GLASGOW, UK — Could using the drug combination sacubitril/valsartan, an angiotensin receptor/neprilysin inhibitor, in heart failure patients increase their risk of cognitive impairment?
That is a hypothetical concern raised recently because neprilysin is one of several enzymes degrading amyloid-β peptides in the brain, some of which are neurotoxic and linked to Alzheimer-type dementia.
To address it, a recent international study with VA participation examined the effect of sacubitril/valsartan compared with valsartan on cognitive function in patients with heart failure with preserved ejection fraction in a prespecified substudy of PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). Researchers from the Minneapolis, MN, VAMC and the Ralph H. Johnson VAMC in Charleston, SC, participated in the study published in the journal Circulation.1
In PARAGON-HF, researchers conducted a serial assessment of cognitive function in a subset of patients with the Mini-Mental State Examination (MMSE; score range, 0-30, with lower scores reflecting worse cognitive function).
For the recent substudy, the prespecified primary analysis was the change from baseline in MMSE score at 96 weeks, as well as other post hoc analyses including cognitive decline (fall in MMSEs score of ≥3 points), cognitive impairment (MMSE score <24), or the occurrence of dementia-related adverse events. Of 2,895 patients included in the substudy with baseline MMSE score measured, 1,453 patients with a mean age of 73 were assigned to sacubitril/valsartan and 1,442 to valsartan only. Median follow-up was 32 months.
Results indicate that the mean±SD MMSE score at randomization was 27.4±3.0 in the sacubitril/valsartan group. While 10% had an MMSE score <24; the corresponding numbers were nearly identical in the valsartan group.
“The mean change from baseline to 96 weeks in the sacubitril/valsartan group was -0.05 (SE, 0.07); the corresponding change in the valsartan group was -0.04 (0.07),” the researchers report. “The mean between-treatment difference at week 96 was -0.01 (95% CI, -0.20 to 0.19; P=0.95). Analyses of a ≥3-point decline in MMSE, decrease to a score <24, dementia-related adverse events and combinations of these showed no difference between sacubitril/valsartan and valsartan. No difference was found in the subgroup of patients tested for apolipoprotein E ε4 allele genotype.”
The study team concludes that patients with heart failure with preserved ejection fraction in PARAGON-HF had relatively low baseline MMSE scores. Cognitive change, measured by MMSE, was not found to differ between treatment with sacubitril/valsartan and treatment with valsartan in patients with heart failure with preserved ejection fraction.
Background information in the articles points out that inhibition of the enzyme neprilysin is believed to be beneficial in heart failure because the approach prevents the breakdown of natriuretic peptides. On the other hand, neprilysin also degrades amyloid-β (Aβ) peptides in the brain, some of which are neurotoxic and linked to Alzheimer-type dementia. That is what led to the concern about a theoretical risk of cognitive impairment related to the accumulation of neurotoxic Aβ peptides in the central nervous system of patients treated with sacubitril/valsartan.
Even before the recent substudy, however, the risk was considered low, because multiple other enzymatic pathways and transport proteins are involved in the clearance of Aβ peptides in the brain, and past research didn’t indicate a higher incidence of dementia-related adverse events (AEs) in patients treated with sacubitril/valsartan.
“However, the patients in PARADIGM-HF were relatively young (age being an important risk factor for cognitive decline), and follow-up was relatively short (longer exposure is more likely to show an effect of treatment),” the authors advise. “AE reporting is also an insensitive way of detecting cognitive decline, and a formal assessment of cognitive function was not conducted.”
- Dewan P, Shen L, Pedro Ferreira J, Jhund PS, Anand IS, et. Al. Effect of Sacubitril/Valsartan on Cognitive Function in Patients With Heart Failure With Preserved Ejection Fraction: A Prespecified Analysis of PARAGON-HF. Circulation. 2024 Jun 6. doi: 10.1161/CIRCULATIONAHA.124.068774. Epub ahead of print. PMID: 38841854.