Treatment Of Heart Failure With Reduced Ejection Fraction Research Articles

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.

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.