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

Rates of In-Hospital Decongestion and Association with Mortality and Cardiovascular Outcomes Among Patients Admitted for Acute Heart Failure

BackgroundDecongestion is an important goal in the management of acute heart failure. Whether the rate of decongestion is associated with mortality and cardiovascular outcomes is unknown. MethodsUsing data from 4133 patients from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial, we used multivariable Cox regression models to evaluate the association between rates of in-hospital change in assessments of volume overload, including b-type natriuretic peptide (BNP), N-terminal pro b-type natriuretic peptide (NT-proBNP), as well as change in hemoconcentration, with risk of all-cause mortality and a composite outcome of cardiovascular mortality or heart failure hospitalization. ResultsMore rapid rates of in-hospital decongestion were associated with decreased risk of mortality and the composite outcome over a median 10-month follow-up. In reference to the quartile of slowest decline, the quartile with the fastest BNP and NT-proBNP decline had lower hazards of mortality (hazard rate [HR] = 0.43 [0.31, 0.59] and HR = 0.27 [0.19, 0.40], respectively) and composite outcome (HR = 0.49 [0.39, 0.60] and HR = 0.54 [0.42, 0.71], respectively). In reference to the quartile of slowest increase, the quartile with the fastest hematocrit increase had lower hazards of mortality (HR = 0.77 [0.62, 0.95]) and composite outcome (HR = 0.75 [0.64, 0.88]). Results were also consistent when models were repeated using propensity-score matching. ConclusionsFaster rates of decongestion are associated with reduced risk of mortality and a composite of cardiovascular mortality and heart failure hospitalization. It remains unknown whether more rapid decongestion provides cardiovascular benefit or whether it serves as a proxy for less treatment resistant heart failure.

248 Use of a Propensity Score to Examine Association between Rates of In-Hospital Decongestion and Mortality and Cardiovascular Outcomes Among Patients admitted for Acute Heart Failure

OBJECTIVES/GOALS: Decongestion, or fluid removal, is an important goal in the management of acute heart failure (AHF) among patients with heart failure with reduced ejection fraction (HFrEF). We sought to examine whether the rate of decongestion is associated with mortality and cardiovascular (CV) outcomes. METHODS/STUDY POPULATION: Using data from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial (n=4133), we evaluated the rate of decongestion by using linear mixed models to derive the in-hospital slope of b-type natriuretic peptide (BNP) and hematocrit as proxies of volume overload and hemoconcentration, respectively. A propensity score was developed to match patients from the quartile with most rapid rates of decongestion to the three quartiles with slower rates. Cox proportional hazards regression models were fitted to assess the association between rate of decongestion with risk of all-cause mortality and a composite of CV mortality or AHF hospitalization. RESULTS/ANTICIPATED RESULTS: Slower rates of in-hospital decongestion were associated with increased risk of both outcomes over a median 10-month follow-up. Those with slower rates of BNP decline, in comparison to the propensity-score matched patients with the most rapid rates of BNP decline, had higher hazards of mortality (HR=1.73 [1.23, 2.42]) and the composite outcome (HR=1.48 [1.18, 1.86]). Those with slower rates of hematocrit increase, in comparison to the propensity-score matched patients with the most rapid rates of hematocrit increase, showed a trend toward higher hazard of mortality (HR=1.17 [0.95, 1.43]) and an increased risk of the composite outcome (HR=1.26 [1.08, 1.47]). DISCUSSION/SIGNIFICANCE: Among patients with HFrEF admitted for AHF, slower rates of decongestion are associated with increased risk of mortality, CV mortality and AHF hospitalization. It remains unknown whether more rapid decongestion provides cardiovascular benefit or if it serves as a proxy for less treatment resistant heart failure.

Rates of Reversal of Volume Overload in Hospitalized Acute Heart Failure: Association With Long-term Kidney Function

Achievement of decongestion in acute heart failure (AHF) is associated with improved survival and cardiovascular outcomes but can be associated with acute declines in estimated glomerular filtration rate (eGFR). We examined whether the rate of in-hospital decongestion is associated with longer term kidney function decline. Post hoc analysis of trial data. Patients with≥2 measures of kidney function (n= 3,500) from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial. In-hospital rate of change in assessments of volume overload, including B-type natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and clinical congestion score (0-12); and rate of change in hemoconcentration including measures of hematocrit, albumin, and total protein. Incident chronic kidney disease GFR category 4 or worse (chronic kidney disease [CKD] categories G4-G5; defined by a new eGFR of<30 mL/min/1.73 m2) and eGFR decline of >40%. Multivariable cause-specific hazards models. Over median 10-month follow-up period, faster decreases in volume overload and more rapid increases in hemoconcentration were associated with a decreased risk of incident CKD G4-G5 and eGFR decline of >40%. In adjusted analyses, for every 6% faster decline in BNP per week, there was a 32% lower risk of both incident CKD G4-G5 (HR, 0.68 [95% CI, 0.58-0.79]) and eGFR decline of >40% (HR, 0.68 [95% CI, 0.57-0.80]). For every 1% faster increase per week in absolute hematocrit, there was a lower risk for both incident CKD G4-G5 (HR, 0.73 [95% CI, 0.64-0.84]) and eGFR decline of >40% (HR, 0.82 [95% CI, 0.71-0.95]), with results consistent for other biomarkers. Possibility of residual confounding. These results provide reassurance that more rapid decongestion in patients with AHF does not increase the risk of adverse kidney outcomes in patients with heart failure.

Association of Volume Overload With Kidney Function Outcomes Among Patients With Heart Failure With Reduced Ejection Fraction

IntroductionIn patients with heart failure with reduced ejection fraction (HFrEF), volume overload is associated with mortality. Few studies that have examined the relation between volume and long-term kidney function outcomes in HFrEF.MethodsUsing data from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial, we used multivariable Cox regression models to evaluate the association between volume overload as evaluated by B-type natriuretic peptide (BNP) and N-terminal pro B-type natriuretic peptide (NT-proBNP), and a clinical congestion score (scale of 0–12) composed of pedal edema, jugular venous distension, rales, and orthopnea with the occurrence of estimated glomerular filtration rate (eGFR) decline by >40%, and incident chronic kidney disease (CKD) stage ≥4 defined by eGFR of <30 ml/min per 1.73 m2, over a median 10-month follow-up.ResultsAmong 3718 patients (mean eGFR 59 ± 22 ml/min per 1.73 m2), 340 (9%) reached an eGFR decline >40% and 337 (10%) developed incident CKD stage ≥4. In multivariable models, compared with those in the quartile of lowest NT-proBNP, those within the highest quartile had a significantly higher risk of eGFR decline by >40% (hazard ratio [HR] = 2.62 [95% confidence interval {CI} = 1.62, 4.23]) and incident CKD stage ≥4 (HR = 2.66 [95% CI = 1.49, 4.77]), with similar trends for BNP. Similarly in multivariable models, patients in the quartile of highest congestion score had a 48% increased risk for eGFR decline by >40% (HR = 1.48 [95% CI = 1.07, 2.06]) and a 42% increased risk for CKD stage ≥4 (HR = 1.42 [95% CI = 1.01, 1.99]), compared with the lowest quartile.ConclusionVolume overload, as indicated both by elevated natriuretic peptides and clinical signs and symptoms, is associated with increased risk for clinically important kidney function outcomes in HFrEF.

Acute Kidney Function Declines in the Context of Decongestion in Acute Decompensated Heart Failure

ObjectivesThis study aimed to examine whether incorporation of a comprehensive set of measures of decongestion modifies the association of acute declines in kidney function with outcomes. BackgroundIn-hospital acute declines in kidney function occur in approximately 20% to 30% of patients admitted with acute decompensated heart failure (ADHF) and may be associated with adverse outcomes. MethodsUsing data from EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan), we used multivariable Cox regression models to evaluate the association between in-hospital changes in estimated glomerular filtration rate (eGFR) with death and a composite outcome of cardiovascular death and hospitalization for heart failure. We evaluated eGFR declines within the context of changes in markers of volume overload including b-type natriuretic peptide (BNP), N-terminal prohormone of B-type natriuretic peptide (NT-proBNP), and weight, as well as changes in measures of hemoconcentration including hematocrit, albumin, and total protein. ResultsAmong 3,715 patients over a median follow-up of 9.9 months, every 30% decline in eGFR was associated with higher risk of both death (hazard ratio [HR]: 1.19; 95% confidence interval [CI]: 1.07 to 1.31) and the composite outcome (HR: 1.09; 95% CI: 1.01 to 1.18) in adjusted models. The acute decline in eGFR was no longer associated with higher risk of either outcome as long as there was evidence of decongestion, either by declines in BNP, NT-proBNP, or weight or by increases in hematocrit, albumin or total protein. Interaction testing between decline in eGFR and changes in hematocrit, albumin, and total protein was statistically significant (p interaction of <0.01 for death and p interaction of ≤0.01 for composite for all 3 biomarkers). Interaction between change in eGFR and changes in BNP (p interaction = 0.07 for death; p interaction = 0.08 for composite), NT-proBNP (p interaction = 0.15 for death; p interaction = 0.18 for composite) and weight (p interaction = 0.13 for death; p interaction = 0.19 for composite) did not meet statistical significance. ConclusionsOverall, acute declines in eGFR are associated with adverse outcomes, with evidence of modification by changes in markers of decongestion, suggesting that they are no longer associated with adverse outcomes if these markers are concomitantly improving.

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.

Vasopressin and Vasopressin Antagonists in Heart Failure.

Despite the introduction of multiple new pharmacological agents over the past three decades in the field of heart failure (HF), overall prognosis remains poor. Hyponatremia is prevalent in HF patients and has been suggested as a contributor to poor response to standard therapy. Elevated levels of arginine vasopressin (AVP), a peptide hormone produced in the hypothalamus, play a role in development of hyponatremia, and AVP and its surrogate, copeptin, are related to changes in osmolality, hemodynamics, neuro-hormones as well as in overall outcome in HF patients. Of current pharmacological interest are the selective and non-selective vasopressin receptor antagonists (VRAs), which inhibit vasoconstriction and cardiac remodeling mediated by the V1a receptors in smooth blood vessels, and water retention (increased urine osmolality and decreased water excretion) by increasing aquaporin-2 water channels mediated by the V2 receptors in the renal collecting tubules. The optimal use of VRAs is yet to be determined, especially in patients with congestive HF. Although long-term effects on improvement in mortality have not been shown in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, the only long-term outcome trial to date, many short-term studies indicate beneficial aquaretic- and hemodynamic-effects of the VRAs. In contrast to loop diuretics, these new agents tend to increase urine flow and the excretion of electrolyte-free water (so-called aquaresis) in patients with HF, without substantial changes in sodium or potassium excretion. This chapter reviews the role of AVP and copeptin in HF, and the treatment potential of VRAs in HF.

Combining Diuretic Response and Hemoconcentration to Predict Rehospitalization After Admission for Acute Heart Failure.

Both diuretic response and hemoconcentration are indicators of decongestion and have individually been found to predict rehospitalization after admission for acute heart failure (HF). This study examines the value of combining diuretic response and hemoconcentration to better predict patients at low risk for rehospitalization after admission for acute HF. Diuretic response (defined as weight change per 40 mg of furosemide on day 4 after admission) and hemoconcentration (change in hemoglobin at discharge or day 7) were tested both individually and combined to predict the risk of HF and cardiovascular rehospitalization 60 days after hospitalization for acute HF. Analyses were performed in 1180 patients enrolled in the Placebo-Controlled Randomized Study of the Selective Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) trial and validated in 1776 patients enrolled in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial. Poor diuretic response was associated with low systolic blood pressure, high blood urea nitrogen, and history of coronary revascularization in both data sets (all P<0.05). Hemoconcentration was mainly associated with better renal function (P<0.05). Patients who displayed both favorable diuretic response and hemoconcentration had a markedly lower risk of rehospitalization for HF in PROTECT (multivariable HR, 0.41; 95% CI, 0.24 to 0.70; P<0.001) compared with all other patients. This finding was confirmed in EVEREST (multivariable HR, 0.52; 95% CI, 0.33 to 0.82; P=0.004) for patients with favorable diuretic response and hemoconcentration compared with all other patients. Combining 2 indicators of decongestion, hemoconcentration and diuretic response improves risk prediction for early rehospitalization after an admission for acute HF and may provide clinicians with an easily accessible tool to identify low-risk patients. URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00354458 and NCT00071331.

In-Hospital Diuretic Agent Use and Post-Discharge Clinical Outcomes in Patients Hospitalized for Worsening Heart Failure: Insights From the EVEREST Trial

ObjectivesThe aim of this study was to characterize the association between decongestion therapy and 30-day outcomes in patients hospitalized for heart failure (HF). BackgroundLoop diuretic agents are commonly prescribed for the treatment of symptomatic congestion in patients hospitalized for HF, but the association between loop diuretic agent dose response and post-discharge outcomes has not been well characterized. MethodsCox proportional hazards models were used to estimate the association among average loop diuretic agent dose, congestion status at discharge, and 30-day post-discharge all-cause mortality and HF rehospitalization in 3,037 subjects hospitalized with worsening HF enrolled in the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan) study. ResultsIn univariate analysis, subjects exposed to high-dose diuretic agents (≥160 mg/day) had greater risk for the combined outcome than subjects exposed to low-dose diuretic agents (18.9% vs. 10.0%; hazard ratio: 2.00; 95% confidence interval: 1.64 to 2.46; p < 0.0001). After adjustment for pre-specified covariates of disease severity, the association between diuretic agent dose and outcomes was not significant (hazard ratio: 1.11; 95% confidence interval: 0.89 to 1.38; p = 0.35). Of the 3,011 subjects with clinical assessments of volume status, 2,063 (69%) had little or no congestion at hospital discharge. Congestion status at hospital discharge did not modify the association between diuretic agent exposure and the combined endpoint (p for interaction = 0.84). ConclusionsShort-term diuretic agent exposure during hospital treatment for worsening HF was not an independent predictor of 30-day all-cause mortality and HF rehospitalization in multivariate analysis. Congestion status at discharge did not modify the association between diuretic agent dose and clinical outcomes.

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.

Length of hospital stay and 30‐day readmission following heart failure hospitalization: insights from the EVEREST trial

Previous reports have provided conflicting data regarding the relationship between length of stay (LOS) and subsequent readmission risk among patients hospitalized for heart failure (HF). 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 geographic 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. The present analysis included 4020 patients enrolled from 20 countries who were alive at discharge. Median [interquartile range (IQR)] LOS was 8 (4-11) days. The 30-day readmission rates were 15.7% [95% confidence interval (CI) 14.6-16.8] for all-cause; 5.6% (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. 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 (≥14 days) vs. the bottom (≤3 days) quintile for LOS was 1.39 (95% CI 0. 92-2.11) for all-cause readmissions, 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. With the exception of Western Europe, these findings remained largely consistent across geographic regions. In this large multinational cohort of hospitalized HF patients, longer LOS was associated with a higher risk for all-cause, CV non-HF, and non-CV readmissions, but a lower risk of HF readmissions within 30 days of discharge. These results may inform strategies to reduce readmissions.

Abstract 12797: Temporal Changes in Mortality Risk Post-Discharge After Hospitalization for Heart Failure

Importance: In observational studies, the risk for adverse events among patients admitted for heart failure (HF) is highest immediately post-discharge and declines over time. This ‘vulnerable phase’ concept has led to research and quality of care initiatives focusing primarily on early post-discharge period. However, whether this risk trajectory represents lowering of individual patient risk or changes in the population risk profile is not known. Methods: Survival and longitudinal models were used to assess temporal changes in mortality risk post-discharge in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial. Post hoc analysis of EVEREST included 4017 patients &gt;18 years old discharged alive after hospitalization for HF with an ejection fraction of &lt;40% at 359 sites from 2003-2006 and randomized to receive oral tolvaptan or placebo. Results: After a median of 9.8 months, 971 patients died (24.2%). Mortality at 1 year was 24.2%. Cumulative mortality rate declined from 15.9/100 patient-years immediately post-discharge to 13.4 at 30 days and 12.8 at 90 days; it rose steadily thereafter. The risk variation between quintiles of baseline risk was considerably larger than the temporal variation within risk strata. In a longitudinal model assessing updated mortality risk after each follow up visit, mortality risk increased during the 90 days preceding readmission and then followed a trajectory similar to the index admission. The net increase in mortality attributable to readmission was ~37%. Conclusions and Relevance: Among hospitalized HF patients, although there is a transiently elevated risk in 90 days before and after discharge, the patient’s clinical risk profile rather than temporal change remains the main determinant of mortality risk.

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.

Association of low body temperature and poor outcomes in patients admitted with worsening heart failure: a substudy of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial

Risk stratification in patients admitted with worsening heart failure (HF) is essential for tailoring therapy and counselling. Risk models are available but rarely used, in part because many require laboratory and imaging results that are not routinely available. Body temperature is associated with prognosis in other illnesses, and we hypothesized that low body temperature would be associated with worse outcomes in patients admitted with worsening HF. The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial was an event-driven, randomized, double-blind, placebo-controlled study of tolvaptan in 4133 patients hospitalized for worsening HF with an EF <40%. Co-primary endpoints were all-cause mortality and cardiovascular (CV) death or HF rehospitalization. Body temperature was measured orally at randomization and entered in analyses both as a continuous variable and categorized into three groups (<36 °C, 36-36.5 °C, and >36.5 °C) using Cox regression models. The composite of CV death or HF rehospitalization occurred in 1544 patients within 1 year. For every 1 °C decrease in body temperature, the risk of adverse outcomes increased by 16% [hazard raio (HR) 1.16, 95% confidence interval (CI) 1.04-1.28], after adjustment for age, gender, race, systolic blood pressure, EF, blood urea nitrogen, and serum sodium. In fully adjusted analysis, the risk of adverse outcomes in the lowest body temperature group (<36 °C) was 51% higher than that of the index group (>36.5 °C) (HR 1.35, 95% CI 1.15-1.58). Low body temperature is an independent marker of poor cardiovascular outcomes in patients admitted with worsening HF and reduced EF.

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.

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.

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.