No increased cognitive impairment with evolocumab plus statins
The addition of evolocumab to statin therapy to reduce LDL-C levels does not result in an increased risk of patient-reported cognitive impairment in individuals with atherosclerotic cardiovascular disease (ASCVD), according to results from the FOURIER* trial.
“These data confirm the neurocognitive safety of intensive LDL-C reduction with evolocumab, while simultaneously reducing recurrent CV events in high-risk patients, and suggest that very low achieved LDL-C levels may be safely targeted for high-risk patients,” said corresponding author Professor Robert P. Giugliano from Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts, US.
FOURIER participants were aged 40–85 years with ASCVD and LDL-C levels ≥70 mg/dL or non-HDL-C levels ≥100 mg/dL despite optimal statin therapy with or without ezetimibe. They were randomized to receive subcutaneous evolocumab or placebo in addition to statins. At the final visit (median 2.2 years), 22,655 patients (mean age 62.5 years, about 76 percent male) completed a 23-item survey based on the Everyday Cognition (ECog) scale which assessed changes in memory and executive domains from baseline. The changes were assessed with a four-point scale where a score of 1 denoted no change or improvement from baseline, 2 denoted questionable or occasionally worse, 3 denoted consistently a little worse, and 4 denoted consistently much worse.
Cognitive decline at the end of the trial, defined as an ECog score ≥2, occurred at a comparable rate in evolocumab and placebo recipients. [J Am Coll Cardiol 2020;75:2283-2293]
These findings applied to total ECog score (3.6 percent vs 3.7 percent of placebo vs evolocumab recipients; p=0.62), as well as for the subdomains of memory function (5.8 percent vs 6.0 percent; p=0.53) and executive total function (3.6 percent vs 3.7 percent; p=0.83). Declines in executive planning were also comparable between placebo and evolocumab recipients (4.3 percent vs 4.4 percent; p=0.47), as were declines in executive organization (3.7 percent vs 4.1 percent; p=0.088) and executive divided attention (6.4 percent vs 6.5 percent; p=0.86).
Rate of decline in total cognitive, memory, and executive function scores was also similar between patients who achieved very low LDL-C levels (<20 mg/dL) and those with LDL-C levels ≥100 mg/dL (3.8 percent vs 4.5 percent; p=0.57 [total], 5.8 percent vs 6.9 percent; p=0.92 [memory], and 3.9 percent vs 4.6 percent; p=0.48 [executive]).
The researchers noted that the single assessment of cognitive function presented a limitation. Furthermore, while ECog is an acceptable tool to assess daily function, it does not include all aspects of cognitive function. Further research is necessary to examine if these findings extend over a longer period, they said.
In an accompanying editorial, Professor Jennifer G. Robinson from the University of Iowa, Iowa City, Iowa, US, also noted the possibility of “healthy volunteer bias” and the relatively young age of the survey responders, the latter not the age group at highest risk for cognitive decline. The exclusion of patients with a history of haemorrhagic stroke was also a limitation.
“It is unclear if this expectation of safety can be extrapolated to periods of >3 years, or to patients who are older than 75 years, are at very high ASCVD risk, or with a history of ischaemic or haemorrhagic stroke. An altered safety profile may influence the potential for a net CV risk reduction benefit from the addition of PCSK9 mAbs**. Longer follow-up and more diverse trial populations are needed,” she said.