In this study patients randomised to sacubitril-valsartan vs enalapril showed a 20% relative risk reduction in the primary outcome of death from cardiovascular causes or first hospitalisation for worsening HF.1

Neprilysin inhibitor therapy has the potential to significantly impact cardiovascular morbidity and mortality among patients with HFrEF.

The results were demonstrated over a median follow-up of 27 months, when the trial was stopped early, because of the overwhelming benefit which sacubitril-valsartan showed.1,2

While the short-term benefits of the addition of neprilysin inhibition together with angiotensin receptor blocker (ARB), as in sacubitril-valsartan, were shown in PARADIGM-HF, the long-term absolute risk reduction from ARNI therapy were not presented. The merit of its widespread use among diverse subpopulations, had, therefore, not been well described.1,2

The question that needed asking

What is the long-term absolute risk reduction from adding a neprilysin inhibitor to standard therapy, including a renin-angiotensin system blocker, in patients with heart failure with reduced ejection fraction (HFrEF)?

This was challenged in respect of cardiovascular death or HF hospitalisation and all-cause mortality, as quantified by the number needed to treat (NNT). Using data from PARADIGM-HF, five-year NNT values for ARNI therapy incremental to ACEI therapy were estimated for the primary endpoint, cardiovascular death, or HF hospitalisation was 14.1

NNT values ranging from 12 to 19 were established among different subpopulations. These values were similar across clinically relevant subgroups, reflecting the lack of significant heterogeneity in clinical benefits of ARNI therapy across different sub-populations.1

On analysis of all-cause mortality data presented in PARADIGM-HF, further estimates were made for five-year NNT values in the overall cohort. The NNT value was 21 with ARNI incremental to ACEI, with values ranging from 16 to 31 among different subgroups. Compared with imputed placebo, the five-year estimated NNT for all-cause mortality with ARNI was 11 in patients with HFrEF.1,2,4,5

How do these values compare with other HFrEF therapies?

Selected landmark clinical trials have been evaluated to estimate five-year NNT values for the endpoint of all-cause mortality with other well-established HFrEF therapies, compared with control.1

The estimated five-year NNT values were found to be 18 for ACEI, 24 for angiotensin receptor blockers, 8 for β-blockers, 15 for mineralocorticoid antagonists, 14 for implantable cardioverter defibrillator, and 14 for cardiac resynchronisation therapy. Neprilysin inhibitor therapy has the potential to significantly impact cardiovascular morbidity and mortality among patients with HFrEF.1,2

Using actuarial estimates from the PARADIGM-HF trial, and assuming that the protective effects of sacubitril–valsartan remain consistent with long-term use, it has been extrapolated from the available short-term follow-up data to estimate that treatment with sacubitril–valsartan would result in a projected benefit of one to two years of increased life expectancy and survival free from heart failure for patients such as those in the PARADIGM-HF trial.3

The PARADIGM-HF extension of five-year estimated NNT values, quantify the long-term benefit of ARNI therapy incremental to ACEI overall and among diverse patient subpopulations.1

Taken together, these results further support current guidelines recommendations for optimal implementation of ARNI therapy among eligible patients with HFrEF.1,2,4,5

2020 Heart Failure Society of South Africa:5

Update in relation to 2016 European Society of Cardiology Chronic HF guidelines

Valsartan/ Sacubitril issued a Class I, LOE B recommendation for the use as ‘a replacement for an ACEI/ARB’, in ambulatory patients with HFrEF who remain symptomatic, despite optimal treatment with an ACEI, a beta-blocker and a mineralocorticoid receptor antagonist to further reduce:

  • The risk of heart failure hospitalisation
  • The risk of death due to heart failure.

ZA2104196757 / Exp. 19/04/2023


1. Srivastava PK, Claggett BL, Solomon SD, et al. Estimated 5-Year Number Needed to Treat to Prevent Cardiovascular Death or Heart Failure Hospitalization With Angiotensin Receptor-Neprilysin Inhibition vs Standard Therapy for Patients With Heart Failure With Reduced Ejection Fraction. An Analysis of Data From the PARADIGM-HF Trial. JAMA Cardiol, 2018;3(12):1226-1231. doi:10.1001/jamacardio.2018.3957

2. McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med, 2014;371(11):993-1004.

3. Claggett B, Packer M, McMurray JJ, et al. PARADIGM-HF Investigators. Estimating the long-term treatment benefits of sacubitril valsartan. N Engl J Med, 2015;373(23):2289-2290. doi:10.1056/NEJMc1509753.

4. Ponikowski P, Voors AA, Anker SD, et al, for the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J, 2016;37:2129-2200.

5. Hitzeroth J, Mpe M, Klug E, et al, on behalf of the Heart Failure Society of South Africa. 2020 Heart Failure Society of South Africa perspective on the 2016 European Society of Cardiology Chronic Heart Failure Guidelines. S Afr Med J, 2020;110(9b):938-951. v110i8.14681.