ARNI does not impair cognitive function

PERSPECTIVE- Efficacy and safety of sacubitril/valsartan compared to valsartan on cognitive function in patients with chronic heart failure and preserved ejection fraction trial

News - Aug. 26, 2022

Presented at the ESC congress 2022 by: Prof. John McMurray, MD – Glasgow, UK

Introduction and methods

There was a concern that sacubitril/valsartan might impair cognitive function. Sacubitril is a neprilysin inhibitor and it was suspected that sustained neprilysin inhibition might lead to accumulation of amyloid β-peptides, as neprilysin is normally involved in proteolytic degradation of amyloid β-peptides. Some amyloid β-peptides may be neurotoxic and are linked to impaired cognitive function.

PERSPECTIVE was a randomized, double-blinded, controlled trial that investigated whether sacubitril/valsartan, compared with valsartan, impairs cognitive function by causing accumulation of amyloid β-peptides in the brain in patients with HFmrEF or HFpEF. A total of 592 patients (average age 72.4 years, 46.8% women) from 20 countries were randomized to sacubitril/valsartan (n=295) or valsartan (n=297) and followed for 3 years. The primary endpoint was change cognitive function from baseline to 3 years follow-up evaluated by the CogState cognitive test battery, which assessed 3 cognitive domains: Attention, Episodic Memory, and executive function. These tests were conducted every 6 months for 3 years. The secondary endpoint was change from baseline to 3 years follow-up in amyloid β deposition in the brain which was assessed amyloid PET brain imaging.

Main results

  • The majority (~60%) of patients had some cognitive impairment at baseline.
  • There was no difference in cognitive function between the sacubitril/valsartan group and the valsartan group (difference at 36 months: -0.0180, 95% CI -0.1230 to 0.0870, P=0.74).
  • Amyloid PET brain imaging showed no significant difference between the two groups, but there was a trend to less amyloid β-peptides accumulation in the brain with sacubitril/valsartan, compared with valsartan.


This 3-year randomized controlled trial showed that sabubitril/valsartan does not impair cognitive function or cause accumulation of amyloid β-peptides in the brain in patients with HFmrEF or HFpEF.

Prof. McMurray said: “This trial should remove any concern about the safety of neprilysin inhibition related to cognition.”

-Our reporting is based on the information provided at the ESC Congress-

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