Jan van Wijngaarden

Anemia and Mortality in Heart Failure Patients: A Systematic Review and Meta-Analysis

OBJECTIVES The aim of this study was to assess the effect of anemia on mortality in chronic heart failure (CHF). BACKGROUND Anemia is frequently observed in patients with CHF, and evidence suggests that anemia might be associated with an increased mortality. METHODS A systematic literature search in MEDLINE (through November 2007) for English language articles was performed. In addition, a manual search was performed. We included cohort studies and retrospective secondary analyses of randomized controlled trials whose primary objective was to analyze the association between anemia and mortality in CHF. Of a total of 1,327 initial studies, we included 34 studies, comprising 153,180 patients. Information on study design, patient characteristics, outcome, and potential confounders were extracted. RESULTS Anemia was defined by criteria used in the original articles. Of the 153,180 CHF patients, 37.2% were anemic. After a minimal follow-up of 6 months, 46.8% of anemic patients died compared with 29.5% of nonanemic patients. Crude mortality risk of anemia was odds ratio 1.96 (95% confidence interval: 1.74 to 2.21, p < 0.001). Lower baseline hemoglobin values were associated with increased crude mortality rates (r = -0.396, p = 0.025). Adjusted hazard ratios showed an increased adjusted risk for anemia (hazard ratio 1.46 [95% confidence interval: 1.26 to 1.69, p < 0.001]). Subgroup analysis showed no significant difference between mortality risk of anemia in diastolic or systolic CHF. CONCLUSIONS Anemia is associated with an increased risk of mortality in both systolic and diastolic CHF. Anemia should, therefore, be considered as a useful prognosticator, and therapeutic strategies aimed to increase hemoglobin levels in CHF should be investigated.

Added value of a physician-and-nurse-directed heart failure clinic: results from the Deventer–Alkmaar heart failure study

Aim: To determine whether an intensive intervention at a heart failure (HF) clinic by a combination of a clinician and a cardiovascular nurse, both trained in HF, reduces the incidence of hospitalisation for worsening HF and/or all-cause mortality (primary end point) and improves functional status (including left ventricular ejection fraction, New York Heart Association (NYHA) class and quality of life) in patients with NYHA class III or IV. Setting: Two regional teaching hospitals in The Netherlands. Methods: 240 patients were randomly allocated to the 1-year intervention (n = 118) or usual care (n = 122). The intervention consisted of 9 scheduled patient contacts—at day 3 by telephone, and at weeks 1, 3, 5, 7 and at months 3, 6, 9 and 12 by a visit—to a combined, intensive physician-and-nurse-directed HF outpatient clinic, starting within a week after hospital discharge from the hospital or referral from the outpatient clinic. Verbal and written comprehensive education, optimisation of treatment, easy access to the clinic, recommendations for exercise and rest, and advice for symptom monitoring and self-care were provided. Usual care included outpatient visits initialised by individual cardiologists in the cardiology departments involved and applying the guidelines of the European Society of Cardiology. Results: During the 12-month study period, the number of admissions for worsening HF and/or all-cause deaths in the intervention group was lower than in the control group (23 vs 47; relative risk (RR) 0.49; 95% confidence interval (CI) 0.30 to 0.81; p = 0.001). There was an improvement in left ventricular ejection fraction (LVEF) in the intervention group (plus 2.6%) compared with the usual care group (minus 3.1%; p = 0.004). Patients in the intervention group were hospitalised for a total of 359 days compared with 644 days for those in the usual care group. Beneficial effects were also observed on NYHA classification, prescription of spironolactone, maximally reached dose of β-blockers, quality of life, self-care behaviour and healthcare costs. Conclusion: A heart failure clinic involving an intensive intervention by both a clinician and a cardiovascular nurse substantially reduces hospitalisations for worsening HF and/or all-cause mortality and improves functional status, while decreasing healthcare costs, even in a country with a primary-care-based healthcare system.

The Diagnostic Value of Physical Examination and Additional Testing in Primary Care Patients With Suspected Heart Failure

Background— Early diagnosis of nonacute heart failure is crucial because prompt initiation of evidence-based treatment can prevent or slow down further progression. To diagnose new-onset heart failure in primary care is challenging. Methods and Results— This is a cross-sectional diagnostic accuracy study with external validation. Seven hundred twenty-one consecutive patients suspected of new-onset heart failure underwent standardized diagnostic work-up including chest x-ray, spirometry, ECG, N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurement, and echocardiography in specially equipped outpatient diagnostic heart failure clinics. The presence of heart failure was determined by an outcome panel using the initial clinical data and 6-month follow-up data, blinded to biomarker data. Of the 721 patients, 207 (28.7%) had heart failure. The combination of 3 items from history (age, coronary artery disease, and loop diuretic use) plus 6 from physical examination (pulse rate and regularity, displaced apex beat, rales, heart murmur, and increased jugular vein pressure) showed independent diagnostic value (c-statistic 0.83). NT-proBNP was the most powerful supplementary diagnostic test, increasing the c-statistic to 0.86 and resulting in net reclassification improvement of 69% (P<0.0001). A simplified diagnostic rule was applied to 2 external validation datasets, resulting in c- statistics of 0.95 and 0.88, confirming the results. Conclusions— In this study, we estimated the quantitative diagnostic contribution of elements of the history and physical examination in the diagnosis of heart failure in primary care outpatients, which may help to improve clinical decision making. The largest additional quantitative diagnostic contribution to those elements was provided by measurement of NT-proBNP. For daily practice, a diagnostic rule was derived that may be useful to quantify the probability of heart failure in patients with new symptoms suggestive of heart failure.

Added value of a physician-and-nurse-directed heart failure clinic. Results from the DEAL-HF study

Aim: To determine whether an intensive intervention at a heart failure (HF) clinic by a combination of a clinician and a cardiovascular nurse, both trained in HF, reduces the incidence of hospitalisation for worsening HF and/or all-cause mortality (primary end point) and improves functional status (including left ventricular ejection fraction, New York Heart Association (NYHA) class and quality of life) in patients with NYHA class III or IV. Setting: Two regional teaching hospitals in The Netherlands. Methods: 240 patients were randomly allocated to the 1-year intervention (n = 118) or usual care (n = 122). The intervention consisted of 9 scheduled patient contacts—at day 3 by telephone, and at weeks 1, 3, 5, 7 and at months 3, 6, 9 and 12 by a visit—to a combined, intensive physician-and-nurse-directed HF outpatient clinic, starting within a week after hospital discharge from the hospital or referral from the outpatient clinic. Verbal and written comprehensive education, optimisation of treatment, easy access to the clinic, recommendations for exercise and rest, and advice for symptom monitoring and self-care were provided. Usual care included outpatient visits initialised by individual cardiologists in the cardiology departments involved and applying the guidelines of the European Society of Cardiology. Results: During the 12-month study period, the number of admissions for worsening HF and/or all-cause deaths in the intervention group was lower than in the control group (23 vs 47; relative risk (RR) 0.49; 95% confidence interval (CI) 0.30 to 0.81; p = 0.001). There was an improvement in left ventricular ejection fraction (LVEF) in the intervention group (plus 2.6%) compared with the usual care group (minus 3.1%; p = 0.004). Patients in the intervention group were hospitalised for a total of 359 days compared with 644 days for those in the usual care group. Beneficial effects were also observed on NYHA classification, prescription of spironolactone, maximally reached dose of β-blockers, quality of life, self-care behaviour and healthcare costs. Conclusion: A heart failure clinic involving an intensive intervention by both a clinician and a cardiovascular nurse substantially reduces hospitalisations for worsening HF and/or all-cause mortality and improves functional status, while decreasing healthcare costs, even in a country with a primary-care-based healthcare system.

Adequacy of endogenous erythropoietin levels and mortality in anaemic heart failure patients

AIMS We examined the adequacy of endogenous erythropoietin (EPO) levels for the degree of anaemia in patients with chronic heart failure (CHF) and its relation to prognosis. METHODS AND RESULTS We studied 74 anaemic CHF patients from a cohort of 240 patients. The adequacy of endogenous EPO levels was assessed by derived observed/predicted (O/P) ratio. A ratio value < 0.92 indicates EPO levels lower than expected, whereas a value > 1.09 indicates EPO levels higher than expected. The primary endpoint was mortality. During a median follow up of 4.9 years, 35 of the 74 (47.3%) anaemic patients died. EPO levels lower than expected were observed in 29 patients (39%), whereas EPO levels higher than expected were present in 22 anaemic patients (29%). The Kaplan-Meier analysis revealed that anaemic patients with EPO levels higher than expected had a significantly higher mortality rate compared to patients with EPO levels as expected or EPO levels lower than expected (log-rank: P = 0.024). A higher O/P ratio was an independent predictor of increased mortality risk adjusted for variables including age, sex, haemoglobin, NT-proBNP, and renal function; hazard ratio (HR): 1.020 95%CI (1.004-1.036), P = 0.012. CONCLUSION EPO levels higher than expected, suggesting resistance to the hormone, are common in CHF patients and are associated with a higher mortality.

Incremental Prognostic Power of Novel Biomarkers (Growth-Differentiation Factor-15, High-Sensitivity C-Reactive Protein, Galectin-3, and High-Sensitivity Troponin-T) in Patients With Advanced Chronic Heart Failure

Elevated natriuretic peptides provide strong prognostic information in patients with heart failure (HF). The role of novel biomarkers in HF needs to be established. Our objective was to evaluate the prognostic power of novel biomarkers, incremental to the N-terminal portion of the natriuretic peptide (NT-proBNP) in chronic HF. Concentrations of circulating NT-proBNP, growth differentiation factor 15 (GDF-15), high-sensitivity C-reactive protein (hs-CRP), galectin-3 (Gal-3), and high-sensitivity troponin T (hs-TnT) were measured and related to all-cause long-term mortality. Of 209 patients (age 71 ± 10 years, 73% male patients, 97% New York Heart Association class III), 151 (72%) died during a median follow-up of 8.7 ± 1 year. The calculated area under the curve for NT-proBNP was 0.63, GDF-15 0.78, hs-CRP 0.66, Gal-3 0.68, and hs-TnT 0.68 (all p <0.01). Each marker was predictive for mortality in univariate analysis. In multivariate analysis, elevated concentrations of GDF-15 (hazard ratio [HR] 1.41, confidence interval [CI] 1.1 to 178, p = 0.005), hs-CRP (HR 1.38, CI 1.15 to 1.67, p = 0.001), and hs-TnT (HR 1.27, CI 1.06 to 1.53, p = 0.008) were independently related to mortality. All novel markers had an incremental value to NT-proBNP, using the integrated discrimination improvement. In conclusion, in chronic HF, GDF-15, hs-CRP, and hs-TnT are independent prognostic markers, incremental to NT-proBNP, in predicting long-term mortality. In this study, GDF-15 is the most predictive marker, even stronger than NT-proBNP.

Heart failure programmes in countries with a primary care-based health care system. Are additional trials necessary? Design of the DEAL-HF study

Several randomised studies of heart failure (HF) management programmes in the United States, Australia and Europe have shown a considerable reduction in hospitalisation rates for HF. In this article, a comprehensive review of these studies will be provided and their applicability to countries, with a primary care‐based healthcare system, will be discussed. In addition, the design of the Deventer‐Alkmaar HF Project (DEAL‐HF), a randomised study of the effect of a nurse and physician‐directed intervention over 1 year in The Netherlands, will also be presented.

Truncating titin mutations are associated with a mild and treatable form of dilated cardiomyopathy

Truncating titin mutations (tTTN) occur in 25% of dilated cardiomyopathy (DCM) cases, but the phenotype and severity of disease they cause have not yet been systematically studied. We studied whether tTTN variants are associated with a clinically distinguishable form of DCM.

Early or late intervention in patients with transient ST-segment elevation acute coronary syndrome: Subgroup analysis of the ELISA-3 trial

To investigate incidence and patient characteristics of transient ST‐segment elevation (TSTE) ACS and to compare outcome of early versus late invasive treatment.

The first titin (c.59926 + 1G > A) founder mutation associated with dilated cardiomyopathy

Truncating variants in the gene encoding titin (TTNtv) are found in 13–25% of dilated cardiomyopathy (DCM) cases.1,2 In DCM patients, TTNtv are associated with early arrhythmic risk, composed of atrial fibrillation (AF), non-sustained and/or sustained ventricular tachycardia.3 TTNtv in the Aband region, or in constitutively expressed exons of TTN, are generally believed to be pathogenic, but assigning pathogenicity can be challenging because TTNtv are also found in control populations.4 Here we describe the TTN c.59926+1G >A splice-site variant located in the Aband (chr2:179456704C>T, build GRCh37; NM_001267550.2 reference sequence) that we have identified in multiple probands with DCM. Written informed consent was obtained from all participants following local medical ethics committee guidelines. Our study and all experiments conformed with the principles of the Declaration of Helsinki.