Co-Delivery of Valsartan and Metformin from a Thermosensitive Hydrogel-Nanoparticle System Promotes Collagen Production in Proliferating and Senescent Primary Human Dermal Fibroblasts.

Aging negatively impacts skin health, notably through the senescent cell phenotype, which reduces collagen production and leads to thinner, more fragile skin prone to injuries and chronic wounds. We designed a drug delivery system that addresses these age-related issues using a hybrid hydrogel-nanoparticle system that utilizes a poly(δ-valerolactone-co-lactide)-b-poly(ethylene-glycol)-b-poly(δ-valerolactone-co-lactide) (PVLA-PEG-PVLA) hydrogel. This hydrogel allows for the local, extended release of therapeutics targeting both proliferating and senescent cells. The PVLA-PEG-PVLA hydrogel entrapped valsartan, and metformin-loaded liposomes functionalized with a fibronectin-mimetic peptide, PR_b. Metformin acts as a senomorphic, reversing aspects of cellular senescence, and valsartan, an angiotensin receptor blocker, promotes collagen production. This combination treatment partially reversed the senescent phenotype and improved collagen production in senescent dermal fibroblasts from both young and old adults. Our codelivery hydrogel-nanoparticle system offers a promising treatment for improving age-related dermal pathologies.

Clinical outcome in hypertensive patients treated with amlodipine plus bisoprolol or plus valsartan.

OBJECTIVE: Several guidelines do not recommend beta-blocker as the first-line treatment for hypertension because of its inferior efficacy in stroke prevention. Combination therapy with beta-blocker is commonly used for blood pressure control. We compared the clinical outcomes in patients treated with amlodipine plus bisoprolol (A + B), a ß1-selective beta-blocker and amlodipine plus valsartan (A + V). METHODS: A population-based cohort study was performed using data from the Taiwan National Health Insurance Research Database. From 2012 to 2019, newly diagnosed adult hypertensive patients who received initial amlodipine monotherapy and then switched to A + V or A + B were included. The efficacy outcomes included all-cause death, atherosclerotic cardiovascular disease (ASCVD) event (cardiovascular death, myocardial infarction, ischemic stroke, and coronary revascularization), hemorrhagic stroke, and heart failure. Multivariable Cox proportional hazards model was used to evaluate the relationship between outcomes and different treatments. RESULTS: Overall, 4311 patients in A + B group and 10980 patients in A + V group were included. After a mean follow-up of 4.34 ± 1.79 years, the efficacy outcomes were similar between the A + V and A + B groups regarding all-cause death (adjusted hazard ratio [aHR] 0.99, 95% confidence interval [CI] 0.83-1.18), ASCVD event (aHR 0.97, 95% CI 0.84-1.12), and heart failure (aHR 1.06, 95% CI 0.87-1.30). The risk of hemorrhagic stroke was lower in A + B group (aHR 0.70, 95% CI 0.52-0.94). The result was similar when taking death into consideration in competing risk analysis. The safety outcomes were similar between the 2 groups. CONCLUSIONS: There was no difference of all-cause death, ASCVD event, and heart failure in A + B vs. A + V users. But A + B users had a lower risk of hemorrhagic stroke.

Extemporaneous combination therapy with nebivolol/valsartan for the treatment of hypertension: a study of real-world evidence in Europe.

OBJECTIVE: To explore real-life use of the extemporaneous combination of nebivolol and valsartan (NV-EXC) in adult hypertensive patients in Europe. METHODS: Retrospective analysis of patients starting NV-EXC treatment conducted using prescription databases in Italy, Germany, Hungary, and Poland. The selection period during which study patients were identified covered a time span ranging from 3 to 9 years (until 30 June 2020) according to availability of the different data sources. Patient demographics, clinical information, and treatment adherence, measured by proportion of days covered, were evaluated. Additionally, the potential eligibility of Italian patients for the single pill combination (SPC) of nebivolol and valsartan over a one-year period was estimated. RESULTS: The study included 170,682 patients initiating NV-EXC across the databases. Most patients were females (from 51 to 60%) and primarily aged over 60 years. Few patients received prescriptions of both available dosages of valsartan (80 and 160 mg) during follow-up (from 3.2 to 8.5%). Common comorbidities included dyslipidemia (19.2%) and diabetes (19.1%). Around 59.5% of patients did not require cardiologic visits during the study period. Adherence to NV-EXC, as indicated by the Italian database, was low in 53.3% of patients, with only 16.1% showing high adherence. The Italian database revealed 680 prevalent NV-EXC users in 2019, estimating a potential 30,222 adult patients eligible for the nebivolol/valsartan SPC. CONCLUSIONS: The combination of nebivolol and valsartan is frequently prescribed for hypertension, but adherence remains a challenge. A potential nebivolol/valsartan SPC holds promise in enhancing adherence and optimizing therapeutic outcomes for hypertension management.

Sacubitril/valsartan compared to equivalent/sub-equivalent dose angiotensin receptor blocker or angiotensin-converting enzyme inhibitor in heart failure with reduced ejection fraction: a meta-analysis of randomized trials.

PURPOSE: The objective of this meta-analysis is to determine how sacubitril/valsartan (SV) compares to equivalent and sub-equivalent angiotensin receptor blockers (ARB) or angiotensin-converting enzyme inhibitors (ACEI) in patients with heart failure with reduced ejection fraction (HFrEF). METHODS: The databases of PubMed and EMBASE were used to identify those randomized controlled trials which compared SV to ARB/ACEI in patients with HFrEF. Only those trials that reported outcomes regarding total mortality, cardiovascular mortality, and worsening heart failure were considered. Meta-analysis was performed separately in those patients receiving equivalent doses of ARB/ACEI and those receiving sub-equivalent doses. Equivalent doses were SV 97/103 = valsartan 160 mg twice daily = enalapril 20 mg twice daily = ramipril 5 mg twice daily. Meta-analyses were performed using Review Manager 5.4. RESULTS: Twelve randomized trials were identified involving 17,484 patients: 11,291 in the sub-equivalent group (8 trials) and 6193 in the equivalent group (4 trials). Meta-analyses showed there were no statistical differences regarding the outcomes of total mortality, cardiovascular mortality, and worsening heart failure in the equivalent dosing group. However, SV reduced total mortality (risk ratio (RR) = 0.85, 95% confidence interval (CI) = 0.78-0.93, p < 0.001), cardiovascular mortality (RR = 0.81, 95% CI = 0.73-0.90, p ≤ 0.001) and worsening heart failure (RR = 0.77, 95% CI = 0.64-0.92, p = 0.005) in the sub-equivalent group. CONCLUSION: When compared to equivalent doses of ARB/ACEI, SV is not superior in reducing mortality and worsening heart failure. SV is superior when compared to sub-equivalent doses of ACEI.

Efficacy of early administration of sacubitril/valsartan after coronary artery revascularization in patients with acute myocardial infarction complicated by moderate-to-severe mitral regurgitation: a randomized controlled trial.

Effects of angiotensin receptor/neprilysin inhibitors (ARNI) on ventricular remodeling in patients with heart failure, especially heart failure with reduced ejection fraction (HFrEF), are better than those of angiotensin-converting enzyme inhibitors (ACEI). Acute myocardial infarction (AMI) complicated by mitral regurgitation exacerbates ventricular remodeling and increases the risk of heart failure. There is limited evidence on the effects of early administration of ARNI in patients with AMI complicated by mitral regurgitation. The aim of this trial was to examine the effectiveness and the safety of early administration of sacubitril/valsartan after coronary artery revascularization in patients with AMI complicated by moderate-to-severe mitral regurgitation. This was a randomized, single-blind, parallel-group, controlled trial. From June 2021 to June 2022, we enrolled 142 consecutive patients with AMI complicated by moderate-to-severe mitral regurgitation and followed them for 12 months. The patients received standard treatment for AMI and were randomly assigned to receive ARNI or benazepril. The primary efficacy end points were the differences in mitral regurgitant jet area (MRJA), mitral regurgitant volume (MRV), concentration of n-terminal pro-brain natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), and left ventricular end-diastolic volume and end-systolic volume (LVEDV and LVESV) between groups and within groups at baseline, 1, 3, 6, and 12 months. Secondary end points included the rates of heart failure hospitalization, all-cause mortality, refractory angina, malignant arrhythmias, recurrent myocardial infarction, and stroke. Safety end points included the rates of hyperkalemia, renal dysfunction, hypotension, angioedema, and cough. The ARNI group had significantly lower NT-proBNP levels than the benazepril group at 1 month and later (P < 0.001). MRJA and MRV significantly improved in the ARNI group compared with the benazepril group at 12 months (MRJA: - 3.21 ± 2.18 cm2 vs. - 1.83 ± 2.81 cm2, P < 0.05; MRV: - 27.22 ± 15.22 mL vs. - 13.67 ± 21.02 mL, P < 0.001). The ARNI group also showed significant reductions in LVEDV and LVESV (P < 0.05) and improvement in LVEF (P < 0.05). Secondary end point analysis showed a significantly higher rate of heart failure hospitalization in the benazepril group compared with the ARNI group (HR = 2.03, 95% CI 1.12-3.68, P = 0.021). Safety end point analysis showed a higher rate of hypotension in the ARNI group (P < 0.05). Early use of sacubitril/valsartan after coronary artery revascularization in patients with AMI complicated by moderate-to-severe mitral regurgitation can significantly reduce mitral regurgitation, improve ventricular remodeling, and decrease heart failure hospitalization. Nevertheless, caution is needed to avoid hypotension. Chinese Clinical Trial Registry (ChiCTR2100054255) registered on December 11, 2021.

Comparison of effects of telmisartan versus valsartan on post-induction hypotension during noncardiac surgery: a prospective observational study.

BACKGROUND: Telmisartan is considered more potent than valsartan. Hemodynamic response during anesthesia induction may be influenced by anti-hypertension (HTN) medication. The present study compared the effect of anti-HTN medications on post-induction hypotension during noncardiac surgeries. METHODS: This observational study standardized the anesthetic regimen across patients, with hypotension defined as mean blood pressure (BP) of less than 65 mmHg. The hemodynamic changes within 5 min before and after endotracheal intubation, and within 10 min before and after surgical incision were measured. Transthoracic echocardiographic evaluation of the left ventricle (LV) during anesthesia induction was performed. The primary endpoint was the decline in mean BP after anesthetic administration in telmisartan and valsartan groups. Multivariate logistic regression analysis was used to identify predictors of post-induction hypotension. RESULTS: Data from 157 patients undergoing noncardiac surgery were analyzed. No significant differences were found in mean BP decline between the two groups during anesthesia induction. Hemodynamic changes and LV ejection fraction (EF) during anesthesia induction were similar between the groups. Age and preoperative initial mean BP in operation room (OR) were associated with post-induction hypotension in both groups. CONCLUSIONS: The angiotensin receptor blocker (ARB) type did not influence post-induction hypotension during anesthesia induction. Age and preoperative initial mean BP in OR were associated with post-induction hypotension in patients taking ARBs.

Low- vs high-dose ARNI effects on clinical status, exercise performance and cardiac function in real-life HFrEF patients.

PURPOSE: Only a few studies are available on dose-related effects of sacubitril/valsartan (angiotensin receptor neprilysin inhibition (ARNI)) in real-life patients with heart failure and reduced ejection fraction (HFrEF). We sought to investigate clinical and functional effects in real-life HFrEF patients receiving ARNI at a different cumulative dose. METHODS: This was an observational study in consecutive outpatients admitted for HFrEF from October 2017 to June 2019. The PARADIGM criteria were needed for enrolment. ARNI was uptitrated according to blood pressure, drug tolerability, renal function and kaliemia. At least 10-month follow-up was required in each patient. Clinical assessment, Kansas City Cardiomyopathy Questionnaire (KCCQ) score, 6-min walk test and strain echocardiography were performed in each patient on a regular basis during the observational period. At the end of the study, patients were divided into two groups based on the median yearly dose of the ARNI medication. RESULTS: A total of 90 patients, 64 ± 11 years, 82% males, were enrolled. The cut-off dose was established in 75 mg BID, and the study population was divided into group A (≤ 75 mg), 52 patients (58%), and group B (> 75 mg), 38 patients (42%). The follow-up duration was 12 months (range 11-13). NYHA class, KCCQ score and 6MWT performance ameliorated in both groups, with a quicker time to benefit in group B. The proportion of patients walking > 350 m increased from 21 to 58% in group A (p < 0.001), and from 29 to 82% in group B (p < 0.001). A positive effect was also disclosed in the left ventricular remodelling, strain deformation and diastolic function. CONCLUSION: One-year ARNI treatment was effective in our real-life HFrEF patient population, leading to clinical and functional improvement in both study groups, slightly greater and with a shorter time to benefit in group B.

Impact of sacubitril/valsartan on implantable defibrillator eligibility in heart failure: a real-world experience.

OBJECTIVE: Current guidelines recommend an implantable cardiac defibrillator (ICD) in patients with symptomatic heart failure and reduced ejection fraction (HFrEF; left ventricular ejection fraction [LVEF] ≤35%) despite ≥3 months of optimal medical therapy. Recent observations demonstrated that sacubitril/valsartan induces beneficial reverse cardiac remodeling in eligible HFrEF patients. Given the pivotal role of LVEF in the selection of ICD candidates, we sought to assess the impact of sacubitril/valsartan on ICD eligibility and its predictors in HFrEF patients. PATIENTS AND METHODS: We retrospectively evaluated 48 chronic HFrEF patients receiving sacubitril/valsartan and previously implanted with an ICD in primary prevention. We assumed that ICD was no longer necessary if LVEF improved >35% (or >30% if asymptomatics) at follow-up. RESULTS: Over a median follow-up of 11 months, sacubitril/valsartan induced a significant drop in LV end-systolic volume (-16.7 ml/m2, p=0.023) and diameter (-6.8 mm, p=0.022), resulting in a significant increase in LVEF (+3.9%, p<0.001). As a consequence, 40% of previously implanted patients resulted no more eligible for ICD at follow-up. NYHA class improved in 50% of the population. A dose-dependent effect was noted, with higher doses associated to more reverse remodeling. Among patients deemed no more eligible for ICD, lower NYHA class (odds ratio (OR) 3.73 [95% CI 1.05; 13.24], p=0.041), better LVEF (OR 1.23 [95% CI 1.01; 1.48], p=0.032) and the treatment with the intermediate or high dose of sacubitril/valsartan (OR 5.60 [1.15; 27.1], p=0.032) were the most important predictors of status change. CONCLUSIONS: In symptomatic HFrEF patients, sacubitril/valsartan induced beneficial cardiac reverse remodeling and improved NYHA class. These effects resulted in a significant reduction of patients deemed eligible for ICD in primary prevention.

Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial.

Hypertrophic cardiomyopathy (HCM) is often caused by pathogenic variants in sarcomeric genes and characterized by left ventricular (LV) hypertrophy, myocardial fibrosis and increased risk of heart failure and arrhythmias. There are no existing therapies to modify disease progression. In this study, we conducted a multi-center, double-blind, placebo-controlled phase 2 clinical trial to assess the safety and efficacy of the angiotensin II receptor blocker valsartan in attenuating disease evolution in early HCM. In total, 178 participants with early-stage sarcomeric HCM were randomized (1:1) to receive valsartan (320 mg daily in adults; 80-160 mg daily in children) or placebo for 2 years ( NCT01912534 ). Standardized changes from baseline to year 2 in LV wall thickness, mass and volumes; left atrial volume; tissue Doppler diastolic and systolic velocities; and serum levels of high-sensitivity troponin T and N-terminal pro-B-type natriuretic protein were integrated into a single composite z-score as the primary outcome. Valsartan (n = 88) improved cardiac structure and function compared to placebo (n = 90), as reflected by an increase in the composite z-score (between-group difference +0.231, 95% confidence interval (+0.098, +0.364); P = 0.001), which met the primary endpoint of the study. Treatment was well-tolerated. These results indicate a key opportunity to attenuate disease progression in early-stage sarcomeric HCM with an accessible and safe medication.

Early treatment with combination of SS31 and entresto effectively preserved the heart function in doxorubicin-induced dilated cardiomyopathic rat.

BACKGROUND: This study tested the hypothesis that early administration of SS31 and entresto (En) was superior to either one alone on preserving the heart function in setting of dilated cardiomyopathy (DCM) induced by doxorubicin (Dox) [accumulated dosage of 12.5 mg/kg/administered by intraperitoneal (IP) at 4 separated time points within 20 days] in rat. METHODS AND RESULTS: Adult-male SD rats (n = 40) were equally categorized into groups 1 (sham-control), 2 (DCM), 3 (DCM + SS31/0.7 mg/kg/day/IP, since day-14 after DCM induction to day-60), 4 [DCM + En (30 mg/kg/day/orally since day-14 after DCM induction to day-60)] and 5 (DCM + combined SS31-En), and animals were euthanized by day 60. By day 60, left-ventricular ejection-fraction (LVEF) was highest in group 1, lowest in group 2 and significantly higher in group 5 than in groups 3 and 4 (all p < 0.0001), but it showed no difference between groups 3/4. The microscopic study showed that the fibrosis area/cardiomyocyte size and DNA-damaged (γ-H2AX+)/inflammatory (CD14+//CD68+) markers, and flow analysis of inflammatory (Ly6G+/MPO+/CD11b/c+) and early/late apoptosis (AN-V+/PI-//AN-V+/PI+) cells exhibited an opposite pattern of LVEF among the five groups (all p < 0.0001). The protein expressions of inflammatory upstream (TLR2/TLR4/MyD88/Mal/ TRAF6/IKK-α/IKK-ß) and downstream (p-NF-κb/TNF-α/IL-1ß/MMP-9), oxidative-stress/mitochondrial-damaged (NOX-1/NOX-2/cytosolic cytochrome-C/cyclophilin-D/DRP1) and autophagic/apoptotic (ratio of LC3B-II/LC3B-I and mitochondrial-Bax/caspase3/9) signaling pathways also exhibited an opposite pattern of LVEF among the five groups (all p < 0.0001). CONCLUSION: Combined SS31-En therapy was superior to either one alone on protecting the heart structural and functional integrities against Dox-induced DCM damage.

Blocking angiotensin 2 receptor attenuates diabetic nephropathy via mitigating ANGPTL2/TL4/NF-κB expression.

BACKGROUND: Diabetic nephropathy (DN) is a consequence of diabetes mellitus (DM) and is associated with early changes in renal angiotensin II (ANG II). These changes were evaluated using ANG II blocker valsartan early from week two of diabetes (experiment I, renoprotective) and late from week nine of diabetes (experiment II, renotherapeutic) to the end of both experiments at week twelve. METHODS AND RESULTS: In both experiments, adult male Wister rats were divided into (i) vehicle group; (ii) valsartan received oral 30 mg/Kg/day; (iii) diabetic received single 50 mg/Kg intraperitoneal streptozotocin injection; (iv) renoprotection, diabetic rats received valsartan treated in experiments I and II. DM effects on urine albumin excretion, blood pressure, and renal ANG II were measured. Urinary nephrin, kidney injury molecule-1 (KIM-1), renal angiopoietin-like protein 2 (ANGPTL2), and toll-like receptor 4 (TLR 4) mRNA expression were tested. DM-initiated fibrotic markers integrin, α-smooth muscle actin expression, and collagen IV and apoptotic protein caspase 3 were tested. DM induced early changes starting from week four in the tested variables. At week twelve, in both experiments, valsartan intervention showed a significant reduction in ANG II, ANGPTL2, TLR 4 and integrin expression and improvement in albuminuria, blood pressure, urinary biomarkers, fibrotic and apoptotic markers. CONCLUSIONS: Changes leading to DN starts early in the disease course and ANG II reduction decreased the expression of ANGPTL2 and integrin which preserve the glomerular barrier. Blocking ANG II was able to decrease TLR 4 and inflammatory cytokines leading to decreasing DN.

Clinical evidence of initiating a very low dose of sacubitril/valsartan: a prospective observational analysis.

Sacubitril/valsartan is superior to enalapril in reducing the risks of cardiovascular death and preventing hospitalization in patients with heart failure and reduced ejection fraction (HFrEF). However, patients often do not receive sacubitril/valsartan because of concerns about hypotension. We examined the feasibility of initiating sacubitril/valsartan at a very low dose (VLD) in potentially intolerant patients with HFrEF and subsequent dose up-titration, treatment persistence and outcomes. We analyzed 206 patients with HFrEF grouped according to starting sacubitril/valsartan dose. The VLD group (n = 106) commenced 25 mg twice daily, and the standard-dose (SD) group (n = 100) started on ≥ 50 mg twice daily. Baseline systolic blood pressure was 103 ± 12 mmHg vs. 119 ± 14 mmHg in the SD group (P < 0.001). The maximal target dose achievement rate was higher in the SD group (27.0% vs 9.4%, p = 0.001) and the VLD group experienced more dose up-titrations and fewer down-titrations than the SD group. The VLD group had a decrease in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) similar to the SD group and a similar increase in left ventricular ejection fraction. There were no significant differences in symptomatic hypotension, worsening renal function, hyperkalemia, cardiovascular mortality, and rehospitalization due to HF between the two groups during follow-up period. In patients considered by the treating physician likely to be intolerant of sacubitril/valsartan, initiation with 25 mg twice daily was generally possible and patients remained in therapy, with similar decreases in NT-proBNP and increases in left ventricular ejection fraction to those observed in patients receiving SD sacubitril/valsartan.

Synchronized determination of sacubitril and valsartan with some co-administered drugs in human plasma via UPLC-MS/MS method using solid-phase extraction.

An accurate and sensitive UPLC-MS/MS method was developed and validated for the simultaneous estimation of the newly developed combination of sacubitril and valsartan and the co-administered drugs nebivolol, chlorthalidone and esomeprazole in human plasma. Solid-phase extraction was conducted for the purification and extraction of the drugs from human plasma. Chromatographic separation was carried out on an Agilent SB-C18 (1.8 µm, 2.1 × 50 mm) column using losartan as internal standard. Isocratic elution was applied using acetonitrile-0.1% formic acid in water (85: 15, v/v) as mobile phase. Detection was carried out using a triple-quadrupole tandem mass spectrometer using multiple reaction monitoring, at positive mode at m/z 412.23 → 266.19 for sacubitril, m/z 436.29 → 235.19 for valsartan, m/z 405.8 → 150.98 for nebivolol, m/z 346.09 → 198 for esomeprazole and a selected combination of two fragments m/z 423.19 → 207.14 and 423.19 → 192.2 for losartan (internal standard), and in negative ionization mode at m/z 337.02 → 190.12 for chlorthalidone. The method was linear over the concentration ranges 30-2,000 ng/ml for sacubitril, 70-2,000 ng/ml for valsartan, esomeprazole and chlorthalidone and 70-5,000 pg/ml for nebivolol. The developed method is sensitive and selective and could be applied for dose adjustment, bioavailability and drug-drug interaction studies.

Sacubitril/valsartan versus enalapril on exercise capacity in patients with heart failure with reduced ejection fraction: A randomized, double-blind, active-controlled study.

Sacubitril/valsartan reduces mortality in patients with heart failure with reduced ejection fraction (HFrEF) when compared with enalapril. However, it is unknown the effect of both treatments on exercise capacity. We compared sacubitril/valsartan versus enalapril in patients with HFrEF based on peak oxygen consumption (VO2) and 6-minute walk test (6-MWT). METHODS: We included 52 participants with HFrEF with a left ventricular ejection fraction <40% to receive either sacubitril/valsartan (target dose of 400 mg daily) or enalapril (target dose of 40 mg daily). Peak VO2 was measured by using cardiopulmonary exercise testing. Six-minute walk test was also performed. RESULTS: At 12 weeks, the sacubitril/valsartan (mean dose 382.6 ± 57.6 mg daily) group had increased peak VO2 of 13.1% (19.35 ± 0.99 to 21.89 ± 1.04 mL/kg/min) and enalapril (mean dose 34.4 ± 9.2 mg daily) 5.6% (18.58 ± 1.19 to 19.62 ± 1.25 mL/kg/min). However, no difference was found between groups (P = .332 interaction). At 24 weeks, peak VO2 increased 13.5% (19.35 ± 0.99 to 21.96 ± 0.98 mL/kg/min) and 12.0% (18.58 ± 1.19 to 20.82 ± 1.18 mL/kg/min) in sacubitril/valsartan (mean dose 400 ± 0 mg daily) and enalapril (mean dose 32.7 ± 11.0 mg daily), respectively. However, no differences were found between groups (P= .332 interaction). At 12 weeks, 6-MWT increased in both groups (sacubitril/valsartan: 459 ± 18 to 488 ± 17 meters [6.3%] and enalapril: 443 ± 22 to 477 ± 21 meters [7.7%]). At 24 weeks, sacubitril/valsartan increased 18.3% from baseline (543 ± 26 meters) and enalapril decreased slightly to 6.8% (473 ± 31 meters), but no differences existed between groups (P= .257 interaction). CONCLUSIONS: Compared to enalapril, sacubitril/valsartan did not substantially improve peak VO2 or 6-MWT after 12 or 24 weeks in participants with HFrEF. (NEPRIExTol-HF Trial, ClinicalTrials.gov number, NCT03190304).

Effect of Neprilysin Inhibition on Left Ventricular Remodeling in Patients With Asymptomatic Left Ventricular Systolic Dysfunction Late After Myocardial Infarction.

BACKGROUND: Patients with left ventricular (LV) systolic dysfunction after myocardial infarction are at a high risk of developing heart failure. The addition of neprilysin inhibition to renin angiotensin system inhibition may result in greater attenuation of adverse LV remodeling as a result of increased levels of substrates for neprilysin with vasodilatory, antihypertrophic, antifibrotic, and sympatholytic effects. METHODS: We performed a prospective, multicenter, randomized, double-blind, active-comparator trial comparing sacubitril/valsartan 97/103 mg twice daily with valsartan 160 mg twice daily in patients ≥3 months after myocardial infarction with a LV ejection fraction ≤40% who were taking a renin angiotensin system inhibitor (equivalent dose of ramipril ≥2.5 mg twice daily) and a ß-blocker unless contraindicated or intolerant. Patients in New York Heart Association class ≥II or with signs and symptoms of heart failure were excluded. The primary outcome was change from baseline to 52 weeks in LV end-systolic volume index measured using cardiac magnetic resonance imaging. Secondary outcomes included other magnetic resonance imaging measurements of LV remodeling, change in NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin I, and a patient global assessment of change questionnaire. RESULTS: From July 2018 to June 2019, we randomized 93 patients with the following characteristics: mean age, 60.7±10.4 years; median time from myocardial infarction, 3.6 years (interquartile range, 1.2-7.2); mean LV ejection fraction, 36.8%±7.1%; and median NT-proBNP, 230 pg/mL (interquartile range, 124-404). Sacubitril/valsartan, compared with valsartan, did not significantly reduce LV end-systolic volume index; adjusted between-group difference, -1.9 mL/m2 (95% CI, -4.9 to 1.0); P=0.19. There were no significant between-group differences in NT-proBNP, high-sensitivity cardiac troponin I, LV end-diastolic volume index, left atrial volume index, LV ejection fraction, LV mass index, or patient global assessment of change. CONCLUSIONS: In patients with asymptomatic LV systolic dysfunction late after myocardial infarction, treatment with sacubitril/valsartan did not have a significant reverse remodeling effect compared with valsartan. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03552575.

Sacubitril/valsartan treatment has differential effects in modulating diabetic kidney disease in db/db mice and KKAy mice compared with valsartan treatment.

Although renin-angiotensin blockade has shown beneficial outcomes in patients with diabetes, renal injury progresses in most of these patients. Therefore, there remains a need for new therapeutic targets in diabetic kidney disease. Enhancement of vasoactive peptides, such as natriuretic peptides, via neprilysin inhibition, has been a new approach. A first-in-class drug, sacubitril/valsartan (Sac/Val), a combination of the angiotensin II receptor blocker Val and neprilysin inhibitor prodrug Sac, has been shown to be more effective than renin-angiotensin blockade alone in the treatment of heart failure with reduced ejection fraction. In this study, we tested the effects of Sac/Val in diabetic kidney disease. We administered Sac/Val or Val to two type 2 diabetes mouse models, db/db mice or KKAy mice. After 3 mo of treatment, Sac/Val attenuated the progression of proteinuria, glomerulosclerosis, and podocyte loss in both models of diabetic mice. Val shared a similar improvement but to a lesser degree in some parameters compared with Sac/Val. Sac/Val but not Val decreased the blood glucose level in KKAy mice. Sac/Val exerted renal protection through coordinated effects on antioxidative stress and anti-inflammation. In both diabetic models, we revealed a new mechanism to cause inflammation, self-DNA-activated cGMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling, which was activated in diabetic kidneys and prevented by Sac/Val or Val treatment. The present data suggest that Sac/Val has sufficient therapeutical potential to counter the pathophysiological effects of diabetic kidney disease, and its effectiveness could be better than Val alone.NEW & NOTEWORTHY The first-in-class drug sacubitril/valsartan, a combination of the angiotensin II receptor blocker valsartan and neprilysin inhibitor sacubitril, was tested for its effects in diabetic kidney disease using db/db mice and KKAy mice. We found that Sac/Val has sufficient therapeutical potential to counter the pathophysiological effects of diabetic kidney disease. We further revealed a new mechanism to cause inflammation, self-DNA-activated cGAS-STING signaling, which was activated in diabetic kidneys and prevented by sacubitril/valsartan or valsartan treatment.

Clinical Characteristics and Outcomes of Patients With Heart Failure With Reduced Ejection Fraction and Chronic Obstructive Pulmonary Disease: Insights From PARADIGM-HF.

Background Chronic obstructive pulmonary disease (COPD) is a common comorbidity in heart failure with reduced ejection fraction, associated with undertreatment and worse outcomes. New treatments for heart failure with reduced ejection fraction may be particularly important in patients with concomitant COPD. Methods and Results We examined outcomes in 8399 patients with heart failure with reduced ejection fraction, according to COPD status, in the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor Blocker-Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. Cox regression models were used to compare COPD versus non-COPD subgroups and the effects of sacubitril/valsartan versus enalapril. Patients with COPD (n=1080, 12.9%) were older than patients without COPD (mean 67 versus 63 years; P<0.001), with similar left ventricular ejection fraction (29.9% versus 29.4%), but higher NT-proBNP (N-terminal pro-B-type natriuretic peptide; median, 1741 pg/mL versus 1591 pg/mL; P=0.01), worse functional class (New York Heart Association III/IV 37% versus 23%; P<0.001) and Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (73 versus 81; P<0.001), and more congestion and comorbidity. Medical therapy was similar in patients with and without COPD except for beta-blockade (87% versus 94%; P<0.001) and diuretics (85% versus 80%; P<0.001). After multivariable adjustment, COPD was associated with higher risks of heart failure hospitalization (hazard ratio [HR], 1.32; 95% CI, 1.13-1.54), and the composite of cardiovascular death or heart failure hospitalization (HR, 1.18; 95% CI, 1.05-1.34), but not cardiovascular death (HR, 1.10; 95% CI, 0.94-1.30), or all-cause mortality (HR, 1.14; 95% CI, 0.99-1.31). COPD was also associated with higher risk of all cardiovascular hospitalization (HR, 1.17; 95% CI, 1.05-1.31) and noncardiovascular hospitalization (HR, 1.45; 95% CI, 1.29-1.64). The benefit of sacubitril/valsartan over enalapril was consistent in patients with and without COPD for all end points. Conclusions In PARADIGM-HF, COPD was associated with lower use of beta-blockers and worse health status and was an independent predictor of cardiovascular and noncardiovascular hospitalization. Sacubitril/valsartan was beneficial in this high-risk subgroup. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01035255.

Renal protective effect of sacubitril/valsartan in patients with heart failure.

Sacubitril/valsartan is a combined neprilysin inhibitor/angiotensin II receptor blocker designed for treatment of heart failure (HF). Nonetheless, its renal protective effect remained an issue of debate. This retrospective cohort study investigated the renal protective effect of sacubitril/valsartan in HF patients. HF patients on sacubitril/valsartan or valsartan for > 30 days were matched for gender, age, estimated glomerular filtration rate (eGFR), and left ventricular ejection fraction (LVEF) to be enrolled into analysis. The follow-up period was 18 months. The outcomes included end eGFR, renal function decline defined as 20% reduction of eGFR, mortality, and HF-related hospitalization. Each group had 137 patients after matching. The mean age was 72.7 years and 65.7% were male. Mean eGFR was 70.9 mL/min/1.73 m2 and LVEF was 54.0% at baseline. Overall, the eGFR of sacubitril/valsartan groups was significantly higher than valsartan group at the end (P < 0.01). Subgroup analysis showed that the difference in eGFR was significant in subgroups with LVEF ≥ 40% or eGFR ≥ 60 mL/min/1.73 m2. Multivariate Cox regression model showed that sacubitril/valsartan group had significantly reduced risk for renal function decline (hazard ratio: 0.5, 95% confidence interval: 0.3-0.9). Kaplan-Meier curve showed no difference in the risk for cardiovascular mortality, all-cause mortality or HF-related hospitalization. We showed renal protective effect of neprilysin inhibition in HF patients and specified that subgroups with LVEF ≥ 40% or eGFR ≥ 60 mL/min/1.73 m2 were sensitive to this effect, suggesting an optimal subgroup of this treatment.