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The New England Journal of Medicine Sep 2014We compared the angiotensin receptor-neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies,... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
We compared the angiotensin receptor-neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients.
METHODS
In this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes.
RESULTS
The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P=0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group.
CONCLUSIONS
LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF ClinicalTrials.gov number, NCT01035255.).
Topics: Aged; Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Double-Blind Method; Drug Combinations; Enalapril; Female; Heart Failure; Hospitalization; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neprilysin; Stroke Volume; Tetrazoles; Valsartan
PubMed: 25176015
DOI: 10.1056/NEJMoa1409077 -
Circulation Mar 2016Heart failure affects ≈5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and... (Review)
Review
Heart failure affects ≈5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the US Food and Drug Administration approved the first of a new class of drugs for the treatment of heart failure: Valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses 2 of the pathophysiological mechanisms of heart failure: activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared with enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacological properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension.
Topics: Abnormalities, Drug-Induced; Aminobutyrates; Angioedema; Angiotensin Receptor Antagonists; Biphenyl Compounds; Bradykinin; Contraindications; Drug Combinations; Drug Costs; Drug Synergism; Enalapril; Enzyme Inhibitors; Female; Follow-Up Studies; Heart Failure; Humans; Hyperkalemia; Hypertension; Kidney; Multicenter Studies as Topic; Natriuretic Peptides; Neprilysin; Pregnancy; Prodrugs; Prospective Studies; Pyridines; Randomized Controlled Trials as Topic; Stroke Volume; Tetrazoles; Thiazepines; Valsartan
PubMed: 26976916
DOI: 10.1161/CIRCULATIONAHA.115.018622 -
JACC. Heart Failure Jun 2018The purpose of this study was to evaluate the renal effects of sacubitril/valsartan in patients with heart failure and reduced ejection fraction. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
The purpose of this study was to evaluate the renal effects of sacubitril/valsartan in patients with heart failure and reduced ejection fraction.
BACKGROUND
Renal function is frequently impaired in patients with heart failure with reduced ejection fraction and may deteriorate further after blockade of the renin-angiotensin system.
METHODS
In the PARADIGM-HF (Prospective Comparison of ARNI with ACE inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, 8,399 patients with heart failure with reduced ejection fraction were randomized to treatment with sacubitril/valsartan or enalapril. The estimated glomerular filtration rate (eGFR) was available for all patients, and the urinary albumin/creatinine ratio (UACR) was available in 1872 patients, at screening, randomization, and at fixed time intervals during follow-up. We evaluated the effect of study treatment on change in eGFR and UACR, and on renal and cardiovascular outcomes, according to eGFR and UACR.
RESULTS
At screening, the eGFR was 70 ± 20 ml/min/1.73 m and 2,745 patients (33%) had chronic kidney disease; the median UACR was 1.0 mg/mmol (interquartile range [IQR]: 0.4 to 3.2 mg/mmol) and 24% had an increased UACR. The decrease in eGFR during follow-up was less with sacubitril/valsartan compared with enalapril (-1.61 ml/min/1.73 m/year; [95% confidence interval: -1.77 to -1.44 ml/min/1.73 m/year] vs. -2.04 ml/min/1.73 m/year [95% CI: -2.21 to -1.88 ml/min/1.73 m/year ]; p < 0.001) despite a greater increase in UACR with sacubitril/valsartan than with enalapril (1.20 mg/mmol [95% CI: 1.04 to 1.36 mg/mmol] vs. 0.90 mg/mmol [95% CI: 0.77 to 1.03 mg/mmol]; p < 0.001). The effect of sacubitril/valsartan on cardiovascular death or heart failure hospitalization was not modified by eGFR, UACR (p interaction = 0.70 and 0.34, respectively), or by change in UACR (p interaction = 0.38).
CONCLUSIONS
Compared with enalapril, sacubitril/valsartan led to a slower rate of decrease in the eGFR and improved cardiovascular outcomes, even in patients with chronic kidney disease, despite causing a modest increase in UACR.
Topics: Albuminuria; Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensins; Biphenyl Compounds; Blood Pressure; Creatinine; Drug Combinations; Enalapril; Enzyme Inhibitors; Female; Glomerular Filtration Rate; Heart Failure; Humans; Male; Middle Aged; Neprilysin; Renal Insufficiency, Chronic; Stroke Volume; Tetrazoles; Treatment Outcome; Valsartan
PubMed: 29655829
DOI: 10.1016/j.jchf.2018.02.004 -
The Lancet. Diabetes & Endocrinology May 2017Diabetes is an independent risk factor for heart failure progression. Sacubitril/valsartan, a combination angiotensin receptor-neprilysin inhibitor, improves morbidity... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Diabetes is an independent risk factor for heart failure progression. Sacubitril/valsartan, a combination angiotensin receptor-neprilysin inhibitor, improves morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF), compared with the angiotensin-converting enzyme inhibitor enalapril, and improves peripheral insulin sensitivity in obese hypertensive patients. We aimed to investigate the effect of sacubitril/valsartan versus enalapril on HbA and time to first-time initiation of insulin or oral antihyperglycaemic drugs in patients with diabetes and HFrEF.
METHODS
In a post-hoc analysis of the PARADIGM-HF trial, we included 3778 patients with known diabetes or an HbA ≥6·5% at screening out of 8399 patients with HFrEF who were randomly assigned to treatment with sacubitril/valsartan or enalapril. Of these patients, most (98%) had type 2 diabetes. We assessed changes in HbA, triglycerides, HDL cholesterol and BMI in a mixed effects longitudinal analysis model. Time to initiation of oral antihyperglycaemic drugs or insulin in subjects previously not treated with these agents were compared between treatment groups.
FINDINGS
There were no significant differences in HbA concentrations between randomised groups at screening. During the first year of follow-up, HbA concentrations decreased by 0·16% (SD 1·40) in the enalapril group and 0·26% (SD 1·25) in the sacubitril/valsartan group (between-group reduction 0·13%, 95% CI 0·05-0·22, p=0·0023). HbA concentrations were persistently lower in the sacubitril/valsartan group than in the enalapril group over the 3-year follow-up (between-group reduction 0·14%, 95% CI 0·06-0·23, p=0·0055). New use of insulin was 29% lower in patients receiving sacubitril/valsartan (114 [7%] patients) compared with patients receiving enalapril (153 [10%]; hazard ratio 0·71, 95% CI 0·56-0·90, p=0·0052). Similarly, fewer patients were started on oral antihyperglycaemic therapy (0·77, 0·58-1·02, p=0·073) in the sacubitril/valsartan group.
INTERPRETATION
Patients with diabetes and HFrEF enrolled in PARADIGM-HF who received sacubitril/valsartan had a greater long-term reduction in HbA than those receiving enalapril. These data suggest that sacubitril/valsartan might enhance glycaemic control in patients with diabetes and HFrEF.
FUNDING
Novartis.
Topics: Aged; Aminobutyrates; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Drug Combinations; Enalapril; Female; Heart Failure; Humans; Male; Middle Aged; Tetrazoles; Valsartan
PubMed: 28330649
DOI: 10.1016/S2213-8587(17)30087-6 -
BMC Medicine Oct 2022For hypertensive patients without a history of stroke or myocardial infarction (MI), the China Stroke Primary Prevention Trial (CSPPT) demonstrated that treatment with... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
For hypertensive patients without a history of stroke or myocardial infarction (MI), the China Stroke Primary Prevention Trial (CSPPT) demonstrated that treatment with enalapril-folic acid reduced the risk of primary stroke compared with enalapril alone. Whether folic acid therapy is an affordable and beneficial treatment strategy for the primary prevention of stroke in hypertensive patients from the Chinese healthcare sector perspective has not been thoroughly explored.
METHODS
We performed a cost-effectiveness analysis alongside the CSPPT, which randomized 20,702 hypertensive patients. A patient-level microsimulation model based on the 4.5-year period of in-trial data was used to estimate costs, life years, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) for enalapril-folic acid vs. enalapril over a lifetime horizon from the payer perspective.
RESULTS
During the in-trial follow-up period, patients receiving enalapril-folic acid gained an average of 0.016 QALYs related primarily to reductions in stroke, and the incremental cost was $706.03 (4553.92 RMB). Over a lifetime horizon, enalapril-folic acid treatment was projected to increase quality-adjusted life years by 0.06 QALYs or 0.03 life-year relative to enalapril alone at an incremental cost of $1633.84 (10,538.27 RMB), resulting in an ICER for enalapril-folic acid compared with enalapril alone of $26,066.13 (168,126.54 RMB) per QALY gained and $61,770.73 (398,421.21 RMB) per life-year gained, respectively. A probabilistic sensitivity analysis demonstrated that enalapril-folic acid compared with enalapril would be economically attractive in 74.5% of simulations at a threshold of $37,663 (242,9281 RMB) per QALY (3x current Chinese per capita GDP). Several high-risk subgroups had highly favorable ICERs < $12,554 (80,976 RMB) per QALY (1x GDP).
CONCLUSIONS
For both in-trial and over a lifetime, it appears that enalapril-folic acid is a clinically and economically attractive medication compared with enalapril alone. Adding folic acid to enalapril may be a cost-effective strategy for the prevention of primary stroke in hypertensive patients from the Chinese health system perspective.
Topics: Humans; Cost-Benefit Analysis; Enalapril; Folic Acid; Hypertension; Primary Prevention; Quality-Adjusted Life Years; Stroke
PubMed: 36280851
DOI: 10.1186/s12916-022-02601-z -
Circulation. Heart Failure Feb 2021In patients stabilized during hospitalization for acute decompensated heart failure (HF), initiation of sacubitril/valsartan compared with enalapril decreased the risk... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In 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.
METHODS
PIONEER-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 m (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).
RESULTS
The relative risk reduction in cardiovascular death or rehospitalization for HF with sacubitril/valsartan versus enalapril was consistent across all high-risk subgroups ( 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 ( interaction=NS for each).
CONCLUSIONS
In 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.
Topics: Acute Disease; Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Cardiotonic Agents; Cardiovascular Diseases; Chronic Disease; Drug Combinations; Enalapril; Glomerular Filtration Rate; Heart Failure; Hospitalization; Humans; Hyperkalemia; Hypotension; Intensive Care Units; Natriuretic Peptide, Brain; Peptide Fragments; Renal Insufficiency; Risk; Valsartan
PubMed: 33530704
DOI: 10.1161/CIRCHEARTFAILURE.120.007034