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

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.