Feared ARNI Effect on Cognition Hasn’t Come to Fruition

Heart failure patients on angiotensin receptor-neprilysin inhibition (ARNI) therapy for several years had no excess cognitive decline — rather, the treatment was associated with protection of the brain on observational analysis.

U.S. adults with systolic heart failure who started using sacubitril/valsartan (Entresto) in 2015-2019 had a significantly lower incidence of neurocognitive diagnoses up to 5 years later compared with a propensity-matched cohort of peers staying on angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) alone:

• Alzheimer’s disease: 1.11% vs 1.24% (HR 0.63, 95% CI 0.47-0.85)
• Dementia: 4.18% vs 6.49% (HR 0.70, 95% CI 0.61-0.80)
• Cognitive decline: 11.82% vs 14.53% (HR 0.82, 95% CI 0.75-0.89)

Thus, the fears about off-target effects of ARNI therapy were not realized in a study of 19,553 matched pairs, reported Prabhjot Grewal, MD, of Stony Brook University Hospital in New York, and colleagues, in a digital poster at the Heart Failure Society of America meeting held both virtually and in Denver.

This year, sacubitril/valsartan became the first drug to win a broad heart failure indication, reaching into the normal ejection fraction range, for prevention of cardiovascular death and hospitalization on the basis of the PARAGON-HF trial. The ARNI drug had been FDA approved for heart failure with reduced ejection fraction since 2015.

“Experimental studies with sacubitril/valsartan have fueled theoretical concerns about neurocognitive side effects, but long-term clinical data are scarce,” Grewal noted.

She explained the theory that neprilysin inhibition by sacubitril would inadvertently interfere with the degradation of beta amyloid in the central nervous system, where neprilysin is expressed in addition to the kidneys where it is most abundant.

Yet cognitive decline in heart failure can be related to multiple factors such as the circulatory deficit itself; vascular dementia stemming from comorbidities such as hypertension and vascular disease; and Alzheimer’s disease or Lewy body dementia. Through their effects in ameliorating the heart failure state and lowering blood pressure, drugs such as ACE inhibitors and sacubitril/valsartan could improve cognition, according to Mandeep Mehra, MBBS, MSc, of Brigham and Women’s Hospital and Harvard Medical School in Boston.

“Thus, even if a drug like sacubitril may cause worsening of one type of cognitive decline, it may be counterbalanced by positive effects on other domains since the reasons for cognitive decline in such patients are almost always multi-factorial and the signals may therefore be obfuscated in general analyses,” explained Mehra, who was not involved in the study.

The study relied on electronic health record (EHR) data collected from the TriNetX network spanning 46 U.S. sites. Investigators created 19,553 matched pairs averaging age 63, with 67.5% being men and nearly 65% white.

ARNI therapy’s association with reduced neurocognitive events applied to both men and women, as well as Black and white patients.

Estimated Kaplan-Meier mortality was 25.6% versus 32.3% between ARNI and control groups (log-rank P<0.001).

The authors acknowledged that the observational study was subject to potential ascertainment bias due to the reliance on ICD codes in EHR data.

The lack of systematic characterization aside, the study also leaves room for residual confounding despite propensity matching, Mehra cautioned.

“This is why we require a prospective study that includes mechanistic end points (degree of beta amyloid protein deposition) in concert with functional outcomes (sensitive measures of cognitive decline) while ensuring that sufficient time is allowed to be evaluated since these are slow and subtle effects,” he said.

Mehra noted that one such study, the PERSPECTIVE trial, is now fully enrolled and will likely be reported next year.

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