Primary care REFerral for EchocaRdiogram (REFER) in heart failure: a diagnostic accuracy study.

BACKGROUND: Symptoms of breathlessness, fatigue, and ankle swelling are common in general practice but deciding which patients are likely to have heart failure is challenging. AIM: To evaluate the performance of a clinical decision rule (CDR), with or without N-Terminal pro-B type natriuretic peptide (NT-proBNP) assay, for identifying heart failure. DESIGN AND SETTING: Prospective, observational, diagnostic validation study of patients aged >55 years, presenting with shortness of breath, lethargy, or ankle oedema, from 28 general practices in England. METHOD: The outcome was test performance of the CDR and natriuretic peptide test in determining a diagnosis of heart failure. The reference standard was an expert consensus panel of three cardiologists. RESULTS: Three hundred and four participants were recruited, with 104 (34.2%; 95% confidence interval [CI] = 28.9 to 39.8) having a confirmed diagnosis of heart failure. The CDR+NT-proBNP had a sensitivity of 90.4% (95% CI = 83.0 to 95.3) and specificity 45.5% (95% CI = 38.5 to 52.7). NT-proBNP level alone with a cut-off <400 pg/ml had sensitivity 76.9% (95% CI = 67.6 to 84.6) and specificity 91.5% (95% CI = 86.7 to 95.0). At the lower cut-off of NT-proBNP <125 pg/ml, sensitivity was 94.2% (95% CI = 87.9 to 97.9) and specificity 49.0% (95% CI = 41.9 to 56.1). CONCLUSION: At the low threshold of NT-proBNP <125 pg/ml, natriuretic peptide testing alone was better than a validated CDR+NT-proBNP in determining which patients presenting with symptoms went on to have a diagnosis of heart failure. The higher NT-proBNP threshold of 400 pg/ml may mean more than one in five patients with heart failure are not appropriately referred. Guideline natriuretic peptide thresholds may need to be revised.

The impact of age on clinical outcomes following cardiac resynchronisation therapy.

BACKGROUND: Cardiac resynchronisation therapy (CRT) is an established treatment for selected patients with symptomatic left ventricular (LV) systolic dysfunction. Heart failure (HF) is primarily a disease of the elderly; however, these patients are underrepresented in CRT trials. Our aim was to evaluate the impact of age on clinical outcomes following CRT. METHODS: A consecutive series of 177 patients was identified and divided into those aged ≤ 7 5 years (n = 131, mean ± SD 62.1 ± 11.2 years) and those aged >75 years (n = 46, mean ± SD 80.7 ± 4.1 years). The primary end point was a composite of all-cause mortality or HF hospitalisation. RESULTS: During a median ± IQR follow up of 28.5 ± 33.7 months, the event rate for the primary end point was significantly higher in the elderly compared to younger patients (20.1 vs. 11.1 %, respectively, logrank p = 0.020). This was mainly driven by an excess mortality rate among those aged >75 years (10 vs. 4.7%, respectively, logrank p = 0.018) whereas HF hospitalisation rates were similar between groups (10 vs. 6.4%, respectively, logrank p = 0.301). After adjusting for comorbidities and ICD status, the difference in the composite end point rates was attenuated and no longer significant (HR 1.580, 95% CI 0.899-2.778; p = 0.112 for >75 vs. ≤ 75 years). Notably, both groups demonstrated similar response rates to CRT in terms of symptomatic improvement, reverse LV remodelling and neurohormonal activation. CONCLUSIONS: CRT is equally effective in the elderly as in younger patients to reduce adverse clinical outcomes. For those who fulfil the prerequisite selection criteria, it should be considered as a valid therapeutic option.

Heart failure epidemiology: European perspective.

Heart failure poses an increasing problem for global healthcare systems. The epidemiological data which has been accrued over the last thirty years has predominantly been accumulated from experience within North America and Europe. Initial large cohort, prospective longitudinal studies produced the first publications; however latterly the focus has shifted onto epidemiological data governing hospitalisation and mortality. The emphasis behind this shift has been the resource implications with regards to repetitive, costly and prolonged hospitalisation. The European experience in heart failure, though similar to North America has recently demonstrated differences in hospitalisation which may underlie the differences between healthcare system configuration. Heart failure however remains an increasing global problem and the endpoint of a variety of cardiovascular diseases. Allied with the fact of increasingly elderly populations and prior data demonstrating a steep rise in prevalent cases within more elderly populations, it is likely that the increasing burden of disease will continue to pose challenges for modern healthcare. Despite the predicted increase in the number of patients affected by heart failure, over the last thirty years, a clear management algorithm has evolved for the use of pharmacotherapies (neuro-hormonal antagonists), device based therapies (Implantable Cardioverting Defibrillator (ICD) and Cardiac Resynchronisation Therapy (CRT)) and mechanical therapies including left ventricular assist devices and cardiac transplantation. Though the management of such patients has been clearly delineated in national and international guidelines, the underuse of all available and appropriate therapies remains a significant problem. When comparing various epidemiological studies from different settings and timepoints, it should be remembered that rates of prevalence and incidence may vary depending upon the definition used, methods of accumulating information (with the possibility of bias) and the chosen cut point of defining left ventricular systolic dysfunction (LVSD).

Newly diagnosed heart failure: change in quality of life, mood, and illness beliefs in the first 6 months after diagnosis.

OBJECTIVES: This study sought to examine how patients' mood and quality of life (QoL) change during the early high-risk period after a diagnosis of heart failure (HF) and to identify factors that may influence change. DESIGN: A within-subjects, repeated-measures design was used. Assessments took place within 4 weeks of diagnosis and 6 months later. METHODS: One hundred and sixty six patients with HF completed assessments of their mood, QoL, and beliefs about HF and its treatment. Correlation analysis was conducted between the variables and analysis of variance and t-tests were used to assess differences in categorical variables. To examine which variables predicted mood and QoL, hierarchical multiple regressions were conducted. RESULTS: At follow-up, patients' beliefs indicated a realization of the chronicity of their HF, however their beliefs about the consequences of having HF did not change and their satisfaction with their treatment remained high. QoL and anxiety improved significantly over time but there was no significant change in depressed mood. As would be expected, improvement in symptoms was a key factor in improved mood and QoL. Other significant explanatory variables included age, comorbid chronic obstructive pulmonary disease, depressed mood, patients' beliefs about the consequences of their HF and their concerns about treatment. CONCLUSIONS: This study suggests that addressing patients' mood and beliefs about their illness and its treatment may be additional ways of improving patient QoL in the early period after the diagnosis of HF.

Effect of heart rate reduction by ivabradine on left ventricular remodeling in the echocardiographic substudy of BEAUTIFUL.

AIMS: Occlusive coronary artery disease (CAD) is associated with left ventricular (LV) remodeling, LV systolic dysfunction, and heart failure. The BEAUTIFUL Echo substudy aimed to evaluate the effects of heart rate reduction with ivabradine on LV size (primary end-point: change in LV end-systolic volume index [LVESVI]) and function and the cardiac biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP). METHODS AND RESULTS: The substudy was carried out in 86 centers participating in the BEAUTIFUL study. 2D echocardiography was performed at baseline, and after 3 and 12 months in patients with stable CAD and LV systolic dysfunction receiving ivabradine or placebo at the same time-points. All data were read and analyzed centrally. Of 525 patients completing the study, 426 had adequate echocardiographic readings (n = 220 ivabradine; n = 206 placebo). Treatment with ivabradine was associated with a decrease in the primary end-point LVESVI (change from baseline to last value, -1.48 ± 13.00 mL/m(2)) versus an increase with placebo (1.85 ± 10.54 mL/m(2)) (P=0.018). There was an increase in LV ejection fraction with ivabradine (2.00 ± 7.02%) versus no change with placebo (0.01 ± 6.20%) (P=0.009). Reduction in LVESVI was related to the degree of heart rate reduction with ivabradine. There were no differences in any other echocardiographic parameters or NT-proBNP. Change in LVESVI was related to the log change in NT-proBNP in the ivabradine group only (r = 0.18, P = 0.006). CONCLUSIONS: Our observations suggest that ivabradine may reverse detrimental LV remodeling in patients with CAD and LV systolic dysfunction.

Improving survival in the 6 months after diagnosis of heart failure in the past decade: population-based data from the UK.

OBJECTIVE: To investigate the secular trend in survival after a new diagnosis of heart failure in the UK population. DESIGN AND SETTING: Comparison of all-cause mortality in the 6 months after diagnosis of heart failure in population-based studies in the south east of England in 2004-5 (Hillingdon-Hastings Study) and 1995-7 (Hillingdon-Bromley Studies). PARTICIPANTS: 396 patients in the 2004-5 cohort and 552 patients in the 1995-7 cohort with incident (new) heart failure. MAIN OUTCOME MEASURES: All-cause mortality. RESULTS: All-cause mortality rates were 6% (95% CI 3% to 8%) at 1 month, 11% (8% to 14%) at 3 months and 14% (11% to 18%) at 6 months in the 2004-5 cohort compared with 16% (13% to 20%), 22% (19% to 25%) and 26% (22% to 29%), respectively, in the 1995-7 cohort (difference between the two cohorts, p<0.001). The difference in survival was not explained by any difference in the demographics or severity of heart failure at presentation. There was a difference at baseline and thereafter in the use of neurohormonal antagonists (beta-blockers and angiotensin-converting enzyme inhibitors). CONCLUSIONS: Although early mortality remains high among patients with newly diagnosed heart failure in the UK general population, there is strong evidence of a marked improvement in survival from 1995-7 to 2004-5, perhaps partly explained by an increased usage of neurohormonal antagonists.

Value of BNP to estimate cardiac risk in patients on cardioactive treatment in primary care.

UNLABELLED: Cardiac dysfunction may be suspected in patients with cardiovascular disease but identifying those with the highest risk is problematic. B-type natriuretic peptide (BNP) is a strong marker of heart failure in un-treated patients. This study evaluates a combined BNP and clinical algorithm for detecting cardiac dysfunction and the risk of death, in patients receiving cardioactive medication. METHODS: 459 stable general practice patients, who were taking typical heart failure drugs for any indication, were included. Echocardiography, ECG, and assay of NT-proANP and BNP (two methods) were performed. Regression models were used to identify items in a Risk Score to detect cardiac dysfunction. RESULTS: A Risk Score based on history of myocardial infarction (1 point), abnormal ECG (2 points), atrial fibrillation (1 point) and raised BNP (1-2 points) detected cardiac dysfunction with an AUC of ROC of 0.85. A Risk Score > or = 2 had a sensitivity of 90%, specificity of 58%, and positive and negative predictive values of 37% and 96%. Risk Score and LVEF<0.36 also predicted mortality. Abnormal BNP defined as either >100 pg/ml (Shionogi), or as age and sex related values, had similar predictive value. CONCLUSION: In patients on cardioactive medication, a structured Risk Score based on raised BNP, history of MI, atrial fibrillation and abnormal ECG was useful for identifying patients for immediate further examination and those who could be evaluated later.

Exercise responses following heart transplantation: 5 year follow-up.

Heart transplantation is an established treatment for end stage heart failure. In addition to increased life expectancy, heart transplant recipients report a remarkable improvement in symptoms and functional capacity. Exercise performance following heart transplantation, however, remains impaired even in the absence of exertional symptoms. We have assessed the response to exercise in 47 patients with cardiac failure prior to and then at yearly intervals to five years post transplantation. All patients performed incremental symptom limited exercise tests during which minute ventilation (V'E), oxygen consumption (V'O2) and carbon dioxide production (V'CO2) and heart rate (HR) were measured. Ventilatory response (V'E/V'CO2), anaerobic threshold (V'O2 AT %predicted) and heart rate response (HR/VO2) were calculated. The dead space to tidal volume ratio (VD/VT) and alveolar-arterial oxygen gradient (A-aO2) were computed from transcutaneous monitoring. Despite substantial improvement in subjective functional capacity, heart transplant recipients continue to have limited exercise performance [Maximal V'O2% predicted pre-transplant 41.3 (2.2); 1 year 48.6 (1.7), p <0.001: V'O2 AT% 31.5 (1.1); 1 year 35.6 (1.0); respectively p<0.05]. The maximal oxygen uptake continued to improve at two years post-transplant but, thereafter, there was no further significant change at up to 5 years post transplant [50.9 (1.5)]. At one year post-transplantation peak HR [65.2 (0.9) vs 79.1(1.4)] and the HR/VO2 response [24.0(1.8) vs 79.6(4.2)] were significantly reduced compared to pre-transplant values. The heart rate response remained lower compared to predicted at 5 years post-transplant although there was a significant increase compared to one year post-transplant (32.9 vs 24.0mls/bt). There was a weak but significant relationship between maximal VO2 and peak HR (0.39, p<0.05) and HR/VO2 (r= 0.37, p<0.05) at one year post-transplant. Prior to transplantation the ventilatory response to exercise was elevated [V'E/V'CO2 45.6 (2.5)] and decreased significantly following transplantation [1 yr 34.1 (1.3), respectively p<0.001]. In addition, despite significant improvement in VD/VT after transplantation, it remained higher than normal [Pre VD/VT at maximum exercise 0.35 (0.02); 1 yr 0.31 (0.02); p<0.05]. There was a further fall in the VE/VCO2 and VD/VT at two years post-transplantation with no further change at up to 5 years post transplantation [VE/VCO2 32.0 (1.0); VD/VT 0.29 (0.01)]. Although cardiac output is markedly improved after transplantation, due to chronotropic incompetence associated with denervation, its response remains subnormal and this may explain the residual abnormalities of ventilatory and gas exchange responses to exercise following transplantation.

Lessons from the management of chronic heart failure.

In seeking to implement evidence based medicine for the patient with heart failure occurring after a myocardial infarction (MI), much can be learnt from the long road to delivery of best care for the patient with chronic heart failure (CHF) caused by left ventricular systolic dysfunction. Both patient groups are part of the same cardiovascular continuum. A mass of evidence has accrued for the beneficial effects of angiotensin converting enzyme inhibitors, beta blockers, and aldosterone antagonists on both morbidity and mortality across a wide spectrum of patient severity. This evidence has informed the development of management guidelines, although registry data showed that uptake of treatments remained low, leading to research focused on how heart failure care could be delivered more effectively. This has resulted in a range of heart failure management programmes, many of which have been shown to reduce hospital admission rates and to improve adherence with treatments. Multidisciplinary heart failure management programmes that span primary and secondary care are now considered a routine "standard" to be aspired to in delivering effective CHF care. Applying such an approach to the care of the post-MI heart failure patient should be equally important.

The prognostic use of right heart catheterization data in patients with advanced heart failure: how relevant are invasive procedures in the risk stratification of advanced heart failure in the era of neurohormones?

BACKGROUND: Right heart catheterization long has been a routine investigation in advanced heart failure, and its measurements have been linked variably to prognosis. However, in the modern era, newer potential markers of prognosis are coming to light. This study reconsiders the use of right heart catheterization data and compares their use to that of N-terminal pro-brain natriuretic peptide (NT-proBNP), a neurohormone linked with prognosis in chronic heart failure. METHODS: We assessed prospectively the prognostic potential of baseline right heart catheterization data in 97 consecutive patients with advanced heart failure referred to the Scottish Cardiopulmonary Transplant Unit for consideration of cardiac transplantation. Patients underwent baseline routine investigation, including right heart catheterization and blood draws for NT-proBNP analysis. Patients were observed for a median of 370 days. RESULTS: The primary end-point of all-cause mortality was reached in 17 patients (17.5%), and the secondary end-point of all-cause mortality or urgent cardiac transplantation was reached in 21 (21.6%) patients. Univariate predictors of all-cause mortality included pulmonary artery systolic pressure (PASP), pulmonary artery wedge pressure (PAWP), and NT-proBNP concentration greater than their median values. Univariate predictors of the secondary end-point included right atrial pressure, PASP, PAWP, and NT-proBNP concentration greater than their median values, and left ventricular ejection fraction, cardiac output, and cardiac index less than their median values. In multivariate analyses, however, only NT-proBNP concentration remained an independent predictor of all-cause mortality. Both NT-proBNP concentration and PAWP were independent predictors of all-cause mortality and of the need for urgent cardiac transplantation. CONCLUSION: Baseline data from routine right heart catheterization are of limited prognostic use in advanced heart failure. A baseline NT-proBNP concentration is a superior, non-invasive method of risk stratification in this era of measuring neurohormones.

NT-proBNP and the diagnosis of heart failure: a pooled analysis of three European epidemiological studies.

Many studies have shown that the B-type natriuretic peptides (BNP and NT-proBNP) are proven diagnostic markers for heart failure due to left ventricular systolic dysfunction. The manner in which they are to be used is still being unravelled; most single centre studies have chosen the best concentration of the peptide on ROC analysis as their cut-point resulting in numerous different values for both BNP and NT-proBNP appearing in the literature. We report a different approach of defining an age and sex corrected abnormal concentration for NT-proBNP, derived from normal individuals within a large sample of 3051 subjects pooled from three European epidemiology studies and applying that to the entire population to detect HF and LVD. Three thousand and fifty one subjects were studied. Of these 10% (305) had significant LVD and 3.1% (94) had HF. The median concentrations of NT-proBNP (IQR) in normals, those with LVD and in heart failure subjects were 20 pg/ml (10.30), 117.3 pg/ml (28.145) and 269.6 pg/ml (54.323), P<0.001, respectively. The area under the ROC curve for NT-proBNP for the detection of 'heart failure' was 0.85 and 0.69 for LVD. NT-proBNP was an independent predictor of the presence of HF on multivariate analysis. An abnormal NT-proBNP was defined as being >95th centile for normals, age and sex corrected, and diagnosed HF with a sensitivity of 75% and a negative predictive value of 99%. In an additional analysis in a breathless subgroup of our population, in 30% a raised NT-proBNP concentration could be explained by HF due to LVD, in another 64% the high BNP level was associated with some other structural of functional cardiac abnormality or renal impairment. We were unable to assign a possible cause to the high NT-proBNP values in 5.9% of this breathless subgroup of the population. An abnormal NT-proBNP concentration is an accurate diagnostic test both for the exclusion of HF in the population and in ruling out LVD in breathless subjects. An elevated NT-proBNP merely indicates the presence of 'cardio-renal distress' and should prompt referral for further investigation.

Survival differences between heart failure in general practices and in hospitals.

OBJECTIVES: To compare the survival of patients thought to have heart failure in general practice (GP-HF) with that of patients with heart failure in hospital (hospital-HF), patients with heart disease but without heart failure (non-HF), and a control group without heart disease. DESIGN AND SETTING: Cross sectional study from general practice with a prospective follow up from 5.3 to 7.4 years. PARTICIPANTS: 2157 community participants, 1999 of whom lived outside nursing homes, were selected because they were registered with four general practitioners at entry. Study participants were divided into the four groups after a review of general practice case notes, questionnaires, and interviews. MAIN OUTCOME MEASURES: Five year survival and multivariate predictors of all cause mortality. RESULTS: Five year survival was 76% in the control group (n = 571, mean age at entry 74.1 years), 71% in non-HF patients (n = 218, 74.4 years), 61% in GP-HF patients (n = 67, 75.8 years), and 39% in hospital-HF patients (n = 33, 76.7 years). The median survival times were 6.8 years for GP-HF patients and 3.9 years for hospital-HF patients. Significant predictors of mortality in the multivariate Cox model of 1979 patients living outside nursing homes were hospital-HF (hazard ratio (HR) 2.1, p = 0.002), GP-HF (HR 1.7, p = 0.004), non-HF heart disease (HR 1.4, p = 0.03), previous myocardial infarction (HR 1.6, p = 0.04), no response to questionnaire (HR 2.0, p < 0.0001), higher age (for every 10 years, HR 2.4, p < 0.0001), and male sex (HR 2.1, p < 0.0001). Other factors such as atrial fibrillation, hypertension, and diabetes were not significant. CONCLUSION: Heart failure in general practice is associated with a worse survival than that seen in the control group but is better than for patients who have been treated at least once for heart failure in a hospital.

Clinical applications of B-type natriuretic peptide (BNP) testing.

Many claims have been made in recent years regarding the utility of plasma B-type natriuretic peptide (BNP) concentration measurements in the diagnosis, risk stratification and monitoring of patients with heart failure. This paper summarizes the current evidence and provides guidance for practising clinicians. Overall, plasma BNP testing appears to be of most value in the diagnostic arena, where it is likely to improve the performance of non-specialist physicians in diagnosing heart failure. In clinical practice, BNP testing is best used as a 'rule out' test for suspected cases of new heart failure in breathless patients presenting to either the outpatient or emergency care settings; it is not a replacement for echocardiography and full cardiological assessment, which will be required for patients with an elevated BNP concentration. Although work is ongoing in establishing the 'normal' values of BNP, heart failure appears to be highly unlikely below a plasma concentration of 100 pg/ml. However, as BNP levels rise with age and are affected by gender, comorbidity and drug therapy, the plasma BNP measurement should not be used in isolation from the clinical context.

N-terminal pro-brain natriuretic peptide. A new gold standard in predicting mortality in patients with advanced heart failure.

AIMS: The selection of patients for cardiac transplantation (CTx) is notoriously difficult and traditionally involves clinical assessment and an assimilation of markers of the severity of CHF such as the left ventricular ejection fraction (LVEF), maximum oxygen uptake (peak VO2) and more recently, composite scoring systems e.g. the heart failure survival score (HFSS). Brain natriuretic peptide (BNP) is well established as an independent predictor of prognosis in mild to moderate chronic heart failure (CHF). However, the prognostic ability of NT-proBNP in advanced heart failure is unknown and no studies have compared NT-proBNP to standard clinical markers used in the selection of patients for transplantation. The purpose of this study was to examine the prognostic ability of NT-proBNP in advanced heart failure and compare it to that of the LVEF, peak VO2 and the HFSS. METHODS AND RESULTS: We prospectively studied 142 consecutive patients with advanced CHF referred for consideration of CTx. Plasma for NT-proBNP analysis was sampled and patients followed up for a median of 374 days. The primary endpoint of all-cause mortality was reached in 20 (14.1%) patients and the combined secondary endpoint of all-cause mortality or urgent CTx was reached in 24 (16.9%) patients. An NT-proBNP concentration above the median was the only independent predictor of all cause mortality (chi2=6.03, P=0.01) and the combined endpoint of all cause mortality or urgent CTx (chi2 =12.68, P=0.0004). LVEF, VO2 and HFSS were not independently predictive of mortality or need for urgent cardiac transplantation in this study. CONCLUSION: A single measurement of NT-proBNP in patients with advanced CHF, can help to identify patients at highest risk of death, and is a better prognostic marker than the LVEF, VO2 or HFSS.

The prevalence of haemochromatosis gene mutations in the West of Scotland and their relation to ischaemic heart disease.

OBJECTIVES: Excess iron stores have been postulated to enhance the risk of ischaemic heart disease. This study aims to determine whether the two major mutations of the haemochromatosis (HFE) gene (C282Y and H63D) are associated with ischaemic heart disease (IHD) or myocardial infarction (MI). DESIGN: Cross sectional case-control study. SETTING: The geographical area studied by the MONICA (monitoring trends and determinants in cardiovascular disease) heart attack register for North Glasgow in Scotland, UK. PATIENTS: 1009 control subjects chosen at random from general practitioner registers were studied. Additionally, 924 subjects who had survived a first MI sustained between 1985 and 1992 were identified from the MONICA register. MAIN OUTCOME MEASURES: C282Y and H63D mutations, previous MI, and presence or absence of IHD. RESULTS: Mutant gene prevalences in the whole control population were as follows: C282Y: homozygote 0.9%, heterozygote 17.7%; H63D: homozygote 2.1%, heterozygote 25.5%; and compound heterozygote: 2.4%. Analysis by chi(2) test and logistic regression analysis did not identify any significant difference in genotype prevalence between normal control, IHD control, and MI survivor groups. CONCLUSIONS: The C282Y homozygote and heterozygote prevalences are among the highest reported worldwide. No association between IHD or MI and HFE genotype was identified. However, these results need to be interpreted in the light of the cross sectional case-control nature of the study.