Efficacy Of Vasopressin Antagonism In Heart Failure Outcome Study With Tolvaptan Trial Research Articles

PO098 Reverse Myocardial Remodeling and Reduction of Inflammatory Markers In Patients With Heart Failure Treated With Sacubitril / Valsartan

Patients with chronic heart failure with reduced ejection fraction (HFrEF) benefit from medical and device therapies targeting sudden cardiac death (SCD). Contemporary estimates of SCD risk after hospitalization for heart failure are limited. We describe the incidence, timing, and clinical predictors of SCD after hospitalization for HFrEF (≤40%) in the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) trial. Multiple logistic regression analyses tested >30 baseline covariates (including treatment randomization, demographics, comorbid conditions, natriuretic peptides, ejection fraction, and medical and device therapies) to identify predictors of 1-year SCD. Of the 4,024 trial patients discharged alive (97%), there were 268 who experienced SCD (7%) and 703 who experienced non-SCD (17%) during median follow-up of 9.9 months. Implantable cardioverter defibrillator use at baseline was 14.5%. Estimates of SCD at 1, 3, 6, and 12 months were 0.8%, 2.3%, 4.1%, and 7.4%, respectively. Most patients were readmitted before SCD (n = 147, 55%). Male gender, black race, diabetes mellitus, and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use were potential predictors of 1-year SCD after hospitalization for HFrEF (all p <0.10); however, this final model demonstrated poor discrimination (C-statistic 0.57). In conclusion, in the EVEREST trial, patients hospitalized for HFrEF faced risks of 1-year postdischarge SCD of 7%, which accrued gradually over time, and were balanced with high competing risks of nonsudden death (17%). Traditional clinical characteristics fail to adequately predict SCD risk. Further data are needed to identify patients at greatest relative risk for SCD (compared with non-SCD) after hospitalization for HFrEF.

Sudden Death After Hospitalization for Heart Failure With Reduced Ejection Fraction (from the EVEREST Trial)

Patients with chronic heart failure with reduced ejection fraction (HFrEF) benefit from medical and device therapies targeting sudden cardiac death (SCD). Contemporary estimates of SCD risk after hospitalization for heart failure are limited. We describe the incidence, timing, and clinical predictors of SCD after hospitalization for HFrEF (≤40%) in the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) trial. Multiple logistic regression analyses tested >30 baseline covariates (including treatment randomization, demographics, comorbid conditions, natriuretic peptides, ejection fraction, and medical and device therapies) to identify predictors of 1-year SCD. Of the 4,024 trial patients discharged alive (97%), there were 268 who experienced SCD (7%) and 703 who experienced non-SCD (17%) during median follow-up of 9.9 months. Implantable cardioverter defibrillator use at baseline was 14.5%. Estimates of SCD at 1, 3, 6, and 12 months were 0.8%, 2.3%, 4.1%, and 7.4%, respectively. Most patients were readmitted before SCD (n = 147, 55%). Male gender, black race, diabetes mellitus, and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use were potential predictors of 1-year SCD after hospitalization for HFrEF (all p <0.10); however, this final model demonstrated poor discrimination (C-statistic 0.57). In conclusion, in the EVEREST trial, patients hospitalized for HFrEF faced risks of 1-year postdischarge SCD of 7%, which accrued gradually over time, and were balanced with high competing risks of nonsudden death (17%). Traditional clinical characteristics fail to adequately predict SCD risk. Further data are needed to identify patients at greatest relative risk for SCD (compared with non-SCD) after hospitalization for HFrEF.

Temporal Changes in Postdischarge Mortality Risk After Hospitalization for Heart Failure (from the EVEREST Trial)

In observational studies of patients hospitalized for heart failure (HHF), risk of death is highest immediately after discharge and decreases over time. It is unclear whether this population risk trajectory reflects (1) lowering of individual patient mortality risk with increasing time from index hospitalization or (2) temporal changes in population case-mix with earlier postdischarge death for "sicker" patients. Survival rate and longitudinal models were used to estimate temporal changes in postdischarge all-cause mortality risk in 3,993 HHF patients discharged alive in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial. After median follow-up of 9.9 months, 971 patients died (24.2%). Predicted mortality rate decreased from 15.9 per 100 patient-years immediately after discharge to 13.4 at 30 days and 12.8 at 90 days; mortality rate increased steadily thereafter. Risk variation between quintiles of risk was considerably larger than the temporal variation within risk strata. In a longitudinal model serially reassessing predicted patient mortality risk after each follow-up visit using data collected at these visits, predicted mortality risk increased during the 90 days preceding subsequent heart failure readmission and then followed a postdischarge trajectory similar to the index admission. In conclusion, although there is transiently elevated individual patient risk in the 90 days before and after discharge, the patient's individual risk profile, rather than temporal change in risk relative to hospitalization, remains the main determinant of mortality. For purposes of reducing all-cause mortality in HF patients, preventative and therapeutic measures may be best implemented as long-term interventions for high mortality risk patients based on serial risk assessments, irrespective of recent hospitalization.

Abstract 12794: Hospital Length of Stay and Readmissions Post Heart Failure Hospitalization in the EVEREST Trial

Background: Previous reports have provided conflicting data regarding the relationship between length of stay (LOS) and subsequent readmissions risk among patients hospitalized for heart failure (HF). Methods: We performed a post-hoc analysis of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial to evaluate the differences in LOS overall and between geographical regions (North America, South America, Western Europe, and Eastern Europe) in association with all-cause and cause specific (HF, cardiovascular [CV] non-HF and non-CV) readmissions within 30 days of discharge after HF hospitalization. Results: The median (IQR) LOS among the 4,133 patients enrolled from 20 countries across 359 sites was 8 (4-11) days. The 30-day readmissions rates were 15.6% (95% confidence intervals [CI] 14.6-16.8) for all-cause; 5.5% (95%CI 4.9-6.3) for HF; 4.4% (95%CI 3.8-5.1) for CV non-HF and 5.8% (95%CI 5.1-6.6) for non-CV readmissions. Overall there was a positive correlation between LOS and all cause readmissions (r=0.09; 95%CI 0.06-0.12). The adjusted odds ratio for the top (&gt;14 days) versus the bottom (&lt;3 days) quintile for LOS was 1.39 (95%CI 0. 92-2.11) for all-cause; 0.43 (95%CI 0.24-0.79) for HF; 2.99 (95%CI 1.49-6.02) for CV non-HF and 1.72 (95%CI 1.05-2.81) for non-CV readmissions, Figure 1. These findings remained consistent in analyses within patient characteristic subgroups and also largely within regions. Conclusions: Longer hospital LOS was associated with a higher risk for all-cause, CV non-HF, and non-CV readmissions, and with a lower risk of HF readmissions. These results may have important bearing in developing clinical and research strategies to reduce readmissions.

Mineralocorticoid Receptor Antagonist Use in Hospitalized Patients With Heart Failure, Reduced Ejection Fraction, and Diabetes Mellitus (from the EVEREST Trial)

Despite the well-established benefits of mineralocorticoid receptor agonists (MRAs) in heart failure with reduced ejection fraction, safety concerns remain in patients with concomitant diabetes mellitus (DM) because of common renal and electrolyte abnormalities in this population. We analyzed all-cause mortality and composite cardiovascular mortality and HF hospitalization over a median 9.9months among 1,998 patients in the placebo arm of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial by DM status and discharge MRA use. Of the 750 patients with DM, 59.2% were receiving MRAs compared with 62.5% in the non-DM patients. DM patients not receiving MRAs were older, more likely to be men, with an ischemic heart failure etiology and slightly worse renal function compared with those receiving MRAs. After adjustment for baseline risk factors, among DM patients, MRA use was not associated with either mortality (hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.75 to 1.15) or the composite end point (HR 0.94; 95% CI 0.80 to 1.10). Similar findings were seen in non-DM patients (mortality [HR 1.01; 95% CI 0.84 to 1.22] or the composite end point [HR 0.98; 95% CI 0.85 to 1.13] [p >0.43 for DM interaction]). In conclusion, in-hospital initiation of MRA therapy was low (15% to 20%), and overall discharge MRA use was only 60% (with regional variation), regardless of DM status. There does not appear to be clear, clinically significant in-hospital hemodynamic or even renal differences between those on and off MRA. Discharge MRA use was not associated with postdischarge end points in patients hospitalized for worsening heart failure with reduced ejection fraction and co-morbid DM. DM does not appear to influence the effectiveness of MRA therapy.

The Prognostic Significance of Heart Rate in Patients Hospitalized for Heart Failure With Reduced Ejection Fraction in Sinus Rhythm: Insights From the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan) Trial

The purpose of this study was to characterize the relationship between heart rate and post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction (EF) in sinus rhythm. A reduction in heart rate improves clinical outcomes in patients with chronic heart failure and in sinus rhythm, but the association between heart rate and post-discharge outcomes in patients with HHF is presently unclear. This post-hoc analysis of the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan) trial examined 1,947 patients with HHF and EF≤40% not in atrial fibrillation/flutter or pacemaker dependent. The median follow-up period was 9.9 months. At baseline, patients with a higher heart rate tended to be younger with lower EF and were more likely to have worse New York Heart Association functional class and higher natriuretic peptide levels. After adjustment for clinical risk factors, baseline heart rate was not predictive of all-cause mortality (p≥ 0.066). However, at≥70 beats/min, every 5-beat increase in 1-week post-discharge heart rate was independently associated with increased all-cause mortality (hazard ratio: 1.13 [95% confidence interval: 1.05 to 1.22]; p= 0.002). Similarly, every 5-beat increase≥70 beats/min in 4-week post-discharge heart rate was predictive of all-cause mortality (hazard ratio: 1.12 [95% confidence interval: 1.05 to 1.19]; p= 0.001). In this large cohort of patients with HHF with reduced EF and in sinus rhythm, baseline heart rate did not correlate with all-cause mortality. In contrast, at≥70 beats/min, higher heart rate in the early post-discharge period was independently predictive of death during subsequent follow-up. Further study of post-discharge heart rate as a potential therapeutic target in this high-risk population is encouraged.

Haemoconcentration, renal function, and post‐discharge outcomes among patients hospitalized for heart failure with reduced ejection fraction: insights from the EVEREST trial

Haemoconcentration has been studied as a marker of decongestion in patients with hospitalization for heart failure (HHF). We describe the relationship between haemoconcentration, worsening renal function, post-discharge outcomes, and clinical and laboratory markers of congestion in a large multinational cohort of patients with HHF. In 1684 patients with HHF with ejection fraction (EF) ≤40% assigned to the placebo arm of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, absolute in-hospital haematocrit change was calculated as the change between baseline and discharge or day 7 (whichever occurred first). Patient characteristics, changes in renal function, and outcomes over a median follow-up of 9.9 months were compared by in-hospital haematocrit change. Overall, 26% of patients had evidence of haemoconcentration (i.e., ≥3% absolute increase in haematocrit). Patients with greater increases in haematocrit tended to have better baseline renal function. Haemoconcentration correlated with greater risk of in-hospital worsening renal function, but renal parameters generally returned to baseline within 4 weeks post-discharge. Patients with haemoconcentration were less likely to have clinical congestion at discharge, and experienced greater in-hospital decreases in body weight and natriuretic peptide levels. After adjustment for baseline clinical risk factors, every 5% increase of in-hospital haematocrit change was associated with a decreased risk of all-cause death [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.70-0.95]. Haematocrit change was also associated with decreased cardiovascular mortality or heart failure (HF) hospitalization at ≤100 days post-randomization (HR 0.73, 95% CI 0.71-0.76). In this large cohort of patients with HHF with reduced EF, haemoconcentration was associated with greater improvements in congestion and decreased mortality and HF re-hospitalization despite an increased risk of in-hospital worsening renal function.

Diuretic Resistance and Clinical Outcomes in Patients Hospitalized for Worsening Heart Failure: Insights from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) Trial

Diuretic Resistance and Clinical Outcomes in Patients Hospitalized for Worsening Heart Failure: Insights from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) Trial

Association between diabetes mellitus and post‐discharge outcomes in patients hospitalized with heart failure: findings from the EVEREST trial

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. 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 χ(2) 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. 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.

Prognostic Significance of Serum Total Cholesterol and Triglyceride Levels in Patients Hospitalized for Heart Failure With Reduced Ejection Fraction (from the EVEREST Trial)

Lower cholesterol levels are associated with worse outcomes in patients with chronic heart failure (HF) and have been shown to predict in-hospital mortality. The relation between lipid profile and postdischarge outcomes in patients hospitalized for worsening HF is less clear. In this post hoc analysis of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST), 3,957 patients hospitalized for worsening HF with ejection fractions ≤40% were examined. Baseline total cholesterol and triglyceride levels were measured <48 hours after admission and evaluated as continuous variables. The primary end points of all-cause mortality and cardiovascular mortality or hospitalization for HF were compared using Cox regression models. Patient characteristics at randomization were also compared among quartiles of total cholesterol. Patients with lower total cholesterol tended to have lower blood pressure, ejection fractions, serum sodium, and albumin, and were more likely to have worse HF functional class, to have higher natriuretic peptide levels, and to have histories of diabetes mellitus, renal insufficiency, and coronary revascularization (all p values <0.001). After adjustment for baseline clinical risk factors, total cholesterol was predictive of all-cause mortality (hazard ratio 0.73, 95%confidence interval 0.63 to 0.85, p <0.001) and cardiovascular mortality or hospitalization for HF (hazard ratio 0.73, 95% confidence interval 0.66 to 0.82, p <0.001) at median follow-up of 9.9 months. Lower baseline triglyceride level was also associated with worse outcomes. In conclusion, lower baseline total cholesterol is correlated with a high-risk patient profile and is a marker of disease severity in patients hospitalized for worsening HF with reduced ejection fraction. Baseline total cholesterol and triglyceride levels are predictive of mortality and HF rehospitalization beyond traditional risk factors.

Prognostic Value of Monocyte Count in Patients Hospitalized for Heart Failure With Reduced Ejection Fraction (from the EVEREST Trial)

Monocytes play a critical role in the pathophysiology of heart failure (HF), but few studies have evaluated the prognostic implications of an increased monocyte count in patients with HF and reduced ejection fraction (EF). The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) examined the effects of tolvaptan in patients with worsening HF and EF ≤40%. This post hoc analysis evaluated the primary end points of all-cause mortality and cardiovascular mortality or HF hospitalization in 3,717 patients. At baseline, 265 (7.1%) had an increased monocyte count defined by ≥800/μl. Patients with increased monocyte count tended to have an increased EF and were less likely to have a history of diabetes mellitus, hypercholesterolemia, or coronary revascularization but were more likely to have higher HF functional class and to be taking HF therapies such as diuretics, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, and digoxin (p <0.05 for all comparisons). At median follow-up of 9.9 months, increased monocyte count was predictive of all-cause mortality (hazard ratio 1.27, 95% confidence interval 1.003 to 1.60, p = 0.047) but was not associated with cardiovascular mortality or HF hospitalization (hazard ratio 1.06, 95% confidence interval 0.87 to 1.30, p = 0.55). Similar results were seen when monocyte count was analyzed as a continuous variable. However, after adjustment for baseline clinical risk factors, monocyte count was not predictive of either primary end point. In conclusion, increased monocyte count occurs in a minority of patients hospitalized with HF and is associated with poor postdischarge prognosis. However, it does not contribute prognostic value above other more traditional risk factors.

Clinical course and predictive value of liver function tests in patients hospitalized for worsening heart failure with reduced ejection fraction: an analysis of the EVEREST trial

Abnormal liver function tests (LFTs) are common in ambulatory heart failure (HF). The aim of this study was to characterize abnormal LFTs during index hospitalization. A post-hoc analysis was carried out of the placebo group of the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) trial, which enrolled patients hospitalized for HF with an ejection fraction (EF) ≤40% and no history of primary significant liver disease or acute hepatic failure. LFTs (abbreviation, cut-offs for abnormal values) including serum albumin (ALB, <3.3 g/dL), aspartate transaminase (AST, >34 IU/L), alanine transaminase (ALT, >34 IU/L), alkaline phosphatase (AP, >123 IU/L),γ-glutamyl transferase (GGT, >50 IU/L), and total bilirubin (T Bili, >1.2 mg/dL) were measured at baseline, discharge/day 7, and post-discharge. Co-primary endpoints were all-cause mortality (ACM) and cardiovascular mortality or first HF hospitalization (CVM + HFH). Study participants had a mean age of 65.6 ±12.0 years, were mostly male, reported high prevalences of medical co-morbidities, and were well treated with evidence-based therapies. Baseline LFT abnormalities were common (ALB 17%, AST 21%, ALT 21%, AP 23%, GGT 62%, and T Bili 26%). Abnormal T Bili was the only marker to decrease substantially from baseline (26%) to discharge/day 7 (19%). All LFTs, except AP, improved post-discharge. Lower baseline ALB and elevated T Bili were associated with higher rates of ACM, and in-hospital decreases in ALB and increases in T Bili were associated with higher rates of both ACM and CVM + HFH. LFT abnormalities are common during hospitalization for HF in patients with reduced EF and were persistent at discharge. Baseline and in-hospital changes in ALB and T Bili provide additional prognostic value.

Evaluation of costs associated with tolvaptan-mediated length-of-stay reduction among heart failure patients with hyponatremia in the US, based on the EVEREST trial

Background:The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial showed that tolvaptan use improved heart failure (HF) signs and symptoms without serious adverse events.Objective:To evaluate the potential cost savings associated with tolvaptan usage among hospitalized hyponatremic HF patients.Methods:The Healthcare Cost and Utilization Project (HCUP) 2008 Nationwide Inpatient Sample (NIS) database was used to estimate hospital cost and length of stay (LOS), for diagnosis-related group (DRG) hospitalizations of adult (age ≥18 years) HF patients with complications and comorbidities or major complications and comorbidities. EVEREST trial data for patients with hyponatremia were used to estimate tolvaptan-associated LOS reductions. A cost offset model was constructed to evaluate the impact of tolvaptan on hospital cost and LOS, with univariate and multivariate Monte Carlo sensitivity analyses.Results:Tolvaptan use among hyponatremic EVEREST trial HF patients was associated with shorter hospital LOS than placebo patients (9.72 vs 11.44 days, respectively); 688,336 hospitalizations for HF DRGs were identified from the HCUP NIS database, with a mean LOS of 5.4 days and mean total hospital costs of $8415. Using an inpatient tolvaptan treatment duration of 4 days with a wholesale acquisition cost of $250 per day, the cost offset model estimated a LOS reduction among HF hospitalizations of 0.81 days and an estimated total cost saving of $265 per admission. Univariate and multivariate sensitivity analysis demonstrated that cost reduction associated with tolvaptan usage is consistent among variations of model variables.Conclusions:The estimated LOS reduction and cost savings projected by the cost offset model suggest a clinical and economic benefit to tolvaptan use in hyponatremic HF patients.Study Limitations:The EVEREST trial data may not generalize well to the US population. Clinical trial patient profiles and relative LOS reductions may not be applicable to real-world patient populations.

Hospitalizations for Heart Failure in the United States—A Sign of Hope

HEART FAILURE (HF) IS THE MOST COMMON CAUSE OF hospitalization in patients older than 65 years in the United States. In the early 1990s, data from clinical trials and registries demonstrated that in patients hospitalized with HF, mortality and rehospitalization rates could be as high as 15% and 30%, respectively, at 60 to 90 days after discharge. During this period, major efforts were directed toward reducing the length of stay in patients hospitalized with HF. Performance measures were developed and later adopted by the Centers for Medicare & Medicaid Services (CMS) with the intent to improve postdischarge outcomes. Although these measures were implemented across the country, the rehospitalization rate for patients with HF did not appear to decrease. Recently, because of changes in CMS reimbursement patterns, the focus has shifted toward 30-day postdischarge readmission rates as a measure of care. In this issue of JAMA, Chen et al reviewed administrative data of more than 55 million Medicare fee-for-service beneficiaries,withameanageof79years,whowerehospitalizedwith a discharge diagnosis of HF. Black patients represented 11% of the total studypopulation.Theoverall ratesof risk-adjusted hospitalizationforHFdeclined30%over thestudyperiodfrom 2845 per 100 000 person-years in 1998 to 2007 per 100 000 person-years in2008.Theauthorsattribute thisdecline inhospitalizations to reductions in the incidence of coronary artery disease, improved control of blood pressure, increased use of evidence-based therapies, and possibly changes in admission thresholds. In contrast to this significant reduction in hospitalizations forHF,1-year risk-adjustedall-causemortality rate declined minimally but remained high at approximately 30%. This report is a substantial contribution to existing HF epidemiological literature because it is the first to document an improvementinhospitalizationrates inHFintheUnitedStates. These improvementsappear tobemoreevident inrecentyears during which major progress has been made in promoting evidence-basedtherapies forcoronaryarterydisease.However, thissubstantialdecline inhospitalizationrateswassignificantly less in black men than in white men. Another important observation was that the decreases in hospitalization rates across states were not uniform. The authors also noted that comorbidities such as hypertension and renal dysfunction increased over time. Approximately 40% of these patients had diabetes and 30% had chronic obstructive pulmonary disease. The general reduction in admission rates may reflect improvements in overall management of HF risk factors, as suggested by Chen et al, but the persistently high 1-year mortality rates suggest that postdischarge practices for patients with HF have not been as effective. Although the admission rates for HF have decreased based on Medicare data reported by Chen et al, the available data suggest that rehospitalization rates after an index admission for HF have remained unchanged or have even increased over a similar time frame. It is important to recognize that among patients discharged following hospital admission for HF, a significant number of rehospitalizations are not related to HF. In the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome StudywithTolvaptan) trial conducted inpatientsadmitted for worsening HF with reduced ejection fraction, the total rehospitalizationrateexceeded50%at9.9months,andless thanhalf of rehospitalizations were due to HF. This occurred despite the studypopulationbeing relativelyyoung forHF(meanage, 62years),withfewmajorcomorbidconditions.IntheDIG(Digitalis Investigation Group) ancillary trial that studied outpatients with HF and preserved ejection fraction, the total hospitalization rate exceeded 65% during a mean follow-up of 37 months.Ofthesehospitalizations,only35%wererelatedtoHF. Inbothstudies,totalcardiovascularhospitalizationsrepresented a large proportion of the hospitalizations. Targeting total rehospitalization rather than rehospitalization for HF rates may be especially important given the aging population and their associated cardiac and noncardiac comorbid conditions. Chen et al suggested that the reduction in HF admissions may be related to changes in the threshold for admission in emergency departments. Lee et al reported that patients with HF who were discharged home directly from the emergency department, representing 30% of total HF presentations in their cohort, had a high risk-adjusted early death compared with patients who were admitted. If the reduction in number of hospitalizations noted by Chen et al is

Worsening kidney function in decompensated heart failure: treat the heart, don't mind the kidney

This editorial refers to ‘Changes in renal function during hospitalization and soon after discharge in patients admitted for worsening heart failure in the placebo group of the EVEREST trial’, by J.E.A. Blair et al. doi:10.1093/eurheartj/ehr238. In a post-hoc analysis of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST), Blair and co-workers found that worsening kidney function shortly after hospitalization and in the early post-discharge period independently predicted cardiovascular mortality and re-hospitalizations because of heart failure (HF).1 These findings confirmed previous evidence that worsening kidney function following hospitalization for decompensated HF is a strong independent predictor of long-term adverse outcomes. An intriguing finding of the above study, however, was that worsening kidney function was also associated with a decrease in body weight and circulating levels of the B-type natriuretic peptide (BNP), changes that reflected an amelioration of fluid congestion and that per se were expected to predict improved outcomes in the long term. To explain this apparent paradox, we have to go back to the old days of Arthur J. Merril who in 1946 measured renal plasma flow and the glomerular filtration rate (GFR) by using the sodium para -amino hippurate and inulin renal clearance techniques, in 37 subjects admitted because of HF from different aetiologies.2 In these patients, the renal plasma flow was reduced to one-third to one-fifth of normal, whereas the cardiac output was rarely reduced below half the resting value. On the basis of these findings, he suggested that in HF there is a specific diversion of blood away from the kidneys, organs which normally receive ∼20% of the cardiac output. Despite the large reduction in …

The Science of Quality-of-Life-Directed Care!

Aspirations have no limit, barring reality. The obstacles imposed by reality to temper aspirations can be divided into 3 categories. First are those obstacles that are not negotiable (eg, 24 hours in a day, we all must die). Second are those that are negotiable, easily or with difficulty, but come at an acceptable opportunity cost. Such obstacles often are the foundation of aspirations and inspirations alike; examples of achievements in medicine and elsewhere overcoming them are too numerous to illustrate. Third are those that are negotiable but come only at a high opportunity cost. Here, the devil really does lie in the details, because the definition of opportunity cost is not absolute; hence, the debate. Let us examine the article by Allen et al1 in the current issue of Circulation: Cardiovascular Quality and Outcomes in this framework. Article see p 389 The primary concern of healthcare providers is to deliver the best treatment to all patients, with an aim to extend longevity and improve quality of life. This concern is even more important for patients with chronic diseases. During the past 2 decades, several drugs and devices have been shown to improve mortality risk from heart failure with depressed ejection fraction.2–4 Allen and colleagues1 very nobly contend that mortality should not be the only outcome that we focus on, and that improving quality of life should be an important aim. How can one disagree with this assertion? To help to achieve this goal, the authors assessed the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) trial database5 to identify factors related to 6-month mortality or unfavorable quality of life (defined as Kansas City Cardiomyopathy Questionnaire scores <45) after discharge for decompensated heart failure. As might be expected from a large …

Effects of tolvaptan on physician-assessed symptoms and signs in patients hospitalized with acute heart failure syndromes: Analysis from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) Trials

A rapid and sustained relief of heart failure (HF) symptoms and signs is an important goal of management in patients hospitalized for acute HF syndromes (AHFS). To date, no novel therapy in AHFS have been shown to improve signs and symptoms throughout hospitalization. This study explores the clinical effects of tolvaptan, a vasopressin-2-receptor antagonist, in addition to standard medical therapies on physician-assessed signs and symptoms in hospitalized AHFS patients. The EVEREST trial randomized 4,133 patients admitted with worsening HF and reduced ejection fraction (≤ 40%) within 48 hours after hospital admission. On each inpatient day, investigators assessed dyspnea, orthopnea, fatigue, jugular venous distension (JVD), rales, and pedal edema by predefined ordinal scales. Responder analyses were performed for each sign and symptom, with significant clinical response defined as a change in one point on the measurement scale. Post hoc analysis demonstrated greater likelihood of clinical improvement in physician-assessed dyspnea, edema, orthopnea, and JVD among tolvaptan-treated subjects (P < .05) as early as inpatient day 1. This difference was observed throughout hospitalization only for JVD and orthopnea through day 3. The addition of tolvaptan to standard therapy for AHFS improves physician-assessed signs and symptoms during hospitalization without serious adverse short- or long-term effects.

Continental Differences in Clinical Characteristics, Management, and Outcomes in Patients Hospitalized With Worsening Heart Failure: Results From the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) Program

Our aim was to examine continental and regional differences in baseline characteristics and post-discharge clinical outcomes in the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) trial. Continental and regional differences in clinical trials of acute heart failure syndromes (AHFS) have not been well studied. We analyzed data from the EVEREST trial, which randomized 4,133 patients hospitalized for worsening (HF) and left ventricular ejection fraction < or =40% to oral tolvaptan, a vasopressin antagonist, or placebo and followed for a median of 9.9 months. Baseline characteristics, mortality, and outcomes were analyzed across North America (n = 1,251), South America (n = 688), Western Europe (564 patients), and Eastern Europe (n = 1,619). There were major differences between the 4 groups in the severity, etiology, and management of HF. Unadjusted 1-year mortality and cardiovascular mortality/HF hospitalization were 30.4% and 52.5% in North America, 27.2% and 41.6% in South America, 27.1% and 47.3% in Western Europe, and 20.5% and 35.3% in Eastern Europe. After adjustment, South American patients had the highest overall mortality (hazard ratio: 1.42, 95% confidence interval: 1.15 to 1.76), while Eastern European patients had the lowest cardiovascular death and HF hospitalization rate (hazard ratio: 0.84, 95% confidence interval: 0.73 to 0.97), compared with patients in North America. Major continental and regional differences in HF severity, etiology, and management exist among AHFS patients, resulting in varied post-discharge outcomes, despite pre-defined selection criteria. These differences should be taken into account when planning global trials in AHFS. (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan [EVEREST]; NCT00071331).