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EBBINGHAUS PCSK9

Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects

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Year of Publication: 2017

Authors: Robert P. Giugliano, François Mach, Kenton Zavitz, ..., Brian R. Ott

Journal: New England Journal of Medicine

Citation: N Engl J Med 2017;377:633–643. DOI:10.1056/NEJMoa1701131

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa1701131

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa1701131

Clinical Question

Does the addition of evolocumab to statin therapy negatively affect cognitive function in patients with clinically evident cardiovascular disease?

Bottom Line

Evolocumab did not worsen cognitive function compared to placebo when added to statin therapy over a median follow-up of 19 months, even in patients achieving very low LDL cholesterol levels.

        Major Points
        Substudy of the FOURIER trial using the CANTAB tool to objectively assess cognition.
1204 patients included in the primary analysis, randomized to evolocumab or placebo.
No significant differences in executive function (primary endpoint) or working memory, episodic memory, or psychomotor speed (secondary endpoints).
Mean change in executive function score: −0.21 (evolocumab) vs −0.29 (placebo); P<0.001 for noninferiority; P=0.85 for superiority.
No association between cognitive decline and LDL-C level, even among patients with LDL <25 mg/dL.
Self-assessed cognition (ECog questionnaire) also showed no difference between groups.

      

Design

Study Type: Multicenter, double-blind, placebo-controlled randomized trial (cognitive substudy)

Randomization: 1

Blinding: Double-blind (participants and investigators)

Enrollment Period: September 2014 – August 2015

Follow-up Duration: Median 19 months

Centers: Multinational (29 countries)

Countries:

Sample Size: 1204

Analysis: Mixed-effects linear models, noninferiority design; subgroup and LDL-C stratification analyses

Inclusion Criteria

Enrollment in FOURIER trial
Age 40–85 years
Clinically evident atherosclerosis
LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL on statins

Exclusion Criteria

Dementia or mild cognitive impairment
Neurological or psychiatric disorder confounding cognition
Inability to complete tablet-based CANTAB testing

Baseline Characteristics

Characteristic	Comorbidities	Qualifying Event
Hypertension	86.3
Diabetes	37.2
Prior Stroke	18.9
Smoker	31.6

Arms

Field	Evolocumab	Control
Intervention	140 mg SC every 2 weeks or 420 mg monthly	Matching placebo injections + statin
Duration	Median 19 months	Median 19 months

Outcomes

Outcome	Type	Control	Intervention	P-value
Change in spatial working memory strategy index of executive function (CANTAB)	Primary	-0.29	-0.21	0.85
Working memory (between-errors test)	Secondary	-0.93	-0.52	0.36
Episodic memory (paired associate learning test)	Secondary	-1.53	-1.53	0.49
Psychomotor speed (5-choice reaction time)	Secondary	0.9 ms	5.2 ms	0.06
Global composite CANTAB z-score	Secondary	0.061	0.031	0.12
Cognitive adverse events	Adverse		1.9% (evolocumab) vs. 1.3% (placebo)
Subjective cognitive decline (ECog questionnaire)	Adverse		No increase in either group

Subgroup Analysis

No consistent subgroup heterogeneity; LDL <25 mg/dL subgroup showed no cognitive harm

Criticisms

Short follow-up duration (median 19 months)
Excluded patients with cognitive impairment at baseline
CANTAB is not commonly used in clinical practice
No baseline ECog questionnaire to assess subjective changes over time

Funding

Amgen

Based on: EBBINGHAUS PCSK9 (New England Journal of Medicine, 2017)