Dementia-related adverse events in PARADIGM-HF and other trials in heart failure with reduced ejection fraction.

Cannon, J. A. et al. (2017) Dementia-related adverse events in PARADIGM-HF and other trials in heart failure with reduced ejection fraction. European Journal of Heart Failure, 19(1), pp. 129-137. (doi: 10.1002/ejhf.687) (PMID:27868321) (PMCID:PMC5248626)

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Aims: 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 with enalapril. As neprilysin is also one of many enzymes clearing amyloid-β peptides from the brain, there is a theoretical concern about the long-term effects of sacubitril/valsartan on cognition. Therefore, we have examined dementia-related adverse effects (AEs) in PARADIGM-HF and placed these findings in the context of other recently conducted HFrEF trials. Methods and results: 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. We systematically searched AE reports, coded using the Medical Dictionary for Regulatory Activities (MedDRA), using Standardized MedDRA Queries (SMQs) with ‘broad’ and ‘narrow’ preferred terms related to dementia. In PARADIGM-HF, 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 AEs: 15 (0.36%) on enalapril and 12 (0.29%) on sacubitril/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%) AEs (HR 1.01, 95% CI 0.75–1.37), respectively. The rates of dementia-related AEs in both treatment groups in PARADIGM-HF were similar to those in three other recent trials in HFrEF. Conclusion: We found no evidence that sacubitril/valsartan, compared with enalapril, increased dementia-related AEs, 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.

Item Type:Articles
Additional Information:on behalf of the PARADIGM-HF Investigators and Committees.
Glasgow Author(s) Enlighten ID:Cannon, Dr Jane and Jhund, Dr Pardeep and McMurray, Professor John
Authors: Cannon, J. A., Shen, L., Jhund, P. S., Kristensen, S. L., Køber, L., Chen, F., Gong, J., Lefkowitz, M. P., Rouleau, J. L., Shi, V. C., Swedberg, K., Zile, M. R., Solomon, S. D., Packer, M., and McMurray, J. J.V.
Subjects:?? ARNI ??
?? Dementia ??
?? Heart failure ??
?? Neprilysin inhibition ??
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:European Journal of Heart Failure
ISSN (Online):1879-0844
Published Online:20 November 2016

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