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

Philip D. Harvey, Marwan N. Sabbagh, John E. Harrison, Henry N. Ginsberg, M. John Chapman, Garen Manvelian, Angele Moryusef, Jonas Mandel, Michel Farnier

Research output: Contribution to journalArticleAcademicpeer-review

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 subtili-sin/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),orezetimibe (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.
Original languageEnglish
Pages (from-to)374-381
JournalEuropean Heart Journal
Volume39
Issue number5
DOIs
Publication statusPublished - 2018

Cite this

Harvey, Philip D. ; Sabbagh, Marwan N. ; Harrison, John E. ; Ginsberg, Henry N. ; Chapman, M. John ; Manvelian, Garen ; Moryusef, Angele ; Mandel, Jonas ; Farnier, Michel. / 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. In: European Heart Journal. 2018 ; Vol. 39, No. 5. pp. 374-381.
@article{121a2ede9fc5439eadf1e7fee3dc2d37,
title = "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",
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 subtili-sin/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),orezetimibe (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.",
author = "Harvey, {Philip D.} and Sabbagh, {Marwan N.} and Harrison, {John E.} and Ginsberg, {Henry N.} and Chapman, {M. John} and Garen Manvelian and Angele Moryusef and Jonas Mandel and Michel Farnier",
year = "2018",
doi = "10.1093/eurheartj/ehx661",
language = "English",
volume = "39",
pages = "374--381",
journal = "European Heart Journal",
issn = "0195-668X",
publisher = "Oxford University Press",
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}

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. / Harvey, Philip D.; Sabbagh, Marwan N.; Harrison, John E.; Ginsberg, Henry N.; Chapman, M. John; Manvelian, Garen; Moryusef, Angele; Mandel, Jonas; Farnier, Michel.

In: European Heart Journal, Vol. 39, No. 5, 2018, p. 374-381.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - 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

AU - Harvey, Philip D.

AU - Sabbagh, Marwan N.

AU - Harrison, John E.

AU - Ginsberg, Henry N.

AU - Chapman, M. John

AU - Manvelian, Garen

AU - Moryusef, Angele

AU - Mandel, Jonas

AU - Farnier, Michel

PY - 2018

Y1 - 2018

N2 - 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 subtili-sin/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),orezetimibe (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.

AB - 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 subtili-sin/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),orezetimibe (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.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/29186504

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DO - 10.1093/eurheartj/ehx661

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SP - 374

EP - 381

JO - European Heart Journal

JF - European Heart Journal

SN - 0195-668X

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