Unexpected Cognitive Effect of ARNI Therapy in Heart Failure
Despite fears about cognitive decline in heart failure patients taking angiotensin receptor-neprilysin inhibition (ARNI), an observational study found that the drug instead had a protective effect.
Adults with systolic heart failure taking sacubitril/valsartan (Entresto) starting from 2015–2019 had fewer neurocognitive diagnoses up to 5 years later compared with a those staying on angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) alone.
- Alzheimer’s disease: 1.11% on ARNI vs 1.24% on ACE inhibitors/ARBs
- Dementia: 4.18% vs 6.49%
- Cognitive decline: 11.82% vs 14.53%
On the basis of the PARAGON-HF trial, sacubitril/valsartan won a broad heart failure indication, reaching into the normal ejection fraction range, for prevention of cardiovascular death and hospitalisation.
“Experimental studies with sacubitril/valsartan have fueled theoretical concerns about neurocognitive side effects, but long-term clinical data are scarce,” noted Prabhjot Grewal, MD, of Stony Brook University Hospital in New York, who reported the findings for the Heart Failure Society of America annual virtual meeting.
She explained that neprilysin inhibition by sacubitril could theoretically 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.
However there are many factors in cognitive decline in heart failure, such as the circulatory deficit itself; vascular dementia resulting from comorbidities such as hypertension and vascular disease; and Alzheimer’s disease or Lewy body dementia. By ameliorating heart failure and improving blood pressure, drugs such as ACE inhibitors and sacubitril/valsartan could protect 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 authors acknowledged that the observational study lacked systematic characterisation, and also leaves room for residual confounding despite propensity matching.
“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,” Mehra said, adding that the PERSPECTIVE trial will likely publish findings in 2022.
Source: MedPage Today
