Receptor Neprilysin Inhibitor Research Articles

Angiotensin receptor-neprilysin inhibition and combination use of guideline-directed medical therapies in acute heart failure.

Angiotensin receptor-neprilysin inhibition and combination use of guideline-directed medical therapies in acute heart failure.

Comparative analysis of renin-angiotensin system inhibitors/angiotensin receptor neprilysin inhibitor and mineralocorticoid receptor antagonists in heart failure with mildly reduced ejection fraction

Abstract Background Apart from sodium-glucose co-transporter 2 inhibitors, the efficacy of renin–angiotensin system inhibitors/angiotensin receptor neprilysin inhibitors (RASI/ARNI)j8788 as well as mineralocorticoid receptor antagonist (MRA) in patients with heart failure with mildly reduced ejection fraction remains uncertain. We assessed the association between these medications and outcomes in patients with heart failure with mildly reduced ejection fraction (HFmrEF). Methods Patients with HFmrEF from our university hospital-integrated Medical Database were included. Associations between the medications and cardiovascular mortality/heart failure hospitalization were evaluated using Cox regressions in a 1:1 propensity score-matched cohort. Inverse probability of treatment weighting was employed to balance baseline patient characteristics. Results Of 2584 patients with HFmrEF, 17% received MRA and 43% received RASI/ARNI. Predictors of MRA use included older age, slightly higher ejection fraction, lower NT-proBNP level, and eGFR >60 mL/min/1.73 m^2. Predictors of RASI/ARNI use included higher body mass index, lower NT-proBNP level, normal uric acid level, normal potassium level, and eGFR >60 mL/min/1.73 m^2. MRA use was not associated with a lower risk of cardiovascular death and hospitalization for heart failure (hazard ratio [HR] = 0.89, 95% confidence interval [CI]: 0.78–1.02 and HR = 1.01, 95% CI: 0.94–1.09, respectively). Conversely, RASI/ARNI use was associated with a lower risk of cardiovascular death but not hospitalization for heart failure (HR = 0.82, 95% CI: 0.71–0.94 and HR = 0.995, 95% CI: 0.924–1.07, respectively). Notably, landmark analysis revealed no significant difference in the risk of outcomes when the follow-up duration exceeded two years. Conclusions The effect of MRA on cardiovascular death and hospitalization for heart failure was neutral, whereas RASI/ARNI was associated with a lower risk of cardiovascular death. Our findings suggest that RASi use may be more beneficial than MRA use in patients with HFmrEF.

The influence of the daily salt-intake on the antihypertensive action and atrial natriuretic peptide level in patietns with angiotensin receptor neprilysin inhibition

Abstract Background The angiotensin receptor–neprilysin inhibitor (ARNI) is a drug which acts through angiotensin receptor blocking effect and the increase in atrail natriuretic peptide (ANP) through neprilysin inhibitor in hypertension (HT). These combined effects result in a reduced risk of hospitalization for heart failure or death from cardiovascular causes. ANP is also known for its various cardioprotective effects including vasodilator and natriuretic action. Acording to Guyton's pressure-natriuresis curve, the efficacy of angiotensin receptor blocker drugs is diminished in HT cases with high daily salt inatke. However, whether the effect of ARNI on HT is attenuated in patients with high daily salt intake remains unclear. Purpose The present study investigated the influence of a daily salt intake on the antihypertensive action and ANP level in patients with ARNI. Methods Fourty-four consecutive essential HT patients on ARNI were enrolled. Blood pressure and ANP level were measured at baseline (before taking ARNI) and 3 weeks later. ARNI (200mg) was prescribed and maintained during the study. In addtion, the daily salt intake was calculated using creatinine and natrium levels in urine, age, and body weight according to Japanese hypertensive guideline at baseline and 3 weeks later. Results The average age was 70±8 years old. About 50% (N=23) was male. The mean sytolic and diastolic blood pressure was 148±14mmHg and 89±10mmHg, respectively. The mean daily salt intake was 9.5±2.2 g/day at baseline. The mean ANP level was 529±300pg/ml. At follow up (3 weeks later), the mean systolic and diastolic blood pressure significanly went down to 132± 18 mmHg and 70± 9 mmHg, respectively (p=0.03). ANP level also increased from 529±300pg/ml to 793±580pg/ml. However, the mean daily salt intake was almost same as the baseline at 9.4±3.2 g/day. The patients were divided into 2 groups; high daily salt intake (N=20 with mean daily salt intake 10.5±1.7g/day)) and low daily salt intake (N=24 with 8.4±3.1g/day) groups compared to the baseline. The absolute and percentage changes in systolic blood pressure were almost same in the high and low daily salt intake groups (-12.7±15.8mmHg vs -13.7±14.2mmHg, p=0.75; -5.8±6.5% vs.-7.0±9.6%, p=0.58, respectively). However, the change rate in ANP level was significantly higer in the high daily salt intake group than in the low daily salt intake group (155±63 vs. 12±16%, p=0.01). Conclusion ARNI demonstrates effectiveness in lowering the blood pressure even in patients with higher salt intake, unlike angiotensin receptor blocker. In cases with high salt intake, the notable increase in ANP levels may contribute to decreasing blood pressure through vasodilator and natriuretic action.

Angiotensin receptor-neprilysin inhibition and improved ventricular-arterial coupling in heart failure with reduced ejection fraction.

Sacubitril/valsartan improves outcome in chronic heart failure (HF) with reduced ejection fraction (EF). The underlying mechanisms on left ventricular (LV) myocardial function are incompletely understood. In this study, 117 patients with symptomatic HF and LV-EF ≤ 40% were enrolled prospectively. Non-invasive pressure-volume analysis was calculated from transthoracic echocardiography with simultaneous arm-cuff blood pressure measurements. Primary outcome parameters were LV end-systolic elastance (Ees; a measure of LV contractility), effective arterial elastance (Ea; a measure of afterload), and the ventricular-arterial coupling ratio (Ea/Ees). Mean age was 65±13 years, 30% were female, and 54.7% had ischemic heart disease. During six months of follow-up, eight patients died, three withdrew their consent, and four were lost to follow-up. 102 patients were included in pressure-volume analyses. After six months of sacubitril/valsartan treatment, Ees increased (0.66mmHg/ml [IQR 0.45-0.94] vs. 0.78mmHg/ml [IQR 0.57-1.10], p=0.001), Ea decreased (1.76mmHg/ml [IQR 1.48-2.13] vs. 1.62mmHg/ml [IQR 1.36-1.96], p=0.014), and the Ea/Ees ratio improved (2.52 [IQR 1.88-4.05] vs. 1.93 [IQR 1.50-2.63], p<0.001). LV end-diastolic pressure and LV volumes were reduced, and LVEF increased from 33% to 43% (both p<0.001). Clinical improvement occurred in NYHA functional class, NT-proBNP level, and 6-minute walking distance. Change in LVEF correlated with change in Ees (r=0.33, p=0.0008), while change in NT-proBNP was associated with change in LVEDP (r=0.42, p<0.0001). In conclusion, sacubitril/valsartan is associated with improved ventricular-arterial coupling by enhancing LV contractility and reducing afterload. Beyond LV reverse remodeling, optimized ventricular-arterial interaction may contribute to the favorable outcome of sacubitril/valsartan treatment in HF with reduced EF.

Translating the 2021 ESC heart failure guideline recommendations in daily practice: Results from a heart failure survey. A scientific statement of the ESC Council for Cardiology Practice and the Heart Failure Association of the ESC.

Real-world data show that guidelines are insufficiently implemented, and particularly guideline-directed medical therapies (GDMT) are underused in patients with heart failure and reduced ejection fraction (HFrEF) in clinical practice. The Council for Cardiology Practice and the Heart Failure Association of the European Society of Cardiology (ESC) developed a survey aiming to (i) evaluate the perspectives of the cardiology community on the 2021 ESC heart failure (HF) guidelines, (ii) pinpoint disparities in disease management, and (iii) propose strategies to enhance adherence to HF guidelines. A 22-question survey regarding the diagnosis and treatment of HFrEF was delivered between March and June 2022. Of 457 physicians, 54% were general cardiologists, 19.4% were HF specialists, 18.9% other cardiac specialists, and 7.7% non-cardiac specialists. For diagnosis, 52.1% employed echocardiography and natriuretic peptides (NPs), 33.2% primarily used echocardiography, and 14.7% predominantly relied on NPs. The first drug class initiated in HFrEF was angiotensin-converting enzyme inhibitors/angiotensin receptor-neprilysin inhibitor (ACEi/ARNi) (91.2%), beta-blockers (BB) (73.8%), mineralocorticoid receptor antagonists (MRAs) (53.4%), and sodium-glucose cotransporter 2 (SGLT2) inhibitors (48.1%). The combination ACEi/ARNi + MRA+ BB was preferred by 39.3% of physicians, ACEi/ARNi + SGLT2 inhibitors + BB by 33.3%, and ACEi/ARNi + BB by 22.2%. The time required to initiate and optimize GDMT was estimated to be <1 month by 8.3%, 1-3 months by 52%, 3-6 months by 31.8%, and >6 months by 7.9%. Compared to general cardiologists, HF specialists/academic cardiologists reported lower estimated time-to-initiation, and more commonly preferred a parallel initiation of GDMT rather than a sequential approach. Participants generally followed diagnostic and treatment guidelines, but variations in HFrEF management across care settings or HF specialties were noted. The survey may raise awareness and promote standardized HF care.

Efficacy and safety of angiotensin receptor-neprilysin inhibition in heart failure patients with end-stage kidney disease on maintenance dialysis: A systematic review and meta-analysis.

Angiotensin receptor-neprilysin inhibitor (ARNI) has played an increasingly important role in the management of heart failure (HF). However, the evidence on the benefits of ARNI in HF patients with end-stage kidney disease (ESKD) undergoing dialysis is limited. This study aimed to investigate the efficacy and safety of ARNI in patients with concomitant HF and ESKD on maintenance dialysis. We systematically searched the MEDLINE, Embase, Web of Science, Cochrane, and ClinicalTrials.gov databases for studies reporting outcomes after ARNI treatment in HF patients with ESKD on dialysis. All meta-analyses were performed using the random effects model. Twenty-six studies comprising 2494 patients with concomitant HF and ESKD undergoing dialysis were included. Our synthesis showed a significant improvement in left ventricular ejection fraction (LVEF) between before and after ARNI treatment (mean change: 8.05%; 95% confidence interval [CI] 5.57-10.54). Compared to the conventional group, the ARNI group showed a greater improvement in LVEF (mean difference: 4.03%; 95% CI 2.90-5.16). This effect was more pronounced in patients with HF with reduced ejection fraction (pinteraction < 0.0001). Patients treated with ARNI had a lower risk of all-cause mortality (risk ratio [RR] 0.64; 95% CI 0.45-0.92; p = 0.01) but had a similar rate of HF hospitalization (RR 0.71; 95% CI 0.43-1.18; p = 0.19). ARNI treatment showed benefits in the improvement of left ventricular end-systolic diameter, left ventricular mass index, left atrial diameter, and E/e' ratio (p < 0.05), while it did not significantly increase the risk of severe hyperkalaemia (p = 0.33) or symptomatic hypotension (p = 0.53). This meta-analysis provided insights into the benefits of ARNI in HF patients with ESKD undergoing dialysis by improving left ventricular function, reversing left ventricular remodelling, and reducing the risk of all-cause mortality, without increasing the risk of HF hospitalizations, severe hyperkalaemia, and symptomatic hypotension.

In-hospital initiation of angiotensin receptor-neprilysin inhibition in acute heart failure: the PREMIER trial.

The efficacy and safety of early sacubitril/valsartan (Sac/Val) initiation after acute heart failure (AHF) has not been demonstrated outside North America. The present study aimed to evaluate the effect of in-hospital Sac/Val therapy initiation after an AHF episode on N-terminal pro-B-type natriuretic peptide (NT-proBNP) level in Japanese patients. This was an investigator-initiated, multicentre, prospective, randomized, open-label, blinded-endpoint pragmatic trial. After haemodynamic stabilization within 7 days after hospitalization, eligible inpatients were allocated to switch from angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to Sac/Val (Sac/Val group) or to continue angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (control group). The primary efficacy endpoint was the 8-week proportional change in geometric means of NT-proBNP levels. A total of 400 patients were equally randomized, and 376 (median age 75 years, 31.9% women, de novo heart failure rate 55.6%, and median left ventricular ejection fraction 37%) were analysed. The per cent changes in NT-proBNP level geometric means at Weeks 4/8 were -35%/-45% (Sac/Val group) and -18%/-32% (control group), and their group ratio (Sac/Val vs. control) was 0.80 (95% confidence interval 0.68-0.94; P = .008) at Week 4 and 0.81 (95% confidence interval 0.68-0.95; P = .012) at Week 8, respectively. In the pre-specified subgroup analyses, the effects of Sac/Val were confined to patients with a left ventricular ejection fraction < 40% and were more evident in those in sinus rhythm and taking mineralocorticoid receptor antagonists. No adverse safety signal was evident. In-hospital Sac/Val therapy initiation in addition to contemporary recommended therapy triggered a greater NT-proBNP level reduction in Japanese patients hospitalized for AHF. These findings may expand the evidence on Sac/Val therapy in this clinical situation outside North America. ClinicalTrial.gov (NCT05164653) and Japan Registry of Clinical Trials (jRCTs021210046).

Sacubitril/valsartan alleviates sepsis-induced myocardial injury in rats via dual angiotensin receptor-neprilysin inhibition and modulation of inflammasome/caspase 1/IL1β pathway

Sepsis is a life-threatening situation that ultimately affects cardiac function, leading to cardiomyopathy and myocardial injury as a result of uncontrolled response to infection.Till now, there is limited effective treatment to rescue those cases. Thus, novel therapeutic strategies should be identified to achieve better outcomes for septic patients. For the first time, we aimed to evaluate the effect of sacubitril/valsartan (Sac/Val) on sepsis-induced cardiac injury. Wistar male adult albino rats were randomly divided into four groups; Group I received the vehicle; Group II was given the vehicle plus 1 ml saline containing viable Escherichia coli (E. coli) (2.1 × 109 cfu) by intraperitoneal (i.p.) injection on the 1st and 2nd days; Group III received i.p. injection as group II plus oral administration of Sac/Val (30 mg/kg/day) and Nitro- ω-L-arginine (L-NNA) (25 mg/kg/day) for 7 days. Group IV was administered i.p. injection as group II plus oral administration of Sac/Val (30 mg/kg/day) for 7 days. Our data (n = 10) revealed successful induction of sepsis as it showed a significant increase in the measured cardiac enzymes, malondialdehyde (MDA), angiotensin II (Ang II), neprilysin, inflammasome, caspase 1, interleukin (IL)1β, and caspase 3 with cardiac histopathological changes, but there was a significant decrease in the antioxidants and blood pressure (BP). Co-administration of Sac/Val could obviously improve these changes. Interestingly, L-NNA given group showed a decrease in the cardioprotective effect of Sac/Val. Sac/Val could ameliorate sepsis induced cardiac damage via inhibition of Ang II and neprilysin with anti-inflammatory, anti-oxidant and anti-apoptotic properties.

Percutaneous repair of moderate-to-severe or severe functional mitral regurgitation in patients with symptomatic heart failure: Baseline characteristics of patients in the RESHAPE-HF2 trial and comparison to COAPT and MITRA-FR trials.

The RESHAPE-HF2 trial is designed to assess the efficacy and safety of the MitraClip device system for the treatment of clinically important functional mitral regurgitation (FMR) in patients with heart failure (HF). This report describes the baseline characteristics of patients enrolled in the RESHAPE-HF2 trial compared to those enrolled in the COAPT and MITRA-FR trials. The RESHAPE-HF2 study is an investigator-initiated, prospective, randomized, multicentre trial including patients with symptomatic HF, a left ventricular ejection fraction (LVEF) between 20% and 50% with moderate-to-severe or severe FMR, for whom isolated mitral valve surgery was not recommended. Patients were randomized 1:1 to a strategy of delivering or withholding MitraClip. Of 506 patients randomized, the mean age of the patients was 70 ± 10 years, and 99 of them (20%) were women. The median EuroSCORE II was 5.3 (2.8-9.0) and median plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 2745 (1407-5385) pg/ml. Most patients were prescribed beta-blockers (96%), diuretics (96%), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors (82%) and mineralocorticoid receptor antagonists (82%). The use of sodium-glucose cotransporter 2 inhibitors was rare (7%). Cardiac resynchronization therapy (CRT) devices had been previously implanted in 29% of patients. Mean LVEF, left ventricular end-diastolic volume and effective regurgitant orifice area (EROA) were 31 ± 8%, 211 ± 76 ml and 0.25 ± 0.08 cm2, respectively, whereas 44% of patients had mitral regurgitation severity of grade 4+. Compared to patients enrolled in COAPT and MITRA-FR, those enrolled in RESHAPE-HF2 were less likely to have mitral regurgitation grade 4+ and, on average, HAD lower EROA, and plasma NT-proBNP and higher estimated glomerular filtration rate, but otherwise had similar age, comorbidities, CRT therapy and LVEF. Patients enrolled in RESHAPE-HF2 represent a third distinct population where MitraClip was tested in, that is one mainly comprising of patients with moderate-to-severe FMR instead of only severe FMR, as enrolled in the COAPT and MITRA-FR trials. The results of RESHAPE-HF2 will provide crucial insights regarding broader application of the transcatheter edge-to-edge repair procedure in clinical practice.

Generalizable Approach to Quantifying Guideline-Directed Medical Therapy.

Quantifying guideline-directed medical therapy (GDMT) intensity is foundational for improving heart failure (HF) care. Existing measures discount dose intensity or use inconsistent weighting. The Kansas City Medical Optimization (KCMO) score is the average of total daily to target dose percentages for eligible GDMT, reflecting the percentage of optimal GDMT prescribed (range, 0-100). In Change the Management of Patients With HF, we computed KCMO, HF collaboratory (0-7), and modified HF Collaboratory (0-100) scores for each patient at baseline and for 1-year change in established GDMT at the time (mineralocorticoid receptor antagonist, β-blocker, ACE [angiotensin-converting enzyme] inhibitor/angiotensin receptor blocker/angiotensin receptor neprilysin inhibitor). We compared baseline and 1-year change distributions and the coefficient of variation (SD/mean) across scores. Among 4532 patients at baseline, mean KCMO, HF collaboratory, and modified HF Collaboratory scores were 38.8 (SD, 25.7), 3.4 (1.7), and 42.2 (22.2), respectively. The mean 1-year change (n=4061) for KCMO was -1.94 (17.8); HF collaborator, -0.11 (1.32); and modified HF Collaboratory, -1.35 (19.8). KCMO had the highest coefficient of variation (0.66), indicating greater variability around the mean than the HF collaboratory (0.49) and modified HF Collaboratory (0.53) scores, reflecting higher resolution of the variability in GDMT intensity across patients. KCMO measures GDMT intensity by incorporating dosing and treatment eligibility, provides more granularity than existing methods, is easily interpretable (percentage of ideal GDMT), and can be adapted as performance measures evolve. Further study of its association with outcomes and its usefulness for quality assessment and improvement is needed.

Association between visit frequency, continuity of care, and pharmacy fill adherence in heart failure patients

Despite advances in medical therapy for heart failure with reduced ejection fraction (HFrEF), major gaps in medication adherence to guideline-directed medical therapies (GDMT) remain. Greater continuity of care may impact medication adherence and reduced hospitalizations. We conducted a cross-sectional study of adults with a diagnosis of HF and EF ≤40% with ≥2 outpatient encounters between January 1, 2017 and January 10, 2021, prescribed ≥1 of the following GDMT: 1) Beta Blocker, 2) Angiotensin Converting Enzyme Inhibitor/Angiotensin Receptor Blocker/Angiotensin Receptor Neprilysin Inhibitor, 3) Mineralocorticoid Receptor Antagonist, 4) Sodium Glucose Cotransporter-2 Inhibitor. Continuity of care was calculated using the Bice-Boxerman Continuity of Care Index (COC) and the Usual Provider of Care (UPC) index, categorized by quantile. The primary outcome was adherence to GDMT, defined as average proportion of days covered ≥80% over 1 year. Secondary outcomes included all-cause and HF hospitalization at 1-year. We performed multivariable logistic regression analyses adjusted for demographics, insurance status, comorbidity index, number of visits and neighborhood SES index. Overall, 3,971 individuals were included (mean age 72 years (SD 14), 71% male, 66% White race). In adjusted analyses, compared to individuals in the highest COC quartile, individuals in the third COC quartile had higher odds of GDMT adherence (OR 1.26, 95% CI 1.03-1.53, P = .024). UPC tertile was not associated with adherence (all P > .05). Compared to the highest quantiles, the lowest UPC and COC quantiles had higher odds of all-cause (UPC: OR 1.53, 95%CI 1.23-1.91; COC: OR 2.54, 95%CI 1.94-3.34) and HF (UPC: OR 1.81, 95%CI 1.23-2.67; COC: OR 1.77, 95%CI 1.09-2.95) hospitalizations. Continuity of care was not associated with GDMT adherence among patients with HFrEF but lower continuity of care was associated with increased all-cause and HF-hospitalizations.

Characterisation of the octogenarians presenting to the diagnostic heart failure clinic: SHEAF registry

IntroductionHeart failure (HF) incidence is increasing in older adults with high hospitalisation and mortality rates. Treatment is complicated by side effects and comorbidities. We investigated the clinical characteristics of octogenarians...

Development and validation of a prognostic model for predicting post-discharge mortality risk in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI)

BackgroundAccurately predicting post-discharge mortality risk in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) remains a complex and critical challenge. The primary objective of this study was to develop and validate a robust risk prediction model to assess the 12-month and 24-month mortality risk in STEMI patients after hospital discharge.MethodsA retrospective study was conducted on 664 STEMI patients who underwent PPCI at Xiangtan Central Hospital Chest Pain Center between 2020 and 2022. The dataset was randomly divided into a training cohort (n = 464) and a validation cohort (n = 200) using a 7:3 ratio. The primary outcome was all-cause mortality following hospital discharge. The least absolute shrinkage and selection operator (LASSO) regression model was employed to identify the optimal predictive variables. Based on these variables, a regression model was constructed to determine the significant predictors of mortality. The performance of the model was evaluated using receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA).ResultsThe prognostic model was developed based on the LASSO regression results and further validated using the independent validation cohort. LASSO regression identified five important predictors: age, Killip classification, B-type natriuretic peptide precursor (NTpro-BNP), left ventricular ejection fraction (LVEF), and the usage of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors (ACEI/ARB/ARNI). The Harrell's concordance index (C-index) for the training and validation cohorts were 0.863 (95% CI: 0.792–0.934) and 0.888 (95% CI: 0.821–0.955), respectively. The area under the curve (AUC) for the training cohort at 12 months and 24 months was 0.785 (95% CI: 0.771–0.948) and 0.812 (95% CI: 0.772–0.940), respectively, while the corresponding values for the validation cohort were 0.864 (95% CI: 0.604–0.965) and 0.845 (95% CI: 0.705–0.951). These results confirm the stability and predictive accuracy of our model, demonstrating its reliable discriminative ability for post-discharge all-cause mortality risk. DCA analysis exhibited favorable net benefit of the nomogram.ConclusionThe developed nomogram shows potential as a tool for predicting post-discharge mortality in STEMI patients undergoing PPCI. However, its full utility awaits confirmation through broader external and temporal validation.

Prognostic Models for Mortality and Morbidity in Heart Failure With Preserved Ejection Fraction

Accurate risk prediction of morbidity and mortality in patients with heart failure with preserved ejection fraction (HFpEF) may help clinicians risk stratify and inform care decisions. To develop and validate a novel prediction model for clinical outcomes in patients with HFpEF using routinely collected variables and to compare it with a biomarker-driven approach. Data were used from the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial to derive the prediction model, and data from the Angiotensin Receptor Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction (PARAGON-HF) and the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-PRESERVE) trials were used to validate it. The outcomes were the composite of HF hospitalization (HFH) or cardiovascular death, cardiovascular death, and all-cause death. A total of 30 baseline candidate variables were selected in a stepwise fashion using multivariable analyses to create the models. Data were analyzed from January 2023 to June 2023. Models to estimate the 1-year and 2-year risk of cardiovascular death or hospitalization for heart failure, cardiovascular death, and all-cause death. Data from 6263 individuals in the DELIVER trial were used to derive the prediction model and data from 4796 individuals in the PARAGON-HF trial and 4128 individuals in the I-PRESERVE trial were used to validate it. The final prediction model for the composite outcome included 11 variables: N-terminal pro-brain natriuretic peptide (NT-proBNP) level, HFH within the past 6 months, creatinine level, diabetes, geographic region, HF duration, treatment with a sodium-glucose cotransporter 2 inhibitor, chronic obstructive pulmonary disease, transient ischemic attack/stroke, any previous HFH, and heart rate. This model showed good discrimination (C statistic at 1 year, 0.73; 95% CI, 0.71-0.75) in both validation cohorts (C statistic at 1 year, 0.71; 95% CI, 0.69-0.74 in PARAGON-HF and 0.75; 95% CI, 0.73-0.78 in I-PRESERVE) and calibration. The model showed similar discrimination to a biomarker-driven model including high-sensitivity cardiac troponin T and significantly better discrimination than the Meta-Analysis Global Group in Chronic (MAGGIC) risk score (C statistic at 1 year, 0.60; 95% CI, 0.58-0.63; delta C statistic, 0.13; 95% CI, 0.10-0.15; P < .001) and NT-proBNP level alone (C statistic at 1 year, 0.66; 95% CI, 0.64-0.68; delta C statistic, 0.07; 95% CI, 0.05-0.08; P < .001). Models derived for the prediction of all-cause and cardiovascular death also performed well. An online calculator was created to allow calculation of an individual's risk. In this prognostic study, a robust prediction model for clinical outcomes in HFpEF was developed and validated using routinely collected variables. The model performed better than NT-proBNP level alone. The model may help clinicians to identify high-risk patients and guide treatment decisions in HFpEF.

Management of hypertension in heart transplant recipients: an ongoing conundrum.

Hypertension remains one of the most common clinical problems leading to significant posttransplant complications. This study reviews the pathophysiology of hypertension in the postcardiac transplant phase and provides an update on currently available antihypertensive therapies for heart transplant patients. The true prevalence of hypertension in the heart transplant population remains unknown. Effective blood pressure (BP) control is key to prevent left ventricular remodeling, diastolic dysfunction and stroke. Calcium channel blockers (CCBs) are the most commonly and preferred agents in the early posttransplant phase and may have renal protective effects. Angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) can all be used as second line antihypertensive agents and may have a role in preventing other long-term complications such as calcineurin-inhibitor induced nephropathy. Although more data are needed, sodium-glucose co-transporter 2 inhibitors (SGLT2i) appeared to be well tolerated and could be considered especially in the presence of type diabetes and chronic kidney disease. Conversely, angiotensin receptor-neprilysin inhibition (ARNI) have not been studied in the heart transplant population therefore cannot be recommended at this time. Hypertension is very common after heart transplant. Early steroid wean and traditional risk factor modification play an important part in the management of post-heart transplant hypertension. CCB, ACEI, ARB are the preferred antihypertensive agents to improve postcardiac transplant complications. Novel therapies such as SGLT2i appear well tolerated and may have benefits in both BP and glycemic control in heart transplant; however, larger trials are needed.

Physician perceptions, attitudes, and strategies towards implementing guideline-directed medical therapy in heart failure with reduced ejection fraction. A survey of the Heart Failure Association of the ESC and the ESC Council for Cardiology Practice.

Recent guidelines recommend four core drug classes (renin-angiotensin system inhibitor/angiotensin receptor-neprilysin inhibitor [RASi/ARNi], beta-blocker, mineralocorticoid receptor antagonist [MRA], and sodium-glucose cotransporter 2 inhibitor [SGLT2i]) for the pharmacological management of heart failure (HF) with reduced ejection fraction (HFrEF). We assessed physicians' perceived (i) comfort with implementing the recent HFrEF guideline recommendations; (ii) status of guideline-directed medical therapy (GDMT) implementation; (iii) use of different GDMT sequencing strategies; and (iv) barriers and strategies for achieving implementation. A 26-question survey was disseminated via bulletin, e-mail and social channels directed to physicians with an interest in HF. Of 432 respondents representing 91 countries, 36% were female, 52% were aged <50 years, and 90% mainly practiced in cardiology (30% HF). Overall comfort with implementing quadruple therapy was high (87%). Only 12% estimated that >90% of patients with HFrEF without contraindications received quadruple therapy. The time required to initiate quadruple therapy was estimated at 1-2 weeks by 34% of respondents, 1 month by 36%, 3 months by 24%, and ≥6 months by 6%. The average respondent favoured traditional drug sequencing strategies (RASi/ARNi with/followed by beta-blocker, and then MRA with/followed by SGLT2i) over simultaneous initiation or SGLT2i-first sequences. The most frequently perceived clinical barriers to implementation were hypotension (70%), creatinine increase (47%), hyperkalaemia (45%) and patient adherence (42%). Although comfort with implementing all four core drug classes in patients with HFrEF was high among physicians, a majority estimated implementation of GDMT in HFrEF to be low. We identified several important perceived clinical and non-clinical barriers that can be targeted to improve implementation.

Effect of heart failure pharmacotherapies in patients with heart failure with mildly reduced ejection fraction.

The study sought to comprehensively investigate the effect of heart failure (HF) pharmacotherapies in patients with HF with mildly reduced ejection fraction (HFmrEF). In the absence of randomized controlled trials, guideline recommendations concerning HF-related therapies in patients with HFmrEF are limited. Consecutive patients hospitalized with HFmrEF were retrospectively included at one institution from 2016 to 2022. The prognostic value of treatment with beta-blockers (BB), angiotensin-converting enzyme inhibitors, receptor blockers, or receptor-neprilysin inhibitor (ACEi/ARB/ARNI), mineralocorticoid receptor antagonists (MRA), and sodium-glucose-linked transport protein 2 inhibitors (SGLT2i) was investigated for all-cause mortality at 30 months (a median follow-up) and HF-related rehospitalization. A total of 2109 patients with HFmrEF were included. Treatment with BB [27.0 vs. 35.0%; hazard ratio (HR) = 0.737; 95% confidence interval (CI) 0.617-0.881; P = 0.001], ACEi/ARB/ARNI (25.9 vs. 37.6%; HR = 0.612; 95% CI 0.517-0.725; P = 0.001), and SGLT2i (11.9 vs. 29.5%; HR = 0.441; 95% CI 0.236-0.824; P = 0.010) was associated with a lower risk of 30-month all-cause mortality, which was still demonstrated after multivariable adjustment and propensity score matching. In contrast, MRA treatment was not associated with long-term prognosis. The risk of HF-related rehospitalization was not affected by HF pharmacotherapies. Finally, the lowest risk of long-term all-cause mortality was observed in patients with combined use of BB, ACEi/ARB/ARNI, and SGLT2i (HR = 0.456; 95% CI 0.227-0.916; P = 0.027). Beta-blockers, ACEi/ARB/ARNI, and SGLT2i were independently associated with a lower risk of all-cause mortality in patients with HFmrEF, specifically when applied as combined 'HF triple therapy'. Randomized studies are needed to investigate the effect of HF-related pharmacotherapies in patients with HFmrEF.

Guideline-directed medical therapy assessment in heart failure patients undergoing percutaneous mitral valve repair.

Achieving optimized guideline-directed medical therapy (GDMT) is recommended prior to transcatheter mitral valve edge-to-edge repair (M-TEER) for secondary mitral regurgitation (SMR). We aimed to propose and validate an easy-to-use score for assessing the quality of GDMT in patients with heart failure with reduced ejection fraction (HFrEF) undergoing M-TEER. Among the 1641 EuroSMR patients enrolled in the EuroSMR Registry who underwent M-TEER, a total of 1072 patients [median age 74, interquartile range (IQR) 67-79years, 29% female] had complete data on GDMT and a left ventricular ejection fraction≤40% and were included in the current study. We proposed a GDMT score that considers the dosage levels of three medication classes (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors, beta-blockers, and mineralocorticoid receptor antagonists), with a maximum score of 12 points indicating optimal GDMT. The primary outcome was all-cause mortality. The median GDMT score was 4 points (IQR 3-6). All three domains of the scoring system were associated with all-cause mortality (P<0.05 for all). The overall GDMT score was associated with all-cause mortality (hazard ratio 0.90, 95% confidence interval 0.86-0.95 for each 1-point increase in the GDMT score). This association remained significant after adjusting for renal function and co-morbidities. This study demonstrates the utility of a simple GDMT scoring system for assessing the adequacy of GDMT in HFrEF patients with relevant SMR undergoing M-TEER. The GDMT score has potential applications in guiding the design of future clinical trials and aiding clinical decision-making processes.

Web-Based Dynamic Nomogram for Predicting Risk of Mortality in Heart Failure with Mildly Reduced Ejection Fraction.

This study aimed to develop an integrative dynamic nomogram, including N-terminal pro-B type natural peptide (NT-proBNP) and estimated glomerular filtration rate (eGFR), for predicting the risk of all-cause mortality in HFmrEF patients. 790 HFmrEF patients were prospectively enrolled in the development cohort for the model. The least absolute shrinkage and selection operator (LASSO) regression and Random Survival Forest (RSF) were employed to select predictors for all-cause mortality. Develop a nomogram based on the Cox proportional hazard model for predicting long-term mortality (1-, 3-, and 5-year) in HFmrEF. Internal validation was conducted using Bootstrap, and the final model was validated in an external cohort of 338 consecutive adult patients. Discrimination and predictive performance were evaluated by calculating the time-dependent concordance index (C-index), area under the ROC curve (AUC), and calibration curve, with clinical value assessed via decision curve analysis (DCA). Integrated discrimination improvement (IDI) and net reclassification improvement (NRI) were used to assess the contributions of NT-proBNP and eGFR to the nomogram. Finally, develop a dynamic nomogram using the "Dynnom" package. The optimal independent predictors for all-cause mortality (APSELNH: A: angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitor (ACEI/ARB/ARNI), P: percutaneous coronary intervention/coronary artery bypass graft (PCI/CABG), S: stroke, E: eGFR, L: lg of NT-proBNP, N: NYHA, H: healthcare) were incorporated into the dynamic nomogram. The C-index in the development cohort and validation cohort were 0.858 and 0.826, respectively, with AUCs exceeding 0.8, indicating good discrimination and predictive ability. DCA curves and calibration curves demonstrated clinical applicability and good consistency of the nomogram. NT-proBNP and eGFR provided significant net benefits to the nomogram. In this study, the dynamic APSELNH nomogram developed serves as an accessible, functional, and effective clinical decision support calculator, offering accurate prognostic assessment for patients with HFmrEF.

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.