Effects of Empagliflozin on Fluid Overload, Weight, and Blood Pressure in CKD.

SIGNIFICANCE STATEMENT: SGLT2 inhibitors reduce risk of kidney progression, AKI, and cardiovascular disease, but the mechanisms of benefit are incompletely understood. Bioimpedance spectroscopy can estimate body water and fat mass. One quarter of the EMPA-KIDNEY bioimpedance substudy CKD population had clinically significant levels of bioimpedance-derived "Fluid Overload" at recruitment. Empagliflozin induced a prompt and sustained reduction in "Fluid Overload," irrespective of sex, diabetes, and baseline N-terminal pro B-type natriuretic peptide or eGFR. No significant effect on bioimpedance-derived fat mass was observed. The effects of SGLT2 inhibitors on body water may be one of the contributing mechanisms by which they mediate effects on cardiovascular risk. BACKGROUND: CKD is associated with fluid excess that can be estimated by bioimpedance spectroscopy. We aimed to assess effects of sodium glucose co-transporter 2 inhibition on bioimpedance-derived "Fluid Overload" and adiposity in a CKD population. METHODS: EMPA-KIDNEY was a double-blind placebo-controlled trial of empagliflozin 10 mg once daily in patients with CKD at risk of progression. In a substudy, bioimpedance measurements were added to the main trial procedures at randomization and at 2- and 18-month follow-up visits. The substudy's primary outcome was the study-average difference in absolute "Fluid Overload" (an estimate of excess extracellular water) analyzed using a mixed model repeated measures approach. RESULTS: The 660 substudy participants were broadly representative of the 6609-participant trial population. Substudy mean baseline absolute "Fluid Overload" was 0.4±1.7 L. Compared with placebo, the overall mean absolute "Fluid Overload" difference among those allocated empagliflozin was -0.24 L (95% confidence interval [CI], -0.38 to -0.11), with similar sized differences at 2 and 18 months, and in prespecified subgroups. Total body water differences comprised between-group differences in extracellular water of -0.49 L (95% CI, -0.69 to -0.30, including the -0.24 L "Fluid Overload" difference) and a -0.30 L (95% CI, -0.57 to -0.03) difference in intracellular water. There was no significant effect of empagliflozin on bioimpedance-derived adipose tissue mass (-0.28 kg [95% CI, -1.41 to 0.85]). The between-group difference in weight was -0.7 kg (95% CI, -1.3 to -0.1). CONCLUSIONS: In a broad range of patients with CKD, empagliflozin resulted in a sustained reduction in a bioimpedance-derived estimate of fluid overload, with no statistically significant effect on fat mass. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03594110 ; EuDRACT: 2017-002971-24 ( https://eudract.ema.europa.eu/ ).

Empagliflozin in Patients with Chronic Kidney Disease.

BACKGROUND: The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. METHODS: We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m2 of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m2 with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to <10 ml per minute per 1.73 m2, a sustained decrease in eGFR of ≥40% from baseline, or death from renal causes) or death from cardiovascular causes. RESULTS: A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P<0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P = 0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. CONCLUSIONS: Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo. (Funded by Boehringer Ingelheim and others; EMPA-KIDNEY ClinicalTrials.gov number, NCT03594110; EudraCT number, 2017-002971-24.).

[Diabetic Kidney Disease - How to Protect the Kidney?] / Diabetes mellitus Typ 2: Wie schützen wir die Nieren am besten?

In diabetes, progression of cardio-renal disease is still the most important determinant of disease burden. Hence, the potential of glycaemic control is not the only measure any more to decide whether a new therapeutic approach is selected. Therapies with compelling cardiovascular and renal-protective effects are available. The two most promising new treatment concepts are sodium glucose co-transporter 2 (SGLT-2) inhibition and glucagon-like peptide-1 (GLP-1) receptor agonism. For both treatment concepts, prominent reductions in cardiovascular event rates and renal disease progression have been proven.To date, these beneficial effects appear to be more significant with SGLT-2 inhibitors than with GLP-1 receptor agonists, and further clinical trials with SGLT-2 inhibitors in patients with more advanced diabetic and non-diabetic kidney disease are currently underway. Furthermore, there are two new treatment concepts for attenuation of diabetic kidney disease progression close to finalization: selective antagonism of the mineralocorticoid receptor with finerenone and selective antagonism of the endothelin-1 receptor with atrasentan. Hence, in the near future, more treatment approaches might be available to face the major challenges in diabetes mellitus.

Prevalence of cardiovascular risk factors and diseases in patients with multiple myeloma undergoing autologous peripheral blood stem cell transplantation.

Multiple myeloma (MM) is the second most common hematologic malignancy and occurs similar to cardiovascular diseases (CVD), in the sixth/seventh decade. The aim of this retrospective cohort study was to evaluate the prevalence and prognostic value of cardiovascular risk factors (CVRF) and CVD in 325 patients with MM undergoing autologous peripheral blood stem cell transplantation (PBSCT) at the University Hospital of Würzburg between 03/2004 and 12/2011. Mean age in the total cohort was 61 years. Among CVRF, prevalence of arterial hypertension was highest (59.7%), followed by overweight (54.2%) and positive smoking history (18.2%). The prevalence of heart failure (3.1%) or coronary heart disease (4.8%) was low. During a median follow-up of 36 months, 18% of the patients died. Hypertension (HR = 1.83, p = 0.048) as well as positive smoking history (HR = 2.13, p = 0.02) were independently associated with increased mortality risk in multivariate analysis. In a subgroup analysis of 100 patients echocardiographic parameters were compared before and after PBSCT. Echocardiography revealed a significant reduction of left atrial diameters (-1.5 mm, p = 0.009) and septum thickness (-1.0 mm, p = 0.001), non-significant reduction of systolic function, and an increase of the prevalence of diastolic dysfunction (+14%; p = 0.01). In this study CVRF, especially hypertension and smoking, are strong predictors of poor survival in patients with MM undergoing autologous PBSCT. Echocardiography before and after treatment shows subtle changes in systolic function but an increase of the prevalence of diastolic dysfunction.

The omega-3 index in patients with heart failure: A prospective cohort study.

BACKGROUND: Epidemiologic studies on the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in heart failure are scarce, while one large intervention trial demonstrated a modest benefit. METHODS: This is a secondary analysis from the Interdisciplinary Network Heart Failure (INH) program. Patients hospitalized for systolic heart failure were enrolled and followed for 36 months. At baseline, whole blood samples from 899 patients were analyzed for fatty acid composition using a standardized analytical procedure (HS-Omega-3 Index®, O3-I). Associations of the O3-I with markers of heart failure severity, clinical characteristics, biomarkers, and mortality were analyzed. RESULTS: The mean O3-I was 3.7 ±â€¯1.0%. Patient mean age was 68 ±â€¯12 years (72% male, 43% in New York Heart Association (NYHA) class III or IV, mean LVEF 30 ±â€¯8%). During follow-up 258 patients (28.7%) died. After adjustment for potential confounders, the O3-I showed weak associations with uncured malignancy, end-systolic diameter of the left atrium, left ventricular end-diastolic and end-systolic diameters, and blood lipids and other laboratory parameters (all p < 0.05), but not with NYHA class, left ventricular ejection fraction, and the underlying cause of heart failure. The O3-I did not predict the 3-year mortality risk. CONCLUSIONS: Our results show a marked depletion of omega-3 fatty acids in patients hospitalized for decompensated heart failure (suggested target range 8-11%). Although the O3-I was associated with a panel of established risk indicators in heart failure, it did not predict mortality risk. CLINICAL TRIAL REGISTRATION: www.controlled-trials.com; ISRCTN23325295.

Prognostic potential of midregional pro-adrenomedullin following decompensation for systolic heart failure: comparison with cardiac natriuretic peptides.

AIMS: Whereas guidelines recommend the routine use of natriuretic peptides (NPs) in heart failure (HF) care, the clinical relevance and prognostic potential of midregional pro-adrenomedullin (MR-proADM) is less well established. We aimed to compare the prognostic potential of MR-proADM after acute decompensation for systolic HF with that of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and midregional pro-atrial NP (MR-proANP), to investigate the significance of high/rising MR-proADM, and to evaluate the incremental prognostic yield of repeat measurements. METHODS AND RESULTS: The Interdisciplinary Network Heart Failure (INH) programme enrolled patients hospitalized for acute systolic HF and followed them for 18 months (100% complete). Of 1022 INH participants, 917 (68 ± 12 years, 28% female) who had biomaterials available were enrolled. High MR-proADM was associated with more impaired left ventricular function, higher comorbidity burden, lower doses of HF medications, and lower likelihood of left ventricular reverse remodelling. Compared with NPs, MR-proADM had superior prognostic significance (concordance index 0.72 for all-cause mortality), improved Cox regression models including NPs (P < 0.001), and was the only biomarker also predicting non-cardiac death (hazard ratio 1.8 vs. 1.0). In the setting of low NPs, patients with high MR-proADM experienced non-cardiac death more often. Six month MR-proADM enhanced models including baseline MR-proADM (P < 0.001) for prediction of all-cause death (net reclassification index: 0.48, 95% confidence interval 0.19-0.78). CONCLUSION: MR-proADM was found to correlate with the global disease burden in HF and proved a potent prognostic indicator, capturing the risk for both cardiac and non-cardiac death. Serial MR-proADM measurements further enhanced risk assessment, thus facilitating substantial reclassification.

Prognostic significance of serial high-sensitivity troponin I measurements following acute cardiac decompensation-correlation with longer-term clinical outcomes and reverse remodelling.

BACKGROUND: This study investigated the correlation of levels of and changes in serial high-sensitivity cardiac troponin I (hsTnI) with subsequent clinical event rates and changes in cardiac morphology and function in patients hospitalized for acutely decompensated heart failure (ADHF). METHODS AND RESULTS: HsTnI levels were determined in 875 ADHF patients before discharge from hospital (baseline cohort) and clinical outcomes assessed after 180days. HsTnI was re-measured at 180days in 456/875 patients (follow-up cohort). Follow-up hsTnI values were grouped according to baseline hsTnI tertiles; echocardiographic changes from 0-180days and event rates from 180-540days were assessed in these subgroups. At baseline and 180-day follow-up, hsTnI levels were elevated (>0.06ng/mL) in 322/875 (37%) and 68/456 (15%) patients, respectively. At 180days, 85/875 patients (9.7%) had died (cardiovascular causes: 56/875 [6.4%]). Hazard ratios (HR) and 95% confidence intervals (CI) for all-cause and cardiovascular mortality (per two-fold hsTnI increase) were 1.2 (1.0-1.3; p=0.004) and 1.2 (1.1-1.4; p=0.001), respectively. In the follow-up cohort, 35/456 patients (7.7%) died between days 180 and 540 (cardiovascular death: 20/456, 4.4%). HsTnI was a significant predictor of cardiovascular re-hospitalization within 180-540days (HR 1.2, 95% CI 1.0-1.4; p=0.028). Patients with hsTnI in the lowest tertile at follow-up had more frequent and more pronounced reverse cardiac remodelling on echocardiography. CONCLUSIONS: Elevated baseline hsTnI was common and associated with adverse clinical outcomes. Changes in hsTnI from baseline to 180-day follow-up predicted longer-term risk. Low or decreasing hsTnI was associated with better reverse cardiac remodelling and more favourable long-term outcomes. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com. Unique identifier: ISRCTN23325295.

Frequency and prognostic impact of mid-expiratory flow reduction in stable patients six months after hospitalisation for heart failure with reduced ejection fraction.

AIM: This study investigates the prevalence and prognostic impact of central and small airways obstruction (CAO and SAO) in patients with stable heart failure (HF). METHODS & RESULTS: Spirometry was performed in 585 outpatients (mean age 65±12years, 75% male) six months after hospitalisation for acute decompensation secondary to HF with ejection fraction <40%. We assessed forced expiratory volume in the first second (FEV1), forced vital capacity (FVC) and mid-expiratory flow (MEF) at 50% of FVC. CAO was defined by FEV1/FVC <0.7. SAO was defined by FEV1/FVC ≥0.7 plus MEF <60% of predicted value. CAO and SAO were excluded in 359 patients (61% of all). MEF <60% predicted was found in 226 patients (39% of all), among those 88 with CAO (15% of all) and 138 (24% of all) with SAO. During a twelve month follow-up, 42 patients (7.2%) died. Mortality rates of patients with CAO and SAO were comparable (12.5% and 10.9%, respectively, p=0.74), and both higher than in patients without airways obstruction (4.5%, both p<0.01). In univariable Cox regression analysis, both CAO and SAO were associated with 2-fold increased all-cause mortality risk (hazard ratios [95% confidence intervals]: 2.78 [1.33-6.19], p=0.007 and 2.51 [1.24-5.08], p=0.010, respectively). Adjustment for determinants of CAO and SAO, prognostic markers of heart failure and comorbidities attenuated the association of mortality with CAO but not with SAO. CONCLUSIONS: SAO is more common than CAO and indicates an increased mortality risk in HF. Thus, reduced MEF may be a feature of patients at risk and merits special attention in HF management.

Diagnostic and prognostic utility of mid-expiratory flow rate in older community-dwelling persons with respiratory symptoms, but without chronic obstructive pulmonary disease.

BACKGROUND: The maximal expiratory flow at 50 % of the forced vital capacity (MEF50) is the flow where half of forced vital capacity (FVC) remains to be exhaled. A reduced MEF50 has been suggested as a surrogate marker of small airways disease. The diagnostic and prognostic utility of this easy to assess spirometric variable in persons with respiratory symptoms, but without COPD is unclear. METHODS: We used data from the UHFO-COPD cohort in which 405 community-dwelling persons aged 65 years or over, and a general practitioner's diagnosis of chronic obstructive pulmonary disease (COPD) underwent pulmonary function testing and echocardiography. In total 161 patients had no COPD according to the spirometric GOLD criteria. We considered MEF50 as reduced if < 60 % of predicted. RESULTS: Of the 161 patients without COPD (mean age 72 ± 5.7 years; 35 % male; follow-up 4.5 ± 1.1 years), 61 (37.9 %) had a reduced MEF50. They were older, had more pack-years of smoking, more respiratory symptoms, and used more frequently inhaled medication than the remaining 100 subjects. A reduced MEF50 was nearly twice as often associated with newly detected heart failure (HF) at assessment (29.5 % vs. 15.6 %, p = 0.045). In age-and sex-adjusted Cox regression analysis, a reduced MEF50 was significantly associated with episodes of acute bronchitis (hazard ratio 2.54 95 % confidence interval (1.26; 5.13) P = 0.009), and in trend with pneumonia (2.14 (0.98; 4.69) P = 0.06) and hospitalizations for pulmonary reasons (2.28 (0.93; 5.62) P = 0.07). CONCLUSIONS: In older community-dwelling persons with pulmonary symptoms but without COPD, a reduced MEF50 may help to uncover unrecognized HF, and identify those at a higher risk for episodes of acute bronchitis, pneumonia and hospitalizations for pulmonary reasons. Echocardiography and close follow-up should be considered in these patients.

Nurse-coordinated collaborative disease management improves the quality of guideline-recommended heart failure therapy, patient-reported outcomes, and left ventricular remodelling.

BACKGROUND: Heart failure (HF) pharmacotherapy is often not prescribed according to guidelines. This longitudinal study investigated prescription rates and dosages of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB), beta-blockers, and mineralocorticoid receptor antagonists (MRA), and concomitant changes of symptoms, echocardiographic parameters of left ventricular (LV) function and morphology and results of the Short Form-36 (SF-36) Health Survey in participants of the Interdisciplinary Network Heart Failure (INH) programme. METHODS AND RESULTS: The INH study evaluated a nurse-coordinated management, HeartNetCare-HF(TM) (HNC), against Usual Care (UC) in patients hospitalized for decompensated HF [LV ejection fraction (LVEF) ≤40% before discharge). A total of 706 subjects surviving >18 months (363 UC, 343 HNC) were examined 6-monthly. At baseline, 92% received ACEi/ARB, (HNC/UC 91/93%, P = 0.28), 86% received beta-blockers (86/86%, P = 0.83), and 44% received MRA (42/47%, P = 0.07). After 18 months, beta-blocker use had increased only in HNC (+7.6%, P < 0.001). Guideline-recommended target doses were achieved more frequently in HNC for ACEi/ARB (HNC/UC: 50/25%, P < 0.001) and beta-blockers (39/15%, P < 0.001). The following variables were more improved and/or better in subjects undergoing HNC compared with UC: LVEF (47 ± 12 vs. 44 ± 12%, P = 0.004, change +17/+14%, P = 0.010), LV end-diastolic diameter (59 ± 9 vs. 61 ± 9.6 mm, P = 0.024, change -2.3/-1.4 mm, P = 0.13), New York Heart Association class (1.9 ± 0.7 vs. 2.1 ± 0.7, P = 0.001, change -0.44/-0.25, P = 0.002) and SF-36 physical component summary score (41.6 ± 11.2 vs. 38.5 ± 11.8, P = 0.004, change +3.3 vs. +1.1 score points, P < 0.02). CONCLUSIONS: Prescription rates and dosages of ACEi/ARB and beta-blockers improved more in HNC than UC patients. Concomitantly, participation in HNC was associated with significantly better clinical outcomes and more favourable echocardiographic changes after 18 months.

Prognostic value of aldosterone and cortisol in patients hospitalized for acutely decompensated chronic heart failure with and without mineralocorticoid receptor antagonism.

BACKGROUND: Serum aldosterone and cortisol independently predict an increased mortality risk in heart failure (HF), and mineralocorticoid receptor antagonism (MRA) improves survival. The prognostic relevance of aldosterone and cortisol with MRA is unclear. METHODS AND RESULTS: In this post hoc analysis of a prospective cohort, study serum levels of aldosterone and cortisol were measured at baseline in 842 patients with systolic HF. The mean age was 68 ± 12 years (27% female, 45% in New York Heart Association functional class III/IV, 43% with MRA; median follow-up 38 months [interquartile range 30-43 mo]). Crude mortality in the total cohort was 43% (patients with vs without MRA: 34% vs 41%; P = .052). In MRA-naïve patients, higher levels of both aldosterone and cortisol were predictive of increased mortality risk in multivariable Cox regression: hazard ratio (HR) with 95% confidence interval of highest vs lowest tertile for aldosterone: 1.51 [1.02-2.24] (P = .040); and for cortisol: 1.94 [1.28-2.93] (P = .002). In MRA-treated patients, aldosterone (highest vs lowest tertile: HR 1.65 [1.01-2.71]; P = .048) but not cortisol (HR 0.77 [0.44-1.27]; P = .33) was associated with all-cause mortality. Further subgroup analysis revealed that particularly patients with low cortisol and high aldosterone levels had the worst prognosis (HR 5.01 [2.22-11.3]; P < .001), compared with the reference of low cortisol and low aldosterone. Subjects with this profile had larger ventricles and more often coronary artery disease. CONCLUSIONS: In systolic HF, the prognostic value of aldosterone and cortisol levels differs in dependency of MRA intake. The pathophysiologic link between low cortisol, high aldosterone, and increased mortality risk in patients with MRA needs to be clarified.

Chronic obstructive pulmonary disease in heart failure: accurate diagnosis and treatment.

Coincidence of COPD and heart failure (HF) is challenging as both diseases interact on multiple levels with each other, and thus impact significantly on diagnosis, disease severity classification, and choice of medical therapy. The current overview aims to educate caregivers involved in the daily management of patients with HF and (possibly) concurrent COPD in how to deal with clinically relevant issues such as interpreting spirometry, the potential role of extensive pulmonary function testing, and finally, the potential beneficial, but also detrimental effects of medication used for HF and COPD on either disease.

Airway obstruction in systolic heart failure--COPD or congestion?

BACKGROUND: The diagnosis of chronic obstructive pulmonary disease (COPD) in patients with systolic heart failure (SHF) is challenging because symptoms of both conditions overlap. We aimed to estimate the prevalence, correlates and prognostic impact of true COPD in patients with SHF. METHODS: To diagnose COPD under stable conditions according to the guidelines, pulmonary function testing (PFT) was performed in 619 patients six months after hospitalization for congestive SHF. In 272 patients, PFT had been also performed prior to discharge. RESULTS: In the total cohort, COPD was reported in 23% (144/619). PFT under stable conditions revealed that COPD was absent in 73% (449/619), unconfirmed in 18% (112/619), and proven in 9% (58/619). In 272 patients with serial PFT, initial airway obstruction was found in 19% (51/272) but had resolved in 47% of those (24/51) after six months. Initial hyperinflation detected by bodyplethysmography strongly predicted proven COPD six months later: odds ratio for elevated intrathoracic gas volume 12.8, 95% confidence interval (CI) 2.5-65.9; p=0.002. After a median follow-up of 34 months, 27% of the total cohort (165/619) had died. Only proven COPD was associated with an increased mortality risk after adjustment for age, sex, NYHA functional class, ejection fraction, atrial fibrillation, smoking, renal dysfunction and diabetes: hazard ratio 1.64, 95%CI 1.03-2.63; p=0.039. CONCLUSIONS: Airway obstruction is a dynamic phenomenon in SHF. Therefore, a valid diagnosis of COPD in SHF demands serial PFT under stable conditions with special attention to hyperinflation. COPD proven by PFT is associated with an increased all-cause mortality risk.

The impact of heart failure on the classification of COPD severity.

BACKGROUND: Pulmonary restriction-a reduction of lung volumes-is common in heart failure (HF), rendering severity grading of chronic obstructive pulmonary disease (COPD) potentially problematic in subjects with both diseases. We compared pulmonary function in patients with either HF or COPD, or the combination to assess whether grading of COPD using the Global Initiative of Chronic Obstructive Lung Disease classification is hampered in the presence of HF. METHODS AND RESULTS: In 2 cohorts involving 591 patients with established HF and 405 with a primary care diagnosis of COPD, the presence of HF and COPD was assessed according to guidelines. HF severity was staged according to the NYHA classification system into Classes I-IV. COPD was diagnosed if the ratio of post-bronchodilator forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC) was <0.70, and categorized in GOLD stages I-IV according to post-bronchodilator-predicted FEV1 levels (FEV1% ≥80%; 50-79%; 30-49%; <30%). In total, 557 patients with HF only, 108 with HF+COPD, and 194 with COPD only were studied. Patients, who had neither HF nor COPD according to definition, or HF with reversible obstruction in post-bronchodilator pulmonary function tests were excluded from this analysis (n = 137). Compared with COPD only, patients with HF plus COPD had higher levels of post-bronchodilator FEV1/FVC (median [quartiles] 0.57 [0.47-0.64] vs 0.62 [0.55-0.66] and lower total lung capacity % (115 [104-126]% vs 105 [95-117]%, P < .001) P < .001), but comparable levels of post-bronchodilator FEV1% (70 [56-84]% vs 68 [54-80]%, P = .22) and thus similar distributions of GOLD stages I-IV in both groups (24/56/19/4% vs 31/50/19/1%, P = .57). In patients with HF only, 25% exhibited pre-bronchodilator FEV1% levels of <80% (FEV1% 94 [80-108]%), despite a pre-bronchodilator FEV/FVC ratio ≥0.7 in this group. The reduction of FEV1 in patients with HF only was associated with HF severity. CONCLUSIONS: In stable HF, FEV1 may be significantly reduced even in the absence of "real" airflow obstruction. In this situation, diagnosing COPD according to GOLD criteria (based on FEV1/FVC) still seems feasible, because both FEV1 and FVC are usually decreased to an equal extent in HF. However, classifying COPD based on FEV1 levels may overrate obstruction severity in patients with combined disease (HF plus COPD), and thus may lead to unjustified use of bronchodilators.

Dysnatraemia in heart failure.

AIMS: To investigate in detail the correlates of dysnatremia, and to estimate its differential prognostic relevance in patients with heart failure with reduced or preserved LVEF. Background Hyponatraemia has been shown to carry important prognostic information in patients with heart failure with reduced left ventricular ejection fraction (LVEF). However, exact serum sodium cut-off levels are not defined and the implications for heart failure with preserved ejection fraction (HF-pEF) are unclear. The prognostic value of hypernatraemia has not been investigated systematically. Therefore, the aim of this study was to investigate in detail the correlates of dysnatraemia, and to estimate its differential prognostic relevance in patients with heart failure with reduced or preserved LVEF. METHODS AND RESULTS: One thousand consecutive patients with heart failure of any cause and severity from the Würzburg Interdisciplinary Network for Heart Failure registry were included. Non-linear models for the association between serum sodium and mortality risk were calculated using restricted cubic splines and Cox proportional hazard regression. Median follow-up time for survivors was 5.1 years. Results Independent correlates of dysnatraemia included guideline-recommended medication for chronic heart failure, indicators of renal function, and reverse associations with established cardiac risk factors. Overall mortality was 56%. Both hyponatraemia (n = 72) and hypernatraemia (n = 98) were associated with a significantly increased mortality risk: hazard ratio (HR) 2.10, 95% confidence interval (CI) 1.60-2.77; and HR 1.91, 95% CI 1.49-2.45, respectively. A U-shaped association of serum sodium with mortality risk was found. Prognosis was best for patients with high normal sodium levels, i.e. 140-145 mmol/L. CONCLUSIONS: Both hypo- and hypernatraemia indicate a markedly compromised prognosis in heart failure regardless of LVEF. Sodium levels within the reference range carry differential information on survival, with serum levels of 135-139 mmol/L indicating an increased mortality risk.

"GOLD or lower limit of normal definition? A comparison with expert-based diagnosis of chronic obstructive pulmonary disease in a prospective cohort-study".

BACKGROUND: The Global initiative for chronic Obstructive Lung Disease (GOLD) defines COPD as a fixed post-bronchodilator ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC) below 0.7. Age-dependent cut-off values below the lower fifth percentile (LLN) of this ratio derived from the general population have been proposed as an alternative. We wanted to assess the diagnostic accuracy and prognostic capability of the GOLD and LLN definition when compared to an expert-based diagnosis. METHODS: In a prospective cohort study, 405 patients aged ≥ 65 years with a general practitioner's diagnosis of COPD were recruited and followed up for 4.5 (median; quartiles 3.9; 5.1) years. Prevalence rates of COPD according to GOLD and three LLN definitions and diagnostic performance measurements were calculated. The reference standard was the diagnosis of COPD of an expert panel that used all available diagnostic information, including spirometry and bodyplethysmography. RESULTS: Compared to the expert panel diagnosis, 'GOLD-COPD' misclassified 69 (28%) patients, and the three LLNs misclassified 114 (46%), 96 (39%), and 98 (40%) patients, respectively. The GOLD classification led to more false positives, the LLNs to more false negative diagnoses. The main predictors beyond the FEV1/FVC ratio for an expert diagnosis of COPD were the FEV1 % predicted, and the residual volume/total lung capacity ratio (RV/TLC). Adding FEV1 and RV/TLC to GOLD or LLN improved the diagnostic accuracy, resulting in a significant reduction of up to 50% of the number of misdiagnoses. The expert diagnosis of COPD better predicts exacerbations, hospitalizations and mortality than GOLD or LLN. CONCLUSIONS: GOLD criteria over-diagnose COPD, while LLN definitions under-diagnose COPD in elderly patients as compared to an expert panel diagnosis. Incorporating FEV1 and RV/TLC into the GOLD-COPD or LLN-based definition brings both definitions closer to expert panel diagnosis of COPD, and to daily clinical practice.