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Patients with heart failure with preserved ejection fraction were assigned to receive sacubitril–valsartan or valsartan. At a median of 35 months, there was no significant between-group difference in the composite outcome of total hospitalizations for heart failure or death from cardiovascular causes.

Patients with acute decompensated heart failure were randomly assigned to receive sacubitril–valsartan or enalapril. At 8 weeks, the sacubitril–valsartan group had a greater reduction in the N-terminal pro–B-type natriuretic peptide concentration than the enalapril group.

The angiotensin receptor–neprilysin inhibitor LCZ696 was compared with the ACE inhibitor enalapril in patients with advanced heart failure. LCZ696 was superior to enalapril in all outcomes. Neprilysin inhibition may replace ACE inhibition for the treatment of heart failure. Angiotensin-converting–enzyme (ACE) inhibitors have been the cornerstone of the treatment for heart failure and a reduced ejection fraction for nearly 25 years, since enalapril was shown to reduce the risk of death in two trials. 1 , 2 Long-term treatment with enalapril decreased the relative risk of death by 16% among patients with mild-to-moderate symptoms. 2 The effect of angiotensin-receptor blockers (ARBs) on mortality has been inconsistent, 3 , 4 and thus, these drugs are recommended primarily for patients who have unacceptable side effects (primarily cough) while receiving ACE inhibitors. Subsequent studies showed that the use of beta-blockers and mineralocorticoid-receptor antagonists, when added to ACE . . .

Heart failure with preserved ejection fraction is associated with substantial morbidity and mortality, but effective treatments are lacking. We assessed the efficacy and safety of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), in patients with this disorder. PARAMOUNT was a phase 2, randomised, parallel-group, double-blind multicentre trial in patients with New York Heart Association (NYHA) class II–III heart failure, left ventricular ejection fraction 45% or higher, and NT-proBNP greater than 400 pg/mL. Participants were randomly assigned (1:1) by central interactive voice response system to LCZ696 titrated to 200 mg twice daily or valsartan titrated to 160 mg twice daily, and treated for 36 weeks. Investigators and participants were masked to treatment assignment. The primary endpoint was change in NT-proBNP, a marker of left ventricular wall stress, from baseline to 12 weeks; analysis included all patients randomly assigned to treatment groups who had a baseline and at least one postbaseline assessment. This trial is registered at Clinicaltrials.gov, number NCT00887588. 149 patients were randomly assigned to LCZ696 and 152 to valsartan; 134 in the LCZ696 group and 132 in the valsartan group were included in analysis of the primary endpoint. NT-proBNP was significantly reduced at 12 weeks in the LCZ696 group compared with the valsartan group (LCZ696: baseline, 783 pg/mL [95% CI 670–914], 12 weeks, 605 pg/mL [512–714]; valsartan: baseline, 862 pg/mL [733–1012], 12 weeks, 835 [710–981]; ratio LCZ696/valsartan, 0·77, 95% CI 0·64–0·92, p=0·005). LCZ696 was well tolerated with adverse effects similar to those of valsartan; 22 patients (15%) on LCZ696 and 30 (20%) on valsartan had one or more serious adverse event. In patients with heart failure with preserved ejection fraction, LCZ696 reduced NT-proBNP to a greater extent than did valsartan at 12 weeks and was well tolerated. Whether these effects would translate into improved outcomes needs to be tested prospectively. Novartis.

LCZ696 is a first-in-class inhibitor of the angiotensin II receptor and neprilysin. We aimed to establish whether the dual actions of LCZ696 lead to further lowering of blood pressure, compared with the angiotensin-receptor blocker valsartan. 1328 patients aged 18–75 years with mild-to-moderate hypertension were randomly assigned (double-blind) to 8 weeks' treatment in one of eight groups: 100 mg (n=156 patients), 200 mg (n=169), or 400 mg (n=172) LCZ696; 80 mg (n=163), 160 mg (n=166), or 320 mg (n=164) valsartan; 200 mg AHU377 (n=165); or placebo (n=173). The primary endpoint was the mean difference across the three single-dose pairwise comparisons of LCZ696 versus valsartan (100 mg vs 80 mg, 200 mg vs 160 mg, and 400 mg vs 320 mg) in mean sitting diastolic blood pressure during the 8-week treatment period. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00549770. 1215 patients completed the 8-week treatment period. The average reduction in mean sitting diastolic blood pressure across the doses of LCZ696 versus the appropriate comparator dose of valsartan showed significantly greater reductions with LCZ696 (mean reduction: −2·17 mm Hg, 95% CI −3·28 to −1·06; p<0·0001). The reduction in mean sitting diastolic blood pressure was significantly different for 200 mg LCZ696 versus 160 mg valsartan (−2·97 mm Hg, 95% CI −4·88 to −1·07, p=0·0023) and for 400 mg LCZ696 versus 320 mg valsartan (−2·70 mm Hg, −4·61 to −0·80, p=0·0055). LCZ696 was well tolerated and no cases of angio-oedema were reported; only three serious adverse events occurred during the 8-week treatment period, of which none was judged to be related to the study drug, and no patients died. Compared with valsartan, dual-acting LCZ696 provides complementary and fully additive reduction of blood pressure, which suggests that the drug holds promise for treatment of hypertension and cardiovascular disease. Novartis.

Debates have been existed regarding the treatment of moderate ischemic mitral regurgitation (IMR) in patients undergoing coronary artery bypass grafting (CABG). While it might have priority on reducing the risk of recurrent IMR, studies showed that concomitant mitral valve repair increases the risk of adverse outcomes, such as neurological events, as well as the in-hospital costs. In recent studies, angiotensin receptor/neprilysin inhibitor (ARNI) was discovered to have potential benefit in reducing the severity of IMR. The ARNI-MIMIC is a randomized controlled clinical trial aiming to reduce the risk of recurrent IMR in isolated CABG patients. A total of 220 eligible patients with moderate IMR will be allocated into control (non-ARNI) and intervention (ARNI) groups in a 1:1 pattern after isolated CABG. Patients in the intervention group will be administered with continuous sacubitril/valsartan for 6 months postoperatively, while patients in the control group will receive guideline recommended therapy only. All of the patients will be invited to complete 6-month follow-up. The primary endpoint is the change in the effective regurgitant orifice area (EROA) of the mitral valve, which is obtained by echocardiography and calculated by subtracting the follow-up EROA from the preoperative EROA. This trial aims to investigate the potential role of ARNI as compared to the control in moderate IMR patients undergoing isolated CABG. If ARNI is proven to reduce the risk of moderate IMR recurrence, patients will benefit from both improved life quality and decreased medical costs. The This study was approved by the Institutional Review Board of Fuwai Hospital on October 18th 2024, with an approval number of 2024-2446. The results of this trail will be disseminated through international academic conferences and publication in medical journals regardless of the study outcomes. ClinicalTrials.gov ID NCT06917664

•Subanalyses of key HFpEF trials suggest a preferential benefit for specific heart failure therapies in women.•In PARAGLIDE-HF, treatment with sacubitril/valsartan led to a greater reduction in NT-proBNP levels and was associated with clinical benefit compared to valsartan alone.•In this prespecified subgroup analysis of PARAGLIDE-HF, the efficacy, safety and tolerability of sacubitril/valsartan vs valsartan were similar in both women and men with an ejection fraction >40% and a recent worsening heart failure event.•Future prospective studies are needed to evaluate sex-specific differences in treatment response of HFpEF therapies. Sub-analyses of key trials suggest a preferential benefit for specific heart failure with preserved ejection fraction (HFpEF) therapies in women. This work investigated treatment effects between women and men in the PARAGLIDE-HF (Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF) trial. In this prespecified subgroup analysis, we examined outcomes according to sex in the PARAGLIDE-HF trial. The primary endpoint was time-average proportional change in amino terminal pro-B type natriuretic peptide (NT-proBNP) from baseline through Weeks 4 and 8. We also examined secondary outcomes and tolerability. Overall, 242 women (52%) and 224 men (48%) were randomized. Women had significantly higher LVEF, worse renal function, and less comorbidities than men. In the overall population, the time-averaged reduction in NT-proBNP was significantly greater for sacubitril/valsartan (sac/val) than valsartan (ratio of change 0.85, 95% CI, 0.73-0.999). When examined according to sex, the time-averaged reduction in NT-proBNP was numerically greater with sac/val in both women (ratio of change = 0.86, 95% CI, 0.69-1.070) and men (ratio of change 0.84, 95% CI, 0.67-1.05) with no differential treatment effect (P interaction = .91). Similarly, the secondary hierarchical endpoint favored sac/val over valsartan in both women and men but was not statistically significant. Study drug dosage levels were similar across women and men and there were no sex-specific differences in the incidence of adverse events. In patients with mildly reduced or preserved EF >40% and a recent worsening HF event, the efficacy, safety and tolerability of sac/val vs valsartan were similar in both women and men, suggesting consistent effects across appropriately selected patients regardless of sex. Future prospective studies are needed to further evaluate sex-specific differences in treatment response of HFpEF therapies. Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF; NCT03988634; https://www.clinicaltrials.gov/study/NCT03988634. [Display omitted]

This 8-week, multi-center, open-label study assessed the safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction. Patients (n=32) with mean sitting systolic blood pressure (msSBP) ⩾140 mm Hg (after a 2-5-week washout of previous antihypertensive medications) and estimated glomerular filtration rate (eGFR) ⩾15 and <60 ml min(-1) 1.73 m(-2) received LCZ696 100 mg with an optional titration to 200 and 400 mg in a sequential manner starting from Week 2 in patients with inadequate BP control (msSBP ⩾130 mm Hg and mean sitting diastolic blood pressure (msDBP) ⩾80 mm Hg) and without safety concerns. Safety was assessed by monitoring and recording all adverse events (AEs) and change in potassium and creatinine. Efficacy was assessed as change from baseline in msSBP/msDBP. The mean baseline BP was 151.6/86.9 mm Hg, urinary albumin/creatinine ratio (UACR) geometric mean was 7.3 mg mmol(-1) and eGFR was ⩾30 and <60 in 25 (78.1%) patients and was ⩾15 and <30 in 7 (21.9%) patients. Fourteen (43.8%) patients reported at least one AE, which were mild in severity. No severe AEs or deaths were reported. There were no clinically meaningful changes in creatinine, potassium, blood urea nitrogen and eGFR. The geometric mean reduction in UACR was 15.1%, and the mean reduction in msSBP and msDBP was 20.5±11.3 and 8.3±6.3 mm Hg, respectively, from baseline to Week 8 end point. LCZ696 was generally safe and well tolerated and showed effective BP reduction in Japanese patients with hypertension and renal dysfunction without a decline in renal function.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) determines the angiotensin converting enzyme 2 (ACE2) down-regulation and related decrease in angiotensin II degradation. Both these events trigger “cytokine storm” leading to acute lung and cardiovascular injury. A selective therapy for COVID-19 has not yet been identified. Clinical trials with remdesivir gave discordant results. Thus, healthcare systems have focused on “multi-targeted” therapeutic strategies aiming at relieving systemic inflammation and thrombotic complications. No randomized clinical trial has demonstrated the efficacy of renin angiotensin system antagonists in reducing inflammation related to COVID-19. Dexamethasone and tocilizumab showed encouraging data, but their use needs to be further validated. The still-controversial efficacy of these treatments highlighted the importance of organ injury prevention in COVID-19. Neprilysin (NEP) might be an interesting target for this purpose. NEP expression is increased by cytokines on lung fibroblasts surface. NEP activity is elevated in acute respiratory distress syndrome and it is conceivable that it is also high in COVID-19. NEP is implicated in the degradation of natriuretic peptides, bradykinin, substance P, adrenomedullin, and apelin that account for prevention of organ injury. Thus, NEP/angiotensin receptor type 1 (AT1R) inhibitor sacubitril/valsartan (SAC/VAL) may increase levels of these molecules and block AT1Rs required for ACE2 endocytosis in SARS-CoV-2 infection. Moreover, SAC/VAL has a positive impact on acute heart failure that is very frequently observed in deceased COVID-19 patients. The current review aims to summarize actual therapeutic strategies for COVID-19 and to examine the data supporting the potential benefits of SAC/VAL in COVID-19 treatment.

It is over 4 years since the Prospective Comparison of angiotensin receptor/neprilysin inhibitor (ARNI) with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial was published in New England Journal of Medicine. The PARADIGM-HF trial was the one that contributed to the official approval to use ARNI simultaneously with cardiac resynchronisation therapy (CRT) or implantable cardioverter-defibrillator (ICD) in patients who receive optimal medical treatment and still presented NYHA II-IV class symptoms according to the 2016 European Society of Cardiology Guidelines for the diagnosis and treatment of acute and chronic heart failure. The aim of this article is to summarise current knowledge on the activity of ARNI in a selected group of patients with heart failure with reduced ejection fraction (HFrEF) based on a recent PARADIGM-HF subanalysis in the field of renal function in patients with and without chronic kidney disease, glycaemia control in patients with diabetes, ventricular arrhythmias and sudden cardiac death and health-related quality of life. This article includes also recently announced findings on the TRANSITION study which revealed that HFrEF therapy with ARNI might be safely initiated after an acute decompensated heart failure episode, including patients with heart failure de novo and ACEI/ARB naïve, both hospitalised or shortly after discharge, in contrary to the PARADIGM-HF trial, where patients had to be administered a stable dose of an ACEI/ARB equivalent to enalapril 10 mg a day for at least 4 weeks before the screening.