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Hot Line - Neprilysin inhibition does not affect cognitive function in patients with heart failure

The neprilysin inhibitor, sacubitril, is used in combination with valsartan for the treatment of heart failure (HF) with reduced ejection fraction. As neprilysin is postulated to have a role in the degradation of amyloid β in the brain, sacubitril could theoretically increase amyloid β plaque deposition and potentially increase the risk of Alzheimer’s disease.1 To fully assess the long-term neurocognitive effects and safety of sacubitril/valsartan, the double-blind PERSPECTIVE trial was conducted and results were presented by Professor John McMurray (University of Glasgow - Glasgow, UK) in a Hot Line session yesterday.

PERSPECTIVE enrolled patients aged ≥60 years with symptomatic chronic HF and mildly reduced or preserved ejection fraction (LVEF >40%), with HF hospitalisation in the prior 12 months and/or NT-proBNP >200 pg/mL. Patients with known or suspected cognitive impairment were excluded. A total of 592 patients were randomised 1:1 to sacubitril/valsartan (target dose 97/103 mg twice daily) or valsartan (target dose 160 mg twice daily). The average age of participants was 72.4 years; around half (46.8%) were women.

There was no difference between the groups in the primary endpoint of change in cognitive function from baseline to 3-year follow up, evaluated using the CogState global cognition composite score (GCCS).

The difference in least-squares mean change in GCCS with sacubitril/valsartan versus valsartan was −0.0180 (95% CI −0.1230 to 0.0870; p=0.74), with non-inferiority indicated by a Cohen's d effect size of −0.0277 (95% CI −0.1101 to 0.0778).

The principal secondary outcome was the change from baseline to 3 years in amyloid β deposition in the brain measured using positron emission tomography (PET) in 491 patients. The difference in least-squares mean change in the standardised uptake value ratio was −0.0292 (95% CI −0.0593 to 0.0010; p=0.058), indicating that amyloid β deposition in the brain tended to be less in patients treated with sacubitril/valsartan compared with valsartan.

Sacubitril/valsartan was well tolerated, with fewer deaths (9.5% versus 13.1%) and adverse events leading to treatment discontinuation (16.0% versus 20.5%) compared with valsartan.

Prof. McMurray comments, “The concern about increased cerebral amyloid β deposition with sacubitril/valsartan was always hypothetical and multiple enzymatic and other amyloid β clearance pathways exist in the brain that would likely compensate for any decreased clearance related to neprilysin inhibition.2 The trend towards decreased amyloid deposition on PET scanning is a surprise and may just reflect the play of chance. The absence of any negative effect on cognitive function is very important in removing a concern some doctors had about long-term treatment with sacubitril/valsartan.”


1. Galo J, et al. Am J Cardiovasc Drugs. 2021;21:267–270.

2. Cannon JA, et al. Eur J Heart Fail. 2017;19:129–137.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.