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Rationale and design of TRANSITION: a randomized trial of pre-discharge vs. post-discharge initiation of sacubitril/valsartan.

ABSTRACT: AIMS:The prognosis after hospitalization for acute decompensated heart failure (ADHF) remains poor, especially <30 days post-discharge. Evidence-based medications with prognostic impact administered at discharge improve survival and hospital readmission, but robust studies comparing pre-discharge with post-discharge initiation are rare. The PARADIGM-HF trial established sacubitril/valsartan as a new evidence-based therapy in patients with heart failure (HF) and reduced left ventricular ejection fraction (<40%) (rEF). In common with other landmark studies, it enrolled patients who were ambulatory at the time of inclusion. In addition, there is also still limited knowledge of initiation and up-titration of sacubitril/valsartan in ACEi/ARB- naïve patients and in de novo HF with rEF patients. METHODS AND RESULTS:TRANSITION is a multicentre, open-label study in which ~1000 adults hospitalized for ADHF with rEF are randomized to start sacubitril/valsartan in a pre-discharge arm (initiated ?24 h after haemodynamic stabilization) or a post-discharge arm (initiated within Days 1-14 after discharge). The protocol allows investigators to select the appropriate starting dose and dose adjustments according to clinical circumstances. Over a 10 week treatment period, the primary and secondary objectives assess the feasibility and safety of starting sacubitril/valsartan in-hospital, early after haemodynamic stabilization. Exploratory objectives also include assessment of HF signs and symptoms, readmissions, N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T levels, and health resource utilization parameters. CONCLUSIONS:TRANSITION will provide new evidence about initiating sacubitril/valsartan following hospitalization for ADHF, occurring either as de novo ADHF or as deterioration of chronic HF, and in patients with or without prior ACEI/ARB therapy. The results of TRANSITION will thus be highly relevant to the management of patients hospitalized for ADHF with rEF.

SUBMITTER: Pascual-Figal D

PROVIDER: S-EPMC5880658 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Rationale and design of TRANSITION: a randomized trial of pre-discharge vs. post-discharge initiation of sacubitril/valsartan.

Pascual-Figal Domingo D Wachter Rolf R Senni Michele M Belohlavek Jan J Noè Adele A Carr David D Butylin Dmytro D

ESC heart failure 20171214 2

<h4>Aims</h4>The prognosis after hospitalization for acute decompensated heart failure (ADHF) remains poor, especially <30 days post-discharge. Evidence-based medications with prognostic impact administered at discharge improve survival and hospital readmission, but robust studies comparing pre-discharge with post-discharge initiation are rare. The PARADIGM-HF trial established sacubitril/valsartan as a new evidence-based therapy in patients with heart failure (HF) and reduced left ventricular e ...[more]

PMID: 29239515

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Project description:The PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial reported that sacubitril/valsartan (S/V), an angiotensin receptor-neprilysin inhibitor, significantly reduced mortality and heart failure (HF) hospitalization in HF patients with a reduced ejection fraction (HFrEF). However, fewer than 1% of patients in the PARADIGM-HF study had New York Heart Association (NYHA) functional class IV symptoms. Accordingly, data that informed the use of S/V among patients with advanced HF were limited. The LIFE (LCZ696 in Hospitalized Advanced Heart Failure) study was a 24-week prospective, multicenter, double-blinded, double-dummy, active comparator trial that compared the safety, efficacy, and tolerability of S/V with those of valsartan in patients with advanced HFrEF. The trial planned to randomize 400 patients ≥18 years of age with advanced HF, defined as an EF ≤35%, New York Heart Association functional class IV symptoms, elevated natriuretic peptide concentration (B-type natriuretic peptide [BNP] ≥250 pg/ml or N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥800 pg/ml), and ≥1 objective finding of advanced HF. Following a 3- to 7-day open label run-in period with S/V (24 mg/26 mg twice daily), patients were randomized 1:1 to S/V titrated to 97 mg/103 mg twice daily versus 160 mg of V twice daily. The primary endpoint was the proportional change from baseline in the area under the curve for NT-proBNP levels measured through week 24. Secondary and tertiary endpoints included clinical outcomes and safety and tolerability. Because of the COVID-19 pandemic, enrollment in the LIFE trial was stopped prematurely to ensure patient safety and data integrity. The primary analysis consists of the first 335 randomized patients whose clinical follow-up examination results were not severely impacted by COVID-19. (Entresto [LCZ696] in Advanced Heart Failure [LIFE STUDY] [HFN-LIFE]; NCT02816736).

Project description:ImportancePre-heart failure with preserved ejection fraction (pre-HFpEF) is common and has no specific therapy aside from cardiovascular risk factor management.ObjectiveTo investigate the hypothesis that sacubitril/valsartan vs valsartan would reduce left atrial volume index using volumetric cardiac magnetic resonance imaging in patients with pre-HFpEF.Design, setting, and participantsThe Personalized Prospective Comparison of ARNI [angiotensin receptor/neprilysin inhibitor] With ARB [angiotensin-receptor blocker] in Patients With Natriuretic Peptide Elevation (PARABLE) trial was a prospective, double-blind, double-dummy, randomized clinical trial carried out over 18 months between April 2015 and June 2021. The study was conducted at a single outpatient cardiology center in Dublin, Ireland. Of 1460 patients in the STOP-HF program or outpatient cardiology clinics, 461 met initial criteria and were approached for inclusion. Of these, 323 were screened and 250 asymptomatic patients 40 years and older with hypertension or diabetes, elevated B-type natriuretic peptide (BNP) greater than 20 pg/mL or N-terminal pro-b-type natriuretic peptide greater than 100 pg/mL, left atrial volume index greater than 28 mL/m2, and preserved ejection fraction greater than 50% were included.InterventionsPatients were randomized to angiotensin receptor neprilysin inhibitor sacubitril/valsartan titrated to 200 mg twice daily or matching angiotensin receptor blocker valsartan titrated to 160 mg twice daily.Main outcomes and measuresMaximal left atrial volume index and left ventricular end diastolic volume index, ambulatory pulse pressure, N-terminal pro-BNP, and adverse cardiovascular events.ResultsAmong the 250 participants in this study, the median (IQR) age was 72.0 (68.0-77.0) years; 154 participants (61.6%) were men and 96 (38.4%) were women. Most (n = 245 [98.0%]) had hypertension and 60 (24.0%) had type 2 diabetes. Maximal left atrial volume index was increased in patients assigned to receive sacubitril/valsartan (6.9 mL/m2; 95% CI, 0.0 to 13.7) vs valsartan (0.7 mL/m2; 95% CI, -6.3 to 7.7; P < .001) despite reduced markers of filling pressure in both groups. Changes in pulse pressure and N-terminal pro-BNP were lower in the sacubitril/valsartan group (-4.2 mm Hg; 95% CI, -7.2 to -1.21 and -17.7%; 95% CI, -36.9 to 7.4, respectively; P < .001) than the valsartan group (-1.2 mm Hg; 95% CI, -4.1 to 1.7 and 9.4%; 95% CI, -15.6 to 4.9, respectively; P < .001). Major adverse cardiovascular events occurred in 6 patients (4.9%) assigned to sacubitril/valsartan and 17 (13.3%) assigned to receive valsartan (adjusted hazard ratio, 0.38; 95% CI, 0.17 to 0.89; adjusted P = .04).Conclusions and relevanceIn this trial of patients with pre-HFpEF, sacubitril/valsartan treatment was associated with a greater increase in left atrial volume index and improved markers of cardiovascular risk compared to valsartan. More work is needed to understand the observed increased cardiac volumes and long-term effects of sacubitril/valsartan in patients with pre-HFpEF.Trial registrationClinicalTrials.gov Identifier: NCT04687111.

Project description:BackgroundThe angiotensin-receptor neprilysin inhibitor (ARNI) sacubitril/valsartan was shown to be superior to the angiotensin receptor blocker (ARB) valsartan in terms of reversing heart failure classification (NYHA classification), reducing N-terminal pro-brain natriuretic peptide (NT-proBNP) level and cardiovascular mortality in many studies. Yet, the efficacy of ARNI did not come from patients with acute myocardial infarction (AMI).MethodsWe searched databases for research published from inception to July 29, 2022, that reported cardiac reverse remodeling (CRR) or security indices. Two reviewers independently screened literature, extracted data, and assessed the risk of bias. Nine studies enrolling 1,369 patients were included to perform a meta-analysis. There were 716 patients in the ARNI group and 653 in the ARB group.ResultsARNI outperformed ARBs in terms of CRR indices, with striking changes in left ventricular ejection fraction (EF) (MD: 4.12%, 95%CI: 2.36, 5.88, P < 0.0001), diameter (MD: -3.40 mm, 95%CI: -4.30, -2.94, P < 0.00001, I 2 = 0%) and left atrial diameter (MD: -2.41 mm, 95%CI: -3.85, -0.97, P = 0.001, I 2 = 0%), other indices there showed no significant improvements. The incidences of major adverse cardiac events (RR: 0.47, 95%CI: 0.34-0.65, P < 0.00001, I 2 = 0%), the heart failure (RR: 0.37, 95%CI: 0.23-0.61, P < 0.0001, I 2 = 0%), readmission (RR: 0.54, 95%CI: 0.36-0.80, P = 0.003, I 2 = 29%) in the sacubitril/valsartan group were lower than the ARB group, while the incidences of cardiac death (RR: 0.56, 95%CI: 0.28, 1.09, P = 0.09), the myocardial infarction (RR: 0.83, 95% CI: 0.39, 1.77, P = 0.63), adverse side effects (RR: 1.67, 95% CI: 0.89, 3.13, P = 0.11) showed no difference.ConclusionThis research indicated that early initiation of sacubitril/valsartan in patients after AMI was superior to ARBs in reducing the risks of major adverse cardiac events, heart failure, readmission, and enhancing left ventricular EF, decreasing diameter, left atrial diameter. As for the other outcomes (the incidences of cardiac death, myocardial infarction, and adverse side effects), sacubitril/valsartan demonstrated no obvious advantage over ARBs.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier [CRD42022307237].

Project description:BackgroundHypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease with a broad spectrum of disease severity. HCM ranges from a benign course to a progressive disorder characterized by angina, heart failure, malignant arrhythmia, syncope, or sudden cardiac death. So far, no medical treatment has reliably shown to halt or reverse progression of HCM or to alleviate its symptoms. While the angiotensin receptor neprilysin inhibitor sacubitril/valsartan has shown to reduce mortality and hospitalization in heart failure with reduced ejection fraction, data on its effect on HCM are sparse.HypothesisA 4-month pharmacological (sacubitril/valsartan) or lifestyle intervention will significantly improve exercise tolerance (ie, peak oxygen consumption) in patients with nonobstructive HCM compared to the optimal standard therapy (control group).MethodsSILICOFCM is a prospective, multicenter, open-label, randomized, controlled, three-arm clinical trial (NCT03832660) that will recruit 240 adult patients with a confirmed diagnosis of nonobstructive HCM. Eligible patients are randomized to sacubitril/valsartan, lifestyle intervention (physical activity and dietary supplementation with inorganic nitrate), or optimal standard therapy alone (control group). The primary endpoint is the change in functional capacity (ie, peak oxygen consumption). Secondary endpoints include: (a) Change in cardiac structure and function as assessed by transthoracic echocardiography and cardiac magnetic resonance (MRI imaging), (b) change in biomarkers (ie, CK, CKMB, and NT-proBNP), (c) physical activity, and (d) quality of life.ResultsUntil December 2019, a total of 41 patients were recruited into the ongoing SILICOFCM study and were allocated to the study groups and the control group. There was no significant difference in key baseline characteristics between the three groups.ConclusionThe SILICOFCM study will provide novel evidence about the effect of sacubitril/valsartan or lifestyle intervention on functional capacity, clinical phenotype, injury and stretch activation markers, physical activity, and quality of life in patients with nonobstructive HCM.

Project description:AimsOptimizing medical cardiac treatment for sleep apnoea (SA) in patients with chronic heart failure and reduced ejection fraction (HFrEF) is an expert Grade C recommendation based on six studies encompassing a total of 67 patients only. Whether sacubitril-valsartan (SV), a cornerstone of HFrEF medical treatment, impacts SA is unknown and requires evaluation.Methods and resultsThe ENTRESTO-SAS trial is a six-centre, prospective, open-label real-life cohort study (NCT02916160). Ambulatory patients eligible for SV (i.e. HFrEF adults who remain symptomatic despite optimal treatment) were evaluated before and after 3 months of SV (including nocturnal ventilatory polygraphy); 118 patients were final analysed [median age was 66 (IQ25-75 : 56-73) years, 81.4% male, 36.5% New York Heart Association III-IV, N-terminal pro-B-type natriuretic peptide level of 1564 (701-3376) ng/L, left ventricular ejection fraction of 30 (25-34)%, 60.7% ischaemic HFrEF, 97.5% initially treated with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, 83.9% with beta-blockers, 64.4% with mineralocorticoid receptor antagonists, and 74.6% with diuretics]. Three groups were defined according to initial central/obstructive apnoea-hypopnoea indices (AHIs): G1 (n = 49, AHIcentral ≥ 5/h and AHIobstructive < 15/h); G2 (n = 27, AHIobstructive ≥ 15/h); and G3 (n = 42, AHIcentral < 5/h and AHIobstructive < 15/h). At 3 months, the AHI (main predefined outcome) decreased significantly by -7.10/h (IQ25-75 : -16.10 to 0.40; P < 0.001) in G1 + G2 without positive airway pressure treatment (45 patients, median initial AHI of 24.20 (IQ25-75 : 16.40-43.50)/h). Of these, 24.4% presented an AHI decrease ≥50% and 37.78% had a final AHI < 15/h (tendency for improvement from an initial value of 20%: P = 0.0574). For G1 patients (n = 37), AHI significantly decreased from a median of 22.90 (16.00-43.50)/h to 19.20 (12.70-31.10)/h (P = 0.002). For G2 patients (n = 8), AHI decreased from a median of 30.10 (26.40-47.60)/h to 22.75 (14.60-36.90)/h (statistically non-significant, P = 0.059).ConclusionsIn this real-life population, SV treatment for 3 months in SA patients is associated with a significant decrease in AHI. These results support the current guidelines that recommend first an optimization of the HFrEF treatment in patients with HFrEF and central SA. A potential positive airway pressure sparing effect merits further investigation.

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.

Project description:ObjectivesThis study sought to describe the short-term health status benefits of angiotensin-neprilysin inhibitor (ARNI) therapy in patients with heart failure and reduced ejection fraction (HFrEF).BackgroundAlthough therapy with sacubitril/valsartan, a neprilysin inhibitor, improved patients' health status (compared with enalapril) at 8 months in the PARADIGM-HF (Prospective Comparison of ARNI with ACE inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) study, the early impact of ARNI on patients' symptoms, functions, and quality of life is unknown.MethodsHealth status was assessed by using the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ) in 3,918 outpatients with HFrEF and left ventricular ejection fraction ≤40% across 140 U.S. centers in the CHAMP-HF (Change the Management of Patients with Heart Failure) registry. ARNI therapy was initiated in 508 patients who were matched 1:2 to 1,016 patients who were not initiated on ARNI (no-ARNI), using a nonparsimonious time-dependent propensity score (6 sociodemographic factors, 23 clinical characteristics), prior KCCQ overall summary (KCCQ-OS) score, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker status.ResultsMultivariate linear regression demonstrated a greater mean improvement in KCCQ-OS in patients initiated on ARNI therapy (5.3 ± 19 vs. 2.5 ± 17.4, respectively; p < 0.001) over a median (interquartile range [IQR]) of 57 (32 to 104) days. The proportions of ARNI versus no-ARNI groups with ≥10-point (large) and ≥20-point (very large) improvements in KCCQ-OS were 32.7% versus 26.9%, respectively, and 20.5% versus 12.1%, respectively, consistent with numbers needed to treat of 18 and 12, respectively.ConclusionsIn routine clinical care, ARNI therapy was associated with early improvements in health status, with 20% experiencing a very large health status benefit compared with 12% who were not started on ARNI therapy. These findings support the use of ARNI to improve patients' symptoms, functions, and quality of life.

Dataset Information

Rationale and design of TRANSITION: a randomized trial of pre-discharge vs. post-discharge initiation of sacubitril/valsartan.

Publications

Rationale and design of TRANSITION: a randomized trial of pre-discharge vs. post-discharge initiation of sacubitril/valsartan.

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