Abstract
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.