diagnosing HF on clinical grounds alone can be unreliable due to difficulty in interpreting signs  and differences between doctors in obtaining symptoms and signs [13, 22]. Many GPs order a chest x-ray, or arrange an ECG . However, although a normal ECG will exclude LVSD in most cases, changes may be subtle and lack of GP interpretation skills may still require referral for specialist opinion. A normal chest x-ray does not exclude HF . A key dilemma facing GPs is deciding which patients to refer for Echo and when; and lack of a systematic method for guiding the diagnosis of HF presents a further obstacle , adding to cost and delay. Diagnostic uncertainty or inaccurate diagnosis can result in diagnosis being delayed until HF symptoms are more obvious and therefore more severe, multiple GP consultations and hospital admissions, or people are treated incorrectly.
A growing body of evidence suggests the potential utility of B-type natriuretic peptides (NPs), namely BNP or NT-proBNP, both released from myocardium in response to wall stretch, as diagnostic cardiac biomarkers of HF. These NP tests provide an exciting opportunity to support the clinical assessment of symptomatic primary care patients, as normal levels can rule out HF given the high sensitivity of these tests (98%) , but confirmatory Echo is needed in patients with elevated peptides to confirm the diagnosis [24–28].
There is uncertainty about the best cut-off levels of NPs in primary care and the cost-effectiveness/benefit has not been established. NP testing is under-used because reliable data on BNP and NT-proBNP performance in the diagnosis of HF are limited mainly to epidemiological sub-studies or to prospective validation in emergency department settings [27, 29–31], with limited data on test performance within symptomatic patients routinely presenting in primary care [24, 28, 32]. Best assay cut-offs have therefore been largely imputed and assay performance against or with ECG and symptom score unclear. Moreover, obesity and certain HF medications can lower peptide levels and elevated levels can be associated with unrelated conditions and other factors such as increased age, gender and renal insufficiency . These factors therefore impair the utility of NPs as a diagnostic marker of HF if used alone. The addition of a B-type NP test to the current diagnostic pathway, with specialist referral if test results are abnormal, is a suggested alternative approach that may be superior and cost-effective . However, the cost-effectiveness of NPs versus standard diagnostic triage is not established.
Current consensus suggests a superior approach would be to combine NP testing with standard clinical assessment. In a recent prospective, randomised controlled trial of 305 elderly patients with symptoms of recent onset breathlessness or oedema GP diagnoses were more accurate with NT-proBNP test results in addition to routine clinical assessment than without, mainly due to the ability to correctly rule out HF . A recent meta-analysis concluded that the use of NPs could help reduce the demand for Echo and cardiology referrals . However, determining the optimal manner in which to combine clinical features from clinical assessment and diagnostic tests, including NP tests, remains extraordinarily challenging.
Clinical decision rules (CDRs) are evidence-based clinical tools designed to be used to help clinician decision-making in a standardised and cost-effective manner, and are developed according to strict methodological procedure [35, 36]. These clinical tools are based on a parsimonious set of variables that can quantify the contribution from history, physical examination and diagnostic tests. They are developed and evaluated in three distinct stages prior to implementation into a clinical setting: 1) creation of the rule, establishing the independent and combined effect of explanatory variables such as symptoms, signs or diagnostic tests; 2) validation of the rule, establishing the accuracy and reliability of the tool in a separate population; and 3) impact analysis of the rule, establishing impact of applying the rule on patient outcome or health professional behaviour.
A number of CDRs have been developed to diagnose HF, using combinations of signs, symptoms and tests [37–39]. However, a major problem with all the studies is spectrum and referral bias since most were based on observational screening studies rather than symptomatic presenting patients and some were hospital rather than community based. Additionally, the tools are impractical outside a research or emergency department setting as they are based on a substantial number of variables; others rely on clinical signs where there is considerable inter-observer variation, even amongst specialists; and others rely on chest x-ray parameters, which would be difficult to apply in general practice.
Our recent NIHR HTA funded systematic review and independent patient data and meta-analysis [40, 41] addressed this issue. We found individual symptoms (such as breathlessness and fluid retention) and signs (such as resting tachycardia and raised jugular venous pressure) are generally weak predictors of HF. Both ECG and BNP have high sensitivity for HF and are good tests at ruling out the diagnosis but BNP is more accurate than ECG. We found BNP and NT-proBNP to be of similar accuracy.
Our systematic review  identified one unpublished study which had developed a decision tool based on simple clinical features . In our individual patient data analysis [40, 41] we further developed this tool and validated it on other primary care data sets. We found that a simplified model, based upon simple clinical features (Male gender, history of myocardial Infarction, basal Crepitations, oEdema: ‘MICE’) and BNP derived from one data set, was found to have good validity when applied to other data sets, with the area under the curve between 0.84 and 0.96, and reasonable calibration. A model substituting ECG for BNP was less predictive. Our systematic review concluded that BNP could substitute for ECG for determining referral to Echo and some patients could be referred with no prior tests on the basis of clinical features alone.
We shall establish the clinical utility of B-type NP tests in informing the diagnosis of diastolic HF as well as LVSD and valve disease. Additionally, we shall determine the probability thresholds of the CDR above which Echo would be the most cost-effective diagnostic strategy, taking into account patient quality of life and survival. The results will contribute to scientific progress by solving the problem wherein GPs have clinical uncertainty about whether an Echo should be done or not for a patient whom they suspect may have HF. There is now an opportunity to provide these data and to potentially demonstrate that the CDR can improve patient management concerning diagnostic accuracy, clinical decision-making and cost-effectiveness.
Our study will build upon the current evidence and address the weaknesses in previous work. We have validated the CDR on primary care data sets but further validation in a symptomatic population in the real-life clinical setting is now indicated. Further exploration of the optimal NP cut-offs and further modelling of cost-effectiveness is also needed. 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. Given the risk of delayed diagnosis of HF, GPs do not have clear guidance on whom to refer for further evaluation. Improving the ability of GPs to appropriately identify patients suspected of having HF is crucial not only to avoid unnecessary hospital admissions and reduce patient burden, but also to improve the quality of care for patients presenting to primary care with suspected HF.
We propose the following objectives:
To prospectively validate the performance of the CDR and compare it to using a natriuretic peptide assay alone on the diagnostic accuracy of HF in primary care
To determine if the CDR, or natriuretic peptide assay can be used in routine clinical practice to establish referral on for echocardiography in patients presenting with symptoms suggestive of HF
To quantify the most reliable cut-off levels of the natriuretic peptide assay in a group of symptomatic presenting patients
To model the cost-effectiveness of using the CDR in primary care