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Background <p>Hydroxychloroquine (HCQ), long used for its immunomodulatory and vasculoprotective properties in autoimmune diseases such as antiphospholipid syndrome, was among the first drugs evaluated for COVID-19. Given the prominent endothelial dysfunction and coagulopathy in severe COVID-19, we investigated whether HCQ could modulate circulating biomarkers of vascular injury.</p> Methods <p>A longitudinal analysis comparing standard of care (SoC; <i>n</i> = 148) with HCQ plus SoC (<i>n</i> = 145) was conducted within the phase 3, multicenter, open-label, randomized, adaptive, controlled trial <i>DisCoVeRy</i> in hospitalized patients with COVID-19 (NCT04315948), which primary outcome was clinical status at day 15, measured by the WHO 7-point ordinal scale. Biomarkers of endothelial activation and coagulopathy—angiopoietin-2, P-selectin, and D-dimer—were measured on days 1, 3, 5, 8, and 11. Linear mixed-effects models assessed the influence of HCQ and baseline severity on biomarker trajectories.</p> Results <p>Severe disease at baseline was associated with higher biomarker levels: angiopoietin-2 (<i>p</i> &lt; 10⁻⁵), P-selectin (<i>p</i> &lt; 10⁻⁶), and D-dimer (<i>p</i> &lt; 10⁻⁷). HCQ had no effect on angiopoietin-2 levels over time (0.002 95%CI: [−&#xa0;0.003;0.007], <i>p</i> = 0.42). P-selectin increased significantly in both non-severe and severe SoC patients, but HCQ had no effect on the slope (0.005 95%CI: [−&#xa0;0.001;0.012], <i>p</i> = 0.12). Regarding D-dimer, neither disease severity nor HCQ significantly affected the slope (−&#xa0;0.004 95%CI: [−&#xa0;0.016;0.009], <i>p</i> = 0.57 and − 0.000 95%CI: [−&#xa0;0.009;0.009], <i>p</i> = 0.98, respectively).</p> Conclusions <p>HCQ was not found to modify the longitudinal evolution of angiopoietin-2, P-selectin, or D-dimer in hospitalized patients with COVID-19. These findings confirm the absence of vascular benefit, reinforcing evidence against HCQ’s clinical utility in COVID-19 and underscoring the need for alternative endothelial-targeted approaches.</p>

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Hydroxychloroquine does not affect endotheliopathy or coagulopathy biomarkers in COVID-19: longitudinal results from the DisCoVeRy randomized trial

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月7日

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  • Clément R. Massonnaud,
  • Maya Hites,
  • Nathan Peiffer-Smadja,
  • Jeanne Rancic,
  • Yazdan Yazdanpanah,
  • Sophie Luneau,
  • Annabelle Dupont,
  • Christelle Delmas,
  • Jean-Luc Diehl,
  • Aurélien Philippe,
  • Sophie Susen,
  • France Mentré,
  • Florence Ader,
  • David M. Smadja

摘要

Background

Hydroxychloroquine (HCQ), long used for its immunomodulatory and vasculoprotective properties in autoimmune diseases such as antiphospholipid syndrome, was among the first drugs evaluated for COVID-19. Given the prominent endothelial dysfunction and coagulopathy in severe COVID-19, we investigated whether HCQ could modulate circulating biomarkers of vascular injury.

Methods

A longitudinal analysis comparing standard of care (SoC; n = 148) with HCQ plus SoC (n = 145) was conducted within the phase 3, multicenter, open-label, randomized, adaptive, controlled trial DisCoVeRy in hospitalized patients with COVID-19 (NCT04315948), which primary outcome was clinical status at day 15, measured by the WHO 7-point ordinal scale. Biomarkers of endothelial activation and coagulopathy—angiopoietin-2, P-selectin, and D-dimer—were measured on days 1, 3, 5, 8, and 11. Linear mixed-effects models assessed the influence of HCQ and baseline severity on biomarker trajectories.

Results

Severe disease at baseline was associated with higher biomarker levels: angiopoietin-2 (p < 10⁻⁵), P-selectin (p < 10⁻⁶), and D-dimer (p < 10⁻⁷). HCQ had no effect on angiopoietin-2 levels over time (0.002 95%CI: [− 0.003;0.007], p = 0.42). P-selectin increased significantly in both non-severe and severe SoC patients, but HCQ had no effect on the slope (0.005 95%CI: [− 0.001;0.012], p = 0.12). Regarding D-dimer, neither disease severity nor HCQ significantly affected the slope (− 0.004 95%CI: [− 0.016;0.009], p = 0.57 and − 0.000 95%CI: [− 0.009;0.009], p = 0.98, respectively).

Conclusions

HCQ was not found to modify the longitudinal evolution of angiopoietin-2, P-selectin, or D-dimer in hospitalized patients with COVID-19. These findings confirm the absence of vascular benefit, reinforcing evidence against HCQ’s clinical utility in COVID-19 and underscoring the need for alternative endothelial-targeted approaches.