Treatment Of Heart Failure With Reduced Ejection Fraction Research Articles

Abstract 4118387: Artificial Intelligence-Enhanced Echocardiogram Assessment Helps Distinguish Cardiomyopathy from Beat-to-Beat Variation in Atrial Fibrillation

Background: Atrial fibrillation (AF) can be associated with reductions in left ventricular ejection fraction (LVEF) that improve upon conversion of AF to sinus rhythm. Such LVEF changes during AF may be due to LVEF measurement error from beat-to-beat variations related to AF itself. More precise artificial intelligence (AI)-enhanced LVEF assessment could help distinguish between such LVEF “pseudo-reduction” during AF and true cardiomyopathy, thus potentially preventing unnecessary downstream workup and treatment. Methods: Using a transthoracic echocardiogram database at a large academic medical center, we identified all patients whose LVEF fell below 50% while in AF who had subsequent LVEF recovery to over 50% within 90 days after converting from AF to sinus rhythm. For echocardiograms in AF, we compared the clinically assessed LVEF with AI-enhanced LVEF assessment by EchoNet-Dynamic, a validated deep learning algorithm. Results: In our cohort of 84 patients, the mean age was 74 years old, 36.9% were female, and 26.2% non-White. The mean LVEF recovery was 19.3% (95% CI 17.1-21.5%) after converting from AF to sinus rhythm with a mean duration of 27.4 days between the AF and sinus rhythm echocardiograms (Figure 1). For AF echocardiograms, the LVEF when reassessed by deep learning was 8.4% (6.3-10.5%) higher than the original clinical read, resulting in 30.3% of patients being reclassified as no longer having a reduced LVEF less than 50% while in AF. Among these patients with LVEF reductions during AF, 27.4% and 19.0% were given a new or worsened heart failure with reduced ejection fraction (HFrEF) diagnosis, 15.5% underwent ischemic testing, and 17.9% were started on new HFrEF medications. Discussion: LVEF reductions during AF can lead to new HFrEF diagnosis, workup, and treatment. However, such LVEF reductions may be temporary and partially explained by undermeasurement of LVEF during AF. AI-enhanced LVEF assessment may help reduce such measurement errors during AF and thereby prevent overdiagnosis of HFrEF. Further research is needed to understand the clinical significance of true but temporary LVEF reductions during AF.

Abstract 4129974: Increased Expression of Histone Deacetylases-2 and -6 in Left Ventricular Myocardium of Dogs with Chronic Heart Failure

Background: Histone deacetylases (HDACs) -2 and -6 are localized in the nucleus and cytoplasm of cells and have been implicated in the development of left ventricular (LV) hypertrophy, cardiac interstitial fibrosis, inflammation and worsening of LV systolic and diastolic function thus contributing to progressive worsening of heart failure (HF) with reduced ejection fraction (HFrEF) as well as HF with preserved ejection fraction (HFpEF). There is considerable interest in the application of small molecules that inhibit the activity of HDAC proteins in HF in the hope of fostering clinical benefit. Purpose: In the present study we examined the expression of HDAC-2 and -6 in LV tissue from normal (NL) dogs and dogs with chronic HF (LVEF <35%) produced by multiple sequential intracoronary microembolizations. Methods: Studies were performed in LV tissue from 7 NL dogs and 7 HF dogs. HDAC-2 and -6 protein levels were determined by Western blotting in the lysate of homogenate and 9000g supernatant (cytosolic) fractions prepared from powder of approximately 200 mg frozen LV tissue. After determining the protein by Lowry method, approximately 30 μg homogenate and 15 μg supernatant for HDAC-2 and 8 μg protein for both homogenate and supernatant for HDAC-6 were separated on 4%-20% SDS-PAGE and transferred on PVDF membrane. Band intensities were quantified in densitometric units (du). All data were normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Results: HDAC-2 proteins levels normalized to GAPDH were higher in the cytosol (0.59 ± 0.10 vs. 0.17 ± 0.04, p<0.05 vs. NL) and homogenate (0.75 ± 0.12 vs. 0.55 ± 0.10, not statistically significant) of LV tissue of dogs with HF compared to NL dogs. HDAC-6 protein levels were higher in the homogenate (2.54 ± 0.36 vs. 0.57 ± 0.19, p<0.05 vs. NL) and the cytosol (0.96 ± 0.15 vs. 0.78 ± 0.13, not statistically significant) of LV tissue of dogs with HF compared to NL dogs. Conclusions: These findings indicate upregulation of protein levels of HDAC-2 and -6 isoforms in LV myocardium of dogs with chronic HF. These abnormalities are likely to contribute to worsening HF. Selective inhibition of HDAC-2 and -6 represents a potential therapeutic approach for the treatment of both HFrEF and HFpEF.

Abstract 4139191: ETX-258 - A GalOmic™ siRNA for the Treatment of Heart Failure Following Myocardial Infarction

Introduction: Heart failure with reduced ejection fraction (HFrEF) remains a significant clinical challenge, evidenced by high hospitalization rates and five-year mortality. Current treatments are limited by side effects, poor patient compliance, and the necessity for gradual drug titration. These challenges highlight the need for new therapies that are both safe and effective in targeting the structural remodeling pivotal to disease progression post-myocardial infarction (MI). e-therapeutics (ETX) uniquely combines computation and RNAi to discover life-transforming medicines. ETX’s RNAi platform, GalOmic™, enables generation of specific, potent, and long-acting siRNA therapies that effectively silence novel gene targets in hepatocytes. This highly specific mechanism of action limits unwanted side effects, positioning it as a promising approach to HFrEF treatment. Methods: Potent siRNAs against a hepatic target with cardioprotective potential were designed in silico. Candidate siRNAs were screened in vitro in HEK293 cells and in vivo in C57BL/6J mice to select the lead GalOmic™ siRNA, ETX-258. MI was induced by ligation of the left anterior descending artery in C57BL/6J mice after which ETX-258 was injected subcutaneously weekly for 6 weeks. Eplerenone, a mineralocorticoid receptor antagonist which is part of the current treatment regimen for HFrEF, was used as a comparator. Cardiac function was assessed by echocardiography at 2-, 4- and 6-weeks post-MI. Cardiac damage and structural remodeling were evaluated using circulating biomarkers of cardiac function and histological assessment. Results: ETX-258 was selected as a highly active siRNA for the treatment of heart failure with a long duration of action. Post-MI treatment with ETX-258 significantly improved key echocardiographic parameters of cardiac function, including ejection fraction and total cardiac output, achieving results comparable to eplerenone. Additionally, both structural cardiac parameters and markers of damage and remodeling showed significant improvements, reaching similar levels in both ETX-258 and eplerenone-treated mice. Conclusions: High unmet need remains for HFrEF patients despite existing therapies. These results highlight the potential of ETX-258 to improve cardiac function and pathogenic structural remodeling post-MI. This, paired with the long duration of action and favorable safety profile of GalOmic™ siRNAs, makes ETX-258 a promising candidate for further clinical development.

Abstract 4126262: The impact of angiotensin receptor neprilysin inhibitors on the elderly population with heart failure and reduced ejection fraction: data from the real world

Heart failure (HF) remains a disease of increasing prevalence and morbidity. Validation of new lines of therapy in the elderly are required due to the progressive ageing of the world's population and scarce evidence in elderly patients with HF with reduced ejection fraction (HFrEF). The purpose of our study is to analyse the effect of Angiotensin Receptor–Neprilysin Inhibitors (ARNI) in this subgroup of patients. We conducted a single-centre, real-world observational study. We consecutively enrolled all patients aged ≥75 years diagnosed with HFrEF (defined as an ejection fraction <40%) and theorical indication for treatment with ARNI from November 2019 to January 2021. The main outcomes analysed were all cause mortality and admission due to HF. In order to avoid potential confounding factors, we performed a propensity-score (PS) matched analysis. Patients matching was performed in a 1:1 ratio with the nearest neighbour method. A total of 364 patients were recruited (total population). The mean age was 84.1 years of which 67% were male. 81% were hypertensive and 33.5% diabetic. The main cause of ventricular dysfunction was ischemic with 50.2%. At inclusion 55.8% were in NYHA functional class II and the mean LVEF was 29.8%. After PS matching, we selected 184 patients (study population), 92 with ARNI. As compared with non ARNI group, the ARNI patients showed higher use of mineralocorticoid receptor antagonists (MRA) (59.8% vs 43.5%, p< 0.05) and SGLT2 inhibitors (40.2% vs 6%, p<0.05). Other treatments were otherwise similar in both groups. There were not significant differences in relation with age, etiology or comorbidities between ARNI group and non-ARNI group. During a median follow-up of 39 months, total mortality was 31.5% (58 patients). After a Cox logistic regression analysis, ARNI therapy was shown to be an independent protective variable with respect to total mortality [HR 0.6 (0.4-1), p 0.05]. The figure shows the Kaplan-Meier survival curves for total mortality in patients with and without ARNI treatment. In summary, treatment of HFrEF remains a significant challenge in managing HF patients, especially in the elderly. According to our data, treatment with ARNI in elderly patients with HFrEF was associated with a lower rate of all-cause mortality. Our data show us that ARNI therapy could improve prognosis in the elderly with HFrEF in a real-world study.

Angiotensin-Converting Enzyme Inhibitor Washout Period Prior to Angiotensin Receptor/Neprilysin Inhibitor Initiation in the Inpatient Setting.

The 2022 AHA-ACC HFSA Guideline for Management of Heart Failure recommend initiating an angiotensin receptor/neprilysin inhibitor (ARNI) in patients with heart failure with reduced ejection fraction (HFrEF) who can tolerate an angiotensin-converting enzyme inhibitor (ACEi). The manufacturer recommends initiating a 36-hour washout period when switching from ACEi to ARNI due to an increased risk of adverse effects, including angioedema. This study investigated the adherence to the washout period when transitioning from ACEi to ARNI at a community hospital. The primary objective was to assess the rate of adherence to the 36-hour washout when transitioning patients from ACEi to ARNI. Secondary outcomes included heart failure exacerbation readmission rates within 90 days and the rate of adverse effects (angioedema, hypotension, acute kidney injury, and hyperkalemia). This was a retrospective cohort study including patients with HFrEF who were transitioned from ACEi to ARNI during their hospital stay between March 1, 2016 and December 31, 2022. Patients were excluded if they did not receive an ACEi or ARNI during their admission or if they had an ejection fraction >40%. Pearson chi-square was used to analyze categorical data. Of 33 patients included in this study, 67% received the full 36-hour washout period when transitioning from ACEi to ARNI. There were no significant differences between the rates of hospital readmissions or adverse effects between the groups. No patients experienced hyperkalemia or angioedema. This is the first study to our knowledge to describe real-world prescribing practices when transitioning patients from ACEi to ARNI for the treatment of HFrEF. Larger, multicenter studies are needed to provide more data on prescribing practices outside this single center. Future research should also include pharmacist's role in adhering to the recommended washout.

Guideline-directed medical therapy patterns in heart failure with reduced ejection fraction: the OPTIMA-HF registry

Abstract Background/Introduction European guidelines strongly recommend an optimized pharmacological treatment in patients with heart failure with reduced ejection fraction (HFrEF) with a fast introduction of the four-pillars. Purpose Aim of the Optimization of Therapy in the Italian Management of Heart Failure [OpTIMa-HF] Registry was to collect data on HF patients to describe the current Italian population of HF patients with a specific focus on HFrEF treatment adherence and prescription rates, according to the most recent European Guidelines. Methods OPTIMA-HF is an observational, cross-sectional, multicenter, real-life study conducted in two different clinical settings: HF outpatients’ clinics of Italian University Hospitals and territorial Italian Cardiology outpatients’ services, that enrolled patients with chronic HFrEF receiving at least 1 oral medication for management of HF. Patients were characterized by baseline use and dose of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB)/angiotensin receptor neprilysin inhibitor (ARNI), beta-blocker, mineralocorticoid receptor antagonist (MRA) and sodium glucose co-transporter II inhibitor (SGLT2i). Patient-level factors associated with medication use were examined. Results Overall, 1390 patients from 29 ambulatory cardiology practices and university hospitals were included. Mean age was 69.5 ± 11.9 years, 24% were female, and median EF was 33 (28-37). Among enrolled patients, 72.2% were prescribed ARNI, 17.1% ACEI/ARB, 95% beta-blocker, 75.5% MRA and 63% SGLT2i therapy (Figure 1). Despite high prescription rates for each single class, a still not sufficient number of patients was on treatment with all four pillars, in particular 40.4% considering the presence ARNI and 6.2%. When medications were prescribed, few patients were receiving target doses of ACEI/ARB (31.7%), ARNI (16%), and beta-blocker (33.3%), whereas a higher proportion were receiving target doses of MRA therapy (38%), and all were receiving target dose for SGLT2i. Among patients eligible for all classes of medication, only 1.1% were simultaneously receiving target doses of ACE/ARB/ARNI, beta-blocker, MRA and SGLT2i. Prescription rates did not significantly differ between the type of center (University Hospital vs. territorial Cardiology outpatients’ services). As regards patients not on treatment with any of the four pillars, a small but still present amount of patients had no contraindications to these drugs (Figure 1). Conclusions In this contemporary outpatient HFrEF Italian registry, significant high prescription rates of the four-pillars were observed, however therapy combination rate is still not sufficient and drugs' titration need to be implemented to receive the greatest benefits from an optimized treatment. Strategies to improve guideline-directed use of HFrEF medications remain urgently needed, and these findings may inform targeted approaches to optimize outpatient medical therapy.

Angiotensin receptor-neprilysin inhibitor adherence and outcomes in heart failure with reduced ejection fraction.

Whether medication adherence to angiotensin receptor-neprilysin inhibitor (ARNI) in real-world practice is associated with the reduced risk of all-cause mortality or hospitalization relative to that with traditional renin-angiotensin system (RAS) blockade remains unclear. This study investigated the influence of medication adherence of ARNI and traditional RAS blockade in heart failure with reduced ejection fraction (HFrEF). We conducted a nationwide longitudinal cohort study with patients with HFrEF using data from the Korean National Health Insurance Service data (2017-2021) covering the entire population. A total of 13483 patients with HFrEF who received ARNI were matched 1:1 with 13483 patients who received traditional RAS blockade using propensity score matching. The primary outcome was a composite of all-cause mortality or any hospitalization within one year. Medication adherence was assessed by calculating the proportion of days covered (PDC) relative to total medication prescribed. ARNI and traditional RAS blockade adherence rates were directly compared to analyse their respective associations with the primary outcome. Patients in the ARNI group had a lower rate of the primary outcome than those in the traditional RAS blockade group [hazard ratio (HR) 0.78; 95% confidence interval (CI) 0.75-0.81; P<0.001]. Mean PDC values spanning 1year were 92.6±14.5% and 90.9±17.7% in the ARNI and RAS blockade groups, respectively (P<0.001). Among patients with PDC≥80%, the risk of primary outcome was significantly lower in the ARNI group than in the RAS blockade group (HR 0.75; 95% CI 0.72-0.78; P<0.001) while a risk reduction with ARNI was not observed among patients with PDC<80% (HR 0.95; 95% CI 0.85-1.05; P=0.313). The beneficial effect was more pronounced among patients with PDC≥80% than that among patients with PDC<80% (P for interaction <0.001). In a real-world cohort with HFrEF, ARNI was superior to traditional RAS blockade in reducing the risk of all-cause mortality and hospitalization. The benefit of ARNI was pronounced among patients with high medication adherence but not among those with low medication adherence, highlighting the importance of adherence to ARNI treatment for HFrEF. PARADE-HF ClinicalTrials.gov number, NCT05329727.

Budget Impact Analysis of Dapagliflozin in Treating Patients With Heart Failure With Reduced Ejection Fraction From the Perspective of Malaysian Public Healthcare System

PurposeThis is a budget impact analysis that compared the scenario of treating heart failure with reduced ejection fraction (HFrEF) using dapagliflozin plus standard of care (SoC) versus a scenario without dapagliflozin, from the perspective of Ministry of Health (MOH) Malaysia over a 5-year time horizon. MethodsA Microsoft Excel-based cost calculator was developed for such comparison. The estimated size of eligible population, uptake rates for dapagliflozin, as well as costs related to drugs, clinical events, and adverse events were based on published data, official tariffs, and databases, and expert opinion. Clinical data from the DAPA-HF trial were used to inform efficacy and safety inputs (i.e., hospitalization for heart failure (hHF), cardiovascular death, and adverse events). Results were reported as total annual and cumulative costs (in 2023 Malaysian Ringgits [RM], United States Dollars [USD], and European Union Euros, [EUR]; with exchange rates of 1 USD = RM 4.40 and 1 EUR = RM 4.90]), as well as the number of clinical events. Sensitivity and scenario analyses were also conducted. FindingsThe base-case analysis estimated that over a five-year period, the adoption of dapagliflozin for HFrEF treatment would result in a cumulative cost-saving of RM 2.6 million (USD 0.6 million/EUR 0.5 million), representing a 0.3% reduction in costs, driven primarily by reduced expenditure on hHF. Moreover, dapagliflozin treatment would lead to 731 fewer hHF and 366 fewer cardiovascular deaths. Sensitivity and scenario analyses revealed that the results were most sensitive to assumptions regarding loop diuretic requirements and the cost of dapagliflozin. Although cost savings or a net-zero balance were projected for the first four years, an anticipated 2.5% annual increase in dapagliflozin uptake in the longer term would lead to additional costs for the MOH, starting from the fifth year. ImplicationsIncorporating dapagliflozin into the SoC can improve health outcomes for HFrEF patients and may generate cost savings, potentially easing the economic strain of HFrEF management on Malaysia's public healthcare system in the short term. Nonetheless, a modest increase in budget should be anticipated as more patients gain access to the treatment over time.

Looking for the ideal medication for heart failure with reduced ejection fraction: a narrative review.

The main goals of the pharmacological treatment of Heart failure with reduced ejection fraction (HFrEF) are the reduction of mortality and the prevention of hospitalizations. However, other outcomes such as improvements in cardiac remodeling and clinical status, functional capacity and quality of life, should be taken into account. Also, given the significant inter-individual and intra-individual variability of HF, and the fact that patients usually present with comorbidities, an appropriate treatment for HFrEF should exert a clinical benefit in most patient profiles irrespective of their characteristics or the presence of comorbidities, while providing organ protection beyond the cardiovascular system. The aim of this narrative review is to determine which are the proven effects of the guideline-directed treatments for HFrEF on five key clinical outcomes: cardiovascular mortality and hospitalization due to HF, sudden death, reverse cardiac remodeling, renal protection and evidence in hospitalized patients. Publications that fulfilled the pre-established selection criteria were selected and reviewed. Renin-angiotensin system (RAS) inhibitors, namely angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) or angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers (BB), mineralocorticoid receptor antagonists (MRA), sodium-glucose co-transporter 2 inhibitors (SGLT2i) show a benefit in terms of mortality and hospitalization rates. ARNI, BB, and MRA have demonstrated a significant positive effect on the incidence of sudden death. ARB, ARNI, BB and SGLT2i have been associated with clear benefits in reverse cardiac remodeling. Additionally, there is consistent evidence of renal protection from ARB, ARNI, and SGLT2i in renal protection and of benefits for hospitalized patients from ARNI and SGLT2i. In conclusion, the combination of drugs that gather most beneficial effects in HFrEF, beyond cardiovascular mortality and hospitalization, would be ideally pursued.

Effect of sacubitril/valsartan on hospital readmissions in heart failure with reduced ejection fraction in Saudi Arabia: A multicenter retrospective cohort study.

Sacubitril/valsartan is an angiotensin receptor neprilysin inhibitor (ARNI) that has been shown in multiple clinical trials to have clinical benefits and is recommended by major clinical management guidelines as a first-line treatment for heart failure with reduced ejection fraction (HFrEF). The most significant benefit that was observed in clinical trials is its effect in reducing hospital readmissions. However, little evidence supports its effectiveness in practice, especially in Saudi Arabia. A multicenter retrospective cohort study was conducted using the patient medical records at 2 tertiary hospitals in Saudi Arabia. Eligible patients were adults (≥18 years old) with a confirmed diagnosis of HFrEF who were discharged on either sacubitril/valsartan or angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) in addition to the other recommended therapy for HFrEF. The primary endpoint was the all-cause 30-day readmission rate. The secondary endpoints included all-cause readmissions at 60-day, 90-day, and 12 months. Additionally, 30-day, 60-day, and 90-day readmissions due to HF were evaluated. A total of 398 patients were included in our analysis; 199 (50.0%) received sacubitril/valsartan (group 1), and 199 (50.0%) received ACEI/ARB (group 2). Our results showed that all-cause 30-day readmissions in group 1 were significantly lower than in group 2 (7% vs 25.0%, RR 0.28, 95% Cl 0.16-0.49; P < .001). Additionally, the secondary outcomes showed significantly fewer 60-day, 90-day, and 12-month all-cause readmissions were identified in group 1 compared to group 2 (11% vs 30.7%, RR 0.36, 95% CI 0.23-0.56; P < .001), (11.6%. vs 32.6%, RR 0.35, 95% CI 0.23-0.55; P < .001) and (23.6% vs 51.2%, RR 0.46, 95% CI 0.35-0.62; P < .001), respectively. Furthermore, HF readmissions at 30-day, 60-day, and 90-day in group 1 were significantly lower than in group 2 (P < .05). Sacubitril/valsartan for the treatment of HFrEF is associated with a significantly lower rate of all-cause readmission as well as HF readmissions compared to ACEI/ARB. These benefits extend up to 12 months post-discharge.

Vericiguat in heart failure with reduced ejection fraction: hope or solid reality?

In recent years, thanks to the advent of new classes of drugs (ARNI and SGLT2-i), the prognosis of patients suffering from heart failure with reduced ejection fraction (HFrEF) has gradually improved. Nonetheless, there is a residual risk that is not targeted by these therapies. Currently, it is recognized that vericiguat, an oral stimulator of soluble guanylate cyclase (sGC), can restore the NO-sGC-cGMP pathway, through stimulation and activation of sGC, aiming to increase cGMP levels with a reduction in heart failure-related oxidative stress and endothelial dysfunction. Even though the Victoria trial demonstrated that HFrEF patients in treatment with vericiguat showed a 10% reduction in the composite of cardiovascular mortality and rehospitalization for heart failure, statistically significantly reducing heart failure hospitalization, the international guidelines limit its use as a second-line drug for patients with worsening symptomatology despite optimized medical therapy. Furthermore, vericiguat has proved to be a valid therapeutic ally especially in those patients with comorbidities such that they cannot receive the classic four-pillar therapy of HF (in particular renal failure). In this review, the authors report on randomized clinical trials, substudies, and meta-analysis about vericiguat in HFrEF, emphasizing the strengths that would suggest the possible role of vericiguat as the fifth pillar of the HFrEF treatment, acknowledging that there are still gaps in the evidence that need to be clarified.

Effects of different surgical strategies and left ventricular remodelling on the outcomes of coronary artery bypass grafting in heart failure patients with reduced ejection fraction.

Ischaemic heart failure with reduced ejection fraction (HFrEF) caused by coronary artery disease accounts for the largest proportion of heart failure cases with the worst prognosis. Coronary artery bypass grafting (CABG) is the most effective treatment for ischaemic HFrEF. On-pump and off-pump are the two surgical methods used for CABG. Whether patients with HFrEF should undergo on- or off-pump CABG is controversial in coronary heart disease surgery. The left ventricular end-systolic volume index (LVSEVI) is the gold standard for evaluating the severity of left ventricular remodelling; however, its effect on the perioperative risk and long-term survival rate of patients with HFrEF undergoing CABG remains unclear. This single centre prospective cohort analysis included 118 coronary heart disease patients with symptoms and signs of heart failure and a left ventricular ejection fraction (LVEF) of <40% who were enrolled consecutively from January 2019 to December 2023. Operative mortality, perioperative complications, and long-term survival were compared among patients treated with various LVESVIs and surgical methods. The primary outcomes were cardiac death, myocardial infarction, heart failure, stroke, and revascularization, (percutaneous coronary intervention or redo CABG) with a median follow-up of 38 ± 10 months. The 30-day postoperative mortality of 118 patients was 6.8%. Patients in the off-pump group had significantly higher perioperative mortality than those in the on-pump group (12.5% vs. 3.8%, p = 0.03). In the off-pump group, a higher proportion of patients required perioperative mechanical assistance, such as intra-aortic artery balloon pump (IABP) or extracorporeal membrane oxygenation (ECMO), compared to those in the on-pump group (IABP: 75% vs. 47.4%, p = 0.004; ECMO: 22.5% vs. 1.3%, p = 0.000). Patients in the off-pump group were more likely to have postoperative atrial fibrillation (AF) (35% vs. 14.1%, p = 0.01). In the on-pump group, the incidence of postoperative AF (25% vs. 6.5%, p = 0.02) and IABP use (62.5% vs. 36.9%, p = 0.03) were significantly higher in patients with more severe left ventricular remodelling than in those with less severe left ventricular remodelling. In the off-pump group, patients with more severe left ventricular remodelling had higher ECMO usage (38.9% vs. 9.1%, p = 0.04), incidence of postoperative AF (61.1% vs. 13.6%, p = 0.02), and perioperative mortality (22.2%). Major adverse cardiac event (MACE)-free survival rate was significantly higher in the on-pump group than in the off-pump group, and there was no significant difference in MACE free survival rates between the two groups of patients with different degrees of left ventricular remodelling. On-pump bypass is a better surgical procedure for patients with ischaemic HFrEF, especially those with severe left ventricular remodelling. Left ventricular remodelling increases perioperative mortality but has no effect on long-term survival.

Pharmacotherapy in patients with heart failure with reduced ejection fraction: A systematic review and meta-analysis.

Angiotensin receptor neprilysin inhibitors (ARNIs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-blockers (BBs), and mineralocorticoid receptor antagonists (MRAs) are the cornerstones in treating heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 inhibitors (SGLT-2is) are included in HFrEF treatment guidelines. However, the effect of SGLT-2i and the five drugs on HFrEF have not yet been systematically evaluated. PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) from inception dates to September 23, 2022. Additional trials from previous relevant reviews and references were also included. The primary outcomes were changes in left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter/dimension (LVEDD), left ventricular end-systolic diameter/dimension (LVESD), left ventricular end-diastolic volume (LVEDV), and left ventricular end-systolic volume (LVESV), left ventricular end-systolic volume index (LVESVI), and left ventricular end-diastolic volume index (LVEDVI). Secondary outcomes were New York Heart Association (NYHA) class, 6-min walking distance (6MWD), B-type natriuretic peptide (BNP) level, and N-terminal pro-BNP (NT-proBNP) level. The effect sizes were presented as the mean difference (MD) with 95% confidence interval (CI). We included 68 RCTs involving 16,425 patients. Compared with placebo, ARNI+BB+MRA+SGLT-2i was the most effective combination to improve LVEF (15.63%, 95% CI: 9.91% to 21.68%). ARNI+BB+MRA+SGLT-2i (5.83%, 95% CI: 0.53% to 11.14%) and ARNI+BB+MRA (3.83%, 95% CI: 0.72% to 6.90%) were superior to the traditional golden triangle "ACEI+BB+MRA" in improving LVEF. ACEI+BB+MRA+SGLT-2i was better than ACEI+BB+MRA (-8.05mL/m2, 95% CI: -14.88 to -1.23mL/m2) and ACEI+BB+SGLT-2i (-18.94mL/m2, 95% CI: -36.97 to -0.61mL/m2) in improving LVEDVI. ACEI+BB+MRA+SGLT-2i (-3254.21 pg/mL, 95% CI: -6242.19 to -560.47 pg/mL) was superior to ARB+BB+MRA in reducing NT-proBNP. Adding SGLT-2i to ARNI/ACEI+BB+MRA is beneficial for reversing cardiac remodeling. The new quadruple drug "ARNI+BB+MRA+SGLT-2i" is superior to the golden triangle "ACEI+BB+MRA" in improving LVEF. PROSPERO; No. CRD42022354792.

Risk Factors and Outcomes Associated With Heart Failure With Preserved and Reduced Ejection Fraction in People With Chronic Kidney Disease.

Heart failure (HF) is associated with poor outcomes in people with chronic kidney disease, yet it is unknown whether outcomes differ by HF subtype. This study aimed to examine associations of incident HF with preserved ejection fraction (HFpEF) versus HF with reduced ejection fraction (HFrEF) with progression to end-stage kidney disease (ESKD) and mortality. We studied individuals with chronic kidney disease in the CRIC study (Chronic Renal Insufficiency Cohort) who were free of HF at cohort entry. Incident HF hospitalizations were adjudicated and classified into HFpEF (ejection fraction, ≥50%) or HFrEF (ejection fraction, <50%) based on echocardiograms performed during the hospitalization or at a research study visit. ESKD was defined as need for chronic dialysis or kidney transplant. Cox proportional hazards were used to evaluate the association of time-updated HF subtype with risk of ESKD and mortality, adjusting for demographics, comorbidities, and medication use. Among the 3557 study participants without HF at cohort entry, mean age was 57 years and mean estimated glomerular filtration rate was 45 mL/min per 1.73 m2. A total of 682 participants had incident HF. Incidence rates for HFpEF and HFrEF were 0.9 (95% CI, 0.8-1.0) and 0.7 (95% CI, 0.6-0.8) per 100 person-years, respectively (Pdifference=0.005). Associations of incident HF with progression to ESKD were not statistically different for HFpEF (hazard ratio, 2.06 [95% CI, 1.66-2.56]) and HFrEF (hazard ratio, 1.80 [95% CI, 1.36-2.38]; P=0.42). The associations with mortality were stronger for HFrEF (hazard ratio, 2.73 [95% CI, 2.24-3.33]) compared with HFpEF (hazard ratio, 1.99 [95% CI, 1.65-2.40]; P=0.0002). In a chronic kidney disease population, the rates of HFpEF hospitalizations were greater than that of HFrEF. Risk of ESKD was high but not statically different across HF subtypes. There was a stronger association of HFrEF with mortality. Prevention and treatment of both HFpEF and HFrEF should be central priorities to improve outcomes in chronic kidney disease.

Effects of levothyroxine in subclinical hypothyroidism and heart failure with reduced ejection fraction: An open-label randomized trial

We report a randomized, multicenter, open-label trial (ClinicalTrials.gov: NCT03096613) to investigate the clinical benefits of levothyroxine (L-T4) administration in subclinical hypothyroidism (SCH) patients with heart failure with reduced ejection fraction (HFrEF). Overall, 117 patients were enrolled and received L-T4 plus standard HFrEF treatment (experimental group, N= 57) or standard HFrEF therapy alone (control group, N= 60). The change of 6-min walk test distance in the experimental group was significantly higher than that in the control group at 24weeks (70.08± 85.76m vs. 27.73± 82.00 m, mean difference [95% confidence interval (CI)] 46.90 [12.90, 80.90], p<0.001). Improvements in New York Heart Association (NYHA) classification (p= 0.033) and thyroid function were significant. Adverse event incidence was similar between groups (risk ratio [95% CI]: 0.942 1.053 (0.424, 2.616); p= 0.628). L-T4 addition to HFrEF treatment improved activity tolerance, NYHA class, and thyroid function within 6months, suggesting its potential for combined therapy in HFrEF patients with SCH. Future double-blind, placebo-controlled trials should be performed to confirm these results.

The Clinical Effects of Pharmacotherapy Combined with Blood Flow Restriction and Isometric Exercise Training in Rehabilitating Patients with Heart Failure with Reduced Ejection Fraction.

Heart failure with reduced ejection fraction (HFrEF) is associated with reduced cardiac function and impaired quality of life. Blood flow restriction (BFR) training is emerging as a potential adjunctive therapy. This study aimed at evaluating the efficacy of combination of BFR and isometric exercises on cardiac function, functional status, and quality of life in HFrEF patients. Totally 44 patients with HFrEF were equally divided into a control group and a combined treatment group. Both groups received standard pharmacotherapy and upper limb exercise, with the combined group also undergoing BFR and isometric exercise training. We assessed demographic and clinical characteristics, New York Heart Association (NYHA) functional classification, cardiac function parameters, serum Brain Natriuretic Peptide levels, physical capacity via the 6-minute walking test, and quality of life using the Heart Failure Questionnaire (Minnesota Living with Heart Failure Questionnaire). Post-treatment, the combined group significantly improved in NYHA classification (p = 0.012), with more patients shifting to a better class. Cardiac function improved in both groups, with the combined group showing a greater increase in mean left ventricular ejection fractions (p < 0.001), and reductions in left ventricular end-diastolic and end-systolic diameters (p < 0.05). The addition of BFR training to standard pharmacotherapy with upper limb exercise in HFrEF patients led to significant enhancements in cardiac function, functional status, and quality of life. These findings support the integration of BFR training into conventional HFrEF treatment regimens to maximize patient recovery outcomes.

Estimating the clinical and budgetary impact of using angiotensin receptor neprilysin inhibitor as first line therapy in patients with HFrEF.

Recent updates of international treatment guidelines for heart failure with reduced ejection fraction (HFrEF) differ regarding the use of angiotensin receptor neprilysin inhibitor (ARNI) as first-line treatment. The American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA) 2022 guidelines gives ARNI a Class IA recommendation for HFrEF patients while the European Society of Cardiology's guidelines are less clear when ARNI could be considered as first line treatment option in de novo patients. This study aimed to model the clinical and budgetary outcomes of implementing these guidelines, comparing conservative ARNI prescription patterns with less conservative in Sweden and in the United Kingdom. A health economic model was developed to compare different treatment patterns for HFrEF. Incident cohorts were included on an annual basis and followed over 10years. The model included treatment specific all-cause mortality and hospitalization rates, as well as drug acquisition, monitoring, and hospitalization costs. Increasing the use of ARNI could lead to about 7000-12300 life years gained and 2600-4600 hospitalizations prevented in Sweden. These health benefits come with an additional cost of 112-195 million euros. Similar results were estimated for the United Kingdom, albeit on a larger population. Increasing the proportion of patients receiving ARNI instead of angiotensin converting enzyme inhibitors as first-line treatment of HFrEF will lead to a considerable number of additional life years gained and prevented hospitalizations but with additional cost in terms of health care expenditure in Sweden and in the United Kingdom.

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.

Effect of pueraria on left ventricular remodelling in HFrEF: A systematic review and meta-analysis.

Heart failure with reduced ejection fraction (HFrEF) is a prevalent cardiovascular disease globally, posing a significant burden on healthcare and society. Left ventricular remodelling is the primary pathology responsible for HFrEF development and progression, leading to increased morbidity and mortality. Pueraria, a traditional Chinese herbal medicine and food, is commonly used in China to treat HFrEF. Accumulating evidence suggests that pueraria can effectively reverse left ventricular remodelling in HFrEF patients. This meta-analysis aims to assess the impact of pueraria on left ventricular remodelling in HFrEF patients. Eight electronic databases, including PubMed, EMBASE, Clinicaltrials.gov, Cochrane Library, Wanfang, CNKI, CQVIP, and CBM were searched for literature from inception to June 2023. All randomized controlled trials (RCTs) using pueraria in the treatment of HFrEF were included. The Cochrane Risk of Bias tool was utilized for RCTs' methodological evaluation, while Review Manager 5.4.1 was used to analyze the data. Nineteen RCTs with a total of 1,911 patients (1,077 males and 834 females) were identified. Meta-analysis indicated that combination medication of pueraria and conventional medicine (CM) was superior to the CM alone in raising left ventricular ejection fraction (LVEF; MD = 6.46, 95% CI, 4.88 to 8.04, P < 0.00001), and decreasing left ventricular end-diastolic diameter (LVEDD; MD = -4.78, 95% CI, -6.55 to -3.01, P < 0.00001), left ventricular end-Systolic diameter (LVESD; MD = -3.98, 95% CI, -5.98 to -1.99, P < 0.00001) and N-terminal pro-brain natriuretic peptide (NT-proBNP; MD = -126.16, 95% CI, -185.30 to -67.03, P < 0.0001). Besides, combination medication improved clinical efficacy rate (RR = 3.42, 95% CI, 2.54 to 4.59, P < 0.00001), 6-min walk test (6-MWT; MD = 65.54, 95% CI, 41.77 to 89.31, P < 0.00001), and TCM syndrome score efficacy (RR = 3.03, 95% CI, 1.57 to 5.83, P = 0.0009). Regarding safety, no difference was observed for adverse events (RR = 0.59, 95% CI, 0.22 to 1.54, P = 0.28). The use of pueraria combined with conventional medicine in HFrEF patients has superiority over conventional medicine alone in ameliorating cardiac function and reversing left ventricular remodeling. Moreover, combination medication has no increase in adverse drug events. Given some limitations, more prudence and high-quality clinical trials are needed in the future to verify the conclusions.

Abstract 15872: Development and External Validation of a De Novo Simulation Model to Inform Implementation Strategies for Guideline-Directed Medical Therapy of Heart Failure With Reduced Ejection Fraction

Introduction Guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) includes four medication classes and improves survival. However, uptake and adherence to GDMT remain low. Simulation models to project long-term benefits can inform ongoing trials of GDMT implementation strategies (such as a polypill). As such, we sought to develop and validate a mathematical model of HFrEF and GDMT treatment. Methods We developed a state-transition, Markov model to simulate hospitalizations, urgent care visits, and cardiovascular and non-cardiovascular death among patients with HFrEF on 0, 2, 3, and 4 GDMT drugs. Input parameters were derived from trials, epidemiologic cohorts, national surveys, and published literature. External validation compared model-projected all-cause mortality with data from the Seattle-HF model and three major HFrEF trials (eplerenone in EMPHASIS-HF, sacubitril/valsartan in PARADIGM-HF, and dapagliflozin in DAPA-HF). Goodness-of-fit was assessed by root-mean-square-error (RMSE), with RMSE ≤ 5.0 considered to be a good fit. Results In external validation, the model accurately replicated 5-year survival curves from the Seattle-HF model among treatment-naïve patients age 65 years (RMSE 1.9), 75 years (RMSE 1.2), and 85 years (RMSE 1.9). Model projections demonstrated good fit among individuals on various combinations of GDMT, with RMSE 0.6-2.8 across all combinations tested (Figure). For a 65-year-old with HFrEF, our model projected a mean survival of 6.3 years without GDMT, increased by 2.5 years on 2-drug, 3.4 years on 3-drug, and 4.7 years on 4-drug GDMT. Conclusion Our model replicated survival outcomes with GDMT in HFrEF and demonstrated improved survival associated with more classes of GDMT. Future work will project the long-term health and economic impacts of implementation strategies to improve GDMT uptake and adherence, incorporating healthcare costs and quality-of-life measures.