Data from a large randomized controlled trial in the UK showing a benefit of the use of steroid dexamethasone in hospitalized patients with COVID-19 was released today in the New England Journal of Medicine (NEJM), while two more studies show no benefit for the antimalarial drug hydroxychloroquine.
the NEJM The data, which were originally reported in a press release in mid-June by the lead investigators of the RECOVERY (Randomized Evaluation of COVID-19 Therapy) trial after an interim analysis, show that in patients requiring mechanical ventilation, dexamethasone reduced deaths by 36% compared to usual care. In patients who received oxygen, the incidence of death was 18% lower for patients treated with dexamethasone.
“The RECOVERY trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces mortality at 28 days in patients with Covid-19 receiving respiratory support,” Group researchers Collaborative RECOVERY, which is led by scientists at Oxford University, wrote.
Before the trial, it had been debated whether steroids such as dexamethasone could play a role in COVID-19 treatment. But based on these results, the guidelines from UK medical directors and the National Institutes of Health were quickly updated to recommend the inexpensive and widely available steroid for the treatment of COVID-19 patients requiring ventilation or oxygen, and the drug is now widely used. .
Reduced mortality in dexamethasone patients
In the open, controlled trial, which investigates various treatments in over 11,000 patients hospitalized with COVID-19 in the United Kingdom, 2,104 patients were assigned to receive oral or intravenous dexamethasone daily for up to 10 days, and 4,321 patients routinely received care . The primary outcome was mortality at 28 days.
The results showed, in general, that the 28-day mortality was lower in the dexamethasone group than in the usual care group, with 482 deaths (22.9%) in patients who received dexamethasone and 1,110 deaths (25.7%) in patients. who received usual care (age-adjusted ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93). But the greatest reduction in deaths was observed in patients who needed mechanical ventilation (29.3% in the dexamethasone arm vs. 41.4% in the usual care arm; frequency ratio 0.64; 95% CI, 0.51 to 0.81) and in those who they received oxygen (23.3% vs. 26.2%; rate ratio 0.82, 95% CI 0.72 to 0.94).
However, there was no mortality benefit from dexamethasone among patients who did not require respiratory support. In fact, deaths were higher among patients in the dexamethasone arm (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91 to 1.55).
The results also showed a greater mortality benefit in patients with a longer duration of symptoms, and that patients in the dexamethasone group spent less time in the hospital (median, 12 days versus 13 days) and had a higher probability of discharge. hospital within 28 days (rate index, 1.10; 95% CI, 1.03 to 1.17).
The researchers suggested that the benefits of dexamethasone, which is used in a wide range of conditions for its anti-inflammatory and immunosuppressive effects, are likely related to the treatment of inflammation and the immune response caused by COVID-19.
“The greater mortality benefit of dexamethasone in patients with COVID-19 receiving respiratory assistance and among those recruited after the first week of their disease suggests that at this stage the disease may be dominated by immunopathological elements, with active viral replication it plays a minor role, “they wrote.
Writing in an accompanying editorial, H. Clifford Lane, MD, and Anthony Fauci, MD, of the National Institute of Allergy and Infectious Diseases, said the findings provide “clarity in an area of therapeutic controversy and will likely result in many lives saved.” “
Lane and Fauci also said that more trials like RECOVERY will be needed to improve outcomes in patients with COVID-19.
“Scientifically sound and ethically sound clinical research remains the fastest and most efficient avenue for effective treatment and prevention strategies for patients with COVID-19,” they wrote.
More uninspiring facts about hydroxychloroquine
While the RECOVERY trial results indicate that dexamethasone may help some severely ill COVID-19 patients, two trials investigating the efficacy of hydroxychloroquine found that it provided no benefit to patients with mild COVID-19.
In a study published yesterday in the Annals of internal medicine, Researchers from the University of Minnesota, the University of Manitoba, and McGill University randomized 491 patients with laboratory-confirmed or probable COVID-19 and high-risk exposure to receive 5 days of oral hydroxychloroquine or placebo within 4 days after the onset of symptoms. The aim of the study was to see if starting hydroxychloroquine therapy within the first few days of symptoms could reduce the severity or duration of symptoms and prevent hospitalization.
The researchers emailed the participants on days 1, 3, 5, 10, and 14 to assess the severity of COVID-19 symptoms, adverse effects, medication compliance, and hospitalization status. They assessed symptom severity on a 10-point scale, where 0 indicated no symptoms and 10 indicated severe symptoms.
The initial primary outcome was hospitalization status, intensive care unit stay, or death on day 14. But because the interim analysis showed that the pooled event rate of hospitalization or death rate was substantially less than As expected, the primary endpoint was changed to overall symptom severity for day 14.
The results showed that, among the 423 participants who provided data, hydroxychloroquine was unable to cause a statistically significant difference in the severity or prevalence of symptoms during the 14-day period. Hydroxychloroquine patients had a mean reduction from baseline of 2.60 points on the 10-point symptom severity scale, compared to a 2.33-point reduction for the placebo group (difference in symptom severity: relative, 12%, absolute, -0.27 points, 95% CI, -0.61 to 0.07 points; P = 0.117). On day 14, 24% of participants who received hydroxychloroquine had continuous symptoms compared to 30% of patients who received placebo.
“Hydroxychloroquine did not substantially reduce the severity or prevalence of symptoms over time in non-hospitalized people with COVID-19,” the study authors wrote.
Adverse effects occurred in 43% of patients taking hydroxychloroquine versus 22% of those receiving placebo. Hospitalizations occurred in 4 patients taking hydroxychloroquine, with 1 death, while 10 placebo patients were hospitalized (2 for non-COVID-related problems), and 1 died. The incidence of hospitalization or death did not differ between the groups.
The authors note that the results are limited by the fact that only 58% of participants received evidence of SARS-CoV-2, the virus that causes COVID-19, due to a paucity of evidence at enrollment.
In the other study, a multicentre trial conducted in Spain, 293 outpatients with confirmed SARS-CoV-2 infections were randomized to receive hydroxychloroquine (the intervention arm) within 5 days of symptom onset or no treatment. antiviral (the control arm) The primary outcomes were reduction of viral RNA load on nasopharyngeal swabs up to 7 days after treatment, progression of the patient’s disease, and time to complete resolution of symptoms.
Trial results showed no difference in mean viral load reduction on day 7 (–3.37 and –3.44 Log10 copies per milliliter in the control and intervention arm, respectively; difference, –0.07; 95% CI, –0.44 to 0.29). In addition, hydroxychloroquine treatment did not significantly reduce the risk of hospitalization (7.1% for the control arm versus 5.9% for the intervention arm; risk ratio, 0.75; 95% CI, 0.32 to 1.77) or shortened the time to complete resolution of symptoms (12 days for the control arm versus 10 days for the intervention arm; P = 0.38).
“The results of this randomized controlled trial convincingly rule out any significant virological or clinical benefit of [hydroxychloroquine] in outpatients with mild COVID-19, “the authors wrote in Clinical infectious diseases.
Time to move on from hydroxychloroquine
Jason Gallagher, PharmD, clinical professor and infectious disease specialist at Temple University School of Pharmacy, says the results of this trial add to the growing body of evidence that hydroxychloroquine is not an effective treatment for COVID-19. , either for hospitalized patients or those in the early stages of infection.
“I wish hydroxychloroquine had been successful, but it has been conclusively found to be ineffective,” said Gallagher, who was not involved in any of the studies. “All the well-designed, randomized, controlled trials have found the same thing: it doesn’t work.”
Hope for hydroxychloroquine, which received an emergency use authorization from the US Food and Drug Administration in March, was based on the results of a small French study that found the drug lowered the SARS viral load- CoV-2 when combined with azithromycin in a handful of patients But several observational studies and randomized controlled trials, which are considered the gold standard for determining whether a drug is effective, have found no benefit.
Gallagher believes it is time to investigate other possible therapies for non-hospitalized COVID-19 patients.
“If a therapy is going to be successful in the outpatient treatment of COVID-19, it will be something else,” he said. “It is time to spend our resources elsewhere.”
