Impact of systolic blood pressure on the safety and tolerability of initiating and up-titrating sacubitril/valsartan in patients with heart failure and reduced ejection fraction: insights from the TITRATION study

Eur J Heart Fail. 2018 Mar;20(3):491-500. doi: 10.1002/ejhf.1054. Epub 2017 Nov 22.


Aims: The TITRATION trial investigated two strategies to initiate and up-titrate sacubitril/valsartan (LCZ696) to the same target dose, over a condensed (3-week) or conservative (6-week) period, in patients with heart failure with reduced ejection fraction (HFrEF) and systolic blood pressure (SBP) of ≥100 mmHg. This post hoc analysis examined the relationship between baseline SBP at screening and achievement of the target dose of sacubitril/valsartan of 97 mg/103 mg (also termed 'LCZ696 200 mg') twice per day during the study.

Methods and results: Patients (n = 498) were categorized in four groups based on SBP at screening: 100-110 mmHg (n = 70); 111-120 mmHg (n = 93); 121-139 mmHg (n = 168) and ≥140 mmHg (n = 167). Overall, 72.7%, 76.1%, 85.6% and 82.9%, respectively, of patients in these SBP categories achieved and maintained the target dose of sacubitril/valsartan without down-titration/dose interruption over 12 weeks ('treatment success'). Compared with patients with SBP of 100-110 mmHg, rates of treatment success among patients in the higher SBP groups [111-120 mmHg (P = 0.96); 121-139 mmHg (P = 0.06) and ≥140 mmHg (P = 0.25)] did not differ significantly. A higher percentage of patients with lower SBP (100-110 mmHg) achieved treatment success with gradual up-titration (6 weeks) (∼80%) than with rapid up-titration (∼69%). Similar findings were observed with regard to 'tolerability success' (maintenance of the target dose for at least the final 2 weeks prior to study completion). Hypotension occurred more frequently in patients with lower SBP.

Conclusions: The majority of patients (>80%) with SBP of ≥100 mmHg achieved and maintained the target dose of sacubitril/valsartan if the treatment was titrated gradually. These findings suggest that low SBP should not prevent clinicians from considering the initiation of sacubitril/valsartan.

Trial registration: NCT01922089.

Keywords: Blood pressure; Heart failure; Hypotension; LCZ696; Sacubitril/valsartan; Titration; Tolerability.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aminobutyrates / administration & dosage*
  • Angiotensin Receptor Antagonists / administration & dosage
  • Biphenyl Compounds
  • Blood Pressure / drug effects
  • Cause of Death / trends
  • Double-Blind Method
  • Drug Combinations
  • Drug Tolerance*
  • Europe / epidemiology
  • Female
  • Follow-Up Studies
  • Heart Failure / drug therapy*
  • Heart Failure / mortality
  • Heart Failure / physiopathology
  • Humans
  • Male
  • Middle Aged
  • Neprilysin
  • Stroke Volume / physiology*
  • Survival Rate / trends
  • Systole
  • Tetrazoles / administration & dosage*
  • Treatment Outcome
  • United States / epidemiology
  • Valsartan


  • Aminobutyrates
  • Angiotensin Receptor Antagonists
  • Biphenyl Compounds
  • Drug Combinations
  • Tetrazoles
  • Valsartan
  • Neprilysin
  • sacubitril and valsartan sodium hydrate drug combination

Associated data