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

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  • Alexandre Cavalcanti
  • Fernando Zampieri
  • Regis Rosa
  • ...
  • Otavio Berwanger
Journal NEJM
Date July 23, 2020

A randomized, open-label controlled trial of 504 patients with mild-to-moderate COVID-19 were treated with standard care, hydroxychloroquine or hydroxychloroquine plus azithromycin resulted in no difference in clinical status at 15 days.

Although described by hydroxychloroquine critics as an "early treatment" trial, of note, the median time between symptom onset and randomization was reported to be 7 days and included patients up to 14 days after symptom onset. Notably this is a greater delay in treatment compared to other early treatment studies such as the one by Dr. Vladimir Zelenko (COVID-19 Outpatients – Early Risk-Stratified Treatment with Zinc Plus Low Dose Hydroxychloroquine and Azithromycin: A Retrospective Case Series Study) which had a median time between symptom onset and treatment of only 4 days.

Major Issues

-All patients required hospitalization, presumably for hypoxemia, with many requiring oxygen treatment. (Translation: sicker patients, cytokine storm, thromboembolic sequelae, later illness)

-Rx started one week - two weeks after onset of symptoms. (Translation: This is NOT early treatment)

-No zinc measurements, no zinc Rx (Translation: they ignored a known pharmacologic mechanism of action of HCQ)

-Control group had fewer serial electrocardiographic studies performed than Rx groups (Translation: they may have missed viral induced myocarditis in the control group)

-No mention of K+ or Mg2+ measurement &/or Rx. (Translation: They missed known issues affecting EKG anomalies – Qt interval)

-Statistical anomalies -see first “limitation” below (Translation: their statisticians missed the mark when the study was designed?)

-Trial not blinded (Translation: given other limitation admissions, this appears to be more significant issue)

-Protocol “deviations” - see third “limitation” below, (Translation: they had significant study problems)

-Mixing/corruption of treatment groups - see fourth “limitation” below (Translation: they had significant study problems)

Per the authors: “Our trial has several limitations.” First, although the point estimate of effect suggests no major difference between the groups with respect to the primary outcome, the trial cannot definitively rule out either a substantial benefit of the trial drugs or a substantial harm. For the comparison between hydroxychloroquine and control, for example, our data are compatible with odds ratios as low as 0.69 and as high as 2.11. (What?) Second, the trial was not blinded. Third, despite intense efforts to maintain adherence to the assigned treatments, a lack of medications that were perceived as beneficial by clinicians and patients led to some protocol deviations. Fourth, the use of hydroxychloroquine plus azithromycin was widespread among patients hospitalized with Covid-19 in participating hospitals. The enrollment of patients with no previous use of these medications was challenging, so we decided to enroll patients provided that their previous use since the onset of symptoms was limited to 24 hours. (Recall that HCQ has a half-life of 40-50 days!) Finally, although the median time from symptom onset to randomization was 7 days, we included patients up to 14 days after the beginning of symptoms; it is conceivable that interventions that may limit viral replication (e.g., hydroxychloroquine) may be more effective earlier in the course of the disease. (Conceivable? Absolutely!)

Minor Issues




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