Interventional Cardiology and Cardiovascular Medicine Research, Department of Cardiology and Internal Medicine, Nicolaus Copernicus University, Bydgoszcz, Poland; Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada; SIRIO MEDICINE Research Network, Bydgoszcz, Poland.
Interventional Cardiology and Cardiovascular Medicine Research, Department of Cardiology and Internal Medicine, Nicolaus Copernicus University, Bydgoszcz, Poland; SIRIO MEDICINE Research Network, Bydgoszcz, Poland.
J Am Coll Cardiol. 2023 Jan 24;81(3):224-234. doi: 10.1016/j.jacc.2022.10.030.
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.
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.
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.
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%).
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).
COVID-19 期间的炎症强度与不良结局有关。前蛋白转化酶枯草溶菌素/糜蛋白酶 9（PCSK9）参与低密度脂蛋白受体的动态平衡，可能对血管炎症和 COVID-19 的炎症反应产生影响。
本研究旨在探讨在重症 COVID-19 患者中，PCSK9 抑制剂与安慰剂相比对临床和实验室结局的影响。
这是一项双盲、安慰剂对照、多中心的试验，共纳入 60 例因重症 COVID-19 住院的患者，这些患者有磨玻璃影肺炎和动脉血氧分压与吸入氧分数比值≤300mmHg，按 1:1 随机接受单次 140mg 皮下注射依洛尤单抗或安慰剂。主要终点为 30 天内死亡或需要插管。主要次要终点为 7 天和 30 天从基线的循环白细胞介素（IL）-6 的变化。
与安慰剂组相比，接受 PCSK9 抑制剂治疗的患者在 30 天内死亡或需要插管的发生率较低（23.3% vs. 53.3%，风险差异：-30%；95%CI：-53.40%-6.59%）。PCSK9 抑制剂组血清 IL-6 随时间下降幅度大于安慰剂组（30 天下降：-56% vs. -21%）。基线 IL-6 高于中位数的患者，PCSK9 抑制治疗组死亡率低于安慰剂组（风险差异：-37.50%；95%CI：-68.20%-6.70%）。
与安慰剂相比，PCSK9 抑制剂降低了重症 COVID-19 患者的主要终点，即死亡或需要插管和 IL-6 水平。随机分组时炎症强度较高的患者接受 PCSK9 抑制治疗的存活率更高，这表明炎症强度可能是治疗获益的驱动因素。（PCSK9 抑制剂对 COVID-19 炎症期患者临床结局的影响[IMPACT-SIRIO 5]；NCT04941105）。
