No decreased mortality with high-dose methylprednisolone vs. dexamethasone for COVID-19

Key takeaways:

• Mortality rates did not significantly vary between treatments for COVID-19 pneumonia at day 28.
• Median hospital length of stay was extended by 1 day in those receiving methylprednisolone.

Higher dose methylprednisolone and low-dose dexamethasone treatments in patients with COVID-19 pneumonia showed similar 28-day mortality rates, according to study results published in European Respiratory Journal.

“A protocol of infusive, prolonged, higher dose methylprednisolone did not show major advantages over conventional dexamethasone in COVID-19 pneumonia, confirming the favorable drug class effect of prolonged low-dose glucocorticoids postulated by current guidelines,” Francesco Salton, MD, of the department of pulmonology at University Hospital of Cattinara and the department of medical, surgical and health sciences at the University of Trieste in Italy, and colleagues wrote.

In a multicenter, open-label randomized controlled trial, Salton and colleagues analyzed 677 adults with COVID-19 pneumonia who needed oxygen or noninvasive respiratory support to evaluate higher dose methylprednisolone against low-dose dexamethasone treatment.

Of the total cohort, 337 adults (age, 64.4 years; 70.3% men) received a continuous infusion of 80 mg of methylprednisolone every day for 8 days, which was followed by slow tapering, whereas 340 adults (age, 63 years; 68.5% men) received 6 mg of dexamethasone a day for a maximum of 10 days.

Researchers primarily assessed 28-day mortality, but they also analyzed mechanical ventilation-free days, ICU referral, tracheostomy referral, hospitalization duration and fluctuations in C-reactive protein (CRP) levels, arterial oxygen tension/inspiratory oxygen fraction ratio and WHO Clinical Progression scale at days 3, 7 and 14.

Overall, researchers found that methylprednisolone and dexamethasone showed similar outcomes.

Looking at the main outcome of mortality, the number of patients who died by day 28 was not significantly different between methylprednisolone (n = 35; 10.4%) and dexamethasone (n = 41; 12.1%) treatment. After accounting for different variables, such as respiratory impairment severity, type of respiratory support, baseline arterial oxygen tension/inspiratory oxygen fraction ratio, glucocorticoid use prior to treatment, vaccination status or age, this outcome remained similar between both groups.

In the per-protocol analysis, which only factored in those who followed the study’s protocol, the methylprednisolone group had 279 patients and the dexamethasone group had 286. Mortality was similar between both treatments in this analysis, with no observed significant differences (methylprednisolone, 24 patients; 7.1% vs. dexamethasone, 19 patients; 5.6%), according to researchers.

Notably, four patients from the methylprednisolone group were not included in the per-protocol analysis because they stopped treatment after experiencing an adverse event of agitation, hyperglycemia or gastrointestinal bleeding.

Other outcomes between methylprednisolone and dexamethasone were also comparable in the intention-to-treat analysis including median mechanical-ventilation-free days (23 days vs. 24 days), ICU referral (41 patients vs. 45 patients) and tracheostomy referral (8 patients vs. 9 patients). Notably, median hospitalization length was extended by 1 day in those receiving methylprednisolone (15 days vs. 14 days; P = .005).

In the per-protocol analysis, researchers found less ICU referrals in patients receiving methylprednisolone (7 patients vs. 19 patients; P = .02), and this ended up only being significant in those with arterial oxygen tension/inspiratory oxygen fraction ratio less than 200 mmHg at randomization (methylprednisolone, 5 patients vs. dexamethasone, 13 patients) during analysis of different severity groups of respiratory impairment.

On the other hand, per-protocol analysis demonstrated that methylprednisolone extended the median hospital stay by 2 days (15 days vs. 13 days; P = .001). Stratified analysis showed that this was significant in those with arterial oxygen tension/inspiratory oxygen fraction ratio of 200 mmHg or more (14 days vs. 12 days; P = .009) or those on low-flow oxygen (14 days vs. 12 days; P = .001).

Researchers did see improved CRP levels at days 7 (8.6 mg/L¹ vs. 12.4 mg/L¹; P = 0.006) and 14 (5 mg/L¹ vs. 11.5 mg/L¹; P = .0001) for those receiving methylprednisolone; however, arterial oxygen tension/inspiratory oxygen fraction ratio did not significantly differ in the treatment groups on any of the three studied days. Further, disease progression measured on the WHO scale did not vary for either treatment group.

Both groups also showed a comparable number of reported adverse events linked to the treatment they received (methylprednisolone, 147 vs. dexamethasone, 126), with hyperglycemia occurring the most (113 vs. 93). Further, researchers found that the number of complications that occurred in the hospital did not significantly differ between the two treatments (169 vs. 158).

When discussing the results, researchers wrote about what may be behind the extended length of stay found in the methylprednisolone group.

“We believe there are two leading causes underlying the longer duration of hospitalization among patients treated with methylprednisolone in our study,” Salton and colleagues wrote. “First, the methylprednisolone protocol had a more extended administration schedule due to both titration based on clinical response and an i.v. [intravenous] de-escalation phase. Indeed, the differential length of hospital stay was even larger among patients who completed the assigned treatments. Second, patients in the methylprednisolone group suffered from a more severe respiratory involvement at randomization. Furthermore, we observed an inversely proportional trend between the severity of respiratory status at baseline and the difference in the duration of hospitalization between groups, which is consistent with a possible higher benefit of methylprednisolone treatment in the most severe subgroups.”