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Further Assurance That PCSK9 Inhibitor Doesn't Hurt Cognition

The packaging of Repatha SureClick

The packaging of Repatha SureClick

There was no trade-off of impaired cognition when evolocumab (Repatha) was added to statin therapy for LDL cholesterol lowering, according to patient-reported outcomes from the FOURIER trial.

Similar proportions of patients in the evolocumab and placebo groups reported cognitive decline over a median 2.2 years (3.7% vs 3.6%, P=0.62), as shown on a 23-item survey on memory and executive domains using the Everyday Cognition (ECog) scale.

The survey revealed no differences in total scores and subdomain scores among the 82.2% of the FOURIER trial population who answered questions about their everyday function at the beginning and the end of trial participation, reported Robert Giugliano, MD, SM, of Brigham and Women's Hospital in Boston, and colleagues in the May 12 issue of the Journal of the American College of Cardiology.

Even people who achieved very low LDL cholesterol levels (<20 mg/dL) at week 4 had similar declines in total cognitive score as those whose LDL remained at or above 100 mg/dL.

Study results were consistent across prespecified baseline subgroups, including patients above age 75.

"These data confirm the neurocognitive safety of intensive LDL-C reduction with evolocumab while 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," the FOURIER team concluded.

Previously, a FOURIER substudy had shown that 19 months of evolocumab therapy had no effect on cognition according to formal serial objective cognitive testing.

However, other reports had suggested an association between PCSK9 inhibition and adverse cognitive events, according to an editorial comment by Jennifer Robinson, MD, MPH, of the University of Iowa, Iowa City.

"It seems reasonable to conclude that evolocumab had no apparent adverse cognitive impacts in lower risk patients with cardiovascular disease, but there are insufficient data to conclude that is the case for the highest risk patients," she said of the FOURIER report.

"It is unclear if this expectation can be extrapolated to periods of >3 years or to patients older than 75 years of age, those at very high atherosclerotic cardiovascular disease risk, or those with histories of ischemic or hemorrhagic stroke," according to Robinson, who urged longer follow-up and more diverse trial populations in future research.

FOURIER's main finding was that evolocumab dramatically lowered LDL cholesterol in people with atherosclerotic cardiovascular disease with accompanying reductions in risk of heart attack, stroke, and revascularization.

The randomized, double-blind trial had patients assigned to the PCSK9 inhibitor evolocumab or placebo. Eligible patients were people with LDL at least 70 mg/dL or non-HDL cholesterol at least 100 mg/dL despite statin therapy. They were required to have had a prior MI, prior non-hemorrhagic stroke, or symptomatic peripheral arterial disease.

After a median 2.2 years in the trial, 22,655 individuals completed ECog assessment. These individuals averaged age 62.5 years and were about 76% men.

Study investigators noted the limitation of having ECog evaluation performed only once, at the end of the study.

In addition, there was some healthy volunteer bias, given that people who reported ECog had lower rates of incident major adverse CV events compared with nonresponders.

"The cognitive safety of pharmacologically induced LDL-C levels has long been a concern. Although there have been anecdotal reports of cognitive symptoms related to statins, systematic reviews and meta-analyses of statin trials have found no association between statin therapy and neurocognitive adverse events," Robinson noted.

"The public perception of the adverse effects of statins is often exaggerated, in part as a consequence of media reports. In this context, the use of patient-reported outcomes has a particular significance to reassure patients and doctors," Giugliano's team wrote.

Last Updated May 05, 2020

Disclosures

Amgen was the sponsor of FOURIER.

Giugliano has received grants from Amgen; has received honoraria from Amgen, Daiichi-Sankyo, and Merck; and has received consulting fees from Amgen, Akcea, Amarin, Boehringer Ingelheim, Bristol-Myers Squibb, CVS Caremark, Daiichi-Sankyo, Esperion, GlaxoSmithKline, Lexicon, Merck, Portola, Pfizer, and Servier.

Robinson reported institutional research grants from Acasti, Amarin, Amgen, AstraZeneca, Esperion, The Medicines Company, Merck, Novartis, Novo Nordisk, Regeneron, and Sanofi; and has served as a consultant for The Medicines Company, Novartis, and Pfizer.

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