A randomised trial of anti-GM-CSF otilimab in severe COVID-19 pneumonia (OSCAR).

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) and dysregulated myeloid cell responses are implicated in the pathophysiology and severity of COVID-19. METHODS: In this randomised, sequential, multicentre, placebo-controlled, double-blind study, adults aged 18-79 years (Part 1) or ≥70 years (Part 2) with severe COVID-19, respiratory failure and systemic inflammation (elevated C-reactive protein/ferritin) received a single intravenous infusion of otilimab 90 mg (human anti-GM-CSF monoclonal antibody) plus standard care (NCT04376684). The primary outcome was the proportion of patients alive and free of respiratory failure at Day 28. RESULTS: In Part 1 (n=806 randomised 1:1 otilimab:placebo), 71% of otilimab-treated patients were alive and free of respiratory failure at Day 28 versus 67% who received placebo; the model-adjusted difference of 5.3% was not statistically significant (95% CI -0.8-11.4%, p=0.09). A nominally significant model-adjusted difference of 19.1% (95% CI 5.2-33.1%, p=0.009) was observed in the predefined 70-79 years subgroup, but this was not confirmed in Part 2 (n=350 randomised) where the model-adjusted difference was 0.9% (95% CI -9.3-11.2%, p=0.86). Compared with placebo, otilimab resulted in lower serum concentrations of key inflammatory markers, including the putative pharmacodynamic biomarker CC chemokine ligand 17, indicative of GM-CSF pathway blockade. Adverse events were comparable between groups and consistent with severe COVID-19. CONCLUSIONS: There was no significant difference in the proportion of patients alive and free of respiratory failure at Day 28. However, despite the lack of clinical benefit, a reduction in inflammatory markers was observed with otilimab, in addition to an acceptable safety profile.

Balloon mitral commissurotomy for patients with mitral stenosis in atrial fibrillation: ten-year clinical and echocardiographic actuarial results.

BACKGROUND AND AIM OF THE STUDY: Controversy persists as to whether atrial fibrillation (AF) has a direct negative effect on the outcome of percutaneous balloon mitral commissurotomy (PBMC). The study aim was to assess the effect of AF on immediate and 10-year clinical and echocardiographic actuarial results of patients with rheumatic mitral stenosis undergoing PBMC. METHODS: A total of 195 consecutive patients with AF (group 1) was analyzed and compared with 195 patients in sinus rhythm (group 2), matched for the severity of mitral valve morphological changes. RESULTS: Group 1 patients were older (43.8 + 12 versus 30.5 +/- 12.7 years; p <0.001), and a greater proportion had grade 1 mitral regurgitation (25.1 versus 9.7%; p <0.0001). The procedural success was 89.8% in group 1 and 92.3% in group 2 (p = NS), but group 1 patients had a smaller mitral valve area (2.1 +/- 0.4 versus 2.3 +/- 0.4 cm2; p <0.0001). Patients in AF had a lower 10-year survival (91.4 versus 99.4%; p = 0.018), a lower 10-year event-free-survival (60.3 versus 70%; p = 0.02), and a lower 10-year freedom from restenosis (40 versus 66%; p = 0.048). AF was an independent predictor of overall mortality (OR = 10.79; p <0.033) and of combined events (death, redo PBMC or mitral valve surgery; OR = 1.95; p <0.012), and was a univariate predictor of restenosis (p = 0.048). CONCLUSION: Patients with AF have good immediate results, but poorer long-term outcome after PBMC. AF a marker of worse prognosis in patients with mitral stenosis as it is in the general population.