LCZ696 In Patients Research Articles

The Antihypertensive Effects and Safety of LCZ696 in Patients with Hypertension: A Systemic Review and Meta-Analysis of Randomized Controlled Trials

Background: The management of hypertension remains suboptimal throughout the world. Methods: We performed a random-effects model meta-analysis of randomized controlled trials to determine the effectiveness and safety of sacubitril/valsartan (LCZ696) for the treatment of high arterial pressure. Relevant published articles from PubMed, Cochrane base, and Medline were examined, and the last search date was December 2020. Only published randomized controlled trials and double-blind studies were selected for further analysis. The mean reductions in systolic blood pressure (msSBP) and diastolic blood pressure (msDBP) in the sitting position, as well as the mean reductions in ambulatory systolic blood pressure (maSBP) and ambulatory diastolic blood pressure (maDBP), were assumed as efficacy endpoints. Adverse events (AEs) were considered as safety outcomes. Results: Ten studies with a total of 5931patients were included for analysis. Compared with placebo, LCZ696 had a significant reduction in msSBP (weight mean difference (WMD) = −6.52 mmHg, 95% confidence interval (CI): −8.57 to −4.47; p < 0.001), msDBP (WMD = −3.32 mmHg, 95% CI: −4.57 to −2.07; p < 0.001), maSBP (WMD = −7.08 mmHg, 95% CI: −10.48 to −3.68; p < 0.001), maDBP (WMD = −3.57 mmHg, 95% CI: −5.71 to −1.44, p < 0.001). In subgroup analysis, only 200 mg and 400 mg LCZ696 showed a significant BP reduction. There was no difference in the AE rate between the LCZ696 and placebo groups (WMD = 1.02, 95% CI: 0.83 to 1.27, p = 0.54). Egger’s test revealed a potential publication bias for msSBP (p = 0.025), but no publication bias for other outcomes. Conclusion: LCZ696 may reduce blood pressure more efficaciously than traditional therapy in hypertensive patients without increasing adverse effects.

Sacubitril/Valsartan Improves Left Atrial and Left Atrial Appendage Function in Patients With Atrial Fibrillation and in Pressure Overload-Induced Mice.

LCZ696 (sacubitril/valsartan) is an angiotensin receptor-neprilysin inhibitor and has shown beneficial effects in patients with heart failure. However, whether LCZ696 protects against left atrial (LA) and LA appendage (LAA) dysfunction is still unclear. The present study aimed to assess the efficacy of LCZ696 for improving the function of LA and LAA. We performed both a retrospective study comparing LCZ696 with angiotensin receptor blockers (ARBs) to assess the efficacy of LCZ696 in patients with atrial fibrillation and an animal study in a mouse model with pressure overload. LA peak systolic strain, LAA emptying flow velocity, and LAA ejection fraction (LAAEF) were significantly increased in patients with LCZ696 as compared with ARBs (p = 0.024, p = 0.036, p = 0.026, respectively). Users of LCZ696 had a lower incidence of spontaneous echocardiography contrast (p = 0.040). Next, patients were divided into two groups (LAAEF ≤ 20% and > 20%). Administration of LCZ696 in patients with LAAEF > 20% was more frequent than LAAEF ≤ 20% (p = 0.032). Even after controlling for LAA dysfunction-related risk factors (age, atrial fibrillation type, old myocardial infarction, hypertension, congestive heart failure, and prior stroke or transient ischemic attack), use of LCZ696 remained significantly associated with reduced probability of LAAEF ≤ 20% [odds ratio = 0.011; 95% confidence interval (0.000–0.533), p = 0.023]. To further confirmed effect of LCZ696 in LA function, we constructed a post-transverse aortic constriction model in mice. Mice with LCZ696 treatment showed lower LA dimension and higher left ventricular ejection fraction and LAA emptying flow velocity as compared with mice with vehicle or valsartan treatment. Meanwhile, as compared with vehicle or valsartan, LCZ696 significantly decreased LA fibrosis in mice. In summary, we provide evidence that LCZ696 may be more effective in improving LA and LAA function than ARBs in both humans and mice, which suggests that LCZ696 might be evaluated as a direct therapeutic for atrial remodeling and AF.

Is the cardioprotective effect of LCZ696 linked to increased cardiac regeneration?

LCZ696 treatment reduces the mortality and the risk of hospitalization of patients with hypertension or heart failure with a preserved ejection fraction by 20%. The LCZ696 molecule associates both an angiotensin receptor blocker (valsartan) and an inhibitor of neprilysin (NEP, sacubitril). NEP is an endopeptidase able to degrade several factors such as the natriuretic peptides, angiotensin II, bradykinin, endothelin-1. Despite the cardioprotective effect of LCZ696, its exact mechanism in the heart is not elucidated yet. The aim of this project is to determine whether a part of the cardioprotective effect of this treatment is due to the stimulation of heart regeneration. For this purpose, myocardial infarction was induced in 8–10 weeks-old C57BL/6 mice by ligature of the left anterior descending coronary artery. Mice were treated or not with LCZ696 (at 6 or 60 mg/kg) given by oral gavage once per day and sacrificed 10 days after surgery. For all mice, BrdU (1 mg/ml) was added to drinking water 1 day after surgery and during all the treatment period. The effect of the treatment on heart function, cardiomyocyte proliferation and neovascularization was evaluated. High dose of LCZ696 increases the ejection fraction (+23%) and the fractional shortening (+14%) of infarcted hearts. Heart remodeling (the percentage of increase of the left ventricular diameter) was decreased in systole (−49%). At the cellular level, the number of BrdU+ cardiomyocytes was increased with both doses of LCZ696 (+110% in the infarcted and border zone and + 216% in the remote zone for 6 mg/kg LCZ696). The total number of cardiomyocytes was also increased in the infarcted and border zone (+105%) and in the remote zone (+156%). In contrast, neovascularization measured after CD31 staining didn’t differ between groups. Understanding the cellular mechanisms underlying the beneficial effects of LCZ696 in patients suffering from chronic heart failure is crucial for its further clinical use.

Research progress of LCZ696 in patients with chronic heart failure

Chronic heart failure (CHF) is the performance of end-stage cardiovascular disease and the leading cause of death in recent years.With the rapid development of medical care, the mortality rate of heart failure is still high.This is one in the two major challenges in the cardiovascular field in the 21st century.The new drug LCZ696 is a dual inhibitors of angiotensin receptor blockers (ARB) and neprilysin (NEP), which may lead to new hope for patients with heart failure.In order to determine the efficacy and safety of LCZ696 in the treatment of heart failure, foreign countries have carried out some large-scale trials, such as PARAMOUT, PARADIGM, TITRATION and so on.The results of these studies reflected the superiority of LCZ696 compared with enalapril, valsartan and other drugs in the treatment of chronic heart failure.ARB/antiotensin converting enzyme inhibitors(ACEI) targets the angiotensin receptor to dilate blood vessels and inhibits the sympathetic nerve, but their effects on sodium withdrawal and diuresis are weak.The sacubitril in LCZ696 prevents natriuretic peptide from degrading, strengthens the natriuretic diuretic and further expansion of blood vessels.Thereby it improves water and sodium retention and cardiac function.It can play a better synergistic role combined with valsartan. Key words: LCZ696; Angiotensin receptor blockers; Neprilysin; Heart failure

Combined Neprilysin and RAS Inhibition in Cardiovascular Diseases: A Review of Clinical Studies.

The aim of this comprehensive review article is to emphasize on the possible exploration of a new therapeutic approach in the management of heart failure (HF) and other cardiovascular diseases: the renin-angiotensin-aldosterone system-neprilysin combination inhibitors, also called angiotensin receptor neprilysin inhibitor, valsartan/sacubitril (LCZ696). Sacubitril is an inhibitor of neutral endopeptidase (NEP) which degrades vasoactive peptides such as atrial natriuretic peptide and brain natriuretic peptide. Valsartan is an angiotensin receptor blocker which is usually used in hypertension. Although HF has been a global health burden, for decades there has been lack of novel therapeutic options as many trials failed due to potential side effects. With the published results of the landmark trial Prospective comparison of ARNI with ACEI to Determine the Impact on Global Mortality and morbidity in HF (PARADIGM-HF), a new direction in the treatment of HF is anticipated. This trial showed that LCZ696 was able to reduce the primary composite end point of cardiovascular death or HF hospitalization, and similar reduction was observed for cardiovascular death. This review article also highlights the results of 4 published trials of LCZ696 in both HTN and HF. After the results of PARADIGM-HF trial, the major challenge will be outcome in regular clinical practice, as subjects in the trial were mostly stable New York Heart Association class II patients with no comorbidities. In addition, many trials are simultaneously in progress regarding the use of LCZ696 in patients with diabetes, renal failure, and hepatic impairment. To conclude, sacubitril/valsartan significantly improved morbidity and mortality in patients with chronic HF, but it will need meticulous attention when used in real outpatient practice.

Role of Angiotensin Receptor-Neprilysin Inhibition in Heart Failure.

Numerous evidence-based medical and device therapies proven to reduce morbidity and mortality have advanced care for heart failure with reduced ejection fraction (HFrEF). The primacy of this approach has now been superseded by striking new data resulting in the approval of the combination of valsartan and sacubitril, a neprilysin inhibitor (also known as LCZ696), in 2015 for the treatment of HFrEF. LCZ696 is a novel heart failure drug that simultaneously inhibits the renin-angiotensin system and potentiates the natriuretic peptide system. In the Prospective Comparison of ARNI with ACE-I to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, LCZ696 significantly improved cardiovascular outcomes compared to current guideline-directed medical therapy. Compared to an angiotensin-converting enzyme (ACE) inhibitor, LCZ696 was associated with a 20% reduction in cardiovascular mortality (number needed to treat [NNT] 32) and a similar reduction in total mortality (NNT 36). Morbidity benefits of the drug were seen within 1month of initiation. However, hypotension due to enalapril or the LCZ696 regimen during a run-in phase eliminated 20% of patients. Safety concerns included the risk of angioedema and the theoretical concern of neurocognitive dysfunction due to the protean effects of neprilysin inhibition. The role of LCZ696 in patients with asymptomatic left ventricular systolic dysfunction is uncertain. LCZ696 is currently being evaluated in patients with heart failure with preserved ejection fraction, with promising initial results. LCZ696 represents a novel mechanistic approach to targeting heart failure with reduced ejection fraction, and ongoing studies will address its use in other cardiovascular populations.

LCZ696: The Next Step in Improving RAS Inhibition?

LCZ696 is a single molecule which combines the angiotensin receptor blocker valsartan with the neprilysn inhibitor sacubitril (AHU377). In the recently published PARADIGM-HF trial, LCZ696 proved superior to enalapril in reducing overall mortality, heart failure hospitalizations, and other endpoints in patients with systolic dysfunction heart failure. Increases in counter-regulatory natriuretic peptides which oppose sodium retention, vasoconstriction, and the deleterious structural changes which follow neurohormonal activation are thought to account for these improved outcomes. In two large hypertension studies, LCZ696 has proved to be a potent, effective antihypertensive agent with tolerability similar to valsartan and placebo and potency comparable to amlodipine. Although several have occurred in the heart failure population, there have been no cases of angioedema noted in the hypertension trials, although few black patients-a group at high risk for its occurrence-have been studied. Whether LCZ696 will displace angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) as preferred renin-angiotensin system (RAS) blocking agents in hypertension will require demonstration of improved long-term outcomes compared with currently preferred first-line drugs. In this regard, experience has shown that it is difficult to extrapolate results achieved in heart failure to the treatment of hypertension, a condition in which neurohormonal activation is less critical in determining long-term prognosis. It will be particularly important to demonstrate renal protection with LCZ696 in patients with diabetes, proteinuria, and hypertension-the only therapeutic area other than heart failure in which RAS blockade has proved essential for optimal endpoint reduction. Superiority over available RAS blockers in terms of 'vascular protection' in high-risk populations represents another path to acceptance of LCZ696 as a preferred agent in cardiovascular medicine.

Influence of Diabetes Mellitus on Cardiac Structure and Function and Response to Therapy with LCZ696 in Heart Failure with Preserved Ejection Fraction

Patients with diabetes mellitus (DM) are at increased risk for heart failure regardless of ejection fraction. We assessed the relationship between DM and cardiac structure and function, and response to therapy with the angiotensin receptor neprilysin inhibitor LCZ696 in patients with heart failure and preserved ejection fraction (HFpEF).

Efficacy and Safety of LCZ696, a First-in-Class Angiotensin Receptor Neprilysin Inhibitor, in Asian Patients With Hypertension

Abstract— LCZ696 (Japanese adopted name: sucabitril valsartan sodium hydrate), a first-in-class angiotensin receptor neprilysin inhibitor, concomitantly inhibits neprilysin and blocks angiotensin type 1 receptor. This randomized, double-blind, placebo-controlled study, the first in Asia for this drug, evaluated the dose-related efficacy and safety of LCZ696 in patients with hypertension using 24-hour ambulatory blood pressure (BP) monitoring. Asian patients aged ≥18 years (n=389) with hypertension were randomized to receive LCZ696 100 mg (n=100), 200 mg (n=101), 400 mg (n=96), or placebo (n=92) for 8 weeks . The primary end point was mean difference across the 3 single-dose pairwise comparisons of LCZ696 versus placebo in clinic diastolic BP after 8-week treatment. Key secondary efficacy variables included changes in clinic systolic BP and pulse pressure and changes in 24-hour, daytime, and nighttime ambulatory BPs and pulse pressure. Safety assessments included recording all adverse events and serious adverse events. A total of 362 patients completed the study. Reductions in clinic systolic BP, diastolic BP ( P &lt;0.0001), and pulse pressure ( P &lt;0.001) were significantly greater with all doses of LCZ696 than with placebo. There were also significant reductions in 24-hour, daytime, and nighttime ambulatory systolic BP, diastolic BP, and pulse pressure for all doses of LCZ696 compared with placebo ( P &lt;0.0001). LCZ696 was well tolerated, and no cases of angioedema were reported. In conclusion, LCZ696 is effective for the treatment of hypertension in Asian population and, in general, is safe and well tolerated. Clinical Trial Information— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01193101.

Short-term treatment with LCZ696 in patients with stable chronic heart failure: effect on biomarkers

Purpose: LCZ696 is an angiotensin receptor neprilysin inhibitor (ARNI) developed for the treatment of hypertension and heart failure (HF). Here, we evaluate the responses of plasma biomarkers, including aldosterone, active renin concentration (ARC), renin activity (PRA), and endothelin-1 to LCZ696. Methods: Patients with stable chronic HF (NYHA II-III, LVEF <40%) entered the open-label, 2-dose Phase II uptitration study. After a 24-h run-in period, patient received LCZ696 100mg bid for 7 days, followed by 200mg bid for 14 days. Plasma biomarkers were determined at baseline, and on Day 7 and Day 21, at the end of each dose treatment period. Results: 30 subjects entered the study, and 27 completed the study. The geometric mean ratio to baseline are (95% CI) for aldosterone (pg/mL): 0.93 (0.76, 1.14) on Day 7 and 0.79 (0.65, 0.95)* on Day 21; PRA (ng/mL/h): 3.94 (2.27, 6.87)* on Day 7 and 2.27 (1.20, 4.32)* on Day 21; ARC (pg/mL): 4.30 (2.78, 6.64)* on Day 7 and 3.50 (2.13, 5.76)* on Day 21; endothelin-1 (pg/ml): 0.90 (0.80, 1.01) on Day 7 and 0.80 (0.71, 0.91)* on Day 21 (*p< 0.05). No serious adverse events occurred during the study. Conclusion: Short-term treatment of HF patients with LCZ696 100mg and 200mg bid significantly increased PRA and ARC, and in addition LCZ696 200 mg bid significantly decreased plasma aldosterone and endothelin-1. These results indicate a significant impact on multiple components of the renin angiotensin aldosterone system in NYHA functional class II-III patients, and support the ongoing development programs of LCZ696 in HF and hypertension.

Renal effects of lcz696 in patients with heart failure and preserved ejection fraction: results from paramount

Renal effects of lcz696 in patients with heart failure and preserved ejection fraction: results from paramount