Key Points
- There has been a theoretical concern of potential increased amyloid deposition via neprilysin inhibition in patients using sacubitril/valsartan. In the PERSPECTIVE study, patients with HFpEF and HFmrEF were treated with either sacubitril/valsartan or valsartan. Their cognitive function (as assessed by comprehensive CogState testing) as well as brain amyloid peptide deposition by PET and MRI were determined at three years.
- Treatment with sacubitril/valsartan was not associated with any significant differences in cognitive function via CogState testing or in global amyloid deposition as determined by PET scan at three years.
Sacubitril/Valsartan is now standard of care in patients with heart failure with reduced ejection fraction (HFrEF), and within the past year has also gained FDA approval in the treatment of patients with preserved EF as well. The mechanism of sacubitril involves neprilysin inhibition, and neprilysin is additionally involved in the proteolytic degradation of amyloid peptides. As such, a theoretical concern of sustained neprilysin inhibition via the use of sacubitril/valsartan has been the potential accumulation of amyloid peptides in the brain with subsequent cognitive impairment. In a breaking presentation at the 2022 European Society of Cardiology Conference today, Dr. John McMurray (University of Glasgow) and his team presented “Efficacy and Safety of LCZ696 Compared to Valsartan on Cognitive Function in Patients With Chronic Heart Failure and Preserved Ejection Fraction,” or the PERSPECTIVE trial.
The PERSPECTIVE study (NCT02884206) was a multicenter, randomized, double-blind, active-controlled study assessing the cognitive impact of sacubitril/valsartan compared to valsartan alone in heart failure patients with mid-range or preserved ejection fraction. All recruited patients were adults >60 years old with symptomatic heart failure and EF >40% with either an NT-proBNP >200 pg/mL or a hospitalization for HF within the last year. Some relevant exclusion criteria included elevated serum potassium >5.4mmol/L, eGFR <25 ml/min, or severe hypo- or hypertension. Other neurocognitive-relevant criteria included consent to APOE4 genetic testing, lack of preexisting substantial cognitive impairment (known dementia syndrome or MMSE <24), and absence of contraindication to MRI.
A total of 592 patients were randomized; 297 patients were included in the valsartan cohort, and 295 in the sacubitril/valsartan cohort. Prior to randomization, in the run-in phase, each patient was initiated in 80 mg valsartan BID for 1-5 weeks and then sacubitril/valsartan (49/51mg BID) for 2-4 weeks to ensure tolerance. The mean age was 72, and the pre-existing average MMSE score was 28. CogState cognitive testing was performed every 3 months, PET scans were performed at the outset and at 18 and 36 months, and MRIs were also performed at 18 and 36 months. The primary outcome of CogState global cognition composite score at 36 months was not statistically different between the two groups. Similarly, there were no differences in secondary outcomes, including the standardized uptake value ratio (SUVR) of the global cortical composite in amyloid PET imaging of the brain. In individual components of the brain, sacubitril/valsartan resulted in significantly lower rates of amyloid deposition by the SUVR method, including the cingulum (p=0.003). No new safety concerns were identified relative to previous trials. 25% of patients discontinued treatment in the sacubitril/valsartan arm, as did 30% in the valsartan arm alone.
When discussing the implications of the study at the ESC, Dr. McMurray stated: “This largely theoretical concern that sacubitril/valsartan might cause accumulation of amyloid peptides in the brain with resulting cognitive dysfunction is, I think, disproved by this trial.”