Since 2014, sacubitril/valsartan (Entresto®) is widely prescribed for heart failure. Despite neprilysin inhibition\'s benefits in heart failure, concerns about potential amyloid-beta (Aβ) accumulation and Alzheimer\'s disease (AD) risk have persisted. This narrative review, a decade post-approval, evaluates the risk of amyloid pathology and neurocognitive disorders in long-term sacubitril/valsartan use. Clinical trials, real-world studies, and pharmacovigilance data do not indicate an increased risk of cognitive decline. In patients treated with sacubitril/valsartan blood-based amyloid biomarkers show perturbations, while neuroimaging biomarkers reveal no significant increase in amyloid load. Despite a theoretical risk of amyloid accumulation and AD under treatment with sacubitril/valsartan, current clinical data appears reassuring, and there is no signal indicating an increased risk of cognitive decline, but a perturbation of amyloid blood-based biomarkers, which implies great caution when interpreting biomarkers in this context.

UNASSIGNED: Peripartum cardiomyopathy (PPCM) is a common cause of heart failure (HF) in the peripartum. Some medications are considered safe while breastfeeding. However, sacubitril/valsartan (Entresto), while efficacious, is not recommended in breastfeeding women due to concerns about adverse infant development, and no published data suggest otherwise.
UNASSIGNED: This study aimed to assess the transfer of sacubitril/valsartan into human milk and evaluate the infant\'s risk of drug exposure.
UNASSIGNED: The InfantRisk Human Milk Biorepository released samples and corresponding health information from five breastfeeding maternal-infant dyads exposed to sacubitril/valsartan. Sacubitril, valsartan, and LBQ657 (sacubitril active metabolite) concentrations were determined using liquid chromatography-mass spectrometry (LC/MS/MS) from timed samples 0, 1, 2, 4, 6, 8, 10, and 12 h following medication administration at steady state conditions.
UNASSIGNED: Valsartan levels were below the detection limit of 0.19 ng/mL in all milk samples. Sacubitril was measurable in all milk samples of the five participants, peaking 1 h after drug administration at a mean concentration of 1.52 ng/mL for a total infant dose of 0.00049 mg/kg/12 h and a relative infant dose (RID) calculated at 0.01%. The maximum concentration of its active metabolite LBQ657 in the milk samples was observed 4 h after medication administration and declined over the remaining 12-h dosing interval, for an average concentration of 9.5 ng/mL. The total infant dose was 0.00071 mg/kg/12 h, and the RID was 0.22%. Two mothers reported continuing to breastfeed while taking sacubitril/valsartan; both mothers stated observing no negative effects in their breastfed infants.
UNASSIGNED: The transfer of sacubitril/valsartan into human milk is minimal. These concentrations are unlikely to pose a significant risk to breastfeeding infants, with a combined calculated RID of <0.25%, which is far lower than the industry safety standards (RID <10%).

There exists a paucity of research data reported by analyses performed on randomized clinical trials (RCTs) that encompass quality of life (QOL) and the aftermath for patients suffering from heart failure with reduced ejection fraction (HFrEF). This systematic review and meta-analysis of randomized clinical trials (RCTs) have been done to evaluate the drug sacubitril/valsartan in the treatment of heart failure (HF) with reduced ejection fraction (HFrEF) with a clear focus on the effect it bestows on measures of physical exercise tolerance and quality of life. A thorough systematic search was done in databases including Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, Embase, and PubMed from 1 January 2010 to 1 January 2023. The search only included published RCTs on adult patients aged 18 and above, with heart failure with reduced ejection fraction (HFrEF). Data analysis was performed by using the software RevMan 5.4 (Cochrane Collaboration, London, United Kingdom). The included studies\' bias risk was assessed using the Cochrane Collaboration\'s Risk of Bias tool. The quality of evidence for the primary outcome was done using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. This systematic review and meta-analysis of RCTs yielded 458 studies, of which eight randomized clinical trials were included and analyzed. The meta-analysis of the included trials shows that the I2 value is 61% (i.e., I2 > 50%), demonstrating a substantial heterogeneity within the studies. The left ventricular ejection fraction (LVEF) expressed in percentage was reported in the five studies, and thereby, a subgroup analysis that yielded a confidence interval (CI) of 95% had the standard mean difference of 0.02 (-0.02, 0.07). The trials had disparity between the reporting of effect on peak oxygen consumption (VO2), measured through cardiopulmonary exercise testing (CPET) methods, six-minute walking test (6MWT), overall physical activity, and exercise capacity. Sacubitril/valsartan did not exponentially improve peak VO2 or 6MWT in these trials; however, the patient-reported data suggested that the quality of life was modestly influenced by the drug. A subgroup analysis was performed using the pooled effect value by the random effects model. The findings showed that the sacubitril/valsartan group significantly was better than the control group in improving HFrEF-associated health-related quality of life (HRQoL). This study is a systematic review and meta-analysis of randomized clinical trials that evaluated the drug sacubitril/valsartan in treating heart failure with reduced ejection fraction (HFrEF) and focused on its tangible effect on the measures of physical exercise tolerance and quality of life. It depicts that the statistical scrutiny due to the lack of significant data and parity across studies did not impart significant improvement of either LVEF, peak VO2, or 6MWT with the use of sacubitril/valsartan; however, the reported exercise tolerance, including daytime physical activity, had a modest impact with the said drug. The pooled values demonstrated that the sacubitril/valsartan group significantly outperformed the control group in improving HFrEF HRQoL.

This study tested whether combined dapagliflozin and entresto would be superior to mere one therapy on protecting the residual renal function and integrity of kidney parenchyma in hypertensive kidney disease (HKD) rat. In vitro results showed that the protein expressions of oxidative-stress/mitochondrial-damaged (NOX-1/NOX-2/oxidized-protein/cytosolic-cytochrome-C)/apoptotic (mitochondrial-Bax/cleaved caspeases 3, 9)/cell-stress (p-ERK/p-JNK/p-p38) biomarkers were significantly increased in H2O2-treated NRK-52E cells than those of controls that were reversed by dapagliflozin or entresto treatment. Adult-male SD rats (n = 50) were equally categorized into group 1 (sham-operated-control), group 2 (HKD by 5/6 nephrectomy + DOCA-salt/25 mg/kg/subcutaneous injection/twice weekly), group 3 (HKD + dapagliflozin/orally, 20 mg/kg/day for 4 weeks since day 7 after HKD induction), group 4 (HKD + entresto/orally, 100 mg/kg/day for 4 weeks since day 7 after HKD induction), and group 5 (HKD + dapagliflozin + entresto/the procedure and treatment strategy were identical to groups 2/3/4). By day 35, circulatory levels of blood-urine-nitrogen (BUN)/creatinine and urine protein/creatinine ratio were lowest in group 1, highest in group 2, and significantly lower in group 5 than in groups 3/4, but no difference between groups 3/4. Histopathological findings showed the kidney injury score/fibrotic area/cellular expressions of oxidative-stress/kidney-injury-molecule (8-OHdG+/KIM-1+) exhibited an identical trend, whereas the cellular expressions of podocyte components (synaptopodin/ZO-1/E-cadherin) exhibited an opposite pattern of BUN level among the groups. The protein expressions of oxidative stress/mitochondrial-damaged (NOX-1/NOX-2/oxidized protein/cytosolic-cytochrome-C/cyclophilin-D)/apoptotic (mitochondrial-Bax/cleaved-caspase 3)/mitochondrial-fission (PINK1/Parkin/p-DRP1)/autophagic (LC3BII/LC3BI ratio, Atg5/beclin-1)/MAPK-family (p-ERK/p-JNK/p-p38) biomarkers displayed a similar pattern, whereas the protein expression of mitochondria-biogenesis signaling (SIRT1/PGC-1α-Mfn2/complex I-V) displayed an opposite pattern of BUN among the groups. In conclusion, combined dapagliflozin-entresto therapy offered additional benefits on protecting the residual kidney function and architectural integrity in HKD rat.

BACKGROUND: Since sacubitril/valsartan (LCZ696) has neprilysin inhibition and angiotensin receptor-blocking properties, it is anticipated to have strong antihypertensive effects. However, there is not enough evidence to compare the safety and efficacy of sacubitril/valsartan to those of olmesartan in patients with hypertension.
OBJECTIVE: To compare the efficacy and safety of sacubitril/valsartan versus olmesartan in patients with hypertension.
METHODS: This study follows the guidelines of the Cochrane Handbook. We searched MEDLINE, Cochrane Central, Scopus, and Web of Science databases for relevant clinical trials. We extracted outcome endpoints regarding mean ambulatory systolic/diastolic blood pressure (maSBP/maDBP), mean sitting systolic/diastolic blood pressure (msSBP/msDBP), mean ambulatory/mean sitting pulse pressure (maPP/msPP), the proportion of patients achieving blood pressure control (< 140/90 mmHg), and adverse events. We used Review Manager Software for the conduction of the analysis of this study. The effect estimates of the studies were pooled as Mean difference or risk ratio and 95% confidence interval. We also conducted a subgroup analysis based on the dose of sacubitril/valsartan.
RESULTS: A total of six clinical trials were included. The studies showed an overall low risk of bias. The pooled effect estimate revealed that sacubitril/valsartan significantly reduces maSBP, maDBP, maPP, msSBP, and msDBP measurements compared with olmesartan (p < 0.001). A significantly higher portion of patients achieved blood pressure control in the sacubitril/valsartan group (p < 0.001). The test of subgroup difference showed that 400 mg dose is significantly more effective than 200 mg dose in reducing maSBP. Regarding the safety profile, olmesartan was associated with more side effects due to drug discontinuation and more serious side effects.
CONCLUSIONS: Sacubitril/valsartan or LCZ696 is more effective and safer than olmesartan for controlling blood pressure in patients with hypertension.

Cardiovascular diseases have become a major clinical burden globally. Heart failure is one of the diseases that commonly emanates from progressive uncontrolled hypertension. This gives rise to the need for a new treatment for the disease. Sacubitril/valsartan is a new drug combination that has been approved for patients with heart failure. This review aims to detail the mechanism of action for sacubitril/valsartan in cardiac remodeling, a cellular and molecular process that occurs during the development of heart failure. Accumulating evidence has unveiled the cardioprotective effects of sacubitril/valsartan on cellular and molecular modulation in cardiac remodeling, with recent large-scale randomized clinical trials confirming its supremacy over other traditional heart failure treatments. However, its molecular mechanism of action in cardiac remodeling remains obscure. Therefore, comprehending the molecular mechanism of action of sacubitril/valsartan could help future research to study the drug\'s potential therapy to reduce the severity of heart failure.

BACKGROUND: This study tested whether combined dapagliflozin and entresto treatment would be superior to either one alone for preserving the left-ventricular ejection-fraction (LVEF) in rat after ischemia-reperfusion (IR) injury.
METHODS: Cell culture using H9C2 cells and IR injury in rat with dapagliflozin-entresto treatment were conducted in the present study.
RESULTS: In vitro flow-cytometric result showed that the intracellular and mitochondrial reactive oxygen species and mitochondrial permeability transition pore, and protein levels of oxidative-stress/DNA-damaged markers [NADPH-oxidase-1 (NOX-1)/NOX-2/oxidized-protein/γ-H2A-histone-family member X (γ-H2AX)] were significantly higher in hydrogen peroxide (H2O2) (300μM)-treated H9C2 cells as compared with the controls that were significantly reversed in sacubitril/valsartan and dapagliflozin therapy in the same H2O2-treated condition, whereas the protein expressions of antioxidants [Sirtuin-1 (SIRT1)/SIRT3/superoxide dismutase/catalase/glutathione peroxidase) exhibited an opposite pattern among the groups (all p<0.001). Adult-male-Sprague-Dawley rat (n=40) were equally categorized into group 1 (sham-operated control), group 2 (IR), group 3 (IR+dapagliflozin/20mg/kg/orally at 3h and post-days 1/2/3 after IR), group 4 (IR+entresto/100mg/kg/orally at 3h and post-days 1/2/3 after IR) and group 5 (IR+dapagliflozin+entresto) and the hearts were harvested by day 3 after IR. The 3rd day\'s LVEF was highest in group 1, lowest in group 2 and significantly higher in group 5 than in groups 3/4, but it was similar between the latter two groups (p<0.001). The protein expressions of oxidative-stress (NOX-1/NOX-2/oxidized protein), fibrotic (transforming-growth factor-ß/phosphorylated-Smad3), apoptotic [mitochondrial-Bax/cleaved-caspase-3/cleaved-poly (ADP-ribose) polymerase], mitochondria/DNA damaged (cytosolic-cytochrome-c/γ-H2AX), pressure-overload/heart-failure [brain natriuretic peptide (BNP)/ß-myosin heavy chain] and autophagic (ratio of meiotic cyclins CLB3-II/CLB3-I) biomarkers, and the upstream (high-mobility group box 1/Toll-like receptor-4/MyD88/phosphorylated-nuclear factor-κB and downstream [interleukin (IL)-1ß/IL-6/tumor necrosis factor-α] inflammatory signalings revealed an antithetical features of LVEF among the groups (all p<0.0001). The cellular levels of inflammatory (myeloperoxidase+/CD68+), pressure-overload/heart-failure (BNP+) and DNA-damage (γ-H2AX+) biomarkers as well as infarct area demonstrated an opposite pattern of LVEF among the groups (all p<0.0001).
CONCLUSIONS: Incorporated entresto-dapagliflozin treatment was superior to either one alone on protecting the heart against IR injury.

Objective: To compare video to pharmacist education for patients taking sacubitril/valsartan. Methods: We conducted a randomized controlled trial comparing video to pharmacist education with a second randomized intervention of education delivered through text or phone call at 14 days. The primary outcome compared the change in short term knowledge between groups and the secondary outcome was long term knowledge at 1 month. Results: Forty-three patients were included. Scores improved significantly (P < .05) in the pharmacist group from 54.1% to 85.9% and from 64.3% to 86.1% in the video education group, although there was no difference between groups (31.8% vs 22.9%, P = .13). At 30 days, scores were significantly higher than baseline (difference 16.5%, P < .05) although did decrease from the posttest (difference 7.4%, P < .05). There was no difference at 30 days between those that received text messages versus phone calls (-10% vs -5.5%, respectively; P = .36). Conclusion: We saw improvements in both short term and long term knowledge for patients receiving education through pharmacist or video education. Neither approach was more effective than the other. Clinicians can use either approach based on patient preference.

BACKGROUND: Sacubitril/valsartan is approved for the treatment of chronic heart failure with reduced left ventricular ejection fraction of ≤40% to decrease mortality and morbidity. Nasal pruritus is not a recognized adverse effect in the product information. In this case series, we encountered three patients who presented with nasal pruritus that improved after discontinuation of sacubitril/valsartan.
METHODS: Three patients aged 58-73 years-old presented with pruritus at the nasal septum post-initiation of sacubitril/valsartan. The pruritus did not subside despite the use of anti-histamines. Within 3-6 months, all individuals discontinued sacubitril/valsartan with complete resolution of their nasal pruritus.
CONCLUSIONS: Many physicians may not aware of this unusual but reversible adverse effect of sacubitril/valsartan. Despite the positive prognostic value of sacubitril/valsartan, the constant nasal pruritus had impacted the quality of life of our patients, leading them to discontinue sacubitril/valsartan permanently.

Objective: To evaluate the efficacy, safety, and clinical significance of sacubitril/valsartan (Entresto) in patients with heart failure with a reduced ejection fraction (HFrEF). Data Sources: An extensive search was conducted on Ovid MEDLINE using keywords and medical subject headings LCZ696, sacubitril/valsartan, angiotensin-receptor neprilysin inhibitor, and Entresto. Study Selection and Data Extraction: The search was conducted to retrieve clinical trials comparing sacubitril/valsartan to current guideline-directed therapy for HF. Articles using the limits of clinical trials \"all\" (phase I to IV), in English, and published within the past 5 years were reviewed. Supplemental sources included the Entresto package insert via the manufacturer\'s website. Primary end points included all-cause mortality and time to first hospitalization. Safety end points included incidence and severity of angioedema, cough, hyperkalemia, increased serum creatinine, and hypotension. Data Synthesis: This review critiques both clinical and statistical significance of the \"Prospective Comparison of ARNi with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure\" or PARADIGM-HF and other phase II to III clinical trials. Sacubitril/valsartan showed a 20% reduction in cardiovascular death and first hospitalization from HF compared with enalapril. Despite an overall reduction in adverse events, sacubitril/valsartan had increased occurrences of hypotension and nonserious angioedema. Conclusion: Sacubitril/valsartan is a viable option for newly diagnosed New York Heart Association (NYHA) class II to III and is an alternative to patients who are currently being treated with the maximum doses of current gold standard treatment. Clinicians initiating sacubitril/valsartan must monitor patients closely for signs, symptoms, and history of hypotension and angioedema.