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Sacubitril/valsartan, an angiotensin receptor‐neprilysin inhibitor, has demonstrated a superior blood pressure‐lowering effect compared with renin‐angiotensin system inhibitors in several clinical trials. However, there has been no available evidence on the comparison between sacubitril/valsartan and calcium channel blockers (CCBs), a well‐established class of antihypertensive drugs. In this open‐label, multicenter study, we aimed to demonstrate the efficacy and safety of sacubitril/valsartan versus amlodipine, one of the most widely used CCBs, after 8 weeks of treatment. A total of 359 Japanese patients with essential hypertension (office systolic blood pressure [SBP] ≥ 150 to < 180 mmHg), aged 18–79, were randomly assigned to receive either once‐daily sacubitril/valsartan 200 mg or once‐daily amlodipine 5 mg in a 1:1 allocation ratio. The primary endpoint was the noninferiority of sacubitril/valsartan compared with amlodipine in mean change in 24‐h SBP from baseline to Week 8, followed by a significance test as a secondary endpoint analysis. The mean change in 24‐h SBP in sacubitril/valsartan was noninferior to that in amlodipine (between‐treatment difference −0.62 mmHg [95% confidential interval: −3.23 to 1.98; p = 0.003 for noninferiority; independent t‐test with noninferiority margin 3.0 mmHg]), with no significant difference observed (p = 0.637). There was no significant difference in the incidence of adverse events (AEs). These results suggested that the blood pressure‐lowering effect of sacubitril/valsartan is comparable to that of amlodipine, with no marked differences in tolerability between the two groups. Sacubitril/valsartan, a potent antihypertensive drug comparable to amlodipine, is expected to improve blood pressure control in clinical practice.

In a randomized trial, 5661 patients with acute myocardial infarction and a reduced left ventricular ejection fraction, pulmonary congestion, or both were assigned to receive either sacubitril–valsartan or ramipril. At a median of 22 months, there was no significant difference between the two groups in the incidence of death from cardiovascular causes or incident heart failure.

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.

To investigate the effects of sacubitril valsartan sodium combined with levosimendan on improving cardiac and renal functions in patients with CRS. 90 patients with the cardiorenal syndrome who were hospitalized in our hospital from February 2020 to February 2022 were selected and divided into two groups, the control group, and the joint group, according to both single and double number methods, with 45 cases in each group. Patients who met the diagnostic criteria for CRS, were older than 18 years of age, had NYHA class II to IV, and had stage 1 or 2 chronic kidney disease were included in the study. Patients with severe hypersensitivity to the drugs used in this test, haemodynamic instability, combined hyperthyroidism, malignancy, severe pulmonary hypertension, cardiogenic shock, malignant arrhythmias and pregnant women were excluded. Among them, the control group was treated with sacubitril valsartan sodium alone, and the joint group was treated with levosimendan supplemented with the treatment method of the control group. The treatment effect, the improvement of cardiac and renal function, and the incidence of adverse reactions were compared between the two groups of CRS patients, and the prognostic effect was followed up 6 months after treatment. The total effective rate of treatment in the joint group was 95.56%, which was significantly higher than that in the control group of 80.00%, and the difference was statistically significant by using χ2 test (P < .05). After treatment, LVEF, LVEDD, and NT-proBNP levels in both groups were significantly improved compared with those before treatment (P < .05), and the improvement effect of each index in the joint group was more significant than that in the control group (P < .05). After treatment, the levels of SCr, BUN, and UA in both groups were significantly lower than those before treatment (P < .05), and the levels of each index in the joint group were significantly lower than those in the control group, statistical analyses showed significant differences (P < .05) using t test. The incidence of adverse effects such as tachycardia, premature ventricular contractions, heart failure, and myocardial ischaemia was 22.22% in the combined group, which was significantly lower than 42.22% in the control group, and the difference in the total incidence between the two groups was statistically significant by χ2 test (P < .05). One case of malignant arrhythmia and five cases of recurrence of heart failure occurred 6 months after surgery in the combined group, which were significantly lower than the eight and twelve cases in the control group. Sacubitril valsartan sodium combined with levosimendan can significantly improve the therapeutic effect of CRS, with significant improvement in cardiac and renal function of CRS patients, and its incidence of adverse effects and long-term prognostic effects are lower than those of sacubitril valsartan sodium alone. This combination therapy offers a promising new direction for CRS management, warranting further investigation in larger, multicenter trials.

The win ratio (WR) is an emerging alternative for reporting composite outcomes, prioritizing clinically significant events such as mortality while incorporating surrogate measures. However, its benefits should be weighed against limitations, particularly the influence of lower hierarchical outcomes. This secondary analysis of the PARAGLIDE-HF trial performed a WR sensitivity analysis using a modified hierarchical composite outcome to assess the utility of WR sensitivity analysis and the efficacy of sacubitril/valsartan versus valsartan. PARAGLIDE-HF compared sacubitril/valsartan with valsartan in heart failure (HF) patients with ejection fraction >40% (N = 466). A hierarchical outcome in the primary analysis included cardiovascular death, HF hospitalizations, urgent HF visits, and change in N-terminal pro–B-type natriuretic peptide (NT-proBNP), with a 25% decrease considered a win. In the prespecified subgroup with ejection fraction ≤60% (N = 357), sacubitril/valsartan showed a treatment effect on the hierarchical outcome (WR, 1.46; 95% CI, 1.08-1.97). Sensitivity analyses for this subgroup included: (1) excluding NT-proBNP change, (2) substituting the 25% proportion change of NT-proBNP with 10% or 50%, and (3) including renal outcomes within the hierarchical outcome. In addition to the WR, the win odds (WO), in which 50% of the ties are allocated to both the numerator and denominator of the WR—a potentially more suitable modification of the WR that accounts for the presence of ties—were presented. Excluding NT-proBNP (WR, 1.49; 95% CI, 1.00-2.22; WO, 1.12; 95% CI, 1.00-1.26), adjusting the NT-proBNP threshold from 25% to 10% or 50% (WR, 1.41; 95% CI, 1.06-1.89; WO, 1.27; 95% CI, 1.04-1.56 for 10%; and WR, 1.54; 95% CI, 1.11-2.12; WO, 1.25; 95% CI, 1.06-1.48 for 50%), and incorporating renal outcomes (WR, 1.44; 95% CI, 1.07-1.94; WO, 1.28; 95% CI, 1.05-1.56) consistently favored sacubitril/valsartan. Multiple WR sensitivity analyses support a consistent treatment benefit of sacubitril/valsartan versus valsartan in patients with ejection fraction >40% to 60%. Future studies could consider prespecifying WR sensitivity analysis for comprehensive assessment of treatment effects. PARAGLIDE-HF; ClinicalTrials.gov ID, NCT03988634 (https://clinicaltrials.gov/study/NCT03988634).

Diffuse interstitial fibrosis is associated with adverse outcomes in hypertensive heart disease and may be reversible. Sacubitril/valsartan could offer greater anti-fibrotic effects than valsartan alone. In the REVERSE-LVH phase 2 open-labelled trial (clinicaltrials.gov NCT: 03553810; funded by the National Medical Research Council of Singapore), 78 patients with essential hypertension and left ventricular hypertrophy (LVH) were randomized 1:1 to sacubitril/valsartan or valsartan for 52 weeks. Primary endpoint was a change in interstitial volume, assessed using cardiovascular magnetic resonance. Despite similar 24-hour systolic blood pressure at 52 weeks (125 ± 11 vs. 126 ± 11 mmHg; P  = 0.762), sacubitril/valsartan resulted in a greater absolute reduction in interstitial volume compared to valsartan (−5.2 ± 5.4 vs. −2.5 ± 3.1 mL; P  = 0.006). Secondary endpoints showed significant differences favoring sacubitril/valsartan in LV mass, left atrial volume, estimated LV filling pressure, and improved cardiac circulating biomarkers (N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T). Other markers of cardiac volumes, function and mechanics were similar between the two treatment arms. Here we show the potential myocardial benefits of sacubitril/valsartan beyond blood pressure control, though larger studies are needed to confirm their clinical relevance. Here the authors compare the efficacy between sacubitril/valsartan and valsartan in improving diffuse myocardial fibrosis in patients with hypertensive heart disease, assessed as change in interstitial volume with cardiovascular magnetic resonance. The results show potential myocardial benefits of sacubitril/valsartan beyond blood pressure control.

•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]

In the PARAGLIDE-HF trial, treatment with sacubitril/valsartan (Sac/Val) was associated with greater reduction in NT-proBNP than valsartan (Val) alone in patients stabilized after an episode of worsening heart failure (HF) with left ventricular ejection fraction (LVEF) >40%. Treatment effects were most apparent in the subgroup with LVEF below normal (≤60%). This prespecified analysis sought to compare the detailed treatment effects and adverse event profiles of Sac/Val vs Val in patients with LVEF ≤60% vs >60%. Baseline demographics and clinical characteristics were compared between patients with baseline LVEF ≤60% vs >60%. Rates of recurrent composite events (adjudicated CV death, HF hospitalizations, and urgent HF visits) were compared between groups using a semi-parametric proportional rates model. These recurrent composite events were also analyzed across the continuous LVEF spectrum using restricted cubic splines. Incidence of adverse events were analyzed using a logistic regression model with LVEF ≤60% vs >60%, treatment arm, and in-hospital/out-of-hospital randomization as covariates. The interaction of LVEF category and treatment arm was assessed for all models Compared to those with LVEF >60%, patients with LVEF ≤60% were younger with lower NYHA class, but similar NT-proBNP values at baseline and similar co-morbidity burden. Among patients with LVEF ≤60%, those treated with Sac/Val experienced fewer recurrent composite events compared to those treated with Val (rate ratio 0.60 [95% CI: 0.37-0.99], P = .046); predominantly driven by HF hospitalizations. Patients with LVEF >60% treated with Sac/Val vs Val demonstrated similar rates of recurrent composite events (RR 1.46 [0.77-2.79], P = .24) (interaction P-value = .032). This was consistent with the continuous analysis in which patients treated with Sac/Val were significantly less likely to have events compared with patients with Val at LVEF values below 58%. Patients with LVEF >60% treated with Sac/Val experienced more symptomatic hypotension (OR 3.55 [95% CI: 1.35-9.37], P = .01) compared to those treated with Val, whereas rates of symptomatic hypotension were comparable across treatment groups in patients with LVEF ≤60% (OR 1.36 [0.79-2.32], P = .27, interaction P-value .09). Compared to treatment with Val in patients with worsening HF and LVEF >40%, treatment with Sac/Val is associated with greater clinical benefit in those with LVEF ≤60% than in those with LVEF >60%. Clinicaltrials.gov identifier, NCT03988634.

IntroductionHypertension constitutes the primary health burden of cardiovascular diseases, and the global control of blood pressure (BP) remains insufficient. Single pill combinations (SPCs) are employed as a means to streamline the management of poor BP control due to non-adherence and treatment inertia. The compound reserpine and triamterene tablets constitute a quadruple SPC, comprising reserpine 0.1 mg, dihydralazine 12.5 mg, hydrochlorothiazide 12.5 mg and triamterene 12.5 mg. It is widely employed in primary medical institutions and has favourable efficacy, tolerability and cost-effectiveness.Methods and analysisThe COSPQ-BP trial is a 12-week prospective randomised controlled trial to enrol 1332 patients with primary mild-to-moderate hypertension. Participants who meet the inclusion criteria will be randomly assigned to a 1:1 ratio to an intervention group (compound reserpine and triamterene tablets) or a control group (valsartan/hydrochlorothiazide). The primary outcome will be mean changes from baseline in 24-hour ambulatory systolic BP after intervention for 12 weeks. The secondary outcomes have been predetermined and will primarily encompass the following: (1) changes in other BP measures, as well as changes in blood lipids, blood glucose and uric acid at 12 weeks and (2) evaluation of the impact of starting antihypertensive therapy with compound reserpine and triamterene tablets or valsartan/hydrochlorothiazide on the depressive and anxiety statess of patients.Ethics and disseminationThe study protocol (version number: V5.0, version date: 17 January 2023) has been approved by the ethics committee (Biomedical Ethics Committee of West China Hospital of Sichuan University, approval number: Review (51) in 2023). Written informed consent will be obtained from each participant by researchers. The findings of this study will be disseminated through conference presentations and peer-reviewed publications.Trial registrationThis study was registered at the Chinese Clinical Trials Registry (ChiCTR2300067920). The COSPQ-BP trial is currently enrolling. The study period will be from 1 January 2024 to 31 December 2025.

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.