PCSK9 Inhibition During the Inflammatory Stage of SARS-CoV-2 Infection

• Type of Material: Article
• Authors: Eliano P Navarese, Nicolaus Copernicus University; Przemyslaw Podhajski, Nicolaus Copernicus University; Paul A Gurbel, Sinai Hospital of Baltimore, Lifebridge Health; Klaudyna Grzelakowska, Nicolaus Copernicus University; Eleonora Ruscio, Fondazione Policlinico Universitario A. Gemelli IRCCS; Udaya Tantry, Sinai Hospital of Baltimore, Lifebridge Health; Przemyslaw Magielski, Nicolaus Copernicus University; Aldona Kubica, Nicolaus Copernicus University; Piotr Niezgoda, Nicolaus Copernicus University; Piotr Adamski, Nicolaus Copernicus University; Roman Junik, Nicolaus Copernicus University in Toruń; Grzegorz Przybylski, Nicolaus Copernicus University; Marta Pilaczyńska-Cemel, Nicolaus Copernicus University, Toruń; Manali Rupji, Emory University; Giuseppe Specchia, Policlinico di Monza; Jaroslaw Pinkas, Center of Postgraduate Medical Education; Robert Gajda, Gajda-Med Medical Center in Pułtusk; Diana A Gorog, University of Hertfordshire; Felicita Andreotti, Universitario A. Gemelli IRCCS; Jacek Kubica, Nicolaus Copernicus University
• Language: English
• Date: 2023-01-24
• Publisher: Elsevier
• Publication Version: Final Published Version
• Copyright Statement: © 2023, American College of Cardiology Foundation. Published by Elsevier.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jacc.2022.10.030
• Title of Journal or Parent Work: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
• Volume: 81
• Issue: 3
• Start Page: 224
• End Page: 234
• Keywords: interleukin-6; COVID-19; PCSK9 inhibition; intubation; death; randomized controlled trial

Abstract

Background The intensity of inflammation during COVID-19 is related to adverse outcomes. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in low-density lipoprotein receptor homeostasis, with potential influence on vascular inflammation and on COVID-19 inflammatory response. Objectives The goal of this study was to investigate the impact of PCSK9 inhibition vs placebo on clinical and laboratory outcomes in patients with severe COVID-19. Methods In this double-blind, placebo-controlled, multicenter pilot trial, 60 patients hospitalized for severe COVID-19, with ground-glass opacity pneumonia and arterial partial oxygen pressure to fraction of inspired oxygen ratio ≤300 mm Hg, were randomized 1:1 to receive a single 140-mg subcutaneous injection of evolocumab or placebo. The primary endpoint was death or need for intubation at 30 days. The main secondary endpoint was change in circulating interleukin (IL)-6 at 7 and 30 days from baseline. Results Patients randomized to receive the PCSK9 inhibitor had lower rates of death or need for intubation within 30 days vs placebo (23.3% vs 53.3%, risk difference: –30%; 95% CI: –53.40% to –6.59%). Serum IL-6 across time was lower with the PCSK9 inhibitor than with placebo (30-day decline: –56% vs –21%). Patients with baseline IL-6 above the median had lower mortality with PCSK9 inhibition vs placebo (risk difference: –37.50%; 95% CI: –68.20% to –6.70%). Conclusions PCSK9 inhibition compared with placebo reduced the primary endpoint of death or need for intubation and IL-6 levels in severe COVID-19. Patients with more intense inflammation at randomization had better survival with PCSK9 inhibition vs placebo, indicating that inflammatory intensity may drive therapeutic benefits. (Impact of PCSK9 Inhibition on Clinical Outcome in Patients During the Inflammatory Stage of the COVID-19 [IMPACT-SIRIO 5]; NCT04941105)