Sacubitril/Valsartan and Cognitive Outcomes in Heart Failure With Reduced Ejection Fraction

Prabhjot K Grewal; Alan Abboud; Evangelos Pavlos Myserlis; Marc E Goldschmidt; Javed Butler; Hal A Skopicki; Andreas P Kalogeropoulos

doi:10.1016/j.jacadv.2023.100372

Sacubitril/Valsartan and Cognitive Outcomes in Heart Failure With Reduced Ejection Fraction

JACC Adv. 2023 Jun 7;2(4):100372. doi: 10.1016/j.jacadv.2023.100372. eCollection 2023 Jun.

Authors

Prabhjot K Grewal¹, Alan Abboud², Evangelos Pavlos Myserlis³, Marc E Goldschmidt⁴, Javed Butler^{5

6}, Hal A Skopicki⁴, Andreas P Kalogeropoulos⁴

Affiliations

¹ Department of Medicine, Stony Brook University, Stony Brook, New York, USA.
² Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA.
³ Department of Neurology, Medical University of South Carolina, Charleston, South Carolina, USA.
⁴ Division of Cardiology, Department of Medicine, Stony Brook University, Stony Brook, New York, USA.
⁵ Baylor Scott & White Research Institute, Dallas, Texas, USA.
⁶ Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.

Abstract

Background: Recent trial data refute concerns about neurocognitive off-target effects of neprilysin inhibition with sacubitril and suggest benefit in patients with heart failure and ejection fraction >40%. We hypothesized that sacubitril/valsartan is associated with improved cognitive outcomes in patients with heart failure and reduced ejection fraction (HFrEF).

Objectives: The purpose of this study was to compare 3-year cognitive outcomes in patients with HFrEF who receive sacubitril/valsartan vs angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs).

Methods: Retrospective cohort study of: 1) 11,313 adults with HFrEF (International Classification of Diseases-10th Revision-Clinical Modification [ICD-10-CM] codes: I50.2 or I50.4) started on sacubitril/valsartan between 1/1/2015 and 12/31/2019; and 2) 11,313 propensity matched patients receiving ACEI/ARB during that time. Data were obtained from the TriNetX Research Network, encompassing 41 health care organizations in the United States. Primary endpoint was the composite of cognitive decline (ICD-10-CM: R41.8), dementia (ICD-10-CM: F01-F03), and Alzheimer's disease (ICD-10-CM: G30).

Results: At 3 years, 858 patients on sacubitril/valsartan met the primary endpoint vs 1,209 on ACEI/ARB (3-year incidence: 10.7% vs 15.0%; HR: 0.69; 95% CI: 0.63-0.75; P < 0.001), with consistently lower rates of cognitive decline (9.5% vs 13.3%; HR: 0.69; 95% CI: 0.63-0.76; P < 0.001), dementia (3.4% vs 5.0%; HR: 0.65; 95% CI: 0.57-0.77; P < 0.001), and Alzheimer's disease (0.6% vs 1.3%; HR: 0.48; 95% CI: 0.35-0.66; P < 0.001) in the sacubitril/valsartan cohort. Results were consistent in matched sex and race subgroups. Three-year mortality was 22.0% on sacubitril/valsartan vs 24.6% on ACEI/ARB (HR: 0.89; 95% CI: 0.84-0.94; P < 0.001).

Conclusions: Sacubitril/valsartan was associated with lower 3-year rates of neurocognitive disorders when compared to ACEI/ARBs in patients with HFrEF.

Keywords: Alzheimer’s disease; cognitive decline; dementia; heart failure; neprilysin; sacubitril/valsartan.