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Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study.
Wachter, R, Senni, M, Belohlavek, J, Straburzynska-Migaj, E, Witte, KK, Kobalava, Z, Fonseca, C, Goncalvesova, E, Cavusoglu, Y, Fernandez, A, et al
European journal of heart failure. 2019;(8):998-1007
Abstract
AIMS: To assess tolerability and optimal time point for initiation of sacubitril/valsartan in patients stabilised after acute heart failure (AHF). METHODS AND RESULTS TRANSITION was a randomised, multicentre, open-label study comparing two treatment initiation modalities of sacubitril/valsartan. Patients aged ≥ 18 years, hospitalised for AHF were stratified according to pre-admission use of renin-angiotensin-aldosterone system inhibitors and randomised (n = 1002) after stabilisation to initiate sacubitril/valsartan either ≥ 12-h pre-discharge or between Days 1-14 post-discharge. Starting dose (as per label) was 24/26 mg or 49/51 mg bid with up- or down-titration based on tolerability. The primary endpoint was the proportion of patients attaining 97/103 mg bid target dose after 10 weeks. Median time of first dose of sacubitril/valsartan from the day of discharge was Day -1 and Day +1 in the pre-discharge group and the post-discharge group, respectively. Comparable proportions of patients in the pre- and post-discharge initiation groups met the primary endpoint [45.4% vs. 50.7%; risk ratio (RR) 0.90; 95% confidence interval (CI) 0.79-1.02]. The proportion of patients who achieved and maintained for ≥ 2 weeks leading to Week 10, either 49/51 or 97/103 mg bid was 62.1% vs. 68.5% (RR 0.91; 95% CI 0.83-0.99); or any dose was 86.0% vs. 89.6% (RR 0.96; 95% CI 0.92-1.01). Discontinuation due to adverse events occurred in 7.3% vs. 4.9% of patients (RR 1.49; 95% CI 0.90-2.46). CONCLUSIONS Initiation of sacubitril/valsartan in a wide range of heart failure with reduced ejection fraction patients stabilised after an AHF event, either in hospital or shortly after discharge, is feasible with about half of the patients achieving target dose within 10 weeks. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov ID: NCT02661217.
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Cardiovascular biomarkers in patients with acute decompensated heart failure randomized to sacubitril-valsartan or enalapril in the PIONEER-HF trial.
Morrow, DA, Velazquez, EJ, DeVore, AD, Prescott, MF, Duffy, CI, Gurmu, Y, McCague, K, Rocha, R, Braunwald, E
European heart journal. 2019;(40):3345-3352
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Abstract
AIMS: Circulating high-sensitivity cardiac troponin (hsTn) and soluble ST2 (sST2) reflect myocardial stress in patients with heart failure (HF). Production of cyclic guanosine 3'5' monophosphate (cGMP) in response to activation of natriuretic peptide receptors reduces cardiac afterload and preload. We assessed the effects of sacubitril/valsartan on these biomarkers in patients with reduced ejection fraction and acute decompensated HF (ADHF). METHODS AND RESULTS PIONEER-HF was a randomized, double-blind trial of sacubitril/valsartan vs. enalapril in hospitalized patients with ADHF following haemodynamic stabilization. We measured circulating hsTnT, sST2, and urinary cGMP at baseline, 1, 2 (sST2, cGMP), 4, and 8 weeks (n = 694 with all baseline biomarkers). Ratios of geometric means (timepoint/baseline) were determined and compared as a ratio for sacubitril/valsartan vs. enalapril. Compared with enalapril, sacubitril/valsartan led to a significantly greater decline in hsTnT and sST2. This effect emerged as early as 1 week for sST2 and was significant for both at 4 weeks with a 16% greater reduction in hsTnT (P < 0.001) and 9% greater reduction in sST2 (P = 0.0033). Serial urinary cGMP increased with sacubitril/valsartan compared with enalapril (P < 0.001, 1 week). The significant differences between treatment groups for each biomarker were sustained at 8 weeks. In an exploratory multivariable-adjusted analysis of cardiovascular death or HF-rehospitalization, the concentrations of hsTnT, sST2 at week 1 were significantly associated with subsequent outcome. CONCLUSION Biomarkers of myocardial stress are elevated in patients with ADHF and associated with outcome. Compared with enalapril, sacubitril/valsartan reduces myocardial injury and haemodynamic stress as reflected by biomarkers, with an onset that is apparent within 1-4 weeks. CLINICAL TRIALS REGISTRATION NCT02554890 clinical.trials.gov.
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Effects of the Angiotensin-Receptor Neprilysin Inhibitor on Cardiac Reverse Remodeling: Meta-Analysis.
Wang, Y, Zhou, R, Lu, C, Chen, Q, Xu, T, Li, D
Journal of the American Heart Association. 2019;(13):e012272
Abstract
Background The angiotensin-receptor neprilysin inhibitor (ARNI) sacubitril/valsartan was shown to be superior to the angiotensin-converting enzyme inhibitor enalapril in terms of reducing cardiovascular mortality in the PARADIGM-HF (Prospective Comparison of ARNI with angiotensin-converting enzyme inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) study. However, the impact of ARNI on cardiac reverse remodeling (CRR) has not been established. Methods and Results We conducted a meta-analysis to compare the effects of ARNI versus angiotensin-converting enzyme inhibitors or angiotensin receptor blockers on CRR indices. We searched databases for studies published between 2010 and 2019 that reported CRR indices following ARNI administration. Effect size was expressed as mean difference (MD) with 95% CIs. Twenty studies enrolling 10 175 patients were included. ARNI improved functional capacity in patients with heart failure (HF) and a reduced ejection fraction (EF), including increasing New York Heart Association functional class (MD -0.79, 95% CI -0.86, -0.71) and 6-minute walking distance (MD 27.62 m, 95% CI 15.76, 39.48). ARNI outperformed angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in terms of CRR indices, with striking changes in left ventricular EF, diameter, and volume. However, there were no significant improvements in indices except left ventricular mass index (MD -3.25 g/m2, 95% CI -3.78, -2.72) and left atrial volume (MD -7.20 mL, 95% CI -14.11, -0.29) in HF patients with preserved EF treated with ARNI. Improvements in CRR indices were observed at 3 months and became more significant with longer follow-up to 12 months. The regression equation for the relationship between left ventricular EF and end-diastolic dimension was y=0.041+0.071x+0.045x2+0.006x3. Conclusions ARNI distinctly improved left ventricular size and hypertrophy compared with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in HF with reduced EF patients, even after short-term follow-up. Patients appeared to benefit more in terms of CRR treated with ARNI as early as possible and for at least 3 months. Further large sample trials are required to determine the effects of ARNI on CRR in HF with preserved EF patients.
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B-Type Natriuretic Peptide During Treatment With Sacubitril/Valsartan: The PARADIGM-HF Trial.
Myhre, PL, Vaduganathan, M, Claggett, B, Packer, M, Desai, AS, Rouleau, JL, Zile, MR, Swedberg, K, Lefkowitz, M, Shi, V, et al
Journal of the American College of Cardiology. 2019;(11):1264-1272
Abstract
BACKGROUND Natriuretic peptides are substrates of neprilysin; hence, B-type natriuretic peptide (BNP) concentrations rise with neprilysin inhibition. Thus, the clinical validity of measuring BNP in sacubitril/valsartan-treated patients has been questioned, and use of N-terminal pro-B-type natriuretic peptides (NT-proBNP) has been preferred and recommended. OBJECTIVES The purpose of this study was to determine the prognostic performance of BNP measurements before and during treatment with sacubitril/valsartan. METHODS BNP and NT-proBNP were measured before and after 4 to 6 weeks, 8 to 10 weeks, and 9 months of treatment with sacubitril/valsartan in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. We assessed the association of levels of these natriuretic peptides with the subsequent risk of cardiovascular death or hospitalization for HF. RESULTS Median BNP concentration (before treatment: 202 ng/l [Q1 to Q3: 126 to 335 ng/l]) increased to 235 ng/l (Q1 to Q3: 128 to 422 ng/l) after 8 to 10 weeks of treatment. BNP concentrations doubled in 141 (18%) patients and tripled in 49 (6%) patients during the first 8 to 10 weeks of sacubitril/valsartan. In contrast, such striking increases in NT-proBNP following the use of the neprilysin inhibitor were extremely rare. Treatment with sacubitril/valsartan caused a rightward shift in the distribution of BNP when compared with NT-proBNP, but both peptides retained their prognostic accuracy (C-statistics of 63% to 67% for BNP and C-statistics of 64% to 70% for NT-proBNP) with no difference between the 2 biomarkers. Increases in both BNP and NT-proBNP during 8 to 10 weeks of sacubitril/valsartan were associated with worse outcomes (p = 0.003 and p = 0.005, respectively). CONCLUSIONS Circulating levels of BNP may increase meaningfully early after initiation of sacubitril/valsartan. In comparison, NT-proBNP is not a substrate of neprilysin inhibition, and thus may lead to less clinical confusion when measured within 8 to 10 weeks of drug initiation. However, during treatment, either biomarker predicts the risk of major adverse outcomes in patients treated with angiotensin receptor-neprilysin inhibitors. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255).
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Recent advances in the treatment of chronic heart failure.
Buckley, LF, Shah, AM
F1000Research. 2019
Abstract
After more than a decade of relatively modest advancements, heart failure therapeutic development has accelerated, with the PARADIGM-HF trial and the SHIFT trial demonstrated significant reductions in cardiovascular death and heart failure hospitalization for sacubitril-valsartan and in heart failure hospitalization alone for ivabradine. Several heart failure therapies have since received or stand on the verge of market approval and promise substantive advances in the treatment of chronic heart failure. Some of these improve clinical outcomes, whereas others improve functional or patient-reported outcomes. In light of these rapid advances in the care of adults living with chronic heart failure, in this review we seek to update the general practitioner on novel heart failure therapies. Specifically, we will review recent data on the implementation of sacubitril-valsartan, treatment of functional mitral regurgitation, sodium-glucose co-transporter-2 (SGLT-2) inhibitor therapy, agents for transthyretin amyloid cardiomyopathy, treatment of iron deficiency in heart failure, and the use of biomarkers or remote hemodynamic monitoring to guide heart failure therapy.
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Activity Sensors to Evaluate the Effect of Sacubitril/Valsartan on Quality-of-Life in Heart Failure: rational and design of the AWAKE-HF study.
Khandwalla, RM, Birkeland, K, Heywood, JT, Steinhubl, S, McCague, K, Fombu, E, Grant, D, Riebman, JB, Owens, RL
ESC heart failure. 2019;(6):1313-1321
Abstract
AIMS: Limited data are available regarding the ability of sacubitril/valsartan to provide clinically meaningful health-related quality of life (HRQoL) improvements among individuals with heart failure (HF). Objective measurement of physical activity and sleep using actigraphy can provide insight into daily functioning and HRQoL. METHODS AND RESULTS We designed an 18 week, multicenter, randomized, double-blind, double-dummy, parallel-group study to objectively assess changes in function and HRQoL directly after initiating sacubitril/valsartan vs. enalapril in participants with HF in their home environments. A total of 136 outpatient, ambulatory participants with New York Heart Association Class II or III HF with reduced ejection fraction (HFrEF) will be included in the study. Patients will undergo a 2 week baseline observational phase (continuing current HF treatment); data from the second week of this phase will be the baseline value for comparison with those of subsequent periods. Patients will then enter an 8 week blinded-treatment phase (randomly assigned 1:1 to sacubitril/valsartan or enalapril), followed by an 8 week open-label extension phase (treatment with only sacubitril/valsartan). The primary efficacy endpoint is the change in mean activity counts during the most active 30 min of the participant's day between baseline and the final randomized treatment phase measurement. Secondary endpoints include the change in mean sleep activity during the randomized and open-label phases; questionnaires will also assess HRQoL measures. Rather than analysing pooled actigraphy data, the researchers are considering each participant to be acting as his or her own control. CONCLUSIONS This will be the first study to assess the effects of sacubitril/valsartan on objective measures of sleep and activity in individuals with HFrEF within the context of their daily lives. Wearable accelerometer devices will be used to gain insight into how the medication affects physical activity and sleep.
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Sacubitril/Valsartan: Updates and Clinical Evidence for a Disease-Modifying Approach.
Fabris, E, Merlo, M, Rapezzi, C, Ferrari, R, Metra, M, Frigerio, M, Sinagra, G
Drugs. 2019;(14):1543-1556
Abstract
New therapeutic strategies aimed to tackle the rising socio-economic burden of heart failure (HF) have become an impelling priority. The new pharmacological class of angiotensin (Ang) receptor-neprilysin inhibitors (ARNI) prompted a real conceptual change in the treatment of HF moving from only the inhibition of the renin-Ang-aldosterone system and sympathetic nervous system to a strategy based on the concomitant pharmacological enhancement of endogenous natriuretic peptides. Sacubitril/valsartan, a first-in-class ARNI, has reduced the primary composite endpoint of cardiovascular death or HF hospitalisation, sudden cardiac death, disease progression and improved quality of life, compared with enalapril, in patients on evidence-based contemporary medical therapy. Our review underlines the increasing body of evidence supporting the efficacy of sacubitril/valsartan, which may be considered a new disease-modifying therapy and, after about 30 years of research, a real step forward in HF pharmacological therapy.
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Efficacy of sacubitril valsartan sodium tablet for the treatment of chronic heart failure: A systematic review protocol of randomized controlled trials.
Liu, Z, Wang, J, Li, Y
Medicine. 2019;(47):e18050
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BACKGROUND This study aims to systematically explore the efficacy of sacubitril valsartan sodium tablet (SVST) for the treatment of chronic heart failure (CHF). METHODS Nine electronic databases, including PUBMED, Cochrane Library, EMBASE, PsycINFO, Web of Science, Allied and Complementary Medicine Database, WANGFANG, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure will be searched. Randomized controlled trials on SVST in the treatment of CHF will be collected. The search time limit will be from the establishment of each electronic database until June 1, 2019. Two authors will independently select the literature, carry out the data, and assess the methodological quality. RESULTS This study will systematically investigate the efficacy and safety of SVST for CHF. The outcomes consist of all-cause mortality, change in body weight, urine output, change in serum sodium; and incidence of any expected and unexpected adverse events. CONCLUSION The findings of this study will summarize from evidence-based medicine and a scientific basis for the efficacy and safety of SVST in the clinical treatment of CHF. PROSPERO REGISTRATION NUMBER PROSPERO CRD42019138882.
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Clinical Outcomes in Patients With Acute Decompensated Heart Failure Randomly Assigned to Sacubitril/Valsartan or Enalapril in the PIONEER-HF Trial.
Morrow, DA, Velazquez, EJ, DeVore, AD, Desai, AS, Duffy, CI, Ambrosy, AP, Gurmu, Y, McCague, K, Rocha, R, Braunwald, E
Circulation. 2019;(19):2285-2288
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Angiotensin Receptor Blockers Versus Angiotensin Converting Enzyme Inhibitors for the Treatment of Arterial Hypertension and the Role of Olmesartan.
Omboni, S, Volpe, M
Advances in therapy. 2019;(2):278-297
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Blood pressure lowering by all classes of antihypertensive drugs is accompanied by significant reductions of stroke and major cardiovascular (CV) events. Drugs acting on the renin-angiotensin-aldosterone system, such as angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), showed similar benefit on major CV events to other antihypertensive medications. In real-world practice, ARBs reduced by 10% the incidence of CV mortality, non-fatal myocardial infarction, non-fatal stroke and provided superior protection against CV events than ACEIs in high-risk patients. Despite similar antihypertensive properties and a favourable safety profile for both ACEIs and ARBs, evidence indicates that patients treated with ARBs have lower rates of withdrawal for adverse events and greater persistence to therapy than those treated with ACEIs. Among ARBs, olmesartan is one of the latest generation compounds introduced in clinical practice for treating hypertension: head-to-head comparative trials suggest that the efficacy of olmesartan is superior to that of commonly prescribed ACEIs (ramipril and perindopril). The drug, administered as a monotherapy or in combination with a dihydropyridine calcium channel blocker or a thiazide diuretic, has proved to be effective in maintaining blood pressure stability over 24 h, with a favourable safety profile and low discontinuation rates. These properties are pivotal for considering olmesartan as a useful antihypertensive agent especially for high-risk patients (e.g. elderly, diabetics, patients with metabolic syndrome).Funding: Article preparation and open access fee were funded by Menarini International Operations Luxembourg S.A. (M.I.O.L.).