Systolic blood pressure, cardiovascular outcomes and efficacy and safety of sacubitril/valsartan (LCZ696) in patients with chronic heart failure and reduced ejection fraction: results from PARADIGM-HF

Eur Heart J. 2017 Apr 14;38(15):1132-1143. doi: 10.1093/eurheartj/ehw570.


Background: Compared to heart failure patients with higher systolic blood pressure (SBP), those with lower SBP have a worse prognosis. To make matters worse, the latter patients often do not receive treatment with life-saving therapies that might lower blood pressure further. We examined the association between SBP and outcomes in the Prospective Comparison of angiotensin receptor-neprilysin inhibitor (ARNI) with an angiotensin-converting enzyme (ACE) inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF), as well as the effect of sacubitril/valsartan, compared with enalapril, according to baseline SBP.

Methods: We analysed the effect of treatment on SBP and on the primary composite outcome (cardiovascular death or heart failure hospitalization), its components and all-cause death. We examined baseline SBP as a categorical (<110, 110 to < 120, 120 to < 130, 130 to < 140 and ≥140 mmHg) and continuous variable, as well as average in-trial SBP and time-updated SBP.

Findings: All-cause and cardiovascular mortality rates were highest in patients with the lowest SBP whereas there was a U-shaped relationship between SBP and the rate of heart failure hospitalization. The benefit of sacubitril/valsartan over enalapril was consistent across all baseline SBP categories for all outcomes. For example, the sacubitril/valsartan versus enalapril hazard ratio for the primary endpoint was 0.88 (95%CI 0.74-1.06) in patients with a baseline SBP <110 mmHg and 0.81 (0.65-1.02) for those with a SBP ≥140 mmHg (P for interaction = 0.55). Symptomatic hypotension, study drug dose-reduction and discontinuation were more frequent in patients with a lower SBP.

Interpretation: In PARADIGM-HF, patients with lower SBP at randomization, notably after tolerating full doses of both study drugs during a run-in period, were at higher risk but generally tolerated sacubitril/valsartan and had the same relative benefit over enalapril as patients with higher baseline SBP.

Keywords: AT1-receptor; Angiotensin; Blood pressure; Heart failure; Neprilysin.

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Aminobutyrates / administration & dosage*
  • Aminobutyrates / adverse effects
  • Angiotensin Receptor Antagonists / administration & dosage*
  • Angiotensin Receptor Antagonists / adverse effects
  • Angiotensin-Converting Enzyme Inhibitors / administration & dosage*
  • Angiotensin-Converting Enzyme Inhibitors / adverse effects
  • Biphenyl Compounds
  • Blood Pressure / drug effects
  • Chronic Disease
  • Death, Sudden, Cardiac / etiology
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Combinations
  • Drug Therapy, Combination
  • Enalapril / administration & dosage
  • Enalapril / adverse effects
  • Female
  • Heart Failure / drug therapy*
  • Heart Failure / mortality
  • Hospitalization
  • Humans
  • Hypotension / chemically induced
  • Hypotension / mortality
  • Male
  • Neprilysin / antagonists & inhibitors
  • Stroke Volume / physiology
  • Tetrazoles / administration & dosage*
  • Tetrazoles / adverse effects
  • Treatment Outcome
  • Valsartan / administration & dosage
  • Valsartan / adverse effects


  • Aminobutyrates
  • Angiotensin Receptor Antagonists
  • Angiotensin-Converting Enzyme Inhibitors
  • Biphenyl Compounds
  • Drug Combinations
  • Tetrazoles
  • Enalapril
  • Valsartan
  • Neprilysin
  • sacubitril and valsartan sodium hydrate drug combination