Heart Failure With Reduced Ejection Fraction Population Research Articles

Real-world effectiveness of mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction: a retrospective, non-interventional cohort analysis

Background and purpose: Mineralocorticoid receptor antagonists (MRAs) have been shown in clinical trials to improve outcomes in heart failure with reduced ejection fraction (HFrEF). Yet, it is still uncertain how effective they are in real-world patients with HFrEF. This study aimed to investigate the association between MRAs and outcomes in the overall population and a propensity score-matched cohort, based on patient-level data from the Swedish Heart Failure Registry (SwedeHF). Methods: Patients diagnosed with HFrEF were included from the SwedeHF spanning from 2003 to 2020. Enrollment was based on medication dispensation within 3 months before and 6 months after the index date recorded in the register. Endpoints included all-cause mortality, cardiovascular death, and hospital re-admissions, tracked from the index date until censoring or occurrence of an event. Results: Of 47,103 patients identified through the SwedeHF with HFrEF, 22,368 individuals were not treated with MRA (referred to as MRA naive patients), 21,893 were treated with MRA at a dosage of 25 mg, and 1,423 were treated with MRA at 50 mg once daily. In the overall cohort, the administration of MRA at 25 mg was associated with modest reductions in the risk of all-cause mortality (hazard ratio: 0.92 [0.89–0.95], P < 0.0001) and cardiovascular death (hazard ratio: 0.93 [0.89–0.98], P < 0.01) compared to the MRA naive group. However, both dosages of MRA (25 and 50 mg) were associated with a slight increase in the risk of hospital re-admissions due to heart failure 10% compared to MRA naive patients. These findings were consistent when examining a propensity score-matched cohort. Interaction analysis showed a significantly improved survival rate for patients receiving MRA at 25 mg compared to MRA naive individuals, particularly among those with an estimated glomerular rate ≥30 mL/min/1.73 m2 across all patients and in those aged 70 years and above. Conclusions: The administration of MRA treatment at 25 mg once daily was linked to a modestly improved survival in a real-life HFrEF population, with even more pronounced benefits observed within a specific subgroup. This finding highlights the importance of personalized medicine in providing customized therapeutic advantages.

N-terminal pro-B-type natriuretic peptide concentrations, testing and associations with worsening heart failure events.

In patients with heart failure (HF), we aimed to assess (i) the time trends in N-terminal pro-B-type natriuretic peptide (NT-proBNP) testing; (ii) patient characteristics associated with NT-proBNP testing; (iii) distribution of NT-proBNP levels, focusing on the subgroups with (WHFE) vs. without (NWHFE) a worsening HF event, defined as an HF hospitalization; and (iv) changes of NT-proBNP levels over time. NT-proBNP testing and levels were investigated in HF patients enrolled in the Swedish Heart Failure Registry (SwedeHF) linked with the Stockholm CREAtinine Measurements project from January 2011 to December 2018. Index date was the first registration in SwedeHF. Patterns of change in NT-proBNP levels before (in the previous 6±3months) and after (in the following 6±3months) the index date were categorized as follows: (i) <3000ng/L at both measurements=stable low; (ii) <3000ng/L at the first measurement and ≥3000ng/L at the second measurement=increased; (iii) ≥3000ng/L at the first measurement and <3000ng/L at the second measurement=decreased; and (iv) ≥3000ng/L at both measurements=stable high. Univariable and multivariable logistic regression models, expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs), were performed to assess the associations between (i) clinical characteristics and NT-proBNP testing and (ii) changes in NT-proBNP from 6months prior to the index date and the index date and a WHFE. Consistency analyses were performed in HF with reduced ejection fraction (HFrEF) alone. A total of 4424 HF patients were included (median age 74years, women 34%, HFrEF 53%), 33% with a WHFE. NT-proBNP testing increased over time, up to 55% in 2018, and was almost two-fold as frequent, and time to testing was less than half, in patients with WHFE vs. NWHFE. Independent predictors of testing were WHFE, higher heart rate, diuretic use, and preserved ejection fraction. Median NT-proBNP was 3070ng/L (Q1-Q3: 1220-7395), approximately three-fold higher in WHFE vs. NWHFE. Compared with stable low NT-proBNP levels, increased (OR 4.27, 95% CI 2.47-7.37) and stable high levels (OR 2.48, 95% CI 1.58-3.88) were independently associated with a higher risk of WHFE. Results were consistent in the HFrEF population. NT-proBNP testing increased over time but still was only performed in half of the patients. Testing was associated with a WHFE, with features of more severe HF and for differential diagnosis purposes. Increased and stable high levels were associated with a WHFE. Overall, our data highlight the potential benefits of carrying further implementation of NT-proBNP testing in clinical practice.

Integrating Cost into Shared Decision-Making for Heart Failure with Reduced Ejection Fraction (POCKET-COST-HF): A Trial Providing Out-of-Pocket Costs for Heart Failure Medications during Clinical Encounters

Evidence-based medical therapy for heart failure with reduced ejection fraction (HFrEF) often entails substantial out-of-pocket costs that can vary appreciably between patients. This has raised concerns regarding financial toxicity, equity, and adherence to medical therapy. In spite of these concerns, cost discussions in the HFrEF population appear to be rare, partly because out-of-pocket costs are generally unavailable during clinical encounters. In this trial, out-of-pocket cost information is given to patients and clinicians during outpatient encounters with the aim to assess the impact of providing this information on medication discussions and decisions. Cost-informed decision-making will be facilitated by providing access to patient-specific out-of-pocket cost estimates at the time of clinical encounter. Integrating Cost into Shared Decision-Making for Heart Failure with Reduced Ejection Fraction (POCKET-COST-HF) is a multicenter trial based at Emory Healthcare and University of Colorado Health. Adapting an existing patient activation tool from the EPIC-HF trial, patients and clinicians are presented a checklist with medications approved for treatment of HFrEF with or without patient-specific out-of-pocket costs (obtained from a financial navigation firm). Clinical encounters are audio-recorded, and patients are surveyed about their experience. The trial utilizes a stepped-wedge cluster randomized design, allowing for each site to enroll control and intervention group patients while minimizing contamination of the control arm. This trial will elucidate the potential impact of robust cost disclosure efforts and key information regarding patient and clinician perspectives related to cost and cost communication. It also will reveal important challenges associated with providing out-of-pocket costs for medications during clinical encounters. Acquiring medication costs for this trial requires an involved process and outsourcing of work. In addition, costs may change throughout the year, raising questions regarding what specific information is most valuable. These data will represent an important step towards understanding the role of integrating cost discussions into heart failure care. NCT04793880.

The prognostic value of aortic stenosis and aortic sclerosis in patients with heart failure with reduced ejection fraction

Abstract Background Aortic stenosis (AS) and aortic valve sclerosis (AVS) as assessed by Doppler echocardiography have been associated with adverse clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, further clarification of the role of AV and AVS in the HFrEF population is warranted. Methods A total of 873 patients with stable HFrEF were included in this retrospective cohort study. At referral, the patients had a left ventricular ejection fraction (LVEF) of 45% or lower Baseline clinical and echocardiographic data were retrieved from the heart failure outpatient clinic's database, and the patients were followed through a nationwide register for the outcome of all-cause mortality. The presence of AS and AVS was assessed using Doppler-derived pressure gradients of the aortic valve (AV) from the echocardiogram. Cox-regression models were used to determine the association between AV peak gradient and mortality. Multivariable models were adjusted for demographic, clinical, and echocardiographic parameters (age, sex, diabetes (DM), ischemic heart disease (IHD), BMI, heart rate, mean arterial pressure, total cholesterol and atrial fibrillation (AF), LVEF, left atrial volume index (LAVi), left ventricular mass index (LVMi), E/e’). Results Seventy-four percent of patients were male, and mean age was 66.8 ± 11.4 years. In total, 13% had DM, 57% had IHD, 38% had NYHA III-IV, 8% had implantable cardiac device (including pacemaker, ICD, and CRT), and 15.9% had AF. Mean LVEF was 27.3 ± 9.4% with a mean LVMi of 120.2 g/m2 ± 38.2. Mean AV peak velocity was 1.4 m/s ± 0.5 and median AV peak gradient was 6.3 mmHg (IQR 4.7; 8.9). During a median follow-up of 3.3 years (IQR 1.9 – 4.7 years), 143 patients (16.4 %) reached the outcome. In univariable analysis, AV peak gradient was associated with all-cause mortality (HR 1.23 per 10 mmHg increase, 95% CI 1.05-1.44, p = 0.012). LVEF modified the prognostic value of AV peak gradient (p = 0.026 for interaction). After stratifying the population by the median value of LVEF (cut-off = 28%), AV peak gradient remained prognostic only in patients with LVEF above the median (HR 1.58 per 10 mmHg increase, 95% CI 1.30-1.91, p &amp;lt; 0.001), whereas AV peak gradient was not significantly associated with mortality amongst the patients with LVEF below the median level (HR 1.03 per 10 mmHg increase, 95% CI 0.83-1.37, p = 0.827). After multivariable adjustment, AV peak gradient remained an independent predictor of the outcome in patients in the higher median of LVEF (HR 1.32 per 10 mmHg increase, 95% CI 1.02-1.70, p = 0.035) (Figure 1). Conclusion Presence of AS and AVS (derived by AV peak gradient Doppler echocardiography) is an independent predictor of all-cause mortality amongst HFrEF patients. However, presence of AS and AVS only entails prognostic information amongst the HFrEF patients without severely reduced LVEF.Incidence rates of all-cause mortality

Safety of continuing mineralocorticoid receptor antagonist treatment in patients with heart failure with reduced ejection fraction and severe kidney disease: Data from Swedish Heart Failure Registry.

Mineralocorticoid receptor antagonists (MRAs) improve outcomes in heart failure with reduced ejection fraction (HFrEF) but remain underused and are often discontinued especially in patients with chronic kidney disease (CKD) due to concerns on renal safety. Therefore, in a real-world HFrEF population we investigated the safety of MRA use, in terms of risk of renal events, any mortality and any hospitalization, across the estimated glomerular filtration rate (eGFR) spectrum including severe CKD. We analysed patients with HFrEF (ejection fraction <40%), not on dialysis, from the Swedish Heart Failure Registry. We performed multivariable logistic regression models to investigate patient characteristics independently associated with MRA use, and univariable and multivariable Cox regression models to assess the associations between MRA use and outcomes. Of 33 942 patients, 17 489 (51%) received MRA, 32%, 45%, 54%, 54% with eGFR <30, 30-44, 45-59 or ≥60 ml/min/1.73 m2 , respectively. An eGFR ≥60 ml/min/1.73 m2 and patient characteristics linked with more severe HF were independently associated with more likely MRA use. In multivariable analyses, MRA use was consistently not associated with a higher risk of renal events (i.e. composite of dialysis/renal death/hospitalization for renal failure or hyperkalaemia) (hazard ratio [HR] 1.04, 95% confidence interval [CI] 0.98-1.10), all-cause death (HR 1.02, 95% CI 0.97-1.08) as well as of all-cause hospitalization (HR 0.99, 95% CI 0.95-1.02) across the eGFR spectrum including also severe CKD. The use of MRAs in patients with HFrEF decreased with worse renal function; however their safety profile was demonstrated to be consistent across the entire eGFR spectrum.

Cardiopulmonary Exercise Testing in the Age of New Heart Failure Therapies: Still a Powerful Tool?

New therapies with prognostic benefits have been recently introduced in heart failure with reduced ejection fraction (HFrEF) management. The aim of this study was to evaluate the prognostic power of current listing criteria for heart transplantation (HT) in an HFrEF cohort submitted to cardiopulmonary exercise testing (CPET) between 2009 and 2014 (group A) and between 2015 and 2018 (group B). Consecutive patients with HFrEF who underwent CPET were followed-up for cardiac death and urgent HT. CPET was performed in 487 patients. The composite endpoint occurred in 19.4% of group A vs. 7.4% of group B in a 36-month follow-up. Peak VO2 (pVO2) and VE/VCO2 slope were the strongest independent predictors of mortality. International Society for Heart and Lung Transplantation (ISHLT) thresholds of pVO2 ≤ 12 mL/kg/min (≤14 if intolerant to β-blockers) and VE/VCO2 slope > 35 presented a similar and lower Youden index, respectively, in group B compared to group A, and a lower positive predictive value. pVO2 ≤ 10 mL/kg/min and VE/VCO2 slope > 40 outperformed the traditional cut-offs. An ischemic etiology subanalysis showed similar results. ISHLT thresholds showed a lower overall prognostic effectiveness in a contemporary HFrEF population. Novel parameters may be needed to improve risk stratification.

Effects of sacubitril/valsartan on atrial function and structure as treatment response indicators in patients with heart failure with reduced ejection fraction: an observational prospective study

Abstract Funding Acknowledgements Type of funding sources: None. Background Sacubitril/valsartan (Sac/Val) has been shown to improve mortality and reduce hospitalizations in patients with heart failure with reduced ejection fraction (HFrEF), also through reverse cardiac remodeling. However, temporal changes of functional and structural left atrial parameters, including speckle tracking (ST) analysis, have not been comprehensively characterized yet. Purpose This prospective study sought to: (1) evaluate the impact of Sac/Val on echo parameters, focusing on left atrial function and structure metrics, at two timepoints, 6 and 12 months, after treatment initiation; (2) assess the predictive role of these factors on Sac/Val response at 12 months, including LVEF and biomarker outcomes. Methods From January 2020 to September 2021, HFrEF patients from Policlinico Universitario Agostino Gemelli IRCSS outpatient HF service with indication to Sac/Val treatment were prospectively enrolled; subjects with history of atrial fibrillation and more than moderate mitral regurgitation were excluded. Echocardiographic evaluation was performed before Sac/Val, at 6 and 12 months after treatment initiation. Patients with improvement in left ventricular ejection fraction (LVEF) ≥ 35% and with N-terminal pro-b-type natriuretic peptide (NT pro-BNP) reduction below 1000 pg/mL were considered responders. Results Sixty-six patients (50 males, 16 females) with an age of 64 ± 12 years were finally enrolled, of which 41% were affected by chronic ischemic heart disease. At enrollment, 19 subjects were in New York Heart Association class III-IV, median NT-proBNP was 3063.00 pg/mL and mean LVEF was 30.3±7.7%. LA-EF was 27.8±12.8%, while Left Atrio-ventricular coupling index (LACi) was 0,30±0,12. At ST echocardiography, LV GLS was -8,2±3,0% and LA reservoir strain (LARS) 11,60%. All structural and functional LA parameters significantly improved at T1 and T2: at T2, LARS was 22,51%, LA-EF 37,4±15,8% and LACi 0,28±0,12 (respectively p &amp;lt;0,001, p = 0,05, p = 0,018 compared to baseline). No differences were detected according to dysfunction etiology. Improvements were larger among patients who achieved the pre-specified outcome. LA reservoir strain was the best predictor of positive changes in LVEF and NT-proBNP. Conclusions Precise characterization of LA structural and functional parameters, including ST analysis, may help identifying patients experiencing the highest benefit from Sac/Val, therefore guiding treatment in the HFrEF population.

MP-453086-9 CARDIAC RESYNCHRONIZATION THERAPY IN HEART FAILURE WITH REDUCED EJECTION FRACTION: CONDUCTION SYSTEM PACING VERSUS BIVENTRICULAR PACING: A SYSTEMATIC REVIEW AND META-ANALYSIS

Conduction system pacing (CSP) is considered a more physiological form of pacing in patients requiring cardiac resynchronization therapy (CRT). Recently there are studies showing the benefit of CSP over biventricular pacing (BVP) among patients with heart failure with reduced ejection fraction (HFrEF). However, published data were based on small and mostly single-centered studies. To compare ECG, echocardiographic characteristics, and clinical improvement among patients with HFrEF undergoing CRT with CSP versus BVP. This study protocol is registered in the PROSPERO (CRD42022375155), and the review is conducted per PRISMA protocol. Four major databases were searched from inception till October 20, 2022, for relevant publications comparing conduction system pacing with biventricular pacing for cardiac resynchronization therapy indications in the HFrEF population. All relevant data were extracted in an excel spreadsheet. Data analysis was performed using RevMan 5.4 software. Dichotomous data variables were pooled using an odds ratio (OR) with a 95% confidence interval (CI). Continuous variable pooled using mean difference (MD). A total of 10,072 references were found in the database search. 35 studies were assessed for full days eligibility;18 studies (6 RCTs, 12 observational studies) with a total of 1375 patients were included in the review. Following left bundle branch area pacing (LBBAP), the average paced QRS duration was 28 ms narrower in comparison to BVP (MD -27.69, CI -36.59 to -18.80, n = 515), and a similar result was obtained in His bundle pacing (HBP) vs BVP (MD -31.76, CI -48.74 to -14.77; n= 413). LVEF significantly improved in CSP in comparison to BVP [LBBAP (MD 6.03, CI 4.16-7.91; n= 564); HBP (MD 3.79, CI 0.46-7.11; n= 260); His-Purkinje system pacing (HPSP) (MD 6.60, CI 4.42-8.78; n=477) (FIGURE). There were higher odds of being responders (OR 3.82, CI 1.88-7.75; n = 265)/super responders (OR 2.08, CI 1.53-2.82; n= 811) (per ECHO findings) in the CSP group, and overall mortality (OR 0.61, CI 0.40-0.93; n= 908) and hospitalization for heart failure (HHF) (OR 0.37, CI 0.25-0.55; n= 993) was lower in CSP group. Our analysis showed that CSP was superior to BVP with regard to ECG and echocardiographic parameters, as well as clinical outcomes in terms of mortality and HHF.

Effect of vericiguat on left ventricular structure and function in patients with heart failure with reduced ejection fraction: The VICTORIA echocardiographic substudy.

Vericiguat significantly reduced the primary composite outcome of heart failure (HF) hospitalization or cardiovascular death in the VICTORIA trial. It is unknown if these outcome benefits are related to reverse left ventricular (LV) remodelling with vericiguat in patients with HF with reduced ejection fraction (HFrEF). The aim of this study was to compare the effects of vericiguat versus placebo on LV structure and function after 8 months of therapy in patients with HFrEF. Standardized transthoracic echocardiography (TTE) was performed at baseline and after 8 months of therapy in a subset of HFrEF patients in VICTORIA. The co-primary endpoints were changes in LV end-systolic volume index (LVESVI) and LV ejection fraction (LVEF). Quality assurance and central reading were performed by an echocardiographic core laboratory blinded to treatment assignment. A total of 419 patients (208 vericiguat, 211 placebo) with high-quality paired TTE at baseline and 8 months were included. Baseline clinical characteristics were well balanced between treatment groups and echocardiographic characteristics were representative of patients with HFrEF. LVESVI significantly declined (60.7 ± 26.8 to 56.8 ± 30.4 ml/m2 ; p < 0.01) and LVEF significantly increased (33.0 ± 9.4% to 36.1 ± 10.2%; p < 0.01) in the vericiguat group, but similarly in the placebo group (absolute changes for vericiguat vs. placebo: LVESVI -3.8 ± 15.4 vs. -7.1 ± 20.5 ml/m2 ; p = 0.07 and LVEF +3.2 ± 8.0% vs. +2.4 ± 7.6%; p = 0.31). The absolute rate per 100 patient-years of the primary composite endpoint at 8 months tended to be lower in the vericiguat group (19.8) than the placebo group (29.6) (p = 0.07). In this pre-specified echocardiographic study, significant improvements in LV structure and function occurred over 8 months in both vericiguat and placebo in a high-risk HFrEF population with recent worsening HF. Further studies are warranted to define the mechanisms of vericiguat's benefit in HFrEF.

Inward Displacement: A Novel Method of Regional Left Ventricular Functional Assessment for Left Ventriculoplasty Interventions in Heart Failure with Reduced Ejection Fraction (HFrEF).

Hybrid minimally invasive left ventricular reconstruction is used to treat patients with ischemic heart failure with reduced ejection fraction (HFrEF) and antero-apical scar. Pre- and post-procedural regional functional left ventricular assessment with current imaging techniques remains limited. We evaluated 'inward displacement' as a novel technique of assessing regional left ventricular function in an ischemic HFrEF population who underwent left ventricular reconstruction with the Revivent System. Inward displacement adopts three standard long-axis views obtained during cardiac MRI or CT and assesses the degree of inward endocardial wall motion towards the true left ventricular center of contraction. For each of the standard 17 left ventricular segments, regional inward displacement is measured in mm and expressed as a percentage of the maximal theoretical distance each segment can contract towards the centerline. The left ventricle was divided into three regions, obtaining the arithmetic average of inward displacement or speckle tracking echocardiographic strain at the left ventricular base (segments 1-6), mid-cavity (segments 7-12) and apex (segments 13-17). Inward displacement was measured using computed tomography or cardiac magnetic resonance imaging and compared pre- and post-procedurally in ischemic HFrEF patients who underwent left ventricular reconstruction with the Revivent System (n = 36). In a subset of patients who underwent baseline speckle tracking echocardiography, pre-procedural inward displacement was compared with left ventricular regional echocardiographic strain (n = 15). Inward displacement of basal and mid-cavity left ventricular segments increased by 27% (p < 0.001) and 37% (p < 0.001), respectively, following left ventricular reconstruction. A significant overall decrease in both the left ventricular end systolic volume index and end diastolic volume index of 31% (p < 0.001) and 26% (p < 0.001), respectively, was detected, along with a 20% increase in left ventricular ejection fraction (p = 0.005). A significant correlation between inward displacement and speckle tracking echocardiographic strain was noted within the basal (R = -0.77, p < 0.001) and mid-cavity left ventricular segments (R = -0.65, p = 0.004), respectively. Inward displacement resulted in relatively larger measurement values compared to speckle tracking echocardiography, with a mean difference of absolute values of -3.33 and -7.41 for the left ventricular base and mid-cavity, respectively. Obviating the limitations of echocardiography, inward displacement was found to highly correlate with speckle tracking echocardiographic strain to evaluate regional segmental left ventricular function. Significant improvements in basal and mid-cavity left ventricular contractility were demonstrated in ischemic HFrEF patients following left ventricular reconstruction of large antero-apical scars, consistent with the concept of reverse left ventricular remodeling at a distance. Inward displacement holds significant promise in the HFrEF population being evaluated pre- and post-left ventriculoplasty procedures.

Cost-utility analysis of empagliflozin in heart failure patients with reduced and preserved ejection fraction in China.

Objective: EMPEROR-Reduced and EMPEROR-Preserved studies showed the benefits of empagliflozin along with a reduction in cardiovascular death or hospitalisation for heart failure (HF). Our aim was to evaluate the economics and effectiveness of adding empagliflozin to the standard therapy for HF with reduced ejection fraction (HFrEF) and HF preserved ejection fraction (HFpEF) in China. Methods: A multistate Markov model was constructed to yield the clinical and economic outcomes of adding empagliflozin to the standard therapy for 65-year-old patients with HFrEF and HFpEF. A cost-utility analysis was conducted, mostly derived from the EMPEROR-Reduced study, EMPEROR-Preserved study, and national statistical database. All costs and outcomes were discounted at the rate of 5% per annum. The primary outcomes were total and incremental costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). Sensitivity analyses were also performed. Results: In the HFrEF population, the 10-year incremental cost was $827.52 and the 10-year incremental QALY was 0.15 QALYs, resulting in an ICER of $5,612.06/QALY, which was below the WTP of $12,652.5/QALY. In the HFpEF population, compared with the control group, the incremental cost was $1,271.27, and the incremental QALY was 0.11 QALYs, yielding an ICER of 11,312.65 $/QALY, which was also below the WTP of $12,652.5/QALY. In the HFrEF and HFpEF populations, the results of a one-way sensitivity analysis showed that the risk of cardiovascular death in both groups was the most influential parameter. In the HFrEF population, a probability sensitivity analysis (PSA) revealed that when the WTP thresholds were $12,652.5/QALY and $37,957.5/QALY, the probabilities of being cost-effective with empagliflozin as an add-on were 59.4% and 72.6%, respectively. In the HFpEF population, the PSA results revealed that the probabilities of being cost-effective with empagliflozin as an add-on were 53.1% and 72.2%, respectively. Conclusion: Considering that the WTP threshold was $12,652.5/QALY, adding empagliflozin to standard therapy was proven to be a slightly more cost-effective option for the treatment of HFrEF and HFpEF from a Chinese healthcare system perspective, which promoted the rational use of empagliflozin for HF.

Pharmacist Intervention Increases Optimization Of Guideline-directed Medical Therapy In Heart Failure Patients With Medication Intolerances

Introduction Patients with heart failure with reduced ejection fraction (HFrEF) are frequently not prescribed target doses of guideline-directed medical therapy (GDMT) due to a documented history of medication intolerances. Clinical pharmacist involvement in multidisciplinary HF clinics improves GDMT uptake through assistance with patient education and monitoring of drug safety/efficacy. Hypothesis We hypothesized that a pharmacist-led GDMT titration protocol would increase rates of GDMT use and optimization in patients with previously documented medication intolerances. Methods Patients with HFrEF were referred by HF Cardiologists to a pharmacist-led GDMT titration protocol between June 2019-February 2021. Those with ACC/AHA Stage D HF, NYHA class IV symptoms, or contraindications to medication titration were excluded. Interventions included initiating potassium-lowering therapies, implementing therapeutic interchanges, counseling on diet and adverse effects, and outreach to review symptoms and vital signs. In patients with previously reported medication intolerances, the rate of successful GDMT initiation or uptitration was assessed after pharmacist intervention. Results Among the 79 patients referred to the protocol, 26 (33%) had documented intolerance at enrollment to ACEI/ARB/ARNI, beta-blocker, or MRA. Hyperkalemia (N=11) and symptomatic hypotension (N=11) were the most common previously reported adverse effects. In our cohort, mean age was 59 years, 21 (27%) were female, and mean LVEF was 27%. Compared to those without a prior intolerance, patients with an intolerance were less likely to be prescribed MRA (35% vs. 62%, p = 0.02), but other baseline characteristics were similar. After pharmacist intervention, 20 of the 26 (77%) patients with prior intolerance were able to be initiated or uptitrated on the respective medication class, with high rates of success in those with prior hyperkalemia or symptomatic hypotension but not in those with symptomatic bradycardia from beta-blockers (Figure). Conclusions In a referral cohort of HFrEF patients, one-third of patients were thought to be intolerant to specific GDMT drug classes, but pharmacist involvement facilitated successful initiation or uptitration on these medications in the majority of patients, particularly when the intolerance was related to hyperkalemia or symptomatic hypotension. If this model is applied more broadly in the HFrEF population, these simple and practical interventions could enhance GDMT uptake and improve long-term outcomes. Patients with heart failure with reduced ejection fraction (HFrEF) are frequently not prescribed target doses of guideline-directed medical therapy (GDMT) due to a documented history of medication intolerances. Clinical pharmacist involvement in multidisciplinary HF clinics improves GDMT uptake through assistance with patient education and monitoring of drug safety/efficacy. We hypothesized that a pharmacist-led GDMT titration protocol would increase rates of GDMT use and optimization in patients with previously documented medication intolerances. Patients with HFrEF were referred by HF Cardiologists to a pharmacist-led GDMT titration protocol between June 2019-February 2021. Those with ACC/AHA Stage D HF, NYHA class IV symptoms, or contraindications to medication titration were excluded. Interventions included initiating potassium-lowering therapies, implementing therapeutic interchanges, counseling on diet and adverse effects, and outreach to review symptoms and vital signs. In patients with previously reported medication intolerances, the rate of successful GDMT initiation or uptitration was assessed after pharmacist intervention. Among the 79 patients referred to the protocol, 26 (33%) had documented intolerance at enrollment to ACEI/ARB/ARNI, beta-blocker, or MRA. Hyperkalemia (N=11) and symptomatic hypotension (N=11) were the most common previously reported adverse effects. In our cohort, mean age was 59 years, 21 (27%) were female, and mean LVEF was 27%. Compared to those without a prior intolerance, patients with an intolerance were less likely to be prescribed MRA (35% vs. 62%, p = 0.02), but other baseline characteristics were similar. After pharmacist intervention, 20 of the 26 (77%) patients with prior intolerance were able to be initiated or uptitrated on the respective medication class, with high rates of success in those with prior hyperkalemia or symptomatic hypotension but not in those with symptomatic bradycardia from beta-blockers (Figure). In a referral cohort of HFrEF patients, one-third of patients were thought to be intolerant to specific GDMT drug classes, but pharmacist involvement facilitated successful initiation or uptitration on these medications in the majority of patients, particularly when the intolerance was related to hyperkalemia or symptomatic hypotension. If this model is applied more broadly in the HFrEF population, these simple and practical interventions could enhance GDMT uptake and improve long-term outcomes.

Guideline Directed Medical Therapy In A Safety Net Hospital, Where Do We Stand?

<h3>Background</h3> : Despite a clear mandate to maximize guideline directed medical therapy (GDMT) for patients with heart failure with reduced ejection fraction (HFrEF), large registries have shown sub-optimal rates of both prescription and uptitration. Rates of GDMT in large community safety net hospitals are not well known. Moreover, the patient population of safety net hospitals is markedly different than contemporary registries. Our aim was to create an accessible, self-maintained, electronic health record (EHR) based registry of HFrEF patients that can be leveraged to describe rates of GDMT, and support quality improvement initiatives in a large safety net hospital. <h3>Methods</h3> : Left ventricular ejection fraction (LVEF) was recently made to be a mandatory field for all transthoracic echocardiograms, which is then pulled into the EHR as a discrete field. Using this data, we enrolled all patients with an LVEF ≤ 40% from August 2019-April 2021 at Parkland Health and Hospital System, a large 860 bed safety net hospital for Dallas, Texas (n=2,624). The registry was then queried for an ICD10 diagnosis of heart failure (n=2,555, 97.3%) and patients without an ICD10 diagnosis of heart failure (n=69) were adjudicated manually. Patients with a most recent LVEF ≤ 40% (n=2,447) were queried for heart failure pharmacotherapies and doses. <h3>Results</h3> : Our registry comprises a young, male predominant cohort that is racially and ethnically diverse as seen in table 1. In figure 1a we find prescription rates of GDMT on par with national cohorts with excellent prescription rates of ARNI and SGLT2 inhibitors, particularly in the 1,417 (57.9%) who have been seen in Cardiology or CHF clinics in the last 2 years. We found that the majority of patients on GDMT are on less than 50% of the goal dose as seen in figure 1b. <h3>Conclusion</h3> : The HFrEF population in a large safety-net hospital system was a young diverse population with rates of GDMT prescription similar to national cohorts, with higher rates of ARNI and SGLT2-inhibitors. The registry provides a platform for future quality improvement initiatives to increase GDMT prescription and uptitration.

Multimorbidity And Guideline-Directed Medical Therapy Intensification In Heart Failure: Findings From The EPIC-HF Trial

<h3>Background</h3> Despite proven benefits of guideline directed medical therapy (GDMT) for patients with heart failure with reduced ejection fraction (HFrEF), multiple studies have shown that rates of GDMT prescribing are suboptimal worldwide. An important potential contributor to suboptimal GDMT is the high burden of multimorbidity in the HFrEF population, with estimates showing at least 50% of patients having 5+ co-occurring chronic conditions and taking 10+ medications daily. Large registries examining GDMT prescribing demonstrate associations between individual co-morbidities and GDMT, but data is lacking on the cumulative effect of multimorbidity on GDMT prescription. <h3>Methods</h3> The recently completed 3-site EPIC-HF trial tested the effect of a pre-clinic patient activation tool on GDMT prescribing made following a visit with a cardiology provider and then over the subsequent 6 months. Using this data, we examined the effect of multimorbidity on both baseline GDMT prescription and GDMT initiation and dose intensification (the primary outcome of the EPIC-HF trial). Presence of the following 9 co-morbidities was collected: COPD or other pulmonary disease, liver disease, diabetes, cancer (excluding non-melanoma skin cancer), depression, anxiety or other psychiatric disease, atrial fibrillation or flutter, hypertension, CKD (eGFR <= 60), and obesity (BMI>=30). <h3>Results</h3> Of the 292 patients, 35.6% had 3 or more non-HFrEF comorbidities and 34.6% had 1 or fewer additional comorbidities. The most commonly occurring comorbidities were hypertension (51.7%), obesity (41.4%), CKD (32.9%), diabetes (25%) and atrial fibrillation or flutter (28.1%). Increasing burden of multimorbidity was not associated with less total prescription of GDMT at baseline, and was, in fact, associated with the prescription of higher doses of beta-blocker (median 50% target dose with 3+ additional comorbidities vs 25% with no comorbidities, p=<0.01). When controlling for study arm in the original EPIC-HF trial, the presence of additional comorbidities was associated with decreased likelihood of GDMT intensification (1 comorbidity v. 0: RR 0.61, 95% CI 0.4-0.95; 2 v. 0: RR 0.88 95% CI 0.61-1.27; 3+ v. 0: RR 0.56, 95% CI 0.36-0.86). Individual comorbidities associated with decreased likelihood of GDMT intensification were diabetes (p=0.02), hypertension (p=0.003), and CKD (p=0.047). <h3>Conclusions</h3> Increasing burden of multimorbidity was not associated with less total GDMT prescription at baseline but was associated with decreased up-titration or initiation of GDMT at the study visit.

Contemporary Drug Treatment of Advanced Heart Failure with Reduced Ejection Fraction.

The introduction of multiple new pharmacological agents over the past three decades in the field of heart failure with reduced ejection fraction (HFrEF) has led to reduced rates of mortality and hospitalizations, and consequently the prevalence of HFrEF has increased, and up to 10% of patients progress to more advanced stages, characterized by high rates of mortality, hospitalizations, and poor quality of life. Advanced HFrEF patients often show persistent or progressive signs of severe HF symptoms corresponding to New York Heart Association class III or IV despite being on optimal medical, surgical, and device therapies. However, a subpopulation of patients with advanced HF, those with the most advanced stages of disease, were often insufficiently represented in the major trials demonstrating efficacy and tolerability of the drugs used in HFrEF due to exclusion criteria such as low BP and kidney dysfunction. Consequently, the results of many landmark trials cannot necessarily be transferred to patients with the most advanced stages of HFrEF. Thus, the efficacy and tolerability of guideline-directed medical therapies in patients with the most advanced stages of HFrEF often remain unsettled, and this knowledge is of crucial importance in the planning and timing of consideration for referral for advanced therapies. This review discusses the evidence regarding the use of contemporary drugs in the advanced HFrEF population, covering components such as guideline HFrEF drugs, diuretics, inotropes, and the use of HFrEF drugs in LVAD recipients, and provides suggestions on how to manage guideline-directed therapy in this patient group.

Medical Management of Patients With Heart Failure and Reduced Ejection Fraction.

Treatment options for patients with heart failure (HF) with reduced ejection fraction (HFrEF) have expanded considerably over the past few decades. Whereas neurohormonal modulation remains central to the management of patients with HFrEF, other pathways have been targeted with drugs that have novel mechanisms of action. The angiotensin receptor-neprilysin inhibitors (ARNIs) which enhance levels of compensatory molecules such as the natriuretic peptides while simultaneously providing angiotensin receptor blockade have emerged as the preferred strategy for inhibiting the renin angiotensin system. Sodium glucose cotransporter 2 (SGLT2) inhibitors which were developed as hypoglycemic agents have been shown to improve outcomes in patients with HF regardless of their diabetic status. These agents along with beta blockers and mineralocorticoid receptor antagonists are the core medical therapies for patients with HFrEF. Additional approaches using ivabradine to slow heart rate in patients with sinus rhythm, the hydralazine/isosorbide dinitrate combination to unload the heart, digoxin to provide inotropic support and vericiguat to augment cyclic guanosine monophosphate production have been shown in well-designed trials to have beneficial effects in the HFrEF population and are used as adjuncts to the core therapies in selected patients. This review provides an overview of the medical management of patients with HFrEF with focus on the major developments that have taken place in the field. It offers prospective of how these drugs should be employed in clinical practice and also a glimpse into some strategies that may prove to be useful in the future.

Impact of sacubitril/valsartan on systolic heart failure: Right heart location and clustering analysis.

Heart failure with reduced ejection fraction (HFrEF) is a heterogeneous syndrome. In heart failure (HF) classifications, right ventricle (RV) function was for a long time unrecognized in favor of left ventricular ejection fraction (LVEF). The response to sacubitril/valsartan might differ according to phenotypes and the impact of right ventricular characteristics on this response remains controversial. First, we applied clustering analysis in a HFrEF population undergoing sacubitril/valsartan treatment according to guidelines, to identify phenotypes and their associated clinical outcomes. Secondly, we evaluated RV-remodeling. It is a prospective, observational, single-center study conducted on 108 symptomatic patients (mean age 66 ±12.8 years, 22.2% women). First, the clustering analysis was applied in a HFrEF population undergoing sacubitril/valsartan treatment, according to the guidelines, in order to identify phenotypes and clinical outcomes associated with them. Secondly, we evaluated RV-remodeling. Two distinct clusters were identified. Among the differences between phenotypes, RV (tricuspid annular plane systolic excursion (TAPSE) 16 ±4 mm compared to 19 ±4 mm, p < 0.001; RV free wall strain -19 ±5% compared to -21 ±4%, p = 0.046; RV fraction area change (FAC) 31 ±9% compared to 38 ±9%, p < 0.001), LV-filling pressure (E-wave deceleration time 138 (median: 41) ms compared to 180 (median: 94) ms, p < 0.001; E/e' 16.7 (median: 8.0) ms compared to 13.0 (median: 9.7) ms, p = 0.02) and creatinine level (106 ±34 μmol/L compared to 90 ±19 μmol/L, p = 0.002) were substantially different at the initiation of therapy. Major adverse cardiac events (MACEs) or death occurred in 38 out of 107 patients: 51.1% in cluster 1 compared to 24.2% in cluster 2 (p = 0.0074). A significant improvement in RV-functional parameters was observed under treatment. The TAPSE improved and correlated with the change in left ventricular (LV) function. Yet, it did not correlate with systolic pulmonary artery pressure (sPAP) and LV end-diastolic diameter. The HFrEF phenotype characterized by more severe RV dysfunction has a worse prognosis during sacubitril/valsartan therapy. Both RVand LV functions significantly improve when the patient is treated with sacubitril/valsartan.

Abstract 11864: Ironing Out the Details: Increasing the Screening of Iron Deficiency in Heart Failure Patients and the Promotion of Intravenous Iron Replacement

Background: The American College of Cardiology (ACC) recommends intravenous iron replacement (IVIR) in patients with iron deficiency (ID) and heart failure with reduced ejection fraction (HFrEF). IVIR, in patients with HFrEF and ID, is associated with improvement in patient symptoms, functional capacity, 6-minute walk distance, and quality of life. Emerging data demonstrates IVIR can reduce hospital admissions for HFrEF. The purpose of this study is to enhance screening of ID in the HFrEF population and IVIR in the inpatient setting. Methods: This is a single-center, retrospective chart review using ICD 10 codes I50.2 and I50.42 to query the diagnosis of HFrEF in admissions from January 2018 to June 2020. Patients with recent major surgery within the last three months, use of erythropoietin stimulating agents, blood transfusions within a six-week time period, a history of cirrhosis, and/or a diagnosis of end stage renal disease receiving IVIR were excluded. ID in HFrEF is defined as ferritin &lt;100 micrograms/L or a ferritin of 100-299 micrograms/L with transferrin saturation of &lt;20%, per ACC guidelines. Further analysis was performed on 150 of 600 admissions pulled. Results: Of the 150 admissions analyzed, 108 of 150 were due to decompensated HFrEF and only 22 of the 150 had iron studies performed during admission. Approximately 15 of 22 patients with iron studies had a diagnosis of ID and only 1 of the 15 patients was initiated on IVIR. Additionally, 22 of the 150 total patients were on oral iron replacement and were not placed on IVIR. Discussion: Work-up of ID in patients with HFrEF is frequently omitted in the inpatient setting. In patients that have been diagnosed with ID, few receive appropriate treatment. There should be increased efforts to identify and administer IVIR to hospitalized patients with HFrEF and ID once their acute decompensation has been stabilized. This study aims to increase usage of HFrEF order sets on admissions by including iron studies within the workflow. The initiative includes administering first doses of IVIR in the hospital with subsequent transition to the outpatient setting, providing patient/provider education, and offering clinical decision support at time of ordering.

Sodium-glucose co-transporter-2 inhibitors improve cardiovascular outcomes in heart failure with reduced ejection fraction regardless of ischemic etiology

Abstract Background Coronary artery disease remains the main underlying cause of heart failure (HF), despite the progress in prevention, diagnosis and treatment. Sodium-glucose co-transporter-2 inhibitors have been shown to improve surrogate cardiovascular outcomes in patients with HF with reduced ejection fraction (HFrEF), regardless of diabetes status. Purpose We sought to determine the effect of SGLT-2 inhibitors on the primary composite endpoint (cardiovascular death or hospitalization for HF) across the two hallmark trials in the HFrEF population (EMPEROR Reduced and DAPA-HF), according to ischemic or non-ischemic etiology of HF. Methods We pooled data from EMPEROR reduced and DAPA-HF trials in a total of 8,474 patients with HFrEF, performing a sub-analysis according to the presence of ischemic cardiomyopathy as the underlying cause of HFrEF. Results Treatment with SGLT-2 inhibitors resulted in a significant decrease in the risk for the primary composite outcome in patients with HFrEF of ischemic etiology, equal to 18% (RR=0.82, 95% CI: 0.73–0.92, I2=0%). In patients with HFrEF of non-ischemic etiology, SGLT-2 inhibitors produced a significant decrease in the risk for the primary composite outcome equal to 18% (RR=0.72, 95% CI: 0.63–0.82, I2=0%). Despite the greater effect in patients with non-ischemic HFrEF, no subgroup difference was detected (p=0.16). Generated results are summarized in Figure 1. Conclusions SGLT-2 inhibitors improve surrogate cardiovascular outcomes both in patients with ischemic and non-ischemic HFrEF. Funding Acknowledgement Type of funding sources: None. Figure 1

Sodium-glucose co-transporter-2 inhibitors in the non-diabetic heart failure patient.

Heart failure (HF) with reduced ejection fraction (HFrEF) is a global cause of morbidity and mortality with over 60 million estimated cases worldwide. The burden of HF care is expected to increase with an ageing population as evidenced by the fact that 80% of HF-related hospitalizations occur in those aged above 65. Given the significant morbidity and mortality associated with HFrEF, there is a need for new prognostic therapies that have an impact on morbidity and mortality. In February of 2021, the National institute for Health and Care Excellence (NICE) released new guidance on the utility of Dapagliflozin for the management of heart failure with reduced ejection fraction (HFrEF). NICE advocated that dapagliflozin is a viable treatment option in symptomatic HFrEF patients on optimal medical management. The current list price of dapagliflozin is around £36.59 per 28-tablet pack with an estimated annual cost of £476.98 equating to £6939 per quality-adjusted life year. The guidance was mainly based on evidence produced from the 2019 DAPA-HF trial. This demonstrated that in HFrEF population, the use of dapagliflozin led to a significant reduction in worsening HF events, cardiovascular, and all-cause death. In this article, we summarize the evidence base for sodium-glucose co-transporter-2 inhibitors in the non-diabetic heart failure patient.