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Angiotensin-neprilysin inhibition versus enalapril in heart failure
John J V McMurray1, Milton Packer, Akshay S Desai
1From the British Heart Foundation (BHF) Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M.); the Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas (M.P.); the Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston (A.S.D., S.D.S.); Novartis Pharmaceuticals, East Hanover, NJ (J.G., M.P.L., A.R.R., V.C.S.); Institut de Cardiologie de Montréal, Université de Montréal, Montreal (J.L.R.); the Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden (K.S.); National Heart and Lung Institute, Imperial College London, London (K.S.); and the Medical University of South Carolina and Ralph H. Johnson Veterans Affairs Medical Center, Charleston (M.R.Z.).
Insights
The angiotensin receptor-neprilysin inhibitor LCZ696 significantly reduced death and heart failure hospitalizations compared to enalapril in patients with heart failure with reduced ejection fraction.
Area of Science:
- Cardiology
- Pharmacology
- Clinical Trials
Background:
- Heart failure with reduced ejection fraction (HFrEF) remains a leading cause of mortality and morbidity.
- Enalapril, an angiotensin-converting enzyme inhibitor, has demonstrated survival benefits in HFrEF patients.
- Novel therapeutic strategies are needed to further improve outcomes in HFrEF.
Purpose of the Study:
- To compare the efficacy and safety of LCZ696 (an angiotensin receptor-neprilysin inhibitor) versus enalapril in patients with HFrEF.
- To evaluate the impact of LCZ696 on cardiovascular death and heart failure hospitalizations.
Main Methods:
- A large-scale, double-blind, randomized controlled trial (PARADIGM-HF) involving 8442 patients with HFrEF.
- Patients were assigned to receive either LCZ696 (200 mg twice daily) or enalapril (10 mg twice daily) in addition to standard therapy.
- The primary endpoint was a composite of cardiovascular death or heart failure hospitalization, with a focus on cardiovascular death rates.
Main Results:
- The trial was terminated early due to overwhelming benefit of LCZ696.
- LCZ696 significantly reduced the composite endpoint of cardiovascular death or heart failure hospitalization (hazard ratio, 0.80; P<0.001).
- LCZ696 also demonstrated significant reductions in all-cause mortality, cardiovascular death, and heart failure hospitalizations, with an improved safety profile regarding renal impairment and hyperkalemia.
Conclusions:
- LCZ696 is superior to enalapril in reducing the risks of death and hospitalization for heart failure in patients with HFrEF.
- LCZ696 represents a significant advancement in the management of HFrEF.
- The findings support LCZ696 as a new standard of care for HFrEF.
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.).
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