Title: The REFER (REFer for EchocaRdiogram) study: a prospective validation of a clinical decision rule NT-proBNP or their combination in the diagnosis of heart failure in primary care
Funder: Department of Health (England)

Abstract: DESIGN: Prospective diagnostic validation studySETTING: 20 urban/rural general practices in Midlands Research Practices Consortium POPULATION: Adults (aged 55+) presenting to GPs with new onset symptoms of breathlessness lethargy or ankle oedemaINVESTIGATIONS: No specific intervention will be introduced to influence GP clinical judgment. All patients undergo structured clinical assessment; data used to test performance of clinical decision rule (CDR)OUTCOME MEASURES: Primary Outcomes: 1) Observed test performance of CDR; 2) Test performance of diagnostic accuracy of NT-proBNP; 3) Proportion of LVSD and HFSecondary Outcomes: 1) Test performance of CDR and NT-proBNP; 2) Modelling of CDR test performance & most cost-effective diagnostic strategy; 3) Reliability of GP clinical judgment; 4) Reliability of clinical features; 5) Reliability of ECG interpretation; 6) Estimating best performing cut-offs for NT-proBNP; 7) Use of Echo markers of diastolic function in diagnosis of HF with preserved ejection fractionASSESSMENT: All patients undergo structured clinical assessment including Echo as we have done previously in our ECHOES (Ref:2) study (see flowchart). An expert consensus panel (3 cardiologists)determine final diagnosis based on internationally accepted criteria (Ref:1) presented in 3 steps: 1) Echo results + clinical data except NT-proBNP and CDR variables; 2) then CDR variables provided; 3) then NT-proBNP result providedSAMPLE SIZE: 500 patients from 20 urban and rural general practices. A search of routine practice morbidity data suggest that in a practice of 6000 patients around 60 patients over age 55 per year will present with new onset breathlessness. Assuming a 60% response rate it will take at least 9 months to recruit 25 such patients per practice. Calculations based on sensitivity of 94% and specificity of 48% obtained from application of the CDR in our HTA funded study (Mant et al 2009 Ref:40) and prevalence of HF in a symptomatic population of 30%. A sample size of 500 patients will be sufficient to estimate the CDR sensitivity to within 4% and specificity to within 6% at the 95% confidence levelSTATISTICAL ANALYSIS: CDR classification performance evaluated by comparing observed probabilities with predicted probabilities to estimate sensitivity specificity positive and negative predictive values (95% CIs). GP clinical judgment vs CDR; optimal NP cut-offs calculated using ROC curve analysis. Quality of life clinical events and health care resource use will be used to estimate outcomes associated with using the CDRTIMETABLE: Ethics and R&D approvals have already been granted and the study adopted by UKCRN (No: 7944); general practices have been recruited. Months 1-6: study set up; staff and GP training. Months 7-24 patient recruitment over 18 months. Medical note review and quality of life questionnaire follow-up at 6 and 12 months. Data analysis and dissemination in final 9 months.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: CARDIOVASCULAR