No effect of PCSK9 inhibitor on cognitive functioning in CVD patients, even at LDL-c <25 mg/dL
Primary Results of EBBINGHAUS, a Cognitive Study of Patients Enrolled in the FOURIER Trial
Presented at ACC.17 by Robert P. Giugliano
Preliminary studies and small observational studies have raised concern about a possible link between cholesterol-lowering treatment such as statins and cognitive deficits. In 2012 the FDA added the risk of adverse cognitive effects to the label of all statins. Analyses of large scale randomised controlled trials have, however, not supported these findings. The 2014 Statin Cognitive Safety Task Force concluded that statins are not associated with cognitive side effects.
The brain synthesises cholesterol locally. While monoclonal antibodies such as evolocumab, are too large to cross the intact blood-brain barrier, a meta-analysis of adverse events (AEs) from six trials in 9581 patients suggested an increased risk of cognitive AEs. Event rates were, however, low and unadjudicated: diverse AEs were reported. Moreover, AEs were not correlated with LDL-c achieved.
The EBBINGHAUS was a cognitive study nested in the FOURIER trial. It aimed to test the hypothesis that addition of evolocumab to statin therapy in patients with clinically evident vascular disease does not adversely affect cognitive function. 1974 FOURIER participants patients were enrolled in the FOURIER study (median follow-up 19.8 months). Cognitive tests were performed at baseline, and at 6, 12 and 24 months, and at end of study. Several cognitive endpoints were applied, including the Cambridge Neuropsychological Test Automated Battery (CANTAB), a standardised, well-validated computer tablet-based testing platform. Among other things, it tests a spatial working memory strategy index of executive function. In addition, a patient survey of everyday cognition was conducted at study end, as well as an investigator report of cognitive AEs.
- The primary endpoint was the spatial working memory (SWM) strategy index (# inefficient searches started, lower score represents better performance). The index was the same in both treatment groups at baseline (17.8 and 17.8), and post baseline (17.6 in placebo and 17.5 in evolocumab). Change from baseline was -0.29 for placebo and -0.21 for evolocumab.
- The non-inferiority analysis showed a statistically significant treatment difference in Z-score (0.0) well below the non-inferiority boundary of 0.19 (P<0.001).
- None of the secondary endpoint results differed significantly between treatment groups, and were numerically very similar.
- When stratifying the results based on nadir LDL-achieved, no significant differences were seen in average change in the primary CANTAB endpoint from baseline between treatments in categories of <25 mg/dL, 25-39 mg/dL and ≥40 mg/dL LDL. The same was seen for average change from baseline in composite global score. No significant differences were seen across LDL-c values achieved.
- The patient self-report did not show a difference in the total score on everyday cognition (mean: 1.13, SD: 0.33 for placebo, mean: 1.14, SD: 0.33 for evolocumab), nor on individual components reflecting memory or executive functioning.
- The investigator reported cognitive AEs did not differ significantly between placebo (16/990) and evolocumab (19/983, P=0.59).
These data show that in patients with known CVD on background statin followed for 20 months, no differences were seen between patients receiving evolocumab and placebo in a battery of cognitive tests, in patient-reported everyday cognition, nor in adverse cognitive events reported by a physician. There was no evidence of a difference in cognitive tests by achieved nadir LDL-c, even below 25 mg/dL. No decline in cognitive function was seen between beginning and end of study, in either treatment group.
During the press conference, the experts on the panel referred to dr. Google, who often misinforms patients and keeps myths about possible risks alive. The commenter noted that these data are very reassuring that PCSK9 inhibition with evolocumab is not associated with cognitive decline in those with low LDL-c, nor in the population as a whole.
While the study did not specifically address the question whether statins are associated with cognitive decline, no change in cognitive function was observed over time in the placebo group, meaning patients on statin therapy.
A question was asked about the diverging CV event curves seen in the FOURIER trial over time, and whether a similar effect might be anticipated for the cognitive effects. Longer term cognitive effects will also be assessed in the open label extension study, in which EBBINGHAUS patients can enrol. Obviously, long term information will be informative, but dr. Giugliano shared that for this type of cognitive studies, the set up of EBBINGHAUS was already relatively long and large. He does not expect big surprises, considering that reaction time only decreased by 2-5 ms over the course of months, which is much smaller than the effect of having an alcohol permillage just over the limit allowed for driving (175 ms) or taking a benzodiazepine (30-40ms).
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