Increased Risk of Adverse Neurocognitive Outcomes with Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors

Abdur Rahman Khan, Chirag Bavishi, Haris Riaz, Talha A. Farid, Sobia Khan, Michel Atlas, Glenn Hirsch, Sohail Ikram, Roberto Bolli

Research output: Contribution to journalArticle

Abstract

Background - 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. Methods and Results - 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. Conclusions - 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.

Original languageEnglish (US)
Article numbere003153
JournalCirculation: Cardiovascular Quality and Outcomes
Volume10
Issue number1
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

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Odds Ratio
Confidence Intervals
Stroke
Outcome Assessment (Health Care)
Safety
Meta-Analysis
Incidence
Marketing
Sample Size
Proprotein Convertase 9

Keywords

  • cognitive impairment
  • meta-analysis
  • proprotein convertases
  • stroke
  • subtilisins

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Increased Risk of Adverse Neurocognitive Outcomes with Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors. / Khan, Abdur Rahman; Bavishi, Chirag; Riaz, Haris; Farid, Talha A.; Khan, Sobia; Atlas, Michel; Hirsch, Glenn; Ikram, Sohail; Bolli, Roberto.

In: Circulation: Cardiovascular Quality and Outcomes, Vol. 10, No. 1, e003153, 01.01.2017.

Research output: Contribution to journalArticle

Khan, Abdur Rahman ; Bavishi, Chirag ; Riaz, Haris ; Farid, Talha A. ; Khan, Sobia ; Atlas, Michel ; Hirsch, Glenn ; Ikram, Sohail ; Bolli, Roberto. / Increased Risk of Adverse Neurocognitive Outcomes with Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors. In: Circulation: Cardiovascular Quality and Outcomes. 2017 ; Vol. 10, No. 1.
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T1 - Increased Risk of Adverse Neurocognitive Outcomes with Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors

AU - Khan, Abdur Rahman

AU - Bavishi, Chirag

AU - Riaz, Haris

AU - Farid, Talha A.

AU - Khan, Sobia

AU - Atlas, Michel

AU - Hirsch, Glenn

AU - Ikram, Sohail

AU - Bolli, Roberto

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Background - 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. Methods and Results - 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. Conclusions - 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.

AB - Background - 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. Methods and Results - 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. Conclusions - 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.

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