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Eur Heart J. 2018 Feb 1;39(5):374-381. doi: 10.1093/eurheartj/ehx661.

No evidence of neurocognitive adverse events associated with alirocumab treatment in 3340 patients from 14 randomized Phase 2 and 3 controlled trials: a meta-analysis of individual patient data.

Author information

1
Department of Psychiatry, University of Miami Miller School of Medicine, 1120 NW 14th Street, Suite 1450, Miami, FL, USA.
2
Barrow Neurological Institute, 350 W Thomas Rd, Phoenix, AZ 85013, USA.
3
Alzheimer Center, VUmc, De Boelelaan 1118, 1081 HZ Amsterdam, The Netherlands.
4
IoPPN, Kings's College, 16 De Crespigny Park, London SE5 8AF, UK.
5
Columbia University, 622 West 168 Street, New York, NY 10032, USA.
6
University of Pierre and Marie Curie, 47-83 Boulevard de l'Hôpital, 75013 Paris, France.
7
Regeneron Pharmaceuticals, 777 Old Saw River Road, Tarrytown, NY 10591, USA.
8
Sanofi, 55 Corporate Drive, Bridgewater, NJ 08807, USA.
9
Sanofi, 1 Avenue Pierre Brossolette, 91380 Chilly-Mazarin, France, and IviData Stats, 79 Baudin Street, 92300 Levallois-Perret, France.
10
Point Médical, Rond Point de la Nation, 21000 Dijon, France, and Department of Cardiology, CHU Dijon Bourgogne, 2 Bd Maréchal de Lattre of Tassigny, 21000 Dijon, France.

Abstract

Aims:

Despite patient reports of neurocognitive disorders with lipid-lowering treatments (LLTs), large clinical trials have found no significant association between neurocognitive disorders and LLTs. We assessed incidence of neurocognitive treatment-emergent adverse events (TEAEs) from 14 Phase 2 and 3 trials of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab.

Methods and results:

Patients (most on background maximally tolerated statin) received alirocumab 75/150 mg every 2 weeks (n = 3340; 4029 patient-years of exposure), placebo (n = 1276), or ezetimibe (n = 618). Data were pooled by the control used. Neurocognitive TEAEs were reported by 22 (0.9%) alirocumab-treated patients vs. 9 (0.7%) with placebo in placebo-controlled trials [hazard ratio (HR) 1.24, 95% confidence interval (CI) 0.57-2.68] and 10 (1.2%) with alirocumab vs. 8 (1.3%) with ezetimibe in ezetimibe-controlled trials (HR 0.81, 95% CI 0.32-2.08). Rates of neurocognitive TEAEs were similar in patients receiving alirocumab with LDL cholesterol (LDL-C) levels <25 mg/dL (<0.65 mmol/L; n = 5/839; 0.6%; 0.5/100 patient-years) vs. ≥25 mg/dL (n = 26/2501; 1.0%; 0.8/100 patient-years). One patient (0.1%; ezetimibe-controlled pool) receiving alirocumab had a neurocognitive TEAE leading to discontinuation vs. two (0.2%) patients receiving placebo and three (0.4%) patients receiving ezetimibe. Neurocognitive TEAE incidence was also similar between alirocumab and controls when stratified by age.

Conclusions:

Neurocognitive TEAE incidences were low (≤1.2%), with no significant differences between alirocumab vs. controls up to 104 weeks. No association was found between neurocognitive TEAEs and LDL-C <25 mg/dL based on the completed Phase 2 and 3 trials examined, although long-term effects of very low LDL-C levels induced by PCSK9 inhibitors are currently unknown.

KEYWORDS:

Cholesterol-lowering drugs; Cognitive function ; LDL; PCSK9; Patient safety

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