Managing Endothelial Dysfunction in COVID-19: A Pilot, Double-Blind, Placebo-Controlled, Randomized Clinical Trial at the Lebanese American University Medical Center - Rizk Hospital (MEDIC-LAUMCRH)

Abstract

Background: Coronavirus disease 2019 (Covid-19) is associated with endothelial dysfunction. Pharmacologically targeting the different mechanisms of endothelial dysfunction may improve clinical outcomes and lead to reduced morbidity and mortality Methods: In this pilot, double-blind, placebo-controlled, randomized clinical trial we assigned patients who were admitted to the hospital with mild, moderate, or severe COVID-19 infection to receive, on top of optimal medical therapy, either an endothelial protocol consisting of (Nicorandil, L-arginine, Folate, Nebivolol, and Atorvastatin) or placebo for up to 14 days. The primary outcome was time to recovery, measured by an 8 category ordinal scale and defined by the time to being discharged from the hospital or hospitalized for infection-control or other nonmedical reasons. Secondary outcomes included the composite outcome of ICU admission or the need for mechanical ventilation, all-cause mortality, and the occurrence of side effects Results: Of 42 randomized patients, 37 were included in the primary analysis. The mean age of the patients was 57 years; the mean BMI of study participants was 29.14. History of hypertension was present in 27% of the patients, obesity in 45%, and Diabetes Mellitus in 21.6%. The median(Interquartile range) time to recovery was not significantly different between the endothelial protocol group (6 [4-12] days) and the placebo group (6 [5-8]days)(p-value = 0.854). Furthermore, there were no statistically significant differences in the need for mechanical ventilation or ICU admission, all-cause mortality, and the occurrence of side effects between the endothelial protocol group and the placebo group. Conclusion: Among patients hospitalized with mild, moderate, or severe COVID-19 infection, targeting endothelial dysfunction by administering Nicorandil, L-arginine, Folate, Nebivolol, and Atorvastatin on top of optimal medical therapy did not decrease time to recovery. However, this treatment protocol was associated with an excellent safety profile. Adequately sized prospective randomized controlled trials are needed for the evaluation of the role of treating endothelial dysfunction in COVID-19 infection.

Effects of statins on clinical outcomes in hospitalized patients with COVID-19

“…No cases of myopathy were confirmed and severe thrombocytopenia was diagnosed in four (1.4%) patients using atorvastatin. In the study by Matli et al [5], six patients had adverse events (bradycardia, nausea/vomiting, and hypotension), three (17.7%) among patients receiving atorvastatin 40 mg/day and three (15%) in the placebo group. Gaitán-Duarte et al [6] reported a two-fold increased risk of adverse events among patients receiving rosuvastatin, especially gastrointestinal symptoms and hepatic injuries.…”

“…Search strategy yielded 496 potentially relevant records and six fulltext articles were assessed for eligibility. Five RCTs [2][3][4][5][6] were selected for the meta-analysis (Supplementary file) and a total of 1132 patients were included, 556 in the intervention group and 576 in the control group (placebo or standard protocol). Of the included trials, four used atorvastatin (20 mg/day [2,3] or 40 mg/day [4,5]) and one used rosuvastatin (40 mg/day) [6] as treatment for hospitalized patients with COVID-19 (Supplementary file).…”

“…Five RCTs [2][3][4][5][6] were selected for the meta-analysis (Supplementary file) and a total of 1132 patients were included, 556 in the intervention group and 576 in the control group (placebo or standard protocol). Of the included trials, four used atorvastatin (20 mg/day [2,3] or 40 mg/day [4,5]) and one used rosuvastatin (40 mg/day) [6] as treatment for hospitalized patients with COVID-19 (Supplementary file). Overall, the RCTs had a low risk of selection and attrition bias, but 40% presented a potential risk for performance, detection, and reporting bias.…”