Angiotensin Receptor-neprilysin Inhibitor Therapy Research Articles

Cost-Effectiveness of Medical Therapy for HeartFailure With Mildly Reduced and Preserved Ejection Fraction.

Three medications are now guideline-recommended treatments for heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), however, the cost-effectiveness of these agents in combination has yet to be established. The purpose of this study was to determine the cost-effectiveness of mineralocorticoid receptor antagonists (MRA), angiotensin receptor-neprilysin inhibitors (ARNIs), and sodium glucose co-transporter 2 inhibitors (SGLT2is) in individuals with HFmrEF/HFpEF. Using a 3-state Markov model, we performed a cost-effectiveness study using simulated cohorts of 1,000 patients with HFmrEF and HFpEF. Treatment with 1-, 2-, and 3-drug combinations was modeled. Based on a United States health care sector perspective, outcome data was used to calculate incremental cost-effectiveness ratios (ICERs) in 2023 United States dollars based on a 30-year time horizon. Treatment with MRA, MRA+SGLT2i, and MRA+SGLT2i+ARNI therapy resulted in an increase in life years of 1.04, 1.58, and 1.80 in the HFmrEF subgroup, respectively, and 0.99, 1.54, and 1.77 in the HFpEF subgroup, respectively, compared with placebo. At a yearly cost of $18, MRA therapy resulted in ICERs of $10,000 per quality-adjusted life year (QALY) in both subgroups. The ICER for the addition of SGLT2i therapy ($4,962 per year) was $113,000 per QALY in the HFmrEF subgroup and $141,000 in the HFpEF subgroup. The addition of ARNI therapy ($5,504 per year) resulted in ICERs >$250,000 per QALY in both subgroups. If SGLT2i and ARNI were available at generic pricing the ICERs become <$10,000 per QALY in both EF subgroups. Outcomes were highly sensitive to assumed benefit in cardiovascular death. For patients with heart failure, MRA was of high value, SGLT2i was of intermediate value, and ARNI was of low value in both HFmrEF and HFpEF subgroups. For patients with HFmrEF/HFpEF increased use of MRA and SGLT2i therapies should be encouraged and be accompanied with efforts to lower the cost of SGLT2i and ARNI therapies.

Impact of Insurance Status and Region on Angiotensin Receptor–Neprilysin Inhibitor Prescription During Heart Failure Hospitalizations

BackgroundAn angiotensin receptor–neprilysin inhibitor (ARNI) is the preferred renin-angiotensin system (RAS) inhibitor for heart failure with reduced ejection fraction (HFrEF). Among eligible patients, insurance status and prescriber concern regarding out-of-pocket costs may constrain early initiation of ARNI and other new therapies. ObjectivesIn this study, the authors sought to evaluate the association of insurance and other social determinants of health with ARNI initiation at discharge from HFrEF hospitalization. MethodsThe authors analyzed ARNI initiation from January 2017 to June 2020 among patients with HFrEF eligible to receive RAS inhibitor at discharge from hospitals in the Get With The Guidelines–Heart Failure registry. The primary outcome was the proportion of ARNI prescription at discharge among those prescribed RAS inhibitor who were not on ARNI on admission. A logistic regression model was used to determine the association of insurance status, U.S. region, and their interaction, as well as self-reported race, with ARNI initiation at discharge. ResultsFrom 42,766 admissions, 24,904 were excluded for absolute or relative contraindications to RAS inhibitors. RAS inhibitors were prescribed for 16,817 (94.2%) of remaining discharges, for which ARNI was prescribed in 1,640 (9.8%). Self-reported Black patients were less likely to be initiated on ARNI compared to self-reported White patients (OR: 0.64; 95% CI: 0.50-0.81). Compared to Medicare beneficiaries, patients with third-party insurance, Medicaid, or no insurance were less likely to be initiated on ARNI (OR: 0.47 [95% CI: 0.31-0.72], OR: 0.41 [95% CI: 0.25-0.67], and OR: 0.20 [95% CI: 0.08-0.47], respectively). ARNI therapy varied by hospital region, with lowest utilization in the Mountain region. An interaction was demonstrated between the impact of insurance disparities and hospital region. ConclusionsAmong patients hospitalized between 2017 and 2020 for HFrEF who were prescribed RAS inhibitor therapy at discharge, insurance status, geographic region, and self-reported race were associated with ARNI initiation.

Effect of sacubutril/valsartan on Tp-e, QT, QTc, Tp-e/QTc parameters in heart failure with reduced ejection fraction

Purpose: The purpose of this study is to evaluate ventricular repolarization before, at the first month, and sixth month after Sacubutril/Valsartan, an angiotensin receptor neprilysin inhibitor (ARNI) treatment in heart failure patients with reduced ejection fraction (HFrEF).&#x0D; Materials and Methods: We included 49 patients with HFrEF who switched to ARNI therapy. The 12-lead electrocardiography (ECG) was evaluated before ARNI therapy and also during the first and sixth months of the therapy. We evaluated demographic, clinical, and laboratory parameters, as well as medications and ECG data, including heart rate. Additionally, we examined QT, QTc, Tp-e, Tp-e calculated (Tp-ec), Tp-ec/QTc, Tp-e/QT, and Tp-e/QTc.&#x0D; Results: After receiving ARNI treatment, ventricular repolarization indices were significantly reduced in the first and sixth months compared to before treatment. Specifically, the QTc values decreased from 457.6 ms to 443.8 ms, and the Tp-e/QT ratio decreased from 0.21±0.03 to 0.19±0.03. Additionally, the QTc values decreased from 457.6 ms to 444.9 ms, and the Tp-e/QT ratio decreased from 0.21±0.03 to 0.18±0.03. However, when the first and sixth months under ARNI treatment were compared, no significant difference was found (QTc: 443.8 ms vs. 444.9 ms, Tp-e/QT: 0.19±0.03 vs. 0.18±0.003).&#x0D; Conclusion: ARNI treatment in HFrEF positively affected QTc, Tp-e, and Tp-ec intervals and Tp-e/QT, Tp-e/QTc, and Tp-ec/QTc ratios, which are indicators of ventricular repolarization. Moreover, this effect started in the first month and continued in the sixth month.

Effect of angiotensin receptor neprilysin inhibitor on physical activity in patients with heart failure with reduced ejection fraction, monitored by implantable electronic device home monitoring.

Angiotensin receptor neprilysin inhibitor (ARNI) therapy is a cornerstone in the treatment of heart failure with reduced ejection fraction (HFrEF), with significant improvement in mortality as well as morbidity and quality of life. However, maximal ARNI doses often result in hypotension. Recent studies with 'real world' experience suggest that lower doses of ARNI are as effective as higher doses.In order to evaluate the symptomatic effect of low-dose ARNI in HFrEF patients, we analyzed physical activity data obtained via home monitoring of patients with cardiac implantable electronic devices (CIEDs). We retrospectively analyzed physical activity data obtained from HFrEF patients with CIED-active home monitoring during the years 2021-2022. Patients with ARNI therapy were further divided into subgroups according to the administered dose. Low-dose ARNI included doses of up to 24/26 mg sacubitril/valsartan daily. Intermediate dose and high dose included doses of 72/78-120/130 mg/day, and 144/156-194/206 mg/day, respectively. A total of 122 patients had home monitoring-compatible CIEDs and HFrEF during the study period. Sixty-four of these patients were treated with ARNI. Administration of low-dose ARNI resulted in a 20% increase in daily activity when compared with patients without ARNI treatment ( P = 0.038). Change in physical activity of patients in the intermediate-dose and high-dose groups was not significant. Younger patients, patients with cardiac resynchronization therapy, and patients without diabetes mellitus were more physically active. Low-dose ARNI had a beneficial effect on physical activity in HFrEF patients. MH via CIED provided real-life objective data for patients' follow-up.

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.

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.

Effects of Angiotensin Receptor-Neprilysin Inhibitors (ARNIs) on the Glucose and Fat Metabolism Biomarkers Leptin and Fructosamine.

(1) Background: Heart failure with reduced ejection fraction (HFrEF) remains a major health burden. Angiotensin-Receptor-Neprilysin-Inhibitors (ARNIs) are an established HFrEF therapy which increases natriuretic peptide levels by inhibiting neprilysin. Leptin is a lipid metabolism parameter, which is also involved in glucose metabolism and is suggested to correlate with HF burden. While the hormone also seems to interact with neprilysin, potential associations with ARNI therapy have not been investigated yet. (2) Methods: To study this issue, we measured levels of leptin and fructosamine in consecutive 72 HFrEF patients before initiation of ARNI therapy and 3-6 months after initiation of therapy in two European centers. Biomarker levels were correlated with clinical parameters including ejection fraction, LVEF, and NYHA class. (3) Results: During a follow-up of up to 6 months, clinical parameters improved significantly (LVEF: 30.2 ± 7.8% to 37.6 ± 10.0%, (p < 0.001) and a significant improvement of the mean NYHA class with initial 32 patients in NYHA III or IV and 8 patients in NYHA class III/IV during the follow up (p < 0.001). The initial NT-proBNP levels of 2251.5 ± 2566.8 pg/mL significantly improved to 1416.7 ± 2145 pg/mL, p = 0.008) during follow up. ARNI therapy was also associated with an increase in leptin levels (17.5 ± 23.4 µg/L to 22.9 ± 29.3, p < 0.001) and furthermore, affected glucose metabolism indicated by elevation of fructosamine values (333.9 ± 156.8 µmol/L to 454.8 ± 197.8 µmol/L, p = 0.013). (4) Conclusion: while in the early phase of therapy, ARNI promotes clinical improvement of HFrEF, and it also seems to affect fat and glucose parameters, indicating significant metabolic implications of this therapy regime.

Updates for Cardio‐Kidney Protective Effects by Angiotensin Receptor‐Neprilysin Inhibitor: Requirement for Additional Evidence of Kidney Protection

The incidence of heart failure and chronic kidney disease is increasing, and many patients develop both diseases. Angiotensin receptor-neprilysin inhibitor (ARNI) is a promising therapeutic candidate for both diseases. ARNI has demonstrated superior cardioprotective effects compared with renin-angiotensin system inhibitors (RAS-Is) in large clinical trials such as the PARADIGM-HF (Prospective Comparison of ARNI With ACEI [Angiotensin-Converting Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. It has also been suggested that ARNI can provide renoprotective effects beyond those of RAS-Is in patients with HF. ARNI might have beneficial effects on the kidneys because of its ability to improve cardiac function in patients with heart failure and affect renal hemodynamics by enhancing the effects of hormones such as natriuretic peptide. In contrast, in the PARADIGM-HF trial, ARNI was associated with more albuminuria compared with RAS-I; thus, it is unclear whether long-term ARNI therapy has renoprotective effects. Additionally, ARNI did not provide renoprotective effects beyond RAS-I in patients with chronic kidney disease in the UK HARP-III (United Kingdom Heart and Renal Protection-III) trial. In other words, the patient population in which ARNI is more renoprotective than RAS-I might be limited. Collectively, ARNI may have renoprotective effects in addition to cardioprotective effects, but the evidence to date is applicable only to heart failure. Theoretically, given the molecular mechanism of ARNI, it could also be renoprotective in conditions such as nephrosclerosis, which has low risks of albuminuria and reduced kidney perfusion, but the evidence for such effects is lacking. Further research is needed to clarify whether ARNI therapy is an acceptable treatment strategy for renal protection.

Angiotensin receptor-neprilysin inhibitor delays progression from paroxysmal to persistent atrial fibrillation

Progression from paroxysmal to persistent atrial fibrillation (AF) is linked to adverse clinical outcomes. The present study sought to clarify whether angiotensin receptor-neprilysin inhibitor (ARNI) can delay AF progression. A retrospective cohort study was conducted on consecutive patients with paroxysmal AF admitted at the Second Affiliated Hospital of Nanchang University between January 2017 and January 2022. The risk of AF progression from paroxysmal to persistent was compared between paroxysmal patients treated with ARNI and those who received an angiotensin receptor blocker (ARB). Seven-day Holter monitoring was performed to identify persistent AF. Propensity-score matched analysis was performed to compare the two groups. Cox-regression was used to estimate the hazard ratio (HR) for AF progression events. A total of 1083 patients were screened, and 113 patients in the ARB group and 57 patients in the ARNI group were eligible for analysis. Before propensity-score matching, the ARNI therapy was associated with a lower risk of AF progression than the ARB therapy (HR 0.34; 95% confidence interval [CI] 0.14–0.81; P = 0.015) after a median follow-up of 705 (interquartile range [IQR] 512 to 895) days. Among 170 patients, 47 ARNI-treated patients were successfully matched to 47 ARB-treated patients. After a median follow-up of 724 (541–929) days, compared to ARB, ARNI significantly reduced the risk of AF progression (HR 0.32; 95% CI 0.12–0.88; P = 0.016). ARNI may be superior to ARB in reducing the risk of progression from paroxysmal to persistent AF.

Dapagliflozin in patients with heart failure with mildly reduced and preserved ejection fraction treated with a mineralocorticoid receptor antagonist or sacubitril/valsartan.

The effects of adding a sodium-glucose cotransporter 2 (SGLT2) inhibitor to a mineralocorticoid receptor antagonist (MRA) or an angiotensin receptor-neprilysin inhibitor (ARNI) in patients with heart failure (HF) and mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) are uncertain, even though the use of all three drugs is recommended in recent guidelines. The efficacy and safety of dapagliflozin added to background MRA or ARNI therapy was examined in patients with HFmrEF/HFpEF enrolled in the DELIVER trial. The primary outcome was the composite of worsening HF or cardiovascular death. Of 6263 patients, 2667 (42.6%) were treated with an MRA and 301 (4.8%) with an ARNI at baseline. Patients taking either were younger, more often men and had lower systolic blood pressure and ejection fraction; they were also more likely to have prior HF hospitalization. The benefit of dapagliflozin was similar whether patients were receiving these therapies. The hazard ratio for the effect of dapagliflozin compared to placebo on the primary outcome was 0.86 (95% confidence interval [CI] 0.74-1.01) for MRA non-users versus 0.76 (95% CI 0.64-0.91) for MRA users (pinteraction =0.30). The corresponding values for ARNI non-users and users were 0.82 (95% CI 0.73-0.92) and 0.74 (95% CI 0.45-1.22), respectively (pinteraction =0.75). None of the adverse events examined was more common with dapagliflozin compared to placebo overall or in the MRA and ARNI subgroups. The efficacy and safety of dapagliflozin were similar, regardless of background treatment with an MRA or ARNI. SGLT2 inhibitors may be added to other treatments recommended in recent guidelines for HFmrEF/HFpEF.

Effects of angiotensin receptor-neprilysin inhibitors (ARNIs) on the glucose and fat metabolism biomarkers leptin and fructosamin

Abstract Background Heart Failure with reduced ejection fraction (HFrEF) has a life time risk about 20% among adults aged 40 years or older and a 5-year mortality rate about 60% [1,2]. However novel therapies have shown to improve this outcome. One novel agent are angiotensin receptor-neprilysin inhibitors (ARNIs) that increase the BNP levels via inhibiting neprilsyin [3]. This has beneficial effects on heart failure by reducing preload, inflammation and fibrosis. Neprilysin also interacts with leptin and is known to correlate with the incidence and progression of heart failure if chronically elevated [4]. Furthermore beneficial affects of ARNI therapy on glucose metabolism were reported in a post-hoc analysis of the PARADIGM-HF trial [5]. In this study we aim to investigate the effect of ARNI therapy on the fat metabolism markers leptin and on the glucose metabolism marker fructosamin. Methods In total, we included 74 patients with HFrEF with ischemic (N=37) and non-ischemic (n=37) origin in the present study. The mean NYHA class was II–III, the mean BMI 28 (SD 6.3). Patients had well established heart failure therapy before starting ARNI therapy with sacubitril/valsartan. 88% of patients were on ACE-inhibitors, 86% on beta blockers and 68% on mineralocorticoid receptor antagonists. Serum samples were obtained and analyzed for leptin, fructosamin and pBNP before and 3–6 month after ARNI therapy. The clinical parameters LVEF and NYHA class were assessed before and 3–6 month after ARNI therapy. Results Baseline leptin level was 15.0 (SD 17.2), baseline fructosamin level was 370.1 (SD 167.7) and baseline pBNP level was 1494.9 (SD 1281.4). Under therapy a significant improvement of ejection fraction from 29,8% to 37,5% (7,7 SD 8,5 P≤0.001), an improvement of NYHA stadium from 2.46 (SD 0.62) to 1.96 (SD 0.63, p=0.005) and a significant decrease of pBNP (562.1 SD 1256.4, p=0.018) was found. Along with that, a significant increase in leptin levels (3.6 SD 8.85, p=0.012) and a significant increase in fructosamine levels (93.5 SD 160.6, p=0.013) was shown. Conclusion Under therapy with ARNI we showed a sufficient therapy response with improvement of ejection fraction and decrease of pBNP in line with literature. Surprisingly metabolism biomarkers did significantly worsen under the first three to six month after new ARNI therapy. To distinguish between a side effect of ARNI therapy or consequence of heart failure itself further investigations are needed. Funding Acknowledgement Type of funding sources: None.

The effectiveness of ARNI medication in patients, non-responder to cardiac resynchronization therapy

Abstract Introduction Almost 30% of patients are non-responders to cardiac resynchronization therapy (CRT) with no improvement of heart failure (HF) symptoms and left ventricular ejection fraction (LVEF). Angiotensin Receptor Neprilysin Inhibitor (ARNI), a novel class of medication resulted in a significant improvement in HF with reduced ejection fraction (HFrEF) in recent trials. No data has been reported on the clinical effectiveness of ARNI in the specific HF patient cohort of CRT non-responders (CRT-NR). Objective Herein, we compared the efficacy of ARNI medication in a general HF patient population and in CRT-NR patients. Method CRT-NR patients on ARNI therapy initiated at least 6 months after CRT implantation in years 2019–2021 were enrolled. Criterium for CRT-NR was a no, or less than 10% improvement in LVEF measured with echocardiography 6 months post-implantation. HF patients on ARNI therapy from our HF Clinic were used as controls. Changes in LVEF, in NYHA functional class and in the level of NT-proBNP were compared before ARNI therapy initiation and 6 months thereafter in both groups. Results 70 patients (age: 66,03±9.06 years, 9 women) were enrolled in the CRT-NR and 135 patients (age 62,36±11.26 years; 31 women) in the control group. LVEF increased from 25,25±5.70% to 29,47±6.73% (p&amp;lt;0.001), NYHA class decreased from 2,74±0.55 to 2.03±0.68 (p&amp;lt;0.001) and NT-proBNP from 3884.21±2503.95 to 2676,16±1745.94 (p&amp;lt;0.001) in CRT-NR patients after a 6-month treatment with ARNI. Similar improvement was demonstrated in all parameters in the control group: LVEF increased from 26,64±6.47% to 29,91±6.64% (p&amp;lt;0,001), NYHA class decreased from 2,97±0.54 to 2,18±0.58% (p&amp;lt;0,001) and NT-proBNP from 5355,17±1731.71 to 2062,66±1919.07 (p&amp;lt;0,001). During a mean follow-up of 20,55±11,36 months mortality rates were 17,14% in the CRT-NR group, and 18,51% in the control group. Conclusion ARNI therapy resulted in significant improvement in functional class, LVEF and HF biomarker level in CRT-NR patients, similarly to what was observed in a general HF patient cohort with no CRT. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Project no. TKP2021-EGA-18 has been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the TKP2021-EGA funding scheme.

The Impact of Angiotensin Receptor-Neprilysin Inhibitors on Arrhythmias in Patients with Heart Failure: A Systematic Review and Meta-analysis.

Angiotensin receptor–neprilysin inhibitor (ARNI) use has become increasingly popular. Current guidelines recommend using ARNI therapy for heart failure with reduced (HFrEF) and preserved ejection fraction (HFpEF). As therapies become more widely available, heart failure-associated burdens such as ventricular arrhythmias and sudden cardiac death (SCD) will become increasingly prevalent. We conducted a systematic review and meta-analysis to assess the impact of ARNI therapy on HFrEF and HFpEF pertaining to arrhythmogenesis and SCD. We performed a search of MEDLINE (PubMed), the Cochrane Library, and ClinicalTrials.gov for relevant studies. The odds ratios (ORs) of SCD, ventricular tachycardia (VT), ventricular fibrillation (VF), atrial fibrillation/flutter (AF), supraventricular tachycardia (SVT), and implantable cardioverter-defibrillator (ICD) shocks were calculated. A total of 10 studies, including 6 randomized controlled trials and 4 observational studies, were included in the analysis. A total of 18,548 patients from all studies were included, with 9,328 patients in the ARNI arm and 9,220 patients in the angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB) arm, with a median follow-up time of 15 months. There was a significant reduction in the composite outcomes of SCD and ventricular arrhythmias in patients treated with ARNIs compared to those treated with ACEIs/ARBs (OR, 0.71; 95% confidence interval, 0.54–0.93; P = .01; I2 = 17%; P = .29). ARNI therapy was also associated with a significant reduction in ICD shocks. There was no significant reduction in the VT, VF, AF, or SVT incidence rate in the ARNI group compared to the ACEI/ARB group. In conclusion, the use of ARNIs confers a reduction in composite outcomes of SCD and ventricular arrhythmias among patients with heart failure. These outcomes were mainly driven by SCD reduction in patients treated with ARNIs.

Angiotensin receptor-neprilysin inhibitor therapy and recurrence of atrial fibrillation after radiofrequency catheter ablation: A propensity-matched cohort study.

BackgroundCompared with conventional medicines, angiotensin receptor-neprilysin inhibitor (ARNI) could further improve the prognosis for multiple cardiovascular diseases, such as heart failure, hypertension, and myocardial infarction. However, the relationship between ARNI therapy and the recurrence of atrial fibrillation (AF) after radiofrequency catheter ablation is currently unknown.MethodsThis study is a retrospective cohort study. Patients with consecutive persistent or paroxysmal AF undergoing first-time radiofrequency ablation were enrolled from February 2018 to October 2021. We compared the risk of AF recurrence in patients with catheter ablation who received ARNI with the risk of AF recurrence in those who received the angiotensin-converting enzyme inhibitor (ACEI). The propensity-score matched analysis was conducted to examine the effectiveness of ARNI. We used a Cox regression model to evaluate AF recurrence events.ResultsAmong 679 eligible patients, 155 patients with ARNI treatment and 155 patients with ACEI treatment were included in the analyses. At a median follow-up of 228 (196–322) days, ARNI as compared with ACEI was associated with a lower risk of AF recurrence [adjusted hazard ratio (HR), 0.39; 95% confidence interval (CI), 0.24–0.63; p < 0.001]. In addition, no interaction was found in the subgroup analysis.ConclusionAngiotensin receptor-neprilysin inhibitor treatment was associated with a decreased risk of AF recurrence after first-time radiofrequency catheter ablation.

Missed opportunities in medical therapy for patients with heart failure in an electronically-identified cohort

BackgroundNational registries reveal significant gaps in medical therapy for patients with heart failure and reduced ejection fraction (HFrEF), but may not accurately (or fully) characterize the population eligible for therapy.ObjectiveWe developed an automated, electronic health record-based algorithm to identify HFrEF patients eligible for evidence-based therapy, and extracted treatment data to assess gaps in therapy in a large, diverse health system.MethodsIn this cross-sectional study of all NYU Langone Health outpatients with EF ≤ 40% on echocardiogram and an outpatient visit from 3/1/2019 to 2/29/2020, we assessed prescription of the following therapies: beta-blocker (BB), angiotensin converting enzyme inhibitor (ACE-I)/angiotensin receptor blocker (ARB)/angiotensin receptor neprilysin inhibitor (ARNI), and mineralocorticoid receptor antagonist (MRA). Our algorithm accounted for contraindications such as medication allergy, bradycardia, hypotension, renal dysfunction, and hyperkalemia.ResultsWe electronically identified 2732 patients meeting inclusion criteria. Among those eligible for each medication class, 84.8% and 79.7% were appropriately prescribed BB and ACE-I/ARB/ARNI, respectively, while only 23.9% and 22.7% were appropriately prescribed MRA and ARNI, respectively. In adjusted models, younger age, cardiology visit and lower EF were associated with increased prescribing of medications. Private insurance and Medicaid were associated with increased prescribing of ARNI (OR = 1.40, 95% CI = 1.02–2.00; and OR = 1.70, 95% CI = 1.07–2.67).ConclusionsWe observed substantial shortfalls in prescribing of MRA and ARNI therapy to ambulatory HFrEF patients. Subspecialty care setting, and Medicaid insurance were associated with higher rates of ARNI prescribing. Further studies are warranted to prospectively evaluate provider- and policy-level interventions to improve prescribing of these evidence-based therapies.

Angiotensin Receptor Neprilysin Inhibition and Associated Outcomes by Race and Ethnicity in Patients With Heart Failure With Reduced Ejection Fraction: Data From CHAMP-HF.

BackgroundThere are limited data on the use of angiotensin receptor neprilysin inhibitors (ARNIs) in minority populations with heart failure (HF) with reduced ejection fraction. We used data from the CHAMP‐HF (Change the Management of Patients With Heart Failure) registry to evaluate ARNI initiation and associated changes in health status and clinical outcomes across different races and ethnicities.Methods and ResultsCHAMP‐HF was a prospective, observational registry of US outpatients with chronic HF with reduced ejection fraction. We compared patients starting ARNI with patients not starting ARNI using a propensity‐matched analysis. Patients were grouped as Hispanic, non‐Hispanic Black, non‐Hispanic White, or non‐Hispanic other individuals, where “non‐Hispanic other” consists of all patients who did not identify as Hispanic, Black, or White. Health status was assessed using the 12‐item Kansas City Cardiomyopathy Questionnaire. Outcomes were analyzed with multivariable models that included race and ethnicity, ARNI initiation, and an interaction term between race and ethnicity and ARNI initiation. Cox proportional hazards models were used for death/HF hospitalization, and multiple regression was used for change in Kansas City Cardiomyopathy Questionnaire score. The analysis included 1516 patients, with 758 patients in each group (ARNI and no ARNI). Changes in Kansas City Cardiomyopathy Questionnaire score after ARNI initiation were similar among all race and ethnicity groups (mean [SD], non‐Hispanic White individuals, 3.5 [19.0]; non‐Hispanic Black individuals, 2.0 [17.0]; non‐Hispanic other individuals, 5.5 [20.3]; and Hispanic individuals, 3.2 [20.1]), with no statistically significant interaction between race and ethnicity and ARNI initiation (P=0.21). There was similarly no statistically significant interaction between race and ethnicity and ARNI initiation for HF hospitalization (P=0.82) or all‐cause mortality (P=0.92).ConclusionsIn a large registry of outpatients with HF with reduced ejection fraction, the association between ARNI initiation and outcomes did not differ by race and ethnicity. These data support the use of ARNI therapy for chronic HF with reduced ejection fraction irrespective of race and ethnicity.

Angiotensin receptor-neprilysin inhibitors for hypertension-hemodynamic effects and relevance to hypertensive heart disease.

Angiotensin receptor-neprilysin inhibitors have multiple beneficial effects on the cardiovascular system. The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan has been shown to effectively reduce ambulatory 24-h blood pressure in patients with hypertension, and improvements in many aspects of hemodynamic function have also been reported. Overall hemodynamic effects on arterial stiffness and nocturnal blood pressure play an important role in the pathogenesis of hypertensive heart disease. Therefore, these could represent mechanistic targets underlying the effects of angiotensin receptor-neprilysin inhibitors on the continuum of cardiovascular disease from hypertension to heart failure. Other potential mechanisms include reductions in circulating volume and sympathetic activity, both of which contribute to the protection against target organ damage and positive changes in cardiac biomarkers seen during angiotensin receptor-neprilysin inhibitor therapy. The mechanisms of action and beneficial effects of angiotensin receptor-neprilysin inhibitors are complementary to those of a number of other treatment options for hypertension, suggesting the possibility of additive or even synergistic benefits. Based on available data, there are a number of patient groups who will benefit from antihypertensive treatment with an angiotensin receptor-neprilysin inhibitor, including those with salt-sensitive hypertension, structural hypertension, resistant hypertension, and hypertension in the presence of heart failure. Overall, angiotensin receptor-neprilysin inhibitors regulate blood pressure and pulse pressure via multiple mechanisms and provide cardiovascular protection. This provides an option for effective intervention early in the vicious cycle of elevated blood pressure and central pressures with progression toward heart failure that should help to address the growing worldwide heart failure epidemic.

Use Of Sacubitril-valsartan And Associated Outcomes By Race And Ethnicity In Patients With Heart Failure With Reduced Ejection Fraction: Data From Champ-HF

Background There are limited data on the use of angiotensin receptor-neprilysin inhibitors (ARNI) in minority demographic populations with heart failure with reduced ejection fraction (HFrEF). We used data from CHAMP-HF to describe ARNI use and associated health status and clinical outcomes across different races and ethnicities. Methods CHAMP-HF was a prospective, observational cohort registry of outpatients in the United States with chronic HFrEF. We compared patients starting ARNI therapy to those not starting ARNI using a propensity-matched analysis. Patients were grouped as Hispanic or Non-Hispanic Black, Non-Hispanic White, or Non-Hispanic Other. Health status was assessed using the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ), calculated from pre-match KCCQ score and post-match KCCQ score at least two weeks after the match. Outcomes were analyzed with multivariable models that included race/ethnicity group, ARNI use, and an interaction term between race/ethnicity and ARNI use. Cox proportional hazards models were used for death and HF hospitalization and multiple regression was used for change in KCCQ score. Results 1,516 patients from the CHAMP-HF registry were included, with 758 patients in each group (ARNI and no-ARNI). Changes in KCCQ score before and after ARNI initiation were similar among all race/ethnicity groups studied, including Hispanic and non-Hispanic Black patients. There was no significant interaction between race/ethnicity and ARNI use for change in KCCQ score (Table). In addition, there was no statistically significant interaction between race/ethnicity and ARNI use for HF hospitalization (P=0.82) or all-cause mortality (P=0.92). Conclusion In a large registry of outpatients with HFrEF, the association between ARNI initiation and outcomes, including changes in health status, did not differ by race and ethnicity. These data support the use of ARNI therapy for chronic HFrEF irrespective of race and ethnicity. There are limited data on the use of angiotensin receptor-neprilysin inhibitors (ARNI) in minority demographic populations with heart failure with reduced ejection fraction (HFrEF). We used data from CHAMP-HF to describe ARNI use and associated health status and clinical outcomes across different races and ethnicities. CHAMP-HF was a prospective, observational cohort registry of outpatients in the United States with chronic HFrEF. We compared patients starting ARNI therapy to those not starting ARNI using a propensity-matched analysis. Patients were grouped as Hispanic or Non-Hispanic Black, Non-Hispanic White, or Non-Hispanic Other. Health status was assessed using the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ), calculated from pre-match KCCQ score and post-match KCCQ score at least two weeks after the match. Outcomes were analyzed with multivariable models that included race/ethnicity group, ARNI use, and an interaction term between race/ethnicity and ARNI use. Cox proportional hazards models were used for death and HF hospitalization and multiple regression was used for change in KCCQ score. 1,516 patients from the CHAMP-HF registry were included, with 758 patients in each group (ARNI and no-ARNI). Changes in KCCQ score before and after ARNI initiation were similar among all race/ethnicity groups studied, including Hispanic and non-Hispanic Black patients. There was no significant interaction between race/ethnicity and ARNI use for change in KCCQ score (Table). In addition, there was no statistically significant interaction between race/ethnicity and ARNI use for HF hospitalization (P=0.82) or all-cause mortality (P=0.92). In a large registry of outpatients with HFrEF, the association between ARNI initiation and outcomes, including changes in health status, did not differ by race and ethnicity. These data support the use of ARNI therapy for chronic HFrEF irrespective of race and ethnicity.

ARNI in HFrEF-One-Centre Experience in the Era before the 2021 ESC HF Recommendations.

Background: Sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor (ARNI), has demonstrated a survival benefit and reduces heart failure hospitalization in patients with heart failure with reduced left ventricular ejection fraction (HFrEF); however, our experience in this field is limited. This study aimed to summarize a real clinical practice of the use of ARNI in HFrEF patients hospitalized due to HFrEF in the era before the 2021 ESC HF recommendations, as well as assess their clinical outcome with regard to ARNI administration. Methods and Materials: Overall, 613 patients with HFrEF hospitalized in 2018–2020 were enrolled into a retrospective one-centre cross-sectional analysis. The study population was categorized into patients receiving (82/13.4%) and not-receiving (531/82.6%) ARNI. Clinical outcomes defined as rehospitalization, number of rehospitalizations, time to the first rehospitalization and death from any cause were analysed in the 1–2 year follow-up in the ARNI and non-ARNI groups, matched as to age and LVEF. Results: Clinical characteristics revealed the following differences between ARNI and non-ARNI groups: A higher percentage of cardiovascular implantable electronic devices (CIED) (p = 0.014) and defibrillators with cardiac resynchronization therapy (CRT-D) (p = 0.038), higher frequency of atrial fibrillation (p = 0.002) and history of stroke (p = 0.024) were in the ARNI group. The percentage of patients with HFrEF NYHA III/IV presented an increasing trend to be higher in the ARNI (64.1%) as compared to the non-ARNI group (51.5%, p = 0.154). Incidence of rehospitalization, number of rehospitalizations and time to the first rehospitalization were comparable between the groups. There were no differences between the numbers of deaths of any cause in the ARNI (28%) and non-ARNI (28%) groups. The independent negative predictor of death in the whole population of ARNI and non-ARNI groups was the coexistence of coronary artery disease (CAD) (beta= −0.924, HR 0.806, p = 0.011). Conclusions: Our current positive experience in ARNI therapy is limited to extremely severe patients with HFrEF. Regardless of the more advanced HF and HF comorbidities, the patients treated with ARNI presented similar mortality and rehospitalizations as the patients treated by standard therapy.

Emerging therapies: The potential roles SGLT2 inhibitors, GLP1 agonists, and ARNI therapy for ARNI pulmonary hypertension.

Pulmonary hypertension (PH) is a highly morbid condition. PH due to left heart disease (PH‐LHD) has no specific therapies and pulmonary arterial hypertension (PAH) has substantial residual risk despite several approved therapies. Multiple lines of experimental evidence link metabolic dysfunction to the pathogenesis and outcomes in PH‐LHD and PAH, and novel metabolic agents hold promise to improve outcomes in these populations. The antidiabetic sodium–glucose cotransporter 2 (SGLT2) inhibitors and glucagon‐like peptide‐1 (GLP1) agonists targeting metabolic dysfunction and improve outcomes in patients with LHD but have not been tested specifically in patients with PH. The angiotensin receptor/neprilysin inhibitors (ARNIs) produce significant improvements in cardiac hemodynamics and may improve metabolic dysfunction that could benefit the pulmonary circulation and right ventricle function. On the basis of promising preclinical work with these medications and clinical rationale, we explore the potential of SGLT2 inhibitors, GLP1 agonists, and ARNIs as therapies for both PH‐LHD and PAH.