Report suggests dexamethasone reduces mortality in patients seriously ill with COVID-19

Outline of the currently available evidence for dexamethasone in the management of COVID-19 | Updated 6 July 2020

Update: 6 July 2020

Based on the preliminary findings from the RECOVERY trial (described below), the National COVID-19 Clinical Evidence Taskforce have updated their living guidelines to include conditional recommendations as follows, regarding the use of dexamethasone:

  1. Consider using dexamethasone 6mg daily IV or oral for up to 10 days in adults with  COVID-19 who are receiving oxygen (including mechanically ventilated patients).
  2. Do not routinely use dexamethasone to treat COVID-19 in adults who do not require oxygen.

Dexamethasone may still be considered for other evidence-based indications in people who have COVID-19.

The Taskforce is continually monitoring research on treatments for COVID-19. These recommendations will be revisited when more complete and detailed reporting of the RECOVERY trial is made available.

What are conditional recommendations?

A conditional (weak) recommendation for an intervention is one where treatment benefit probably outweighs harm for the majority. Uncertainty exists but most patients would likely want this option. 

In general, clinicians should ‘think twice’ and consider individual patient factors within a shared decision-making model eg, patient’s values, preferences, comorbidities, polypharmacy, burden of care or personal limitations that may result in an alternative course of action.

A conditional recommendation against an intervention is one where treatment harm probably outweighs benefit for the majority. Uncertainly exists and most patients would likely decline this option.

For more information visit the Australian National COVID-19 Clinical Evidence Taskforce

Update: 25 June 2020

A preliminary report from the RECOVERY Collaborative Group has provided additional data suggesting that dexamethasone 6 mg per day for up to 10 days conferred no benefit, and the possibility of harm, among COVID-19 patients who were hospitalised but not requiring oxygen or respiratory support.

The report reaffirms that dexamethasone was associated with a reduction in mortality among patients with more severe COVID-19 disease, ie, those who required respiratory support including oxygen, non-invasive and invasive mechanical ventilation (data presented in article below).

The authors suggest that beneficial effect of corticosteroid treatment in severe viral respiratory infections may be dependent on the treatment being initiated later in the disease, once active viral replication has declined and inflammation is the dominant pathology.

This might explain why hospitalised patients with COVID-19 who did not require oxygen or respiratory support, and those recruited in the early stages of illness, received no benefit (and possible harm) from dexamethasone.

More data will help to interpret these findings, with robust safety data required to validate the inclusion of dexamethasone into clinical practice.

The preliminary results have not been peer reviewed. The report was submitted on 22 June 2020.

Read the RECOVERY preliminary report: Dexamethasone for COVID-19 – Preliminary report

Learn more about the adverse effects and common side effects of dexamethasone

This article is written for health professionals.

Preliminary results from UK-based trial RECOVERY have reported that the glucocorticoid dexamethasone reduced death by up to one-third among hospitalised patients requiring ventilation for severe respiratory complications of COVID-19.1 The results have been announced via a statement from the chief investigators of the trial. As of 18 June 2020, they have not been peer reviewed or published.

The news has been welcomed by the global health community including the World Health Organisation, the UK Department of Health and Social Care, the Australian National COVID-19 Clinical Evidence Taskforce and the Australian Health Protection Principal Committee (AHPCC).

 

What is the evidence for dexamethasone in COVID-19?

RECOVERY is a randomised clinical trial established during the SARS-CoV-2 outbreak to test a range of potential treatments for COVID-19, including low-dose dexamethasone.1

COVID-19 (coronavirus disease) is the infectious disease caused by the virus SARS-CoV-2.

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is a new strain of coronavirus that first started causing severe disease symptoms in humans around December 2019.

Coronaviruses are a large family of viruses known to cause respiratory infections. These can range from the common cold to more serious diseases such as Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS).2


Since March 2020 over 11,500 patients have been enrolled in the RECOVERY trial from more than 175 public hospitals across the UK. In addition to low-dose dexamethasone, other treatments that are currently being trialled are lopinavir with ritonavir, azithromycin, tocilizumab and convalescent plasma.1,3

In the dexamethasone arm, a total of 2,104 patients were randomised to receive usual care (for the participating hospital) plus a daily dose of dexamethasone 6 mg for 10 days (oral or intravenous). This group was compared with 4,321 patients randomised to usual care alone.1

Primary outcome was all-cause mortality at 28 days after randomisation, and follow-up was completed for 94% of participants.1,3

Dexamethasone was not associated with a survival benefit in patients with mild to moderate COVID-19 infection who were managed without respiratory support including supplemental oxygen or ventilation (RR 1.22, 95% CI 0.86 to 1.75, p=0.14).1

Dexamethasone was associated with a reduction in mortality in patients with more severe COVID-19 disease. It reduced deaths by one-third in ventilated patients (rate ratio [RR] 0.65, 95% CI 0.48 to 0.88, p=0.0003) and by one-fifth in other patients receiving oxygen only (RR 0.80, 95% CI 0.67 to 0.96, p=0.0021), compared to standard care alone.1

The RECOVERY chief investigators pointed to the public health importance of the preliminary data stating that, ‘Based on these results, 1 death would be prevented by treatment of around 8 ventilated patients or around 25 patients requiring oxygen alone.’1 Professor Peter Horby, one of the chief investigators, further noted, ‘Dexamethasone is inexpensive, on the shelf, and can be used immediately to save lives worldwide.’1

However, they emphasised there was no evidence of benefit for patients who did not require oxygen and that no participants in the dexamethasone arm of the RECOVERY trial had been studied outside the hospital setting.

Read more about the RECOVERY trial

 

What do Australian guidelines say about the evidence?

The Australian National COVID-19 Clinical Evidence Taskforce released a statement on 16 June 2020 acknowledging the importance of the preliminary findings from the RECOVERY trial. Once peer-reviewed data has been released, the Taskforce intends to incorporate the findings into its rapid guideline development process so it can make appropriate recommendations about use of this medicine for patients with COVID-19 in Australia.4

 

About dexamethasone

Dexamethasone is a prescription-only synthetic adrenocorticosteroid with glucocorticoid activity.5

Corticosteroids regulate gene expression which can produce;

  • glucocorticoid effects eg, glucogenesis, proteolysis, lipolysis, suppression of inflammation and immune responses, and
  • mineralocorticoid effects eg, hypertension, sodium and water retention, potassium loss.6

Dexamethasone is one of the more potent glucocorticoids – about 25 to 30 times as potent as hydrocortisone. Unlike hydrocortisone, dexamethasone exerts little if any mineralocorticoid activity effects.5,6

Due to their anti-inflammatory and immunosuppressant effects, corticosteroids such as dexamethasone are used to manage a wide range of symptoms and conditions including:5-7

  • chemotherapy-induced and post-operative nausea and vomiting
  • collagen diseases eg, systemic lupus erythematosus (SLE)
  • endocrine disorders eg, adrenal insufficiency
  • gastrointestinal disorders eg, ulcerative colitis
  • leukaemia and lymphoma
  • certain paediatric respiratory infections eg, croup
  • oedema eg, cerebral oedema due to malignancy, neurosurgery or stroke
  • pulmonary disorders eg, chronic asthma and respiratory insufficiency
  • rheumatic diseases eg, rheumatoid arthritis and osteoarthritis
  • skin diseases eg, psoriasis and dermatitis.

Dexamethasone may also be used in prevention eg, neonatal respiratory syndrome, and as an adjunct in the treatment of shock.

 

Adverse effects and common side effects of dexamethasone

Dexamethasone can be associated with adverse effects eg, allergic reactions, as well as side effects associated with prolonged therapy and/or high-dose therapy. These effects can include:5

  • anti-inflammatory and immune suppression eg, increased susceptibility to and severity of infections with masking of clinical symptoms and signs, opportunistic infections, recurrence of dormant tuberculosis
  • cardiovascular effects eg, thromboembolism, hypertension, myocardial rupture following recent cardiac infarction
  • endocrine effects eg, adrenal suppression, hyperglycaemia, increased requirements for insulin or oral hypoglycaemic agents
  • fluid and electrolyte imbalances eg, sodium retention with oedema and hypertension, potassium loss, hypokalaemia alkalosis, hypocalcaemia
  • neurological effects eg, increased intracranial pressure
  • Other adverse effects include anaphylaxis and hypersensitivity reactions, dermatological effects, gastrointestinal effects, leucocytosis, metabolic effects, musculoskeletal effects, ocular effects, psychiatric effects.

Precautions for dexamethasone use

In the context of COVID-19, the following precautions for dexamethasone should be considered where applicable:4,5

  • Corticosteroids may increase susceptibility to or mask the symptoms of infection.
  • The immunosuppressive effects of glucocorticoids may result in activation of latent infection or exacerbation of intercurrent infections eg, varicella, measles.
  • While immunosuppression is most likely to occur in patients on long-term, high-dose systemic corticosteroid treatment, patients receiving moderate doses for short periods, or low doses over a prolonged period may also be at risk.
  • The effects of anticoagulant agents are usually decreased (but may be increased in some patients) with concurrent corticosteroid treatment. Close monitoring of the INR or prothrombin time is recommended.
  • Concurrent administration of dexamethasone with anticoagulants, heparin, streptokinase, urokinase, alcohol or non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin may increase the risk of gastrointestinal ulceration or haemorrhage.
  • Potassium loss may occur as a result of dexamethasone administration. Monitoring of serum potassium is recommended.
  • Glucocorticoids may increase blood glucose concentrations. Dose adjustments of medicines such as antidiabetic agents may be necessary.
  • There is the also potential for severe psychiatric reactions. Symptoms typically emerge within a few days or weeks of starting treatment. Most psychiatric effects resolve after either dose reduction or withdrawal.

Find out more about dexamethasone and potential medicine interactions

 

What do your patients need to know?

Patients with confirmed COVID-19

  • In the RECOVERY trial, dexamethasone was given to hospitalised patients with serious respiratory complications from COVID-19.
  • Dexamethasone did not provide any benefit for hospitalised patients with less serious illness associated with COVD-19, ie, those who did not need ventilation or oxygen.
  • The reported findings suggest that use of dexamethasone in additional to usual hospital care could prevent 1 death for every 8 patients with COVID-19 on mechanical ventilation, or 1 death for every 25 patients with COVID-19 on supplemental oxygen.
  • The RECOVERY trial did not test dexamethasone on patients with COVID-19 who had not been hospitalised and so it is difficult to draw conclusions as to what this means for those with COVID-19 being managed in the community.
  • Dexamethasone was not used to prevent the risk of COVID-19 infection.
  • Dexamethasone can have serious side effects and should only be used for approved conditions.

Patients who have been prescribed dexamethasone for approved conditions

  • Dexamethasone has not been shown to prevent infection with COVID-19.
  • Continue to take dexamethasone as prescribed.
  • If you have tested positive for COVID-19, speak to your doctor about your dexamethasone prescription.
  • Do not change your dose of dexamethasone unless instructed by your doctor.
  • Do not share your dexamethasone with anyone else, even if they are in hospital with COVID-19.
  • There is no need to stockpile dexamethasone, but if you are concerned about supply speak to your pharmacist.