Götz Gelbrich

Mode of Action and Effects of Standardized Collaborative Disease Management on Mortality and Morbidity in Patients With Systolic Heart Failure The Interdisciplinary Network for Heart Failure (INH) Study

Background— Trials investigating efficacy of disease management programs (DMP) in heart failure reported contradictory results. Features rendering specific interventions successful are often ill defined. We evaluated the mode of action and effects of a nurse-coordinated DMP (HeartNetCare-HF, HNC). Methods and Results— Patients hospitalized for systolic heart failure were randomly assigned to HNC or usual care (UC). Besides telephone-based monitoring and education, HNC addressed individual problems raised by patients, pursued networking of health care providers and provided training for caregivers. End points were time to death or rehospitalization (combined primary), heart failure symptoms, and quality of life (SF-36). Of 1007 consecutive patients, 715 were randomly assigned (HNC: n=352; UC: n=363; age, 69±12 years; 29% female; 40% New York Heart Association class III-IV). Within 180 days, 130 HNC and 137 UC patients reached the primary end point (hazard ratio, 1.02; 95% confidence interval, 0.81–1.30; P=0.89), since more HNC patients were readmitted. Overall, 32 HNC and 52 UC patients died (1 UC patient and 4 HNC patients after dropout); thus, uncensored hazard ratio was 0.62 (0.40–0.96; P=0.03). HNC patients improved more regarding New York Heart Association class (P=0.05), physical functioning (P=0.03), and physical health component (P=0.03). Except for HNC, health care utilization was comparable between groups. However, HNC patients requested counseling for noncardiac problems even more frequently than for cardiovascular or heart-failure–related issues. Conclusions— The primary end point of this study was neutral. However, mortality risk and surrogates of well-being improved significantly. Quantitative assessment of patient requirements suggested that besides (tele)monitoring individualized care considering also noncardiac problems should be integrated in efforts to achieve more sustainable improvement in heart failure outcomes. Clinical Trial Registration— URL: http://www.controlled-trials.com. Unique identifier: ISRCTN23325295.

Prevention of postoperative nausea and vomiting by metoclopramide combined with dexamethasone: randomised double blind multicentre trial

Abstract Objectives To determine whether 10 mg, 25 mg, or 50 mg metoclopramide combined with 8 mg dexamethasone, given intraoperatively, is more effective in preventing postoperative nausea and vomiting than 8 mg dexamethasone alone, and to assess benefit in relation to adverse drug reactions. Design Four-armed, parallel group, double blind, randomised controlled clinical trial. Setting Four clinics of a university hospital and four district hospitals in Germany. Participants 3140 patients who received balanced or regional anaesthesia during surgery. Main outcome measures Postoperative nausea and vomiting within 24 hours of surgery (primary end point); occurrence of adverse reactions. Results Cumulative incidences (95% confidence intervals) of postoperative nausea and vomiting were 23.1% (20.2% to 26.0%), 20.6% (17.8% to 23.4%), 17.2% (14.6% to 19.8%), and 14.5% (12.0% to 17.0%) for 0 mg, 10 mg, 25 mg, and 50 mg metoclopramide. In the secondary analysis, 25 mg and 50 mg metoclopramide were equally effective at preventing early nausea (0-12 hours), but only 50 mg reduced late nausea and vomiting (> 12 hours). The most frequent adverse drug reactions were hypotension and tachycardia, with cumulative incidences of 8.8% (6.8% to 10.8%), 11.2% (9.0% to 13.4%), 12.9% (10.5% to 15.3%), and 17.9% (15.2% to 20.6%) for 0 mg, 10 mg, 25 mg, and 50 mg metoclopramide. Conclusion The addition of 50 mg metoclopramide to 8 mg dexamethasone (given intraoperatively) is an effective, safe, and cheap way to prevent postoperative nausea and vomiting. A reduced dose of 25 mg metoclopramide intraoperatively, with additional postoperative prophylaxis in high risk patients, may be equally effective and cause fewer adverse drug reactions. Trial registration Current Controlled Trials ISRCTN31625370

Effect of Increased Exercise in School Children on Physical Fitness and Endothelial Progenitor Cells A Prospective Randomized Trial

Background— The aim of this prospective, randomized study was to examine whether additional school exercise lessons would result in improved peak oxygen uptake (primary end point) and body mass index–standard deviation score, motor and coordinative abilities, circulating progenitor cells, and high-density lipoprotein cholesterol (major secondary end points). Methods and Results— Seven sixth-grade classes (182 children, aged 11.1±0.7 years) were randomized to an intervention group (4 classes with 109 students) with daily school exercise lessons for 1 year and a control group (3 classes with 73 students) with regular school sports twice weekly. The significant effects of intervention estimated from ANCOVA adjusted for intraclass correlation were the following: increase of peak &OV0312;o2 (3.7 mL/kg per minute; 95% confidence interval, 0.3 to 7.2) and increase of circulating progenitor cells evaluated by flow cytometry (97 cells per 1×106 leukocytes; 95% confidence interval, 13 to 181). No significant difference was seen for body mass index–standard deviation score (−0.08; 95% confidence interval, −0.28 to 0.13); however, there was a trend to reduction of the prevalence of overweight and obese children in the intervention group (from 12.8% to 7.3%). No treatment effect was seen for motor and coordinative abilities (4; 95% confidence interval, −1 to 8) and high-density lipoprotein cholesterol (0.03 mmol/L; 95% confidence interval, −0.08 to 0.14). Conclusions— Regular physical activity by means of daily school exercise lessons has a significant positive effect on physical fitness (&OV0312;o2max). Furthermore, the number of circulating progenitor cells can be increased, and there is a positive trend in body mass index–standard deviation score reduction and motor ability improvement. Therefore, we conclude that primary prevention by means of increasing physical activity should start in childhood. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Identifier: NCT00176371.

Rationale and design of a randomised, controlled, multicenter trial investigating the effects of selective serotonin re‐uptake inhibition on morbidity, mortality and mood in depressed heart failure patients (MOOD‐HF)

Depression and chronic heart failure (CHF) are common conditions, both of which are clinically and economically highly relevant. Major depression affects 20–40% of CHF patients and predicts adverse outcomes in terms of quality of life, morbidity and mortality as well as health care expenditure, independent of other factors of prognostic relevance.

The novel biomarker growth differentiation factor 15 in heart failure with normal ejection fraction

Heart failure with normal ejection fraction (HFnEF) is an important clinical entity that remains incompletely understood. The novel biomarker growth differentiation factor 15 (GDF‐15) is elevated in systolic heart failure (HFrEF) and is predictive of an adverse outcome. We investigated the clinical relevance of GDF‐15 plasma levels in HFnEF.

Galectin‐3 in patients with heart failure with preserved ejection fraction: results from the Aldo‐DHF trial

Galectin‐3 is a marker of myocardial fibrosis and mediates aldosterone‐induced cardiovascular inflammation and fibrosis. Characteristics of galectin‐3 and its response to spironolactone have not been evaluated in heart failure with preserved ejection fraction (HFpEF). The aim of this study was to determine the association between galectin‐3 levels and patient characteristics in HFpEF; to evaluate the interaction between spironolactone and galectin‐3 levels; and to assess the association between galectin‐3 and clinical outcomes.

Serum aldosterone and its relationship to left ventricular structure and geometry in patients with preserved left ventricular ejection fraction

AIMS Cardiac remodelling might be an important mechanism for aldosterone-mediated cardiovascular (CV) morbidity and mortality. Previous studies relating aldosterone to left ventricular (LV) structure however revealed conflicting results. METHODS AND RESULTS We aimed to evaluate the relationship of serum aldosterone concentration (SAC) and aldosterone-to-renin ratio (ARR) with echocardiographic parameters of LV remodelling in CV risk patients with preserved left ventricular ejection fraction (LVEF). We studied 1575 participants (54.1% female) with CV risk factors and LVEF >50% (61.7 ± 6.1%). Of the total, 94.7% of patients had no overt heart failure. All patients underwent measurement of SAC, ARR, and comprehensive echocardiographic analysis. Overall, multivariate adjusted analysis of covariance (ANCOVA) showed a significant increase in LV mass (P= 0.001), LV mass index (P= 0.001), relative wall thickness (P= 0.011), and LV posterior wall thickness (P< 0.001) with increasing SAC. This overall association of SAC and LV remodelling was driven by a statistic significant effect exclusively in women. In multivariate logistic regression analysis higher SAC levels were independently related to concentric LV hypertrophy [odds ratio (OR; with 95% CI) by comparing SAC levels in the third gender-specific tertile with the first tertile: 1.87; 95% CI: 1.31-2.68; P= 0.001]. Higher SAC levels were positively related to concentric LVH in either sex. We observed no significant associations between the ARR and echocardiographic parameters of LV remodelling. CONCLUSION Circulating aldosterone but not ARR levels are independently related to echocardiographic parameters of LV structure, particularly in women. Higher SAC however was related to concentric LVH in either sex. Our findings in a large CV risk cohort with preserved LVEF indicate aldosterone-mediated pro-hypertrophic effects as a potential pathway for structural alterations of the left ventricular myocardium.

Rationale and design of the 'aldosterone receptor blockade in diastolic heart failure' trial: a double-blind, randomized, placebo-controlled, parallel group study to determine the effects of spironolactone on exercise capacity and diastolic function in patients with symptomatic diastolic heart failure (Aldo-DHF).

Increasing evidence suggests that enhanced aldosterone signalling plays a key role in the onset and progression of diastolic heart failure (DHF). Aldo‐DHF will test the hypothesis that aldosterone receptor blockade by spironolactone will improve exercise capacity and diastolic function in patients with DHF.

Effect of Escitalopram on All-Cause Mortality and Hospitalization in Patients With Heart Failure and Depression: The MOOD-HF Randomized Clinical Trial.

IMPORTANCE Depression is frequent in patients with heart failure and is associated with adverse clinical outcomes. Long-term efficacy and safety of selective serotonin reuptake inhibitors in these patients are unknown. OBJECTIVE To determine whether 24 months of treatment with escitalopram improves mortality, morbidity, and mood in patients with chronic systolic heart failure and depression. DESIGN, SETTING, AND PARTICIPANTS The Effects of Selective Serotonin Re-Uptake Inhibition on Morbidity, Mortality, and Mood in Depressed Heart Failure Patients (MOOD-HF) study was a double-blind, placebo-controlled randomized clinical trial conducted at 16 tertiary medical centers in Germany. Between March 2009 and February 2014, patients at outpatient clinics with New York Heart Association class II-IV heart failure and reduced left ventricular ejection fraction (<45%) were screened for depression using the 9-item Patient Health Questionnaire. Patients with suspected depression were then invited to undergo a Structured Clinical Interview based on the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) to establish the diagnosis. INTERVENTIONS Patients were randomized 1:1 to receive escitalopram (10-20 mg) or matching placebo in addition to optimal heart failure therapy. Study duration was 24 months. MAIN OUTCOMES AND MEASURES The composite primary outcome was time to all-cause death or hospitalization. Prespecified secondary outcomes included safety and depression severity at 12 weeks of treatment (including the titration period), which were determined using the 10-item Montgomery-Åsberg Depression Rating Scale (total possible score, 0 to 60; higher scores indicate more severe depression). RESULTS A total of 372 patients (mean age, 62 years; 24% female) were randomized and had taken at least 1 dose of study medication when the data and safety monitoring committee recommended the trial be stopped early. During a median participation time of 18.4 months (n = 185) for the escitalopram group and 18.7 months (n = 187) for the placebo group, the primary outcome of death or hospitalization occurred in 116 (63%) patients and 119 (64%) patients, respectively (hazard ratio, 0.99 [95% CI, 0.76 to 1.27]; P = .92). The mean Montgomery-Åsberg Depression Rating Scale sum score changed from 20.2 at baseline to 11.2 at 12 weeks in the escitalopram group and from 21.4 to 12.5 in the placebo group (between-group difference, -0.9 [95% CI,-2.6 to 0.7]; P = .26). Safety parameters were comparable between groups. CONCLUSIONS AND RELEVANCE In patients with chronic heart failure with reduced ejection fraction and depression, 18 months of treatment with escitalopram compared with placebo did not significantly reduce all-cause mortality or hospitalization, and there was no significant improvement in depression. These findings do not support the use of escitalopram in patients with chronic systolic heart failure and depression. TRIAL REGISTRATION isrctn.com Identifier: ISRCTN33128015.

Are HIV patients undertreated? Cardiovascular risk factors in HIV: results of the HIV-HEART study.

Background: Antiretroviral therapy improved the survival of patients with human immunodeficiency virus (HIV) infection. With increased life expectancy, HIV-infected patients increasingly are experiencing comorbidities, most notably cardiovascular risk factors (CRFs) and coronary heart disease (CHD). Design: This study utilized a prospective, cross-sectional multicentre long-term design. Methods: In 803 patients (82% male; mean age 44.2 ± 10.3 years) we evaluated the prevalence of CRFs and 10-year risk of CHD using the Framingham risk model. The presence of a risk factor was determined based on the guidelines of the National Cholesterol Education Program (NCEP ATP III), the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7), and the German Society of Cardiology. Results: The most common CRFs were smoking (51.2%), high triglycerides (39.0%), low high-density lipoprotein cholesterol (27.5 %) and high blood pressure (21.4%). In total, 60.3%, 21.6%, and 18.1% of patients were categorized as being at low (<10%), moderate (10–20%), and high (>20%) 10-year risk for CHD, respectively. In patients with hypertension, at least one antihypertensive drug was given in 91/163 (55.8%) patients. The percentage of patients on treatment with diabetes mellitus was 23/41 (56.1%). Anti-platelet therapy was prescribed to 42/102 (41.2%) patients with known CHD or CHD equivalent. In patients of moderate or high CHD risk there were more than 50% and 30% for LDL cholesterol and more than 60% and 40% for total cholesterol untreated. Conclusions: The prevalence of CRFs remains high in an HIV-infected population. CRF management of HIV-infected patients deserves further improvement.