Neprilysin Inhibitor Research Articles

Feasibility, efficacy and safety of early and rapid initiation of evidence-based treatment for patients with HFrEF- a real world experience of the "four drugs in four weeks" strategy

Abstract Background Evidence-based treatment for heart failure with reduced ejection fraction (HFrEF) is associated with improved outcomes for patients. However, there is uncertainty as to how treatment with these foundational drugs should best be implemented. Objectives To evaluate whether early and rapid initiation of medications for patients with HFrEF using a 4 x 4 approach (4 pillars of HFrEF therapy in 4 weeks) is feasible, safe, and effective. Methods We recruited consecutive patients from April to July 2021 with a new diagnosis of HFrEF who were either assessed at our urgent HF clinic or had a recent HF hospitalisation. All patients had regular reviews (every 1-2 weeks, combination of telephone and face-to-face) at our hospital-based HF clinic by a HF consultant or senior HF specialist nurse for initiation and up-titration of guideline-recommended therapy including angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor neprilysin inhibitor (ARNI), beta blockers (BB), mineralocorticoid receptor antagonist (MRA) and sodium glucose co-transporter inhibitor (SGLT2i). Results Of 100 patients approached, 19 patients were considered unsuitable for the 4x4 pathway (79% due to severe frailty or significant comorbidities). 81 patients were enrolled (61% male, median (IQR) age: 73 (67-82) years, median (IQR) NT-proBNP: 3764 (1597-7487) ng/L); 39 (48%) patients achieved "4 drugs at 4 weeks". Of the 42 patients who did not, 33 (79%) had contraindication to one or more of the drug classes at the outset, including renal impairment (28%), bradycardia (18%) and hyperkalaemia (15%). Patients who did not achieve "4 drugs at 4 weeks" were older, more symptomatic, and had higher NTproBNP and worse renal function. During a median follow up of 554 days, 6 (7%) patients died and 31 (38%) experienced the combined outcome of all-cause death / hospitalisation. Patients who did not achieve "4 drugs at 4 weeks", compared to those who did, had a 2.5 fold increased risk of the combined outcome (Figure 1). They were also less likely to be up-titrated to targeted doses of HF medications (Figure 2). There was noticeable improvement in NTproBNP with no significant change in renal function or systolic BP in both groups. Compared to those who did not achieve "4 drugs at 4 weeks", those who did showed larger improvement in LVEF (8% vs 2%) at 6 months. 5 patients (6%) experienced significant side effects during medication up-titration: 4 had symptomatic hypotension and 1 had hyperkalaemia. Conclusion The 4x4 strategy is clinically feasible and safe when implemented in selected patients with HFrEF and may be associated with improved outcomes. Our results support larger studies to further investigate the generalisability and effectiveness of the 4x4 strategy.

Validating the association between a composite metric of guideline-directed medical therapy (GDMT) and clinical outcomes for patients with heart failure with reduced ejection fraction (HFrEF)

Abstract Introduction A composite metric to characterize the overall quality of GDMT for patients with HFrEF is important to evaluate quality-of-care and for clinical research. Purpose We sought to evaluate the associations between GDMT scores and cardiovascular outcomes amongst patients with recently-diagnosed HFrEF within a large national integrated health system within the United States. Methods We identified a cohort of patients with recent-onset HFrEF who received care within the Veterans Affairs system between January 2013 and June 2019. We excluded patients with systolic blood pressure <100mmHg or glomerular filtration rate <30 mL/min/1.73m2. We identified active medical therapy based on the last medication fill 90-180 days after the index date (first date with documented HF diagnosis and EF≤40%). We calculated three different GDMT scores: the original Heart Failure Collaboratory Score, the 4-Pillar Intensification Score, and a modified 4-Pillar Intensification Score that included continuous scoring to further incentivize dose uptitration (Figure 1). Using a landmark analysis, we evaluated the association between a 1 standard deviation (SD) change in the GDMT scores at 6 months with the following outcomes: all-cause death, cardiovascular death, and the composite of cardiovascular death/heart failure hospitalization. We repeated the analyses with adjustment for comorbidities and vital signs. Results Among 108,752 patients with recent-onset HFrEF, the mean age was 70.0 years (SD: 11.1) and 97.6% were men. Treatment rates were the following: evidence-based beta-blockers – 55.2%, renin-angiotensin system inhibitors – 60.2%, angiotensin neprilysin inhibitors – 2.9%, mineralocorticoid receptor antagonists – 17.6%, sodium glucose transporter 2 inhibitors – 0.7%, hydralazine/nitrates – 4.9%, and ivabradine – 0.1%. A one standard deviation increase in each of the GDMT scores was associated with improved clinical outcomes (Table 1). Figure 1 illustrates the association between the modified 4-Pillar Intensification Score and the composite of cardiovascular death/heart failure hospitalization. These associations were attenuated but remained significant with comorbidity adjustment. Results also remained consistent when the study period was restricted to 2016 or later and with inclusion of the last prescription fill between 1-180 days post-index date. Conclusion Our study suggests that GDMT scores are consistently associated with clinical outcomes among patients with HFrEF.

Changes in medical therapy after cardiac resynchronization in patients with heart failure: insights from the U.S. Veterans Affairs healthcare system

Abstract Background Patients with heart failure with reduced ejection fraction (HFrEF) are often not treated with comprehensive guideline directed medical therapy (GDMT) due to hemodynamic and renal limitations. Cardiac resynchronization therapy (CRT) improves hemodynamics in patients with HFrEF and ventricular dyssynchrony. Whether CRT facilitates intensification of GDMT in patients with HFrEF has not been well-studied. Purpose To assess pre-procedure GDMT (B-blocker, ACEI [angiotensin converting enzyme inhibitor]/ARB [angiotensin receptor blocker], ARNI [angiotensin receptor neprilysin inhibitor], MRA [mineralocorticoid receptor antagonist], SGLT2i [sodium-glucose cotransporter-2 inhibitor]) utilization in HFrEF patients who received CRT and to compare changes in GDMT in patients who received CRT with patients who received implantable cardioverter-defibrillator (ICD). Methods Veterans with left ventricular ejection fraction (LVEF) 35% who received CRT or ICD from Feb 22, 2000 – Jul 28, 2022 were identified. Patients with end-stage renal disease were excluded. Changes in GDMT 12-months following device implant were characterized and compared between CRT and ICD recipients. Mixed effects logistic regression models were generated to evaluate associations between receipt of CRT and the composite of therapy initiation, dose increase, or target dose achievement compared with ICD. Models were adjusted for clinical characteristics and pre-implant GDMT utilization. Similar models were developed to evaluate the adjusted associations between CRT and changes in estimated glomerular filtration rate (eGFR) and blood pressure (BP) compared with ICD. Results A total of 2,082 CRT recipients and 7,263 ICD recipients were identified. Pre-procedure heart rate, BP, serum potassium, and eGFR were within normal ranges and similar between groups. Prior to device implant, ACEI/ARB/ARNI were most frequently prescribed (91%), followed by -blockers (88%), MRA (46%), and SGLT2i (33% in post-SGLT2i era). Pre-procedure GDMT was similar between CRT and ICD recipients. At 12 months follow-up, CRT was independently associated with increased odds of therapy initiation, dose increase, or target dose achievement for ACEI/ARB/ARNI, ARNI, B-blockers, and MRA (Figure 1). ICD was associated with a decline in eGFR while CRT was associated with an increase in eGFR (mean [standard deviation]: -0.95 [0.17] vs. +0.6 [0.29]; p<0.01), while no differences were observed in BP or LVEF at 12 months. Conclusions In a large, contemporary cohort of patients with HFrEF, most patients were not prescribed MRA or SGLT2i prior to receiving CRT or ICD despite no apparent renal or blood pressure-related contraindications. CRT is associated with increased odds of the composite of initiation, dose increase, or target dose achievement for ACEI/ARB/ARNI, ARNI, B-blockers, and MRA compared with ICD. GDMT intensification may be mediated by beneficial changes in kidney function in CRT recipients.Figure 1

Impact of a structured educational intervention on attitudes and clinical practices in heart failure among physicians in argentina

Abstract Introduction It is necessary to identify areas for improvement in the care of patients with heart failure (HF), and thus implement educational interventions to optimize the quality of care and their clinical outcomes. Objective The aim of this study was to evaluate the attitudes, knowledge, confidence and care pathways of patients with HF among physicians in Argentina and their subsequent changes after an educational intervention. Methods We conducted a cross-sectional study using a self-administered survey to evaluate clinical practice patterns and attitudes/perceptions regarding the diagnosis, treatment and follow-up of HF patients in the outpatient and inpatient settings. Survey respondents were physicians from 22 centers in Argentina who participated in a comprehensive educational programme for the care of HF patients conducted between March and July 2021. The educational intervention was based on a 30-hour training programme in heart failure clinics and a final examination. Simple road maps were created to address the knowledge gaps identified in the pre-intervention phase. Results A total of 50 physicians were surveyed; the mean age was 41±8 years and 86% were cardiologists. The educational intervention significantly increased physicians' confidence in diagnosing HFpEF, with 52% feeling "confident" or "very confident" before and 84% after the intervention (p<0.001). In outpatients with HFrEF, more physicians reported prioritizing quadruple therapy with SLGT-2i, mineralocorticoid receptor antagonists (MRA), beta-blockers and angiotensin receptor neprilysin inhibitors (ARNI) in the post-intervention period (p<0.05, figure 2). No differences were found in the reported time to optimal medical treatment (p=0.7). After the intervention, the proportion of physicians who felt "confident" or "very confident" in identifying patients who could benefit from an implantable cardioverter-defibrillator increased from 70% to 96% (p=0.01). After the intervention, more doctors considered "relevant" and "very relevant" the administration of hypertonic saline (22% to 52%; p=0.01), and intravenous iron (56% to 80%; p=0.041). Compared to the pre-intervention period, more physicians prioritized quadruple therapy with beta-blockers, MRA, ARNI and SGLT2i (p<0.05, figure 2) at hospital discharge. There was a significant increase in the use of the discharge checklist from 26% to 48% (p=0.05). Conclusions A multifaceted structured educational intervention was effective in improving knowledge and attitudes about the diagnosis and management of patients with HF among physicians in Argentina. The results of the present study demonstrate that an educational intervention can increase knowledge and improve clinical attitudes in the diagnosis of HFpEF and management of outpatients and hospitalized patients with HFrEF. Further studies are needed to determine the impact of such programmes in other countries.

Initiation, titration, and discontinuation - utilization of heart failure medicines in England (EVOLUTION HF UK)

Abstract Background Guidelines advise early initiation and optimisation of several guideline-recommended pharmacological therapies (GRPTs) for managing heart failure (HF) with reduced ejection fraction. Recent guidelines have expanded this list to include two new classes of agents: sodium-glucose cotransporter 2 (SGLT2) inhibitors and angiotensin receptor neprilysin inhibitor (ARNI). Auditing real-world GRPT use is critical in closing the evidence-practice gap. Purpose To generate insights into utilization patterns of novel and established GRPTs after a recent hospitalization for HF (hHF) in England using administrative healthcare records. Methods New users of GRPTs within 12 months of a hHF discharge were identified using linked national electronic health records (Clinical Practice Research Datalink, Hospital Episode Statistics and Office for National Statistics mortality data) between January 2021 — May 2022. Time to initiation of dapagliflozin (the only SGLT2 inhibitor approved for HF in January 2021), sacubitril/valsartan, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs) were considered separately. Titration and discontinuation of the most frequently used drug for each pharmacological class was identified and analysed as representative of the entire class. Doses and discontinuation were assessed in the 12 months following initiation. If a new package isn't collected after the previous one ends, discontinuation is assumed until a new package is collected. Target dose was defined as ≥100% of the guideline-recommended dose. Results Overall, 16,090 new users of GRPTs were identified. Mean times from hHF to GRPT initiation were longer for novel agents (dapagliflozin or sacubitril/valsartan) than for established agents: 195 and 137 vs 48 to 73 days. Similarly, the cumulative percentage of patients initiating a GRPT within 100 days of hHF discharge were lower for novel agents (Figure 1). In the following 12 months, the average target dose achieved was higher for novel agents: 61.8% (dapagliflozin), 32.4% (sacubitril/valsartan), 8.5% (ACE inhibitor: ramipril), 5.9% (ARB: candesartan), 7.6% (beta-blocker: bisoprolol), and 6.6% (MRA: spironolactone). Corresponding discontinuation rates were 32.0%, 24.3%, 36.3%, 38.2%, 23.4%, and 50.1%, respectively (Figure 1 and 2). Conclusion In the UK, early initiation of novel GRPTs after recent hHF in routine clinical practice remains a challenge. For GRPTs requiring uptitration, few patients received the target dose in the 12 months after initiation, and many discontinued treatments. Conversely, dapagliflozin was associated with relatively higher rates of target dose achievement, perhaps because only a single fixed dose is recommended. Our data highlight the need for increased access to appropriate, timely and sustained HF therapeutic optimization.

Heart failure medical therapy and outcomes in patients undergoing transcatheter mitral valve repair for secondary mitral regurgitation: a TVT Registry analysis across 449 US centers

Abstract Background Guidelines recommend medical therapy optimization prior to transcatheter mitral valve repair (TMVr) in patients with heart failure (HF), left ventricular ejection fraction (LVEF) <50%, and severe secondary mitral regurgitation (SMR). Whether TMVr is being performed on the background of optimal guideline directed medical therapy (GDMT) in clinical practice is unknown. Purpose To assess pre-procedure GDMT (B-blockers, ACEI [angiotensin converting enzyme inhibitor]/ARB [angiotensin receptor blocker], ARNI [angiotensin receptor neprilysin inhibitor], MRA [mineralocorticoid receptor antagonist]) use and association with outcomes in patients with HF and LVEF <50% undergoing TMVr. Methods Patients with LVEF <50% who underwent TMVr for SMR from July 2019 – March 2022 in the Transcatheter Valve Therapy Registry were identified. Patients on inotropes or in shock pre-TMVr were excluded. Cox proportional hazards models were constructed to evaluate adjusted associations between pre-TMVr medical therapy (no, single, double, or triple therapy) and risk of the one-year composite outcome of mortality or HF hospitalization. Sensitivity analyses excluded patients with HF with mildly reduced ejection fraction (HFmrEF) (LVEF >40%) or New York Heart Association (NYHA) class I (asymptomatic) prior to TMVr. Results A total of 4,199 patients across 449 sites were identified. Prior to TMVr, B-blockers (85.1%) were prescribed most frequently, followed by ACEI/ARB (44.4%), MRA (28.6%), and ARNI (19.9%). Triple therapy was prescribed for 19.2% of patients, while 38.2% were on double therapy, 36.0% were on single therapy, and 6.5% were on no medical therapy. Triple therapy use varied from 0 - 61% across sites with an adjusted median odds ratio of 1.48 (95% confidence interval [CI] 1.25-3.88, P<0.001), suggesting a 1.5-fold variation in the likelihood that similar risk patients at 2 random US sites received triple therapy pre-TMVr (Figure 1). In patients with one-year follow-up available (n=2,014, 341 sites), the composite rate of one-year mortality or HF hospitalization was lowest in patients on triple therapy (23.1%) compared with double (24.8%), single (35.7%), and no (41.1%) therapy (P≤0.01). Associations persisted after accounting for clinically relevant covariates, with lower risk in patients on triple therapy (adjusted hazard ratio [aHR] 0.73, 95% CI 0.55-0.97) and double therapy (aHR 0.60, 95% CI 0.50-0.74) prior to TMVr compared with no/single therapy. Results were similar when only patients with symptomatic HFrEF were considered (i.e., those with HFmrEF or NYHA class I pre-TMVr were excluded) (Figure 2). Conclusions Under one-fifth of patients who underwent TMVr for SMR were prescribed comprehensive GDMT, with substantial variation across clinical sites. Compared with no or single therapy, triple and double therapy use prior to TMVr was independently associated with reduced risk of mortality or HF hospitalization one-year after intervention.Figure 1Figure 2

Abstract 16755: Changes in Mid-Regional Pro-Adrenomedullin During Treatment With Sacubitril/Valsartan

Background: Adrenomedullin is a vasodilatory peptide with a role in microcirculatory and endothelial homeostasis. Adrenomedullin is a substrate for neprilysin and may therefore play a role in beneficial effects of sacubitril/valsartan (Sac/Val) treatment. Methods: Mid-regional pro-peptide of adrenomedullin (MR-proADM) was measured in 156 patients with heart failure with reduced ejection fraction (HFrEF) treated with Sac/Val and 264 patients with HF with preserved EF (HFpEF) randomized to treatment with Sac/Val or valsartan. Echocardiography and Kansas City Cardiomyopathy Questionnaire results were collected at baseline and after 6 and 12 months in the HFrEF cohort. Results: Median (Q1-Q3) baseline MR-proADM concentrations were 0.80 (0.59-0.99) nMol/L in HFrEF and 0.88 (0.68-1.20) nMoL/L in HFpEF. After 12 weeks of treatment with Sac/Val, MR-proADM increased by median 49% in HFrEF and 60% in HFpEF, while there were no significant changes in valsartan-treated patients (median 2%). Greater increases in MR-proADM were associated with higher Sac/Val doses. Changes in MR-proADM correlated weakly with changes in N-terminal pro-B-type natriuretic peptide, cardiac troponin T and urinary cyclic guanosine monophosphate. Increases in MR-proADM were associated with decreases in blood pressure, but not significantly associated with changes in echocardiographic parameters or health status ( Figure ). Conclusions: MR-proADM concentrations rise substantially following treatment with Sac/Val, in contrast to no change from valsartan. Change in MR-proADM from neprilysin inhibition did not correlate with improvements in cardiac structure and function or health status. More data are needed regarding the role of adrenomedullin and its related peptides in the treatment of HF.

Abstract 16493: An Evaluation of Heart Failure Management in the Non-White Population at a Safety Net Hospital Compared to a National Registry

Introduction: The importance of guideline-directed medical therapy (GDMT) to improve outcomes in patients with heart failure has been proven in multiple studies. However, providers still fall short in prescribing these medications to heart failure patients. This is reflected in the CHAMP-HF registry, one of the largest registries utilized to observe and analyze the use of GDMT for heart failure. The CHAMP-HF registry population includes 3,518 patients from 150 U.S. primary care and cardiology practices. Of this population, approximately 25.1% are non-White. It remains unclear what GDMT treatment patterns are in a majority non-White population. Objective: This study aims to compare GDMT treatment patterns for heart failure at Harbor-UCLA Heart Failure (HUCLA HF) clinic, with a majority-minority population, to the CHAMP-HF registry published data. Methods: This prospective cohort study followed patients who visited the HUCLA HF clinic over four months. Providers used a checklist to prompt them to review each patient’s GDMT at the end of each visit. Patient demographic data and checklist data were entered into the HUCLA HF clinic registry. The registry was used to analyze the utilization of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB), angiotensin receptor neprilysin inhibitor (ARNI), beta-blocker, and mineralocorticoid receptor antagonist (MRA). The percentage of patients using GDMT was compared to those in the CHAMP-HF registry. Results: Overall, the HUCLA HF clinic registry revealed a majority-minority patient population with about 91% of patients classified as non-White patients. The HUCLA HF clinic patients had a higher percentage on max ACE/ARB (21% vs 15.7%), max ARNI therapy (42% vs 13.8%), max beta-blocker therapy (47% vs 15.5%), and max MRA therapy (70% vs 14.5%) compared to the non-White population in the CHAMP-HF registry, respectfully. Conclusions: This study demonstrates greater utilization of GDMT at the HUCLA HF clinic compared to the patients in the CHAMP-HF registry. This difference was likely due to the checklist that reminded the provider to review the GDMT at each visit. Strategies that prompt clinicians to review GDMT must be implemented to maximize its use.

Abstract 17641: Frequency of Reported Euglycemic Ketoacidosis With Sodium-Glucose Cotransporter-2 Inhibitors is Not Increased in Patients With Heart Failure: Analysis of US Food and Drug Administration Adverse Event Reporting System (FAERS)

Introduction: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are first-line therapy for heart failure (HF) but have an associated risk for euglycemic ketoacidosis. Patients with HF exhibit many additional risk factors for euglycemic ketoacidosis. However, no data describes the incidence or risk of euglycemic ketoacidosis in HF. Hypothesis: Reported incidence of euglycemic ketoacidosis with empagliflozin and dapagliflozin is not higher in patients with HF compared to the general population. Methods: Cases of euglycemic ketoacidosis with empagliflozin and dapagliflozin (single or combination products) were identified in the Food and Drug Administration Adverse Event Reporting System (FAERS) from January 2022 to March 2023. HF was identified as those taking at least two of the listed medication categories (angiotensin converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor neprilysin inhibitor, mineralocorticoid receptor antagonist, HF-approved beta blocker) with a loop diuretic or search terms related to cardiac failure from MedDRA. Cases with missing event date, age, gender, and reporter country were removed. Reporting rates of euglycemic ketoacidosis stratified by HF status were examined descriptively. Results: Out of 16,880 adverse event reports involving empagliflozin and dapagliflozin, a total of 432 (2.6%) cases of SGLT2 inhibitor-associated euglycemic ketoacidosis were identified (mean age 65±13 years, 55.6% male, and mean weight of 87±27 kg). Patients who developed euglycemic ketoacidosis were younger and of lower mean weight. The incidence of euglycemic ketoacidosis among patients without HF was 2.8% compared to 0.8% in patients with HF [OR 0.27, 95% CI (0.17, 0.44)]. Mortality or need for hospitalization was not increased in patients experiencing euglycemic ketoacidosis for both the HF cohort (mortality: 5.9% vs. 6.7%; hospitalization: 23.5% vs. 31.1%) and general population (mortality: 0.2% vs. 3.6%; hospitalization: 30.1% vs. 27.3%). Conclusions: Euglycemic ketoacidosis with empagliflozin and dapagliflozin was uncommon, does not appear to be more frequent in patients with HF compared to the general population, and does not appear to be associated with worse outcomes.

Abstract 14848: Interplay of Cardiovascular Risk Factors, Comorbidities, Demographics, and Social Determinants of Health on Adherence to Guideline Directed Medical Therapies in Heart Failure With Preserved Ejection Fraction: The All of Us Research Program

Background: Despite its high prevalence, HFpEF is difficult to diagnose and treat due to its complex pathophysiology. Unlike HFrEF, treatments are limited for HFpEF. A combination of SGLT2i, angiotensin receptor neprilysin inhibitor (ARNi), and mineralocorticoid antagonist (MRA) has been shown to improve cardiovascular outcomes; however, acceptance of GDMT remains an obstacle in clinical practice. We sought to investigate the relationship of social determinants of health (SDOH), demographics, comorbidities, and risk factors with prescription patterns to GDMT for HFpEF. Methods: The All of Us Research Program, which began in May 2018, is a diverse database that prioritizes historically marginalized populations. Demographics, risk factors, and SDOH measurements were compared with use of GDMT for HFpEF adults aged 18 years and over. Multiple logistic regression analysis was used to examine the association among demographics, comorbidities, risk factors and SDOH with use of at least two of the recommended GDMT therapies for HFpEF (SGLT2 inhibitor, angiotensin receptor/ARNi, and MRA). Result: The study found that 38.4% (3773) of the 9823 adults with chronic heart failure had HFpEF. 51% of those with HFpEF do not take any GDMT, 11% take 2/3 of the GDMT, and only 1% take all three. Furthermore, a multiple logistic regression analysis revealed a greater odds of being on at least 2 GDMT for HFpEF among participants with known ASCVD (1.96 [1.41, 2.78]), diabetes (2.15 [1.56, 3.01]), and BMI ≥ 35 kg/m2 (1.02 [1.01, 1.04]). In addition, female sex is also associated with increased odds of being on at least two agents (1.46 [1.08, 2.00]). The likelihood of being prescribed GDMT for HFpEF was not predicted by race, education, income, or health insurance type. Conclusion: Risk factors such as ASCVD, diabetes and obesity were shown to be associated with an increased rate of GDMT use, while sex differences are also present.

Sacubitril/valsartan and the risk of incident dementia in heart failure: a nationwide propensity-matched cohort study.

Sacubitril acts to inhibit neprilysin and as neprilysin is involved in amyloid-beta degradation in the central nervous system, and there is concern that sacubitril/valsartan may increase the risk of dementia. We aimed to compare the risk of incident dementia associated with sacubitril/valsartan and angiotensin II receptor blockers (ARBs). Patients with heart failure with reduced ejection fraction treated with either sacubitril/valsartan or ARB, identified from the Korean National Health Insurance Service database, were matched in a 1:2 ratio using propensity scores (6789 on sacubitril/valsartan and 13,578 on ARBs) and followed up for incident dementia. During a mean follow-up of 2.5years, 526 (2.6%) patients were newly diagnosed with dementia: Alzheimer dementia in 282, vascular dementia in 8, and other dementia in 236. There was no significant difference in the risk of overall dementia (hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.70-1.01), Alzheimer dementia (HR 0.85, 95% CI 0.67-1.10), vascular dementia (HR 0.98, 95% CI 0.23-4.11), and all other dementias (HR 0.81, 95% CI 0.62-1.07) between sacubitril/valsartan users and ARB users. These results were consistent regardless of initial sacubitril/valsartan dose and subgroups including old age, previous mild cognitive impairment, previous stroke, and concomitant antiplatelet or anticoagulation. Sensitivity analysis with a 1-year lag period for dementia assessment confirmed the main analysis. Meanwhile, risk of incident stroke was lower in sacubitril/valsartan users compared to ARBs users. In a nationwide propensity-matched cohort of patients with heart failure, sacubitril/valsartan was not associated with an increased risk of incident dementia compared to ARBs.

Novel Approaches to the Failing Congenital Heart.

Heart failure is the leading cause of morbidity and mortality in adults with congenital heart disease and is characterized by a variety of underlying mechanisms. Here, we aim to elaborate on the medical and technological advancements in the management of heart failure in adult patients with congenital heart disease and highlight the use of imaging modalities to guide therapy. There have been several advances over the past decade with angiotensin receptor neprilysin and sodium-glucose cotransporter-2 inhibitors, atrioventricular valve clips, transcatheter pulmonary valves, catheter ablation, and cardiac resynchronization therapy, as well as the introduction of lymphatic interventions. Expanded use of echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography has guided many of these therapies. Significant innovations in the management of heart failure in adults with congenital heart disease have evolved with advancements in imaging modalities playing a critical role in guiding treatment therapies.

Long-term effects of angiotensin receptor neprilysin inhibitor therapy in heart failure patients with reduced ejection fraction: A retrospective cohort study.

Heart failure is an increasing public health issue with substantial morbidity and mortality rates. This study aimed to evaluate the efficacy, safety, and long-term outcomes of angiotensin receptor neprilysin inhibitor (ARNi) in the treatment of heart failure with reduced ejection fraction (HFrEF) 5 years after treatment initiation. This retrospective study analyzed a cohort of 75 patients diagnosed with HFrEF over a period of 5 years after the initiation of ARNi therapy. The initial clinical condition, laboratory and echocardiographic measurements including left ventricular ejection fraction (LVEF), New York Heart Association functional classes (NYHA-FC) and the prognostic nutritional index were compared to the corresponding values obtained after a 5-year period of ARNi therapy. In addition, the number of annual hospitalizations, mortality rates and any history of adverse effects during the follow-up period were recorded. The N-terminal pro-brain natriuretic peptide (NT-proBNP) level, LVEF, and NYHA-FC values demonstrated significant improvement at the end of the 5-year follow-up period (all parameters, P < .001). Although the observed increase in the prognostic nutritional index was not statistically significant (P = .077), it is worth noting. A significant reduction in daily diuretic doses and hospitalizations due to heart failure was observed following the use of ARNi (all comparisons, P < .001). The prevalence of hypotension was around 16% (being symptomatic in 4%), making it the most frequently observed adverse event. The 5-year cardiovascular mortality rate was 17.3%. The use of ARNi in HFrEF patients was associated with a notable improvement in NYHA-FC, LVEF, and NT-proBNP levels in the long-term, while also leading to a better nutritional status and reduced need for diuretics and annual hospitalization. Additionally, ARNi usage has been associated with improved nutritional status, decreased reliance on diuretics, and reduced frequency of annual hospitalizations. These effects were associated with a lack of significant increase in adverse effects. These results may contribute to a better understanding of ARNi's long-term effects on patient outcomes.

Side-Chain Modified [99mTc]Tc-DT1 Mimics: A Comparative Study in NTS1R-Positive Models

Radiolabeled neurotensin analogs have been developed as candidates for theranostic use against neurotensin subtype 1 receptor (NTS1R)-expressing cancer. However, their fast degradation by two major peptidases, neprilysin (NEP) and angiotensin-converting enzyme (ACE), has hitherto limited clinical success. We have recently shown that palmitoylation at the ε-amine of Lys7 in [99mTc]Tc-[Lys7]DT1 (DT1, N4-Gly-Arg-Arg-Pro-Tyr-Ile-Leu-OH, N4 = 6-(carboxy)-1,4,8,11-tetraazaundecane) led to the fully stabilized [99mTc]Tc-DT9 analog, displaying high uptake in human pancreatic cancer AsPC-1 xenografts but unfavorable pharmacokinetics in mice. Aiming to improve the in vivo stability of [99mTc]Tc-DT1 without compromising pharmacokinetics, we now introduce three new [99mTc]Tc-DT1 mimics, carrying different pendant groups at the ε-amine of Lys7: MPBA (4-(4-methylphenyl)butyric acid)—[99mTc]Tc-DT10; MPBA via a PEG4-linker—[99mTc]Tc-DT11; or a hydrophilic PEG6 chain—[99mTc]Tc-DT12. The impact of these modifications on receptor affinity and internalization was studied in NTS1R-positive cells. The effects on stability and AsPC-1 tumor uptake were assessed in mice without or during NEP/ACE inhibition. Unlike [99mTc]Tc-DT10, the longer-chain modified [99mTc]Tc-DT11 and [99mTc]Tc-DT12 were significantly stabilized in vivo, resulting in markedly improved tumor uptake compared to [99mTc]Tc-DT1. [99mTc]Tc-DT11 was found to achieve the highest AsPC-1 tumor values and good pharmacokinetics, either without or during NEP inhibition, qualifying for further validation in patients with NTS1R-positive tumors using SPECT/CT.

LCZ696 attenuates sepsis-induced liver dysfunction in rats; the role of oxidative stress, apoptosis, and JNK1/2-P38 signaling pathways

AimSepsis is a serious inflammatory response to infection with an annual incidence rate of >48 million cases and 11 million fatalities worldwide. Furthermore, sepsis remains the world's fifth-greatest cause of death. For the first time, the current study aims to evaluate the possible hepatoprotective benefits of LCZ696, a combination of an angiotensin receptor blocker (valsartan) and a neprilysin inhibitor prodrug (sacubitril), on cecal ligation and puncture (CLP)-induced sepsis in rats. Main methodsCLP was employed to induce sepsis. Hepatic malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), interleukin-6 (IL-6), IL-1β, tumor necrosis factor-alpha (TNF-α), and caspase 3 were assessed using ELISA. Serum alanine transaminase (ALT) and aspartate transaminase (AST) were also measured. Western blot assay was used to determine the expression of JNK1/2 and P38 proteins. The histology of liver tissues was also examined. Key findingsCLP resulted in significant elevation of AST, ALT, MDA, IL-6, IL-1β, TNF-α, and caspase 3 levels, and up-regulation of p/t JNK1/2, and p/t P38 proteins, as compared to the sham group. However, level of GSH, and SOD activity were reduced in CLP group. LCZ696 significantly improved all the previously mentioned biochemical and histological abnormalities better than using valsartan alone. SignificanceLCZ696 substantially ameliorated CLP-induced liver damage, compared to valsartan, by reducing proinflammatory mediators, inhibiting the JNK1/2 and P38 signaling pathway, and attenuating apoptosis.

Efficacy of sacubitril / valsartan in the treatment of chronic heart failure: an updated review

Chronic heart failure (CHF) is currently a common disease and the search for new approaches to the treatment of various forms of CHF remains relevant. Sacubitril/valsartan is a member of a new class of angiotensin-neprilysin receptor inhibitors (ARNIs) that act on key neurohormonal mechanisms, including the RAAS and natriuretic peptides. Simultaneous inhibition of RAAS and neprilysin provides more effective neurohormonal modulation, preventing clinical deterioration in patients with CHF. New mechanisms of action of sacubitril/valsartan associated with the inhibition of several targets involved in cardiac hypertrophy, fibrosis, cardiac remodeling and apoptosis have been disclosed. Sacubitril/valsartan is recommended for CHF with low ejection fraction (EF) in addition to traditional therapy with ACE inhibitors, mineralocorticoid receptor antagonists, beta-blockers, and also has an independent effect. A number of studies have shown the effect of sacubitril/valsartan on heart remodeling, a decrease in the level of the NT-proBNP biomarker and an improvement in EF, and according to the PARADIGM-HF study, the drug significantly reduced the risk of cardiovascular mortality by 20% and hospitalizations for CHF by 21%, which found confirmation in three meta-analyses. The use of sacubitril/valsartan in CHF with preserved and intermediate EF showed a beneficial therapeutic effect and a decrease in the level of biomarkers, as well as a significant decrease in the frequency of hospitalizations due to CHF by 15–22%, but without a significant advantage in terms of the effect on mortality, which supported by several meta-analyses of studies. A number of large meta-analyses of studies of sacubitril/valsartan in CHF have shown reverse cardiac remodeling and a reduced risk of atrial fibrillation. Thus, the accumulated data substantiate and expand the possibilities of using sacu-bitril/valsartan in CHF.

Neprilysin inhibitors and risk of Alzheimer's disease: A future perspective.

Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease with multifaceted neuropathological disorders. AD is characterized by intracellular accumulation of phosphorylated tau proteins and extracellular deposition of amyloid beta (Aβ). Various protease enzymes, including neprilysin (NEP), are concerned with the degradation and clearance of Aβ. Indeed, a defective neuronal clearance pathway due to the dysfunction of degradation enzymes might be a possible mechanism for the accumulation of Aβ and subsequent progression of AD neuropathology. NEP is one of the most imperative metalloproteinase enzymes involved in the clearance of Aβ. This review aimed to highlight the possible role of NEP inhibitors in AD. The combination of sacubitril and valsartan which is called angiotensin receptor blocker and NEP inhibitor (ARNI) may produce beneficial and deleterious effects on AD neuropathology. NEP inhibitors might increase the risk of AD by the inhibition of Aβ clearance, and increase brain bradykinin (BK) and natriuretic peptides (NPs), which augment the pathogenesis of AD. These verdicts come from animal model studies, though they may not be applied to humans. However, clinical studies revealed promising safety findings regarding the use of ARNI. Moreover, NEP inhibition increases various neuroprotective peptides involved in inflammation, glucose homeostasis and nerve conduction. Also, NEP inhibitors may inhibit dipeptidyl peptidase 4 (DPP4) expression, ameliorating insulin and glucagon-like peptide 1 (GLP-1) levels. These findings proposed that NEP inhibitors may have a protective effect against AD development by increasing GLP-1, neuropeptide Y (NPY) and substance P, and deleterious effects by increasing brain BK. Preclinical and clinical studies are recommended in this regard.

Neprilysin activity is increased in metabolic dysfunction-associated steatotic liver disease and normalizes after bariatric surgery or GLP-1 therapy

Inhibitors of neprilysin improve glycemia in patients with heart failure and type 2 diabetes (T2D). The effect of weight loss by diet, surgery, or pharmacotherapy on neprilysin activity (NEPa) is unknown. We investigated circulating NEPa and neprilysin protein concentrations in obesity, T2D, metabolic dysfunction-associated steatotic liver disease (MASLD), and following bariatric surgery, or GLP-1-receptor-agonist therapy. NEPa, but not neprilysin protein, was enhanced in obesity, T2D, and MASLD. Notably, MASLD associated with NEPa independently of BMI and HbA1c. NEPa decreased after bariatric surgery with a concurrent increase in OGTT-stimulated GLP-1. Diet-induced weight loss did not affect NEPa, but individuals randomized to 52-week weight maintenance with liraglutide (1.2mg/day) decreased NEPa, consistent with another study following 6-week liraglutide (3mg/day). A 90-min GLP-1 infusion did not alter NEPa. Thus, MASLD may drive exaggerated NEPa, and lowered NEPa following bariatric surgery or liraglutide therapy may contribute to the reported improved cardiometabolic effects.

SAT032 Circulating Neprilysin Activity Is Increased In Type 2 Diabetes And Fatty Liver Disease, And Reduces Following Bariatric Surgery And Liraglutide Therapy

Abstract Disclosure: S.A. Kjeldsen: None. L. Gluud: None. M. Werge: None. J. Pedersen: None. F. Bendtsen: None. K. Alexiadou: None. T. Tan: None. S.S. Torekov: None. E.W. Iepsen: None. N.J. Jensen: None. M. Richter: None. B. Hartmann: None. J.J. Holst: None. B. Holst: None. J. Holt: None. S. Madsbad: None. M.S. Svane: None. K.N. Bojsen-Møller: None. N.J. Wewer Albrechtsen: None. The neutral endopeptidase neprilysin (NEP) cleaves peptides important for metabolism, including GLP-1. Plasma levels of GLP-1 are reduced in patients with T2D, but the reason is unknown. Long-term treatment with the NEP inhibitor sacubitril (in combination with valsartan) improves glycemic control in individuals with T2D and heart failure. Here, we investigate plasma activity and protein levels of NEP in patients with obesity, T2D, and/or NAFLD diagnosed using biopsy or ultrasound, following bariatric surgery (RYGB and sleeve gastrectomy), and after treatment with GLP-1. We hypothesized that NEP activity (NEPa) is increased in patients with T2D, and that GLP-1 agonism reduces NEPa in a weight loss-independent manner. Here we show that plasma levels of NEPa are increased by 51% in patients with T2D (n=33) compared to individuals with normal glucose tolerance (NGT, n=160) (mean ± SD; 2734 ± 3646 vs. 1809 ± 2039 pmol/ml/min, P=0.02). Plasma NEPa was not increased in obesity (n=188) compared to lean controls (n=15) (1944 ± 2392 vs. 1373 ± 1918, P=0.4), but was increased by 76% in NAFLD (n=51) compared to non-NAFLD controls (n=43) (2629 ± 3219 vs. 1497 ± 1404, P=0.02). There were no differences in plasma NEP protein between any of the comparator groups, suggesting that changes in NEPa in metabolic disease are post-translational modifications of the enzyme or other mechanisms influencing NEPa. Bariatric surgery (RYGB, n=66 and SG, n=20) reduced plasma NEPa by 60% (P&amp;lt;0.001), while plasma NEP protein levels were unaltered or increased in individuals with and without preoperative T2D. Six weeks GLP-1 (liraglutide) treatment (3 mg/day) in individuals with overweight and obesity (n=14) reduced NEPa by 28% (P=0.04; apparent after 4 weeks), and at follow-up (3 weeks after discontinuation) NEPa levels returned to baseline, whereas NEP protein levels were unchanged throughout the study. In a study of individuals with obesity randomized to complete a 52-week weight maintenance intervention by diet or liraglutide (1.2 mg/day) following an 8-week diet-induced weight loss period, plasma NEPa was not affected by the initial 12% weight loss (n=48, P=0.3). However, plasma NEPa reduced in response to 52-week liraglutide therapy (n=15, P=0.05). A 90-minute low dose infusion of native GLP-1 (7-36 amide,1 pmol/kg/min) in individuals with overweight and obesity (n=19) did not alter plasma NEPa, which suggests that the attenuating effects on NEPa with GLP-1R agonism is not acute. In conclusion, our data support that plasma NEPa is increased in T2D and NAFLD independent of obesity but may be normalized by bariatric surgery, and that chronic treatment with GLP-1 reduces NEPa. Altered NEPa may therefore contribute to altered metabolism of GLP-1 in diabetes and following bariatric surgery. Whether liraglutide-induced reduction in NEPa contributes to its metabolic effects demands further investigation. Presentation: Saturday, June 17, 2023

Call to action for drug interactions between tirzepatide and heart failure guideline-directed medical therapy

BackgroundNo drug interaction between the guideline-directed medical therapy (GDMT) for heart failure (HF) with reduced ejection fraction (HFrEF) and glucose-dependent insulinotropic polypeptide (GIP)-glucagon-like peptide-1 (GLP-1) agonists is currently indexed in available drug interaction databases or package inserts for tirzepatide, the first dual GIP/GLP-1 agonist. The objective of our case series is to present 3 patients with HF who required modification in GDMT regimens for HFrEF or loop diuretic therapy after tirzepatide initiation. Case summaryThree patients older than 60 years with HFrEF receiving GDMT agents (angiotensin receptor neprilysin inhibitors, beta blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors) were initiated on tirzepatide for weight loss management. After initiating tirzepatide therapy, all 3 patients developed symptomatic hypotension. Two cases had acute kidney injury owing to tirzepatide’s direct vasodilation, natriuresis, reduction in extracellular volume, and weight loss. GDMT regimens and diuretic therapy were significantly modified to improve these adverse reactions. Practice implicationsClinicians must closely monitor vital signs and volume status after initiating tirzepatide for potential need to modify GDMT regimens. Authors request a call to action to index the drug interaction between GDMT agents and tirzepatide in major drug interaction databases for a potential hypotension or dehydration risk.