Mortality In Heart Failure With Reduced Ejection Fraction Patients Research Articles

Association of Positive TwaVR/STaVR ECG Changes with Adverse Outcomes in Heart Failure Patients with Reduced Ejection Fraction Undergoing CABG in Turkey: A Retrospective Study.

Positive T-wave polarity in the augmented vector right lead (Tw-aVR) and ST-segment deviation in the augmented vector right lead (STaVR) have been identified as potential predictors of adverse outcomes in various cardiac conditions. The aim of the study was to examine the effect of positive Tw-aVR and STaVR on in-hospital mortality after coronary artery bypass grafting (CABG) surgery in patients with heart failure with reduced ejection fraction (HFrEF). A five-year retrospective study was conducted on 250 HFrEF patients who underwent CABG at a tertiary care hospital between January 2018 and December 2022. The primary outcome was in-hospital mortality, and the main exposures were positive Tw-aVR and STaVR on preoperative electrocardiograms. Logistic regression models were used to assess the factors associated with in-hospital mortality. Two hundred and fifty patients with a mean age of 67.4 ± 8.1 years were studied. Males constituted 68% of the participants. Among the participants, 60 (24%) had positive Tw-aVR, and 96 (38.4%) had STaVR. The overall in-hospital mortality rate was 7.6%, and patients with positive Tw-aVR and STaVR had significantly higher mortality rates than those without (odds ratio: 3.62 and 2.87, respectively, P < 0.01). These associations remained significant even after controlling for potential confounders such as age (adjusted odds ratio [AOR]: 1.11; 95% confidence interval [CI]: 1.03-1.20; P = 0.008), sex (AOR: 0.82; 95% CI: 0.31-2.18; P = 0.684), diabetes mellitus (AOR: 2.12; 95% CI: 0.88-5.12; P = 0.091), and chronic kidney disease (AOR: 1.79; 95% CI: 0.75-4.27; P = 0.194). Positive Tw-aVR and STaVR were found to be associated with in-hospital mortality in HFrEF patients after CABG. These findings suggest that identifying patients with positive Tw-aVR and STaVR may help identify those at higher risk of adverse outcomes and facilitate closer monitoring and more aggressive interventions.

Safety of midodrine in patients with heart failure with reduced ejection fraction: a retrospective cohort study.

Background: Heart failure with reduced ejection fraction (HFrEF) poses significant health risks. Midodrine for maintaining blood pressure in HFrEF, requires further safety investigation. This study explores midodrine's safety in HFrEF through extensive matched analysis. Methods: Patients with HFrEF (LVEF <50%) without malignancy, non-dialysis dependence, or non-orthostatic hypotension, were enrolled between 28 August 2013, and 27 August 2023. Propensity score matching (PSM) created 1:1 matched groups. Outcomes included mortality, stage 4 and 5 chronic kidney disease (CKD), emergency room (ER) visits, intensive care unit (ICU) admissions, hospitalizations, and respiratory failure. Hazard ratios (HR) with 95% confidence intervals (95% CI) were calculated for each outcome, and Kaplan-Meier survival analysis was performed. Subgroup analyses were conducted based on gender, age (20-<65 vs. ≥65), medication refill frequency, and baseline LVEF. Results: After 1:1 PSM, 5813 cases were included in each group. The midodrine group had higher risks of respiratory failure (HR: 1.16, 95% CI: 1.08-1.25), ICU admissions (HR: 1.14, 95% CI: 1.06-1.23), hospitalizations (HR: 1.21, 95% CI: 1.12-1.31), and mortality (HR: 1.090, 95% CI: 1.01-1.17). Interestingly, midodrine use reduced ER visits (HR: 0.77, 95% CI: 0.71-0.83). Similar patterns of lower ER visit risk and higher risks for ICU admissions, respiratory failure, and overall hospitalizations were observed in most subgroups. Conclusion: In this large-scale study, midodrine use was associated with reduced ER visits but increased risks of respiratory failure, prolonged ICU stays, higher hospitalizations, and elevated mortality in HFrEF patients. Further research is needed to clarify midodrine's role in hemodynamic support and strengthen existing evidence.

Iron Deficiency: A Silent Threat in Patients With Heart Failure With Reduced Ejection Fraction.

Background Iron deficiency is a prevalent and clinically significant comorbidity in patients with heart failure with reduced ejection fraction (HFrEF). Despite its high prevalence, its impact on clinical outcomes, mortality, and various physiological parameters remains a subject of ongoing investigation. The findings of this study are anticipated to contribute valuable insights into the management and prognosis of patients with HFrEF, potentially informing future interventions and improving patient outcomes. This study aimed to assess the clinical profile of iron deficiency and its implications on morbidity and mortality in patients with HFrEF. Methodology A prospective cohort study was conducted at King Edward Memorial Hospital, India, involving 371 patients with HFrEF. Participants underwent comprehensive clinical and laboratory assessments, evaluating iron deficiency with signs, symptoms, comorbidities, dyspnea, elevated jugular venous pressure (JVP), past medical history, and various hematological and biochemical parameters. Results Overall, 50% of HFrEF participants were iron deficient (n = 185), of whom 80% (n = 148) had anemia against 43% (n = 81) anemics in iron repletes (n = 186). Of the 185 iron-deficient patients, 44 (11.86%) had absolute iron deficiency and 141 (38%)had functional iron deficiency. Iron deficiency significantly correlated with increased mortality in HFrEF patients (χ2 (1, N = 371) = 3.88, p = 0.048). A large positive correlation was observed between absolute iron deficiency and dyspnea severity (r2 = 0.949, p = 0.026).Statistically significant differences were found in hemoglobin (anemia), serum iron, serum ferritin, total iron-binding capacity, and transferrin saturation between iron-deficient and iron-replete patients (p < 0.05). However, no statistically significant difference in left ventricular ejection fraction between iron-deficient and replete patients was noted. Conclusions Iron deficiency emerges as more than a mere comorbidity in heart failure, becoming a prognostic factor with multifaceted outcomes. Its impact extends beyond cardiovascular consequences, encompassing adverse manifestations such as anemia, ascites, edema, dyspnea, elevated JVP, and a heightened risk of mortality. This intricate interplay positions iron deficiency as a critical determinant, significantly influencing the clinical trajectory and outcomes for patients with HFrEF.

The effects of Digoxin use on long-term prognosis in patients with heart failure with reduced ejection fraction.

This study aimed to investigate the effect of digoxin on mortality and rehospitalization in heart failure with reduced ejection fraction (HFrEF) patients. Heart failure is a clinical syndrome that requires frequent rehospitalization and has a high mortality. This study aimed to investigate the effect of digoxin on mortality and rehospitalization in patients with heart failure with reduced ejection fraction. The study included 326 patients with HFrEF that were hospitalized for decompensation between September 2014 and January 2016. The patients were divided into two groups: digoxin users and a control group. The study's endpoints were cardiovascular death and rehospitalization after 24-month long-term follow-ups. Rehospitalization was lower in patients taking digoxin (25% vs. 47%, p = 0.001). The mean age of patients taking digoxin (n: 78) was 63.7 ± 12.4 years, among which 64% were males. The mean age of the control group was 65.4 ± 11.8 years, among which 74% were males. However, there was no difference in mortality between the two groups (34% vs. 45%, p = 0.10). While Kaplan-Meier curves revealed no significant differences between mortality rates in the groups (log-rank p = 0.508), a statistical difference was found between the groups in rehospitalization rates (log-rank p = 0.013). A multiple linear regression analysis revealed that smoking (HR: 1.97, CI: 1.24-3.11, p = 0.004), systolic blood pressure (HR: 0.983, CI: 0.974-0.992, p < 0.001), atrial fibrillation (HR: 2.09, CI: 1.17-3.72, p = 0.012), C-reactive protein (CRP) (HR: 1.009, CI: 1.003-1.015, p = 0.004), beta-blockers (HR: 0.891, CI: 0.799-0.972, p = 0.009), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (HR: 0.778, CI: 0.641-0.956, p < 0.001), mineralocorticoid receptor antagonists (HR: 0.41, CI:0.26-0.65, p < 0.001), and digoxin use (HR: 0.59, CI: 0.43-0.80, p = 0.001) are independent predictors of rehospitalization in patients with HFrEF. Our results show that digoxin use does not affect mortality in HFrEF patients. However, rehospitalization decreased in patients taking digoxin in HFrEF.

Cardiac implantable electronic devices and outcomes in heart failure patients with syncope

Abstract Funding Acknowledgements Type of funding sources: Private hospital(s). Main funding source(s): Mayo Clinic Background/Introduction Syncope is a common presentation in heart failure (HF) patients. However, the associations between syncope and prognosis in HF patients with the cardiac implantable electronic device (CIED) have not been demonstrated. It is unclear whether syncope increases all-cause mortality in HF patients with CIED. Purpose We aimed to examine the association between syncope and all-cause mortality in the largest cohort of HF with reduced ejection fraction (HFrEF), mid-ranged ejection fraction (HFmEF), and preserved ejection fraction (HFpEF) patients with and without CIED. Methods A retrospective cohort of patients with HF and syncope at our hospital between 2010 and 2015 were identified, and 1:1 propensity was matched with a control group of HF patients without syncope. A chart review was conducted. The multivariate Cox regression model was applied to estimate the association between syncope and the all-cause mortality endpoint. Results 3,449 HF patients were diagnosed with syncope (mean age, 72.8±14.5 years; 41.5% women), and the propensity-matched control HF patients without syncope (n=3,449) aged 72.8±14.3 years, and 42.5% women were selected. Cardiac implantable electronic devices were implanted more in HF patients with syncope (32.5% versus 13.7%, p&amp;lt;0.001). Implantable cardioverter defibrillators were implanted more in HF patients with syncope (15.6% versus 8.3%, p&amp;lt;0.001) as well as pacemakers (16.9% versus 7.5%, p&amp;lt;0.001) and cardiac resynchronization therapy devices (6.9% versus 4.8%, p=0.015). Among HF patients with CIED, syncope significantly increased the risk of all-cause mortality in HFrEF patients (hazard ratio [HR]=1.479, 95% confidence interval [CI]: 1.197-1.828, p&amp;lt;0.001) but not in HFpEF (HR=0.980, 95%CI: 0.793-1.210, p=0.849)(Figure 1). Syncope also tended to increase the risk of all-cause mortality in HFmEF patients with CIED but was not significant (HR=1.193, 95%CI: 0.762-1.865, p=0.762)(Figure 1). Among HF patients without CIED, syncope did not increase the risk of all-cause mortality in HFrEF (HR=0.923, 95%CI: 0.806-1.057, p=0.247), HFmEF (HR=1.074, 95%CI: 0.848-1.360, p=0.554), or HFpEF (HR=0.964, 95%CI: 0.883-1.052, p=0.406). Conclusions Syncope significantly increased the risk of all-cause mortality in HFrEF patients but not in HFmEF or HFpEF patients with CIED. The association of syncope and increased mortality in HFrEF patients with CIED suggests that syncope may be a marker and a factor of mortality and warrants further investigation.

Retrospective analysis of SGLT2 inhibitors in heart failure with preserved ejection fraction.

Heart failure (HF) is one of the leading causes of cardiovascular morbidity and mortality. HF with preserved ejection fraction (HFpEF), or diastolic failure, accounts for half of all HF cases and differs from HF with reduced ejection fraction (HFrEF). Patients with HFpEF are typically older, female, and commonly seen with chronic kidney disease (CKD), one of the leading independent risk factors for mortality in these patients. Unfortunately, drugs that had shown significant improvements in mortality in HFrEF have not shown similar benefits in HFpEF. Recently, sodium glucose transporter 2 inhibitors (SGLT2i) have been shown to reduce cardiovascular morbidity and mortality in HFrEF patients and slow down CKD progression. This study aimed to elucidate the impact of this drug class on mortality and risk of end stage renal disease in patients with HFpEF, which is currently unclear. We retrospectively analysed the Research Data Warehouse containing electronic health records from de-identified patients (n=1266290) from the University of Mississippi Medical Center from 2013 to 2022. HFpEF patients had an average follow-up of 4±2years. Factors associated with increased all-cause mortality during HFpEF included age, male sex, and CKD. Interestingly, the only treatments associated with significant improvements in survival were angiotensin converting enzyme inhibitors/angiotensin receptor blockers and SGLT2i, regardless of CKD or diabetes status. Additionally, SGLT2i use was also associated with significant decrease in the risk of end stage renal disease. Our results support the use of SGLT2i in an HFpEF population with relatively high rates of hypertension, CKD, and black race and suggests that improvements in mortality may be through preserving kidney function.

How to identify patients with low muscle mass linked to physical capacity and physical activity in heart failure

Abstract Introduction Skeletal muscle wasting is frequent in heart failure (HF) patients, and low muscle mass (MM) is associated with increased morbidity and mortality. Current recommendations suggest the usage of dual-energy X-ray absorptiometry (DXA)-derived appendicular lean mass (ALM) adjusted for height squared to identify low MM. However, it has recently been suggested that ALM adjusted for body mass index (BMI) has a higher predictive value. The relationships between low MM, muscle strength, exercise capacity and daily physical activity (PA) are poorly understood in heart failure with reduced ejection fraction (HFrEF). Purpose This study examined the relationships between low MM defined by two different indices and muscle strength, physical capacity tests and accelerometer measurements. Methods A total of 104 HFrEF patients underwent DXA, maximal isometric knee-extensor strength test, cardiopulmonary exercise testing, 6-minute walking test and accelerometry. Two adjusted indices for low MM were assessed: ALM/m2 and ALM/BMI. We performed Pearson correlations to examine the relationships between low MM and muscle strength, exercise capacity and daily PA. Furthermore, we identified patients with low MM based on the two indices. For ALM/m2 we used guideline-recommended cut-offs and for ALM/BMI we used the mean value since no cut-offs has been validated. Results The ALM/m2-index showed no significant correlation to peak oxygen uptake (VO2peak), 6-minute walking distance (6MWD), average PA or daily time spent in moderate-to-vigorous physical activity (MVPA). A moderate correlation was found to maximal muscle strength was found (r=0.61, p&amp;lt;0.001). The ALM/BMI-index was moderately correlated to maximal muscle strength (r=0.65, p&amp;lt;0.001), VO2peak (r=0.40, p&amp;lt;0.001), 6MWD (r=0.41, p&amp;lt;0.001), average daily PA (r=0.27, p=0.012) and daily time spent in MVPA (r=0.29, p=0.007). Patients with low MM identified by ALM/m2 did not differ from patients with preserved MM with regards to VO2peak, 6MWD or accelerometer measurements. A difference in maximal muscle strength was found (95.7±35.6 Nm vs 116±44.8, p=0.02). Patients with low MM identified by ALM/BMI had lower maximal muscle strength (94.8±36.1 Nm vs 121.9±44.4 Nm, p=0.001), lower VO2peak (13.2±3.5 mL/kg/min vs 16.4±3.7 mL/kg/min, p&amp;lt;0.001), shorter 6MWD (370.5±99.4 m vs 467.3±93.9 m, p&amp;lt;0.001), average daily PA (15.1±4.4 ENMO* vs 17.3±5.3 ENMO*, p=0.04) and daily time spent in MVPA (14.2±16.7 min vs 24.7±21.6 min, p=0.01) compared to patients with preserved MM. Conclusion In HFrEF patients low MM identified by ALM/BMI seems to correlate better to well-established markers for physical capacity (VO2peak and 6MWD), muscle strength and daily PA compared to ALM/m2. No cut-offs have been established for ALM/BMI and there is a need for longitudinal studies to determine the association with mortality in HFrEF patients. *ENMO = Euclidean Norm Minus One, an acceleration metric. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The Karen Elise Jensens Foundation

Clinical outcomes of transcatheter aortic valve replacement stratified by left ventricular ejection fraction: A single centre pilot study

IntroductionTo define baseline echocardiographic, electrocardiographic (ECG) and computed tomographic (CT) findings of patients with heart failure undergoing transcatheter aortic valve replacement (TAVR) and analyze their overall procedural outcomes. MethodsBetween 2018 and 2021, patients with severe aortic stenosis (AS) who performed transcatheter aortic valve replacement (TAVR) in Sabah Al Ahmad Cardiac Centre, Al Amiri Hospital were identified. A retrospective review of patients' parameters including pre-, intra-, and post-procedural data was conducted. Patients were grouped in 2 subgroups according to their EF: EF <40% (HFrEF) and EF ≥ 40%. The data included patients’ baseline characteristics, electrocardiographic and echocardiographic details along with pre-procedural CT assessment of aortic valve dimensions. Primary outcomes including post-operative disturbances, pacemaker implantation and in-hospital mortality following TAVR were additionally analyzed. ResultsA total of 61 patients with severe AS underwent TAVR. The mean age was 73.5 ± 9, and 21 (34%) of the patients were males. The mean ejection fraction (EF) was 55.5 ± 9.7%. Of 61 patients, 12 (20%) were identified as heart failure with reduced EF (<40%). These patients were younger, more often males, and were more likely to have coronary artery disease (75% versus 53.1%). Left ventricular hypertrophy and diastolic dysfunction was documented in 75% and 58.3% of patients with heart failure with reduced ejection fraction (HFrEF) respectively. Post TAVR conduction disturbances, with the commonest being LBBB was observed in 41.7%. Permanent pacemaker was implanted in 3 of patients with HFrEF (25%). There were no significant differences between the two groups with regards to in hospital mortality (p = 0.618). ConclusionSevere AS with EF <40% constitute a remarkable proportion of patients undergoing TAVR. Preliminary results of post-operative conduction disturbances and in hospital mortality in HFrEF patients were concluded to not differ from patients with LVEF ≥40%.

Association of lipoprotein (a) and 1year prognosis in patients with heart failure with reduced ejection fraction.

AimCurrent study was to evaluate relationship between baseline serum lipoprotein (a) [Lp(a)] level and prognosis in patients with heart failure with reduced ejection fraction (HFrEF) and to explore whether the relationship would be modified by baseline high‐sensitivity C‐reactive protein (Hs‐CRP) level.Methods and resultsThis is an observational prospective study. HFrEF patients from outpatient clinic were consecutively recruited (n = 362). Based on Lp(a) cutoff (30 mg/dL), patients were divided into normal and high Lp(a) groups; and based on Hs‐CRP cutoff (3 mg/dL), patients were divided into low‐degree and high‐degree groups. The 1 year rate of HF rehospitalization was similar between these two groups (22.7% vs. 24.1%, P = 0.18), while the 1 year rate of cardiovascular mortality was higher in Lp(a) ≥ 30 mg/dL versus Lp(a) < 30 mg/dL groups (20.3% vs. 13.3%, P = 0.009), as was composite endpoint (44.4% vs. 36.0%, P < 0.001). After adjusting for covariates, elevated Lp(a) level remained associated with a higher risk of cardiovascular mortality [hazard ratio (HR) 1.22 and 95% confidence interval (CI) 1.04–1.64, P = 0.02] and composite endpoint (HR 1.38 and 95% CI 1.16–2.01, P = 0.006). In Hs‐CRP ≥ 3 mg/dL group, elevated Lp(a) level was associated with HF rehospitalization, cardiovascular mortality, and composite endpoint, which was not observed in Hs‐CRP < 3 mg/dL group. The association was greater for cardiovascular mortality (P‐interaction = 0.04) and composite endpoint (P‐interaction = 0.02) in Hs‐CRP ≥ 3 mg/dL versus Hs‐CRP < 3 mg/dL groups.ConclusionElevated Lp(a) level is associated with higher risk of cardiovascular mortality in HFrEF patients, which might be due to enhanced systemic inflammation.

A dose-response relationship of renin-angiotensin system blockers and beta-blockers in patients with acute heart failure syndrome: a nationwide prospective cohort study.

It remains unclear if patients with acute heart failure syndrome (AHFS) need to reach the maximally tolerated doses of renin-angiotensin system blockers (RASBs) or beta-blockers (BBs) to obtain a survival benefit. This study evaluated the dose-response relationship between RASBs or BBs and survival in AHFS patients. In total, 5331 patients in the Korean Acute Heart Failure registry were analysed based on the doses of RASBs and BBs at discharge. In AHFS patients, RASB use at discharge was associated with a significant reduction in all-cause mortality risk. This effect was dose-dependent for heart failure with reduced ejection fraction (HFrEF) but did not attain statistical significance for heart failure with preserved ejection fraction (HFpEF). BB use at discharge was associated with reduced all-cause mortality in HFrEF patients but not in HFpEF patients. In an additional analysis of 4613 patients with dosage information at the first post-discharge follow-up visit, a significantly higher mortality risk was associated with the maintenance or withdrawal of RASBs compared with up-titrating the dose in HFrEF patients. Using RASBs or BBs at discharge was associated with improved survival. A dose-response relationship between RASBs and all-cause mortality was evident in AHFS patients with a reduced ejection fraction but not BBs. It is important to initiate and up-titrate RASBs to the maximally tolerated dose in AHFS patients during the transition period, especially for patients with a reduced ejection fraction.

Impact of Insulin Treatment on the Effect of Eplerenone: Insights From the EMPHASIS-HF Trial.

Patients with heart failure with reduced ejection fraction (HFrEF) and insulin-treated diabetes have a high risk of cardiovascular complications. Mineralocorticoid receptor antagonists may mitigate this risk. We aim to explore the effect of eplerenone on cardiovascular outcomes and all-cause mortality in HFrEF patients with diabetes, including those treated with insulin in the EMPHASIS-HF trial (Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms). The primary outcome was the composite of heart failure hospitalization or cardiovascular death. Cox models with treatment-by-diabetes subgroup interaction terms were used. The median follow-up was 21 (10-33) months. Of the 2737 patients included, 623 (23%) had non-insulin-treated diabetes, 236 (9%) had insulin-treated diabetes and 1878 did not have diabetes. Patients with insulin-treated diabetes were younger, more often women, with higher body mass index, waist circumference, more frequent ischemic heart failure cause, impaired kidney function, and longer diabetes duration. Compared with patients without diabetes, those with insulin-treated diabetes had a 2-fold higher risk of having a primary outcome event. The hazard ratio (95% CI) for the effect of eplerenone, compared with placebo, on the primary outcome was 0.31 (0.19-0.50) in insulin-treated diabetes, 0.69 (0.50-0.93) in non-insulin-treated diabetes, and 0.72 (0.58-0.88) in patients without diabetes; interaction P=0.007. The annualized number needed-to-treat-to-benefit with regards to the primary outcome was 3 (95% CI, 3-4) in patients with insulin-treated diabetes, 16 (13-19) in patients with diabetes not receiving insulin, and 26 (24-28) in patients without diabetes. Patients with insulin-treated diabetes experienced a greater benefit from eplerenone than those with diabetes not treated with insulin and people without diabetes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00232180.

The impact of serum concentration-guided digoxin therapy on mortality of heart failure patients: A long-term follow-up, propensity-matched cohort study.

BackgroundRecently published studies suggested that digoxin may increase mortality in heart failure with reduced ejection fraction (HFrEF). However, in the vast majority of former trials serum digoxin concentration (SDC) was not measured and therapy was not SDC‐guided.AimTo assess the impact of SDC‐guided digoxin therapy on mortality in HFrEF patients.MethodsData of 580 HFrEF patients were retrospectively analyzed. In patients on digoxin, SDC was measured every 3 months and digoxin dosage was SDC‐guided (target SDC: 0.5‐0.9 ng/mL). All‐cause mortality of digoxin users and nonusers was compared after propensity score matching (PSM).ResultsAfter 7.1 ± 4.7 years follow‐up period (FUP) all‐cause mortality of digoxin users (n = 180) was significantly higher than nonusers (n = 297) (propensity‐adjusted HR = 1.430; 95% CI = 1.134‐1.804; P = .003). Patients having SDC of 0.9 to 1.1 ng/mL (n = 60) or > 1.1 ng/mL (n = 44) at any time during the FUP had an increased risk of all‐cause mortality (HR = 1.750; 95% CI = 1.257‐2.436, P = .001 and HR = 1.687; 95% CI = 1.153‐2.466, P = .007), while patients having a maximal SDC < 0.9 ng/mL (n = 76) had similar mortality risk (HR = 1.139; 95% CI = 0.827‐1.570, P = .426), compared to digoxin nonusers.ConclusionsAccording to our propensity‐matched analysis, SDC‐guided digoxin therapy was associated with increased all‐cause mortality in optimally treated HFrEF patients, especially with SDC ≥0.9 ng/mL. These results reinforce the expert opinion that digoxin in HFrEF can only be used among carefully selected patients with close SDC monitoring.

Sustained adherence to ESC guideline-recommended medications is associated with lower long-term mortality in heart failure and reduced ejection fraction: Insights from the EPICAL2 cohort.

The real-life prognostic impact on long-term survival of continuous or discontinuous adherence to ESC guideline-recommended drugs in heart failure with reduced ejection fraction (HFrEF) patients has rarely been investigated. Here, we present the long-term association of longitudinal prescription of guideline-recommended drugs with 3-year all-cause and cardiovascular (CV) mortality in HFrEF patients. We used data from the EPICAL2 cohort study of 624 hospitalized HFrEF patients. Using the sequence analysis, we classified patients into five groups of long-term adherence according to the continuity/discontinuity of their prescription adherence to guidelines over a 3-year follow-up, as follow: 316 (50.6%) patients in the sustained adherence group, 163 (26.1%) in the sustained non-adherence group, 79 (12.6%) in the adherence to non-adherence group, 43 (6.9%) in the non-adherence to adherence group and 23 (3.7%) in the multiple switches group. The associations between all-cause mortality and CV mortality and the adherence groups were determined by Cox and Fine-Gray models, respectively. To account for immortal time bias, we performed a landmark analysis at 24months. Patients who died, prior to the landmark time, were excluded from this analysis and long-term adherence groups were redefined. After adjustment for confounding factors, as compared to the sustained non-adherence group, the sustained adherence group showed lower all-cause and CV mortality (hazard ratio HR=0.37 [0.25-0.56] and sub-distribution hazard ratio SHR=0.33 [0.20-0.56]). Both clinical outcomes were also significantly improved in the adherence to non-adherence group (HR=0.25 [0.13-0.45] and SHR=0.20 [0.10-0.41]), the non-adherence to adherence (HR=0.24 [0.11-0.55] and SHR=0.11 [0.04-0.30]), and for the multiple switches group (HR=0.13 [0.07-0.51] and SHR=0.12 [0.08-0.43]). Results from landmark analysis were comparable to the main results. As in all observational studies, our results may be affected by residual confounding related to unmeasured confounders, although we attempted to adjust for many confounders. Even a discontinuous prescription of the recommended drugs over time was associated with better long-term outcomes. In other words, whatever the time of HFrEF evolution, prescribing recommended drugs at some point was always better than never prescribing.

Abstract P164: Urban-rural Disparities Amongst Heart Failure Patients With Reduced Ejection Fraction

Intro: Differences in health care delivery between urban and rural populations have been described, but the extent to which this impacts treatment and outcomes in patients with heart failure with reduced ejection fraction (HFrEF) within a large, rural HF referral network has not been evaluated to date. Objective: To describe differences in guideline directed medical therapy (GDMT) usage and cardiovascular (CV) mortality in urban vs rural dwelling individuals with HFrEF in Vermont. Methods: A retrospective analysis was performed on adult HFrEF patients residing in Vermont referred to University of Vermont Medical Center between January 1, 2015-2017. The study included all patients with a documented EF &lt; 35% on echo. Demographics, risk factors, use of GDMT, and all-cause CV mortality were obtained. Urban and rural designations were based on the ZIP code version of the Rural-Urban Commuting Area (RUCA) classification system. Poisson regression analysis was used to compare the relative risk for mortality and use of GDMT by rurality. Results: 838 patients were identified (mean age 71.4 + 12.9 years old; 66.5% male) and divided into 3 RUCA groups (urban, rural, isolated). Adjusting for age, sex, hypertension, diabetes mellitus, atrial fibrillation and smoking status, no difference was seen in GDMT (table 1) between urban and rural patients (relative risk [RR], 1.03; 95% CI, 0.64-1.67). Urban patients were less likely than isolated patients to use GDT (RR, 0.75; 95% CI 0.52-1.08). There was a CV mortality benefit for those in rural (RR, 0.50; 95% CI 0.34-0.73) or isolated areas (RR, 0.74; 95% CI 0.62-0.89) compared to those in urban areas. Conclusion: While GDMT reduces morbidity and mortality in HFrEF patients, it was underutilized throughout Vermont. Findings from this state-wide cohort of decreased CV mortality in rural and isolated areas are contrary to prior studies. This finding highlights the unique socioeconomic environment of Northern New England and has important implications for CHF management and resource allocation.

The subclinical hypothyroid state might predict 30-day readmission in patients admitted with acute heart failure syndrome and reduced left ventricular ejection fraction.

Introduction:Thyroid hormone (TH) has an essential role on the functional capability of cardiac muscle with its gene modulation and induction of vasodilatory effects. There is considerable evidence to suggest the role of TH in patients with acute coronary syndrome, but less is known about its prognostic role in heart failure (HF) patients. We aim to evaluate the association between subclinical hypothyroid state (SCHS) and event rates including 30-day all-cause and HF readmission in patients with an index hospitalization for acute HF syndrome (AHFS).Methodology:A retrospective chart review analysis of 2335 patients admitted with the diagnosis of AHFS between 1 January 2007 and 31 December 2017 was conducted. SCHS was defined as thyroid-stimulating hormone (TSH) level >4.50 mIU/L with a normal thyroxine (T4) level. Patients with pre-existing thyroid disease or receiving thyroid replacement therapy were excluded. HF with preserved ejection fraction (HFpEF) was defined as left ventricular ejection fraction (LVEF) >40% and HF with reduced ejection fraction (HFrEF) was defined as having LVEF ⩽40%. Percentage of 30-day, 3-month and 6-month all-cause readmission and mortality rates were calculated in both cohorts of AHFS (HFpEF and HFrEF) with and without SCHS.Results:The mean age of the 2335 AHFS population was 65 (±14.8) years. Of the 2335 patients admitted with AHFS, 1228 (52.6%) patients were found to have HFrEF and 1107 (47.4%) with HFpEF. There were 170 (7.3%) patients with AHFS found to have SCHS. There were more males than females (54% versus 46%). The percentage of hospital readmission within 30 days was higher for patients with SCHS compared with those without SCHS in the HFrEF group (42% versus 30%, p = 0.001). Hospital readmission within 30 days for patients with SCHS compared with those without SCHS in the HFpEF group did not differ (36.5% versus 31%, p = 0.47). Additionally, all-cause mortality was higher among patients with SCHS compared with patients without SCHS in the HFrEF group (18.7% versus 7.0%, p < 0.001). All-cause mortality was found similar in both arms of the HFpEF group (9.5% versus 7.7%, p = 0.73).Conclusion:During an index hospital admission for AHFS, SCHS was an independent predictor of readmission in 30 days in patients with HFrEF but not in patients with HFpEF. Additionally, it was related to adverse outcome such as all-cause mortality in HFrEF patients but not in HFpEF patients. Further studies regarding the concept of tissue thyroid and the potential for a therapeutic target are warranted.

P5449Neurohumoral regulation of the low-, medium- and high-renin HFrEF phenotypes

Abstract Background Previous investigations of plasma Renin-Angiotensin-System (RAS) fingerprints of patients with heart failure with reduced ejection fraction (HFrEF) revealed the existence of low, medium and high renin phenotypes independently of disease severity. Plasma renin serves as an excellent surrogate for angiotensin levels. The different renin phenotypes could not only hypothetically respond differently to RAS blockade but associated alterations of other vasoactive peptide systems could elucidate disease mechanisms and novel targets for heart failure therapy. The study aimed to investigate the relation between RAS regulation and pathophysiologically relevant vasoactive peptide systems based on different renin phenotypes. Methods We prospectively enrolled 369 patients with stable HFrEF. Laboratory markers including NT-proBNP and active renin concentration (ARC) were assessed. Plasma NEP levels (sNEP), bioactive adrenomedullin (bio-ADM) and big-endothelin1 (bigET-1) were measured by ELISA (R&amp;D systems, UK; Sphingotec GmbH, Germany and Eagle Biosciences, Austria). NEP activity was determined by a fluorimetric peptide cleavage assay. The correlation between biomarkers and association with all-cause mortality was assessed. sNEP, bio-ADM and bigET-1 levels as well as NEP activity between the different renin phenotypes (i.e. &lt;15. percentile, 15.-85. percentile and &gt;85. percentile of ARC) was compared. Results Median age was 65 (IQR 53–73) years, 75% of patients were male. Median NT-proBNP levels were 1936 (IQR 855–4126) pg/mL. Median ARC was 155 (29–569) μIE/mL, the low, medium and high renin HFrEF phenotypes showed median ARC levels of 4.2μIE/mL (IQR 2.0–7.8), 155.1μIE/mL (IQR 43.3–353.5) and 2360μIE/mL (IQR 1483–3250) μIE/mL. Median bigET-1 was 0.62pmol/L (IQR 0.42–1.10), bio-ADM 26.0pg/mL (IQR 16.1–46.7), sNEP 413pg/mL (IQR 0–4111) and NEP activity 2.36nmol/mL/min (IQR 1.16–4.59). There was no correlation between sNEP and NEP activity [r=0.09, p=0.088]. ARC did not show a meaningful correlation with any of the four biomarkers [p=ns for sNEP, NEP activity and bigET-1; r=0.13, p=0.018 for bio-ADM]. In the univariate analysis ARC, bigET-1, bio-ADM but not sNEP and NEP activity, were associated with outcome. This association remained significant after adjustment for age, gender and kidney function for all three markers and for ARC after adding NT-proBNP [adj. HR per 1-IQR increase of ARC 1.27 (95% CI 1.04–1.22), p=0.003]. There were no differences in bigET-1, bio-ADM and sNEP or NEP activity stratified by the different renin phenotypes (Figure1). Figure 1 Conclusions ARC is a risk factor for mortality in HFrEF patients, independently of NT-proBNP. Plasma NEP levels and activity neither correlated with each other nor were associated with outcome. Bio-ADM and bigET-1 were strong risk factors for all-cause mortality. Interestingly, neither NEP nor bio-ADM or bigET-1 were related to RAS-activation, suggesting that there is no direct relationship with RAS regulation.

Effect on Mortality of Higher Versus Lower β-Blocker (Metoprolol Succinate or Carvedilol) Dose in Patients With Heart Failure

This study aimed to compare the effect of β-blocker dose and heart rate (HR) on mortality in patients with heart failure with reduced ejection fraction (HFrEF). The Veteran Affairs databases were queried to identify all patients diagnosed with HFrEF based on International Classification of Diseases Ninth Revision codes from 2007 to 2015 and β-blocker (carvedilol or metoprolol succinate) use. 36,168 patients on low dose β blocker were then matched with 36,168 patients on high dose β-blocker using propensity score matching. The impact of β-blocker dose and HR was assessed on overall mortality using Cox proportional hazard model. After dividing average HR into separate quartiles and adjusting for patient characteristics, high β-blocker dose was associated with lower overall mortality as compared with a low dose of β blocker (hazard ratio 0.75, 95% confidence interval 0.73 to 0.77, p <0.01) independent of the HR achieved. The results held for all 4 quartiles of average HR. A higher β-blocker dose or a lower HR were independently and jointly associated with lower mortality for all quartiles of HR. In conclusion, higher dose of β-blocker therapy and a lower achieved HR were independently associated with a reduction in mortality in HFrEF patients.

Albumin-to-globulin ratio as an independent predictor of mortality in chronic heart failure.

Albumin-to-globulin ratio (AGR) is emerged as a marker of impaired prognosis. We determined the predictive value of AGR in patients with heart failure with reduced ejection fraction (HFrEF). 999 patients with HFrEF were enrolled. Rates of 1-year all-cause mortality were compared between AGR quartiles (Q). Moreover, multivariate survival analysis in Cox's regression model and receiver operating characteristic analyses were performed. 90-day and 1-year mortality was the highest in AGR Q1. AGR was an independent predictor of 90-day and 1-year mortality. Receiver operating characteristic analysis revealed moderate diagnostic value in predicting 90-day (AGR cutoff <1.2) and 1-year (AGR cutoff <1.38) mortality. AGR had a good prognostic value and remained an independent predictor of mortality in HFrEF patients.

Long-Term Prognostic Significance of Plasma B-Type Natriuretic Peptide Level in Patients With Acute Heart Failure With Reduced, Mid-Range, and Preserved Ejection Fractions

Plasma B-type natriuretic peptide (BNP) is an important prognostic marker in patients with acute heart failure (AHF). However, it is unclear which BNP parameter, on admission, at discharge, or change during hospitalization, has the highest predictive performance for long-term adverse outcomes, and whether its prognostic impact differs according to the new European heart failure (HF) phenotype classification by left ventricular ejection fraction: heart failure with reduced ejection fraction (HFrEF), heart failure with mid-range ejection fraction (HFmrEF), and heart failure with preserved ejection fraction (HFpEF). We examined 1,792 patients with AHF consisting of 860 (48%) HFrEFs, 318 (18%) HFmrEFs, and 614 (34%) HFpEFs. Prognostic performance of each BNP parameter was assessed by the Harrell c-index. During a median follow-up of 664 days, 344 (19%) patients died. Discharge BNP had the highest c-index (0.69) for mortality among all BNP parameters (p <0.001). In multivariate Cox proportional hazard modeling, discharge BNP was associated with mortality in HFrEF, HFmrEF, and HFpEF patients with significant interaction (hazard ratio [HR] 1.95, 95% confidence interval [CI] 1.57 to 2.41; HR 1.76, 95% CI 1.10 to 2.82; HR 1.46, 95% CI 1.12 to 1.91, respectively; p = 0.011 for interaction). Moreover, the c-index of discharge BNP for mortality in HFrEF patients (0.72) was higher than that in HFmrEF patients (0.68) and HFpEF patients (0.65). Similar results were obtained for mortality or HF rehospitalization as alternative outcomes, except there was no statistically significant interaction among HF phenotypes. In conclusion, discharge BNP is a more reliable marker than other BNP parameters on long-term outcome prediction in patients with AHF, but its prognostic impact may be weakened in HFmrEF and HFpEF compared with HFrEF.

Differential Responses of Post-Exercise Recovery of Leg Blood Flow and Oxygen Uptake Kinetics in HFpEF versus HFrEF.

The goals of the current study were to compare leg blood flow, oxygen extraction and oxygen uptake (VO2) after constant load sub-maximal unilateral knee extension (ULKE) exercise in patients with heart failure with reduced ejection fraction (HFrEF) compared to those with preserved ejection fraction (HFpEF). Previously, it has been shown that prolonged whole body VO2 recovery kinetics are directly related to disease severity and all-cause mortality in HFrEF patients. To date, no study has simultaneously measured muscle-specific blood flow and oxygen extraction post exercise recovery kinetics in HFrEF or HFpEF patients; therefore it is unknown if muscle VO2 recovery kinetics, and more specifically, the recovery kinetics of blood flow and oxygen extraction at the level of the muscle, differ between HF phenotypes. Ten older (68±10yrs) HFrEF (n = 5) and HFpEF (n = 5) patients performed sub-maximal (85% of maximal weight lifted during an incremental test) ULKE exercise for 4 minutes. Femoral venous blood flow and venous O2 saturation were measured continuously from the onset of end-exercise, using a novel MRI method, to determine off-kinetics (mean response times, MRT) for leg VO2 and its determinants. HFpEF and HFrEF patients had similar end-exercise leg blood flow (1.1±0.6 vs. 1.2±0.6 L/min, p>0.05), venous saturation (42±12 vs. 41±11%, p>0.05) and VO2 (0.13±0.08 vs. 0.11±0.05 L/min, p>0.05); however HFrEF had significantly delayed recovery MRT for flow (292±135sec. vs 105±63sec., p = 0.004) and VO2 (95±37sec. vs. 47±15sec., p = 0.005) compared to HFpEF. Impaired muscle VO2 recovery kinetics following ULKE exercise differentiated HFrEF from HFpEF patients and suggests distinct underlying pathology and potential therapeutic approaches in these populations.