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1.  The past, present and future of renin–angiotensin aldosterone system inhibition☆ 
International journal of cardiology  2012;167(5):1677-1687.
The renin–angiotensin aldosterone system (RAAS) is central to the pathogenesis of cardiovascular disease. RAAS inhibition can reduce blood pressure, prevent target organ damage in hypertension and diabetes, and improve outcomes in patients with heart failure and/or myocardial infarction. This review presents the history of RAAS inhibition including a summary of key heart failure, myocardial infarction, hypertension and atrial fibrillation trials. Recent developments in RAAS inhibition are discussed including implementation and optimization of current drug therapies. Finally, ongoing clinical trials, opportunities for future trials and issues related to the barriers and approvability of novel RAAS inhibitors are highlighted.
doi:10.1016/j.ijcard.2012.10.007
PMCID: PMC4145865  PMID: 23121914
Renin–angiotensin aldosterone system; Hypertension; Heart failure; Myocardial infarction; Clinical trials
3.  Baseline characteristics and treatment of patients in Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) 
European Journal of Heart Failure  2014;16(7):817-825.
Aim
To describe the baseline characteristics and treatment of the patients randomized in the PARADIGM-HF (Prospective comparison of ARNi with ACEi to Determine Impact on Global Mortality and morbidity in Heart Failure) trial, testing the hypothesis that the strategy of simultaneously blocking the renin–angiotensin–aldosterone system and augmenting natriuretic peptides with LCZ696 200 mg b.i.d. is superior to enalapril 10 mg b.i.d. in reducing mortality and morbidity in patients with heart failure and reduced ejection fraction.
Methods
Key demographic, clinical and laboratory findings, along with baseline treatment, are reported and compared with those of patients in the treatment arm of the Studies Of Left Ventricular Dysfunction (SOLVD-T) and more contemporary drug and device trials in heart failure and reduced ejection fraction.
Results
The mean age of the 8442 patients in PARADIGM-HF is 64 (SD 11) years and 78% are male, which is similar to SOLVD-T and more recent trials. Despite extensive background therapy with beta-blockers (93% patients) and mineralocorticoid receptor antagonists (60%), patients in PARADIGM-HF have persisting symptoms and signs, reduced health related quality of life, a low LVEF (mean 29 ± SD 6%) and elevated N-terminal-proB type-natriuretic peptide levels (median 1608 inter-quartile range 886–3221 pg/mL).
Conclusion
PARADIGM-HF will determine whether LCZ696 is more beneficial than enalapril when added to other disease-modifying therapies and if further augmentation of endogenous natriuretic peptides will reduce morbidity and mortality in heart failure and reduced ejection fraction.
doi:10.1002/ejhf.115
PMCID: PMC4312884  PMID: 24828035
Heart failure; Natriuretic peptides; Neutral endopeptidase; Renin–angiotensin system
4.  Risk stratification for sudden cardiac death: current status and challenges for the future† 
European Heart Journal  2014;35(25):1642-1651.
Sudden cardiac death (SCD) remains a daunting problem. It is a major public health issue for several reasons: from its prevalence (20% of total mortality in the industrialized world) to the devastating psycho-social impact on society and on the families of victims often still in their prime, and it represents a challenge for medicine, and especially for cardiology. This text summarizes the discussions and opinions of a group of investigators with a long-standing interest in this field. We addressed the occurrence of SCD in individuals apparently healthy, in patients with heart disease and mild or severe cardiac dysfunction, and in those with genetically based arrhythmic diseases. Recognizing the need for more accurate registries of the global and regional distribution of SCD in these different categories, we focused on the assessment of risk for SCD in these four groups, looking at the significance of alterations in cardiac function, of signs of electrical instability identified by ECG abnormalities or by autonomic tests, and of the progressive impact of genetic screening. Special attention was given to the identification of areas of research more or less likely to provide useful information, and thereby more or less suitable for the investment of time and of research funds.
doi:10.1093/eurheartj/ehu176
PMCID: PMC4076664  PMID: 24801071
Sudden cardiac death; Risk stratification; Electrical instability; Autonomic nervous system; Cardiac function ; Genetics
5.  Association between diabetes mellitus and post-discharge outcomes in patients hospitalized with heart failure: findings from the EVEREST trial 
European Journal of Heart Failure  2012;15(2):194-202.
Aims
We evaluated the impact of diabetes mellitus (DM) and diabetic therapy on outcomes in patients with reduced ejection fraction (EF) after hospitalization for heart failure (HF). DM is prevalent in patients hospitalized with HF, yet inconclusive data exist on the post-discharge outcomes of this patient population.
Methods and results
Post-hoc analysis was performed on the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) study, a randomized trial of patients hospitalized with HF (n = 4133) with median follow-up of 9.9 months. DM status was determined from intake questionnaires and cross-verified by medication history. Univariate relationships were examined using χ2 test, t-test, and Wilcoxon tests. The two primary outcomes of (i) all-cause mortality (ACM) and (ii) cardiovascular mortality or HF hospitalization (CVM + HFH) were assessed for those with and without DM and by diabetic treatment strategy using log rank tests and multivariable Cox regression models. DM was present in 40% of participants. Patients with DM were more likely to have hypertension, coronary artery disease, and chronic kidney disease. Diabetes was associated with ACM and CVM + HFH (both P < 0.001). Following multivariate risk adjustment, DM was associated with ACM, but this estimate was imprecise [hazard ratio (HR) 1.16; 95% confidence interval (CI) 1.00–1.34] and remained associated with CVM or HFH (HR 1.17; 95% CI 1.04–1.31). Diabetic control strategy did not independently affect outcomes.
Conclusion
Diabetes is common in patients hospitalized for heart failure with a reduced EF. These patients have a higher post-discharge CVM and higher HF hospitalizations compared with patients with no diabetes. Different diabetic treatment regimens did not appear to influence post-discharge outcomes.
doi:10.1093/eurjhf/hfs153
PMCID: PMC4176083  PMID: 23059198
Heart failure; Diabetes mellitus; Outcomes; Insulin
6.  Influence of documented history of coronary artery disease on outcomes in patients admitted for worsening heart failure with reduced ejection fraction in the EVEREST trial 
Aims
Data on the prognosis of heart failure (HF) patients with coronary artery disease (CAD) have been conflicting. We describe the clinical characteristics and mode-specific outcomes of HF patients with reduced ejection fraction (EF) and documented CAD in a large randomized trial.
Methods and results
EVEREST was a prospective, randomized trial of vasopressin-2 receptor blockade, in addition to standard therapy, in 4133 patients hospitalized with worsening HF and reduced EF. Patients were classified as having CAD based on patient-reported myocardial infarction (MI) or coronary revascularization. We analysed the characteristics and outcomes [all-cause mortality and cardiovascular (CV) mortality/HF hospitalization] of patients with and without documented CAD. All events were centrally adjudicated. Documented CAD was present in 2353 patients (57%). Patients with CAD were older and had more co-morbidities compared with those without CAD. Patients with CAD were more likely to receive a beta-blocker, but less likely to receive an angiotensin-converting enzyme (ACE) inhibitor or aldosterone antagonist (P < 0.01). After risk adjustment, patients with documented CAD had similar mortality [hazard ratio (HR) 1.12, 95% confidence interval (CI) 0.97–1.30], but were at an increased risk for CV mortality/HF hospitalization (HR 1.25, 95% CI 1.12–1.41) due to an increased risk for HF hospitalization (HR 1.26, 95% CI 1.10–1.44). Patients with CAD had increased HF- and MI-related events, but similar rates of sudden cardiac death.
Conclusion
Documented CAD in patients hospitalized for worsening HF with reduced EF was associated with a higher burden of co-morbidities, lower use of HF therapies (except beta-blockers), and increased HF hospitalization, while all-cause mortality was similar.
doi:10.1093/eurjhf/hfs139
PMCID: PMC4176134  PMID: 22968743
Heart failure; Coronary artery disease; Outcomes; Hospitalization
7.  Association of Arginine Vasopressin Levels with Outcomes and the Effect of V2 Blockade in Patients Hospitalized for Heart Failure with Reduced Ejection Fraction: Insights from the EVEREST Trial 
Circulation. Heart failure  2012;6(1):47-52.
Background
Arginine vasopressin (AVP) levels are elevated in proportion to heart failure (HF) severity and are associated with higher cardiovascular mortality in ambulatory patients. However, the relationship between baseline and trends in AVP with outcomes in patients hospitalized for worsening HF with reduced ejection fraction (EF) is unclear.
Methods and Results
The EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) trial investigated the effects of tolvaptan in patients with worsening HF and EF≤40%. The present analysis examined baseline and follow-up AVP levels in 3,196 EVEREST patients with valid AVP measurements. Co-primary endpoints included all-cause mortality (ACM), and the composite of cardiovascular mortality or HF hospitalization (CVM/H). Median follow-up was 9.9 months. Times to events were compared with univariate log-rank tests and multivariable Cox regression models, adjusted for baseline risk factors. After adjusting for baseline covariates, elevated AVP levels were associated with increased ACM (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.13 –1.55) and CVM/H (HR 1.23, 95% CI 1.08 –1.39). There was no interaction of baseline AVP with treatment assignment in terms of survival (p=0.515). Tolvaptan therapy increased the proportion of patients with elevated AVP (p<0.001), but this had no effect on mortality (HR 0.95, 95% CI 0.72 – 1.24).
Conclusions
Elevated baseline AVP level was independently predictive of mortality, but did not identify a group of patients who had improved outcomes with tolvaptan treatment. Tolvaptan treatment increased AVP levels during follow-up, but this incremental increase was not associated with worsened outcomes.
doi:10.1161/CIRCHEARTFAILURE.112.970012
PMCID: PMC3790140  PMID: 23239836
heart failure; drugs; hormones; outcomes
8.  Heart failure in young adults: 20-year trends in hospitalization, aetiology, and case fatality in Sweden 
European Heart Journal  2013;35(1):25-32.
Aims
To describe trends in incidence and case fatality among younger (18–54 years) and older (55–84 years) Swedish patients with heart failure (HF).
Methods and results
Through linking the Swedish national hospital discharge and the cause-specific death registries, we identified patients aged 18–84 years that were discharged 1987–2006 with a diagnosis of HF. Age-specific mean incidence rates per 100 000 person-years were calculated in four 5-year periods. Kaplan–Meier survival curves were plotted up to 3 years. From 1987 to 2006, there were 443 995 HF hospitalizations among adults 18–84 years. Of these, 4660 (1.0%) and 13 507 (3.0%) occurred in people aged 18–44 and 45–54 years (31.6% women), respectively. From the first to the last 5-year period, HF incidence increased by 50 and 43%, among people aged 18–34 and 35–44 years, respectively. Among people ≥45 years, incidence peaked in the mid-1990s and then decreased. Heart failure in the presence of cardiomyopathy increased more than two-fold among all age groups. Case fatality decreased for all age groups until 2001, after which no further significant decrease <55 years was observed.
Conclusion
Increasing HF hospitalization in young adults in Sweden opposes the general trend seen in older patients, a finding which may reflect true epidemiological changes. Cardiomyopathy accounted for a substantial part of this increase. High case fatality and lack of further case fatality reduction after 2001 are causes for concern.
doi:10.1093/eurheartj/eht278
PMCID: PMC3877433  PMID: 23900697
Heart failure; Incidence; Prognosis; Comorbidity; Young adults
9.  Effects of person-centred care in patients with chronic heart failure: the PCC-HF study 
European Heart Journal  2011;33(9):1112-1119.
Aims
Person-centred care (PCC) emphasizes a partnership in care between patients and healthcare professionals and is advocated by WHO as a key component of quality health care. We evaluated outcomes of PCC in hospitalized patients with chronic heart failure (CHF) with respect to the length of hospital stay (LOS), activities of daily living (ADL), health-related quality of life (HRQL) and 6-month readmission rate.
Methods and results
During 2008–2010, 248 consecutive patients hospitalized for symptoms of worsening CHF were enrolled in a controlled before and after designed study. A Usual care group (n= 123) was recruited according to pre-defined criteria to map usual CHF care and assess outcomes at five designated hospital wards. Based on the mapping, a panel of in-house clinicians and researchers developed measures aimed at aligning usual care with basic PCC principles. These measures were incorporated into a study protocol to guide care procedures at the same five wards. Person-centred care was then implemented at these wards and evaluated in 125 patients. Both length of hospital stay and 6-month readmission were extracted from patient records. Activities of daily living were evaluated at baseline and discharge and HRQL was evaluated at baseline and after 3 months. In the analysis of all patients, the LOS was reduced by 1 day (P= 0.16) while retaining ADL (P= 0.07). When PCC was fully implemented (per protocol analysis), LOS was reduced by 2.5 days (P= 0.01) and the ADL-level better preserved (P= 0.04). Health-related quality of life and time-to-first readmission did not differ.
Conclusion
In this proof-of-concept study, our findings suggest that a fully implemented PCC approach shortens hospital stay and maintains functional performance in patients hospitalized for worsening CHF, without increasing risk for readmission or jeopardizing patients' HRQL.
doi:10.1093/eurheartj/ehr306
PMCID: PMC3751966  PMID: 21926072
Patient-centred care; Chronic heart failure; Disease management programmes; Person-centered medicine; Person-centered care
10.  Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) 
European Journal of Heart Failure  2013;15(9):1062-1073.
Aims
Although the focus of therapeutic intervention has been on neurohormonal pathways thought to be harmful in heart failure (HF), such as the renin–angiotensin–aldosterone system (RAAS), potentially beneficial counter-regulatory systems are also active in HF. These promote vasodilatation and natriuresis, inhibit abnormal growth, suppress the RAAS and sympathetic nervous system, and augment parasympathetic activity. The best understood of these mediators are the natriuretic peptides which are metabolized by the enzyme neprilysin. LCZ696 belongs to a new class of drugs, the angiotensin receptor neprilysin inhibitors (ARNIs), which both block the RAAS and augment natriuretic peptides.
Methods
Patients with chronic HF, NYHA class II–IV symptoms, an elevated plasma BNP or NT-proBNP level, and an LVEF of ≤40% were enrolled in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortailty and morbidity in Heart Failure trial (PARADIGM-HF). Patients entered a single-blind enalapril run-in period (titrated to 10 mg b.i.d.), followed by an LCZ696 run-in period (100 mg titrated to 200 mg b.i.d.). A total of 8436 patients tolerating both periods were randomized 1:1 to either enalapril 10 mg b.i.d. or LCZ696 200 mg b.i.d. The primary outcome is the composite of cardiovascular death or HF hospitalization, although the trial is powered to detect a 15% relative risk reduction in cardiovascular death.
Perspectives
PARADIGM-HF will determine the place of the ARNI LCZ696 as an alternative to enalapril in patients with systolic HF. PARADIGM-HF may change our approach to neurohormonal modulation in HF.
Trial registration
NCT01035255
doi:10.1093/eurjhf/hft052
PMCID: PMC3746839  PMID: 23563576
Chronic heart failure; Renin–angiotensin; ACE inhibitor; Angiotensin receptor blocker; Natriuretic peptides; Neprilysin; Neutral endopeptidase; Angiotensin receptor neprilysin inhibitor; LCZ696
11.  Baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) 
McMurray, John J.V. | Anand, Inder S. | Diaz, Rafael | Maggioni, Aldo P. | O'Connor, Christopher | Pfeffer, Marc A. | Solomon, Scott D. | Tendera, Michal | van Veldhuisen, Dirk J. | Albizem, Moetaz | Cheng, Sunfa | Scarlata, Debra | Swedberg, Karl | Young, James B. | Amuchastegui, M. | Belziti, C. | Bluguermann, J. | Caccavo, M. | Cartasegna, L. | Colque, R. | Cuneo, C. | Fernandez, A. | Gabito, A. | Goicochea, R. | Gonzalez, M. | Gorosito, V. | Grinfeld, L. | Hominal, M. | Kevorkian, R. | Litvak Bruno, M. | Llanos, J. | Mackinnon, I. | Manuale, O. | Marzetti, E. | Nul, D. | Perna, E. | Riccitelli, M. | Sanchez, A. | Santos, D. | Schygiel, P. | Toblli, J. | Vogel, D. | Aggarwal, A. | Amerena, J. | De Looze, F. | Fletcher, P. | Hare, D. | Ireland, M. | Krum, H. | Lattimore, J. | Marwick, T. | Sindone, A. | Thompson, P. | Waites, J. | Altenberger, J. | Ebner, C. | Lenz, K. | Pacher, R. | Poelzl, G. | Charlier, F. | de Ceuninck, M. | De Keulenaer, G. | Dendale, P. | Maréchal, 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European Journal of Heart Failure  2013;15(3):334-341.
Aims
This report describes the baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) which is testing the hypothesis that anaemia correction with darbepoetin alfa will reduce the composite endpoint of death from any cause or hospital admission for worsening heart failure, and improve other outcomes.
Methods and results
Key demographic, clinical, and laboratory findings, along with baseline treatment, are reported and compared with those of patients in other recent clinical trials in heart failure. Compared with other recent trials, RED-HF enrolled more elderly [mean age 70 (SD 11.4) years], female (41%), and black (9%) patients. RED-HF patients more often had diabetes (46%) and renal impairment (72% had an estimated glomerular filtration rate <60 mL/min/1.73 m2). Patients in RED-HF had heart failure of longer duration [5.3 (5.4) years], worse NYHA class (35% II, 63% III, and 2% IV), and more signs of congestion. Mean EF was 30% (6.8%). RED-HF patients were well treated at randomization, and pharmacological therapy at baseline was broadly similar to that of other recent trials, taking account of study-specific inclusion/exclusion criteria. Median (interquartile range) haemoglobin at baseline was 112 (106–117) g/L.
Conclusion
The anaemic patients enrolled in RED-HF were older, moderately to markedly symptomatic, and had extensive co-morbidity.
doi:10.1093/eurjhf/hfs204
PMCID: PMC3576902  PMID: 23329651
Heart failure; Anaemia
12.  Effect of ivabradine on recurrent hospitalization for worsening heart failure in patients with chronic systolic heart failure: the SHIFT Study 
European Heart Journal  2012;33(22):2813-2820.
Aims
We explored the effect of treatment with ivabradine, a pure heart rate-slowing agent, on recurrent hospitalizations for worsening heart failure (HF) in the SHIFT trial.
Methods and results
SHIFT was a double-blind clinical trial in which 6505 patients with moderate-to-severe HF and left ventricular systolic dysfunction, all of whom had been hospitalized for HF during the preceding year, were randomized to ivabradine or to placebo on a background of guideline-recommended HF therapy (including maximized β-blockade). In total, 1186 patients experienced at least one additional HF hospitalization during the study, 472 suffered at least two, and 218 suffered at least 3. Patients with additional HF hospitalizations had more severe disease than those without. Ivabradine was associated with fewer total HF hospitalizations [902 vs. 1211 events with placebo; incidence rate ratio, 0.75, 95% confidence interval (CI), 0.65–0.87, P = 0.0002] during the 22.9-month median follow-up. Ivabradine-treated patients evidenced lower risk for a second or third additional HF hospitalization [hazard ratio (HR): 0.66, 95% CI, 0.55–0.79, P < 0.001 and HR: 0.71, 95% CI, 0.54–0.93, P = 0.012, respectively]. Similar observations were made for all-cause and cardiovascular hospitalizations.
Conclusion
Treatment with ivabradine, on a background of guidelines-based HF therapy, is associated with a substantial reduction in the likelihood of recurrent hospitalizations for worsening HF. This benefit can be expected to improve the quality of life and to substantially reduce health-care costs.
doi:10.1093/eurheartj/ehs259
PMCID: PMC3498004  PMID: 22927555
Heart failure; Hospitalization; Ivabradine; Left ventricular systolic dysfunction; Heart rate
13.  Impacts of patient characteristics on hospital care experience in 34,000 Swedish patients 
BMC Nursing  2012;11:8.
Background
Standardized patient surveys are widely used for assessing quality of healthcare from the patient perspective. An important purpose of such surveys is to identify disparities in care among different patient groups. The purpose of this study was to 1.) evaluate aspects of the validity of the adapted Swedish version of the Picker Patient Care Experience -15 (PPE-15) survey and 2.) examine the explanatory value of various socio-demographic and health characteristics in predicting patients’ care experiences.
Methods
A retrospective cross-sectional study design was used. Patients discharged from internal medicine wards at regional and university hospitals in different parts of Sweden during 2010 were invited to participate in the regularly administered national care-experience survey for hospital care. The internal validity of the PPE-15 was assessed with Cronbach’s alpha and item-scale correlations. Pearson product–moment correlation coefficients were used to compare PPE-15 total scores with overall care satisfaction ratings and Spearman correlation coefficients were used to compare PPE-15 total scores with various patient characteristics. Multiple linear regression analysis was performed to examine the influence of various patient characteristics on PPE-15 scores.
Results
The response rate was 66% (n = 34 603). Cronbach’s alpha was 0.87. The correlation between the PPE-15 total score and overall care satisfaction was high (0.62, p < 0.0001). Good self-rated health (SRH) and having Swedish as native language were associated with better care experiences and poorer experiences with greater healthcare utilization, higher age, functional impairment and being female. All examined characteristics, except language, were significant predictors in the regression model and SRH was the strongest predictor; however, the model explained only 7% of the total variance. Vulnerable patients (i.e. poor SRH and functional impairment) reported significantly less positive care experiences than did non-vulnerable patients (mean PPE-15 score 75 vs 85; p < 0.0001).
Conclusions
Our results supported the internal validity of the Swedish adapted version of the PPE-15. The explanatory value of the examined patient socio-demographic and health characteristics was low, suggesting the need for exploring other patient-related determinants of care experiences. Our findings also suggest a care paradox: patients in greatest need of hospital care are least satisfied with the quality of the care they receive.
doi:10.1186/1472-6955-11-8
PMCID: PMC3482554  PMID: 22697398
Patient-reported outcome; Self-rated health; Functional status; Frail; Care experience; Care disparity; Patient-centred care
14.  Patients with worsening chronic heart failure who present to a hospital emergency department require hospital care 
BMC Research Notes  2012;5:132.
Background
Chronic heart failure (CHF) is a major public health problem characterised by progressive deterioration with disabling symptoms and frequent hospital admissions. To influence hospitalisation rates it is crucial to identify precipitating factors.
To characterise patients with CHF who seek an emergency department (ED) because of worsening symptoms and signs and to explore the reasons why they are admitted to hospital.
Method
Patients (n = 2,648) seeking care for dyspnoea were identified at the ED, Sahlgrenska University Hospital/Östra. Out of 2,648 patients, 1,127 had a previous diagnosis of CHF, and of these, 786 were included in the present study with at least one sign and one symptom of worsening CHF.
Results
Although several of the patients wanted to go home after acute treatment in the ED, only 2% could be sent home. These patients were enrolled in an interventional study, which evaluated the acute care at home compared to the conventional, in hospital care. The remaining patients were admitted to hospital because of serious condition, including pneumonia/respiratory disease, myocardial infarction, pulmonary oedema, anaemia, the need to monitor cardiac rhythm, pathological blood chemistry and difficulties to communicate.
Conclusion
The vast majority of patients with worsening CHF seeking the ED required hospital care, predominantly because of co-morbidities. Patients with CHF with symptomatic deterioration may be admitted to hospital without additional emergency room investigations.
doi:10.1186/1756-0500-5-132
PMCID: PMC3315737  PMID: 22401538
Chronic heart failure; Hospitalisation; Deterioration; Emergency care
15.  Effects of selective heart rate reduction with ivabradine on left ventricular remodelling and function: results from the SHIFT echocardiography substudy 
European Heart Journal  2011;32(20):2507-2515.
Aims
The SHIFT echocardiographic substudy evaluated the effects of ivabradine on left ventricular (LV) remodelling in heart failure (HF).
Methods and results
Eligible patients had chronic HF and systolic dysfunction [LV ejection fraction (LVEF) ≤35%], were in sinus rhythm, and had resting heart rate ≥70 bpm. Patients were randomly allocated to ivabradine or placebo, superimposed on background therapy for HF. Complete echocardiographic data at baseline and 8 months were available for 411 patients (ivabradine 208, placebo 203). Treatment with ivabradine reduced LVESVI (primary substudy endpoint) vs. placebo [−7.0 ± 16.3 vs. −0.9 ± 17.1 mL/m2; difference (SE), −5.8 (1.6), 95% CI −8.8 to −2.7, P< 0.001]. The reduction in LVESVI was independent of beta-blocker use, HF aetiology, and baseline LVEF. Ivabradine also improved LV end-diastolic volume index (−7.9 ± 18.9 vs. −1.8 ± 19.0 mL/m2, P= 0.002) and LVEF (+2.4 ± 7.7 vs. −0.1 ± 8.0%, P< 0.001). The incidence of the SHIFT primary composite outcome (cardiovascular mortality or hospitalization for worsening HF) was higher in patients with LVESVI above the median (59 mL/m2) at baseline (HR 1.62, 95% CI 1.03–2.56, P= 0.04). Patients with the largest relative reductions in LVESVI had the lowest event rates.
Conclusion
Ivabradine reverses cardiac remodelling in patients with HF and LV systolic dysfunction.
doi:10.1093/eurheartj/ehr311
PMCID: PMC3195263  PMID: 21875858
Heart failure; Heart rate; Ventricular remodelling; Systolic dysfunction; Ivabradine
16.  Critical elements of clinical follow-up after hospital discharge for heart failure: insights from the EVEREST trial 
European Journal of Heart Failure  2010;12(4):367-374.
Aims
Hospitalized heart failure (HF) patients are at high risk for death and readmission. We examined the incremental value of data obtained 1 week after HF hospital discharge in predicting mortality and readmission.
Methods and results
In the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with tolvaptan, 1528 hospitalized patients (ejection fraction ≤40%) with a physical examination, laboratories, and health status [Kansas City Cardiomyopathy Questionnaire (KCCQ)] assessments 1 week after discharge were included. The ability to predict 1 year cardiovascular rehospitalization and mortality was assessed with Cox models, c-statistics, and the integrated discrimination improvement (IDI). Not using a beta-blocker, rales, pedal oedema, hyponatraemia, lower creatinine clearance, higher brain natriuretic peptide, and worse health status were independent risk factors for rehospitalization and death. The c-statistic for the base model (history and medications) was 0.657. The model improved with physical examination, laboratory, and KCCQ results, with IDI increases of 4.9, 7.0, and 3.2%, respectively (P < 0.001 each). The combination of all three offered the greatest incremental gain (c-statistic 0.749; IDI increase 10.8%).
Conclusion
Physical examination, laboratories, and KCCQ assessed 1 week after discharge offer important prognostic information, suggesting that all are critical components of outpatient evaluation after HF hospitalization.
doi:10.1093/eurjhf/hfq019
PMCID: PMC3732083  PMID: 20197265
Heart failure; Prognosis; Health status; Hospitalization; Mortality; BNP
17.  Effects of tolvaptan on dyspnoea relief from the EVEREST trials 
European Heart Journal  2009;30(18):2233-2240.
Aims
To describe the effects of tolvaptan therapy on dyspnoea relief based on timing of delivery, influence of concomitant therapies, and baseline patient and clinical characteristics. Also, the influence of clinical trial design on dyspnoea measurement, from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trials.
Methods and results
Post hoc analysis was performed based on the endpoint of patient-assessed dyspnoea. Changes from baseline at inpatient Day 1 were compared between treatment groups by the van Elteren test. Pre-determined subgroup analyses were also performed. Tolvaptan's effects are greatest within 12 h after first dose with an additional, but modest dyspnoea improvement benefit irrespective of time after admission. Overall, patients continue to report dyspnoea improvement up to 60 h after admission. The window of enrolment, up to 48 h after admission, combined with measurement on ‘Day 1’ led to a wide range over when dyspnoea was assessed.
Conclusion
Post hoc analysis suggests that tolvaptan modestly improves dyspnoea compared with standard therapy alone, regardless if given early or relatively late after hospitalization, and also across major pre-specified subgroups, despite ongoing background therapy aimed at relieving signs and symptoms. Significant variability around when dyspnoea was assessed, in addition to the persistence of dyspnoea despite ongoing background therapy, may influence how future clinical trials assess dyspnoea in acute heart failure syndromes.
doi:10.1093/eurheartj/ehp253
PMCID: PMC2742783  PMID: 19561338
Acute heart failure syndromes; Heart failure; Dyspnoea; Vasopressin antagonists; Clinical trials
18.  Effects of metoprolol and carvedilol on pre‐existing and new onset diabetes in patients with chronic heart failure: data from the Carvedilol Or Metoprolol European Trial (COMET) 
Heart  2007;93(8):968-973.
Background
β Blocker treatment may worsen glucose metabolism.
Objective
To study the development of new onset diabetes in a large cohort of patients with heart failure treated with either metoprolol or carvedilol.
Design
Prospective and retrospective analysis of a controlled clinical trial.
Setting
Multinational multicentre study.
Patients
3029 patients with chronic heart failure.
Interventions
Randomly assigned treatment with carvedilol (n = 1511, target dose 50 mg daily) or metoprolol tartrate (n = 1518, target dose 100 mg daily).
Results
Diabetic events (diabetic coma, peripheral gangrene, diabetic foot, decreased glucose tolerance or hyperglycaemia) and new onset diabetes (clinical diagnosis, repeated high random glucose level or glucose lowering drugs) were assessed in 2298 patients without diabetes at baseline. Diabetic events occurred in 122/1151 (10.6%) patients in the carvedilol group and 149/1147 (13.0%) patients in the metoprolol group (hazard ratio (HR) = 0.78; 95% confidence interval (CI) 0.61 to 0.99; p = 0.039). New onset diabetes was diagnosed in 119/1151 (10.3%) v 145/1147 (12.6%) cases in the carvedilol and metoprolol treatment groups (HR = 0.78, CI 0.61 to 0.997; p = 0.048), respectively. Patients with diabetes at baseline had an increased mortality compared with non‐diabetic subjects (45.3% v 33.9%; HR = 1.45, CI 1.28 to 1.65). Both diabetic and non‐diabetic subjects at baseline had a similar reduction in mortality with carvedilol compared with metoprolol (RR = 0.85; CI 0.69 to 1.06 and RR = 0.82; CI 0.71 to 0.94, respectively).
Conclusion
A high prevalence and incidence of diabetes is found in patients with heart failure over a course of 5 years. New onset diabetes is more likely to occur during treatment with metoprolol than during treatment with carvedilol.
doi:10.1136/hrt.2006.092379
PMCID: PMC1994413  PMID: 17237130
β adrenergic receptor antagonists; carvedilol; diabetes mellitus; heart failure; metoprolol
19.  Predictors of Development of Diabetes in Patients With Chronic Heart Failure in the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) Program 
Diabetes Care  2009;32(5):915-920.
OBJECTIVE
The purpose of this study was to identify predictors of incident diabetes during follow-up of nondiabetic patients with chronic heart failure (CHF) in the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) program.
RESEARCH DESIGN AND METHODS
A total of 1,620 nondiabetic patients had full baseline datasets. We compared baseline demographic, medication, and laboratory data for patients who did or did not develop diabetes and conducted logistic regression and receiver operator characteristic curve analyses.
RESULTS
Over a median period of 2.8 years, 126 of the 1,620 patients (7.8%) developed diabetes. In multiple logistic regression analysis, the following baseline characteristics were independently associated with incident diabetes in decreasing order of significance by stepwise selection: higher A1C (odds ratio [OR] 1.78 per 1 SD increase; P < 0.0001), higher BMI (OR 1.64 per 1 SD increase; P < 0.0001), lipid-lowering therapy (OR 2.05; P = 0.0005), lower serum creatinine concentration (OR 0.68 per 1 SD increase; P = 0.0018), diuretic therapy (OR 4.81; P = 0.003), digoxin therapy (OR 1.65; P = 0.022), higher serum alanine aminotransferase concentration (OR 1.15 per 1 SD increase; P = 0.027), and lower age (OR 0.81 per 1 SD increase; P = 0.048). Using receiver operating characteristic curve analysis, A1C and BMI yielded areas under the curve of 0.723 and 0.712, respectively, increasing to 0.788 when combined. Addition of other variables independently associated with diabetes risk minimally improved prediction of diabetes.
CONCLUSIONS
In nondiabetic patients with CHF in CHARM, A1C and BMI were the strongest predictors of the development of diabetes. Other minor predictors in part reflected CHF severity or drug-associated diabetes risk. Identifying patients with CHF at risk of diabetes through simple criteria appears possible and could enable targeted preventative measures.
doi:10.2337/dc08-1709
PMCID: PMC2671104  PMID: 19196892
20.  Chronic obstructive pulmonary disease is an independent predictor of death but not atherosclerotic events in patients with myocardial infarction: analysis of the Valsartan in Acute Myocardial Infarction Trial (VALIANT) 
European Journal of Heart Failure  2009;11(3):292-298.
Aims
Chronic obstructive pulmonary disease is an independent predictor of mortality in patients with myocardial infarction (MI). However, the impact on mode of death and risk of atherosclerotic events is unknown.
Methods and results
We assessed the risk of death and major cardiovascular (CV) events associated with chronic obstructive pulmonary disease in 14 703 patients with acute MI enrolled in the Valsartan in Acute Myocardial Infarction (VALIANT) trial. Cox proportional hazards models were used to evaluate the relationship between chronic obstructive pulmonary disease and CV outcomes. A total of 1258 (8.6%) patients had chronic obstructive pulmonary disease. Over a median follow-up period of 24.7 months, all-cause mortality was 30% in patients with chronic obstructive pulmonary disease, compared with 19% in those without. The adjusted hazard ratio (HR) for mortality was 1.14 (95% confidence interval 1.02–1.28). This reflected increased incidence of both non-CV death [HR 1.86 (1.43–2.42)] and sudden death [HR 1.26 (1.03–1.53)]. The unadjusted risk of all pre-specified CV outcomes was increased. However, after multivariate adjustment, chronic obstructive pulmonary disease was not an independent predictor of atherosclerotic events [MI or stroke: HR 0.98 (0.77–1.23)]. Mortality was significantly lower in patients receiving beta-blockers, irrespective of airway disease.
Conclusion
In high-risk patients with acute MI, chronic obstructive pulmonary disease is associated with increased mortality and non-fatal clinical events (both CV and non-CV). However, patients with chronic obstructive pulmonary disease did not experience a higher rate of atherosclerotic events.
doi:10.1093/eurjhf/hfp001
PMCID: PMC2645058  PMID: 19176539
Chronic obstructive pulmonary disease; Heart failure; Left ventricular systolic dysfunction; Myocardial infarction
21.  Reviewers 2008 
European Journal of Heart Failure  2009;11(3):225-226.
doi:10.1093/eurjhf/hfp026
PMCID: PMC2645054
22.  Liver function abnormalities and outcome in patients with chronic heart failure: data from the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program 
European Journal of Heart Failure  2009;11(2):170-177.
Aims
The prevalence and importance of liver function test (LFT) abnormalities in a large contemporary cohort of heart failure patients have not been systematically evaluated.
Methods and results
We characterized the LFTs of 2679 patients with symptomatic chronic heart failure from the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity program (CHARM). We used multivariable modelling to assess the relationships between baseline LFT values and long-term outcomes. Liver function test abnormalities were common in patients with chronic heart failure, ranging from alanine aminotransferase elevation in 3.1% of patients to low albumin in 18.3% of patients; total bilirubin was elevated in 13.0% of patients. In multivariable analysis, elevated total bilirubin was the strongest LFT predictor of adverse outcome for both the composite outcome of cardiovascular death or heart failure hospitalization (HR 1.21 per 1 SD increase, P < 0.0001) and all-cause mortality (HR 1.19 per 1 SD increase, P < 0.0001). Even after adjustment for other variables, elevated total bilirubin was one of the strongest independent predictors of poor prognosis (by global chi-square).
Conclusion
Bilirubin is independently associated with morbidity and mortality. Changes in total bilirubin may offer insight into the underlying pathophysiology of chronic heart failure.
doi:10.1093/eurjhf/hfn031
PMCID: PMC2639422  PMID: 19168515
Heart failure; Bilirubin; Liver function tests; Hepatic congestion; Prognosis; Death; Laboratory tests
23.  Effects of low-dose oral enoximone administration on mortality, morbidity, and exercise capacity in patients with advanced heart failure: the randomized, double-blind, placebo-controlled, parallel group ESSENTIAL trials 
European Heart Journal  2009;30(24):3015-3026.
Aims
Use of inotropic agents in patients with heart failure (HF) has been limited by adverse effects on outcomes. However, administration of positive inotropes at lower doses and concomitant treatment with beta-blockers might increase benefit–risk ratio. We investigated the effects of low doses of the positive inotrope enoximone on symptoms, exercise capacity, and major clinical outcomes in patients with advanced HF who were also treated with beta-blockers and other guideline-recommended background therapy.
Methods and results
The Studies of Oral Enoximone Therapy in Advanced HF (ESSENTIAL) programme consisted of two identical, randomized, double-blind, placebo-controlled trials that differed only by geographic location (North and South America: ESSENTIAL-I; Europe: ESSENTIAL-II). Patients with New York Heart Association class III–IV HF symptoms, left ventricular ejection fraction ≤30%, and one hospitalization or two ambulatory visits for worsening HF in the previous year were eligible for participation in the trials. The trials had three co-primary endpoints: (i) the composite of time to all-cause mortality or cardiovascular hospitalization, analysed in the two ESSENTIAL trials combined; (ii) the 6 month change from baseline in the 6 min walk test distance (6MWTD); and (iii) the Patient Global Assessment (PGA) at 6 months, both analysed in each trial separately. ESSENTIAL-I and -II randomized 1854 subjects at 211 sites in 16 countries. In the combined trials, all-cause mortality and the composite, first co-primary endpoint did not differ between the two treatment groups [hazard ratio (HR) 0.97; 95% confidence interval (CI) 0.80–1.17; and HR 0.98; 95% CI 0.86–1.12, respectively, for enoximone vs. placebo]. The two other co-primary endpoints were analysed separately in the two ESSENTIAL trials, as prospectively designed in the protocol. The 6MWTD increased with enoximone, compared with placebo, in ESSENTIAL-I (P = 0.025, not reaching, however, the pre-specified criterion for statistical significance of P < 0.020), but not in ESSENTIAL-II. No difference in PGA was observed in either trial.
Conclusion
Although low-dose enoximone appears to be safe in patients with advanced HF, major clinical outcomes are not improved.
doi:10.1093/eurheartj/ehp338
PMCID: PMC2792716  PMID: 19700774
Advanced heart failure; Inotropic agents; Enoximone
25.  Worsening chronic heart failure and the link to frequent hospital admissions and need of specialist care 
Background
Worsening chronic heart failure (CHF) is largely characterised by disabling symptoms, poor quality of life, frequent hospital admissions and need of specialist care. Lack of alternative care results in involuntary hospitalisation.
Aim
In a pilot study evaluate home care (HC) versus conventional care (CC) in relation to medical safety, health-related quality of life (HRQL) and cost-utility in patients with worsening CHF.
Method
Thirty-one patients with deteriorating CHF were randomised to HC or CC when seeking medical attention at hospital. Patients in the HC group were discharged from the hospital and were followed-up in their homes by a specialist nurse. Patients in the control group were treated in hospital with usual care. Follow-ups were conducted for both groups, 1, 4, 8 and 12 months after inclusion in the study. Health-related quality of life assessed by EuroQol-5D VAS, Standard Gamble technique, SF-36 and Kansas City cardiomyopathy Questionnaire. All health care related costs were assessed and cost utility analysis was performed to compare cost/QALYs between groups.
Results
There was no significant difference in clinical events, adverse events or in HRQL. The total cost related to CHF was lower in the HC group after 12 months. Median direct health care related costs in HC were € 1122 and in CC € 5670 (p 0.05). Cost/QALYs ranged € 74–580 in HC compared to CC € 289–1013, calculated from each follow-up. The cost utility ratio was (CC/HC) 2.55 (SG) and 2.65 (VAS).
Conclusion
Reductions in cost of care for selected patients with CHF eligible for hospital care might be achieved by a very early discharge from hospital followed by home visits. More importantly, HC seems to be safe and no difference was found in HRQL between two groups. This pilot study provides clinicians with useful information in their decisions concerning CHF patient management, who are reluctant to hospitalisation.
PMCID: PMC2430295
chronic heart failure; healthcare cost; quality-adjusted life years; home care; cost-utility analysis; safety

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