No Detrimental Impact on Cognition With Entresto for Heart Failure

BARCELONA — Patients who were treated with sacubitril/valsartan (Entresto) for heart failure with moderately reduced or preserved left ventricular ejection fraction did not appear to experience worsening cognition function compared with similar patients who were treated with valsartan alone, researchers reported here.

After 3 years of follow-up, the difference in the least squares mean change in the Cogstate global cognitive composite score was 0.0180 points (P=0.74), which was not significant but did prove noninferiority, said John McMurray, MD, MB, ChB, of the University of Glasgow in Scotland, during a press conference at the European Society of Cardiology Congress.

“There was no evidence that neprilysin inhibition increased the risk of cognitive impairment due to accumulation of amyloid beta in the brain in patients with heart failure with moderately reduced ejection fraction and heart failure with preserved ejection fraction,” he noted. “The concern about increased cerebral amyloid beta deposition with sacubitril/valsartan was always hypothetical and multiple enzymatic and other amyloid beta clearance pathways exist in the brain that would likely compensate for any decreased clearance related to neprilysin inhibition.”

The principal secondary outcome was the change from baseline to 3 years in amyloid beta deposition in the brain measured with PET in 491 patients. The difference in least squares mean change in the standardized uptake value ratio was -0.0292 (95% CI -0.0593 to 0.0010, P=0.058), indicating that there was less amyloid beta deposition in the brain in patients treated with sacubitril/valsartan compared with valsartan alone.

“The trend towards decreased amyloid deposition on PET scanning is a surprise and may just reflect the play of chance,” McMurray noted. “The absence of any negative effect on cognitive function is very important in removing a concern some doctors had about long-term treatment with sacubitril/valsartan.”

Neprilysin is one of multiple enzymes involved in the proteolytic degradation of amyloid beta peptides associated with Alzheimer’s type dementia. Concerns have been raised that their accumulation in the brain during sustained neprilysin inhibition could cause or worsen cognitive impairment, the researchers explained.

The FDA required a randomized trial evaluating the effects of sacubitril/valsartan compared with valsartan alone on cognitive function assessed by a comprehensive neurocognitive battery and PET imaging in patients with chronic heart failure before approval.

However, “the results of PERSPECTIVE are unlikely to change clinical practice,” said Dipti Itchhaporia, MD, of the University of California Irvine and immediate past president of the American College of Cardiology. “Sacubitril/valsartan is the first drug in more than a decade that shows a mortality benefit in heart failure, but it is underutilized.”

“I think that cost issues are the reason it isn’t prescribed more often, rather than concerns about cognition,” she told MedPage Today. “The fact that the study found no hint of a problem with cognition is reassuring, but there probably were very few clinicians who withheld the drug because of cognition worries.”

For this study, McMurray and colleagues enrolled 592 patients from 137 centers in 20 countries (mean age 72.4 years, 46.8% women). Eligibility criteria included a diagnosis of heart failure with a left ventricular ejection fraction of 40% or more, age ≥60 years, and a history of hospitalization due to worsening heart failure symptoms in the past year.

The participants were randomly assigned to either sacubitril/valsartan at a target dose of 97/103 mg twice daily or valsartan at a target dose of 160 mg twice daily.

Sixty percent of patients had some indication of cognitive impairment at baseline. Patients with heart failure are at increased risk of developing dementia compared with the general population, McMurray noted.

Adverse events leading to discontinuation occurred among 47 patients taking sacubitril/valsartan and 61 patients on valsartan alone.