Cannon JA, Shen L, Jhund PS, et al.
Eur J Heart Fail. 2016;published online ahead of print

Background

As neprilysin is one of many enzymes clearing amyloid-β peptides from the brain, there are concerns about a possible relationship between neprilysin inhibition and amyloid-β-related cognitive decline, in heart failure (HF) patients treated with the angiotensin receptor – neprilysin inhibitor (ARNI) sacubitril/valsartan [1-3].

In this paper, cognition- and memory-related AEs are reported in the PARADIGM-HF trial, in which sacubitril/valsartan was compared with the ACE-inhibitor enalapril. These AEs were also evaluated in three other HF trials, to place these findings in the context: Val-HeFT, ATMOSPHERE, and CORONA. All these trials involved patients with HF and reduced ejection fraction (HFrEF); Val-HeFT compared valsartan with placebo, CORONA compared rosuvastatin with placebo and ATMOSPHERE compared enalapril with aliskiren and the combination.

Main results
PARADIGM-HF trial:

• The most commonly reported dementia-related AEs in the sacubitril/valsartan group (vs. the enalapril group) were ‘confusional state’ (12 vs. 18), ‘somnolence’ (11 vs. 9), ‘delirium’ (10 vs. 8), and ‘amnesia/amnestic disorder’ (11 vs. 7).
• Six cases (0.14%) of unspecified dementia were identified in the sacubitril/valsartan group and 10 cases (0.24%) in the enalapril group. The number of specific types of dementia in the sacubitril/valsartan group, compared with the enalapril group were: alzheimer’s type dementia (2 vs. 2), senile dementia (0 vs. 2), vascular dementia (2 vs. 1), hippocampal sclerosis (1 vs. 0), and pre-senile dementia (1 vs. 0).
• The age-adjusted annual rate of dementia-related AEs was 0.95 (95% CI: 0.75–1.15) per 100 patient-years in the sacubitril/valsartan group and 0.98 (95% CI: 0.77–1.19) per 100 patient-years in the enalapril group.

Val-HeFT trial:

• There was one case of vascular dementia in the placebo group and none in the valsartan group. Two cases of specific dementia were reported in the valsartan group and none in the placebo group.
• The age-adjusted annual rate of dementia-related AEs was 2.43 (95% CI: 1.94–2.92) per 100 patient-years in the placebo group and 3.46 (95% CI: 2.87–4.04) per 100 patient-years in the valsartan group.

ATMOSPHERE trial: 

• Thirteen cases (0.56%) of unspecified dementia were identified in the enalapril group, 11 cases (0.47%) in the aliskiren group, and 11 cases (0.47%) in the combination therapy group. Additionally there were 4 cases of specific dementia in the enalapril group, 9 cases in the aliskiren group, and 6 cases in the combination treatment group, adding up to 17, 20, and 17 cases, respectively.
• The age-adjusted annual rate of dementia-related AEs was 0.71 (95% CI: 0.52–0.91) per 100 patient-years in the enalapril group, 1.14 (95% CI: 0.89–1.39) per 100 patient-years in the aliskiren group, and 1.17 (95% CI: 0.92–1.42) per 100 patient-years in the combination therapy group.

CORONA trial:

• Eleven cases (0.44%) of unspecified dementia were identified in the placebo group and 14 cases (0.56%) in the rosuvastatin group. Moreover, 8 cases (0.32%) of specific dementia were identified in the placebo group and 14 cases (0.56%) in the rosuvastatin group, adding up to 19 and 28 cases, respectively.
• The age-adjusted annual rate of dementia-related AEs was 1.03 (95% CI: 0.8–1.24) per 100 patient-years in the placebo group and 1.06 (95% CI: 0.86–1.27) per 100 patient-years in the rosuvastatin group.

In the PARADIGM-HF and the ATMOSPHERE studies, the baseline characteristics associated with dementia-related AEs were: older age, higher alcohol intake, history of atrium fibrillation, coronary heart disease, chronic lung disease or stroke, higher NT-proBNP and lower estimated eGFR.

Conclusion

The incidence of dementia-related AEs in HF patients treated with sacubitril/valsartan in PARADIGM-HF was similar to that in patients treated with enalapril in PARADIGM-HF, as well as in patients enrolled in other recent HF trials in which valsartan, rosuvastatin, aliskiren and enalapril were evaluated. These data do not support the concerns about adverse cognitive effects of sacubitril/valsartan.

Find this article online at Eur J Heart Fail

References

1. Nalivaeva NN, Belyaev ND, Kerridge C, et al. Amyloid-clearing proteins and their epigenetic regulation as a therapeutic target in Alzheimer’s disease. Front Aging Neurosci 2014;6:235
2. Langenickel TH, Tsubouchi C, Ayalasomayajula S, et al. The effect of LCZ696 (sacubitril/valsartan) on amyloid-β concentrations in cerebrospinal fluid in healthy subjects. Br J Clin Pharmacol 2016;81:878–90.
3. Baranello RJ, Bharani KL, Padmaraju V, et al. Amyloid-beta protein clearance and degradation (ABCD) pathways and their role in Alzheimer’s disease. Curr Alzheimer Res 2015;12:32–46.