Reported possible complications related to SARS-CoV-2 infection, including thromboembolic events in the lungs and cerebrovascular system and acute cardiac injury, are also discussed, as is the interest in monitoring large patient cohorts and analysing linked datasets at a population level to determine other rare and longer term COVID-19 complications.
Thevarajan and colleagues performed a comprehensive review and summary of available evidence for the diagnosis and management of COVID-19. Highlighting the recent clinical trials that have guided current clinical practice, this review also serves to demonstrate the need for ongoing clinical trials to prevent the introduction of COVID-19 therapies without appropriate assessment of their efficacy.1
Dexamethasone (6 mg daily for up to 10 days)2 is now widely considered to be standard of care for patients with severe or critical COVID-19. Remdesivir, a novel nucleotide analogue, was the first reported therapy with proven efficacy for the treatment of SARS-CoV-2 infected patients. However, the primary efficacy reported in the largest clinical trial was a reduced time to recovery not reduction in mortality.3 Use of remdesivir has been limited by availability of the drug.
Although widely proposed as potential effective treatments based primarily on in-vitro data and limited single-arm studies, hydroxychloroquine (or chloroquine) and lopinavir-ritonavir have not demonstrated efficacy when tested in clinical trials.4,5 The results from trials involving convalescent plasma, inhaled or subcutaneous interferon beta, favipiravir, ivermectin and IL-6 pathway inhibitors are awaited, although press releases from pharmaceutical companies were not supportive of sarilumab or tocilizumab.6,7 Overall, the results to date support the use of nonproven, experimental therapy in clinical trials only.
From NEJM Journal Watch Remdesivir trial results published: the first ‘ACTT’
In a large randomised, controlled trial, remdesivir improved time to recovery among hospitalised patients with severe COVID-19.1
The US National Institutes of Health sponsored the Adaptive Covid-19 Treatment Trial (ACTT-1), a placebo-controlled, randomised trial of remdesivir for treatment of COVID-19. Unpublished results were announced previously, but now the eagerly awaited details, including important subgroup analyses, have been published. Patients hospitalised with COVID-19 and evidence of lower respiratory tract involvement were enrolled between 21 February and 19 April, 2020. Participants were randomised 1:1 to receive intravenous remdesivir or placebo for 10 days or until discharge. Preliminary results from 1059 participants are now reported. (Additional follow-up is ongoing.)
Participants in the remdesivir group had a shorter time to recovery than those in the placebo group (11 vs 15 days; rate ratio for recovery, 1.32). The benefit was most apparent in participants who were on supplemental oxygen but not intubated (rate ratio for recovery, 1.47). Among those on mechanical ventilation or extracorporeal membrane oxygenation at time of enrolment, time to recovery was not different between the remdesivir and placebo groups (rate ratio for recovery, 0.95), but the confidence interval was wide. Mortality estimates by day 14 were nonsignificantly lower in the remdesivir group than in the placebo group (7.1% vs 11.9%). Rates of kidney and liver adverse events were similar in the remdesivir and placebo groups.
This large placebo-controlled trial supports the use of remdesivir in hospitalised patients with severe COVID-19. The benefit in improving time to recovery is most evident in those who are on supplemental oxygen but not intubated. Possibly, people who are mechanically ventilated also would derive benefit, but these preliminary results do not show an impact, perhaps because follow up was too short. (Mechanically ventilated patients take longer to recover than less ill patients.) As for many infectious diseases, starting antiviral therapy before illness has progressed too far may be most likely to help, but more data and longer follow up on critically ill patients are needed. Nevertheless, this trial is a landmark. For HIV, it took years to show a clinical effect of the first antiviral drug; for COVID-19, it took months. Clearly, much more must be done to improve outcomes for people with severe COVID-19 – morbidity and mortality are still too high – but this first ‘ACTT’ is a good start.