title: Increased Risk of Adverse Neurocognitive Outcomes With Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors.
abstract: There is encouraging evidence of the efficacy of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors; however, their long-term safety remains unclear. We performed a meta-analysis of studies to evaluate the long-term safety of PCSK9 inhibitors.
  
  
  
  Our search strategy yielded 11 studies (9 smaller early-phase and 2 larger outcome trials). The outcomes assessed were cumulative serious adverse events, musculoskeletal adverse events, neurocognitive adverse events, and stroke. Odds ratio (OR) was calculated using the Mantel-Haenszel method. Subgroup analysis was done to assess the difference in safety between the smaller early-phase studies and the larger outcome studies. Our meta-analysis suggested no difference in the incidence of serious adverse events (OR, 1.00; 95% confidence interval [CI], 0.88-1.15), musculoskeletal adverse events (OR, 1.01; 95% CI, 0.87-1.13), neurocognitive adverse events (OR, 1.29; 95% CI, 0.64-2.59), or stroke (OR, 1.44; 95% CI, 0.57-3.65) with the use of PCSK9 inhibitors. Subgroup analysis of the 2 large outcome studies did suggest an increased incidence of neurocognitive adverse events (OR, 2.85; 95% CI, 1.34-6.06) with the use of PCSK9 inhibitors. However, the overall incidence of neurocognitive adverse events and stroke was <1%, whereas the cumulative incidence of serious adverse events and musculoskeletal events was >10% in both the groups.
  
  
  
  Our analysis suggests that PCSK9 inhibitors are not associated with an increased risk of cumulative severe adverse effects, musculoskeletal effects, or stroke. There is a signal toward adverse neurocognitive effects, seen in the outcome studies with a larger sample size and longer follow-up. There should be close monitoring, for the increased risk of neurocognitive events in the ongoing outcome studies and post-marketing surveillance.
authors.affiliation: From the Division of Cardiovascular Medicine (A.R.K., T.A.F., S.K., G.H., S.I., R.B.), Institute of Molecular Cardiology (A.R.K., T.A.F., R.B.), and Kornhauser Health Sciences Library (M.A.), University of Louisville, KY; Division of Cardiovascular Medicine, St Lukes Roosevelt Hospital, New York, NY (C.B.); and Department of Internal Medicine, Cleveland Clinic, OH (H.R.).
authors.forename: Abdur Rahman
authors.initials: AR
authors.lastname: Khan
authors.affiliation: From the Division of Cardiovascular Medicine (A.R.K., T.A.F., S.K., G.H., S.I., R.B.), Institute of Molecular Cardiology (A.R.K., T.A.F., R.B.), and Kornhauser Health Sciences Library (M.A.), University of Louisville, KY; Division of Cardiovascular Medicine, St Lukes Roosevelt Hospital, New York, NY (C.B.); and Department of Internal Medicine, Cleveland Clinic, OH (H.R.).
authors.forename: Chirag
authors.initials: C
authors.lastname: Bavishi
authors.affiliation: From the Division of Cardiovascular Medicine (A.R.K., T.A.F., S.K., G.H., S.I., R.B.), Institute of Molecular Cardiology (A.R.K., T.A.F., R.B.), and Kornhauser Health Sciences Library (M.A.), University of Louisville, KY; Division of Cardiovascular Medicine, St Lukes Roosevelt Hospital, New York, NY (C.B.); and Department of Internal Medicine, Cleveland Clinic, OH (H.R.).
authors.forename: Haris
authors.initials: H
authors.lastname: Riaz
authors.affiliation: From the Division of Cardiovascular Medicine (A.R.K., T.A.F., S.K., G.H., S.I., R.B.), Institute of Molecular Cardiology (A.R.K., T.A.F., R.B.), and Kornhauser Health Sciences Library (M.A.), University of Louisville, KY; Division of Cardiovascular Medicine, St Lukes Roosevelt Hospital, New York, NY (C.B.); and Department of Internal Medicine, Cleveland Clinic, OH (H.R.).
authors.forename: Talha A
authors.initials: TA
authors.lastname: Farid
authors.affiliation: From the Division of Cardiovascular Medicine (A.R.K., T.A.F., S.K., G.H., S.I., R.B.), Institute of Molecular Cardiology (A.R.K., T.A.F., R.B.), and Kornhauser Health Sciences Library (M.A.), University of Louisville, KY; Division of Cardiovascular Medicine, St Lukes Roosevelt Hospital, New York, NY (C.B.); and Department of Internal Medicine, Cleveland Clinic, OH (H.R.).
authors.forename: Sobia
authors.initials: S
authors.lastname: Khan
authors.affiliation: From the Division of Cardiovascular Medicine (A.R.K., T.A.F., S.K., G.H., S.I., R.B.), Institute of Molecular Cardiology (A.R.K., T.A.F., R.B.), and Kornhauser Health Sciences Library (M.A.), University of Louisville, KY; Division of Cardiovascular Medicine, St Lukes Roosevelt Hospital, New York, NY (C.B.); and Department of Internal Medicine, Cleveland Clinic, OH (H.R.).
authors.forename: Michel
authors.initials: M
authors.lastname: Atlas
authors.affiliation: From the Division of Cardiovascular Medicine (A.R.K., T.A.F., S.K., G.H., S.I., R.B.), Institute of Molecular Cardiology (A.R.K., T.A.F., R.B.), and Kornhauser Health Sciences Library (M.A.), University of Louisville, KY; Division of Cardiovascular Medicine, St Lukes Roosevelt Hospital, New York, NY (C.B.); and Department of Internal Medicine, Cleveland Clinic, OH (H.R.).
authors.forename: Glenn
authors.initials: G
authors.lastname: Hirsch
authors.affiliation: From the Division of Cardiovascular Medicine (A.R.K., T.A.F., S.K., G.H., S.I., R.B.), Institute of Molecular Cardiology (A.R.K., T.A.F., R.B.), and Kornhauser Health Sciences Library (M.A.), University of Louisville, KY; Division of Cardiovascular Medicine, St Lukes Roosevelt Hospital, New York, NY (C.B.); and Department of Internal Medicine, Cleveland Clinic, OH (H.R.).
authors.forename: Sohail
authors.initials: S
authors.lastname: Ikram
authors.affiliation: From the Division of Cardiovascular Medicine (A.R.K., T.A.F., S.K., G.H., S.I., R.B.), Institute of Molecular Cardiology (A.R.K., T.A.F., R.B.), and Kornhauser Health Sciences Library (M.A.), University of Louisville, KY; Division of Cardiovascular Medicine, St Lukes Roosevelt Hospital, New York, NY (C.B.); and Department of Internal Medicine, Cleveland Clinic, OH (H.R.). rbolli@louisville.edu.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bolli
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D016009:Chi-Square Distribution; D002986:Clinical Trials as Topic; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000139:chemically induced* / Q000175:diagnosis / Q000453:epidemiology / Q000523:psychology; D050171:Dyslipidemias / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology; D005260:Female; D006801:Humans; D000960:Hypolipidemic Agents / Q000009:adverse effects*; D015994:Incidence; D008055:Lipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D000091362:PCSK9 Inhibitors; D000071449:Proprotein Convertase 9 / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D015842:Serine Proteinase Inhibitors / Q000009:adverse effects*; D020521:Stroke / Q000139:chemically induced* / Q000175:diagnosis / Q000453:epidemiology / Q000503:physiopathology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; D000960:Hypolipidemic Agents; D008055:Lipids; D000091362:PCSK9 Inhibitors; D015842:Serine Proteinase Inhibitors; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
keywords: cognitive impairment; meta-analysis; proprotein convertases; stroke; subtilisins