Solomon SD, Claggett B, Desai AS, et al.
Circ Heart Fail. 2016;9:e002744

Background

In the PARADIGM-HF trial, in which heart failure (HF) patients with NYHA class II-IV were randomised to receive either sacubitril/valsartan (LCZ696) 200 mg twice daily or enalapril 10 mg twice daily, LCZ696 significantly reduced CV death, all-cause mortality and HF hospitalisation compared with enalapril [1]. At the beginning of this study, patients with LVEF ≤ 40% were recruited, but 1 year later, this entry criterion was lowered to ≤ 35% [2], in order to ensure a high event rate in light of the anticipated increased use of MRAs after the EMPHASIS-HF results [3]. LVEF predicts morbidity and mortality in HF patients with reduced LVEF [4,5]. The lowering of the LVEF inclusion criterion has been interpreted as a reason for restricted administration of LCZ696 in patients with LVEF between 35% and 40%, although at the time of LVEF criterion change already about 25% of patients enrolled were in the LVEF range between 35% and 40%.  
This post hoc analysis of the PARADIGM-HF trial evaluated the relationship between LVEF and outcomes, as well as the effectiveness of LCZ696 compared with enalapril, across the spectrum of EF.

Main results

• The risk of all outcomes increased with decreasing LVEF. Each 5-point reduction in LVEF was associated with:

- a 9% increased risk of CV death or HF hospitalisation (HR: 1.09; 95% CI: 1.05–1.13; P<0.001)
- a 9% increased risk for CV death (HR: 1.09; 95% CI: 1.04–1.14)
- a 9% increased risk in HF hospitalisation (HR: 1.09; 95% CI: 1.04–1.14)
- a 7% increased risk in all-cause mortality (HR: 1.07; 95% CI: 1.03–1.12)

• LCZ696 was effective across the LVEF spectrum for the primary outcome, with no evidence of heterogeneity, when modelled either in tertiles (P interaction=0.87) or continuously (P interaction=0.95).
  No evidence for an interaction for individual outcomes were observed (for CV death: P interaction=0.55, for HF hospitalisation P interaction=0.78, for all-cause mortality P interaction = 0.93)

Conclusion

In HF patients with reduced LVEF who participated the PARADIGM-HF trial, LVEF was a significant independent predictor of all outcomes and this relationship was approximately linear between LVEF of 15% and 40%. There was no evidence of effect modification by EF for the benefit of LCZ696, since patients at the lower end and higher end of the EF spectrum benefited equally. These findings suggest that LCZ696 is effective independently of EF in HF patients with reduced LVEF.

Find this article online at Circulation Heart Failure

References

1. McMurray JJ, Packer M, Desai AS, et al. PARADIGMHF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–1004
2. McMurray JJ, Packer M, Desai AS, et al. PARADIGM-HF Committees and Investigators. 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). Eur J Heart Fail. 2013;15:1062–1073
3. Zannad F, McMurray JJ, Krum H, et al.; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364:11–21. doi: 10.1056/NEJMoa1009492.
4. Solomon SD, Skali H, Anavekar NS, et al. Changes in ventricular size and function in patients treated with valsartan, captopril, or both after myocardial infarction. Circulation. 2005;111:3411–3419
5. Lewis EF, Moye LA, Rouleau JL, et al. CARE Study. Predictors of late development of heart failure in stable survivors of myocardial infarction: the CARE study. J Am Coll Cardiol. 2003;42:1446–1453