Treatment Of Heart Failure With Reduced Ejection Fraction Research Articles

Bone quality, mineral density, and fractures in heart failure.

The trabecular bone score (TBS) indirectly estimates bone quality and predicts low-impact fractures independently of bone mineral density (BMD). However, there is still a paucity of data linking bone and heart diseases, mainly with gaps in the TBS analysis. In this cross-sectional study, we evaluated TBS, BMD, and fractures in patients with heart failure with reduced ejection fraction (HFrEF) and in sex-, BMI- and age-matched controls, and we assessed the fracture probability using the FRAX tool, considering active search for fractures by vertebral fracture assessment (VFA) and the adjustment for the TBS. TBS values were 1.296 ± 0.14 in 85 patients (43.5% women; age 65 ± 13 years) and 1.320 ± 0.11 in 142 controls (P = 0.07), being reduced (< 1.31) in 51.8% and 46.1% of them, respectively (P = 0.12). TBS was lower in patients than in the controls when BMD was normal (P = 0.04) and when the BMI was 15-37 kg/m2 (P = 0.03). Age (odds ratio [OR] 1.05; P = 0.026), albumin (OR 0.12; P = 0.046), statin use (OR 0.27; P = 0.03), and energy intake (OR 1.03; P = 0.014) were associated with reduced TBS. Fractures on VFA occurred in 42.4% of the patients, and VFA and TBS adjustment increased the fracture risk by 16%-23%. Patients with HFrEF had poor bone quality, with a better discriminating impact of the TBS assessment when BMD was normal, and BMI was suitable for densitometric analysis. Variables related to the prognosis, severity, and treatment of HFrEF were associated with reduced TBS. VFA and TBS adjustment increased fracture risk.

The Pathophysiology and New Advancements in the Pharmacologic and Exercise-Based Management of Heart Failure With Reduced Ejection Fraction: A Narrative Review.

Heart failure with reduced ejection fraction (HFrEF) is a clinical syndrome whose management has significantly evolved based on the pathophysiology and disease process. It is widely prevalent, has a relatively high mortality rate, and is comparatively more common in men than women. In HFrEF, the series of maladaptive processes that occur lead to an inability of the muscle of the left ventricle to pump blood efficiently and effectively, causing cardiac dysfunction. The neurohormonal and hemodynamic adaptations play a significant role in the advancement of the disease and are critical to guiding the treatment and management of HFrEF. The first-line therapy, which includes loop diuretics, β-blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, hydralazine/isosorbide-dinitrate, and mineralocorticoid receptor antagonists (MRAs), has been proven to provide symptomatic relief and decrease mortality and complications. The newly recommended drugs for guideline-based therapy, angiotensin receptor/neprilysin inhibitor (ARNI), sodium-glucose cotransporter 2 inhibitors, soluble guanylate cyclase, and myosin activators and modulators have also been shown to improve cardiac function, reverse cardiac remodeling, and reduce mortality rates. Recent studies have demonstrated that exercise-based therapy has resulted in an improved quality of life, exercise capacity, cardiac function, and decreased hospital readmission rates, but it has not had a considerable reduction in mortality rates. Combining multiple therapies alongside holistic advances such as exercise therapy may provide synergistic benefits, ultimately leading to improved outcomes for patients with HFrEF. Although first-line treatment, novel pharmacologic management, and exercise-based therapy have been shown to improve prognosis, the existing literature suggests a need for further studies evaluating the long-term effects of MRA and ARNI.

Looking into the Kinetics of NT-proBNP and sST2 Changes in Patients with Heart Failure Treated with Sacubitril/Valsartan: A Hint to Different Therapeutic Pathways.

N-terminal pro-B-type natriuretic peptide (NT-proBNP) and soluble interleukin 1 receptor-like 1 ST2 (sST2) are biomarkers used to grade heart failure with reduced ejection fraction (HFrEF) severity. Both are potential targets of HFrEF treatment, but the first is associated with the patient's hemodynamic status, while the second is more indicative of the inflammatory status and of myocardial fibrosis. The aim of this study was to assess the kinetics of these biomarkers after treatment with sacubitril/valsartan in HFrEF. We analyzed blood samples of patients with HFrEF at baseline (before sacubitril/valsartan treatment), after 1, 2, and 3 months (respectively, after a month taking the 24/26 - 49/51 - 97/103 mg twice daily, or b.i.d., doses), and 6 months after the maximum-tolerated dose was reached (end study). We obtained samples from 72 patients with HFrEF (age 64.0 ± 10.5 years, 83% males). NT-proBNP and sST2 values progressively and significantly reduced to 37% and 16%, respectively, with a greater reduction for NT-proBNP (p < 0.001). Specifically, NT-proBNP reduced from 1144 [593-2586] pg/mL to 743 [358-1524] pg/mL and sST2 from 27.3 [20.5-35.0] ng/mL to 23.1 [15.9-30.7] ng/mL, p for trend < 0.001 in both cases. The reduction of the two biomarkers over time occurred with statistically significant different kinetics: deferred for sST2 and faster for NT-proBNP. No significant changes in renal function and potassium levels were recorded. These findings suggest that, in patients with HF, sacubitril/valsartan effects on the cardiovascular system share a double pathway: a first, hemodynamic, faster pathway and a second, non-hemodynamic anti-fibrotic, delayed one. Both likely contribute to the sacubitril/valsartan benefits in HFrEF.

Optimization of guideline-directed medical treatment for heart failure patients with reduced ejection fraction.

With the increasing number of medications demonstrating mortality benefits in heart failure with reduced ejection fraction (HFrEF), the pharmacological treatment of HFrEF is entering a new phase. To enhance outcomes in heart failure patients through medical treatment, the choice of appropriate medications and simultaneous and rapid uptitration are critical. However, there are several challenges encountered during this medication uptitration, including issues like hypotension, fatigue, worsening renal function, and hyperkalemia. This paper addresses strategies for effectively managing these challenges to successfully reach the maximum tolerated dose in patients. Additionally, it will discuss the management of comorbidities often associated with heart failure, the importance of exercise and rehabilitation, and the significance of proper nutrition intake, in addition to guideline-directed medical therapy.

Abstract P3137: The C-terminus Of Rad Is Required For Regulation Of The Cardiac Ca V 1.2 Channel

Background: Heart failure with reduced ejection fraction (HFrEF) is a leading cause of hospitalization and death. Current therapies fail to address loss of contractile force. Targeting dysfunctional Ca 2+ handling proteins involved in excitation-contraction, such as Ca v 1.2 may offer a means to improve quality of life and attenuate adverse cardiac remodeling. RAD is a key target bridging sympathetic modulation of Ca v 1.2 function. During stress, the beta-adrenergic (β-AR) effector, protein kinase A (PKA), phosphorylates RAD, modulating Ca v 1.2 current (I Ca,L ) and increasing cardiac contraction. RAD inhibits current, whereas Rad-knockout phenocopies a β-AR/PKA phosphorylated modulated current. Across RGK family members the highly conserved C-terminus is necessary for membrane association and block of I Ca,L in immortalized cell lines. The RAD C-terminus significance is unknown in adult mammalian cardiomyocytes. Hypothesis: RAD lacking a C-terminus will be unable to localize to surface membrane Ca v 1.2 channels; thus Ca v 1.2 activity will be modulated. Methods and Results: A 3xFLAG epitope was added to the N-terminus of the endogenous mouse Rrad gene. Full-length FLAG-RAD mice were compared to mice with truncated RAD (A277X). Ventricular cardiomyocytes were isolated for immunocytochemistry and ex vivo electrophysiology. Confocal microscopy was used to visualize localization of FLAG-tagged RAD. Full-length FLAG-RAD showed a repeating t-tubular pattern that co-localizes with Ca v 1.2 staining whereas FLAG-RAD A277X failed to show this pattern. A277X I Ca,L showed significantly hyperpolarized activation midpoint (-17 mV) and 2-fold increase in maximal conductance. Additionally, current decay was faster in A277X showing a significant 2-fold decrease in the current 30 ms after peak current. Conclusions: Myocardial Ca v 1.2 channels in a RAD C-terminal deletion model phenocopy Ca v 1.2 function modulated in response to β-AR stimulation. Mechanistically, the polybasic RAD C-terminus confers Ca v 1.2 regulation via membrane association of RAD. Interfering with RAD at the C-terminus residues constitute a specific target for boosting heart function as a treatment for HFrEF.

Different kinetics of NT-proBNP and sST2 highlight different therapeutic pathways of sacubitril/valsartan

Abstract Funding Acknowledgements Type of funding sources: None. Background N-terminal pro-B-type natriuretic peptide (NT-proBNP) and soluble interleukin 1 receptor-like 1 ST2 (sST2) are biomarkers used to grade heart failure with reduced ejection fraction (HFrEF) severity. Both are potential targets of HFrEF treatment, but the first is associated with the patient’s hemodynamic status, while the second is more indicative of the inflammatory status and of myocardial fibrosis. Purpose The aim of this study was to assess the kinetics of these biomarkers after treatment with sacubitril/valsartan in HFrEF. Methods We analyzed blood samples of HFrEF patients at baseline (before sacubitril/valsartan treatment), after 1, 2, 3 months (respectively after a month taking the 24/26 – 49/51 – 97/103mg b.i.d. doses), and 6 months after the maximum tolerated dose was reached (end-study). Results We obtained samples from 72 HFrEF patients (age 64.0±10.5, 83% males) (Table 1). NT-proBNP and sST2 values progressively and significantly reduced up to 37% and 16%, respectively, with a greater reduction for NT-proBNP (p&amp;lt;0.001). Specifically, NT-proBNP reduced from 1144 [593-2586] to 743 [358-1524] pg/mL and sST2 from 27.3 [20.5-35.0] to 23.1 [15.9-30.7] ng/mL, p for trend &amp;lt;0.001 in both cases). The reduction of the two biomarkers over time occurred with statistically significant different kinetics: deferred for sST2 and faster for NT-proBNP (Figure 1). No significant changes in renal function and potassium levels were recorded. Conclusions These findings suggest that, in HF patients, sacubitril/valsartan effects on the cardiovascular system share a double pathway: a first, hemodynamic, faster pathway and a second, non-hemodynamic anti-inflammatory, delayed one. Both likely contribute to the sacubitril/valsartan benefits in HFrEF.Table 1Figure 1

Predicted impact of atrial flow regulator on survival in heart failure with reduced and preserved ejection fraction.

We aim to assess the theoretical impact of the atrial flow regulator (AFR) on survival in heart failure. The prospective, multicentre, open-label, non-randomised PRELIEVE study (NCT03030274) assessed the safety and efficacy of the Occlutech AFR device in patients with symptomatic heart failure with reduced ejection fraction (HFrEF) (left ventricular ejection fraction (LVEF)≥15% and <40%) or heart failure with preserved ejection fraction (HFpEF) (LVEF ≥40% and <70%) and elevated PCWP (≥15mmHg at rest or ≥25mmHg during exercise). In this analysis, after the first 60 patients completed 12months of follow-up, the theoretical impact of AFR implantation on survival was assessed by comparing the observed mortality rate with the median predicted probability for one-year mortality. Each subject's risk of mortality was predicted from individual baseline data using the Meta-Analysis Global Group in Chronic HF (MAGGIC) prognostic model. A total of 87 patients (46% female, median age 69years [IQR 62-74]) had undergone successful device implantation for the treatment of HFrEF (53%) and HFpEF (47%). Sixty patients had a complete 12month follow-up. The median follow-up was 351days (interquartile range [IQR] 202-370). Six (7%) patients died during follow-up (8.6 deaths per 100 patient-years; 95% confidence interval [CI] 2.7 to 15.5), all of which had HFrEF. The median predicted mortality rate for the overall study population was 12.2 deaths per 100 patient-years (95% CI 10.2 to 14.7). While the observed mortality rate (0 deaths per 100 patient-years) was significantly lower than the median predicted mortality rate (9.3 deaths per 100 patient-years; 95% CI 8.4 to 11.1) in patients with HFpEF (-9.3 deaths per 100 patient-years; 95% CI -11.1 to -8.4), there was no difference in patients with HFrEF (-3.6 deaths per 100 patient-years; 95% CI -9.5 to 3.0). Four deaths were HF-related deaths (5.7 HF-related deaths per 100 patient-years; 95% CI 1.4 to 11.9; 10.8 HF-related deaths per 100 patient-years; 95% CI 2.5 to 23.1 in the HFrEF subgroup). In patients with HFpEF, the mortality rate following AFR implantation was lower than the predicted mortality rate. Dedicated randomised, controlled trials are needed - and currently ongoing - to investigate whether the AFR improves mortality.

Cost-effectiveness of adding empagliflozin to the standard of care for patients with heart failure with reduced ejection fraction from the perspective of healthcare system in Malaysia.

Objective: The aim of this study was to determine the cost-effectiveness of adding empagliflozin to the standard of care versus SoC alone for the treatment of patients with heart failure (HF) with reduced ejection fraction (HFrEF) from the perspective of the Ministry of Health of Malaysia. Methods: A cohort-based transition-state model, with health states defined as Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) quartiles and death, was used to determine the lifetime direct medical costs and quality-adjusted life years (QALYs) for both treatment groups. The risks of all-cause death, cardiovascular death, and health state utilities were estimated from the EMPEROR-Reduced trial. The incremental cost-effectiveness ratio (ICER) was assessed against the cost-effectiveness threshold (CET) as defined by the country's gross domestic product per capita (RM 47,439 per QALY) to determine cost-effectiveness. Sensitivity analyses were conducted to assess the key model parameters' uncertainty in respect to the incremental cost-effectiveness ratio. A scenario analysis was performed using health states as defined by the New York Heart Association classes. Results: Compared to SoC alone, empagliflozin + SoC for the treatment of HFrEF was more expensive (RM 25,333 vs. RM 21,675) but gained more health utilities (3.64 vs. 3.46), resulting in an ICER of RM 20,400 per QALY in the KCCQ-CSS model. A NYHA-based scenario analysis generated an ICER of RM 36,682 per QALY. A deterministic sensitivity analysis confirmed the robustness of the model in identifying the empagliflozin cost as the main driver of cost-effectiveness. The ICER was reduced to RM 6,621 when the government medication purchasing prices were used. A probabilistic sensitivity analysis with a CET of 1xGDP per capita reached 72.9% probability for empagliflozin + SoC against SoC being cost-effective. Conclusion: Empagliflozin + SoC compared to SoC alone for the treatment of HFrEF patients was cost-effective from the perspective of the MoH of Malaysia.

Medical Treatment in Heart Failure with Reduced Ejection Fraction: A Proposed Algorithm Based on the Patient's Electrolytes and Congestion Status.

In heart failure (HF) with reduced ejection fraction (HFrEF), four classes of drugs (β-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor neprilysin inhibitors, mineralocorticoid receptor antagonists, and the most recent Sodium-Glucose Co-Transporters 2 Inhibitors) have demonstrated positive results in randomized controlled trials (RCTs). Nevertheless, the latest RCTs are not proper for comparison since they were carried out at various times with dissimilar background therapies and the patients enrolled did not have the same characteristics. The difficulty of extrapolating from these trials and proposing a common framework appropriate for all cases is thus obvious. Despite the fact that these four agents are now the fundamental pillars of HFrEF treatment, the built-up algorithm of initiation and titration is a matter of debate. Electrolyte disturbances are common in HFrEF patients and can be attributed to several factors, such as the use of diuretics, renal impairment, and neurohormonal activation. We have identified several HFrEF phenotypes according to their sodium (Na+) and potassium (K+) status in a "real world" setting and suggest an algorithm on how to introduce the most appropriate drug and set up therapy based on the patients' electrolytes and the existence of congestion.

P309 DIFFERENT KINETICS OF NT–PROBNP AND SST2 HIGHLIGHT DIFFERENT THERAPEUTIC PATHWAYS OF SACUBITRIL/VALSARTAN

Abstract Background N–terminal pro–B–type natriuretic peptide (NT–proBNP) and soluble interleukin 1 receptor–like 1 ST2 (sST2) are biomarkers used to grade heart failure with reduced ejection fraction (HFrEF) severity. The first is associated with the patient’s hemodynamic status, while the second is indicative of the inflammatory component and of myocardial fibrosis and both are potential targets of HFrEF treatment. Aim of the study: The aim of this study was to assess the kinetics of these biomarkers after treatment with sacubitril/valsartan in HFrEF. Methods We analyzed blood samples of HFrEF patients at baseline (before sacubitril/valsartan treatment), after 1, 2, 3 months (respectively after a month taking the 24/26 – 49/51 – 97/103mg doses), and 6 months after the maximum tolerated dose was reached (end–study). Results We obtained samples from 34 HFrEF patients (age 65.9±9.0, 74% males). NT–proBNP and sST2 values progressively and significantly reduced up to 21%±33 and 9%±16, respectively, with a greater reduction for NT–proBNP (p&amp;lt;0.05). Specifically, NT–proBNP reduced from 1286 [609–3205] to 877 [437–1866] pg/mL and sST2 from 29.3 [19.5–34.1] to 20.4 [15.6–28.9] ng/mL, p&amp;lt;0.05 in both cases). The reduction of the two biomarkers over time occurred with statistically significant different kinetics: deferred for sST2 and faster for NT–proBNP. No significant changes in renal function and potassium levels were recorded. Conclusions These findings suggest that, in HF patients, sacubitril/valsartan effects on the cardiovascular system share a double pathway: a first, hemodynamic, faster pathway and a second, non–hemodynamic, delayed pathway. Both likely contribute to the sacubitril/valsartan benefits in HFrEF.

P80 EFFICACY OF DAPAGLIFLOZIN IN EARLY IMPROVEMENT OF QUALITY OF LIFE IN OUTPATIENT WITH CHRONIC HEART FAILURE

Abstract Sodium glucose cotransporter–2 inhibitors reduce mortality and hospitalizations in patients with heart failure with reduced ejection fraction (HFrEF). As a consequence, they are recommended by the European guidelines as mandatory pillar for HFrEF treatment with a strong recommendation (IA). In order to confirm the quality of life improvement shown in prespecified analysis of randomised controlled trial, we administered the Kansas City Cardiomyopathy Questionnaire (KCCQ–12) to 21 patients treated with Dapagliflozin 10mg in an outpatient setting of four Heart Failure Unit of Val Padana Hospitals. Among 21 HFrEF patients included in the analysis 11 have had coronary artery disease, 12 had hypertensive or dilatative cardiomyopathy etiology. The average age of our population was 73 yrs (54–89), 67% were male and 33% female, every patient were in NYHA II class and average BNP was 315 pg/mL. All the patients received Dapagliflozin for the entire observation period without any discontinuation for adverse event or intolerance. Every patient received KCCQ–12 questionnaire twice: at Time 0 when the first dose of Dapagliflozin was administered and after 3 months (Time 1) to verify the variation of the score. During the follow–up different therapy or dose regimen change has not occurred, as baseline therapies were already optimized. Only one patient changed furosemide dosage, reduce it from 75 to 50 mg/die without significant changes in body weight. After 3 months from the first administration of Dapagliflozin the KCCQ–12 summary score has increased by 10,27 points (from baseline avg value to 57,89 – 22% increase (Figure 1). Each of the single components of the score (physical limitation, symptoms frequency, QOL single score, social limitation) had increase in a consistent way from baseline values (Figure 2) In conclusion our data from an outpatient setting of real–world chronic HF population confirm the results of secondary analysis of the Trials and show that adding Dapagliflozin to the standard of care therapy leads to an early improvement in quality of life and physical limitations as quantified by KCCQ–12 questionnaire results. Furthomore, the KCCQ–12 seems to be a reliable and a useful health status instrument to evaluate the performance of HF outpatients, especially to test the benefits of new therapies.

P468 CLINICAL CHARACTERISTICS OF PATIENTS AFFECTED BY HEART FAILURE PATIENTS WITH REDUCED EJECTION FRACTION AND UNDERGOING SGLT2I THERAPY

Abstract Background The type–2 sodium–glucose cotransporters inhibitors (SGLT2i) are a new relevant therapeutic option for patients affected by chronic heart failure with reduced ejection fraction (HFrEF). The aim of this study was to evaluate the clinical characteristics and therapy of HFrEF patients undergoing SGLT2i therapy. Methods We evaluated the consecutive patients affected by HFrEF in whom the SGLT2i therapy was prescribed since December 2021. At baseline clinical visit, ECG, echocardiography, assessment of sodium, potassium, fasting glucose, hemoglobin, hematocrit, glomerular filtration rate (GFR) by creatinine were assessed. Results Ninety patients were enrolled. In the Table clinical characteristics and therapy are reported. Interestingly, most of patients were already trated with the classes of drugs currently recommended fo HFrEF treatment. Conclusions In this “real world” study, SGLT2i were prescribed in HFrEF patients most of all already in therapy with the other classes of drugs currently recommended for their treatment. These data further support the use of this therapeutic approach in routine clinical practice.

Update on Percutaneous Treatment for HFrEF: A Great Armamentarium for a Poor Ventricular Function.

Pharmacological treatment is the cornerstone therapy of heart failure with reduced ejection fraction (HFrEF). In addition, several percutaneous techniques have been developed to treat symptomatic patients, with specific heart failure (HF) phenotypes (e.g., valvular heart disease) that require non-pharmacological treatment. Given their prognostic relevance, it is imperative to deliver high-level patient care. This review provides a clinical overview on the available data regarding transcatheter devices in the armamentarium of contemporary interventional cardiologists, focusing on the clinical and anatomical selection criteria.

Revascularization in Ischemic Heart Failure with Reduced Left Ventricular Ejection Fraction

Coronary artery disease (CAD) is estimated to account for over 60% of heart failure (HF) patients and is associated with worse outcomes than a non-ischemic etiology. In patients with ischemic HF, myocardial revascularization has multiple mechanisms of action based on the concept that blood flow restoration of viable but underperfused myocardium might reverse the hibernation of the left ventricle and prevent future spontaneous myocardial infarction, which could potentially improve patients' outcomes. Here, we aim to elaborate on indications, timing, type, and impact of completeness of revascularization in patients with heart failure with reduced ejection fraction (HFrEF) and ischemic etiology. For decades, coronary artery bypass graft surgery has been the pilar of revascularization in patents with multivessel CAD and reduced EF. Recent development in the interventional field led to overall increase of percutaneous coronary intervention (PCI) adoption in treatment of ischemic HFrEF. However, recently published randomized study demonstrated no added benefit of PCI over optimal medical therapy in patients with severe ischemic cardiomyopathy challenging the beneficial role of revascularization in this setting. Since the decision on revascularization in ischemic cardiomyopathy frequently cannot be made based strictly on guidelines, tailored treatment strategy should be mandated with the essential role of multidisciplinary approach. These decisions should be based on capability to achieve complete revascularization, with the consideration that in certain situations it may not be accomplished.

Pharmacotherapy treatment patterns at hospital discharge and clinical outcomes among patients with heart failure with reduced ejection fraction.

This study aimed to assess the prescribing patterns of evidence-based pharmacotherapy and their association with clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF) in Thailand. A retrospective cohort study of patients with HFrEF was conducted. Treatment with a β-blocker and renin-angiotensin system inhibitors (RASIs) with or without mineralocorticoid receptor antagonists (MRAs) at discharge was regarded as guideline-directed medical therapy (GDMT). All others were considered non-GDMT. The primary endpoint was the composite of all-cause mortality or heart failure (HF) rehospitalization. Inverse-probability-treatment-weighted adjusted Cox proportional hazard models were used to examine the treatment effects. In total, 653 patients with HFrEF (mean age 64.1 ± 14.3 years; 55.9% male) were included. GDMT with β-blockers and RASIs with or without MRAs was prescribed at a rate of 35.4%. During a median of 1-year follow-up, 167 patients (27.5%) had a composite event, 81 patients (13.3%) had all-cause mortality, and 109 patients (18.0%) had HF rehospitalization. Patients treated with GDMT at discharge showed significantly lower rates of the primary endpoint (adjusted hazard ratio [HR] 0.63; 95% CI 0.44-0.89; p = 0.009) compared with patients who did not receive GDMT. The use of GDMT was also associated with a significantly lower risk of all-cause mortality (adjusted HR 0.59; 95% CI 0.36-0.98; p = 0.045) and HF rehospitalization (adjusted HR 0.65; 95% CI 0.43-0.96; p = 0.031). For HFrEF treatment, GDMT initiation at hospital discharge was associated with a significantly reduced risk of all-cause mortality and HFrehospitalization. Nevertheless, prescribing GDMT remains underused, and it could be encouraged to improve HF outcomes in real-world settings.

Cost-effectiveness of dapagliflozin and empagliflozin for treatment of heart failure with reduced ejection fraction

BackgroundThe differences in cost and efficacy between dapagliflozin and empagliflozin in combination with standard of care (SoC) raise the question of which regimen would be cost-effective in treating heart failure with reduced ejection fraction (HFrEF). This study evaluates the cost-effectiveness of dapagliflozin plus SoC (dapagliflozin-SoC) versus empagliflozin plus SoC (empagliflozin-SoC) or SoC alone for treatment of HFrEF. MethodsWe developed a Markov model to estimate the cost-effectiveness of dapagliflozin-SoC, empagliflozin-SoC, and SoC alone from the healthcare system perspective over a lifetime horizon. Data on efficacy of dapagliflozin-SoC, empagliflozin-SoC, and SoC were obtained from randomized controlled trials. Costs were measured in 2022 US dollars, and effectiveness was measured in quality-adjusted life years (QALYs). ResultsAmong three strategies, dapagliflozin-SoC was the most cost-effective strategy and dominated empagliflozin-SoC in an extended sense. Compared with SoC alone, dapagliflozin-SoC and empagliflozin-SoC had incremental cost-effectiveness ratios (ICER) of $56,782 and $89,258 per QALY, respectively. Dapagliflozin-SoC cost more $5524 but yielded more 0.20 QALYs than empagliflozin-SoC, with the ICER of $27,861 per QALY. The cost-effectiveness of dapagliflozin-SoC, empagliflozin-SoC, and SoC alone did not depend on diabetic status. However, empagliflozin-SoC was no longer cost-effective versus SoC alone in HFrEF patients without CKD, and dapagliflozin-SoC was not cost-effective versus empagliflozin-SoC in HFrEF patients with CKD. ConclusionDapagliflozin-SoC was cost-effective versus empagliflozin-SoC or SoC alone for treatment of HFrEF.

Representation matters: a call for inclusivity and equity in heart failure clinical trials.

The burden of heart failure remains substantial worldwide, and heart failure with reduced ejection fraction (HFrEF) affects approximately half of this population. Despite this global prevalence of HFrEF, the majority of contemporary clinical trials in HFrEF have underenrolled individuals from minoritized sex, gender, race, ethnicity, and socioeconomic groups. Moreover, significant disparities in access to HFrEF treatment and outcomes exist across these same strata. We provide a call to action for the inclusion of diverse populations in HFrEF clinical trials; catalogue several barriers to adequate representation in HFrEF clinical trials; and propose strategies to broaden inclusivity in future HFrEF trials.

755 ATRIAL NATRIURETIC PEPTIDE STIMULATES AUTOPHAGY/MITOPHAGY AND IMPROVES MITOCHONDRIAL DISFUNCTION IN CHRONIC HEART FAILURE

Abstract Background Mitochondrial dysfunction, causing increased reactive oxygen species production, is a molecular feature of heart failure (HF) and it has been reported in circulating leucocytes of patients with HF with reduced ejection fraction (HFrEF). Atrial natriuretic peptide (ANP) exerts many cardiac beneficial effects, including the ability to protect cardiomyocytes by promoting autophagy. Objective To test the impact of ANP on autophagy/mitophagy responses, altered mitochondrial structure and function and increased oxidative stress in chronic HFrEF patients. Experimental design. The present study used both ex-vivo and in-vivo approaches. We examined sixteen consecutive chronic HFrEF patients referring to the outpatient clinic of the Cardiology unit of Sant’Andrea Hospital in Rome. Out of them, for the ex-vivo study we enrolled 10 patients matching the following inclusion criteria: age under 75 years and left ventricle ejection fraction &amp;lt;40%. For the in-vivo study we recruited six patients and evaluated them before and after 2-month treatment with the Angiotensin Receptor Neprilysin inhibitor (ARNi) sacubitril/valsartan started at the dosage of 49/51 mg twice daily, rapidly uptitrated at the dosage of 97/103 mg twice daily, while maintaining unchanged the remaining therapy. Patients with recent hospitalizations for acute HF or other acute conditions within the last 3 months before the enrollment, with malignancy, inflammatory or infectious diseases, diabetes mellitus, history of cigarette smoking and alcohol abuse were excluded. Results The ex-vivo direct exposure to αANP caused an improvement of mitochondrial membrane potential with a restoration of the mitochondrial protonmotive force (p&amp;lt;0.05) and promoted the recovery of the IMM extension with a significant improvement in the IMM/OMM index (p&amp;lt;0.05). The production of ROS was significantly decreased after the exposure to αANP (p&amp;lt;0.05). Analyzing the mitochondrial stress, we observed that the treatment with αANP induced a down-modulation of p66shc mRNA (p&amp;lt;0.01). The αANP treatment induced a rapid and significant autophagic response. The cytofluorimetric analysis showed a significant increase of LysoTracker levels highlighting a rise of intracellular acidic compartments (p&amp;lt;0.05), with the up modulation of the LC3 and Beclin mRNA levels (p&amp;lt;0.01 and p&amp;lt;0.05 respectively). The significant reduction in mitochondrial mass observed in treated PBMCs evoked an increase of the mitophagic process related to αANP (p&amp;lt;0.01). In vivo, the efficacy of the treatment with sacubitril/valsartan was proved by the increase in αANP levels (p&amp;lt;0.01) whereas levels of NT-proBNP decreased (p&amp;lt;0.05). PBMCs collected after treatment were characterized by lower mitochondrial oxidative stress levels and were provided of structurally more intact mitochondria characterized by better functional performances (p&amp;lt;0.05). PBMCs of the treated patients showed an increased level of acid compartments associated with an up-modulation of LC3 and Beclin mRNA levels and a reduction of mitochondrial mass (p&amp;lt;0.05). Also in this experimental context, the activation of autophagy was confirmed by ultrastructural morphometric evaluation (p&amp;lt;0.05). Conclusions αANP stimulates both autophagy and mitophagy responses, counteracts mitochondrial dysfunction and damage ultimately reducing mitochondrial oxidative stress generation in PBMCs from chronic HF patients. These properties were confirmed upon sacubitril/valsartan administration, a therapeutic approach indicated for HFrEF treatment.

141 DIFFERENT KINETICS OF NT-PROBNP AND S-ST2 HIGHLIGHT DIFFERENT THERAPEUTIC THERAPEUTIC PATHWAYS OF SACUBITRIL/VALSARTAN

Abstract Background N-terminal pro-B-type natriuretic peptide (NT-proBNP) and soluble interleukin 1 receptor-like 1 ST2 (sST2) are biomarkers used to grade heart failure with reduced ejection fraction (HFrEF) severity. The first is associated with the patient's hemodynamic status, while the second is indicative of the inflammatory component and of myocardial fibrosis and both are potential targets of HFrEF treatment. Aim of the study The aim of this study was to assess the kinetics of these biomarkers after treatment with sacubitril/valsartan in HFrEF. Methods We analyzed blood samples of HFrEF patients at baseline (before sacubitril/valsartan treatment), after 1, 2, 3 months (respectively after a month taking the 24/26–49/51–97/103mg doses), and 6 months after the maximum tolerated dose was reached (end-study). Results We obtained samples from 34 HFrEF patients (age 65.9±9.0, 74% males). NT-proBNP and sST2 values progressively and significantly reduced up to 21%±33 and 9%±16, respectively, with a greater reduction for NT-proBNP (p&amp;lt;0.05). Specifically, NT-proBNP reduced from 1286 [609-3205] to 877 [437-1866] pg/mL and sST2 from 29.3 [19.5-34.1] to 20.4 [15.6-28.9] ng/mL, p&amp;lt;0.05 in both cases). The reduction of the two biomarkers over time occurred with statistically significant different kinetics: deferred for sST2 and faster for NT-proBNP. No significant changes in renal function and potassium levels were recorded. Conclusions These findings suggest that, in HF patients, sacubitril/valsartan effects on the cardiovascular system share a double pathway: a first, hemodynamic, faster pathway and a second, non-hemodynamic, delayed pathway. Both likely contribute to the sacubitril/valsartan benefits in HFrEF.

Cost-effectiveness of empagliflozin for the treatment of heart failure with reduced ejection fraction in China.

To determine the pharmacoeconomics of empagliflozin for the treatment of heart failure (HF) with reduced ejection fraction in China and to provide evidence-based reference for clinical rational drug selection and medical decision-making. We used the Markov model to evaluate the cost-effectiveness of empagliflozin for the treatment of HF with reduced ejection fraction (HFrEF). We evaluated the cost-effectiveness of the standard treatment in addition to empagliflozin (empagliflozin group) vs. the cost-effectiveness of the standard treatment alone (standard treatment group). We found that each additional quality-adjusted life year (QALY) in the empagliflozin group costed $3,842.20 more, which was less than China's gross domestic product (GDP) per capita in 2021 ($11,981). The steady-state mortality in the two groups was the key factor affecting the incremental cost-effectiveness ratio (ICER). Probabilistic sensitivity analysis revealed that when the willingness-to-pay (WTP) threshold was one time the GDP per capita in 2021 ($11,981) and three times the GDP per capita in 2021 ($35,943), the probability of the empagliflozin group being cost-effective was 85.8 and 91.6%, respectively. Compared with the standard treatment alone, the addition of empagliflozin to the standard treatment was more cost-effective for the treatment of HFrEF in China.