Managing endothelial dysfunction in COVID‐19 with statins, beta blockers, nicorandil, and oral supplements: A pilot, double‐blind, placebo‐controlled, randomized clinical trial

Abstract

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. 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 eight 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 intensive care unit (ICU) admission or the need for mechanical ventilation, all‐cause mortality, and the occurrence of side effects. Of 42 randomized patients, 37 were included in the primary analysis. The mean age of the patients was 57 years; the mean body mass index 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, or the occurrence of side effects between the endothelial protocol group and the placebo group. 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. Based on this study’s findings, targeting endothelial dysfunction did not result in a clinically significant improvement in outcome and, as such, larger trials targeting this pathway are not recommended.

Statins in hospitalized COVID‐19 patients: A systematic review and meta‐analysis of randomized controlled trials

“…6,29 Only one pervious meta-analysis 30 included five RCTs found that statins did not reduce the length of stay, ICU admission and death associated with COVID-19. However, one included trial 31 had four other drugs (folic acid, L-arginine, nicorandil, and nebivolol) in the treatment group in addition to atorvastatin, which may have exaggerated the efficacy of statins. Our results differ from most other metaanalyses, 6,29 probably partly because only RCTs were included and partly because of the inclusion of three very recent trials.…”

Atherosclerosis, Cardiovascular Disease, and COVID-19: A Narrative Review

“…Thus, in the RESIST trial, the treatment with atorvastatin did not prevent clinical deterioration [ 87 ]. Additionally, the use of atorvastatin increased the length of stay at the hospital and frequency of ICU admission in patients with COVID-19 [ 88 ], and Matli et al observed no improvement in the clinical outcomes in those with COVID-19 treated with atorvastatin [ 89 ]. Finally, and according to Hejazi et al, atorvastatin significantly reduced the supplemental oxygen need, hospitalization duration, and serum high-sensitivity C reactive protein (hs-CRP) in mild to moderate hospitalized COVID-19 patients [ 90 ].…”

Treating COVID-19: Targeting the Host Response, Not the Virus

“…At least 24 observational studies have reported similar results [ 26 , 158 , 169 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 ]. The results of six RCTs of inpatient statin treatment have also been reported [ 199 , 200 , 201 , 202 , 203 , 204 ]. All of these results are summarized in Table 4 .…”

“…Daily statin treatment had no effect on mortality, but three of the six studies were very small [ 199 , 200 , 204 ], four used what was probably too low a dose of atorvastatin (20 mg instead of 40 mg) [ 199 , 200 , 201 , 202 ], and one dealt only with ICU patients [ 202 ], which may have been too late in the course of illness. Two RCTs examined simultaneous treatment with several drugs [ 200 , 203 ]. One additional RCT reported the results of statin/aspirin treatment on mortality [ 207 ].…”