Glycaemic control and insulin therapy are significant confounders of the obesity paradox in patients with heart failure and diabetes mellitus.

BACKGROUND: A high body mass index (BMI) confers a paradoxical survival benefit in patients with heart failure (HF) or diabetes mellitus (DM). There is, however, controversy whether an obesity paradox is also present in patients with HF and concomitant DM. In addition, the influence of glycaemic control and diabetes treatment on the presence or absence of the obesity paradox in patients with HF and DM is unknown. METHODS: We identified 2936 patients with HF with reduced ejection fraction (HFrEF) in the HF registries of the universities of Heidelberg, Germany, and Hull, UK (general sample). Of these, 598 (20%) were treated for concomitant DM (DM subgroup). The relationship between BMI and all-cause mortality was analysed in both the general sample and the DM subgroup. Patients with concomitant DM were stratified according to HbA1c levels or type of diabetes treatment and analyses were repeated. RESULTS: We found an inverse BMI-mortality relationship in both the general sample and the DM subgroup. However, the obesity paradox was less pronounced in patients with diabetes treated with insulin and it disappeared in those with poor glycaemic control as defined by HbA1c levels > 7.5%. CONCLUSION: In patients with HFrEF, a higher BMI is associated with better survival irrespective of concomitant DM. However, insulin treatment and poor glycaemic control make the relationship much weaker.

Prevalence, predictors, and prognostic implications of PR interval prolongation in patients with heart failure.

AIMS: To determine the prevalence, incidence, predictors, and prognostic implications of PR interval prolongation in patients referred with suspected heart failure. METHODS AND RESULTS: Consecutive patients referred with suspected heart failure were prospectively enrolled. After excluding patients with implantable cardiac devices and atrial fibrillation, 1420 patients with heart failure and reduced ejection fraction (HeFREF) [age: median 71 (interquartile range IQR 63-78) years; men: 71%; NT-ProBNP: 1319 (583-3378) ng/L], 1094 with heart failure and normal ejection fraction (HeFNEF) [age: 76 (70-82) years; men: 47%; NT-ProBNP: 547 (321-1171) ng/L], and 1150 without heart failure [age: 68 (60-75) years; men: 51%; NT-ProBNP: 86 (46-140) ng/L] were included. The prevalence of first-degree heart block [heart rate corrected PR interval (PRc) > 200 ms] was higher in patients with heart failure (21% HeFREF, 20% HeFNEF, 9% without heart failure). In patients with HeFREF or HeFNEF, longer baseline PRc was associated with greater age, male sex, and longer QRS duration, and, in those with HeFREF, treatment with amiodarone or digoxin. Patients with heart failure in the longest PRc quartile had worse survival compared to shorter PRc quartiles, but PRc was not independently associated with survival in multivariable analysis. For patients without heart failure, shorter baseline PRc was independently associated with worse survival. CONCLUSION: PRc prolongation is common in patients with HeFREF or HeFNEF and associated with worse survival, although not an independent predictor of outcome. The results of clinical trials investigating the therapeutic potential of shortening the PR interval by pacing are awaited.

Statins attenuate but do not eliminate the reverse epidemiology of total serum cholesterol in patients with non-ischemic chronic heart failure.

BACKGROUND: In patients with chronic heart failure (CHF) increasing levels of total serum cholesterol are associated with improved survival - while statin usage is not. The impact of statin treatment on the "reverse epidemiology" of cholesterol is unclear. METHODS: 2992 consecutive patients with non-ischemic CHF due to left ventricular systolic dysfunction from the Norwegian CHF Registry and the CHF Registries of the Universities of Hull, UK, and Heidelberg, Germany, were studied. 1736 patients were individually double-matched on both cholesterol levels and the individual propensity scores for statin treatment. All-cause mortality was analyzed as a function of baseline cholesterol and statin use in both the general and the matched sample. RESULTS: 1209 patients (40.4%) received a statin. During a follow-up of 13,740 patient-years, 360 statin users (29.8%) and 573 (32.1%) statin non-users died. When grouped according to total cholesterol levels as low (≤3.6mmol/L), moderate (3.7-4.9mmol/L), high (4.8-6.2mmol/L), and very high (>6.2mmol/L), we found improved survival with very high as compared with low cholesterol levels. This association was present in statin users and non-users in both the general and matched sample (p<0.05 for each group comparison). The negative association of total cholesterol and mortality persisted when cholesterol was treated as a continuous variable (HR 0.83, 95%CI 0.77-0.90, p<0.001 for matched patients), but it was less pronounced in statin users than in non-users (F-test p<0.001). CONCLUSIONS: Statins attenuate but do not eliminate the reverse epidemiological association between increasing total serum cholesterol and improved survival in patients with non-ischemic CHF.

Simulated case management of home telemonitoring to assess the impact of different alert algorithms on work-load and clinical decisions.

BACKGROUND: Home telemonitoring (HTM) of chronic heart failure (HF) promises to improve care by timely indications when a patient's condition is worsening. Simple rules of sudden weight change have been demonstrated to generate many alerts with poor sensitivity. Trend alert algorithms and bio-impedance (a more sensitive marker of fluid change), should produce fewer false alerts and reduce workload. However, comparisons between such approaches on the decisions made and the time spent reviewing alerts has not been studied. METHODS: Using HTM data from an observational trial of 91 HF patients, a simulated telemonitoring station was created and used to present virtual caseloads to clinicians experienced with HF HTM systems. Clinicians were randomised to either a simple (i.e. an increase of 2 kg in the past 3 days) or advanced alert method (either a moving average weight algorithm or bio-impedance cumulative sum algorithm). RESULTS: In total 16 clinicians reviewed the caseloads, 8 randomised to a simple alert method and 8 to the advanced alert methods. Total time to review the caseloads was lower in the advanced arms than the simple arm (80 ± 42 vs. 149 ± 82 min) but agreements on actions between clinicians were low (Fleiss kappa 0.33 and 0.31) and despite having high sensitivity many alerts in the bio-impedance arm were not considered to need further action. CONCLUSION: Advanced alerting algorithms with higher specificity are likely to reduce the time spent by clinicians and increase the percentage of time spent on changes rated as most meaningful. Work is needed to present bio-impedance alerts in a manner which is intuitive for clinicians.

What impact do anxiety, depression, perceived control and technology capability have on whether patients with chronic heart failure take-up or continue to use home tele-monitoring services? Study design of ADaPT-HF.

BACKGROUND: Home tele-monitoring (HTM) is used to monitor the clinical signs and symptoms of patients with chronic heart failure (CHF) in order to reduce unplanned hospital admissions. However, not all patients who are referred will agree to use HTM, and some patients choose to withdraw early from its use. AIMS: ADaPT-HF will investigate whether depression, anxiety, low perceived control, reduced technology capability, level of education, age or the severity or complexity of a patient's illness can predict refusal of, or early withdrawal from, HTM in patients with CHF. METHODS: The study will recruit 288 patients who have been recently admitted to hospital with heart failure who have been referred for HTM. At the time of referral, patients will complete depression (nine-item Patient Health Questionnaire), anxiety (seven-item Generalised Anxiety Disorder questionnaire), perceived control (eight-item revised Controlled Attitudes Scale) and technology capability (ten-item Technology Readiness Index 2.0) screening questionnaires. In addition, data on demographics, diagnosis, clinical examination, socio-economic status, history of comorbidities, medication, biochemistry and haematology will be recorded. The primary outcome will be a composite of refusal of or early withdrawal from HTM. The principle analysis will be made using logistic regression. CONCLUSION: By establishing which factors influence a patient's decision to refuse or withdraw early from HTM, it may be possible to redesign HTM referral processes. It may be that patients with CHF who also have depression, anxiety, low control and poor technology skills should not be referred until they receive appropriate support or that they should be managed differently when they do receive HTM. The results of ADAPT-HF may provide a way of making more efficient and cost-effective use of HTM services.

Long-term changes of renal function in relation to ace inhibitor/angiotensin receptor blocker dosing in patients with heart failure and chronic kidney disease.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have become cornerstones of therapy for chronic heart failure (CHF). Guidelines advise high target doses for ACEIs/ARBs, but fear of worsening renal function may limit dose titration in patients with concomitant chronic kidney disease (CKD). METHODS: In this retrospective observational study, we identified 722 consecutive patients with systolic CHF, stable CKD stage III/IV (estimated glomerular filtration rate [eGFR] 15-60 mL min(-1) 1.73 m(-2)) and chronic ACEI/ARB treatment from the outpatient heart failure clinics at the Universities of Hull, UK, and Heidelberg, Germany. Change of renal function, worsening CHF, and hyperkalemia at 12-month follow-up were analyzed as a function of both baseline ACEI/ARB dose and dose change from baseline. RESULTS: ΔeGFR was not related to baseline dose of ACEI/ARB (P = .58), or to relative (P = .18) or absolute change of ACEI/ARB dose (P = .21) during follow-up. Expressing change of renal function as a categorical variable (improved/stable/decreased) as well as subgroup analyses with respect to age, sex, New York Heart Association functional class, left ventricular ejection fraction, diabetes, concomitant aldosterone antagonists, CKD stage, hypertension, ACEI vs ARB, and congestion status yielded similar results. There was no association of dose/dose change with incidence of either worsening CHF or hyperkalemia. CONCLUSIONS: In patients with systolic CHF and stable CKD stage III/IV, neither continuation of high doses of ACEI/ARB nor up-titration was related to adverse changes in longer-term renal function. Conversely, down-titration was not associated with improvement in eGFR. Use of high doses of ACEI/ARB and their up-titration in patients with CHF and CKD III/IV may be appropriate provided that the patient is adequately monitored.

Is the diagnostic coding position of acute heart failure related to mortality? A report from the Euro Heart Failure Survey-1.

AIMS: Most studies on acute heart failure (HF) exploring the relationship between admissions to hospital for HF and subsequent outcomes have focused only on HF coded as the primary diagnosis, but many other patients have admissions complicated by HF requiring attention. Failure to quantify the total hospital burden of HF underestimates its health economic impact, leading to underprovision of resources for its care. METHODS AND RESULTS: The First Euro Heart Failure Survey (EHFS-1) screened consecutive deaths and discharges, regardless of cause, from medical wards in 115 hospitals from 24 European countries during 2000-2001, to identify patients with known or suspected HF. Information on presenting symptoms and signs were gathered. Of 10 701 patients enrolled, HF was reported as the primary reason for admission in 4234 (40%), a secondary reason for admission if it complicated or prolonged stay in 1772 (17%), and in 4695 (43%) patients it was uncertain whether HF was actively contributing to the admission. Mortality on the index admission was 301 (7%), 290 (16%), and 189 (4%), respectively, with hazard ratios of 1.73 (P < 0.001) and 3.26 (P < 0.001) compared with the 'uncertain' group. In the 12 weeks following discharge, 287 (7%) patients with a primary, 117 (8%) with a secondary, and 238 (5%) with an incidental or uncertain diagnosis of HF died. CONCLUSION: Patients admitted to hospital with HF as a secondary rather than a primary diagnosis have a high mortality. More attention should be focused on patients with a secondary diagnosis of HF in terms of both care and research.

Regional circulatory distribution of novel cardiac bio-markers and their relationships with haemodynamic measurements.

BACKGROUND: Regional sampling may identify sites of production or removal of novel biomarkers in the circulation; their relationship to haemodynamic measurements may clarify their association with the pathophysiology of heart failure. METHODS: Samples were obtained from up to eight circulatory sites from 22 patients with left ventricular dysfunction undergoing elective cardiac catheterisation. The plasma concentrations (PC) of six biomarkers [mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-endothelin-1 (CT-proET-1), mid-regional pro-adreno-medullin (MR-proADM), high sensitivity pro-calcitonin (hsPCT), copeptin and galectin-3 (Gal-3)] were measured. RESULTS: Plasma concentrations of MR-proANP were highest in the pulmonary artery (PA) and left ventricle, suggesting myocardial production. Lower concentrations of copeptin, CT-proET-1, MR-proADM and hsPCT were found in the supra-renal inferior vena cava (SRIVC) sample suggesting renal extraction. Plasma concentrations of Galectin-3 varied little by sampling site. Plasma concentrations of MR-proANP (R=0.69, P=0.002), MR-proADM (R=0.51, P=0.03), CT-proET-1 (R=0.60, P=0.009) and Copeptin (R=0.47, P<0.05) measured from PA samples correlated with PA systolic pressure. There was no relation between any measured marker and cardiac index. CONCLUSIONS: Regional sampling shows variation in the plasma concentration of various novel peptides that provides clues to sites of net production and removal. Plasma concentrations of several biomarkers were positively correlated with pulmonary artery pressure.

Early Indication of Decompensated Heart Failure in Patients on Home-Telemonitoring: A Comparison of Prediction Algorithms Based on Daily Weight and Noninvasive Transthoracic Bio-impedance.

BACKGROUND: Heart Failure (HF) is a common reason for hospitalization. Admissions might be prevented by early detection of and intervention for decompensation. Conventionally, changes in weight, a possible measure of fluid accumulation, have been used to detect deterioration. Transthoracic impedance may be a more sensitive and accurate measure of fluid accumulation. OBJECTIVE: In this study, we review previously proposed predictive algorithms using body weight and noninvasive transthoracic bio-impedance (NITTI) to predict HF decompensations. METHODS: We monitored 91 patients with chronic HF for an average of 10 months using a weight scale and a wearable bio-impedance vest. Three algorithms were tested using either simple rule-of-thumb differences (RoT), moving averages (MACD), or cumulative sums (CUSUM). RESULTS: Algorithms using NITTI in the 2 weeks preceding decompensation predicted events (P<.001); however, using weight alone did not. Cross-validation showed that NITTI improved sensitivity of all algorithms tested and that trend algorithms provided the best performance for either measurement (Weight-MACD: 33%, NITTI-CUSUM: 60%) in contrast to the simpler rules-of-thumb (Weight-RoT: 20%, NITTI-RoT: 33%) as proposed in HF guidelines. CONCLUSIONS: NITTI measurements decrease before decompensations, and combined with trend algorithms, improve the detection of HF decompensation over current guideline rules; however, many alerts are not associated with clinically overt decompensation.

Is heart rate important for patients with heart failure in atrial fibrillation?

OBJECTIVES: This study sought to investigate the relationship between resting ventricular rate and mortality in patients with chronic heart failure (CHF) and reduced left ventricular ejection fraction (LVEF) who were in sinus rhythm (SR) or atrial fibrillation (AF). BACKGROUND: Slower heart rates are associated with better survival in patients with CHF in SR, but it is not clear whether this is true for those in AF. METHODS: We assessed 2,039 outpatients with CHF and LVEF ≤50% undergoing baseline assessment, of whom 24% (n = 488) were in AF; and 841 outpatients reassessed after attempted treatment optimization at 1 year, of whom 22% (n = 184) were in AF. Cox proportional hazards models were used to assess the relationships between heart rate and survival in patients with CHF and AF or sinus rhythm. We analyzed heart rate and rhythm data recorded at the baseline review and after 1-year follow-up. Proportional hazards assumptions were checked by Schoenfeld and Martingale residuals. RESULTS: The median survival for those in AF was 6.1 years (interquartile range [IQR]: 5.3 to 6.9 years) and 7.3 years (IQR: 6.5 to 8.1 years) for those in SR. In univariable analysis, patients with AF had a worse survival (hazard ratio [HR]: 1.26, 95% confidence interval [CI]: 1.08 to 1.47; p = 0.003) but after covariate adjustment, survival rates were similar. After adjusting Cox regression models, there was no association between heart rate (per 10 beats/min increments) and survival in patients with AF before (HR: 0.94, 95% CI: 0.88 to 1.00, p = 0.07) or after (HR: 1.00, 95% CI: 0.99 to 1.00, p = 0.84) therapy optimization. For patients in SR, higher heart rates were associated with worse survival, both before (HR: 1.10, 95% CI: 1.05 to 1.15, p <0.0001) and after (HR: 1.13, 95% CI: 1.03 to 1.24, p = 0.008) therapy optimization. CONCLUSIONS: In patients with CHF and a reduced LVEF, slower resting ventricular rate is associated with better survival for patients in SR but not for those with AF.

Development of a composite model derived from cardiopulmonary exercise tests to predict mortality risk in patients with mild-to-moderate heart failure.

OBJECTIVE: Cardiopulmonary exercise testing (CPET) is used to predict outcome in patients with mild-to-moderate heart failure (HF). Single CPET-derived variables are often used, but we wanted to see if a composite score achieved better predictive power. METHODS: Retrospective analysis of patient records at the department of cardiology, Castle Hill Hospital, Kingston-upon-Hull. 387 patients (median (25th-75th percentile)) (age 65 (56-72) years; 79% men; LVEF 34 (31-37) %) were included. Patients underwent a symptom-limited, maximal CPET on a treadmill. During a median follow-up of 8.6±2.1 years in survivors, 107 patients died. Survival models were built and validated using a hybrid approach between the bootstrap and Cox regression. Nine CPET-derived variables were included. Z-score defined each variable's predictive strength. Model coefficients were converted to a risk score. RESULTS: Four CPET-related variables were independent predictors of all-cause mortality in the survival model: the presence of exertional oscillatory ventilation (EOV), increasing slope of the relation between ventilation and carbon dioxide production (VE/VCO2 slope), decreasing oxygen uptake efficiency slope (OUES), and an increase in the lowest ventilatory equivalent for carbon dioxide (VEqCO2 nadir). Individual predictors of mortality ranged from 0.60 to 0.71 using Harrell's C-statistic, but the optimal combination of EOV+VE/VCO2 slope+OUES+VEqCO2 nadir reached 0.75. The Hull CPET risk score had a significantly higher area under the curve (0.78) when compared to the HF Survival Score (AUC=0.70; p<0.001). CONCLUSIONS: A composite risk score using variables from CPET out-performs the traditional single variable approach in predicting outcome in patients with mild-to-moderate HF.

The in vitro stability of novel cardiovascular and sepsis biomarkers at ambient temperature.

BACKGROUND: The in vitro stability of a biomarker can determine whether it should be used in clinical practice where long delays between sampling and assay are common. We measured the in vitro stability of five novel biomarkers that are being evaluated for their diagnostic and/or prognostic utility in patients with heart failure: mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adreno-medullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), C-terminal pro-arginine vasopressin (copeptin) and ultrasensitive procalcitonin (PCT). METHODS: Peripheral venous blood samples were obtained from 19 patients with chronic heart failure into four EDTA tubes. The first tubes were centrifuged immediately at 4°C with the other tubes stored at 20°C for 4, 24 or 72 hours (h) before centrifuging. Supernatant plasma was frozen and stored at -80°C until assay. The levels of analyte in samples processed with and without delay were compared using correlation analysis, paired t-tests and Bland-Altman plots. RESULTS: Copeptin and PCT were stable up to 72 h at 20°C in whole blood and MR-proANP and MR-proADM up to 24 h. However, CT-proET-1 showed some signs of degradation after only 4 h with 94% of analyte recovered after 24 h, dropping to 80% after 72 h. CONCLUSIONS: MR-proANP, MR-proADM, copeptin and PCT are stable biomarkers and therefore suitable for introduction into routine clinical practice in a primary or secondary care setting where delays in sample preparation and assay are likely. Ideally, samples for measurement of CT-proET-1 should be centrifuged soon after venepuncture but the analyte is stable enough for most routine clinical purposes.

Do patients with chronic heart failure have chest pain?

OBJECTIVE: In questionnaire surveys, patients with chronic heart failure frequently report "pain" as a symptom. We investigated the prevalence of chest pain as a possible cause for pain, particularly in patients with prior myocardial infarction. DESIGN: Questionnaire survey. SETTING: Community heart failure clinic. PATIENTS: 1 786 patients with heart failure due to left ventricular systolic dysfunction (mean ± SD age 70.1 ± 11.0 years; 73% male; left ventricular ejection fraction (LVEF) 35.3 ± 9.9%; 65.6 with underlying ischaemic heart disease (IHD)). INTERVENTION: Patients with chronic heart failure completed a questionnaire. MAIN OUTCOME MEASURES: Answers to the questions: (1) "In the last week, how many days did you get angina chest pain?"; and "In the last month, how much did the following affect you:" (2) "chest pains at rest"; (3) "chest pains during normal activity". RESULTS: 73% of those with IHD, and 84% of those without had had no angina in the previous week; 79% and 82%, respectively, had at most "little" chest pain at rest; 67% and 76%, respectively, had at most "little" chest pain during exertion. Angina increased with NYHA class, but there was no relation between angina and sex of patient, age or LVEF. There was a weak relation between chest pain and an adverse outcome in the patients with ischaemic heart disease. CONCLUSIONS: Although pain is commonly reported in patients with chronic heart failure, it seems unlikely that the pain is due to angina, even in patients with underlying coronary heart disease.

Identifying patients at risk of death or hospitalisation due to worsening heart failure using decision tree analysis: evidence from the Trans-European Network-Home-Care Management System (TEN-HMS) study.

OBJECTIVES: To stratify patients recently discharged from hospital with heart failure (HF) according to their risk of death and/or hospitalisation for worsening HF (WHF), to enable timely and appropriate monitoring and intervention. METHODS: Data from the TEN-HMS study were used in this analysis. Chi-square automatic interaction detector (CHAID) decision trees were constructed using a 10-fold cross-validation to predict events at 1-year and compared with logistic regression (LR) models using ROC curve analysis. RESULTS: 284 patients were used for training and 160 patients available at 4-month for validation. Amino-terminal pro-brain natriuretic peptide (NT-proBNP) was the strongest predictor of mortality identifying groups with high (>13,492 pg/ml), medium (3127-13,492 pg/ml) and low (≤ 3127 pg/ml) risk, followed by MI, systolic blood pressure, age, heart rhythm, study randomisation group and serum sodium. NT-proBNP was also the strongest predictor for death or hospitalization for WHF identifying groups with high (>13,492 pg/ml), medium (584-13,492 pg/ml), and low (≤ 584 pg/ml), followed by MI, creatinine, heart rhythm, potassium and urea. CHAID trees tended to perform better than LR-models (prediction of the composite outcome: ROC area with 95% CI, 0.797 (0.745-0.849) for CHAID and 0.738 (0.680-0.796) for LR-model; p=0.041; prediction of mortality: 0.892 (0.853-0.931) for CHAID and 0.858 (0.813-0.904) for LR; p=0.15). CONCLUSIONS: Decision trees are an alternative classification method used to differentiate risk in patients with HF. The resultant models are concise, free of subjective variables and understood easily by clinicians. Further exploration of their potential and validation in other data-sets is justified.

Heart rate achieved or beta-blocker dose in patients with chronic heart failure: which is the better target?

AIMS: To investigate whether the mortality of patients with chronic heart failure (CHF) due to left ventricular systolic dysfunction (LVSD) is more strongly related to beta-blocker dose or to heart rate. It is known that beta-blockers reduce mortality in patients with CHF and LVSD, but the primary mechanism of action is uncertain. METHODS AND RESULTS: Patients with an ejection fraction ≤40%, who were in sinus rhythm both at an initial (visit 1) and at a 4-month clinic review (visit 2), were followed for a maximum of 36 months. The relationships between heart rate, beta-blocker dose, and survival in a multivariable model were examined. Of 654 eligible patients, 381 (58%) were started on beta-blockers prior to the initial visit, increasing to 537 (82%) by visit 2. During follow-up, 142 (22%) patients died. Neither resting heart rate nor beta-blocker dose at visit 1 predicted mortality (P = 0.09 and P = 0.99), but resting heart rate at visit 2 did (P = 0.02). Beta-blocker use at visit 2 was associated with better outcome (P = 0.03) but with little variation in outcome according to dose. Patients with a heart rate of 58-64 b.p.m. at visit 2 had the best prognosis. CONCLUSIONS: The use of beta-blockers and resting heart rate at visit 2 both independently indicated prognosis, but beta-blocker dose did not. Beta-blockers may reduce mortality by several mechanisms; one that may be specific to blockade of adrenergic receptors and another related to heart rate reduction. Achieving a target heart rate range may be an appropriate therapeutic goal for patients with CHF.

Relationship between plasma concentrations of N-terminal pro brain natriuretic peptide and the characteristics and outcome of patients with a clinical diagnosis of diastolic heart failure: a report from the PEP-CHF study.

AIM: The aim of this study was to explore the relationships between plasma concentrations of N-terminal pro brain natriuretic peptide (NT-proBNP) and characteristics and prognosis of patients with heart failure and preserved (HFPEF) left ventricular ejection fraction (LVEF). No substantial trial has shown that treatment alters prognosis in patients with HFPEF due, in part, to much lower than anticipated event rates. The lack of a simple, objective test to identify patients with HFPEF at increased risk of cardiovascular events would be valuable. METHODS AND RESULTS: The Perindopril in Elderly People with Chronic Heart Failure Trial (PEP-CHF) was a randomized, controlled trial comparing perindopril and placebo in patients with symptoms and signs of heart failure who had an LVEF >40% and evidence of LV diastolic dysfunction. The primary endpoint was all-cause mortality or heart failure-related hospitalization. NT-proBNP was measured in 375 patients. Quartile thresholds were 176, 409, and 1035 pg/mL. Patients in the highest quartile of NT-proBNP were older, had lower body mass, more often had atrial fibrillation, had greater atrial and ventricular dimensions and a lower LVEF, and were more likely to receive loop diuretic therapy. Compared with the first quartile of NT-proBNP, the hazard ratios for the primary endpoint in the second {1.38 [95% confidence interval (CI) 0.64-2.99]}, third [2.84 (95% CI 1.42-5.72)], and fourth [4.47 (95% CI 2.30-8.72)] quartiles were increased. In a multivariable model, NT-proBNP, but not echocardiographic measures, was associated with outcome. CONCLUSIONS: NT-proBNP is a powerful prognostic marker in patients with HFPEF.

Limited role for ivabradine in the treatment of chronic heart failure.

OBJECTIVE: To quantify the proportion of patients attending a community heart failure clinic with left ventricular systolic impairment who might be suitable for ivabradine therapy. BACKGROUND: High resting heart rate is an important and potentially modifiable risk factor in patients with heart failure. The SHIFT study suggested that ivabradine was beneficial when added to conventional treatment including a ß-blocker in heart failure patients in sinus rhythm whose resting heart rates remained 70 beats per minute (bpm) or greater and who had worse than moderate left ventricular impairment. METHODS AND RESULTS: The primary cohort included 2211 patients with a left ventricular ejection fraction (LVEF) of 50% or less. Patients were seen at baseline, then reviewed at 4 and 12 months. 'Suitability' for ivabradine was assessed as: LVEF 35% or less, sinus rhythm and a resting heart rate of 70 bpm or greater. The proportion of patients who were 'suitable' for ivabradine therapy fell from 19.4% (n=429) at baseline, to 14.1% (n=185) at 4 months and finally 9% (n=82) by the 12-month clinic visit. The proportion fell to 5.3% (n=48) if only patients with New York Heart Association class I symptoms and/or no ß-blocker therapy were excluded. CONCLUSIONS: After uptitration of heart failure medications, the number of patients 'suitable' for ivabradine therapy was small. First and foremost, ß-blocker therapy should be commenced and titrated. The decision to add ivabradine should be made after allowing adequate time to uptitrate conventional medical therapy.

Determinants and prognostic value of pulmonary arterial pressure in patients with chronic heart failure.

AIMS: The epidemiology of pulmonary arterial hypertension (PAH) in patients with heart failure (HF) is poorly described. Our aim was to investigate the determinants and prognostic significance of PAH in a large representative outpatient population with HF. METHODS AND RESULTS: Routine measurement of right ventricular tricuspid pressure gradient (RVTG) was attempted among unselected, consecutive referrals to an HF clinic. The diagnosis of HF was based on symptoms, signs, echocardiography, and N-terminal pro-brain natriuretic peptide (NT-proBNP). Of 2100 patients referred, 1380 were diagnosed as HF, of whom 1026 had left ventricular systolic dysfunction (LVSD) and 354 did not. Right ventricular tricuspid pressure gradient could be measured in 270 (26%) patients with and 143 (40%) without LVSD. The highest RVTG quartile [RVTG > 35 mmHg equivalent to an estimated PA systolic pressure (PASP) > 45 mmHg] constituted 7% of all those with HF and was associated with higher LV filling pressures, LV end-diastolic volume, LVSD, and more severe mitral regurgitation (MR). During a median (inter-quartile range) follow-up of 66 (56-74) months, mortality was 40.3%. Mortality was similar in the lowest quartile of RVTG and in those in whom RVTG could not be measured and rose with increasing RVTG quartile (log-rank: 26.9; P < 0.0001). The highest RVTG quartile, age, blood pressure, and log NT-proBNP independently predicted mortality. Right ventricular tricuspid pressure gradient >35 mmHg had a 96% specificity to discriminate between those with and without HF in patients without LVSD. CONCLUSION: Using a definition of PASP > 45 mmHg, 7% of the patients with HF have PAH, which is associated with worse LV function, MR, and prognosis. Whether PAH is a target for therapy in this population remains to be elucidated.

Statistical methods in epidemiology. IX. Survival (failure-time) models.

PURPOSE: This article introduces readers to survival (failure-time) models, with a focus on Kaplan-Meier curves, Cox regression and sample size estimation. METHODS: An example is used to show readers how to calculate a Kaplan-Meier curve from first principles. RESULTS: What makes survival data unique is censoring. Readers should understand censoring before undertaking an analysis of survival data. CONCLUSION: The Cox model continues to set the standard for survival models, and will continue well into the future.