Sacubitril/valsartan does not impair cognitive function in HFpEF: PERSPECTIVE
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In adults with HF with preserved or mildly reduced ejection fraction, neprilysin inhibition with sacubitril/valsartan did not impair cognitive function compared with valsartan, according to a speaker.
In a blinded, 3-year randomized controlled trial that included serial cognitive function testing and brain imaging, researchers also found that sacubitril/valsartan (Entresto, Novartis) was not associated with accumulation of amyloid beta-peptides in the brain compared with valsartan.
“This should remove any concern about the safety of neprilysin inhibition, in other words, the use of sacubitril, related to cognition,” John J.V. McMurray, MD, professor of cardiology at the Institute of Cardiovascular and Medical Sciences at University of Glasgow in Scotland, said during a press conference at the European Society of Cardiology Congress. “It is questionable whether there ever was a safety concern, but it had been raised, and I believe we have addressed it.”
Cognitive impairment and dementia are common in people with HF with a major impact on ability for self-care, treatment adherence and outcomes, McMurray said. Neprilysin is one of multiple enzymes involved in the degradation of amyloid beta-peptides, one of which may be neurotoxic and might accumulate during sustained neprilysin inhibition, he said.
Assessing cognitive function
For the PERSPECTIVE study, McMurray and colleagues analyzed data from 592 adults aged 60 years or older without known cognitive impairment and chronic symptomatic HF, including HF hospitalization in the prior 12 months or an N-terminal pro-B natriuretic peptide level above 200 pg/mL. The mean age of participants was 72 years and 46.8% were women.
Researchers randomly assigned participants to sacubitril/valsartan (target dose, 97/103 mg twice daily) or valsartan (target dose, 160 mg twice daily) for 3 years. Researchers measured serial cognitive function via the CogState global cognition composite score (GCCS), which includes seven tasks assessing attention, episodic memory and executive function, and in 491 patients conducted brain imaging via PET to assess amyloid beta-peptide accumulation. The primary endpoint was change in cognitive function from baseline to 3 years; the principal secondary outcome was change from baseline to 3 years in brain amyloid beta-peptide depositions.
“It was a balance between trying to do as long a term trial as possible but recognizing that patient and investigator fatigue practically limit what we can do,” McMurray told Healio about the 3-year duration of the study, which included 1,200 baseline brain MRI scans. “Treatment discontinuation also increases with trial duration, resulting in measurements of treatment effect becoming less meaningful. Three years was a compromise trying to balance all these considerations.”
Within the cohort, 60% of participants had some cognitive impairment at baseline.
Change in GCCS from baseline to 3 years did not differ between patients treated with sacubitril/valsartan compared with those assigned valsartan. The difference in least-squares mean change in GCCS was –0.018 (95% CI, –0.123 to 0.087; P = .74). The Cohen's d effect size was –0.0277 (95% CI –0.1101 to 0.0778), indicating noninferiority.
“There was a bit of a decline [overall] during follow-up, but there was absolutely no difference between the two drugs,” McMurray said.
For amyloid beta-peptide measurements, the difference in least-squares mean change in the standardized uptake value ratio was –0.0292 (95% CI, –0.0593 to 0.001; P = .058), indicating that amyloid beta deposition in the brain tended to be less in patients treated with sacubitril/valsartan compared with valsartan.
Sacubitril/valsartan was well-tolerated compared with valsartan, with fewer deaths (9.5% vs. 13.1%) and fewer adverse events leading to treatment discontinuation (16% vs. 20.5%).
Other uses for sacubitril/valsartan
McMurray said the findings may also “open new avenues” for the use of sacubitril/valsartan, particularly for hypertension.
“It is a very potent BP-lowering drug, but its use in hypertension hasn’t really been developed because of this cloud about potential cognitive problems,” McMurray said.
Additionally, the trial revealed a high prevalence of subtle cognitive dysfunction at baseline, McMurray said, which deserves further investigation.
“The last take-home is cognitive impairment in HF is remarkably common, we really do not know why. We need to find out and we need to think about how to treat it because of course it has very serious consequences.”
Perspective
Back to TopJ. Emanuel Finet, MD, FACC, FHFSA
Neurocognitive decline in the HF population is indeed significant, as was demonstrated in this trial, and many times underrecognized. The PERSPECTIVE trial results are reassuring, discrediting the theoretical concern that neprilysin inhibition by sacubitril could lead to significant neurocognitive dysfunction due to increased amyloid beta-peptide deposits in the brain. On the contrary, these results even seem to suggest that sacubitril/valsartan could contribute to a lesser degree of brain amyloid deposits, which could delay long-term neurocognitive decline. These are exciting findings, as sacubitril/valsartan continues to consistently unveil positive outcomes across the HF spectrum. Given its excellent antihypertensive properties and tolerability, it is poised to become an essential pillar of the armamentarium for other chronic CV conditions that require afterload reduction, such as hypertension and some forms of valvular heart disease.
Perspective
Back to Top
Javed Butler, MD, MPH, MBA, FACC, FAHA, FESC
Sacubitril/valsartan has been shown to significantly reduce the risk for CV mortality, HF hospitalization and sudden cardiac death, and improve quality of life. There was a concern raised if neprilysin inhibition would increase beta amyloid deposition in the brain and lead to subsequent impact on cognition in general or the development of Alzheimer's disease. Data from PERSPECTIVE take away all such concerns and if anything, the deposition tended to be lower with sacubitril/valsartan.
These data further confirm the safety profile of sacubitril/valsartan on top of existing data on efficacy and hope this will lead to increased use of this therapy in patients with HF.
The baseline cognitive deficits in patients with HF needs to be studied further.
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McMurray JJV, et al. Hot Line I. Presented at: European Society of Cardiology Congress; Aug. 26-29, 2022; Barcelona, Spain (hybrid meeting).
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