PDF: EBBINGHAUS PCSK9
(2017)Objective
Evolocumab – To evaluate the effect of the PCSK9 inhibitor evolocumab on cognitive function in patients with established atherosclerotic cardiovascular disease receiving statin therapy.
Study Summary
• No significant differences in executive function, memory, or psychomotor speed.
• Cognitive safety confirmed even at very low LDL levels.
Intervention
Randomized, double-blind, placebo-controlled cognitive substudy of the FOURIER trial. Patients received evolocumab (140 mg every 2 weeks or 420 mg monthly) or placebo on top of statins. Cognitive testing was performed using the CANTAB battery at baseline, 24 weeks, annually, and trial end. Primary endpoint: change in spatial working memory strategy index. Secondary endpoints: working memory errors, episodic memory, psychomotor speed.
Inclusion Criteria
Patients aged 40–85 with established cardiovascular disease and LDL ≥70 mg/dL or non-HDL ≥100 mg/dL, on stable moderate- or high-intensity statins. Excluded if dementia, mild cognitive impairment, or other cognitive confounders were present.
Study Design
Arms: Evolocumab + Statin vs. Placebo + Statin
Patients per Arm: Evolocumab: 586; Placebo: 618 (primary-analysis population)
Outcome
• Working memory errors: -0.52 vs. -0.93 (P=0.36)
• Episodic memory errors: -1.53 vs. -1.53 (P=0.49)
• Psychomotor speed: +5.2 vs. +0.9 msec (P=0.06)
• Cognitive adverse events: 1.9% in evolocumab vs. 1.3% in placebo
• No association between LDL levels (even <25 mg/dL) and cognitive outcomes
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.
Study Design
- Study Type
- Multicenter, double-blind, placebo-controlled randomized trial (cognitive substudy)
- Randomization
- Yes
- Blinding
- Double-blind (participants and investigators)
- Sample Size
- 1204
- Follow-up
- Median 19 months
- Centers
- Multinational (29 countries)
Primary Outcome
Definition: Change in spatial working memory strategy index of executive function (CANTAB)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| -0.29 | -0.21 | - (-0.19 to 0.19) | 0.85 |
Limitations & 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
Citation
N Engl J Med 2017;377:633–643. DOI:10.1056/NEJMoa1701131