Adding azithromycin to hydroxychloroquine does not improve clinical outcomes in COVID-19 patients

1. The addition of azithromycin to standard of care, which included hydroxychloroquine, did not improve clinical outcomes compared to standard of care alone for patients with severe COVID-19.

2. There was no significant difference in length of hospital stay, proportion of secondary infections, occurrence of adverse events, or QTc interval prolongation between the groups.

Evidence Rating Level: 1 (Excellent)

Study Rundown: There is limited evidence on the safety and efficacy of adding azithromycin to treat patients hospitalized with severe COVID-19. This multicenter, open-label, randomized clinical trial aimed to assess whether adding azithromycin to hydroxychloroquine was superior to hydroxychloroquine alone in improving the 15-day and 29-day clinical statuses of patients with severe COVID-19. At the time of this study, health authorities in Brazil recommended the use of chloroquine or hydroxychloroquine for all patients with severe SARS-CoV-2 infection. Patients in the experimental (azithromycin and hydroxychloroquine) and control (hydroxychloroquine only) group had a similar clinical status at day 15 from treatment-onset. The rate of adverse events such as ventricular arrhythmias, resuscitated cardiac arrest, acute kidney failure, and QTc interval prolongation were similar between both groups. A major limitation of this study was including only those with severe COVID-19, making the findings less generalizable for patients with mild to moderate disease. In addition, it is unclear whether giving azithromycin alone is more effective for COVID-19 than in combination with hydroxychloroquine. Finally, a small proportion of patients in the control group violated the protocol by taking a macrolide during the study which may have biased the study results.

Click to read the study in The Lancet

Relevant Reading: Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19

In-depth [randomized controlled trial]: This randomized clinical trial included data from 57 centers in Brazil between March 28, 2020 and May 19, 2020. Patients included in this study were ≥ 18 years of age, had suspected or confirmed COVID-19 with less than two weeks of symptom-onset, and had one or more of the following: oxygen supplementation of > 4L/min flow; use of high-flow nasal cannula; use of non-invasive positive-pressure ventilation; or use of mechanical ventilation. Among 447 patients, 397 had confirmed COVID-19 and were randomly assigned to either the experimental (azithromycin plus hydroxychloroquine; n=214) group or control (hydroxychloroquine only; n=183) group. The experimental group received 500 mg of azithromycin once daily along with 400 mg of hydroxychloroquine twice daily for 10 days. Patients in both groups were allowed to use corticosteroids, immunomodulators, antibiotics, and antivirals as a supplement. The primary outcome for this study was clinical status at 15 days post-randomization, measured using a six-point ordinal scale (1 = not admitted to hospital and 6 = death).

The median age of participants was 59.8 years (IQR 50.6-70.1) and majority (n=252, 66%) were male. In addition, 196 (49%) patients were on mechanical ventilation at baseline, while 93 (23%) presented with shock. The median time from onset of symptoms to randomization was 8.0 days (IQR 6.0-10.0). At seven days after the start of treatment, the odds of being in a higher level in the six-point ordinal scale was greater among the azithromycin group compared to the control group (OR 1.60, 95% CI 1.08-2.35, p=0.018). However, no such differences existed between both groups by day 15 (OR 1.36, 95% CI 0.94-1.97, p=0.11) and day 29 (OR 1.43, 95% CI 0.96-2.12, p=0.081). While the number of fatalities, at day 29, was higher (90 out of 214, 42%) in the azithromycin group (vs. 73 out of 183, 40% in the control group), this was not statistically significant (HR 1.08, 95% CI 0.79-1.47, p=0.63). The median length of hospital stay was not significantly different in the azithromycin group (26 days, IQR 11-29) compared to control (18 days, IQR 11-29; median difference 8.00, 95% CI 0.81-15.19, p=0.064). The number of patients with a secondary infection was also similar between groups (87 out of 214, 41% in the experimental group vs. 65 out of 183, 36% in the control group; RR 1.11, 95% CI 0.92-1.33, p=0.29). Finally, there was no difference between groups with respect to serious adverse events (n=102, 42% in the azithromycin group vs. n=75, 38% in the control group, p=0.35) and the proportion of patients with QTc interval prolongation (n=47, 20% in the azithromycin group vs. n=42, 21% in the control group, p=0.66). Overall, findings of this study illustrate that the addition of azithromycin is not superior to standard of card, using hydroxychloroquine, in improving clinical status among patients with severe COVID-19 at 15 and 29 days after start of treatment.

Image: PD

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