Managing endothelial dysfunction in COVID ‐19 with statins, beta blockers, nicorandil, and oral supplements: A pilot, double‐blind , placebo‐controlled , randomized clinical trial
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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.
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SciScore for 10.1101/2022.02.02.22270341: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The trial protocol was approved by the institutional review board at the Lebanese American University, approval number LAUMCRH.GG2.4/Jan/2021 and was supervised by an independent board responsible for monitoring data safety. Sex as a biological variable In addition, other exclusion criteria included inability to tolerate oral medications, patients already taking beta-blockers, Nicorandil, PDE5 inhibitors, or Riociguat, patients with shock defined by SBP<90 mmHg for more than 30 minutes not responding to IV fluids with evidence of end-organ damage, severe bradycardia (<50 bpm) or heart block greater than first-degree (except in patients with a functioning artificial pacemaker), … SciScore for 10.1101/2022.02.02.22270341: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The trial protocol was approved by the institutional review board at the Lebanese American University, approval number LAUMCRH.GG2.4/Jan/2021 and was supervised by an independent board responsible for monitoring data safety. Sex as a biological variable In addition, other exclusion criteria included inability to tolerate oral medications, patients already taking beta-blockers, Nicorandil, PDE5 inhibitors, or Riociguat, patients with shock defined by SBP<90 mmHg for more than 30 minutes not responding to IV fluids with evidence of end-organ damage, severe bradycardia (<50 bpm) or heart block greater than first-degree (except in patients with a functioning artificial pacemaker), decompensated heart failure and sick sinus syndrome (unless a permanent pacemaker is in place), severe hepatic impairment (Child-Pugh class C) or active liver disease with unexplained persistent elevations of serum transaminases, pregnant or breastfeeding patients, hypersensitivity to any of the medications in the trial, patients who took the protocol for less than 48 hours, myocarditis, acute pulmonary edema, hypovolemia, patients enrolled in a different randomized study and/or COVID-19 interventional study. Randomization Design: This study is a single-center, pilot, double-blind, placebo-controlled, randomized clinical trial (ClinicalTrials.gov Identifier: NCT04631536) at the Lebanese American University Medical Center - Rizk Hospital. Blinding Patients and investigators were blinded to randomization throughout the study period up until the final analysis. Power Analysis At least 17 patients in each group and minimum total sample size for both arms=34 were expected to make a difference of 4 days in time to clinical improvement, with a power of 80%. Table 2: Resources
Software and Algorithms Sentences Resources Statistical Analysis: Calculations were done using the G*Power software.. G*Powersuggested: (G*Power, RRID:SCR_013726)Data was entered on Excel and analyzed using SPSS version 25.0. Excelsuggested: NoneSPSSsuggested: (SPSS, RRID:SCR_002865)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:This pilot has several limitations that warrant careful interpretation of the results. The relatively low sample size in this trial could have had inadequate power to exclude small, but clinically meaningful findings, since it was designed to explore a potential signal for the use of endothelial protocol in COVID-19, not to provide definitive evidence on the subject. This pilot was restricted to subjects with non-severe disease. The patients had several coexisting diseases and were subjected to a diverse medication regimen. Consequently, larger scale studies are thus necessary to demonstrate efficacy and confirm safety of the suggested protocol.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04631536 Recruiting Managing Endothelial Dysfunction in COVID-19 : A Randomized … Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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