Physicians' Academy for Cardiovascular Education

Consistent benefit of ARNI in HF regardless of background therapy

Okumura N et al., Circ Heart Fail. 2016;9:e003212

Effects of Sacubitril/Valsartan in the PARADIGM-HF Trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) According to Background Therapy

Okumura N, Jhund PS, Gong J, et al, on behalf of the PARADIGM-HF Investigators and Committees
Circ Heart Fail. 2016;9:e003212


Sacubitril/valsartan, a first-in-class angiotensin receptor neprilysin inhibitor, is recommended as a more effective alternative to an ACE inhibitor for HF patients with reduced EF on other evidence-based treatments for this indication [1,2].
In this analysis, the outcomes of patients in the PARADIGM-HF study [3,4] receiving sacubitril/valsartan compared with enalapril were assessed, according to background use of β-blockers, mineralocorticoid receptor antagonists (MRAs), diuretics, digitalis glycosides implanted cardioverter/defibrillator devices, and previous coronary revascularisation. Only subgroups with over 1000 patients were considered.

Main results

Most randomised patients were treated with a diuretic (80%) and β-blocker (93%), and 47% of those taking a β-blocker received ≥50% of the recommended dose. Moreover, 56% were treated with an MRA, 30% with digoxin, 15% had a defibrillating device (ICD/CRT), and 31% had undergone coronary revascularisation.
Overall, the sacubitril/valsartan versus enalapril hazard ratio was:
  • HR: 0.80; 95% CI: 0.73–0.87; P<0.001 for the primary composite end point (CV death or HF hospitalisation)
  • HR: 0.80; 95% CI: 0.71–0.89; P<0.001 for CV death.
The effect of sacubitril/valsartan was consistent across all treatment subgroups examined. The hazard ratio for the primary end point ranged from 0.74 to 0.85 and for CV death from 0.75 to 0.89, with no significant treatment-by-subgroup interaction. In particular, for the primary endpoint: 
  • HR: 0.83; 95% CI: 0.65-1.04 for patients not on diuretics
  • HR: 0.80; 95% CI: 0.72-0.87 for patients on diuretics
  • HR: 0.74; 95% CI: 0.65-0.84 for patients not on MRAs
  • HR: 0.85; 95% CI: 0.76-0.96 for patients on MRAs
  • HR: 0.81; 95% CI: 0.73-0.91 for patients not on digoxin
  • HR: 0.78; 95% CI: 0.67-0.90 for patients on digoxin
  • HR: 0.79; 95% CI: 0.72-0.87 for patients without ICD/CRT
  • HR: 0.84; 95% CI: 0.67-1.04 for patients with ICD/CRT
  • HR: 0.83; 95% CI: 0.74-0.92 for patients without previous coronary revascularisation
  • HR: 0.74; 95% CI: 0.63-0.86 for patients with previous coronary revascularisation
  • HR: 0.82; 95% CI: 0.72-0.93 for patients on < 50% of β-blocker target dose
  • HR: 0.82; 95% CI: 0.72-0.94 for patients on ≥50% of β-blocker target dose


In this analysis of the PARADIGM-HF study, a consistent benefit of sacubitril/valsartan, compared with enalapril was observed, regardless of background therapy, including the use of a diuretic, MRA, digoxin, and implanted cardiac defibrillator. A similar benefit was also observed in patients with and without previous coronary revascularisation and irrespective of β-blocker dose.
Find this article online at Circ Heart Fail


1. Moe GW, Ezekowitz JA, O’Meara E, et al; Canadian Cardiovascular Society. The 2014 Canadian Cardiovascular Society Heart Failure Management Guidelines Focus Update: anemia, biomarkers, and recent therapeutic trial implications. Can J Cardiol. 2015;31:3–16.
2. Braunwald E. The path to an angiotensin receptor antagonist-neprilysin inhibitor in the treatment of heart failure. J Am Coll Cardiol. 2015;65:1029–1041.
3. McMurray JJ, Packer M, Desai AS, et al; PARADIGMHF 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.
4. McMurray JJ, Packer M, Desai AS, Gong J, et al; PARADIGMHF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–1004.