Clinical Evidence Summaries

Clinical evidence summaries (CES) provide healthcare professionals with current information on potential therapeutic options and interventions related to COVID-19. The information is updated as new evidence becomes available. The summaries are not exhaustive of the subject matter and do not replace clinical judgement. The responsibility for making decisions appropriate to the circumstances of the individual patient remains at all times with the healthcare professional.

Should ACE Inhibitors and Angiotensin II Receptor Blockers be Stopped for COVID-19?

Two recent articles by Madeddu in the British Medical Journal (BMJ) and Fang et the Lancet Respiratory Medicine have raised concerns about angiotensin-converting enzyme inhibitors (ACE-i) and angiotensin II receptor blockers (ARB) potentially increasing the risk of COVID-19 and related respiratory distress syndrome. The authors hypothesise that angiotensin-converting enzyme 2 (ACE2) is upregulated in patients treated with ACE-i or ARB, which would facilitate COVID-19 infection as ACE2 is a functional receptor of the virus. Madeddu maintains that ACE-i and ARB should not be suspended due to the lack of epidemiological data, and Fang et al. suggest that patients with cardiac disease, hypertension, or diabetes currently under treatment with ACE-i or ARB should be monitored for these medications.

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Should Anticoagulants be used for venous thromboembolism (VTE) prophylaxis in COVID-19?

Numerous reports have emerged regarding the hypercoagulable state and occurrence of VTE in COVID-19 patients. Early studies from China revealed derangements in inflammatory and coagulation markers, such as procalcitonin, C-reactive protein, fibrinogen, platelets, prothrombin time, activated partial thromboplastin time, and D-dimer. Similar biochemical derangements have also been seen in subsequent reports from Italy, France, and UK.

Differences in coagulation markers have been observed between those with severe and non-severe COVID-19. D-dimer levels tend to be higher in severe COVID-19 infections, but platelet count and clotting time (prothrombin time and activated partial thromboplastin time) are less consistent. Non-survivors (case fatalities) tend to have prolonged clotting time, and higher D-dimer levels compared to survivors (2.12 mcg/ml vs 0.61 mcg/ml). D-dimer greater than 1 mcg/ml has been found to be predictive of poor COVID-19 prognosis. While the true incidence of VTE in COVID-19 is unknown, it is currently estimated to be around 8% in all COVID-19 patients1 and up to 69% in critically ill patients. Differences in incidence have been observed between those with severe and non-severe COVID-19. In COVID-19 patients admitted to intensive care unit (ICU), VTE has ranged from 25% in China2 to 69% in France, and found to be markedly higher in non-survivors compared to survivors [based on the InternationalSociety on Thrombosis and Haemostasis (ISTH) criteria; 71.4% vs 0.6%].   Several professional bodies around the world have published guidelines on anticoagulant thromboprophylaxis in COVID-19, although recommendations vary. This review examines available evidence regarding the prophylactic use of anticoagulants to reduce VTE in COVID-19.

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Should Antimalarials be used for COVID-19?

An  article  by  Gao  et  al.  titled “Breakthrough:  Chloroquine  phosphate  has  shown  apparent efficacy  in  treatment  of COVID-19 associated  pneumonia  in  clinical  studies”  announced  preliminary findings  of  15  clinical  trials  from 10 hospitals  in  China  on  19  February  2020. The  authors  reported that  results  from  more  than 100 patients  have  shown chloroquine,  an  antimalarial  treatment,  is efficacious  in  preventing exacerbation  of  pneumonia,  improving  lung imaging  findings, promoting virus  free  conversion,  and shortening  the  disease  course.  This  led  them  to  recommend chloroquine  as  a  treatment  option for COVID-19 in  the  7th  edition  of  Chinese  Guidelines for  the Prevention,  Diagnosis, and  Treatment  of Novel  Coronavirus-induced  Pneumonia. Preliminary  results of  a  clinical  study  by  Gautret  et  al. published  on  17  March  2020  reported  that hydroxychloroquine is  effective  in  treating  COVID-19.

In  view  of  early  study  findings,  U.S.  President  Trump  publically  advocated  the  use  of hydroxychloroquine  and azithromycin  in  COVID-19.  Following  this  event,  news  of  chloroquine poisoning  from  inappropriate  over  the  counter use  of  the  medication,  including  a  report  of  a fatality,  have  surfaced  in  the  U.S.  and  Nigeria.

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Should Baricitinib be used for COVID-19?

Baricitinib is a Janus-associated kinase inhibitor (JAK inhibitor) acting against JAK1 and JAK2. It is currently approved by regulatory agencies (including US FDA, EMA and HSA) to treat rheumatoid arthritis.

Artificial intelligence has identified a group of drugs (including baricitinib) that could inhibit receptormediated endocytosis, which is the mechanism that most viruses use to enter cells. A known regulator of endocytosis is the adaptor-associated protein kinase-1 (AAK1) and disruption of this regulator may interrupt the passage of the virus into cells and the intracellular assembly of virus particles. Baricitinib has shown particularly high affinity for AAK1 and also binds cyclin G-associated kinase (GAK) another regulator of endocytosis. Further, there is growing interest in using baricitinib in combination with direct-acting antivirals, including lopinavir, ritonavir and remdesivir, since it has minimal interaction with the relevant cytochrome P450 drug-metabolising enzyme. However, there are also concerns with its use as baricitinib can inhibit a variety of inflammatory cytokines including interferon-α, which plays an important role in curbing virus activity.

While other JAK inhibitors such as ruxolitinib and fedratinib may also have activity against COVID-19, the predicted unbound plasma exposure required to inhibit receptor mediated endocytosis with these treatments greatly exceeds their tolerated doses. Therefore, they are unlikely to be suitable for patient with COVID-19 to reduce viral infectivity.

Recently, online news articles have listed JAK inhibitors, such as baricitinib, as potential COVID-19 treatment options.

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Should Convalescent Plasma be used for COVID-19?

Convalescent plasma is blood plasma from a person who has recovered from an infection. It contains antibodies against the infection such as SARS-CoV-2. Recovered patients with high titres of neutralising antibodies can donate plasma for administration to those at-risk to prevent infection (prophylaxis) or to those with confirmed disease to reduce symptoms and mortality. This is known as passive antibody therapy or passive immunotherapy.

Convalescent plasma can be fractionated to immunoglobulin for intravenous use (IVIG), which contains concentrated globulin from pooled human plasma with the benefit that it can be given in a smaller volume and is a more uniform product compared with plasma. Hyperimmune immunoglobulin (H-IVIG) is IVIG chosen for its high titre of specific antibodies.

Published articles have suggested convalescent plasma could be a potential treatment option for COVID-19 citing its use and perceived efficacy in SARS, Ebola virus, H1N1, and MERS outbreaks and international news coverage has reported on its use in China.

The Food and Drug Administration (FDA) in the USA has issued Emergency Use Authorisation (EUA) for COVID-19 convalescent plasma in patients who are hospitalised with COVID-19.7 The FDA concluded that the known and potential benefits outweigh the known and potential risks of COVID-19 convalescent plasma, while noting that well-conducted randomised controlled trials (RCTs) remain necessary for a definitive demonstration of efficacy. In addition, the FDA, National Institutes of Health (NIH) and the Centers for Disease Control and Prevention (CDC) have developed guidance to coordinate collection and use of COVID-19 plasma.

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Should Dexamethasone be used for COVID-19?

Dexamethasone is a corticosteroid that has been used since the 1960s to reduce inflammation. It is included in the World Health Organization (WHO) Essential Medicines List and is approved by regulatory agencies (including US FDA, EMA and HSA) for a range of conditions, including adrenocortical insufficiency, inflammatory disorders, cancer and shock.

The full spectrum of COVID-19 infection ranges from asymptomatic disease to mild respiratory tract illness to severe pneumonia, acute respiratory distress syndrome (ARDS), multiorgan failure, and death. Clinical presentation of some critically ill patients with COVID-19 suggest a “Cytokine Storm Syndrome” or hyperinflammatory state in which the immunosuppressive effects of corticosteroids may be beneficial.

Corticosteroids were widely used during outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), however, their efficacy has been controversial and largely based on observational studies with conflicting results.

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Should Favipiravir be used for COVID-19?

A news article titled “Japanese flu drug 'clearly effective' in treating coronavirus, say China” was published in the Guardian on 18 Mar 2020. Favipiravir (brand name Avigan), an antiviral drug, is a new type of RNA-dependent RNA polymerase (RdRp) inhibitor which can block the replication of RNA viruses and may have antiviral action against SARS-CoV-2.

It was approved in Japan in 2014 for the treatment of novel or re-emerging pandemic influenza virus infections. Use is limited to cases in which other influenza antiviral drugs are not sufficiently effective because favipiravir was only investigated in non-clinical studies in avian influenza A (H5N1 and H7N9), and efficacy against seasonal influenza A or B has not been sufficiently demonstrated. 

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Should Ibuprofen be used for COVID-19?

A news article titled “COVID-19: Ibuprofen should not be used for managing symptoms, say doctors and scientists” was published in BMJ on 17 Mar 2020. It claims that anti-inflammatory drugs (eg. ibuprofen, cortisone) could aggravate infection in patients with suspected COVID-19 and paracetamol should be used in these patients; however different views were expressed.

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Should Interleukin-6 Inhibitors be used for COVID-19?

The 7th edition of the Chinese Clinical Guidance for COVID-19 Pneumonia Diagnosis and Treatment published by China National Health Commission on 4 March 20201 included tocilizumab (IL-6 receptor inhibitor) as an option for patients with severe COVID-19, extensive lung lesions and elevated IL-6 levels. This was following reports of positive outcomes from the use of tocilizumab to control dangerous lung inflammation in 21 patients with severe COVID-19 in China.

Clinical experts have observed that many patients with severe COVID-19 appear to have features of cytokine storm syndrome. Some have hypothesised that tocilizumab, which is licensed in the US and Europe for chimeric antigen receptor T-cell-induced severe or life-threatening cytokine release syndrome, may be effective in a subgroup of patients who have cytokine storm syndrome associated with severe COVID-19. 

Subsequently, tocilizumab, sarilumab and siltuximab, which are commercially available anti-IL-6 drugs, have been cited in media articles as potential treatment options for COVID-19. Twelve other anti-IL6 drugs are in clinical or preclinical development.

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Should Protease Inhibitors be used for COVID-19?

Protease inhibitors developed to treat HIV infection, have previously been trialed as a treatment for patients with Severe Acute Respiratory Syndrome (SARS-CoV); however their clinical efficacy was inconclusive. As SARS-CoV and COVID-19 both belong to the Coronavirus family, protease inhibitors are currently being studied as a potential antiviral treatment for COVID-19 infection. Most ongoing trials are focusing on lopinavir/ritonavir (brand names: Kaletra, Aluvia), following reports of its efficacy in a patient with COVID-19 in South Korea.

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Should Remdesivir be used for COVID-19?

Remdesivir  is  a  novel  nucleotide  analog  prodrug  (broad  spectrum  antiviral).  It  was  developed  as  a treatment  for  Ebola  and  Marburg  virus  infections,  although  when  trialed  in  patients  with  Ebola  virus  it failed  to  show  a  survival  benefit.  Remdesivir  has  subsequently  shown  reasonable  antiviral  activity against  more  distantly  related  viruses  including  MERS-coronavirus;  therefore  activity  against  other coronaviruses  including  SARS-CoV-2  infection  is  predicted.  Review  articles  identified  remdesivir  as one  of  several  possible  treatments  for  COVID-19.  Lu  (2020)  stated  that  remdesivir  “may  be  the  best potential  drug  for  the  treatment  of  [COVID-19]”  given  the  drug  had  completed  the  clinical  program  for Ebola  virus  infection  with  relatively  complete  safety  and  pharmacokinetics  data  in  humans.

The Health Sciences Authority (HSA) in Singapore has issued a conditional registration for remdesivir to treat adults with COVID-19 who have an oxygen saturation ≤ 94% or who require supplemental oxygen, invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO). Prescription is restricted to infectious disease physicians and the manufacturer is required to submit further data in the future for HSA analysis. The US Food and Drug Administration (FDA) has issued emergency use authorisation for remdesivir to treat severe COVID-19 in hospitalised adults and children on the basis of initial data from two trials: NCT04280705 and NCT04292899. The European Medicines Agency (EMA) lists remdesivir as an investigational product for COVID-19 and has recommended conditions for compassionate use in patients with COVID-19. Remdesivir has received exceptional approval in Japan, while other jurisdictions, such as Taiwan and South Korea have approved it for emergency use for patients with SARS-CoV-2 infection.

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