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Efficacy and safety of sacubitril/valsartan compared with enalapril in patients with chronic heart failure and reduced ejection fraction: Results from PARADIGM-HF India sub-study.
Jain, AR, Aggarwal, RK, Rao, NS, Billa, G, Kumar, S
Indian heart journal. 2020;(6):535-540
Abstract
OBJECTIVES To determine efficacy and safety of sacubitril/valsartan compared with enalapril in Indian patients of PARADIGM-HF trial. METHODS A randomized, double-blind, active-controlled, phase III sub-study (NCT01035255) was conducted between April 2010 and May 2014. Patients with chronic heart failure (HF), aged >18 years with left ventricular ejection fraction ≤40% were randomized (1:1) to receive either sacubitril/valsartan 200 mg twice-daily or enalapril 10 mg twice-daily. The primary endpoint was to compare efficacy of sacubitril/valsartan to enalapril in delaying time-to-first occurrence of the composite endpoint (cardiovascular [CV] death or HF hospitalization). RESULTS The trial was stopped after a median follow-up of 27 months, because the boundary for benefit with sacubitril/valsartan had crossed. Among 637 Indian patients in PARADIGM-HF (sacubitril/valsartan, n = 322 and enalapril, n = 315), the primary outcome, CV death, and the first hospitalization for HF occurred in 21.81% and 24.76% (HR 0.89; 95% CI, 0.646-1.231), 17.45% and 20.63% (HR 0.87; 95% CI, 0.605-1.236), and 7.48% and 9.52% (HR 0.78; 95% CI, 0.461-1.350) patients in the sacubitril/valsartan and enalapril group, respectively. The all-cause mortality (19.0% vs. 21.9%) and adverse events (78.4% vs. 82.2%) were comparatively lower in the sacubitril/valsartan than enalapril group. No significant difference was seen between the benefits of treatment in Indian and the total PARADIGM-HF cohort (p value for interaction >0.05). CONCLUSION Results support the use of sacubitril/valsartan in Indian patients with chronic HF with reduced ejection fraction with treatment benefits similar to global PARADIGM-HF cohort.
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[First Experience of Clinical Application of LCZ696--an AT1-angiotensin Receptors and Neprilysin Inhibitor--in Patients With Chronic Heart Failure and Reduced Ejection Fraction].
Kobalava, ZhD, Pavlikova, EP, Averkov, OA, Merai, I, Babaeva, LA, Amirbegishvili, IM, Kotovskaya, YV, Moisfev, VS
Kardiologiia. 2015;(7):14-25
Abstract
UNLABELLED Simultaneous inhibition of the renin-angiotensin-aldosterone system and the system of degradation of natriuretic peptides can potentially provide unique therapeutic effects in patients with chronic heart failure (CHF) with reduced ejection fraction (EF). Aim of this study was to assess tolerability of therapy with LCZ696--first representative of a class of inhibitors of angiotensin receptor and neutral endopeptidase neprilysin--and to study its pharmacodynamic effects. METHODS We included into open uncontrolled study 30 patients with stable functional class II-III CHF and EF ≤ 40%. After 24-hour run-in period during which angiotensin converting enzyme inhibitors (ACEI) were withdrawn the patients were given LCZ696 (100 mg/day for 7 days followed by 200 mg/day for 14 days). Other CHF therapy remained unchanged. RESULTS Transition from therapy with ACEI to LCZ696 was well tolerated. Three patients were excluded because of hyperkalemia ≥ 5mmol/l. After 21 days of treatment elevation of plasma biomarkers of inhibition of neprilysin and angiotensin receptors occurred: cyclic guanosine monophosphate, renin concentration and activity rose 1.38, 3.50, and 2.27 times from baseline level (p < 0.05 for all). After 7 and 21 days of LCZ696 administration we noted significant lowering of NT-proBNP; significant lowering of aldosterone and endothelin-1 in blood plasma, was observed on day 21. CONCLUSION Administration of LCZ696 to patients with CHF with reduced ejection fraction (EF) was well tolerated and associated with potentially favorable for this category of patients dynamics of biomarkers.
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A new class of drugs for systolic heart failure: The PARADIGM-HF study.
Sabe, MA, Jacob, MS, Taylor, DO
Cleveland Clinic journal of medicine. 2015;(10):693-701
Abstract
The PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) found a combination drug containing sacubitril (a neprilysin inhibitor) and valsartan (an angiotensin II receptor blocker) superior to enalapril (an angiotensin-converting enzyme inhibitor) in patients with systolic heart failure. Recently approved by the US Food and Drug Administration, sacubitril-valsartan is the first new drug in over a decade to decrease death rates in patients with systolic heart failure.
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The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial.
Solomon, SD, Zile, M, Pieske, B, Voors, A, Shah, A, Kraigher-Krainer, E, Shi, V, Bransford, T, Takeuchi, M, Gong, J, et al
Lancet (London, England). 2012;(9851):1387-95
Abstract
BACKGROUND Heart failure with preserved ejection fraction is associated with substantial morbidity and mortality, but effective treatments are lacking. We assessed the efficacy and safety of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), in patients with this disorder. METHODS PARAMOUNT was a phase 2, randomised, parallel-group, double-blind multicentre trial in patients with New York Heart Association (NYHA) class II-III heart failure, left ventricular ejection fraction 45% or higher, and NT-proBNP greater than 400 pg/mL. Participants were randomly assigned (1:1) by central interactive voice response system to LCZ696 titrated to 200 mg twice daily or valsartan titrated to 160 mg twice daily, and treated for 36 weeks. Investigators and participants were masked to treatment assignment. The primary endpoint was change in NT-proBNP, a marker of left ventricular wall stress, from baseline to 12 weeks; analysis included all patients randomly assigned to treatment groups who had a baseline and at least one postbaseline assessment. This trial is registered at Clinicaltrials.gov, number NCT00887588. FINDINGS 149 patients were randomly assigned to LCZ696 and 152 to valsartan; 134 in the LCZ696 group and 132 in the valsartan group were included in analysis of the primary endpoint. NT-proBNP was significantly reduced at 12 weeks in the LCZ696 group compared with the valsartan group (LCZ696: baseline, 783 pg/mL [95% CI 670-914], 12 weeks, 605 pg/mL [512-714]; valsartan: baseline, 862 pg/mL [733-1012], 12 weeks, 835 [710-981]; ratio LCZ696/valsartan, 0·77, 95% CI 0·64-0·92, p=0·005). LCZ696 was well tolerated with adverse effects similar to those of valsartan; 22 patients (15%) on LCZ696 and 30 (20%) on valsartan had one or more serious adverse event. INTERPRETATION In patients with heart failure with preserved ejection fraction, LCZ696 reduced NT-proBNP to a greater extent than did valsartan at 12 weeks and was well tolerated. Whether these effects would translate into improved outcomes needs to be tested prospectively. FUNDING Novartis.
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Metabolic manipulation of glioblastoma in vivo by retrograde microdialysis of L-2, 4 diaminobutyric acid (DAB).
Bergenheim, AT, Roslin, M, Ungerstedt, U, Waldenström, A, Henriksson, R, Ronquist, G
Journal of neuro-oncology. 2006;(3):285-93
Abstract
OBJECTIVES To study the metabolic effects in vivo of L-2, 4 diaminobutyric acid (DAB) administered by retrograde microdialysis in glioblastoma and to evaluate the feasibility of the technique. METHODS In 10 patients with glioblastoma, a stereotactic biopsy was performed followed by implantation of microdialysis catheters. One or two catheters were implanted in tumor tissue and two reference catheters were implanted in normal brain tissue and subcutaneous abdominal tissue, respectively. Tumor catheters were perfused with 80 or 120 mmol/l DAB and reference catheters were perfused with a Ringer solution, all with a flow rate of 2.0 microl/min. Treatment was given for at mean 9.1 (5-19) days. RESULTS The treatment was well tolerated by the patients with the exception of two patients in whom a transient brain edema appeared. No complications related to the technique were encountered. During treatment, an increase in the extracellular amino acids alanine, glycine, glutamate, aspartate, serine, threonine, and taurine was found demonstrating a significant influence on the intracellular pool of free amino acids induced by DAB. No change in glucose metabolism or glycerol was evident. The metabolism in normal brain was unaffected during treatment. CONCLUSIONS Retrograde microdialysis is a feasible method for intracerebral administration of drugs to tumor tissue in patients with glioblastoma. We found it possible to deliver DAB to glioblastoma tumors in fully mobilized patients and to assess the metabolic effects induced by the treatment. The changes in extracellular amino acids were in concordance to what was expected from in vitro studies. Elevation of glutamate and taurine may be regarded as markers for an induced cellular toxicity while the unchanged level of glycerol may indicate no direct effects on phospholipase activity and membrane phospholipid composition. The effects were restricted to the tumor compartment. Although an improved survival could possibly be suspected no dramatic effect on outcome could be detected. However, the series was small and, most probably, the time for treatment was too short.