Background: Inhibition of neprilysin, an enzyme degrading natriuretic and other vasoactive peptides, is beneficial in heart failure with reduced ejection fraction, as shown in PARADIGM-HF which compared the angiotensin receptor neprilysin inhibitor (ARNI) LCZ696 (sacubitril-valsartan) to enalapril. As neprilysin is also one of many enzymes clearing amyloid-β peptides from the brain, there is theoretical concern about the long-term effects of LCZ696 on cognition. Therefore, we examined dementia-related adverse effects in PARADIGM-HF.
Methods: Patients with NYHA class II-IV heart failure (HF), a LVEF ≤40% and a mildly elevated BNP/NT proBNP were randomized to LCZ696 200mg bid or enalapril 10mg bid in a 1:1 ratio. We searched adverse event reports (AERs) coded using the Medical Dictionary for Regulatory Activities (MedRA) using Standardized MedRA Queries (SMQs) with "broad" and "narrow" preferred terms (PTs) related to cognition, memory, dementia-like and related events.
Results: 8399 patients aged 18-96 yrs were randomized and followed for a median of 2.25 yrs (up to 4.3 yrs). The narrow SMQ search identified 27 relevant AERs: 15 (0.35%) on enalapril and 12 (0.29%) on LCZ696 (HR 0.79, 0.37-1.70). The numbers using the broad search were: 83 (1.96%) and 86 (2.05%), respectively, HR 1.03 (0.76, 1.39). The most common PTs in each treatment group are shown in the Table.
Conclusion: We found no evidence that LCZ696, compared with enalapril, increased dementia-related adverse events in PARADIGM-HF.