Spectrum Of Ejection Fraction Research Articles

Prognostic value of growth differentiation factor-15 in heart failure among whole ejection fraction phenotypes.

The utility of growth differentiation factor-15 (GDF-15) in predicting long-term adverse outcomes in heart failure (HF) patients is not well established. This study explored the relationship between GDF-15 levels and adverse outcomes in HF patients across various ejection fraction (EF) phenotypes associated with coronary heart disease (CHD) and evaluated the added prognostic value of incorporating GDF-15 into the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score-based model. This single-centre cohort study included 823 HF patients, categorized into 230 (27.9%) reduced EF (HFrEF), 271 (32.9%) mid-range EF (HFmrEF), and 322 (39.1%) preserved EF (HFpEF) groups. The median age was 68.0years (range: 56.0-77.0), and 245 (29.8%) were females. Compared with the HFrEF and HFmrEF groups, the HFpEF group had a higher GDF-15 concentration (P=0.002) and a higher MAGGIC risk score (P<0.001). We examined the associations between GDF-15 levels and the risks of all-cause mortality and HF rehospitalization using Cox regression models. The C-index, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) metrics were employed to assess the incremental prognostic value. During the 9.4year follow-up period, 425 patients died, and 484 were rehospitalized due to HF. Multivariate Cox regression analysis revealed that elevated GDF-15 levels were significantly associated with an increased risk of all-cause mortality [hazard ratio (HR)=1.36, 95% confidence interval (CI): 1.20-1.54; P<0.001] and HF rehospitalization (HR=1.75, 95% CI: 1.57-1.95; P<0.001) across all HF phenotypes. This association remained significant when GDF-15 was treated as a categorical variable (high GDF-15 group: all-cause death: HR=1.73, 95% CI: 1.40-2.14; P<0.001; HF rehospitalization: HR=3.37, 95% CI: 2.73-4.15; P<0.001). Inclusion of GDF-15 in the MAGGIC risk score-based model provided additional prognostic value for all HF patients (Δ C-index=0.021, 95% CI: 0.002-0.041; IDI=0.011, 95% CI: 0.001-0.025; continuous NRI=0.489, 95% CI: 0.174-0.629) and HF rehospitalization (Δ C-index=0.034, 95% CI: 0.005-0.063; IDI=0.021, 95% CI: 0.007-0.032; continuous NRI=0.307, 95% CI: 0.147-0.548), particularly in the HFpEF subgroup. GDF-15 is identified as an independent risk factor for adverse outcomes in HF patients across the entire EF spectrum in the context of CHD. Integrating GDF-15 into the MAGGIC risk score-based model enhances its prognostic capability for adverse outcomes in the general HF population. This incremental prognostic effect was observed specifically in the HFpEF subgroup and not in other subgroups.

A cost-effectiveness analysis of empagliflozin for heart failure patients across the full spectrum of ejection fraction in Spain: combined results of the EMPEROR-Preserved and EMPEROR-Reduced trials

ABSTRACT Background Heart failure (HF) is a chronic condition with considerable clinical burden for patients and economic burden for healthcare systems. Treatment for HF is typically based on ejection fraction (EF) phenotype. The cost-effectiveness of empagliflozin + standard of care (SoC) compared to SoC has been examined for HF phenotypes below or above 40% EF separately, but not across the full spectrum of EF in Spain. Methods The results of two preexisting, validated, and published phenotype-specific Markov cohort models were combined using a population-weighted approach, reflecting the incidence of each phenotype in the total HF population in Spain. A probabilistic sensitivity analysis was performed by sampling each model’s probabilistic results. Results Empagliflozin + SoC compared to SoC resulted in increased life-years (LYs) (6.48 vs. 6.35), quality-adjusted LYs (QALYs) (4.80 vs. 4.63), and healthcare costs (€19,090 vs. €18,246), over a lifetime time horizon for the combined HF population in Spain. The incremental cost-effectiveness ratio (ICER) was €5,089/QALY. All subgroup, scenario, and probabilistic ICERs were consistently below €10,000/QALY. Conclusions Empagliflozin is the first treatment with established efficacy and cost-effectiveness for HF patients across EF from the perspective of healthcare payers in Spain. Empagliflozin also proved to be cost-effective for all subgroups of patients included in the analysis.

Sacubitril/Valsartan in Patients Hospitalized With Decompensated Heart Failure

BackgroundThe efficacy and safety of sacubitril/valsartan in patients hospitalized with heart failure (HF) across the spectrum of left ventricular ejection fraction (EF) has not been described. ObjectivesData from randomized trials of sacubitril/valsartan in HF patients with EF ≤40% (PIONEER-HF [Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode] trial) and >40% (PARAGLIDE-HF [Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF] trial) following recent worsening heart failure (WHF) were pooled to examine treatment effect across the EF spectrum. MethodsThe PIONEER-HF and PARAGLIDE-HF trials were double-blind, randomized trials of sacubitril/valsartan vs control therapy (enalapril or valsartan, respectively). All participants in the PIONEER-HF trial and 69.5% in the PARAGLIDE-HF trial were enrolled during hospitalization for HF after stabilization. The remainder in the PARAGLIDE-HF trial were enrolled ≤30 days after a WHF event. The primary endpoint of both trials was time-averaged proportional change in N-terminal pro–B-type natriuretic peptide (NT-proBNP) from baseline through weeks 4 and 8. Adjudicated clinical endpoints were analyzed through the end of follow-up, adjusting for trial. ResultsThe pooled analysis included 1,347 patients (881 from PIONEER-HF, 466 from PARAGLIDE-HF). Baseline characteristics included median age 66 years, 36% women, 31% Black, 34% de novo HF, and median EF 30%. The reduction in NT-proBNP was 24% greater with sacubitril/valsartan vs control therapy (n = 1,130; ratio of change = 0.76; 95% CI: 0.69-0.83; P < 0.0001). Cardiovascular death or hospitalization for HF was reduced by 30% with sacubitril/valsartan vs control therapy (HR: 0.70; 95% CI: 0.54-0.91; P = 0.0077). This effect was consistent across the spectrum of EF ≤60%. Sacubitril/valsartan increased symptomatic hypotension (risk ratio: 1.35; 95% CI: 1.05-1.72). ConclusionsIn patients stabilized after WHF, sacubitril/valsartan led to a greater reduction in plasma NT-proBNP and improved clinical outcome compared with control therapy, in particular across the spectrum of EF ≤60%. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890; Changes in NT-proBNP, Safety, and Tolerability in HFpEF Patients With a WHF Event [HFpEF Decompensation] Who Have Been Stabilized and Initiated at the Time of or Within 30 Days Post-decompensation [PARAGLIDE-HF]; NCT03988634)

Association between body mass index and outcomes in heart failure across the ejection fraction spectrum: data from the Swedish Heart Failure Registry

Abstract Background Despite overweight/obesity being a well-known cardiovascular (CV) risk factor, high body mass index (BMI) has been suggested to be associated with longer survival in patients with heart failure (HF). Data on large populations are lacking, as well as whether this advantage might be consistent across the ejection fraction (EF) spectrum, i.e. reduced (HFrEF), mildly reduced (HFmrEF) and preserved (HFpEF, where obesity may have a greater causative role). Purpose To assess the association between BMI and outcomes in a large and unselected contemporary cohort of patients with HF across the EF spectrum. Methods Patients with HF registered in the Swedish HF Registry (SwedeHF) between May 2000 and December 2021, with no missing values for EF and BMI, were selected. Linkage with the Cause of Death Registry and the National Patient Registry provided data on mortality, hospitalizations and comorbidities. Patients were categorised according to BMI class (underweight &amp;lt;18.5 kg/m2; normal weight 18.5-24.9 kg/m2; overweight 25.0-29.9 kg/m2; obesity&amp;gt;30-34.9 kg/m2). The primary outcome was all-cause death, secondary outcomes were CV death and HF hospitalization (HHF). The associations between BMI categories and outcomes were analysed by univariable and multivariable Cox proportional hazards models, both in the whole cohort and according to EF classes; this association was also explored by modeling BMI as a continuous variable through restricted cubic splines. Missing data were handled by chained equation multiple imputation. Results 69,874 patients (mean age 74 years, 36% females) were included, of whom 3% underweight, 35% with normal weight, 35 % overweight, obese 27%. Figure 1 reports the proportions of the different BMI categories according to EF: obesity was significantly more common in HFpEF. Regardless of EF, obese patients were younger, with lower N-terminal B-type natriuretic peptide, higher New York Heart Association class, and with diabetes and hypertension as compared with the other three BMI classes. Compared with normal weight, both overweight and obesity were independently associated with lower mortality risk, while underweight with higher mortality, with consistent results in HFrEF, HFmrEF and HFpEF; the same associations were found for CV death or all three EF classes, while underweight only was associated with HHF in HFrEF. When BMI was modelled as restricted cubic splines, a reverse J-shaped adjusted association was found between BMI and risk of all-cause death (Figure 2). Conclusion HF patients with overweight and obesity had a lower mortality risk compared with patients with normal or underweight patients across all EF classes, at least up to BMI&amp;gt;40 kg/m2. Our results are consistent with the previously suggested potential survival benefit in overweight patients, calling for future research to understand this apparent paradox.Figure 1

Abstract 14826: Effect of Torsemide vs Furosemide After Discharge for Acute Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction: Observations From Transform-HF

Introduction: TRANSFORM-HF trial showed no significant difference in mortality or hospitalization outcomes in patients randomized to torsemide (T) versus furosemide (F) following a heart failure (HF) hospitalization (HFH). However, outcomes and responses to some therapies differ across ejection fraction (EF) subgroups. Methods: We compared baseline patient characteristics and described treatment effects for various endpoints in TRANSFORM-HF stratified by EF: HF with reduced (EF≤40%;HFrEF) vs mildly reduced (41-49%;HFmrEF) vs preserved (≥50%;HFpEF) EFs. We also evaluated the prognostic association between EF and outcomes. Study endpoints were all-cause mortality and hospitalization at 30 days and 12 months (separately and as composites), and total hospitalizations. Results: Our analysis included 2635 patients with EF data. Participants with HFpEF were older (72 [62-79] years) with lower eGFR (52 [36-72] ml/min/1.73m 2 ) compared to the other EF cohorts, while patients with HFrEF had lower systolic blood pressure (112 [101-125] mmHg) and higher NT-proBNP levels (4554 [2368-9620] pg/ml). The neutral treatment effect for all studied endpoints did not differ across EF groups (all interaction p-values&gt;0.05, Figure 1A). There was no significant difference in the rates of mortality and/or hospitalization at 12 months between patients in the three EF groups (HFrEF 59.2, HFmrEF 61, HFpEF 63 events/100 patient-years, p=0.24, Figure 1B). Even after adjusting for covariates the relative risk or rate ratio for all endpoints did not differ across EF groups. Conclusions: Despite baseline differences between EF cohorts in TRANSFORM-HF, there were no significant differences in the study endpoints with T versus F across the EF spectrum. In contrast to previous observations, the adjusted risk ratios for all study endpoints did not differ by baseline EF. Following a HFH, there is substantial risk for all-cause mortality and subsequent hospitalization independent of EF.

Sex differences in long-term outcomes following acute heart failure hospitalization: Findings from the Get With The Guidelines-Heart Failure registry.

Sex differences in long-term outcomes following hospitalization for heart failure (HF) across ejection fraction (EF) subtypes are not well described. In this study, we evaluated the risk of mortality and rehospitalization among males and females across the spectrum of EF over 5 years of follow-up following an index HF hospitalization event. Patients hospitalized with HF between 1 January 2006 and 31 December 2014 from the American Heart Association's Get With The Guidelines-Heart Failure registry with available 5-year follow-up using Medicare Part A claims data were included. The association between sex and risk of mortality and readmission over a 5-year follow-up period for each HF subtype (HF with reduced EF [HFrEF, EF ≤40%], HF with mildly reduced EF [HFmrEF, EF 41-49%], and HF with preserved EF [HFpEF, EF >50%]) was assessed using adjusted Cox models. The effect modification by the HF subtype for the association between sex and outcomes was assessed by including multiplicative interaction terms in the models. A total of 155 670 patients (median age: 81 years, 53.4% female) were included. Over 5-year follow-up, males and females had comparably poor survival post-discharge; however, females (vs. males) had greater years of survival lost to HF compared with the median age- and sex-matched US population (HFpEF: 17.0 vs. 14.6 years; HFrEF: 17.3 vs. 15.1 years; HFmrEF: 17.7 vs. 14.6 years for age group 65-69 years). In adjusted analysis, females (vs. males) had a lower risk of 5-year mortality (adjusted hazard ratio [aHR] 0.89, 95% confidence interval [CI] 0.87-0.90, p < 0.0001), and the risk difference was most pronounced among patients with HFrEF (aHR 0.87, 95% CI 0.85-0.89; pinteraction [sex*HF subtype] = 0.04). Females (vs. males) had a higher adjusted risk of HF readmission over 5-year follow-up (aHR 1.06, 95% CI 1.04-1.08, p < 0.0001), with the risk difference most pronounced among patients with HFpEF (aHR 1.11, 95% CI 1.07-1.14; pinteraction [sex*HF subtype] = 0.001). While females (vs. males) had lower adjusted mortality, females experienced a significantly greater loss in survival time than the median age- and sex-matched US population and had a greater risk of rehospitalization over 5 years following HF hospitalization.

Lessons from a pre-specified meta-analysis ofsodium-glucose cotransporter-2 (SGLT2) inhibitors in heart failure: Time for new clinical recommendations.

Cardiovascular disease remains the leading cause of death worldwide with heart failure (HF) being one of the significant contributors to morbidity and mortality. The incidence of HF with preserved ejection fraction (HFpEF) is increasing, especially in young adults making it a growing public health matter. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been shown to reduce the development, progression, and mortality of heart failure in patients with reduced EF regardless of patients' diabetes status but their clinical benefits in patients with heart failure and preserved ejection fraction are less well-established. Recent trials have shown reductions in cardiovascular death and heart failure events in patients with mildly reduced or preserved ejection fraction (EF), although with uncertainty around the consistency of clinical benefits across the classes and therapeutic effects. Study and Results: The meta-analysis used data from trials on patients with mildly reduced or preserved EF (DELIVER and EMPEROR-Preserved), reduced EF (DAPA-HF and EMPEROR-Reduced), and those hospitalized (SOLOIST-WHF). The endpoints evaluated included a composite of time to cardiovascular (CV) death or first hospitalization for heart failure, cardiovascular death, all-cause death, first and recurrent heart failure hospitalizations, and urgent heart failure visits (not requiring hospitalization). Among 12251 participants in the DELIVER and EMPEROR-Preserved trials, SGLT2 inhibitors reduced composite cardiovascular death or first hospitalization for HF (HR 0.80 [95% CI 0.73-0.87]) with consistent reductions in both components: cardiovascular death (HR 0.88 [95% CI 0.77-1.00]) and first hospitalization for HF (HR 0.74 [95% CI 0.67-0.83]). In the broader analysis of the five trials with a total of 21 947 participants, SGLT2 inhibitors reduced the risk of composite cardiovascular death or hospitalization for HF (HR 0.77 [95% CI 0.72-0.82]), cardiovascular death (0.87 [0.79-0.95]), first hospitalization for heart failure (HR 0.72 [95% CI 0.67-0.78]), and all-cause mortality (HR 0.92 [95% CI 0.86-0.99]). These treatment effects for each of the studied endpoints were consistently observed across all five trials and across the HF subgroups, including those on mildly reduced or preserved ejection fraction. SGLT2 inhibitors significantly reduce the risk of mortality and worsening of heart failure and improve patient symptoms and overall health status across the full spectrum of ejection fraction. SGLT2 inhibitors should be considered foundational therapy in all patients with heart failure, irrespective of LVEF or care setting. The results presented propose an update of the recommendations for the pharmacological treatment of heart failure, to prioritize the use of SGLT2 inhibitors in patients across the full EF spectrum. Future investigations should include the long-term benefits of the use of SGLT2 inhibitors among the different HF subgroups, including the performance of SGLT2 inhibitors in those excluded from the current heart failure trials.

SGLT2 inhibition in heart failure with reduced or preserved ejection fraction: Finding the right patients to treat.

Sodium-glucose transport inhibitors (SGLT2i) are effective in heart failure (HF) with ejection fraction (EF) <40% (referred to as HF with reduced EF - HFrEF) and left ventricular EF (LVEF) >40%. Current evidence suggests that SGLT2i should be initiated across a large spectrum of EFs and renal function in patients with HF and with and without diabetes. We reviewed the benefits of SGLT2i in the entire spectrum of HF and provided some clues that may guide physicians in their strategy of initiating and maintaining SGLT2i (with or without SGLT1i effect) therapy. Taken together, the evidence thus far arises from an array of trials performed in different settings (acute/chronic), risk categories, and phenotypes of HF (HFrEF/HFpEF), and in addition to the most common HF therapies, supports the homogenous effect of SGLT2i across a large spectrum of patients with HF. SGLT2i appear to be effective and well-tolerated drugs in the majority of clinical HF scenarios, regardless of LVEF, estimated glomerular filtration rate, diabetic status or the level of the acuteness of the clinical setting. Therefore, most patients with HF should be treated with SGLT2i. However, in the face of the therapeutic inertia that has been observed in HF over the past decades, the actual implementation of SGLT2i in routine practice remains the most significant challenge.

328 IMPACT OF INTEGRATED CARE WITH ABC PATHWAY IN PATIENTS WITH ATRIAL FIBRILLATION AND HEART FAILURE: DATA FROM MORE THAN 11000 PATIENTS ENROLLED IN A EUROPEAN REGISTRY

Abstract Background and aim Heart failure (HF) is closely associated with atrial fibrillation (AF). The Atrial fibrillation Better Care (ABC) pathway is recommended in guidelines as a holistic or integrated care approach to AF management. However, few data are specifically available on ABC pathway adherence in AF patients with HF, especially according to HF phenotypes. Therefore, we aimed to retrospectively investigate the effect of ABC management in a large contemporary cohort of AF patients with HF and the impact on the clinical outcomes. Methods We analyzed patients enrolled in the ESC-EHRA EORP-AF General Long-Term Registry. According to the availability of HF status and ejection fraction (EF) values, patients were categorized as follows: i) non-HF; ii) HF EF&amp;gt;40% iii) HF EF≤40%. The primary outcome was a composite outcome of all-cause death and major adverse cardiac events. Results Among the original 11 096 AF patients enrolled, 9175 (82.7%) were included in this analysis (median age 71 years, interquartile range [IQR 63-77], 40.1% were female, with median EF 55% [IQR 45-61%] and median CHA2DS2-VASc 3 [2-4]). In this cohort, 5935 (64.7%) were non-HF patients, and 3240 (35.3%) had HF patients. According to the EF values, 2005 (65%) were categorized as HF EF&amp;gt;40%, and 1235 (35%) were HF EF≤40%. Overall, ABC pathway adherence in HF patients was 23.3% [95% CI: 21.6-25.2], being higher in HF EF≤40% patients (28.0%) and lower in HF EF&amp;gt;40% ones (21.9%). After a median follow-up of 731[IQR 690-748] days, ABC adherence was associated with a lower risk for the composite outcome compared to non-ABC adherent patients in each HF group (HF EF&amp;gt;40%: ABC 15.4% vs no ABC 20.9%; HF EF≤40%: ABC 20.3% vs no ABC 33.9%; both p&amp;lt;0.001). Cox regression analysis showed that ABC adherence was associated with a lower risk of composite outcome in each HF category (HF EF&amp;gt;40%: HR 0.66 [95% CI: 0.46-0.96], p=0.030; HF EF≤40%: HR 0.60 [95% CI: 0.40-0.90], p=0.013). ABC adherence was associated with a consistent risk reduction for the composite outcome across the entire EF spectrum [Figure]. Conclusions In this large contemporary cohort of AF-HF patients, adherence to the ABC pathway was associated with a lower occurrence of the primary outcome, irrespective of baseline EF. ABC pathway is consistently associated with a lower risk for adverse outcomes across the entire spectrum of EF.

Hemodynamically-Guided Management of Heart Failure Across the Ejection Fraction Spectrum: The GUIDE-HF Trial

BackgroundHemodynamically-guided management using an implanted pulmonary artery pressure sensor is indicated to reduce heart failure (HF) hospitalizations in patients with New York Heart Association (NYHA) functional class II-III with a prior HF hospitalization or those with elevated natriuretic peptides. ObjectivesThe authors sought to evaluate the effect of left ventricular ejection fraction (EF) on treatment outcomes in the GUIDE-HF (Hemodynamic-GUIDEd management of Heart Failure) randomized trial. MethodsThe GUIDE-HF randomized arm included 1,000 NYHA functional class II-IV patients (with HF hospitalization within the prior 12 months or elevated natriuretic peptides adjusted for EF and body mass index) implanted with a pulmonary artery pressure sensor, randomized 1:1 to a hemodynamically-guided management group (treatment) or a control group (control). The primary endpoint was the composite of HF hospitalizations, urgent HF visits, and all-cause mortality at 12 months. The authors assessed outcomes by EF in guideline-defined subgroups ≤40%, 41%-49%, and ≥50%, within the trial specified pre–COVID-19 period cohort. ResultsThere were 177 primary events (0.553/patient-year) in the treatment group and 224 events (0.682/patient-year) in the control group (HR: 0.81 [95% CI: 0.66-1.00]; P = 0.049); HF hospitalization was lower in the treatment vs control group (HR: 0.72 [95% CI: 0.57-0.92]; P = 0.0072). Within each EF subgroup, primary endpoint and HF hospitalization rates were lower in the treatment group (HR <1.0 across the EF spectrum). Event rate reduction by EF in the treatment groups was correlated with reduction in pulmonary artery pressures and medication changes. ConclusionsHemodynamically-guided HF management decreases HF-related endpoints across the EF spectrum in an expanded patient population of patients with HF. (Hemodynamic-GUIDEd Management of Heart Failure [GUIDE-HF]; NCT03387813)

Trajectories in New York Heart Association functional class in heart failure across the ejection fraction spectrum: data from the Swedish Heart Failure Registry.

To investigate incidence, predictors and prognostic implications of longitudinal New York Heart Association (NYHA) class changes (i.e. improving or worsening vs. stable NYHA class) in heart failure (HF) across the ejection fraction (EF) spectrum. From the Swedish HF Registry, 13 535 patients with EF and ≥2 NYHA class assessments were considered. Multivariable multinomial regressions were fitted to identify the independent predictors of NYHA change. Over a 1-year follow-up, 69% of patients had stable, 17% improved, and 14% worsened NYHA class. Follow-up in specialty care predicted improving NYHA class, whereas an in-hospital patient registration, lower EF, renal disease, lower mean arterial pressure, older age, and longer HF duration predicted worsening. The association between NYHA change and subsequent outcomes was assessed with multivariable Cox models. When adjusting for the NYHA class at baseline, improving NYHA class was independently associated with lower while worsening with higher risk of all-cause and cardiovascular mortality, and first HF hospitalization. After adjustment for the NYHA class at follow-up, NYHA class change did not predict morbidity/mortality. NYHA class assessment at baseline and follow-up predicted morbidity/mortality on top of the changes. Results were consistent across the EF spectrum. In a large real-world HF population, NYHA class trajectories predicted morbidity/mortality after extensive adjustments. However, the prognostic role was entirely explained by the resulting NYHA class, i.e. the follow-up value. Our results highlight that considering one-time NYHA class assessment, rather than trajectories, might be the preferable approach in clinical practice and for clinical trial design.

SGLT2-Inhibitors on HFpEF Patients. Role of Ejection Fraction.

Results from DELIVER trial and publication of EMPEROR-Preserved with sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with heart failure (HF) with ejection fraction (EF) > 40% represent a significant step forward in the treatment of HF with preserved EF (HFpEF). However, detailed analysis and attenuation of effect at higher EF levels have sparked some doubts about whether empagliflozin is effective across the entire spectrum of EF. HFpEF is no longer considered as one disease entity, but has been reconceptualized as a heterogenous group of phenotypes with derangements in multiple organ systems, driven by comorbidities. This heterogeneity suggests that it should not be considered as a single group in terms of treatment goals or clinical approach. Future research at the higher range of EF should ideally tailor investigations for unequivocally preserved EF (> 50%), consider the dynamic nature of EF over time, and use low-variability imaging techniques such as CMR. Furthermore, classifications based on pathophysiology and HF phenotypes beyond the EF construct will shape the design of future trials and help narrow down groups of patients who may respond to personalized treatment.

Catheter ablation for patients with atrial fibrillation and heart failure: insights from the Swedish Heart Failure Registry.

To investigate the association between catheter ablation for atrial fibrillation (AF) and mortality as well as hospitalization for heart failure (HF) in patients with HF across the ejection fraction (EF) spectrum. Patients with first-time catheter ablation for AF (ablation group) compared to only medical treated AF patients (no ablation group) were identified from the Swedish Heart Failure Registry between 2005 and 2019. The primary outcome (all-cause mortality/first HF hospitalization) was assessed by Cox regression models in a 1:2 propensity score (PS) matched cohort and pre-specified EF subgroups (preserved EF [≥50%], mildly reduced EF [40-49%], reduced EF [&lt;40%]) of this cohort. A total of 452 patients in the ablation group and 43 766 patients in the no ablation group were identified. After PS matching, 434 patients in the ablation group were compared to 868 patients in the no ablation group. Over a median follow-up of 2.6 years (0.0-14.1 years), catheter ablation was associated with a lower risk of the primary outcome (all-cause mortality/first HF hospitalization) (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.65-0.94). Results were consistent across all EF subgroups. In HF with preserved EF (HFpEF), catheter ablation was also associated with a lower risk of recurrent HF hospitalization (incidence rate ratio 0.17, 95% CI 0.07-0.42). In HF patients across the EF spectrum, catheter ablation for AF was associated with lower risk of the primary outcome (all-cause mortality/first HF hospitalization). This study supports catheter ablation as a treatment option for AF in HF patients, including those with HFpEF.

Patient profile and outcomes associated with follow-up in specialty vs. primary care in heart failure.

AimsFactors influencing follow‐up referral decisions and their prognostic implications are poorly investigated in patients with heart failure (HF) with reduced (HFrEF), mildly reduced (HFmrEF), and preserved (HFpEF) ejection fraction (EF). We assessed (i) the proportion of, (ii) independent predictors of, and (iii) outcomes associated with follow‐up in specialty vs. primary care across the EF spectrum.Methods and resultsWe analysed 75 518 patients from the large and nationwide Swedish HF registry between 2000–2018. Multivariable logistic regression models were fitted to identify the independent predictors of planned follow‐up in specialty vs. primary care, and multivariable Cox models to assess the association between follow‐up type and outcomes. In this nationwide registry, 48 115 (64%) patients were planned for follow‐up in specialty and 27 403 (36%) in primary care. The median age was 76 [interquartile range (IQR) 67–83] years and 27 546 (36.5%) patients were female. Key independent predictors of planned follow‐up in specialty care included optimized HF care, that is follow‐up in a nurse‐led HF clinic [odds ratio (OR) 4.60, 95% confidence interval (95% CI) 4.41–4.79], use of HF devices (OR 3.99, 95% CI 3.62–4.40), beta‐blockers (OR 1.39, 95% CI 1.32–1.47), renin–angiotensin system/angiotensin‐receptor‐neprilysin inhibitors (OR 1.21, 95% CI 1.15–1.27), and mineralocorticoid receptor antagonists (OR 1.31, 95% CI 1.26–1.37); and more severe HF, that is higher NT‐proBNP (OR 1.13, 95% CI 1.06–1.20) and NYHA class (OR 1.13, 95% CI 1.08–1.19). Factors associated with lower likelihood of follow‐up in specialty care included older age (OR 0.29, 95% CI 0.28–0.30), female sex (OR 0.89, 95% CI 0.86–0.93), lower income (OR 0.79, 95% CI 0.76–0.82) and educational level (OR 0.77, 95% CI 0.73–0.81), higher EF [HFmrEF (OR 0.65, 95% CI 0.62–0.68) and HFpEF (OR 0.56, 95% CI 0.53–0.58) vs. HFrEF], and higher comorbidity burden, such as presence of kidney disease (OR 0.91, 95% CI 0.87–0.95), atrial fibrillation (OR 0.85, 95% CI 0.81–0.89), and diabetes mellitus (OR 0.92, 95% CI 0.88–0.96). A planned follow‐up in specialty care was independently associated with lower risk of all‐cause [hazard ratio (HR) 0.78, 95% CI 0.76–0.80] and cardiovascular death (HR 0.76, 95% CI 0.73–0.78) across the EF spectrum, but not of HF hospitalization (HR 1.06, 95% CI 1.03–1.10).ConclusionsIn a large nationwide HF population, referral to specialty care was linked with male sex, younger age, lower EF, lower comorbidity burden, better socioeconomic environment and optimized HF care, and associated with better survival across the EF spectrum. Our findings highlight the need for greater and more equal access to HF specialty care and improved quality of primary care.

Comorbidities and cause-specific outcomes in heart failure across the ejection fraction spectrum: A blueprint for clinical trial design

BackgroundComorbidities may differently affect treatment response and cause-specific outcomes in heart failure (HF) with preserved (HFpEF) vs. mid-range/mildly-reduced (HFmrEF) vs. reduced (HFrEF) ejection fraction (EF), complicating trial design. In patients with HF, we performed a comprehensive analysis of type 2 diabetes (T2DM), atrial fibrillation (AF) chronic kidney disease (CKD), and cause-specific outcomes. Methods and resultsOf 42,583 patients from the Swedish HF registry (23% HFpEF, 21% HFmrEF, 56% HFrEF), 24% had T2DM, 51% CKD, 56% AF, and 8% all three comorbidities. HFpEF had higher prevalence of CKD and AF, HFmrEF had intermediate prevalence of AF, and prevalence of T2DM was similar across the EF spectrum. Patients with T2DM, AF and/or CKD were more likely to have also other comorbidities and more severe HF. Risk of cardiovascular (CV) events was highest in HFrEF vs. HFpEF and HFmrEF; non-CV risk was highest in HFpEF vs. HFmrEF vs. HFrEF. T2DM increased CV and non-CV events similarly but less so in HFpEF. CKD increased CV events somewhat more than non-CV events and less so in HFpEF. AF increased CV events considerably more than non-CV events and more so in HFpEF and HFmrEF. ConclusionHFpEF is distinguished from HFmrEF and HFrEF by more comorbidities, non-CV events, but lower effect of T2DM and CKD on events. CV events are most frequent in HFrEF. To enrich for CV vs. non-CV events, trialists should not exclude patients with lower EF, AF and/or CKD, who report higher CV risk.

Secondary valve regurgitation in patients with heart failure with preserved ejection fraction, heart failure with mid-range ejection fraction, and heart failure with reduced ejection fraction.

Secondary mitral regurgitation and secondary tricuspid regurgitation due to heart failure (HF) remain challenging in almost every aspect: increasing prevalence, poor prognosis, notoriously elusive in diagnosis, and complexity of therapeutic management. Recently, defined HF subgroups according to three ejection fraction (EF) ranges (reduced, mid-range, and preserved) have stimulated a structured understanding of the HF syndrome but the role of secondary valve regurgitation (SVR) across the spectrum of EF remains undefined. This review expands this structured understanding by consolidating the underlying phenotype of myocardial impairment with each type of SVR. Specifically, the current understanding, epidemiological considerations, impact, public health burden, mechanisms, and treatment options of SVR are discussed separately for each lesion across the HF spectrum. Furthermore, this review identifies important gaps in knowledge, future directions for research, and provides potential solutions for diagnosis and treatment. Mastering the challenge of SVR requires a multidisciplinary collaborative effort, both, in clinical practice and scientific approach to optimize patient outcomes.

Increased sensitivity to ischemic interval of donor hearts with diminished left ventricular function

Previous studies have demonstrated that carefully selected donor hearts (DHs) with poor left ventricular ejection fraction (EF) may be transplanted with long-term survival equivalent to hearts with normal function. The purpose of this study is to facilitate their selection. Using the United Network for Organ Sharing database, we reviewed all adult heart transplants between January 2000 and March 2016. Regression models were developed to estimate hazard ratios with 95% confidence intervals of post-transplant 1-year mortality and failure of EF to recover at 1 year for DHs with EF ≥50%, EF 40%-49.9%, and EF 30%-30.9%. During the study period, 31,979 DHs were transplanted. Compared with DHs with left ventricular ejection fraction ≥50%, DHs with reduced EF were younger and had slightly lower body mass index. There were no differences in the mechanism of death between groups and no differences in recipient characteristics, except for a higher incidence of African American recipients of hearts with an EF of 40%-49.9%. Of the variables analyzed, only a 1-hour increase in ischemia time had different hazard ratios for 1-year mortality between groups, with increasing hazard as EF diminished. It was also the only variable that predicted failure of recovery of normal EF and that was in the lowest EF group. The impact of DH traits associated with adverse outcomes after heart transplantation that we studied are similar between DHs with EF <50% and those with EF ≥50%. However, limiting ischemic time may be even more important for DHs with diminished left ventricular function, particularly at the low end of the EF spectrum.

Should providers prescribe sacubitril/valsartan based on trial eligibility, approval indication, or guideline recommendations?

Should providers prescribe sacubitril/valsartan based on trial eligibility, approval indication, or guideline recommendations?

Sex-Based Differences in Heart Failure Across the Ejection Fraction Spectrum: Phenotyping, and Prognostic and Therapeutic Implications

ObjectivesThis study assessed sex-related differences in a large cohort of unselected patients with heart failure (HF) across the ejection fraction (EF) spectrum. BackgroundFemales are under-represented in randomized clinical trials. Potential sex-related differences in HF may question the generalizability of trials. MethodsIn the Swedish Heart Failure Registry population multivariate Cox and logistic regression models were fitted to investigate differences in prognosis, prognostic predictors, and treatments across males and females. ResultsOf 42,987 patients, 37% were females (55% with HF with preserved EF [HFpEF], 39% with HF with mid-range EF [HFmrEF], and 29% with HF with reduced EF [HFrEF]). Females were older and more symptomatic and more likely to have hypertension and kidney disease but less likely to have diabetes and ischemic heart disease. After adjustments, females were more likely to use beta-blockers and digoxin but less likely to receive HF device therapy. Crude mortality/HF hospitalization rates for HFpEF (hazard ratio [HR]: 1.16) and HFmrEF (HR: 1.14) were significantly higher in females but lower in females with HFrEF (HR: 0.95). After adjustments, the risk was significantly lower in females regardless of EF (HR: 0.80 in HFrEF, HR: 0.91 in HFmrEF, and HR: 0.93 in HFpEF). The main sex-related differences in prognostic predictors concerned diabetes in HFrEF and anemia in HFmrEF. ConclusionsMales and females with HF showed different characteristics across the EF spectrum. Males reported a lower crude risk of mortality/morbidity in HFpEF and HFmrEF but higher risk of HFrEF, although after adjustments, prognosis was better in females regardless of EF. The observed sex-related differences highlight the need for an adequate representation of females in HF randomized controlled trials to improve generalizability.

Abstract 16910: Complex Heart Failure Phenotypes Differ in Response to Medical Therapy and Exercise Training

Background: Patients with heart failure (HF) are heterogeneous with multiple complex phenotypes across the ejection fraction (EF) spectrum. Phenotype-specific response to various treatments have not been well-described. Hypothesis: Clinical response to specific interventions will vary according to HF phenotype. Methods: Using latent class analysis, six cluster-based HF phenotypes across the EF spectrum were previously identified using patient data from 2130 patients enrolled in HF-ACTION (LVEF ≤ 35%) and 1767 patients enrolled from the Americas in TOPCAT (LVEF ≥ 45%) based on age, sex, race, CAD, BMI, hyperlipidemia, hypertension, diabetes mellitus, atrial fibrillation, COPD, anemia, and renal function, but not LVEF. Response to aerobic exercise training vs. usual care (HF-ACTION) and spironolactone vs. placebo (TOPCAT) were quantified by phenotype. The primary outcome was a composite of cardiovascular mortality (CVM) or HF hospitalization (HFH). Secondary outcomes included CVM, HFH, and all-cause mortality (ACM). Change in peak VO2 at 3 and 12 months were also analyzed in HF-ACTION. Results: Of the established phenotypes, the phenotype composed of elderly non-ischemic patients as well as the non-white/non-ischemic/hypertensive phenotype experienced improvement in combined CVM and HFH, ACM and exercise capacity (28% vs 38%, HR: 0.66 [0.46-0.94], 8% vs 16% HR: 0.49 [0.27-0.91], change in VO2: 1.06±3.01 vs 0.04±3.14, p&lt;0.05). Elderly patients with non-ischemic HFrEF enrolled in HF-ACTION randomized to therapeutic exercise program demonstrated significantly improved exercise capacity compared to usual care (change in VO2: 1.45±2.82 vs -0.09±2.49 and 1.25±3.18 vs 0.66±3.64 respectively, p&lt;0.05). Elderly non-ischemic patients treated with spironolactone in TOPCAT had a lower risk of the primary outcome CVM and HFH (20% vs 27%, HR: 0.67 [0.48-0.95]), driven mostly by reduced CVM (9% vs 17%, HR: 0.52 [0.32-0.84]). Conclusions: Response to varied treatments such as exercise training and spironolactone varies among complex HF phenotypes in both HFpEF and HFrEF. Additional investigation which further characterizes phenotype-specific treatments may help select specific interventions most likely to benefit specific phenotypes.