| 1. |
- McMurray, J. J. V., et al.
(author)
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Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure
- 2014
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In: New England Journal of Medicine. - 0028-4793. ; 371:11, s. 993-1004
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Journal article (peer-reviewed)abstract
- 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. 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. 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. LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure.
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| 2. |
- McMurray, J. J., et al.
(author)
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Baseline characteristics and treatment of patients in Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF)
- 2014
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In: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 16:7
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Journal article (peer-reviewed)abstract
- AIMS: To describe the baseline characteristics and treatment of the patients randomized in the Prospective comparison of ARNi with ACEi to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF), testing the hypothesis that the strategy of simultaneously blocking the renin-angiotensin-aldosterone system and augmenting natriuretic peptides with LCZ696 200 mg bid is superior to enalapril 10 mg bid in reducing mortality and morbidity in patients with heart failure and reduced ejection fraction (HF-REF). METHODS: Key demographic, clinical and laboratory findings, along with baseline treatment, are reported and compared with those of patients in the treatment arm of the Studies Of Left Ventricular Dysfunction (SOLVD-T) and more contemporary drug and device trials in HF-REF. RESULTS: The mean age of patients in PARADIGM-HF is 64 (SD 11) years and 78% are male, in keeping with both SOLVD-T and more recent trials. Despite extensive background therapy with beta-blockers (94% patients) and mineralocorticoid receptor antagonists (58%), patients in PARADIGM-HF have persisting symptoms and signs, reduced health related quality of life, a low LVEF (mean 29+/-SD 6%) and elevated N terminal-proB type-natriuretic peptide levels (median 1611 inter-quartile range 887-3205 pg/ml). CONCLUSION: PARADIGM-HF will determine whether LCZ696 is more beneficial than enalapril when added to other disease-modifying therapies and if further augmentation of endogenous natriuretic peptides will reduce morbidity and mortality in HF-REF.
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| 3. |
- McMurray, J. J., et al.
(author)
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Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF)
- 2013
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In: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 15:9, s. 1062-1073
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Journal article (peer-reviewed)abstract
- AIMS: Although the focus of therapeutic intervention has been on neurohormonal pathways thought to be harmful in heart failure (HF), such as the renin-angiotensin-aldosterone system (RAAS), potentially beneficial counter-regulatory systems are also active in HF. These promote vasodilatation and natriuresis, inhibit abnormal growth, suppress the RAAS and sympathetic nervous system, and augment parasympathetic activity. The best understood of these mediators are the natriuretic peptides which are metabolized by the enzyme neprilysin. LCZ696 belongs to a new class of drugs, the angiotensin receptor neprilysin inhibitors (ARNIs), which both block the RAAS and augment natriuretic peptides.MethodsPatients with chronic HF, NYHA class II-IV symptoms, an elevated plasma BNP or NT-proBNP level, and an LVEF of
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