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Randomized Controlled Trial
. 2023 Jan 24;81(3):224-234.
doi: 10.1016/j.jacc.2022.10.030.

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

Eliano P Navarese  1 , Przemysław Podhajski  2 , Paul A Gurbel  3 , Klaudyna Grzelakowska  2 , Eleonora Ruscio  4 , Udaya Tantry  3 , Przemysław Magielski  5 , Aldona Kubica  6 , Piotr Niezgoda  5 , Piotr Adamski  5 , Roman Junik  7 , Grzegorz Przybylski  8 , Marta Pilaczyńska-Cemel  8 , Manali Rupji  9 , Giuseppe Specchia  10 , Jarosław Pinkas  11 , Robert Gajda  12 , Diana A Gorog  13 , Felicita Andreotti  14 , Jacek Kubica  2
Affiliations
Randomized Controlled Trial

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

Eliano P Navarese et al. J Am Coll Cardiol. .

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).

Keywords: COVID-19; PCSK9 inhibition; death; interleukin-6; intubation; randomized controlled trial.

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Conflict of interest statement

Funding Support and Author Disclosures This research was supported by the Collegium Medicum of Nicolaus Copernicus University (grant ID ZES.WL.2.2021). Dr Navarese has received speaker and consultancy fees from Amgen, Sanofi-Regeneron, Bayer; and has received grants from Abbott, outside the submitted work. Dr Gurbel has received grants and personal fees from Bayer HealthCare LLC, Otitopic Inc, Amgen, Janssen, U.S. WorldMeds LLC, Instrumentation Laboratory, Haemonetics, Medicure Inc, Idorsia Pharmaceuticals, Hikari Dx, and Novartis; has received personal fees from UpToDate, outside the submitted work; has a patent issued (Detection of Restenosis Risk in Patients and Assessment of Cardiac Health and Thrombotic Risk in a Patient); and is an expert witness in litigation involving clopidogrel. Dr Gorog has received institutional research grants from Bayer and Bristol Myers Squibb; and has received speaker fees from AstraZeneca, Bayer, and Boehringer Ingelheim. Dr Andreotti has received lecture/consultancy fees from Amgen, Bayer, BMS/Pfizer, and Daiichi-Sankyo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Trial Flowchart The processes of screening for eligibility, randomization to assigned treatment, and intention-to-treat analysis are displayed. PCSK9 = proprotein convertase subtilisin/kexin type 9.
Figure 2
Figure 2
Death or Need for Intubation Death or need for intubation (primary endpoint) at 30 days among patients administered a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor or placebo. (A) Rates of primary endpoint in the PCSK9 inhibitor and placebo arms. (B) Cumulative incidence curves of 30-day death or need for intubation in the intention-to-treat population. n = number of events; RD = risk difference.
Figure 3
Figure 3
Death Rates by Baseline IL-6 Thirty-day rates of death in patients randomized to receive PCSK9 inhibitor or placebo, stratified according to median serum IL-6 levels ≤51.29 pg/mL and >51.29 pg/mL at baseline. IL = interleukin; other abbreviations as in Figure 2.
Figure 4
Figure 4
Primary Endpoint Marginal Probabilities and Biomarker Changes According to Treatment Arm (A) Individual marginal probabilities of death or need for intubation in the PCSK9 inhibitor or placebo arm across levels of baseline serum IL-6. Serum IL-6 concentrations (B) and low-density lipoprotein cholesterol (LDL-C) levels (C) at baseline and at 7 and 30 days after randomization in the PCSK9 inhibitor and placebo arms. (D) Waterfall plot for greatest percent change in serum IL-6 levels with PCSK9 inhibitor or placebo up to 30 days compared with baseline. ∗Denotes need for intubation. †Denotes a fatal event. Inh = inhibitor; other abbreviations as in Figure 2.
Figure 4
Figure 4
Primary Endpoint Marginal Probabilities and Biomarker Changes According to Treatment Arm (A) Individual marginal probabilities of death or need for intubation in the PCSK9 inhibitor or placebo arm across levels of baseline serum IL-6. Serum IL-6 concentrations (B) and low-density lipoprotein cholesterol (LDL-C) levels (C) at baseline and at 7 and 30 days after randomization in the PCSK9 inhibitor and placebo arms. (D) Waterfall plot for greatest percent change in serum IL-6 levels with PCSK9 inhibitor or placebo up to 30 days compared with baseline. ∗Denotes need for intubation. †Denotes a fatal event. Inh = inhibitor; other abbreviations as in Figure 2.
Central Illustration
Central Illustration
Impact of PCSK9 Inhibition on Clinical Outcome in Patients During the Inflammatory Stage of the COVID-19 Trial In this double-blind, placebo-controlled randomized pilot trial conducted in patients with severe COVID-19, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor reduced the primary endpoint of death or need for intubation and serum interleukin (IL)-6 levels at 30 days compared with placebo. inh = inhibitor; N = number of patients; sc = subcutaneous.
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