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Sacubitril/valsartan: evaluation of safety and efficacy as an antihypertensive treatment.

ABSTRACT: Hypertension (HTN) is a common disease state associated with extensive morbidity and mortality worldwide. It is often difficult for patients with HTN to achieve and maintain a goal blood pressure (BP), despite there being many effective treatment options available. Sacubitril/valsartan is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) that has garnered approval by the US Food and Drug Administration and the European Medicines Agency as a first-line treatment for heart failure with reduced ejection fraction. During clinical trials for heart failure as well as in independent trials for HTN, sacubitril/valsartan has demonstrated safety and efficacy when it comes to BP lowering, making it a promising antihypertensive agent. Most trials of sacubitril/valsartan were 8 to 12 weeks in length and demonstrated a clinically relevant BP lowering that was frequently more significant than its comparators. While more data are needed to confirm its role as an antihypertensive agent, the data available are promising and it is anticipated that sacubitril/valsartan will gain an indication of HTN.

SUBMITTER: Anderson SL

PROVIDER: S-EPMC6089617 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Sacubitril/valsartan: evaluation of safety and efficacy as an antihypertensive treatment.

Anderson Sarah L SL Marrs Joel C JC

Drugs in context 20180806

Hypertension (HTN) is a common disease state associated with extensive morbidity and mortality worldwide. It is often difficult for patients with HTN to achieve and maintain a goal blood pressure (BP), despite there being many effective treatment options available. Sacubitril/valsartan is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) that has garnered approval by the US Food and Drug Administration and the European Medicines Agency as a first-line treatment for heart failure ...[more]

PMID: 30116284

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Project description:ObjectivesThis study sought to evaluate the efficacy and safety of sacubitril/valsartan according to dose level achieved in the PIONEER-HF (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode) trial.BackgroundIn patients hospitalized for acute decompensated heart failure (ADHF), in-hospital initiation and continuation of sacubitril/valsartan as compared with enalapril is well tolerated, achieves a greater reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP), and reduces the risk of cardiovascular death or rehospitalization for HF through 8 weeks. However, not all patients achieve the target dose of sacubitril/valsartan, and its efficacy and safety in such patients are of interest.MethodsPIONEER-HF was a randomized, double-blind, active-controlled trial of sacubitril/valsartan versus enalapril in 881 patients stabilized during hospitalization for ADHF. Blinded study medication was administered for 8 weeks, with initial dosing selected based on the systolic blood pressure at randomization and titrated toward a target of sacubitril/valsartan 97/103 mg twice daily, or enalapril 10 mg twice daily, with an algorithm based on systolic blood pressure and the investigator's assessment of tolerability.ResultsAt 4 weeks, 199 (55%) patients allocated to sacubitril/valsartan and 211 (60%) patients allocated to enalapril were dispensed the target dose. Baseline characteristics were similar in the 2 treatment groups within each dose level. There was no heterogeneity across dose levels in the effect of sacubitril/valsartan on the reduction in NT-proBNP (pinteraction = 0.69), the reduction in cardiovascular death or rehospitalization for heart failure (pinteraction = 0.42), or the pre-specified adverse events of special interest through 8 weeks.ConclusionsIn hemodynamically stabilized patients with ADHF, the efficacy and safety of sacubitril/valsartan are generally consistent across dose levels. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890).

Project description:BackgroundIn patients stabilized during hospitalization for acute decompensated heart failure (HF), initiation of sacubitril/valsartan compared with enalapril decreased the risk of cardiovascular death or rehospitalization for HF without increasing the risk of adverse events. It is unknown whether potentially high-risk subpopulations have a similar risk-benefit profile.MethodsPIONEER-HF (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP [N-terminal pro-B type natriuretic peptide] in Patients Stabilized From an Acute HF Episode) was a multicenter, randomized, double-blind trial of in-hospital initiation of sacubitril/valsartan (n=440) versus enalapril (n=441) in patients stabilized during hospitalization for acute decompensated HF. The composite of cardiovascular death or rehospitalization for HF was adjudicated. Safety outcomes included worsening renal function, symptomatic hypotension, and hyperkalemia. We evaluated heterogeneity in the effect of sacubitril/valsartan on these efficacy and safety outcomes in selected subgroups of clinical concern: patients with baseline systolic blood pressure ≤118 mm Hg (median; n=448), baseline NT-proBNP >2701 pg/mL (median; n=395), estimated glomerular filtration rate <60 mL/minute per 1.73 m2 (n=455), ≥1 additional hospitalization for HF within the prior year (n=343), admission to the ICU during the index hospitalization (n=96), inotrope use during the index hospitalization (n=68), and severe congestion (n=219).ResultsThe relative risk reduction in cardiovascular death or rehospitalization for HF with sacubitril/valsartan versus enalapril was consistent across all high-risk subgroups (P interaction=non-significant [NS] for each). The risks of worsening renal function, symptomatic hypotension, and hyperkalemia with sacubitril/valsartan versus enalapril were also consistent in each high- versus low-risk subgroup (P interaction=NS for each).ConclusionsIn high-risk subpopulations admitted for acute decompensated HF, treatment with sacubitril/valsartan after initial stabilization conferred a consistent reduction in cardiovascular death or rehospitalization for HF and was well tolerated.

Project description:Sacubitril-valsartan has been shown to have superior effects over angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with heart failure (HF) and hypertension. The efficacy and safety of sacubitril-valsartan in patients with HF are controversial. We performed a meta-analysis of randomized controlled trials to assess and compare the effect and adverse events of sacubitril-valsartan, valsartan, and enalapril in patients with HF. We conducted a systematic search using PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov. Randomized controlled trials involving the use of sacubitril-valsartan in patients with HF were included. We assessed the pooled odds ratio (OR) of all-cause mortality, cardiovascular mortality, and hospitalization for HF in fixed-effects models and the pooled risk ratio (RR) of symptomatic hypotension, worsening renal function, and hyperkalaemia in fixed-effects models. Of the 315 identified records, six studies involving 14 959 patients were eligible for inclusion. Sacubitril-valsartan reduced the endpoints of all-cause mortality and cardiovascular mortality in patients with HF with reduced ejection fraction (HFrEF) in three trials with pooled ORs of 0.83 (P = 0.0006) and 0.78 (P < 0.0001), respectively. Regarding the composite outcome of hospitalization for HF in five trials, the pooled OR was 0.79 (P < 0.00001). Compared with enalapril or valsartan, sacubitril-valsartan was associated with a high risk of symptomatic hypotension (RR 1.47, P < 0.00001), low risk of worsening renal function (RR 0.81, P = 0.005), and low rate of serious hyperkalaemia (≥6.0 mmol/L) (RR 0.76, P = 0.0007) in all six trials. Compared with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, sacubitril-valsartan significantly decreased the risk of death from all causes or cardiovascular causes in HFrEF and hospitalization for HF in both patients with HFrEF and HF with preserved ejection fraction. Sacubitril-valsartan reduced the risk of renal dysfunction and serious hyperkalaemia but was associated with more symptomatic hypotension.

Project description:Background: Sacubitril/valsartan is a first-in-class angiotensin-receptor neprilysin inhibitor used to treat heart failure with reduced ejection fraction. The evidence base for this novel medication is largely based on one pivotal phase III trial which was stopped early due to significant clinical benefits being shown. However potential limitations in the trial design have been highlighted in recent medical literature, necessitating a thorough review of the evidence base for sacubitril/valsartan. Methods: This review will be conducted using the PRISMA reporting guidelines. Relevant randomised controlled trials (RCTs) for sacubitril/valsartan will be systematically searched for in Medline (PubMed), Embase, Cochrane library, Google Scholar, Web of Science, Toxline and Scopus. Clinical trials registries will be searched, as will eight grey literature databases. In addition, unpublished clinical study reports (CSRs) of relevant trials will be requested from the European Medicines Agency (EMA) and the Clinical Study Data Request database. Studies will be included if they involve randomising adult patients with heart failure to either sacubitril/valsartan or usual care with either an active comparator or placebo as a control. All relevant clinical and safety outcomes will be reviewed, particularly hospitalisation due to heart failure and cardiovascular mortality. Two reviewers will assess eligibility of selected trials for inclusion. Data extraction will be performed separately for trial publications, clinical trial registries and for CSRs using a piloted form. Methodological quality of included trials from published sources will be assessed separately using the recently updated Cochrane Risk of Bias tool version 2. Narrative synthesis of included studies will be conducted and, if appropriate, meta-analysis for clinical efficacy and safety outcomes. Discussion: This review will collate all available RCT data on sacubitril/valsartan including published and unpublished sources in order to obtain a more complete picture of the evidence base for sacubitril/valsartan. Registration: This protocol has been submitted for registration on PROSPERO.

Project description:Randomized clinical trials have shown that sacubitril-valsartan reduces the risks of mortality and hospitalization in patients with heart failure with reduced ejection fraction (HFrEF), but patients with kidney failure requiring dialysis were excluded. To investigate the comparative effectiveness of sacubitril-valsartan vs angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEIs or ARBs) in patients with HFrEF requiring hemodialysis. This retrospective, 1:1 propensity score-matched comparative effectiveness study included patients who were 18 years or older with HFrEF, enrolled in Medicare Parts A, B, and D, and survived at least 90 days receiving in-center hemodialysis from July 8, 2015, to December 31, 2020. Patients were excluded for less than 180 days of continuous Medicare Parts A, B, and D primary payer coverage or prior dispensing of sacubitril-valsartan. Data analysis was conducted from September 23, 2023, to June 25, 2024. New use of sacubitril-valsartan vs new or continued use of ACEIs or ARBs. The associations between initiation of sacubitril-valsartan therapy and all-cause mortality, cardiovascular mortality, all-cause hospitalization, and HF hospitalization were assessed using Cox proportional hazards regression models in a propensity score-matched sample. Participants included 1:1 matched pairs of 1434 sacubitril-valsartan users and 1434 ACEI or ARB users (mean [SD] age, 64 [13] years). Of the 2868 matched participants, 996 (65%) were male; 987 (34%) were Black or African American and 1677 (58%) were White; and median dialysis vintage was 3.8 (IQR, 1.8-6.3) years. The median follow-up was 0.9 (IQR, 0.4-1.7) years. Sacubitril-valsartan (vs ACEI or ARB) therapy was associated with a reduction in all-cause mortality (hazard ratio [HR], 0.82 [95% CI, 0.73-0.92]) and all-cause hospitalization (HR, 0.86 [95% CI, 0.79-0.93]) but not cardiovascular mortality (HR, 1.01 [95% CI, 0.86-1.19]) or HF hospitalization (HR, 0.91 [95% CI, 0.82-1.02]). There was a decrease in hyperkalemia (HR, 0.71 [95% CI, 0.62-0.81]) and no difference in hypotension (HR, 0.99 [95% CI, 0.83-1.19]). Only 195 participants (14%) ever received the maximum combination dose of sacubitril (97 mg twice daily) and valsartan (103 mg twice daily). In this comparative effectiveness study of patients with HFrEF requiring hemodialysis, sacubitril-valsartan therapy was associated with beneficial effects in all-cause mortality and all-cause hospitalization.

Dataset Information

Sacubitril/valsartan: evaluation of safety and efficacy as an antihypertensive treatment.

Publications

Sacubitril/valsartan: evaluation of safety and efficacy as an antihypertensive treatment.

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