COVID-19 infection was shown to cause endothelial dysfunction .At the level of the endothelium the pathophysiological mechanisms have been hypothesizedand were divided into pro-coagulant, pro-inflammatory, anti-fibrinolytics, impairedbarrier function, vasoconstrictor and pro-oxidant. So far, the pro-coagulant andpro-inflammatory pathways have been studied and as a result dexamethasone andanticoagulation became part of the standard therapies for the disease. However, so far,no RCT has been evaluated on targeting the vasoconstrictive and antioxidant pathways withan aim of revealing clinical benefit.So, with this trial we intend to provide a regiment composed of several medications wehypothesize will act on several downstream pathways that would improve endothelialfunction primarily via the increase in NO production and release.At the time of this proposal there has been no randomized trials evaluating or testingthe use of cardiovascular drugs targeting endothelial dysfunction in COVID-19 patients.As previously noted there has been a call to study these drugs and their effect after astrong research regarding their theorized effectiveness. For evidence, there was arecently published meta-analysis evaluating the role of statins in COVID-19 withpreliminary findings suggested a reduction in fatal or severe disease by 30% anddiscredited the suggestion of harm, that emphasized on the need of well-designedrandomized controlled trial to confirm the role of statins in COVID-19 patients.Our study would help determine the potential therapeutic effect of the endothelialprotocol as adjunct to mainstream management. This study seeks to further our knowledgein treating COVID-19 to ultimately improve clinical outcomes and reduce complications.
Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) is the novel pathogen
responsible coronavirus disease 2019 (COVID-19) first discovered in Wuhan, China. Since
its emergence in late December 2019, many pathophysiological mechanisms have been
proposed with multiple pathways that involve various organ systems . Although considered
at its emergence as a respiratory infection with manifestations ranging from lower
respiratory tract infection to pneumonia and advancing to acute respiratory disease
syndrome (ARDS) in its final stages, recent evidence has highlighted how disseminated the
virus can be affecting almost every organ be it the heart kidneys or blood vessels .
Recent trends in research have focused on elucidating the cardiovascular dysfunction in
COVID-19 patients Especially following studies showing that cardiovascular risk factors
are among the most common presenting comorbidities and that cardiovascular complications
of SARS-CoV-2 are among the most lethal . Initial research revealed that the virus makes
use of the angiotensin-converting enzyme 2 (ACE-2) receptor to infiltrate host cells.
With the ACE-2 receptor being a widely expressed receptor found in multiple cells lining
the lung, heart, gastrointestinal tract, kidneys and endothelial cells. Another prominent
mechanism of infection is immune system dysregulation manifesting as a cytokine storm and
inflammatory response over-activation.
Attempts at laying out a comprehensive or unifying pathogenesis of a COVID-19 infection
have singled out endothelial dysfunction as a core pathway. The endothelium in summary is
monolayer lining the arteries, veins and microvasculature. The endothelium hence plays a
major role in homeostasis with interactive roles in blood pressure regulation,
anti-coagulation and immune protection Moreover, it is thus relevant to note that the
most common comorbidities that present with COVID-19 such as hypertension, diabetes,
obesity and old age are all underlined by pre-existing endothelial damage or dysfunction.
As such, endothelial dysfunction and oxidative stress and their relation to the
manifestation and progression of COVID-19 infections has gain significant traction in
recent publications. This breakthrough exposes several causes of endothelial dysfunction
which include direct lining attack, hypoxia, cytokine storm and suppressed endothelial
nitric oxide synthase (eNOS) with concomitant nitric oxide deficiency. Several studies
have emphasized the role of NO signaling as a major regulator of vascular tone and its
antioxidant, anti-inflammatory and antithrombotic activity. For example, augmenting the
production of NO and its bioavailability by nicorandil has been proposed as a potential
treatment in patients with COVID 19. Nicorandil (a vasodilatory agent composed of
N-[2-hydroxyethyl]-nicotinamide nitrate) used among patients with acute heart failure
emergencies However, it has never been tested in patients with cardiovascular
complications resulting from COVID 19 . Statins are cardioprotective in nature with
recent reports showing that they can be beneficial in COVID-19 . An important mechanism
via which Statins may improve endothelial function include increasing the production of
NO and subsequent vasodilation effect, along with its established major anti-inflammatory
and anti-oxidant properties . Nebivolol, a cardio-selective beta blocker has also shown
non-adrenergic vasodilating properties via the release of NO along with antioxidative and
anti-atherosclerotic activities. Furthermore, eNOS overexpression leads to an increase in
NO formation only when the BH4 synthase GTP-cyclohydrolase 1 (GCH-1) is alsoup-regulated.
So, Folic Acid and L-arginine will be given to supplement our patients with BH4 . We
hypothesize that its administration along with the other previously mentioned agents
would improve endothelial function in patients suffering from COVID 19 via a cumulative
increase in the bioavailability of Nitric Oxide (NO), and thus improving patients'
outcomes
Drug: Atorvastatin + L-arginine + Folic acid + Nicorandil + Nebivolol
active Comparator: Endothelial dysfunction protocol + Standard of Care (dexamethasone,
anticoagulation, vitamin c, zinc). Treatment to be continued until 14 days or
discharge/death whichever occurs first. It includes: Nebivolol 5 mg PO daily, Sigmart 10
mg PO twice daily, Atorvastatin 40 mg PO daily, Folic Acid 5 mg PO daily, L-arginine 1000
mg PO 3 times daily.
Other Name: Nicorandil,L-arginine,Folic acid,Nebivolol
Drug: Placebo
Placebo + Standard of Care (dexamethasone, anticoagulation, vitamin c, zinc)
Inclusion Criteria:
- Adults 18 years of age and above admitted for inpatient treatment of COVID-19
infection
- PCR-confirmed COVID-19 classified as mild, moderate or with severe disease as per
the FDA.
With mild being a positive testing by standard RT-PCR assay or equivalent test and
symptoms of mild illness with COVID-19 that could include fever, cough, sore throat,
malaise, headache, muscle pain, gastrointestinal symptoms, without shortness of breath or
dyspnea. No clinical signs indicative of Moderate, Severe, or Critical Severity.
- Moderate defined as positive testing by standard RT-PCR assay or equivalent testing
and symptoms of moderate illness which could include any symptom of mild illness or
shortness of breath with exertion. Clinical signs suggestive of moderate illness
with COVID-19, such as respiratory rate ≥ 20 breaths per minute, saturation of
oxygen (SpO2) > 93% on room air at sea level, heart rate ≥ 90 beats per minute. No
clinical signs indicative of Severe or Critical Illness Severity.
- Severe symptoms could include any symptom of moderate illness or shortness of breath
at rest, or respiratory distress. Clinical signs indicative of severe systemic
illness with COVID-19, such as respiratory 468 rate ≥ 30 per minute, heart rate ≥
125 per minute, SpO2 ≤ 93% on room air at sea level or 469 PaO2/FiO2 < 300.
- No criteria for Critical Severity.
- Eligible for or taking statin
Exclusion Criteria:
- Participant in another RCT
- Myocarditis
- Patients who are already on beta-blockers
Patients already on Nicorandil.
. Patients taking PDE5 inhibitors or Riociguat
.Shock as defined by SBP<90 for more than 30 minutes not responding to IV fluids with
evidence of end organ damage.
.Severe bradycardia (<50 bpm).
.Heart block greater than first-degree (except in patients with a functioning artificial
pacemaker).
.Decompensated heart failure.
.Sick sinus syndrome (unless a permanent pacemaker is in place).
.Severe hepatic impairment (Child-Pugh class C) or active liver disease.
.Unexplained persistent elevations of serum transaminases.
.Pregnancy or breastfeeding.
.Hypersensitivity to any of the medications.
- Can't take medications orally
- Patient refuses to participate
LAUMCRH
Beirut, Lebanon