Inhibition of neprilysin, an enzyme degrading natriuretic and other vasoactive peptides, is beneficial in heart failure with reduced ejection fraction ( HFrEF ), as shown in PARADIGM-HF which compared the angiotensin receptor-neprilysin inhibitor ( ARNI ) Sacubitril / Valsartan ( Entresto ) with Enalapril.
As neprilysin is also one of many enzymes clearing amyloid-beta peptides from the brain, there is a theoretical concern about the long-term effects of combination of Sacubitril and Valsartan on cognition.
Researchers have examined dementia-related adverse effects in PARADIGM-HF and placed these findings in the context of other recently conducted HFrEF trials.
In PARADIGM-HF, patients with symptomatic HFrEF were randomized to Sacubitril / Valsartan 97/103 mg b.i.d. or Enalapril 10 mg b.i.d. in a 1:1 ratio.
8399 patients aged 18-96 years were randomized and followed for a median of 2.25 years ( up to 4.3 years ).
The narrow SMQ search identified 27 dementia-related adverse effects: 15 ( 0.36% ) on Enalapril and 12 ( 0.29% ) on Sacubitril and Valsartan [ hazard ratio ( HR ) 0.73, 95% confidence interval ( CI ) 0.33-1.59 ].
The broad search identified 97 ( 2.30% ) and 104 ( 2.48% ) adverse effects ( HR 1.01, 95% CI 0.75-1.37 ), respectively.
The rates of dementia-related adverse effects in both treatment groups in PARADIGM-HF were similar to those in three other recent trials in HFrEF.
In conclusion, no evidence was found that Sacubitril and Valsartan, compared with Enalapril, increased dementia-related adverse effects, although longer follow-up may be necessary to detect such a signal and more sensitive tools are needed to detect lesser degrees of cognitive impairment.
Further studies to address this question are warranted. ( Xagena )
Cannon JA et al, Eur J Heart Fail 2017;19:129-137