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EBBINGHAUS: Evolocumab does not affect cognitive outcomes
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WASHINGTON — The addition of evolocumab to statin therapy did not result in memory loss or other cognitive issues, according to results of the EBBINGHAUS study.
The investigators of FOURIER, which compared evolocumab (Repatha, Amgen) vs. placebo for clinical outcomes in patients with atherosclerotic CVD and elevated LDL on background statin therapy, undertook a cognitive substudy because small studies and case series had raised concerns that statins negatively impact cognitive outcomes, later disproven by larger studies, Robert P. Giugliano, MD, SM, cardiovascular medicine specialist at Brigham and Women’s Hospital and a senior investigator at the Thrombolysis in Myocardial Infarction Study Group, said during a presentation at the American College of Cardiology Scientific Session.
“We designed the EBBINGHAUS study ... to assess the following hypothesis: [Did] the addition of evolocumab to statin therapy in patients with clinically evident [CVD] affect cognitive outcomes? We hypothesized that it would not,” Giugliano said.
To determine whether that was true, the researchers enrolled 1,974 patients from FOURIER (mean age, 63 years; 72% men) without dementia or cognitive impairment at baseline, of whom 1,204 who had baseline cognitive testing performed and at least one follow-up cognitive test were included in the primary analysis.
All patients performed Cambridge Neuropsychological Test Automated Battery Assessments at baseline, 6 months, 12 months, 24 months, 48 months and at the end of the study.
The primary outcome was spatial working strategy index of executive function. Secondary outcomes included spatial working memory errors, paired associates learning and reaction time. A global score combining those four outcomes was an exploratory outcome, and patients took a survey of everyday cognition at the study’s end.
For the placebo group, the spatial working strategy index raw score was 17.8 at and after baseline, and for the evolocumab group it was 17.6 at baseline and 17.5 after baseline, Giugliano said.
The treatment difference in z score was near zero, well below the noninferiority boundary of .19, so evolocumab was noninferior to placebo for the primary outcome (P for noninferiority < .001), he said.
There was no significant difference between the groups in spatial working memory errors (P = .36), paired associates learning (P = .49) and reaction time (P = .06), according to the researchers.
The results were consistent regardless of how low a patient’s LDL fell after taking evolocumab, Giugliano said.
In the survey of everyday cognition at the study’s end, there was no difference between the groups in patient score (P = .42), and there was no difference in investigator-reported cognitive adverse events for the primary cohort (P = .42) or the overall population (P = .59), he said.
“We conclude that no differences were apparent between evolocumab and placebo on the battery of cognitive tests [or] the survey ... and no differences stratified by achieved LDL,” Giugliano said at a press conference. – by Erik Swain
Reference:
Giugliano RP, et al. Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; March 17-19, 2017; Washington, D.C.
Disclosure: The study was sponsored by Amgen. Giugliano reports receiving grants from Amgen and Merck and honoraria from the American College of Cardiology, Amgen, Bristol-Myers Squibb, CVS Caremark, Daiichi Sankyo, GlaxoSmithKline, Merck, Pfizer and Sanofi.
Perspective
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Steven E. Nissen, MD, MACC
There has been a concern looming for a long time, both for statins and PCSK9 inhibitors, that cholesterol is necessary to the functioning of brain cells, so people who are treated to very low levels of LDL should be tested for cognitive dysfunction. It’s appropriate that the FDA expressed concerns about this to the companies making the PCSK9 inhibitors. They responded with the EBBINGHAUS trial, a large neurocognitive study. I was impressed that it was very rigorous. Interestingly enough, despite the concerns over the years and maybe some signals along the way, there is really no evidence of adverse cognitive effects. It appears that the brain is not adversely affected by treatment to very low LDL levels. That’s important because when we consider the GLAGOV and FOURIER study results, we now have some incentives to treat people to very low LDL, and we need to know if there will be brain-related issues, and now we don’t see any evidence that there is.
If there is an effect and it’s not seen in a trial of this size, it would have to be very, very rare. The study is pretty conclusive.
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