Aetiology,timing and clinical predictors of early vs. late readmission following index hospitalization for acute heart failure: insights from ASCEND‐HF

Aims

Patients hospitalized for heart failure (HF) are at high risk for 30‐day readmission. This study sought to examine the timings and causes of readmission within 30 days of an HF hospitalization.

Methods and results

Timing and cause of readmission in the ASCEND‐HF (Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure) trial were assessed. Early and late readmissions were defined as admissions occurring within 0–7 days and 8–30 days post‐discharge, respectively. Patients who died in hospital or remained hospitalized at day 30 post‐randomization were excluded. Patients were compared by timing and cause of readmission. Logistic and Cox proportional hazards regression analyses were used to identify independent risk factors for early vs. late readmission and associations with 180‐day outcomes. Of the 6584 patients (92%) in the ASCEND‐HF population included in this analysis, 751 patients (11%) were readmitted within 30 days for any cause. Overall, 54% of readmissions were for non‐HF causes. The median time to rehospitalization was 11 days (interquartile range: 6–18 days) and 33% of rehospitalizations occurred by day 7. Rehospitalization within 30 days was independently associated with increased risk for 180‐day all‐cause death [hazard ratio (HR) 2.38, 95% confidence interval (CI) 1.93–2.94; P < 0.001]. Risk for 180‐day all‐cause death did not differ according to early vs. late readmission (HR 0.99, 95% CI 0.67–1.45; P = 0.94).

Conclusions

In this hospitalized HF trial population, a significant majority of 30‐day readmissions were for non‐HF causes and one‐third of readmissions occurred in the first 7 days. Early and late readmissions within the 30‐day timeframe were associated with similarly increased risk for death. Continued efforts to optimize multidisciplinary transitional care are warranted to improve rates of early readmission.

     

Employment status at time of first hospitalization for heart failure is associated with a higher risk of death and rehospitalization for heart failure

Aims

Employment status at time of first heart failure (HF) hospitalization may be an indicator of both self‐perceived and objective health status. In this study, we examined the association between employment status and the risk of all‐cause mortality and recurrent HF hospitalization in a nationwide cohort of patients with HF.

Methods and results

We identified all patients of working age (18–60 years) with a first HF hospitalization in the period 1997–2015 in Denmark, categorized according to whether or not they were part of the workforce at time of the index admission. The primary outcome was death from any cause and the secondary outcome was readmission for HF. Cumulative incidence curves, binomial regression and Cox regression models were used to assess outcomes. Of 25 571 patients with a first hospitalization for HF, 15 428 (60%) were part of the workforce at baseline. Patients in the workforce were significantly younger (53 vs. 55 years) more likely to be male (75% vs 64%) and less likely to have diabetes (13% vs 22%) and chronic obstructive pulmonary disease (5% vs 10%) (all P < 0.0001). Not being part of the workforce was associated with a significantly higher risk of death [hazard ratio (HR) 1.59; 95% confidence interval (CI) 1.50–1.68] and rehospitalization for HF (HR 1.09; 95% CI 1.05–1.14), in analyses adjusted for age, sex, co‐morbidities, education level, calendar time, and duration of first HF hospitalization.

Conclusion

Not being part of the workforce at time of first HF hospitalization was independently associated with increased mortality and recurrent HF hospitalization.

     

The interaction of sex,height, and QRS duration on the effects of cardiac resynchronization therapy on morbidity and mortality: an individual‐patient data meta‐analysis

Aims

To explore possible associations that may explain the greater benefit from cardiac resynchronization therapy (CRT) reported amongst women.

Methods and results

In an individual‐patient data meta‐analysis of five randomized controlled trials, all‐cause mortality and the composite of all‐cause mortality or first hospitalization for heart failure (HF) were compared among 794 women and 2702 men assigned to CRT or a control group. Multivariable analyses were performed to assess the impact of sex, QRS duration, HF aetiology, left ventricular end‐diastolic diameter (LVEDD), and height on outcome. Women were shorter, had smaller LVEDD, more often left bundle branch block, and less often ischaemic heart disease, but QRS duration was similar between sexes. Women tended to obtain greater benefit from CRT but sex was not an independent predictor of either outcome. For all‐cause mortality, QRS duration was the only independent predictor of CRT benefit. For the composite outcome, height and QRS duration, but not sex, were independent predictors of CRT benefit. Further analysis suggested increasing benefit with increasing QRS duration amongst shorter patients, of whom a great proportion were women.

Conclusions

In this individual‐patient data meta‐analysis, CRT benefit was greater in shorter patients, which may explain reports of enhanced CRT benefit among women. Further analyses are required to determine whether recommendations on the QRS threshold for CRT should be adjusted for height. ( ClinicalTrials.gov numbers: NCT00170300, NCT00271154, NCT00251251).

     

Daily home BNP monitoring in heart failure for prediction of impending clinical deterioration: results from the HOME HF study

Background

Serial measurement of natriuretic peptides may guide management in heart failure (HF) patients. In previous trials, natriuretic peptides were infrequently monitored, which may undervalue the benefit of this approach.

Methods and results

HOME was an adaptive three‐arm randomized clinical study to test whether home monitoring of BNP could reduce HF‐related death, hospitalization due to acute decompensated HF (ADHF), and ADHF treated with intravenous diuretics in the emergency department or outpatient setting. Enrolment was terminated early because of slow enrolment, low event rates, and the belief that an algorithm for assessing BNP trends was needed. Justification for pooling data from all study arms was made and analysis as a single observational study was performed. The analysis resulted in 107 patients who were monitored for a median of 172 days with BNP measures on a median of 74% of days. BNP values were highly variable within a patient. Dispersion between serial BNPs was calculated to be 39.3%, 57.7%, and 73.6% for 1, 60, and 120 days between measures, respectively. A moving average filter (fBNP) was calculated to reduce day‐to‐day fluctuations and track changes from week to week. There were 27 primary events in 17 362 patient days of monitoring; the hazard ratio for time‐varying fBNP was 2.22 (95% confidence interval 1.48–3.34) per unit natural log (corresponding to a 2.72‐fold change in fBNP level).

Conclusion

The HOME HF study demonstrates the feasibility of home BNP measurement and shows the potential value of fBNP as an index of emerging clinical deterioration. Assessment of the clinical value of this is required.

     

Acutely decompensated heart failure with preserved and reduced ejection fraction present with comparable haemodynamic congestion

Aims

Congestion is a central feature of acute heart failure (HF) and its assessment is important for clinical decisions (e.g. tailoring decongestive treatments). It remains uncertain whether patients with acute HF with preserved ejection fraction (HFpEF) are comparably congested as in acute HF with reduced EF (HFrEF). This study assessed congestion, right ventricular (RV) and renal dysfunction in acute HFpEF, HFrEF and non‐cardiac dyspnoea.

Methods and results

We compared echocardiographic and circulating biomarkers of congestion in 146 patients from the MEDIA‐DHF study: 101 with acute HF (38 HFpEF, 41 HFrEF, 22 HF with mid‐range ejection fraction) and 45 with non‐cardiac dyspnoea. Compared with non‐cardiac dyspnoea, patients with acute HF had larger left and right atria, higher E/e', pulmonary artery systolic pressure and inferior vena cava (IVC) diameter at rest, and lower IVC variability (all P < 0.05). Mid‐regional pro‐atrial natriuretic peptide (MR‐proANP) and soluble CD146 (sCD146), but not B‐type natriuretic peptide (BNP), correlated with echocardiographic markers of venous congestion. Despite a lower BNP level, patients with HFpEF had similar evidence of venous congestion (enlarged IVC, left and right atria), RV dysfunction (tricuspid annular plane systolic excursion), elevated MR‐proANP and sCD146, and renal impairment (estimated glomerular filtration rate; all P > 0.05) compared with HFrEF.

Conclusion

In acute conditions, HFpEF and HFrEF presented in a comparable state of venous congestion, with similarly altered RV and kidney function, despite higher BNP in HFrEF.

     

Prevalence of left ventricular systolic dysfunction in pre‐dialysis and dialysis patients with preserved left ventricular ejection fraction

Aims

Patients with chronic kidney disease (CKD) have an excess of cardiovascular morbidity and mortality, with heart failure (HF) being particularly frequent. Reduced left ventricular ejection fraction (LVEF) defines left ventricular (LV) systolic dysfunction and is associated with poor prognosis. However, CKD patients may have HF symptoms with preserved LVEF. In this subgroup of patients, two‐dimensional speckle tracking echocardiography can detect LV systolic dysfunction by analysing LV myocardial deformation. The present study evaluated the prevalence of impaired LV global longitudinal strain (GLS) in CKD patients with preserved LVEF and its prognostic consequences.

Methods and results

Overall, 200 pre‐dialysis and dialysis patients (65% men, mean age 60 ± 14 years) with CKD stage 3b–5 and preserved LVEF (≥50%) were evaluated. Left ventricular systolic dysfunction despite preserved LVEF was defined by LV GLS ≤15.2% (cut‐off value derived from two standard deviations below the mean value of individuals without structural heart disease). Impaired LV GLS (≤15.2%) despite preserved LVEF was observed in 32% of patients. During a median follow‐up of 33 months (interquartile range 17–62 months), 47% of patients underwent renal transplantation, 9% were admitted with HF, and 28% died. Patients with LV GLS ≤15.2% showed significantly worse cumulative event‐free survival rates of the combined endpoint of HF hospitalization and all‐cause mortality compared to patients with LV GLS >15.2% (log‐rank P = 0.018).

Conclusion

The prevalence of impaired LV GLS despite preserved LVEF in pre‐dialysis and dialysis patients is relatively high. Patients with preserved LVEF but impaired LV GLS have an increased risk of HF hospitalization and all‐cause mortality.

     

Implantable cardioverter‐defibrillators in heart failure patients with reduced ejection fraction and diabetes

Aim

There is limited information on the outcomes after primary prevention implantable cardioverter‐defibrillator (ICD) implantation in patients with heart failure (HF) and diabetes. This analysis evaluates the effectiveness of a strategy of ICD plus medical therapy vs. medical therapy alone among patients with HF and diabetes.

Methods and results

A patient‐level combined‐analysis was conducted from a combined dataset that included four primary prevention ICD trials of patients with HF or severely reduced ejection fractions: Multicenter Automatic Defibrillator Implantation Trial I (MADIT I), MADIT II, Defibrillators in Non‐Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE), and Sudden Cardiac Death in Heart Failure Trial (SCD‐HeFT). In total, 3359 patients were included in the analysis. The primary outcome of interest was all‐cause death. Compared with patients without diabetes (n = 2363), patients with diabetes (n = 996) were older and had a higher burden of cardiovascular risk factors. During a median follow‐up of 2.6 years, 437 patients without diabetes died (178 with ICD vs. 259 without) and 280 patients with diabetes died (128 with ICD vs. 152 without). ICDs were associated with a reduced risk of all‐cause mortality among patients without diabetes [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.46–0.67] but not among patients with diabetes (HR 0.88, 95% CI 0.7–1.12; interaction P = 0.015).

Conclusion

Among patients with HF and diabetes, primary prevention ICD in combination with medical therapy vs. medical therapy alone was not significantly associated with a reduced risk of all‐cause death. Further studies are needed to evaluate the effectiveness of ICDs among patients with diabetes.

     

Transcoronary concentration gradients of circulating microRNAs in heart failure

Aims

Circulating levels of microRNAs (miRNAs) are emergent promising biomarkers for cardiovascular disease. Altered expression of miRNAs has been related to heart failure (HF) and cardiac remodelling. We measured the concentration gradients across the coronary circulation to assess their usefulness to diagnose HF of different aetiologies.

Methods and results

Circulating miRNAs were measured in plasma samples simultaneously obtained from the aorta and the coronary venous sinus in patients with non‐ischaemic HF (NICM‐HF, n = 23) ischaemic HF (ICM‐HF, n = 41), and in control patients (n = 11). A differential modulation of circulating levels of miR‐423, ‐34a, ‐21‐3p, ‐126, ‐199 and ‐30a was found across the aetiology groups. Interestingly, a positive transcoronary gradient was found for miR‐423 (P < 0.001) and miR‐34a (P < 0.001) only in the ICM‐HF group. On the contrary, a positive gradient was found for miR‐21‐3p (P < 0.001) and miR‐30a (P = 0.030) only in the NICM‐HF group. Finally, no significant variations were observed in the transcoronary gradient of miR‐126 or miR‐199.

Conclusions

The present findings suggest that circulating levels of miRNAs are differentially expressed in patients with HF of different aetiologies. The presence of a transcoronary concentration gradient suggests a selective release of miRNAs by the failing heart into the coronary circulation. The presence of aetiology‐specific transcoronary concentration gradients in HF patients might provide important information to better understand their role in HF, and suggests they could be useful biomarkers to distinguish HF of different aetiologies.

     

Factors associated with underuse of mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction: an analysis of 11 215 patients from the Swedish Heart Failure Registry

Aim

Mineralocorticoid receptor antagonists (MRAs) improve outcomes in heart failure with reduced ejection fraction (HFrEF), but are underutilized. Hyperkalaemia may be one reason, but the underlying reasons for underuse are unknown. The aim of this study was to investigate the independent predictors of MRA underuse in a large and unselected HFrEF cohort.

Methods and results

We included patients with HFrEF (ejection fraction <40%), New York Heart Association (NYHA) class II–IV and heart failure (HF) duration ≥6 months from the Swedish HF Registry. Logistic regression analysis identified independent associations between 39 demographic, clinical, co‐treatment, and socioeconomic predictors and MRA non‐use. Of 11 215 patients, 27% were women; mean age was 75 ± 11 years; only 4443 (40%) patients received MRA. Selected characteristics independently associated with MRA non‐use were in descending order of magnitude: lower creatinine clearance (<60 mL/min), no need for diuretics, no cardiac resynchronization therapy/implantable cardioverter‐defibrillator, higher blood pressure, no digoxin use, higher ejection fraction, outpatient setting, older age, lower income, ischaemic heart disease, male sex, follow‐up in primary vs. specialty care, lower NYHA class, and absence of hypertension diagnosis. Plasma potassium and N‐terminal pro B‐type natriuretic peptide levels were not associated with MRA non‐use.

Conclusion

Mineralocorticoid receptor antagonists remain underused in HFrEF. Their use does not decrease with elevated potassium but does with impaired renal function, even in the creatinine clearance 30–59.9 mL/min range where MRAs are not contraindicated. MRA underuse may be further related to non‐specialist care, milder HF and no use of other HF therapy.

     

Adaptive servo‐ventilation for central sleep apnoea in systolic heart failure: results of the major substudy of SERVE‐HF

Aims

The SERVE‐HF trial investigated the impact of treating central sleep apnoea (CSA) with adaptive servo‐ventilation (ASV) in patients with systolic heart failure. A preplanned substudy was conducted to provide insight into mechanistic changes underlying the observed effects of ASV, including assessment of changes in left ventricular function, ventricular remodelling, and cardiac, renal and inflammatory biomarkers.

Methods and results

In a subset of the 1325 randomised patients, echocardiography, cardiac magnetic resonance imaging (cMRI) and biomarker analysis were performed at baseline, and 3 and 12 months. In secondary analyses, data for patients with baseline and 12‐month values were evaluated; 312 patients participated in the substudy. The primary endpoint, change in echocardiographically determined left ventricular ejection fraction from baseline to 12 months, did not differ significantly between the ASV and the control groups. There were also no significant between‐group differences for changes in left ventricular dimensions, wall thickness, diastolic function or right ventricular dimensions and ejection fraction (echocardiography), and on cMRI (in small patient numbers). Plasma N‐terminal pro B‐type natriuretic peptide concentration decreased in both groups, and values were similar at 12 months. There were no significant between‐group differences in changes in cardiac, renal and systemic inflammation biomarkers.

Conclusion

In patients with systolic heart failure and CSA, addition of ASV to guideline‐based medical management had no statistically significant effect on cardiac structure and function, or on cardiac biomarkers, renal function and systemic inflammation over 12 months. The increased cardiovascular mortality reported in SERVE‐HF may not be related to adverse remodelling or worsening heart failure.

     

Association between mean systolic and diastolic blood pressure throughout the follow‐up and cardiovascular events in acute myocardial infarction patients with systolic dysfunction and/or heart failure: an analysis from the High‐Risk Myocardial Infarction Database Initiative

Background

Observational data have described the association of blood pressure (BP) with mortality as ‘J‐shaped’, meaning that mortality rates increase below a certain BP threshold. We aimed to analyse the associations between BP and prognosis in a population of acute myocardial infarction (MI) patients with heart failure (HF) and/or systolic dysfunction.

Methods and results

The datasets included in this pooling initiative are derived from four trials: CAPRICORN, EPHESUS, OPTIMAAL, and VALIANT. A total of 28 771 patients were included in this analysis. Arithmetic means of all office BP values measured throughout follow‐up were used. The primary outcome was cardiovascular death. The mean age was 65 ± 11.5 years and 30% were female. Patients in the lower systolic BP (SBP) quintiles had higher rates of cardiovascular death (reference: SBP 121–128 mmHg) [adjusted hazard ratio (HR) 2.49, 95% confidence interval (CI) 2.26–2.74 for SBP ≤112 mmHg, and HR 1.29, 95% CI 1.16–1.43 for SBP 113–120 mmHg]. The findings for HF hospitalization and MI were similar. However, stroke rates were higher in patients within the highest SBP quintile (reference: SBP 121–128 mmHg) (HR 1.38, 95% CI 1.11–1.72). Patients who died had a much shorter follow‐up (0.7 vs. 2.1 years), less BP measurements (4.6 vs. 9.8) and lower mean BP (–8 mmHg in the last SBP measurement compared with patients who remained alive during the follow‐up), suggesting that the associations of low BP and increased cardiovascular death represent a reverse causality phenomenon.

Conclusion

Systolic BP values <125 mmHg were associated with increased cardiovascular death, but these findings likely represent a reverse causality phenomenon.

     

Proteomic diversity of high‐density lipoprotein explains its association with clinical outcome in patients with heart failure

Aims

Previously, low high‐density lipoprotein (HDL) cholesterol was found to be one of the strongest predictors of mortality and/or heart failure (HF) hospitalisation in patients with HF. We therefore performed in‐depth investigation of the multifunctional HDL proteome to reveal underlying pathophysiological mechanisms explaining the association between HDL and clinical outcome.

Methods and results

We selected a cohort of 90 HF patients with 1:1 cardiovascular death/survivor ratio from BIOSTAT‐CHF. A novel optimised protocol for selective enrichment of lipoproteins was used to prepare plasma. Enriched lipoprotein content of samples was analysed using high resolution nanoscale liquid chromatography‐mass spectrometry‐based proteomics, utilising a label free approach. Within the HDL proteome, 49 proteins significantly differed between deaths and survivors. An optimised model of 12 proteins predicted death with 76% accuracy (Nagelkerke R²=0.37, P < 0.001). The strongest contributors to this model were filamin‐A (related to crosslinking of actin filaments) [odds ratio (OR) 0.31, 95% confidence interval (CI) 0.15–0.61, P = 0.001] and pulmonary surfactant‐associated protein B (related to alveolar capillary membrane function) (OR 2.50, 95% CI 1.57–3.98, P < 0.001). The model predicted mortality with an area under the curve of 0.82 (95% CI 0.77–0.87, P < 0.001). Internal cross validation resulted in 73.3 ± 7.2% accuracy.

Conclusion

This study shows marked differences in composition of the HDL proteome between HF survivors and deaths. The strongest differences were seen in proteins reflecting crosslinking of actin filaments and alveolar capillary membrane function, posing potential pathophysiological mechanisms underlying the association between HDL and clinical outcome in HF.

     

A flattening oxygen consumption trajectory phenotypes disease severity and poor prognosis in patients with heart failure with reduced,mid‐range,and preserved ejection fraction

Background

In heart failure (HF), a flattening oxygen consumption (VO₂) trajectory during cardiopulmonary exercise test (CPET) reflects an acutely compromised cardiac output. We hypothesized that a flattening VO₂ trajectory is helpful in phenotyping disease severity and prognosis in HF with either reduced (HFrEF), mid‐range (HFmrEF), or preserved (HFpEF) ejection fraction.

Methods and results

Overall, 319 HF patients (198 HFrEF, 80 HFmrEF, and 41 HFpEF) underwent CPET. A flattening VO₂ trajectory was tracked and defined as an inflection of VO₂ linearity as a function of work rate with a second slope downward inflection >35% extent of the first one. Peak VO₂, the minute ventilation/carbon dioxide production (VE/VCO₂) slope, and the presence of exercise oscillatory ventilation (EOV) were also determined. Pulmonary artery systolic pressure (PASP) and tricuspid annular plane systolic excursion (TAPSE) were measured by echocardiography. A flattening VO₂ occurred in 92 patients (28.8%). PASP and TAPSE at rest were significantly higher and lower (P < 0.001), respectively. The primary outcome was the combination of all‐cause death, heart transplantation and left ventricular assist device implantation. The secondary outcome was the primary outcome plus hospitalization for cardiac reasons. In the multivariate model including peak VO₂, VE/VCO₂ slope, EOV and VO₂ trajectory, a flattening VO₂ trajectory and EOV were retained in the regression for primary (X² = 35.78, and 36.36, respectively; P < 0.001) and secondary (X² = 12.45 and 47.91, respectively; P < 0.001) outcomes.

Conclusions

Results point to a flattening VO₂ trajectory as a likely new and strong predictor of events in HF with any ejection fraction. Given the relation of right‐sided cardiac dysfunction to pulmonary hypertension, this oxygen pattern might suggest a real‐time decrease in pulmonary blood flow to the left heart.

     

Contribution of cardiac and extra‐cardiac disease burden to risk of cardiovascular outcomes varies by ejection fraction in heart failure

Aims

Patients with heart failure (HF) often have multiple co‐morbidities that contribute to the risk of adverse cardiovascular (CV) and non‐CV outcomes. We assessed the relative contribution of cardiac and extra‐cardiac disease burden and demographic factors to CV outcomes in HF patients with reduced (HFrEF) or preserved (HFpEF) left ventricular ejection fraction (LVEF).

Methods and results

We utilized data from the CHARM trial, which enrolled HF patients across the ejection fraction spectrum. We decomposed the previously validated MAGGIC risk score into cardiac (LVEF, New York Heart Association class, systolic blood pressure, time since HF diagnosis, HF medication use), extra‐cardiac (body mass index, creatinine, diabetes mellitus, chronic obstructive pulmonary disease, smoker), and demographic (age, gender) categories, and calculated subscores for each patient representing the burden of each component. Cox proportional hazards models were used to estimate the population attributable risk (PAR) associated with each component to the outcomes of death, CV death, HF, myocardial infarction, and stroke relative to patients with the lowest risk score. PARs for each component were depicted across the spectrum of LVEF. in 2675 chronic HF patients from North America [HFrEF (LVEF ≤40%): n = 1589, HFpEF (LVEF >40%): n = 1086] with data available for calculation of the MAGGIC score, the highest risk of death and CV death was attributed to cardiac burden. This was especially evident in HFrEF patients (PAR: 76% cardiac disease vs. 58% extra‐cardiac disease, P < 0.05). Conversely, in HFpEF patients, extra‐cardiac burden accounted for a greater proportion of risk for death than cardiac burden (PAR: 15% cardiac disease vs. 49% extra‐cardiac disease, P < 0.05). For HF hospitalization, the contribution of both cardiac and extra‐cardiac burden was comparable in HFpEF patients (PAR: 42% cardiac disease vs. 53% extra‐cardiac disease, P = NS). In addition, demographic burden was especially high in HFpEF patients, with 62% of deaths attributable to demographic characteristics.

Conclusion

In North American HF patients enrolled in the CHARM trials, the relative contribution of cardiac and extra‐cardiac disease burden to CV outcomes and death differed depending on LVEF. The high risk of events attributable to non‐cardiac disease burden may help explain why cardiac disease‐modifying medication proven to be efficacious in HFrEF patients has not proven beneficial in HFpEF.

     

Pre‐discharge and early post‐discharge troponin elevation among patients hospitalized for heart failure with reduced ejection fraction: findings from the ASTRONAUT trial

Aims

Troponin levels are commonly elevated among patients hospitalized for heart failure (HF), but the prevalence and prognostic significance of early post‐discharge troponin elevation are unclear. This study sought to describe the frequency and prognostic value of pre‐discharge and post‐discharge troponin elevation, including persistent troponin elevation from the inpatient to outpatient settings.

Methods and results

The ASTRONAUT trial (NCT00894387; http://www.clinicaltrials.gov ) enrolled hospitalized HF patients with ejection fraction ≤40% and measured troponin I prior to discharge (i.e. study baseline) and at 1‐month follow‐up in a core laboratory (elevation defined as >0.04 ng/mL). This analysis included 1469 (91.0%) patients with pre‐discharge troponin data. Overall, 41.5% and 29.9% of patients had elevated pre‐discharge [median: 0.09 ng/mL; interquartile range (IQR): 0.06–0.19 ng/mL] and 1‐month (median: 0.09 ng/mL; IQR: 0.06–0.15 ng/mL) troponin levels, respectively. Among patients with pre‐discharge troponin elevation, 60.4% had persistent elevation at 1 month. After adjustment, pre‐discharge troponin elevation was not associated with 12‐month clinical outcomes. In contrast, 1‐month troponin elevation was independently predictive of increased all‐cause mortality [hazard ratio (HR) 1.59, 95% confidence interval (CI) 1.18–2.13] and cardiovascular mortality or HF hospitalization (HR 1.28, 95% CI 1.03–1.58) at 12 months. Associations between 1‐month troponin elevation and outcomes were similar among patients with newly elevated (i.e. normal pre‐discharge) and persistently elevated levels (interaction P ≥ 0.16). The prognostic value of 1‐month troponin elevation for 12‐month mortality was driven by a pronounced association among patients with coronary artery disease (interaction P = 0.009).

Conclusions

In this hospitalized HF population, troponin I elevation was common during index hospitalization and at 1‐month follow‐up. Elevated troponin I level at 1 month, but not pre‐discharge, was independently predictive of increased clinical events at 12 months. Early post‐discharge troponin I measurement may offer a practical means of risk stratification and should be investigated as a therapeutic target.

     

Effect of digoxin in patients with heart failure and mid‐range (borderline) left ventricular ejection fraction

Aims

To evaluate the effects of digoxin in patients with the newly described phenotype of heart failure (HF) and mid‐range ejection fraction (HFmrEF), attributed to mild left ventricular systolic dysfunction.

Methods and results

We carried out a retrospective analysis of the Digitalis Investigation Group (DIG) trial which had 7788 patients available for analysis with a left ventricular ejection fraction (LVEF) ranging between 3% and 85%. We compared the effect of digoxin to placebo in three mutually exclusive groups of patients defined by LVEF category: <40% (HF with reduced LVEF, HFrEF, n = 5874), 40–49% (HFmrEF, n = 1195) and ≥50% (HF with preserved LVEF, HFpEF, n = 719). The primary outcome was the composite of cardiovascular death or HF hospitalisation. Patients with HFmrEF resembled patients with HFrEF, more than those with HFpEF, with respect to age, sex and aetiology but were more like HFpEF patients with respect to blood pressure and the prevalence of hypertension. Event rates in patients with HFmrEF were similar to those in HFpEF and much lower than in HFrEF. Digoxin reduced the primary endpoint in patients with HFrEF, mainly due to reduced HF hospitalisation: the digoxin/placebo hazard ratio (HR) for HF hospitalisation was 0.71 [95% confidence interval (CI) 0.65–0.77]. The digoxin/placebo HR for HF hospitalisation in patients with HFmrEF was 0.80 (95% CI 0.63–1.03) and 0.85 (95% CI 0.62–1.17) in those with HFpEF. The digoxin/placebo HR for the composite of HF death or HF hospitalisation was 0.74 (95% CI 0.68–0.81) in HFrEF, 0.83 (95% CI 0.66–1.05) in HFmrEF and 0.88 (95% CI 0.65–1.19) in HFpEF.

Conclusions

In this study, event rates in patients with HFmrEF were closer to those in HFpEF than HFrEF. Digoxin had most effect on HF hospitalisation in patients with HFrEF, an intermediate effect in HFmrEF, and the smallest effect in HFpEF.

     

Validation of U.S. mortality prediction models for hospitalized heart failure in the United Kingdom and Japan

Aims

Prognostic models for hospitalized heart failure (HHF) were developed predominantly for patients of European origin in the United States of America; it is unclear whether they perform similarly in other health care systems or for different ethnicities. We sought to validate published prediction models for HHF in the United Kingdom (UK) and Japan.

Methods and results

Patients in the UK (n =894) and Japan (n =3158) were prospectively enrolled and were similar in terms of sex (～60% men) and median age (～77 years). Models predicted that British patients would have a higher mortality than Japanese, which was indeed true both for in‐hospital (4.8% vs. 2.5%) and 180‐day (20.7% vs. 9.5%) mortality. The model c‐statistics for the published/derivation (range 0.70–0.76) and Japanese (range 0.75–0.77) cohorts were similar and higher than for the UK (0.62–0.75) but models consistently overestimated mortality in Japan. For in‐hospital mortality, the OPTIMIZE‐HF model performed best, providing similar discrimination in published/derivation, UK and Japanese cohorts [c‐indices: 0.75 (0.74–0.77); 0.75 (0.68–0.81); and 0.77 (0.70–0.83), respectively], and least overestimated mortality in Japan. For 180‐day mortality, the c‐statistics for the ASCEND‐HF model were similar in published/derivation (0.70) and UK [0.69 (0.64–0.74)] cohorts but higher in Japan [0.75 (0.71–0.79)]; calibration was good in the UK but again overestimated mortality in Japan.

Conclusion

Calibration of published prediction models appears moderately accurate and unbiased when applied to British patients but consistently overestimates mortality in Japan. Identifying the reason why patients in Japan have a better than predicted prognosis is of great interest.

     

Real‐world incidence of efficacy and safety outcomes in patients on direct oral anticoagulants with left ventricular systolic dysfunction at a tertiary referral center

Background

Patients with heart failure (HF) have increased risk for thromboembolic events. Real‐world incidences of efficacy and safety outcomes of direct oral anticoagulants (DOACs) in patients with left ventricular systolic dysfunction (LVSD) are of growing clinical interest.

Hypothesis

Real‐world efficacy and safety outcomes of DOACs in patients with LVSD will be similar to those of LVSD or HF subgroups in the RE‐LY, ROCKET‐AF, and ARISTOTLE trials.

Methods

We performed a retrospective review of adult patients with LVSD (left ventricular ejection fraction ≤40%) on DOAC therapy between 2010 and 2016. Incidences of safety and efficacy outcomes of anticoagulation with DOACs were extracted from primary and secondary hospital discharge diagnoses.

Results

DOACs were prescribed to 287 patients with LVSD over a mean follow‐up of 313.3 ± 52.3 days. Many patients had moderate and severe chronic kidney disease (28.9% and 10.1%, respectively) and indications for anticoagulation therapy other than atrial fibrillation (19.9%). For efficacy outcomes, the calculated incidence rates of ischemic stroke and systemic embolism were 1.2 (95% confidence interval [CI]: 0.25‐3.56) and 0.81 (95% CI: 0.10‐2.94) events per 100 person‐years, respectively. For the safety outcomes, incidence rates of GI bleeding and intracranial hemorrhage were 2.4 (95% CI: 0.8‐5.3) and 0.41 (95% CI: 0.1‐2.2) events per 100 patient‐years, respectively.

Conclusions

Our findings are largely compatible with the results of LVSD or HF subgroups in RE‐LY, ROCKET‐AF, and ARISTOTLE trials and add to increasing confidence that DOACs can be safely used for stroke and systemic embolism prevention in patients with LVSD.