Cognitive decline rates same as placebo in FOURIER analysis

Evolocumab (Repatha), a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), added on to statins had no effect on patient-reported cognition in the full study cohort of the FOURIER trial, follow-up analysis showed.

At the end of FOURIER trial, about 82% of participants completed a questionnaire about executive function and memory tasks. Participants randomized to placebo and evolocumab reported cognitive decline at the same rates on memory (5.8% versus 6.0%), executive function (3.6% versus 3.7%), and total cognitive scores (3.6% versus 3.7%), reported Robert Giugliano, MD, of Harvard University, and coauthors in the Journal of the American College of Cardiology.

“In an analysis of 22,655 patients with stable atherosclerotic CV disease, we found no significant impact of evolocumab on patient-reported cognition after a median follow-up period of 2.2 years,” Giugliano and colleagues wrote. “Furthermore, no association was found between on-treatment LDL concentration at 4 weeks and subsequent cognitive function, even among the 2,339 patients who achieved LDL concentrations <20 mg/dl.”

FOURIER was a randomized, placebo-controlled trial (n=27,564) that found add-on evolocumab reduced vascular events in patients with dyslipidemia despite taking a statin, and safely reduced low-density lipoprotein (LDL) cholesterol to a median of 30 mg/dl. Further analyses of the trial reinforced these findings and showed that evolocumab may reduce the risk of aortic stenosis and was associated with benefit across multiple MI subtypes, as previously reported by BreakingMED.

Concerns about cognitive effects of cholesterol-lowering medications or the low levels of cholesterol they can produce were addressed in a previously reported subset of 1,204 FOURIER participants who were evaluated with serial objective cognitive tests and showed no difference in cognitive evaluations between evolocumab and placebo at an average follow-up of 19 months.

Other studies have shown that PCSK9 monoclonal antibodies are associated with adverse cognitive effects. A prior study of add-on evolocumab in 4,465 patients found increased adverse cognitive effects in the evolocumab group, though adverse events, including cognitive complaints, did not vary by the level of LDL achieved. Similarly, increased cognitive adverse events were seen for add-on alirocumab.

FOURIER enrolled patients age 40 to 85 with a history of prior myocardial infarction, previous non-hemorrhagic stroke, or symptomatic peripheral arterial disease who had LDL of 70 mg/dl or higher (or non–high-density lipoprotein cholesterol of 100 mg/dl or more) who were already taking a statin, with or without ezetimibe (Zetia). Participants were randomized to subcutaneous evolocumab (140 mg every 2 weeks or 420 mg monthly) or placebo. Average age of evolocumab and placebo groups was 62.5 years and 76% of both groups were male.

At the end of the FOURIER trial (median follow-up 2.2 years), participants filled out a 23-item questionnaire that included the memory and executive function portions of the 39-item Everyday Cognition (ECog) scale. The memory section asked questions about recalling things like conversations, object locations, or appointments. The executive function section assessed planning, organization, and multitasking.

Patients rated their ability to perform tasks compared to the beginning of the study, indicating whether a task was better or the same (scored as 1), occasionally worse (scored as 2), consistently a little worse (scored as 3), or consistently a lot worse (scored as 4). Cognitive decline was defined as an ECog score ≥ 2.

Executive function subscores also showed no difference for evolocumab versus placebo in executive planning (4.3% versus 4.4%), organization (3.7% versus 4.1%), or multitasking (6.4% versus 6.5%).

Stratification by 4-week LDL levels showed no significant trend across the groups of achieved LDL-C after adjustment for total, memory or executive score. The proportion of patients reporting a decline was similar among the 2,338 patients with 4-week LDL levels <20 mg/dl compared with 3,613 patients with LDL of 100 mg/dl or more (3.8% versus 4.5%, P = 0.57).

In an accompanying editorial, Jennifer Robinson, MD, MPH, of the University of Iowa in Iowa City, wrote, “Should these data be interpreted as definitive evidence that intensive LDL-C lowering with PCSK9 mAbs has no major harmful cognitive effects, at least over a period of 3 years? The answer appears to be a qualified yes, but with three important caveats,” including:

  • Potential health risk bias in the 82% who completed the end-of-study survey; the 18% who did not complete the survey had more risk factors for cognitive impairment.
  • Mean age of FOURIER participants, which was 62.5; cognitive decline accelerates after age 75.
  • Hemorrhagic strokes were excluded from the present study and the proportion with FOURIER-qualifying non-hemorrhagic strokes (19%) was relatively low.

“It is reasonable to conclude that intensive LDL-C lowering with a PCSK9 mAb over a period of 3 years appears to have no adverse cognitive effects in younger, lower risk patients with coronary heart disease and additional high-risk characteristics,” Robinson observed.

“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,” she added.

Other limitations include a single end-of-study, self-reported cognitive evaluation for the overall FOURIER population.

  1. Evolocumab (Repatha) added on to statins had no effect on patient-reported cognition in the full cohort of the FOURIER trial over 2.2 years, follow-up analysis showed.

  2. Be aware that potential health-risk bias, a relatively young age of participants (average age 62.5), and exclusion of certain patients (like those with hemorrhagic strokes) may limit the generalizability of these findings.

Paul Smyth, MD, Contributing Writer, BreakingMED™

The FOURIER trial was supported by a research grant from Amgen.

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 has received research grants to the institution from Acasti, Amarin, Amgen, AstraZeneca, Esperion, The Medicines Company, Merck, Novartis, NovoNordisk, Regeneron, and Sanofi; and has served as a consultant for The Medicines Company, Novartis, and Pfizer.

Cat ID: 102

Topic ID: 74,102,730,102,308,914,130,33,361,192,925