Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19

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Publication
Title Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19
Authors
  • Joseph Magagnoli, MS
  • Siddharth Narendran, MD
  • Felipe Pereira, MD
  • Tammy Cummings, PhD
  • James W. Hardin, PhD
  • S. Scott Sutton, PharmD
  • Jayakrishna Ambati, MD
Journal medRxiv preprint
Date April 21, 2020

A retrospective analysis of 368 hospitalized COVID-19 patients in United States Veterans Health Administration medical centers who were treated with hydroxychloroquine alone (n=97), hydroxychloroquine and azithromycin (n=113) or standard therapy (n=158). Risk of death was determined to be significantly higher in the hydroxychloroquine group (p=0.03), but not in the hydroxychloroquine and azithromycin group (p=0.72) in comparison to the control group.

This study has faced multiple criticisms, including greater baseline morbidity in treatment groups compared to control group as well as use of hydroxychloroquine in late stage COVID-19.

Major Issues

There was a significant difference in baseline characteristics between the treatment and control arms in this retrospective analysis. One key baseline difference is a higher percentage of patients with lymphopenia (low levels of a specific type of white blood cell) in the hydroxychloroquine treatment arms compared to control arm. The study showed lymphopenia was approximately twice as prevalent in the HCQ arms (24.7% in hydroxychloroquine alone, 31.0% in the hydroxychloroquine and azithromycin arm versus 13.9% in the standard therapy arm, p = 0.021). This difference is notable because lymphopenia has been shown to correlate with higher mortality risk in COVID-19.[1]

The difference in patient morbidity can be explained clinically by the likelihood that deteriorating patients were more likely to receive treatment with an experimental therapeutic such as hydroxychloroquine as opposed to patients who were stable or improving.[2]

The study’s conclusions are only supported when including patients who received hydroxychloroquine before and after intubation. As shown in Tables 3 and 4 (“Table 3. Outcomes based on treatment exposure” and “Table 4. Outcomes based on pre-ventilation treatment”), a subgroup analysis of patients who were treated prior to intubation shows no difference in mortality rates (10% in the hydroxychloroquine group, 10.9% hydroxychloroquine and azithromycin group, and 8.4% in the control group, chi-square=0.47, p=0.79).[2] This is highly suggestive that a rather large percentage of patients must have received treatment with hydroxychloroquine after intubation to result in the study’s final conclusion that hydroxychloroquine results in an increased mortality risk.

It’s estimated that treatment with hydroxychloroquine takes between two and three days to reach a supposed therapeutic level.[3] Thus, it is likely that patients who received hydroxychloroquine after intubation did not reach a meaningful blood level until several days after deteriorating to the point of requiring mechanical ventilation.

Minor Issues

Nearly 30% of patients in the control group received azithromycin, and are not distinguished or analyzed in any meaningful way. This could potentially confound the results considering that azithromycin has in-vitro efficacy against SARS-CoV-2.[4] Undetermined at this time, it is possible that azithromycin used alone and not in combination with hydroxychloroquine has a clinical benefit.

Impact

With the exception of this study, there was little to no reputable evidence that hydroxychloroquine use was associated with increased risk of mortality in patients with COVID-19. Yet, days after the preprint was published, the FDA issued a warning on the use of hydroxychloroquine in treatment of COVID-19 stating, “adverse events included abnormal heart rhythms such as QT interval prolongation, dangerously rapid heart rate called ventricular tachycardia and ventricular fibrillation, and in some cases, death.”[5] Based on the timing of this announcement and evidence of harm limited primarily to the VA study, it is likely this study bolstered the FDA’s concern that resulted in this warning.

The effect of the FDA’s warning was decreased patient enrollment in ongoing US clinical trials evaluating hydroxychloroquine in treatment of COVID-19.

The results of this study are limited to treatment in late stage disease. Although the study does not specify mean time between symptom onset and treatment, high mortality rates show a very sick cohort of patients who likely began treatment in late stages of the disease and in some cases even after intubation. This study is not relevant regarding prophylactic or early treatment of COVID-19, which is the treatment approach with the most evidence of positive benefit, albeit limited to mostly observational and retrospective data.

Article revisions

No revisions at this time.

References

  1. Tan L, Wang Q, Zhang D, et al. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Signal Transduct Target Ther. 2020;5(1):33. Published 2020 Mar 27. doi:10.1038/s41392-020-0148-4
  2. 2.0 2.1 Million, M; Roussel, Y; Raoult, D (April 2020). “Response to Magagnoli, MedRxiv, 2020”. Mediterranee Infection. Retrieved on 25 June 2020.
  3. Perinel, S; Launay, M; Botelho-Nevers, E et al (April 2020). “Towards Optimization of Hydroxychloroquine Dosing in Intensive Care Unit COVID-19 Patients”. Clinical Infectious Diseases. https://doi.org/10.1093/cid/ciaa394
  4. Andreani J; Le Bideau M; Duflot I, et al (April 2020). “In vitro testing of combined Hydroxychloroquine and Azithromycin on SARS-CoV-2 shows synergistic effect”. Microbial pathogenesis. Retrieved on 25 June 2020. doi: 10.1016/j.micpath.2020.104228
  5. US Food and Drug Administration (April 2020). “Hydroxychloroquine or Chloroquine for COVID-19: Drug Safety Communication - FDA Cautions Against Use Outside of the Hospital Setting or a Clinical Trial Due to Risk of Heart Rhythm Problems”. Retrieved on 25 June 2020.